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d6e0a88dbccbb831e6fd952689ef2c0dcb7db6a2 | cma | None | # TABLE OF CONTENTS
# LIST OF ABBREVIATIONS
# BACKGROUND
NAC is an interprovincial medical and technical advisory body to the PT health ministries and the blood supplier CBS. NAC provides professional leadership in assisting in identifying, designing and implementing cost-effective blood utilization management initiatives for the optimization of patient care throughout Canada.
S/D Plasma is currently licensed in Canada under the name of Octaplasma™. It is virus inactivated S/D treated human frozen plasma with resulting coagulation activity levels similar to those in single-donor fresh frozen plasma. S/D Plasma treatment is not effective against non-enveloped viruses. For the solvent detergent treatment process, large pools of plasma are treated and then divided into individual units. This pooling and separating lowers the level of proteins in the individual units that cause allergic and immunologic reactions as demonstrated by lower rates of adverse events in hem vigilance studies.
In 2011, the PTs approved the funding and distribution S/D Plasma by CBS for specific patient groups as recommended by the CADTH Panel of Experts in the "Optimal Therapy Recommendation for the Use of Solvent/Detergent-Treated Human Plasma". The original CADTH review was based on systematic review of literature and included an economic (risk-benefit) analysis. Subsequently, the PTBLC requested that NAC develop a further framework to enable the distribution and handling of S/D Plasma, and collaborate with CBS to identify a suitable mechanism by which S/D Plasma would routinely be available for the specific patient groups identified. This NAC Framework for Appropriate Use and Distribution of S/D Plasma provides an update to the 2015 NAC framework document.
At the request of the PTBLC, CADTH completed two evidence-based literature reviews in 2017 related to the use of S/D plasma. These reviews of the literature found no new evidence for the use of S/D plasma in TTP and plasmapheresis, respectively. The original economic (risk-benefit) analysis was not updated. Thus, the PT approved funding for S/D plasma has not been reevaluated and remains based on the original recommendations made by the CADTH Panel of Experts.
In this current revision of the NAC framework document, the specific indications for S/D plasma have been updated by NAC to reflect both current medical practice and the principles outlined by the CADTH expert panel.
The CADTH Panel of Experts recommended S/D plasma for patients receiving high volume plasma transfusions. The specific indications included only patients with TTP, HUS with factor H mutations and patients with clotting factor deficiencies. In the setting of TTP and HUS, patients receive high volume plasma transfusions as part of plasmapheresis treatment. However, plasmapheresis with plasma replacement is indicated in other clinical settings, including (but not limited to) atypical HUS without factor H mutations. Following the principles outlined by the CADTH expert panel and the bioethical principle of justice, NAC recommends that all patients receiving plasmapheresis with plasma replacement should be eligible to receive S/D plasma as per the revised indications below.
The 2015 NAC framework also allowed for medical review of individual cases not meeting the CADTH expert criteria. In this update, we have provided further guidance on the specifics for which approval for S/D plasma should be considered. These would include cases where ABO compatible plasma is not available, and rare cases of patients with previous life-threatening adverse reactions to standard plasma. Additional requests would be considered on an individual basis as outlined in Appendix A.
As part of the request process of S/D plasma, all requests from treating physicians should be reviewed by local transfusion medicine experts for completeness and appropriateness.
Ongoing monitoring of S/D Plasma should continue as a means of mitigating the potential for escalating costs associated with the use of this product outside of the current recommendation. Should utilization of S/D Plasma be observed to deviate from the outlined recommendations, the PTs will review the data and follow-up with the respective hospital(s) as appropriate.
The process by which S/D Plasma is available to patients is supported by the PT Ministries of Health.
# RECOMMENDATIONS
- CBS should retain the inventory of S/D Plasma for all jurisdictions in Canada (with the exception of Quebec) and distribute it to requesting hospitals for patients with indications in accordance with this framework. All requests for S/D Plasma should be reviewed by a local/regional transfusion expert prior to submitting a product request to Canadian Blood Services. Requests received by CBS shall be reviewed in accordance with the approved indications by Canadian Blood Services. o Requests which align with the approved indications as detailed in this document shall be approved. o Requests for S/D plasma outside of the specific indications will be reviewed by a CBS transfusion medical director in consultation with local/regional transfusion expert(s) on individual case basis. Distribution and utilization of S/D Plasma should continue to be monitored. Product disposition shall be reported by hospitals to CBS, with data compiled for reporting to the PTBLC S/D plasma requests shall be subject to the approval process outlined in (Appendix A) and the use of an associated CBS product request form (Appendix B).
# INDICATIONS
The following revised criteria are based on the criteria originally published in the CADTH report dated May 2011. These revised criteria reflect changes in clinical practice, but follow the principles from the initial recommendations by the CADTH Panel of Experts.
S/D Plasma should be considered for:
- Patients who require a high volume or chronic plasma transfusions (primary qualifier) because they have: a. Congenital TTP or, b. A need for plasmapheresis with plasma as a replacement fluid for conditions such as (but not limited to) acquired TTP and HUS or, c. Clotting factor deficiencies for which specific licensed concentrates may not be readily available (e.g., factor V, factor XI).
And who have one of the following secondary qualifiers: Have experienced a recurrent clinically significant allergic reaction to plasma Have an existing lung disorder that would make them more susceptible to effects of TRALI reaction.
Any patient who requires plasma but a blood group compatible product is not available in a timely manner. 3. Patients who have had a previous life-threatening reaction to plasma that could be avoided by the use of S/D plasma, where no alternative therapies are available.
Plasma should be interpreted as any plasma product, e.g.: FFPA, FP, and Cryosupernatant Plasma.
Requests outside the above listed would be subject to review by local transfusion medicine experts and Canadian Blood Services.
An allergic reaction is that which is defined by the TTISS, Public Health Agency of Canada:
a. Minor -a skin reaction characterized by a transient urticarial or other skin rash with pruritus associated with the transfusion. This reaction may be associated with localized angioedema without respiratory distress. b. Severe/Anaphylactic/ Anaphylactoid -in addition to mucocutaneous signs/symptoms there is airway compromise or severe hypotension requiring vasopressor treatment. The respiratory signs/symptoms may be laryngeal (tightness in the throat, dysphagia, dysphoria, hoarseness, strider) or pulmonary (dyspnea, cough, wheezing /bronchospasm, hypoxemia). c. Anaphylactic Shock -in addition to the above mentioned, profound hypotension with loss of consciousness, circulatory collapse or death.
# DOSING, ADMINISTRATION & MONITORING
S/D Plasma is available in 200 mL bags. Administration, dosing and monitoring should be similar to that of frozen plasma, in adherence with existing local transfusion policies and dependent on the clinical situation.
Adverse reactions observed in patients being treated with S/D Plasma should be reported to Health Canada through the Canada Vigilance Program () and the manufacturer, as per local standard process.
# APPENDIX A S/D PLASMA REQUEST APPROVAL PROCESS | # TABLE OF CONTENTS
# LIST OF ABBREVIATIONS
# BACKGROUND
NAC is an interprovincial medical and technical advisory body to the PT health ministries and the blood supplier CBS. NAC provides professional leadership in assisting in identifying, designing and implementing cost-effective blood utilization management initiatives for the optimization of patient care throughout Canada.
S/D Plasma is currently licensed in Canada under the name of Octaplasma™. It is virus inactivated S/D treated human frozen plasma with resulting coagulation activity levels similar to those in single-donor fresh frozen plasma. S/D Plasma treatment is not effective against non-enveloped viruses. For the solvent detergent treatment process, large pools of plasma are treated and then divided into individual units. This pooling and separating lowers the level of proteins in the individual units that cause allergic and immunologic reactions as demonstrated by lower rates of adverse events in hem vigilance studies.
In 2011, the PTs approved the funding and distribution S/D Plasma by CBS for specific patient groups as recommended by the CADTH Panel of Experts in the "Optimal Therapy Recommendation for the Use of Solvent/Detergent-Treated Human Plasma". The original CADTH review was based on systematic review of literature and included an economic (risk-benefit) analysis. Subsequently, the PTBLC requested that NAC develop a further framework to enable the distribution and handling of S/D Plasma, and collaborate with CBS to identify a suitable mechanism by which S/D Plasma would routinely be available for the specific patient groups identified. This NAC Framework for Appropriate Use and Distribution of S/D Plasma provides an update to the 2015 NAC framework document.
At the request of the PTBLC, CADTH completed two evidence-based literature reviews in 2017 related to the use of S/D plasma. These reviews of the literature found no new evidence for the use of S/D plasma in TTP and plasmapheresis, respectively. The original economic (risk-benefit) analysis was not updated. Thus, the PT approved funding for S/D plasma has not been reevaluated and remains based on the original recommendations made by the CADTH Panel of Experts.
In this current revision of the NAC framework document, the specific indications for S/D plasma have been updated by NAC to reflect both current medical practice and the principles outlined by the CADTH expert panel.
The CADTH Panel of Experts recommended S/D plasma for patients receiving high volume plasma transfusions. The specific indications included only patients with TTP, HUS with factor H mutations and patients with clotting factor deficiencies. In the setting of TTP and HUS, patients receive high volume plasma transfusions as part of plasmapheresis treatment. However, plasmapheresis with plasma replacement is indicated in other clinical settings, including (but not limited to) atypical HUS without factor H mutations. Following the principles outlined by the CADTH expert panel and the bioethical principle of justice, NAC recommends that all patients receiving plasmapheresis with plasma replacement should be eligible to receive S/D plasma as per the revised indications below.
The 2015 NAC framework also allowed for medical review of individual cases not meeting the CADTH expert criteria. In this update, we have provided further guidance on the specifics for which approval for S/D plasma should be considered. These would include cases where ABO compatible plasma is not available, and rare cases of patients with previous life-threatening adverse reactions to standard plasma. Additional requests would be considered on an individual basis as outlined in Appendix A.
As part of the request process of S/D plasma, all requests from treating physicians should be reviewed by local transfusion medicine experts for completeness and appropriateness.
Ongoing monitoring of S/D Plasma should continue as a means of mitigating the potential for escalating costs associated with the use of this product outside of the current recommendation. Should utilization of S/D Plasma be observed to deviate from the outlined recommendations, the PTs will review the data and follow-up with the respective hospital(s) as appropriate.
The process by which S/D Plasma is available to patients is supported by the PT Ministries of Health.
# RECOMMENDATIONS
CBS should retain the inventory of S/D Plasma for all jurisdictions in Canada (with the exception of Quebec) and distribute it to requesting hospitals for patients with indications in accordance with this framework. All requests for S/D Plasma should be reviewed by a local/regional transfusion expert prior to submitting a product request to Canadian Blood Services. Requests received by CBS shall be reviewed in accordance with the approved indications by Canadian Blood Services. o Requests which align with the approved indications as detailed in this document shall be approved. o Requests for S/D plasma outside of the specific indications will be reviewed by a CBS transfusion medical director in consultation with local/regional transfusion expert(s) on individual case basis. Distribution and utilization of S/D Plasma should continue to be monitored. Product disposition shall be reported by hospitals to CBS, with data compiled for reporting to the PTBLC S/D plasma requests shall be subject to the approval process outlined in (Appendix A) and the use of an associated CBS product request form (Appendix B).
# INDICATIONS
The following revised criteria are based on the criteria originally published in the CADTH report dated May 2011. These revised criteria reflect changes in clinical practice, but follow the principles from the initial recommendations by the CADTH Panel of Experts.
S/D Plasma should be considered for:
1. Patients who require a high volume or chronic plasma transfusions (primary qualifier) because they have: a. Congenital TTP or, b. A need for plasmapheresis with plasma as a replacement fluid for conditions such as (but not limited to) acquired TTP and HUS or, c. Clotting factor deficiencies for which specific licensed concentrates may not be readily available (e.g., factor V, factor XI).
And who have one of the following secondary qualifiers: Have experienced a recurrent clinically significant allergic reaction to plasma Have an existing lung disorder that would make them more susceptible to effects of TRALI reaction.
# 2.
Any patient who requires plasma but a blood group compatible product is not available in a timely manner. 3. Patients who have had a previous life-threatening reaction to plasma that could be avoided by the use of S/D plasma, where no alternative therapies are available.
Plasma should be interpreted as any plasma product, e.g.: FFPA, FP, and Cryosupernatant Plasma.
Requests outside the above listed would be subject to review by local transfusion medicine experts and Canadian Blood Services.
An allergic reaction is that which is defined by the TTISS, Public Health Agency of Canada:
a. Minor -a skin reaction characterized by a transient urticarial or other skin rash with pruritus associated with the transfusion. This reaction may be associated with localized angioedema without respiratory distress. b. Severe/Anaphylactic/ Anaphylactoid -in addition to mucocutaneous signs/symptoms there is airway compromise or severe hypotension requiring vasopressor treatment. The respiratory signs/symptoms may be laryngeal (tightness in the throat, dysphagia, dysphoria, hoarseness, strider) or pulmonary (dyspnea, cough, wheezing /bronchospasm, hypoxemia). c. Anaphylactic Shock -in addition to the above mentioned, profound hypotension with loss of consciousness, circulatory collapse or death.
# DOSING, ADMINISTRATION & MONITORING
S/D Plasma is available in 200 mL bags. Administration, dosing and monitoring should be similar to that of frozen plasma, in adherence with existing local transfusion policies and dependent on the clinical situation.
Adverse reactions observed in patients being treated with S/D Plasma should be reported to Health Canada through the Canada Vigilance Program (https://www.canada.ca/en/healthcanada/services/drugs-health-products/medeffect-canada/canada-vigilance-program.html) and the manufacturer, as per local standard process.
# APPENDIX A S/D PLASMA REQUEST APPROVAL PROCESS
| None | None |
47e7f3e02188ad3a6221c561cbf06f1363f3fbde | cma | None | To provide guidance on the recommended duration of anticoagulant therapy for venous thromboembolism (VTE).Determining the duration of anticoagulant therapy depends on the assessment of an individual's risk of recurrent thrombosis off anticoagulation versus the risk of major bleeding on anticoagulation. While case-fatality rates of recurrent VTE and major bleeding events are similar during the initial period of VTE treatment, the case fatality rate of recurrent VTE is lower after completion of 3 to 6 months of anticoagulation compared to that for major bleeding. This means that long-term therapy is not always associated with a net mortality benefit, especially in patients at lower risk of recurrent VTE or higher bleeding risk. There are unfortunately no long-term randomized studies comparing short term to indefinite anticoagulation duration.The risk of recurrent VTE after stopping anticoagulation appears to be similar whether anticoagulant therapy is stopped after 3 months vs. after 6 to 24 months of treatment. This suggests that 3 months of treatment is sufficient to treat the acute episode of VTE if the decision is to not continue anticoagulation long-term. Three months is the minimum duration of treatment for proximal deep vein thrombosis (DVT) or pulmonary embolism (PE) because shortening the duration of anticoagulation from 3 or 6 months to 4 or 6 weeks results in doubling of the frequency of recurrent VTE during the first 6 months after stopping anticoagulant therapy. - Major bleeding is variably defined in studies, but contemporary studies usually define it as bleeding that is fatal, occurs in a critical organ/space, results in a reduction of hemoglobin of at least 20 g/L, and/or results in the transfusion of at least 2 units of blood.#
After 3 months, a decision must be made about whether to continue anticoagulation. This decision will depend on balancing the risk of recurrence (which depends mainly on whether the VTE was provoked by a transient risk factor, unprovoked, or related to a major persistent risk factor such as active cancer) and the risk of bleeding (see below).
# Other considerations:
- Type of index event: the risk of VTE recurrence is similar after an episode of proximal DVT versus PE. However, patients who presented initially with PE are more likely to recur with PE than DVT, while those who present initially with DVT are more likely to recur with DVT. The risk of recurrence appears lower (by 50%) after an isolated calf (distal) DVT than after a proximal DVT or PE.
- Burden of anticoagulation (financial, functional, and psychological), and quality of life
- Patient preference: anticoagulant therapy should be stopped when its benefits no longer clearly outweigh its risks or, when patients who have a good understanding of the associated risks, want to stop even if continuing treatment is expected to be of net benefit.
# Bleeding Risk Estimation
The risk of anticoagulant-induced bleeding varies markedly among patients and must be balanced against the benefits of continuing anticoagulation. The risk of anticoagulant-induced bleeding is highest during the first 3 months of treatment and stabilizes after the first year.
Unfortunately, we do not currently have adequately validated bleeding risk tools to provide accurate estimates of bleeding risk in patients with VTE. Bleeding risk scores such as HASBLED were derived in patients with atrial fibrillation (AF), who generally have higher baseline bleeding risk, so major bleeding - estimates from these studies may not apply to patients on anticoagulation for VTE prevention who have already completed 3 to 6 months of therapy.
One approach is to identify variables that appear to be predictors of bleeding in multiple studies in both AF and VTE, to form an overall impression of bleeding risk (see Table 1). Patients with two or more such risk factors may be considered to be at least moderate bleeding risk. One should carefully consider whether extended anticoagulant therapy is warranted in such individuals.
# TABLE 1: BLEEDING RISK FACTORS
- Age > 70
- Active cancer - Anemia - Antiplatelet therapy - Chronic kidney disease - Chronic liver disease - Prior history of bleeding - Thrombocytopenia
There is suggestion that long term use of direct oral anticoagulants (DOACs) (as opposed to warfarin) may provide a better safety profile in terms of major bleeding. In patients who have completed 6 months of anticoagulant therapy, the rate of major bleeding with DOACs approximates the major bleeding risk associated with ASA while having a superior efficacy in terms of reduction in recurrent VTE.
# PATIENTS WITH VTE PROVOKED BY A TRANSIENT RISK FACTOR:
Patients with VTE provoked by a transient risk factor (Table 2) in the 3 months prior to the event have a much lower risk of recurrence than those with an unprovoked VTE or a persistent risk factor. Patients with VTE provoked by a transient risk factor which has resolved should generally receive only 3 months of anticoagulation. However, 6 months may be preferred if: (i) the DVT or PE was very large or very symptomatic; or (ii) symptoms of the initial DVT or PE persist; or (iii) the patient is not ready (confident enough) to stop anticoagulant therapy at 3 months; and (iv) the patient does not have a high risk for bleeding. The stronger the provoking reversible risk factor, the lower the expected risk of recurrence after stopping anticoagulant therapy. As shown in Table 3, the risk of recurrence is lower for VTE provoked by a surgical (i.e. major) risk factor than for those associated with non-surgical (i.e. minor) risk factors. For both, the risk of recurrence is lower than for an unprovoked event or one associated with a persistent strong risk factor.
# PATIENTS WITH AN UNPROVOKED VTE:
Patients with a first episode of unprovoked VTE should receive at least 3 months of anticoagulation, with the decision to continue anticoagulation longer term dependent on the estimated risk of recurrence, the risk of bleeding, and patient preference. In patients with a first unprovoked VTE, the decision to stop anticoagulant therapy or to continue treatment indefinitely is strongly influenced by the preferences of an informed patient. To elicit patient preferences for the purpose of joint decision making, the expected risks of recurrence with and without indefinite anticoagulant therapy and the expected consequences of recurrent VTE and bleeding need to be explained to the patient.
Patients with a first unprovoked episode of proximal DVT or PE, on average, have a risk of recurrence of about 10% in the first year, 25% in the first 5 years and 36% in the first 10 years after stopping anticoagulant therapy. Long-term anticoagulation should be considered for these patients, based on the risks of recurrent VTE and bleeding.
The risk of recurrence after a first unprovoked proximal DVT or PE can be further stratified according to the patient's sex and D-dimer results measured 1 month after stopping anticoagulant therapy:
- men have ~1.5-fold higher risk of recurrence than women (~12% vs. ~8% in the first year after stopping therapy);
- patients with a positive D-dimer versus negative D-dimer have ~2-fold higher risk of recurrence;
- the predictive values of sex and D-dimer results for recurrent VTE are additive: male and Ddimer negative: ~8% in the first year; male and D-dimer positive: ~16% in the first year; female and D-dimer negative: ~5% in the first year; female and D-dimer positive: ~10% in the first year.
# Prognostic models:
Three models to predict the risk of recurrent VTE after anticoagulation discontinuation following a first unprovoked DVT or PE have undergone external validation (e.g., in a patient population or data set separate from which they were derived). However, each have significant limitations as discussed below, which limit broad applicability.
# 1) HERDOO2
# PREDICTORS OF RECURRENCE RULE
- Hyperpigmentation, edema or redness in either leg Unlike other investigators, the HERDOO2 investigators classified unprovoked VTE as all VTE (including estrogen-and pregnancy-related) not occurring in the setting of a major reversible provoking risk factor or cancer. As such, the risk of recurrence in women with less than 2 predictors of recurrence in this model is likely to be higher in those who are older. In low risk women under 50 years of age who discontinued anticoagulants, the risk of recurrent VTE was low regardless of whether their initial event was estrogen associated. However, in women 50 years of age or older with less than 2 predictors of recurrence who stopped anticoagulants, the risk of recurrence was 5.7% per patient year. Therefore, further research is required before this rule can be confidently used in women ≥50 years of age. A subsequent analysis has shown that the HERDOO2 D-dimer cutpoint (and, therefore, rule) is not valid with D-dimer assays other than the VIDAS D-dimer. It is noteworthy that most patients in the HERDOO2 studies had D-dimer testing on a vitamin K antagonist rather than a DOAC.
- VIDAS D-dimer >250 ug/L
# 2) DASH
# PREDICTORS OF RECURRENCE RULE
- Abnormal D-dimer level after approximately 1 month off anticoagulation (+2 points)
- Male sex (+1 point) - Age <65 years (+1 point) - Hormone use at VTE diagnosis (-2 points)
Those with a DASH score of 65 years was >5% even in those with the lowest DASH score. As with the HERDOO2 rule, further research is needed in older patients.
3) The Vienna prediction model, which includes sex, site of index event and D-dimer, uses a nomogram to calculate risk of recurrence at 1 year and 12 years after anticoagulant discontinuation (risk calculator available at ).
Although this model has been validated in a separate pooled data set, its safety and efficacy have not been formally assessed in a clinical impact study in which the results of the model are used to guide patient management decisions.
# PATIENTS WITH PERSISTENT RISK FACTORS:
Patients with strong persistent risk factors (active cancer, high risk thrombophilia) should remain on anticoagulation indefinitely if the bleeding risk is acceptable.
# a) Persistent risk factors that usually prompt continuation of anticoagulation:
- Active cancer: The risk of recurrent VTE is markedly increased in patients with active cancer (perhaps 20% per patient year, initially) and this risk is higher in patients with metastatic disease (compared with localized disease) and in patients on chemotherapy. The risk of recurrent VTE may be lower if the initial event occurred while patients were receiving chemotherapy and chemotherapy was subsequently stopped.
- Antiphospholipid antibody positivity: The presence of persistently positive moderate-tohigh titre antiphospholipid antibodies and/or a lupus anticoagulant and VTE (fitting the criteria for antiphospholipid antibody syndrome) is considered high risk for VTE recurrence (and arterial thrombosis) and these patients should generally receive anticoagulant therapy indefinitely. Consultation with a Thrombosis specialist or Hematologist is suggested.
- High risk hereditary thrombophilia: Given the low prevalence of the higher risk thrombophilias, screening for hereditary thrombophilia is generally not recommended to determine duration of anticoagulation. However, if a patient is known to have antithrombin, protein C or protein S deficiency or is homozygous or compound heterozygous for factor V Leiden or prothrombin G20210A with a history of VTE, the risk of recurrent VTE is higher and the patient may be a candidate for indefinite anticoagulant therapy. Consultation with a Thrombosis specialist or Hematologist is suggested. - Low risk hereditary thrombophilia and/or family history of VTE: The presence of one of the common hereditary thrombophilia conditions (i.e. heterozygosity for factor V Leiden or prothrombin G20210A) does not appear to be a clinically important risk factor for recurrence of VTE either during or after anticoagulant therapy. A positive family history alone does not increase the risk of recurrent VTE.
- Presence of an inferior vena cava filter: The presence of an inferior vena cava filter (IVF) alone should not influence the duration of anticoagulant therapy beyond the duration of treatment for the VTE that triggered the filter insertion.
- Residual abnormalities on ultrasound: These are detected in approximately one third of patients. Although these findings may increase the likelihood of recurrence after stopping anticoagulants, the associated risk is not sufficient to make this a deciding factor in determining duration of anticoagulant therapy.
# PATIENTS WITH A SECOND EPISODE OF VTE
Although a second episode of VTE suggests a higher risk of recurrence, the recommendation for duration of anticoagulant therapy is dependent on whether the VTE was provoked or unprovoked. Indefinite therapy with periodic reviews or as long as the risk factor persists ¶
Cancer-associated VTE Minimum 3 months, then reassess and continue if active cancer or patient continuing to receive anticancer therapy - Although 3 months is the usual length of time-limited treatment, 6 months may be preferred if: (i) the DVT or PE was very large or very symptomatic; or (ii) symptoms of the initial DVT or PE persist; or (iii) the patient is not ready (confident enough) to stop anticoagulant therapy at 3 months; and (iv) the patient does not have a high risk for bleeding. † Absence of a transient risk factor, active cancer or other ongoing clinical risk factor for recurrent VTE. ¶ Patients who have been recommended indefinite anticoagulant therapy should be reassessed periodically (e.g. yearly) to re-estimate the VTE versus bleeding risk balance and review patient preferences. ‡ For patients continuing on long term rivaroxaban (Xarelto®) or apixaban (Eliquis®) beyond 6 months, dose reduction of rivaroxaban to 10 mg once daily or apixaban to 2.5 mg twice daily can be considered based on the results of the EINSTEIN CHOICE and AMPLIFY Extend studies in which these lower doses were as effective and safe as standard dosing.
# SPECIAL CONSIDERATIONS:
# Pediatrics
If possible, pediatric hematologists with experience in thromboembolism should manage children with or at risk for thrombosis, as well as those receiving antithrombotic therapy. When this is not possible, a combination of a neonatologist/pediatrician and an adult hematologist, supported by consultation with an experienced pediatric hematologist, should manage these children.
# Central venous catheter (CVC) associated VTE
# Date of Version: 27Sept2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein. | To provide guidance on the recommended duration of anticoagulant therapy for venous thromboembolism (VTE).Determining the duration of anticoagulant therapy depends on the assessment of an individual's risk of recurrent thrombosis off anticoagulation versus the risk of major bleeding on anticoagulation. While case-fatality rates of recurrent VTE and major bleeding events are similar during the initial period of VTE treatment, the case fatality rate of recurrent VTE is lower after completion of 3 to 6 months of anticoagulation compared to that for major bleeding. This means that long-term therapy is not always associated with a net mortality benefit, especially in patients at lower risk of recurrent VTE or higher bleeding risk. There are unfortunately no long-term randomized studies comparing short term to indefinite anticoagulation duration.The risk of recurrent VTE after stopping anticoagulation appears to be similar whether anticoagulant therapy is stopped after 3 months vs. after 6 to 24 months of treatment. This suggests that 3 months of treatment is sufficient to treat the acute episode of VTE if the decision is to not continue anticoagulation long-term. Three months is the minimum duration of treatment for proximal deep vein thrombosis (DVT) or pulmonary embolism (PE) because shortening the duration of anticoagulation from 3 or 6 months to 4 or 6 weeks results in doubling of the frequency of recurrent VTE during the first 6 months after stopping anticoagulant therapy. * Major bleeding is variably defined in studies, but contemporary studies usually define it as bleeding that is fatal, occurs in a critical organ/space, results in a reduction of hemoglobin of at least 20 g/L, and/or results in the transfusion of at least 2 units of blood.#
After 3 months, a decision must be made about whether to continue anticoagulation. This decision will depend on balancing the risk of recurrence (which depends mainly on whether the VTE was provoked by a transient risk factor, unprovoked, or related to a major persistent risk factor such as active cancer) and the risk of bleeding (see below).
# Other considerations:
• Type of index event: the risk of VTE recurrence is similar after an episode of proximal DVT versus PE. However, patients who presented initially with PE are more likely to recur with PE than DVT, while those who present initially with DVT are more likely to recur with DVT. The risk of recurrence appears lower (by 50%) after an isolated calf (distal) DVT than after a proximal DVT or PE.
• Burden of anticoagulation (financial, functional, and psychological), and quality of life
• Patient preference: anticoagulant therapy should be stopped when its benefits no longer clearly outweigh its risks or, when patients who have a good understanding of the associated risks, want to stop even if continuing treatment is expected to be of net benefit.
# Bleeding Risk Estimation
The risk of anticoagulant-induced bleeding varies markedly among patients and must be balanced against the benefits of continuing anticoagulation. The risk of anticoagulant-induced bleeding is highest during the first 3 months of treatment and stabilizes after the first year.
Unfortunately, we do not currently have adequately validated bleeding risk tools to provide accurate estimates of bleeding risk in patients with VTE. Bleeding risk scores such as HASBLED were derived in patients with atrial fibrillation (AF), who generally have higher baseline bleeding risk, so major bleeding * estimates from these studies may not apply to patients on anticoagulation for VTE prevention who have already completed 3 to 6 months of therapy.
One approach is to identify variables that appear to be predictors of bleeding in multiple studies in both AF and VTE, to form an overall impression of bleeding risk (see Table 1). Patients with two or more such risk factors may be considered to be at least moderate bleeding risk. One should carefully consider whether extended anticoagulant therapy is warranted in such individuals.
# TABLE 1: BLEEDING RISK FACTORS
• Age > 70
• Active cancer • Anemia • Antiplatelet therapy • Chronic kidney disease • Chronic liver disease • Prior history of bleeding • Thrombocytopenia
There is suggestion that long term use of direct oral anticoagulants (DOACs) (as opposed to warfarin) may provide a better safety profile in terms of major bleeding. In patients who have completed 6 months of anticoagulant therapy, the rate of major bleeding with DOACs approximates the major bleeding risk associated with ASA while having a superior efficacy in terms of reduction in recurrent VTE.
# PATIENTS WITH VTE PROVOKED BY A TRANSIENT RISK FACTOR:
Patients with VTE provoked by a transient risk factor (Table 2) in the 3 months prior to the event have a much lower risk of recurrence than those with an unprovoked VTE or a persistent risk factor. Patients with VTE provoked by a transient risk factor which has resolved should generally receive only 3 months of anticoagulation. However, 6 months may be preferred if: (i) the DVT or PE was very large or very symptomatic; or (ii) symptoms of the initial DVT or PE persist; or (iii) the patient is not ready (confident enough) to stop anticoagulant therapy at 3 months; and (iv) the patient does not have a high risk for bleeding. The stronger the provoking reversible risk factor, the lower the expected risk of recurrence after stopping anticoagulant therapy. As shown in Table 3, the risk of recurrence is lower for VTE provoked by a surgical (i.e. major) risk factor than for those associated with non-surgical (i.e. minor) risk factors. For both, the risk of recurrence is lower than for an unprovoked event or one associated with a persistent strong risk factor.
# PATIENTS WITH AN UNPROVOKED VTE:
Patients with a first episode of unprovoked VTE should receive at least 3 months of anticoagulation, with the decision to continue anticoagulation longer term dependent on the estimated risk of recurrence, the risk of bleeding, and patient preference. In patients with a first unprovoked VTE, the decision to stop anticoagulant therapy or to continue treatment indefinitely is strongly influenced by the preferences of an informed patient. To elicit patient preferences for the purpose of joint decision making, the expected risks of recurrence with and without indefinite anticoagulant therapy and the expected consequences of recurrent VTE and bleeding need to be explained to the patient.
Patients with a first unprovoked episode of proximal DVT or PE, on average, have a risk of recurrence of about 10% in the first year, 25% in the first 5 years and 36% in the first 10 years after stopping anticoagulant therapy. Long-term anticoagulation should be considered for these patients, based on the risks of recurrent VTE and bleeding.
The risk of recurrence after a first unprovoked proximal DVT or PE can be further stratified according to the patient's sex and D-dimer results measured 1 month after stopping anticoagulant therapy:
• men have ~1.5-fold higher risk of recurrence than women (~12% vs. ~8% in the first year after stopping therapy);
• patients with a positive D-dimer versus negative D-dimer have ~2-fold higher risk of recurrence;
• the predictive values of sex and D-dimer results for recurrent VTE are additive: male and Ddimer negative: ~8% in the first year; male and D-dimer positive: ~16% in the first year; female and D-dimer negative: ~5% in the first year; female and D-dimer positive: ~10% in the first year.
# Prognostic models:
Three models to predict the risk of recurrent VTE after anticoagulation discontinuation following a first unprovoked DVT or PE have undergone external validation (e.g., in a patient population or data set separate from which they were derived). However, each have significant limitations as discussed below, which limit broad applicability.
# 1) HERDOO2
# PREDICTORS OF RECURRENCE RULE
• Hyperpigmentation, edema or redness in either leg Unlike other investigators, the HERDOO2 investigators classified unprovoked VTE as all VTE (including estrogen-and pregnancy-related) not occurring in the setting of a major reversible provoking risk factor or cancer. As such, the risk of recurrence in women with less than 2 predictors of recurrence in this model is likely to be higher in those who are older. In low risk women under 50 years of age who discontinued anticoagulants, the risk of recurrent VTE was low regardless of whether their initial event was estrogen associated. However, in women 50 years of age or older with less than 2 predictors of recurrence who stopped anticoagulants, the risk of recurrence was 5.7% per patient year. Therefore, further research is required before this rule can be confidently used in women ≥50 years of age. A subsequent analysis has shown that the HERDOO2 D-dimer cutpoint (and, therefore, rule) is not valid with D-dimer assays other than the VIDAS D-dimer. It is noteworthy that most patients in the HERDOO2 studies had D-dimer testing on a vitamin K antagonist rather than a DOAC.
• VIDAS D-dimer >250 ug/L
# 2) DASH
# PREDICTORS OF RECURRENCE RULE
• Abnormal D-dimer level after approximately 1 month off anticoagulation (+2 points)
• Male sex (+1 point) • Age <65 years (+1 point) • Hormone use at VTE diagnosis (-2 points)
Those with a DASH score of <1 have a risk of recurrence of 3.5% per year It should be noted that the risk of recurrence in those >65 years was >5% even in those with the lowest DASH score. As with the HERDOO2 rule, further research is needed in older patients.
3) The Vienna prediction model, which includes sex, site of index event and D-dimer, uses a nomogram to calculate risk of recurrence at 1 year and 12 years after anticoagulant discontinuation (risk calculator available at http://www.meduniwien.ac.at/user/georg.heinze/zipfile/ViennaPredictionModel.html).
Although this model has been validated in a separate pooled data set, its safety and efficacy have not been formally assessed in a clinical impact study in which the results of the model are used to guide patient management decisions.
# PATIENTS WITH PERSISTENT RISK FACTORS:
Patients with strong persistent risk factors (active cancer, high risk thrombophilia) should remain on anticoagulation indefinitely if the bleeding risk is acceptable.
# a) Persistent risk factors that usually prompt continuation of anticoagulation:
• Active cancer: The risk of recurrent VTE is markedly increased in patients with active cancer (perhaps 20% per patient year, initially) and this risk is higher in patients with metastatic disease (compared with localized disease) and in patients on chemotherapy. The risk of recurrent VTE may be lower if the initial event occurred while patients were receiving chemotherapy and chemotherapy was subsequently stopped. [See Clinical Guide: Cancer and Thrombosis]
• Antiphospholipid antibody positivity: The presence of persistently positive moderate-tohigh titre antiphospholipid antibodies and/or a lupus anticoagulant and VTE (fitting the criteria for antiphospholipid antibody syndrome) is considered high risk for VTE recurrence (and arterial thrombosis) and these patients should generally receive anticoagulant therapy indefinitely. Consultation with a Thrombosis specialist or Hematologist is suggested. [See Clinical Guide: Thrombophilia: Antiphospholipid Antibody Syndrome]
• High risk hereditary thrombophilia: Given the low prevalence of the higher risk thrombophilias, screening for hereditary thrombophilia is generally not recommended to determine duration of anticoagulation. However, if a patient is known to have antithrombin, protein C or protein S deficiency or is homozygous or compound heterozygous for factor V Leiden or prothrombin G20210A with a history of VTE, the risk of recurrent VTE is higher and the patient may be a candidate for indefinite anticoagulant therapy. Consultation with a Thrombosis specialist or Hematologist is suggested. • Low risk hereditary thrombophilia and/or family history of VTE: The presence of one of the common hereditary thrombophilia conditions (i.e. heterozygosity for factor V Leiden or prothrombin G20210A) does not appear to be a clinically important risk factor for recurrence of VTE either during or after anticoagulant therapy. A positive family history alone does not increase the risk of recurrent VTE.
• Presence of an inferior vena cava filter: The presence of an inferior vena cava filter (IVF) alone should not influence the duration of anticoagulant therapy beyond the duration of treatment for the VTE that triggered the filter insertion.
• Residual abnormalities on ultrasound: These are detected in approximately one third of patients. Although these findings may increase the likelihood of recurrence after stopping anticoagulants, the associated risk is not sufficient to make this a deciding factor in determining duration of anticoagulant therapy.
# PATIENTS WITH A SECOND EPISODE OF VTE
Although a second episode of VTE suggests a higher risk of recurrence, the recommendation for duration of anticoagulant therapy is dependent on whether the VTE was provoked or unprovoked. Indefinite therapy with periodic reviews or as long as the risk factor persists ¶
Cancer-associated VTE Minimum 3 months, then reassess and continue if active cancer or patient continuing to receive anticancer therapy * Although 3 months is the usual length of time-limited treatment, 6 months may be preferred if: (i) the DVT or PE was very large or very symptomatic; or (ii) symptoms of the initial DVT or PE persist; or (iii) the patient is not ready (confident enough) to stop anticoagulant therapy at 3 months; and (iv) the patient does not have a high risk for bleeding. † Absence of a transient risk factor, active cancer or other ongoing clinical risk factor for recurrent VTE. ¶ Patients who have been recommended indefinite anticoagulant therapy should be reassessed periodically (e.g. yearly) to re-estimate the VTE versus bleeding risk balance and review patient preferences. ‡ For patients continuing on long term rivaroxaban (Xarelto®) or apixaban (Eliquis®) beyond 6 months, dose reduction of rivaroxaban to 10 mg once daily or apixaban to 2.5 mg twice daily can be considered based on the results of the EINSTEIN CHOICE and AMPLIFY Extend studies in which these lower doses were as effective and safe as standard dosing.
# SPECIAL CONSIDERATIONS:
# Pediatrics
If possible, pediatric hematologists with experience in thromboembolism should manage children with or at risk for thrombosis, as well as those receiving antithrombotic therapy. When this is not possible, a combination of a neonatologist/pediatrician and an adult hematologist, supported by consultation with an experienced pediatric hematologist, should manage these children.
# Central venous catheter (CVC) associated VTE
# Date of Version: 27Sept2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein. | None | None |
f09d38f56a9ebc09f796be1b65205dec030c2e78 | cma | None | To summarize the available literature on the risk of venous thromboembolism (VTE) during air travel and provide recommendations for preventative measures while traveling long distances.Long-distance travelling by plane increases the risk of VTE, which includes deep vein thrombosis (DVT) or pulmonary embolism (PE); however, the absolute VTE risk from travel is small.#
The etiology of travel-related thrombosis likely arises from a combination of immobility (blood stasis in the leg veins), hypobaric environment, vessel damage, and dehydration. Known risk factors for travel-associated VTE include advanced age (>40 years), height (>185 cm or 30), hormonal therapy, thrombophilia, pregnancy (including the postpartum period), active cancer, recent major surgery, or a prior history of VTE. Window seating compared to aisle seating has been associated with greater risk and the effect is most pronounced in passengers with BMI >30.
Long distance travelers have a 3-fold increase in VTE risk compared to the general population (3.2 per 1000 patient-years within 8 weeks of a long-haul flight, compared with 1.0 per 1000 patient-years with no travel exposure). The incidence of symptomatic VTE after flights of greater than 4 hours is 1 in 4,656. The risk of symptomatic PE immediately after air travel was 0.39 cases per 1 million travellers, with an increased risk for flight durations greater than 8 hours (1.65 cases per 1 million travellers) versus flights that are 6-8 hours in duration (0.25 cases per 1 million travellers). Individuals who develop a fatal PE while traveling or symptomatic PE in the weeks following air travel are not included in these estimates.
To put it in perspective, this risk is lower than that with other minor provoking risk factors, such as knee arthroscopy or immobilization with a below-knee cast. The risk of DVT is highest in the first 2 weeks after long-distance travel, after which it gradually decreases back to baseline by 8 weeks. Airplane pilots do not appear to be at increased risk of travel-related VTE.
# PREVENTION OF TRAVEL-RELATED VTE:
# General preventative measures:
General preventative measures aim to minimize the impact of environmental factors that predispose to travel-related VTE. While there have been no studies evaluating the efficacy of general preventative measures, accepted recommendations include:
- Getting up and walking every 1-2 hours - Exercising and stretching legs regularly
# Compression stockings
Compression stockings reduce the symptoms of leg swelling and may help prevent DVT while traveling. In a systematic review of 9 randomized trials in which half the passengers wore compression stockings and half the passengers did not, the risk of asymptomatic DVT was reduced by 90% in the group that wore compression stockings. Four of the trials used graduated compression stockings of 20-30 mmHg, and five of the trials used graduated compression stockings of 10-20 mmHg. The small numbers of asymptomatic DVTs diagnosed in these studies were detected on screening leg ultrasound examinations of passengers shortly after their flight. Passengers who had additional risk factors for VTE benefited the most from compression stockings. The clinical significance of the small number of asymptomatic DVTs that were found and prevented is unknown.
# Use of aspirin or anticoagulants
The effectiveness of taking a short course of aspirin or anticoagulants to prevent travel-related VTE is unknown and is not routinely recommended. There are no studies evaluating the use of direct oral anticoagulants for short-term prophylaxis to prevent travel-related VTE. One small randomized trial evaluated the effect of preventing travel-related asymptomatic DVTs using a single injection of lowmolecular-weight heparin (LMWH) (enoxaparin 1 mg/kg) given to high-risk individuals 2-4 hours prior to flying, compared to 3 days of daily aspirin starting 12 hours prior to flying, or no therapy. When participants completed leg ultrasound screening after a long (10-15 hour) flight, there were less asymptomatic DVTs in the LMWH arm (0/82, 0%), compared to the aspirin arm (3/84, 3.6%) or no therapy arm (4/83, 4.82%). Similar to the studies evaluating compression stockings, the clinical significance of the small, asymptomatic DVTs that were found and prevented is unknown.
For individuals who have additional risk factors for VTE, there is little data to guide management. The recommendations below are all based on low quality evidence, and an individualized management plan that takes into account both the risks and benefits of treatment is needed.
# RECOMMENDATIONS:
For all long-distance (>4hr) travelers, general preventative measures are recommended to prevent travel-related VTE, including frequent ambulation, exercising and stretching legs regularly, avoiding constrictive clothing, and keeping hydrated.
For long-distance travelers who are not at increased risk of VTE, the use of compression stockings is not routinely recommended to prevent travel-related VTE.
For long-distance travelers who are not at increased risk of VTE, the use of short-term prophylaxis with an anticoagulant or antiplatelet is not routinely recommended to prevent travel-related VTE.
For long-distance travelers who are at increased risk of VTE (previous unprovoked or travel-related VTE, active cancer, recent surgery or trauma, ≥2 risk factors including combinations of the above with obesity, limited mobility, advanced age, known thrombophilia, pregnancy, or estrogen use) the use of graduated compression stockings is recommended to prevent travel-related VTE, at a stocking strength of 20-30 mmHg.
A short course of prophylactic-dose anticoagulation may be considered in select patients who are at very high risk of VTE, based on an individualized decision that weighs the risks and benefits of therapy and takes into account patient values and preferences. Given peak anticoagulant effects of 2-4 hours with LMWH and direct oral anticoagulants (DOACs), a dose can be taken shortly before the journey starts. The optimal number of doses around travel is unknown. DOACs should not be used in pregnant or breastfeeding women.
For travelers who are already on preventative or treatment doses of anticoagulants for any indication, no additional action is required to prevent travel-related VTE.
Van Adrichem R, et al. Thromboprophylaxis after knee arthroscopy and lower-leg casting. N Engl J Med 2017;376:515-525.
# Date of version: 14November2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein. | To summarize the available literature on the risk of venous thromboembolism (VTE) during air travel and provide recommendations for preventative measures while traveling long distances.Long-distance travelling by plane increases the risk of VTE, which includes deep vein thrombosis (DVT) or pulmonary embolism (PE); however, the absolute VTE risk from travel is small.#
The etiology of travel-related thrombosis likely arises from a combination of immobility (blood stasis in the leg veins), hypobaric environment, vessel damage, and dehydration. Known risk factors for travel-associated VTE include advanced age (>40 years), height (>185 cm or <165 cm), obesity (BMI >30), hormonal therapy, thrombophilia, pregnancy (including the postpartum period), active cancer, recent major surgery, or a prior history of VTE. Window seating compared to aisle seating has been associated with greater risk and the effect is most pronounced in passengers with BMI >30.
Long distance travelers have a 3-fold increase in VTE risk compared to the general population (3.2 per 1000 patient-years within 8 weeks of a long-haul flight, compared with 1.0 per 1000 patient-years with no travel exposure). The incidence of symptomatic VTE after flights of greater than 4 hours is 1 in 4,656. The risk of symptomatic PE immediately after air travel was 0.39 cases per 1 million travellers, with an increased risk for flight durations greater than 8 hours (1.65 cases per 1 million travellers) versus flights that are 6-8 hours in duration (0.25 cases per 1 million travellers). Individuals who develop a fatal PE while traveling or symptomatic PE in the weeks following air travel are not included in these estimates.
To put it in perspective, this risk is lower than that with other minor provoking risk factors, such as knee arthroscopy or immobilization with a below-knee cast. The risk of DVT is highest in the first 2 weeks after long-distance travel, after which it gradually decreases back to baseline by 8 weeks. Airplane pilots do not appear to be at increased risk of travel-related VTE.
# PREVENTION OF TRAVEL-RELATED VTE:
# General preventative measures:
General preventative measures aim to minimize the impact of environmental factors that predispose to travel-related VTE. While there have been no studies evaluating the efficacy of general preventative measures, accepted recommendations include:
• Getting up and walking every 1-2 hours • Exercising and stretching legs regularly
# Compression stockings
Compression stockings reduce the symptoms of leg swelling and may help prevent DVT while traveling. In a systematic review of 9 randomized trials in which half the passengers wore compression stockings and half the passengers did not, the risk of asymptomatic DVT was reduced by 90% in the group that wore compression stockings. Four of the trials used graduated compression stockings of 20-30 mmHg, and five of the trials used graduated compression stockings of 10-20 mmHg. The small numbers of asymptomatic DVTs diagnosed in these studies were detected on screening leg ultrasound examinations of passengers shortly after their flight. Passengers who had additional risk factors for VTE benefited the most from compression stockings. The clinical significance of the small number of asymptomatic DVTs that were found and prevented is unknown.
# Use of aspirin or anticoagulants
The effectiveness of taking a short course of aspirin or anticoagulants to prevent travel-related VTE is unknown and is not routinely recommended. There are no studies evaluating the use of direct oral anticoagulants for short-term prophylaxis to prevent travel-related VTE. One small randomized trial evaluated the effect of preventing travel-related asymptomatic DVTs using a single injection of lowmolecular-weight heparin (LMWH) (enoxaparin 1 mg/kg) given to high-risk individuals 2-4 hours prior to flying, compared to 3 days of daily aspirin starting 12 hours prior to flying, or no therapy. When participants completed leg ultrasound screening after a long (10-15 hour) flight, there were less asymptomatic DVTs in the LMWH arm (0/82, 0%), compared to the aspirin arm (3/84, 3.6%) or no therapy arm (4/83, 4.82%). Similar to the studies evaluating compression stockings, the clinical significance of the small, asymptomatic DVTs that were found and prevented is unknown.
For individuals who have additional risk factors for VTE, there is little data to guide management. The recommendations below are all based on low quality evidence, and an individualized management plan that takes into account both the risks and benefits of treatment is needed.
# RECOMMENDATIONS:
For all long-distance (>4hr) travelers, general preventative measures are recommended to prevent travel-related VTE, including frequent ambulation, exercising and stretching legs regularly, avoiding constrictive clothing, and keeping hydrated.
For long-distance travelers who are not at increased risk of VTE, the use of compression stockings is not routinely recommended to prevent travel-related VTE.
For long-distance travelers who are not at increased risk of VTE, the use of short-term prophylaxis with an anticoagulant or antiplatelet is not routinely recommended to prevent travel-related VTE.
For long-distance travelers who are at increased risk of VTE (previous unprovoked or travel-related VTE, active cancer, recent surgery or trauma, ≥2 risk factors including combinations of the above with obesity, limited mobility, advanced age, known thrombophilia, pregnancy, or estrogen use) the use of graduated compression stockings is recommended to prevent travel-related VTE, at a stocking strength of 20-30 mmHg.
A short course of prophylactic-dose anticoagulation may be considered in select patients who are at very high risk of VTE, based on an individualized decision that weighs the risks and benefits of therapy and takes into account patient values and preferences. Given peak anticoagulant effects of 2-4 hours with LMWH and direct oral anticoagulants (DOACs), a dose can be taken shortly before the journey starts. The optimal number of doses around travel is unknown. DOACs should not be used in pregnant or breastfeeding women.
For travelers who are already on preventative or treatment doses of anticoagulants for any indication, no additional action is required to prevent travel-related VTE.
#
Van Adrichem R, et al. Thromboprophylaxis after knee arthroscopy and lower-leg casting. N Engl J Med 2017;376:515-525.
# Date of version: 14November2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein. | None | None |
eaa8190cf9bb304f7978e7c2b88b98665257984b | cma | None | The information contained in this document has been reaffirmed for scientific validity. While this document is no longer identified to be clinically useful for the Canadian health care provider, it may be relevant to providers abroad. Many healthcare jurisdictions in Canada are facing a third wave of COVID-19 pandemic activity, with some centres rapidly exceeding peak daily case counts, hospital and ICU admissions compared to previous waves of the virus. 1, 2 The current Canadian epidemiological trends are, at least in part, driven by low rates of vaccine coverage and circulation of new variants of concern (VOC) of COVID-19 that have been demonstrated to be more transmissible and severe compared to the wild-type virus which predominated previously. 3,4 #
Pregnancy is a known risk factor for COVID-associated morbidity with data clearly and consistently illustrating that pregnant individuals are at increased risk for hospitalization, ICU admission, mechanical ventilation and death compared to non-pregnant individuals. As a result of these factors, many Canadian centres are facing increased numbers of pregnant individuals infected with COVID-19 being admitted to the hospital and ICU. 5 For many pregnant individuals in Canada, the risk of being unvaccinated and susceptible to COVID-19 is substantial.
The SOGC supports the use of all available COVID-19 vaccines approved in Canada in any trimester of pregnancy and during breastfeeding in accordance with regional eligibility
The four COVID-19 vaccines approved for use in Canada have been demonstrated to be safe and highly effective for preventing serious disease from COVID-19. 6,7 Passive surveillance has been ongoing on a global scale and has not detected adverse pregnancy outcomes related to any COVID-19 vaccinations and emerging evidence shows passive antibody transfer to infants. Given that pregnancy is a demonstrable risk factor for severe COVID-19 disease, and that emerging reports from major Canadian centres have identified an increased burden of disease affecting pregnant individuals, the SOGC recommends that all pregnant people should be eligible to receive a COVID-19 vaccine.
While international reports have emerged documenting extremely rare events of arterial and venous thrombosis associated with low platelets following the adenovirus vector COVID-19 vaccines (AstraZeneca, COVISHIELD, Janssen COVID-19 vaccines), these events occur in as few as 1 in every 125,000 to 1 in 1 million people. 8,9,10,11 Most cases have occurred in women <55 years of age, however, this may reflect a workforce gender bias due to the decision to prioritize front-line health care workers, most of whom identify as female. There is no known association between this syndrome and pregnancy and no physiologic basis to increase this risk in pregnancy. Rare adverse outcomes observed following vaccination with viral vector COVID-19 vaccines should be discussed in context of the disease they are designed to prevent. Specifically, approximately 1 in 10 pregnant individuals will require hospital admission and 1 in 100 pregnant individuals will require intensive care following infection with COVID-19. For some individuals with additional risk factors such as advanced maternal age, obesity and pre-existing medical conditions, the risk of morbidity will be substantially higher. Preventing COVID-19 disease among pregnant individuals must be considered a priority and vaccination is a central tool to protect individuals from severe COVID-19 infection. | The information contained in this document has been reaffirmed for scientific validity. While this document is no longer identified to be clinically useful for the Canadian health care provider, it may be relevant to providers abroad. Many healthcare jurisdictions in Canada are facing a third wave of COVID-19 pandemic activity, with some centres rapidly exceeding peak daily case counts, hospital and ICU admissions compared to previous waves of the virus. 1, 2 The current Canadian epidemiological trends are, at least in part, driven by low rates of vaccine coverage and circulation of new variants of concern (VOC) of COVID-19 that have been demonstrated to be more transmissible and severe compared to the wild-type virus which predominated previously. 3,4 #
Pregnancy is a known risk factor for COVID-associated morbidity with data clearly and consistently illustrating that pregnant individuals are at increased risk for hospitalization, ICU admission, mechanical ventilation and death compared to non-pregnant individuals. As a result of these factors, many Canadian centres are facing increased numbers of pregnant individuals infected with COVID-19 being admitted to the hospital and ICU. 5 For many pregnant individuals in Canada, the risk of being unvaccinated and susceptible to COVID-19 is substantial.
The SOGC supports the use of all available COVID-19 vaccines approved in Canada in any trimester of pregnancy and during breastfeeding in accordance with regional eligibility
The four COVID-19 vaccines approved for use in Canada have been demonstrated to be safe and highly effective for preventing serious disease from COVID-19. 6,7 Passive surveillance has been ongoing on a global scale and has not detected adverse pregnancy outcomes related to any COVID-19 vaccinations and emerging evidence shows passive antibody transfer to infants. Given that pregnancy is a demonstrable risk factor for severe COVID-19 disease, and that emerging reports from major Canadian centres have identified an increased burden of disease affecting pregnant individuals, the SOGC recommends that all pregnant people should be eligible to receive a COVID-19 vaccine.
While international reports have emerged documenting extremely rare events of arterial and venous thrombosis associated with low platelets following the adenovirus vector COVID-19 vaccines (AstraZeneca, COVISHIELD, Janssen COVID-19 vaccines), these events occur in as few as 1 in every 125,000 to 1 in 1 million people. 8,9,10,11 Most cases have occurred in women <55 years of age, however, this may reflect a workforce gender bias due to the decision to prioritize front-line health care workers, most of whom identify as female. There is no known association between this syndrome and pregnancy and no physiologic basis to increase this risk in pregnancy. Rare adverse outcomes observed following vaccination with viral vector COVID-19 vaccines should be discussed in context of the disease they are designed to prevent. Specifically, approximately 1 in 10 pregnant individuals will require hospital admission and 1 in 100 pregnant individuals will require intensive care following infection with COVID-19. For some individuals with additional risk factors such as advanced maternal age, obesity and pre-existing medical conditions, the risk of morbidity will be substantially higher. Preventing COVID-19 disease among pregnant individuals must be considered a priority and vaccination is a central tool to protect individuals from severe COVID-19 infection. | None | None |
8cf4135c092c8cafafa42e16aa4939718c09457c | cma | None | The risk of mortality from COVID-19 disease is higher in patients with cancer, including patients with hematologic malignancies and HSCT recipients. One study found that more severe forms of COVID-19 disease, including those requiring ICU admission, were more frequent in patients with hematologic malignancies hospitalized with COVID-19, and led to mortality nearly four times higher than that of the general population with COVID-19 and 41 times higher than that of hematologic malignancy patients without There are data to suggest that the currently available COVID-19 vaccines have efficacy. 6 COVID-19 vaccines should be encouraged for people with hematologic malignancies and HSCT and/or CAR-T recipients, as per BC Public Health recommendation for age eligibility and are not contraindicated. This recommendation is based on the following: - The National Advisory Committee on Immunization (NACI) recommends that immunosuppressed individuals be offered the vaccine if the benefits of vaccines outweigh the potential risks. 7#
Clinical Guidance on COVID-19 Vaccines for people with hematological malignancy at any stage of treatment and/or who have undergone hematopoietic stem cell transplant or CAR-T cell therapy in the past 6 months Updated: - Patients with blood cancer have an increased risk of death related to COVID-19 infection. - The United Kingdom, the United States, France, and Australia have prioritized patients with cancer for COVID- 19 vaccinations, highlighting the high COVID-19 risk faced by these patients. 8 Is the COVID-19 vaccine efficacious and safe in people with hematologic malignancy patients and HSCT and/or CAR-T recipients?
There is still uncertainty about the efficacy of COVID-19 vaccines in patients with blood cancer and/or have undergone HSCT or CAR-T cell therapy in the last six months. As with most vaccines, there is a potential for diminished immune response in individuals who are immunocompromised due to their disease or treatment. In addition, patients with active cancer or undergoing active cancer treatment seemed to be generally excluded from the COVID-19 vaccine trials. However, in the COMIRNATY (Pfizer-BioNTech) vaccine trial, 3.9% of enrolled participants had a malignancy. 9 There are currently no known factors that would predispose these individuals to adverse events associated with the vaccines. At the time of authorization, there are no known serious warnings or precautions related to the vaccines in patients with cancer. Small exploratory studies have shown lower antibody responses in patients with advanced cancer and haematological malignancies 9 following vaccination compared to controls. However, it is unclear how much antibody is needed for protection and/or the role of other immunological responses.
There is one study that suggests that a third dose of COVID-19 vaccine in immunocompromised patients can increase antibody levels. 15 Small studies on third doses of the mRNA COVID-19 vaccines have shown that immunogenicity (immunity measured in the blood) may increase with a third dose. The safety of a third dose is unknown at this time, but in these small studies reactions were found to be similar to that of prior doses.
The frequency and severity of adverse events following vaccination with an mRNA COVID-19 vaccine in these populations were comparable to that of non-immunosuppressed individuals in these studies and what was reported in clinical trials. Safety data in these populations following vaccination with a viral vector vaccine is not available. 16 Informed consent should include discussion about the possibility that individuals who are immunosuppressed may have a diminished immune response to any of the authorized COVID-19 vaccines. 17 Observed short-term adverse effects with the mRNA-based COVID-19 vaccines have been similar to those seen with seasonal influenza vaccination. Still, they may be more pronounced after the second COVID-19 vaccine dose (e.g. injection site pain/erythema, fever, headache, fatigue, and myalgia/arthralgia). 18 Safety results in the allogeneic HSCT patient population seem comparable. 15 Any long-term side effects of COVID-19 vaccines are not yet known, but Health Canada continues to monitor any adverse events following vaccination through their post-authorization surveillance process.
Immunocompromised patient populations are diverse and the relative degree of immunodeficiency will depend on the underlying condition, the progression of the disease, and the type and timing of treatment received. Therefore, the Clinical Guidance on COVID-19 Vaccines for people with hematological malignancy at any stage of treatment and/or who have undergone hematopoietic stem cell transplant or CAR-T cell therapy in the past 6 months Updated: April 18, 2023 balance of potential benefit and risk associated with COVID-19 vaccination should be assessed on an individual basis (Table 1).
Are there any specific contraindications or exceptions for those within the hematologic malignancy, HSCT and/or CAR-T recipient patient populations?
# Blood counts
Patients with blood cancer and HSCT or CAR-T recipients may experience low blood counts, either due to their disease or treatment, which could impact individual decision-making around receipt of COVID-19 vaccinations and timing of vaccinations relative to their treatments. COVID-19 vaccination should be deferred in patients unwell with neutropenia until well, 10,11 but may be considered in well patients with disease-related chronic neutropenia where neutrophil recovery is not expected. 19
# Allergy
The above noted COVID-19 vaccines are contraindicated in individuals with a history of severe allergic reaction to any component of the vaccines, including non-medicinal ingredients such as polyethylene glycol (PEG) or polysorbate-80, or a history of anaphylaxis after administration of a previous dose of COVID-19 vaccine using a similar platform (mRNA or viral vector). 7 People with a history of anaphylaxis without known or obvious cause, and those with suspected hypersensitivity or non-anaphylactic allergy to COVID-19 vaccine components, are advised to consult with an allergist prior to immunization. 20 BCCDC has a list of the individual components and their purpose in the vaccines. For a complete list of components in the vaccine, consult the vaccine monographs found at: www.bccdc.ca/health-info/diseasesconditions/covid-19/covid-19-vaccine/vaccines-for-covid-19.
People with a history of anaphylactic reaction to a previous dose of an mRNA COVID-19 vaccine, re-vaccination (i.e., administration of a subsequent dose in the series when indicated) may be offered with the same vaccine or the same mRNA platform if a risk assessment deems that the benefits outweigh the potential risks for the individual and if informed consent is provided. Prior to revaccination, consultation with an allergist or another appropriate physician (e.g., Medical Health Officer) is advised. If re-vaccination is going ahead, vaccine administration should be done in a controlled setting with expertise and equipment to manage anaphylaxis, with an extended period of observation of at least 30 minutes after re-vaccination.
Health Canada continues to monitor any adverse events following immunization through their post-authorization surveillance process.
# Other vaccines
Currently, it is recommended that COVID-19 vaccines can be given concomitantly with, or any time before or after any other indicated vaccine. Clinical Guidance on COVID-19 Vaccines for people with hematological malignancy at any stage of treatment and/or who have undergone hematopoietic stem cell transplant or CAR-T cell therapy in the past 6 months Updated: Are there specific recommendations or considerations for safe and/or most effective administration?
- Blood counts
Patients with blood cancer and HSCT or CAR-T recipients may have lowered blood counts related to the underlying disease or therapy. If blood counts (platelet count and neutrophil count) are low due to therapy and timing of recovery can be anticipated, e.g. 1 week prior to the next cyclical chemotherapy or maintenance cycle, the timing of vaccination should be scheduled accordingly (please see Table 1). However, where the timing of blood count recovery is unclear or not anticipated, e.g. marrow failure syndromes, then vaccination should not be delayed solely for this reason.
There is no consensus on an adequate platelet count for IM injections. Still, practical suggestions include using a platelet threshold of >20 x 10 9 /L, administering the vaccine after platelet transfusion if receiving regular transfusions, and applying firm pressure at the injection site for at least 5 minutes. 25
# Anti-coagulant therapy
As per Thrombosis Canada recommendations, 26 anti-coagulation should not be a barrier for administering COVID-19 vaccination to patients on warfarin (INR monitoring not required prior to vaccination), novel oral anticoagulants (apixaban, dabigatran, edoxaban, rivaroxaban) or antiplatelet agents (aspirin, clopidogrel, ticagrelor). Patients on therapeutic dose low-molecular weight heparin (dalteparin, tinzaparin, enoxaparin, nadroparin) or fondaparinux may consider delaying their anti-coagulant dose on the day of vaccination until after the IM injection. For patients on any of the above, applying pressure to the injection site for 3 to 5 minutes post vaccination is recommended to reduce bruising.
# Special considerations for immunotherapy
a. Therapies targeting B-cells including anti-CD20, CD19, CD22 targeting antibodies, or BiTEs: Patients receiving these agents may have a reduced immune response to vaccines in general that can extend to up to 6 months following treatment completion. If possible, patients should receive both doses of vaccine prior to starting these therapies. If patients are on, or have recently been treated with these agents, when they received the first 2 doses of vaccine, a 3 rd dose is recommended to be administered at least 28 days after the 2 nd dose, with consideration given to delaying to 3 months after therapy with B-cell directed therapies due to likelihood of impaired immune response.
# b. Checkpoint inhibitors:
Previous studies have not signalled an increased risk of complications of COVID-19 for patients on checkpoint inhibitors such as CTLA-4 inhibitors (e.g., ipilimumab), PD-1 inhibitors (e.g., nivolumab, pembrolizumab) and PD-L1 inhibitors (e.g., atezolizumab, durvalumab). There have been theoretical concerns of an enhanced immune reaction, particularly with CTLA-4 inhibitors. However, given the seriousness of COVID-19 infection, vaccination is still recommended in this group even if a four-week window cannot be confirmed.
# Timing of COVID-19 vaccines in relation to therapy
There are no known studies regarding the timing of COVID-19 vaccination in relation to therapy for blood cancer. The COMIRNATY (Pfizer-BioNTech), SPIKEVAX (Moderna) and VAXZEVRIA (AstraZeneca) vaccines are given as two injections with optimal protection assumed after the second dose for the general population. Efficacy and duration of immunity are continuously being evaluated and recommendations are evolving rapidly. Therefore, patients should Clinical Guidance on COVID-19 Vaccines for people with hematological malignancy at any stage of treatment and/or who have undergone hematopoietic stem cell transplant or CAR-T cell therapy in the past 6 months Updated: follow current BCCDC guidance for the recommended number of and interval between COVID-19 vaccine doses.
In general, it is preferred that patients complete their COVID-19 vaccination series ideally 14 days prior to starting immunosuppressive therapy. 27 *However, life-saving or prolonging therapy should not be delayed solely to complete vaccination.
Recommendations for timing of COVID-19 vaccination for patients with hematologic malignancies (either completed, starting or already receiving treatment) and patients who have undergone HSCT or CAR-T cell therapy in the past 6 months are described in Table 1 below.
Any other timing should involve a case-by-case assessment based on: a. Risk of morbidity related to COVID-19 infection (including local incidence of the pandemic, cancer type, comorbidities that confer higher risk categories in general population, etc.), b. Cancer-related morbidity due to delay of active treatment, and c. Suboptimal immunity due to insufficient time window between vaccination and immunosuppressive therapy.
Some patients may not have adequate counts either prior to or between cycles of therapy. The benefit likely outweighs the risk, and these patients should proceed to vaccination regardless of neutrophil count and with platelet transfusion support if required. * Ideally high dose systemic corticosteroids (> 0.5 mg/kg/day prednisone or equivalent) should be avoided or completed 28 days prior to vaccination; if this is not possible, proceed with vaccination. † Due to likelihood of impaired immune response to vaccination within 3 months of receiving B-cell directed monoclonal antibodies and ATG, consider delaying to 3 months post-therapy. § Rationale for consideration of delaying COVID-19 vaccination for > 3 months after HSCT and CAR-T cell therapy includes:
- Vaccine response is expected to be sub-optimal;
- Antibody testing cannot be evaluated as standard of practice;
- Revaccination post-HSCT and CAR-T cell therapy is recommended. The attestation form for "Revaccination following Hematopoietic Stem Cell Transplant" can be obtained from transplant physicians.
¥ If local COVID-19 transmission rates are high, consider prioritization of COVID-19 vaccination. Routine post-HSCT vaccinations may be given at the same time as the COVID-19 vaccines but may be delayed at the discretion of the patient or medical professional. 28 Clinical Guidance on COVID-19 Vaccines for people with hematological malignancy at any stage of treatment and/or who have undergone hematopoietic stem cell transplant or CAR-T cell therapy in the past 6 months Updated: | The risk of mortality from COVID-19 disease is higher in patients with cancer, including patients with hematologic malignancies and HSCT recipients. [2][3][4][5] One study found that more severe forms of COVID-19 disease, including those requiring ICU admission, were more frequent in patients with hematologic malignancies hospitalized with COVID-19, and led to mortality nearly four times higher than that of the general population with COVID-19 and 41 times higher than that of hematologic malignancy patients without There are data to suggest that the currently available COVID-19 vaccines have efficacy. 6 COVID-19 vaccines should be encouraged for people with hematologic malignancies and HSCT and/or CAR-T recipients, as per BC Public Health recommendation for age eligibility and are not contraindicated. This recommendation is based on the following: • The National Advisory Committee on Immunization (NACI) recommends that immunosuppressed individuals be offered the vaccine if the benefits of vaccines outweigh the potential risks. 7#
Clinical Guidance on COVID-19 Vaccines for people with hematological malignancy at any stage of treatment and/or who have undergone hematopoietic stem cell transplant or CAR-T cell therapy in the past 6 months Updated: • Patients with blood cancer have an increased risk of death related to COVID-19 infection. [1][2][3][4][5] • The United Kingdom, the United States, France, and Australia have prioritized patients with cancer for COVID- 19 vaccinations, highlighting the high COVID-19 risk faced by these patients. 8 Is the COVID-19 vaccine efficacious and safe in people with hematologic malignancy patients and HSCT and/or CAR-T recipients?
There is still uncertainty about the efficacy of COVID-19 vaccines in patients with blood cancer and/or have undergone HSCT or CAR-T cell therapy in the last six months. As with most vaccines, there is a potential for diminished immune response in individuals who are immunocompromised due to their disease or treatment. In addition, patients with active cancer or undergoing active cancer treatment seemed to be generally excluded from the COVID-19 vaccine trials. However, in the COMIRNATY (Pfizer-BioNTech) vaccine trial, 3.9% of enrolled participants had a malignancy. 9 There are currently no known factors that would predispose these individuals to adverse events associated with the vaccines. At the time of authorization, there are no known serious warnings or precautions related to the vaccines in patients with cancer. [10][11][12][13][14] Small exploratory studies have shown lower antibody responses in patients with advanced cancer and haematological malignancies 9 following vaccination compared to controls. However, it is unclear how much antibody is needed for protection and/or the role of other immunological responses.
There is one study that suggests that a third dose of COVID-19 vaccine in immunocompromised patients can increase antibody levels. 15 Small studies on third doses of the mRNA COVID-19 vaccines have shown that immunogenicity (immunity measured in the blood) may increase with a third dose. The safety of a third dose is unknown at this time, but in these small studies reactions were found to be similar to that of prior doses.
The frequency and severity of adverse events following vaccination with an mRNA COVID-19 vaccine in these populations were comparable to that of non-immunosuppressed individuals in these studies and what was reported in clinical trials. Safety data in these populations following vaccination with a viral vector vaccine is not available. 16 Informed consent should include discussion about the possibility that individuals who are immunosuppressed may have a diminished immune response to any of the authorized COVID-19 vaccines. 17 Observed short-term adverse effects with the mRNA-based COVID-19 vaccines have been similar to those seen with seasonal influenza vaccination. Still, they may be more pronounced after the second COVID-19 vaccine dose (e.g. injection site pain/erythema, fever, headache, fatigue, and myalgia/arthralgia). [2][3][4][5][6][7][8][9]18 Safety results in the allogeneic HSCT patient population seem comparable. 15 Any long-term side effects of COVID-19 vaccines are not yet known, but Health Canada continues to monitor any adverse events following vaccination through their post-authorization surveillance process.
Immunocompromised patient populations are diverse and the relative degree of immunodeficiency will depend on the underlying condition, the progression of the disease, and the type and timing of treatment received. Therefore, the Clinical Guidance on COVID-19 Vaccines for people with hematological malignancy at any stage of treatment and/or who have undergone hematopoietic stem cell transplant or CAR-T cell therapy in the past 6 months Updated: April 18, 2023 balance of potential benefit and risk associated with COVID-19 vaccination should be assessed on an individual basis (Table 1).
Are there any specific contraindications or exceptions for those within the hematologic malignancy, HSCT and/or CAR-T recipient patient populations?
# Blood counts
Patients with blood cancer and HSCT or CAR-T recipients may experience low blood counts, either due to their disease or treatment, which could impact individual decision-making around receipt of COVID-19 vaccinations and timing of vaccinations relative to their treatments. COVID-19 vaccination should be deferred in patients unwell with neutropenia until well, 10,11 but may be considered in well patients with disease-related chronic neutropenia where neutrophil recovery is not expected. 19
# Allergy
The above noted COVID-19 vaccines are contraindicated in individuals with a history of severe allergic reaction to any component of the vaccines, including non-medicinal ingredients such as polyethylene glycol (PEG) or polysorbate-80, or a history of anaphylaxis after administration of a previous dose of COVID-19 vaccine using a similar platform (mRNA or viral vector). 7 People with a history of anaphylaxis without known or obvious cause, and those with suspected hypersensitivity or non-anaphylactic allergy to COVID-19 vaccine components, are advised to consult with an allergist prior to immunization. 20 BCCDC has a list of the individual components and their purpose in the vaccines. For a complete list of components in the vaccine, consult the vaccine monographs found at: www.bccdc.ca/health-info/diseasesconditions/covid-19/covid-19-vaccine/vaccines-for-covid-19.
People with a history of anaphylactic reaction to a previous dose of an mRNA COVID-19 vaccine, re-vaccination (i.e., administration of a subsequent dose in the series when indicated) may be offered with the same vaccine or the same mRNA platform if a risk assessment deems that the benefits outweigh the potential risks for the individual and if informed consent is provided. Prior to revaccination, consultation with an allergist or another appropriate physician (e.g., Medical Health Officer) is advised. If re-vaccination is going ahead, vaccine administration should be done in a controlled setting with expertise and equipment to manage anaphylaxis, with an extended period of observation of at least 30 minutes after re-vaccination.
Health Canada continues to monitor any adverse events following immunization through their post-authorization surveillance process.
# Other vaccines
Currently, it is recommended that COVID-19 vaccines can be given concomitantly with, or any time before or after any other indicated vaccine. [21][22][23][24] Clinical Guidance on COVID-19 Vaccines for people with hematological malignancy at any stage of treatment and/or who have undergone hematopoietic stem cell transplant or CAR-T cell therapy in the past 6 months Updated: Are there specific recommendations or considerations for safe and/or most effective administration?
1. Blood counts
Patients with blood cancer and HSCT or CAR-T recipients may have lowered blood counts related to the underlying disease or therapy. If blood counts (platelet count and neutrophil count) are low due to therapy and timing of recovery can be anticipated, e.g. 1 week prior to the next cyclical chemotherapy or maintenance cycle, the timing of vaccination should be scheduled accordingly (please see Table 1). However, where the timing of blood count recovery is unclear or not anticipated, e.g. marrow failure syndromes, then vaccination should not be delayed solely for this reason.
There is no consensus on an adequate platelet count for IM injections. Still, practical suggestions include using a platelet threshold of >20 x 10 9 /L, administering the vaccine after platelet transfusion if receiving regular transfusions, and applying firm pressure at the injection site for at least 5 minutes. 25
# Anti-coagulant therapy
As per Thrombosis Canada recommendations, 26 anti-coagulation should not be a barrier for administering COVID-19 vaccination to patients on warfarin (INR monitoring not required prior to vaccination), novel oral anticoagulants (apixaban, dabigatran, edoxaban, rivaroxaban) or antiplatelet agents (aspirin, clopidogrel, ticagrelor). Patients on therapeutic dose low-molecular weight heparin (dalteparin, tinzaparin, enoxaparin, nadroparin) or fondaparinux may consider delaying their anti-coagulant dose on the day of vaccination until after the IM injection. For patients on any of the above, applying pressure to the injection site for 3 to 5 minutes post vaccination is recommended to reduce bruising.
# Special considerations for immunotherapy
a. Therapies targeting B-cells including anti-CD20, CD19, CD22 targeting antibodies, or BiTEs: Patients receiving these agents may have a reduced immune response to vaccines in general that can extend to up to 6 months following treatment completion. If possible, patients should receive both doses of vaccine prior to starting these therapies. If patients are on, or have recently been treated with these agents, when they received the first 2 doses of vaccine, a 3 rd dose is recommended to be administered at least 28 days after the 2 nd dose, with consideration given to delaying to 3 months after therapy with B-cell directed therapies due to likelihood of impaired immune response.
# b. Checkpoint inhibitors:
Previous studies have not signalled an increased risk of complications of COVID-19 for patients on checkpoint inhibitors such as CTLA-4 inhibitors (e.g., ipilimumab), PD-1 inhibitors (e.g., nivolumab, pembrolizumab) and PD-L1 inhibitors (e.g., atezolizumab, durvalumab). There have been theoretical concerns of an enhanced immune reaction, particularly with CTLA-4 inhibitors. However, given the seriousness of COVID-19 infection, vaccination is still recommended in this group even if a four-week window cannot be confirmed.
# Timing of COVID-19 vaccines in relation to therapy
There are no known studies regarding the timing of COVID-19 vaccination in relation to therapy for blood cancer. The COMIRNATY (Pfizer-BioNTech), SPIKEVAX (Moderna) and VAXZEVRIA (AstraZeneca) vaccines are given as two injections with optimal protection assumed after the second dose for the general population. [10][11][12] Efficacy and duration of immunity are continuously being evaluated and recommendations are evolving rapidly. Therefore, patients should Clinical Guidance on COVID-19 Vaccines for people with hematological malignancy at any stage of treatment and/or who have undergone hematopoietic stem cell transplant or CAR-T cell therapy in the past 6 months Updated: follow current BCCDC guidance for the recommended number of and interval between COVID-19 vaccine doses.
In general, it is preferred that patients complete their COVID-19 vaccination series ideally 14 days prior to starting immunosuppressive therapy. 27 *However, life-saving or prolonging therapy should not be delayed solely to complete vaccination.
Recommendations for timing of COVID-19 vaccination for patients with hematologic malignancies (either completed, starting or already receiving treatment) and patients who have undergone HSCT or CAR-T cell therapy in the past 6 months are described in Table 1 below.
Any other timing should involve a case-by-case assessment based on: a. Risk of morbidity related to COVID-19 infection (including local incidence of the pandemic, cancer type, comorbidities that confer higher risk categories in general population, etc.), b. Cancer-related morbidity due to delay of active treatment, and c. Suboptimal immunity due to insufficient time window between vaccination and immunosuppressive therapy.
#
** Some patients may not have adequate counts either prior to or between cycles of therapy. The benefit likely outweighs the risk, and these patients should proceed to vaccination regardless of neutrophil count and with platelet transfusion support if required. *** Ideally high dose systemic corticosteroids (> 0.5 mg/kg/day prednisone or equivalent) should be avoided or completed 28 days prior to vaccination; if this is not possible, proceed with vaccination. † Due to likelihood of impaired immune response to vaccination within 3 months of receiving B-cell directed monoclonal antibodies and ATG, consider delaying to 3 months post-therapy. § Rationale for consideration of delaying COVID-19 vaccination for > 3 months after HSCT and CAR-T cell therapy includes:
• Vaccine response is expected to be sub-optimal;
• Antibody testing cannot be evaluated as standard of practice;
• Revaccination post-HSCT and CAR-T cell therapy is recommended. The attestation form for "Revaccination following Hematopoietic Stem Cell Transplant" can be obtained from transplant physicians.
¥ If local COVID-19 transmission rates are high, consider prioritization of COVID-19 vaccination. Routine post-HSCT vaccinations may be given at the same time as the COVID-19 vaccines but may be delayed at the discretion of the patient or medical professional. 28 Clinical Guidance on COVID-19 Vaccines for people with hematological malignancy at any stage of treatment and/or who have undergone hematopoietic stem cell transplant or CAR-T cell therapy in the past 6 months Updated: | None | None |
f0bc7cec325742ecf959ed51c234412225a0ae5d | cma | None | Wildtype JAK2V617F and normal or high erythropoietin level makes PV very unlikely, and patients should be investigated for secondary causes of polycythemia.Investigations for secondary polycythemia that may be indicated include: i. Chest x-ray ii. Pulse oximetry iii. Arterial blood gas including carboxyhemoglobin and methemoglobin levels iv. Kidney and liver function tests v. Abdominal imaging studies (ultrasound or CT scan) vi. Oxyhemoglobin dissociation curve vii. Sleep studies 7. All patients should be treated with phlebotomy to target hematocrit less than 45%. 8. Low-dose acetylsalicyclic acid (ASA) should be used in all patients without a contraindication.In high-risk PV patients (age ≥60 years and/or history of thrombosis), cytoreductive therapy should be used with or without phlebotomy in combination with low dose ASA.Conventional cardiovascular risk factors (diabetes, hypertension, hyperlipidemia) should be aggressively managed, and cigarette smoking should be discouraged. 11. Thromboembolic events should be managed according to accepted management guidelines. 12. Thromboprophylaxis should be used after surgery and in other high-risk situations.Polycythemia vera (PV) is a BCR-ABL1-negative myeloproliferative neoplasm (MPN) characterized by erthryocytosis (with increased red cell mass) that is often accompanied by leukocytosis and thrombocytosis. Constitutive JAK-STAT signaling caused by the JAK2V617F mutation within exon 14 is present in ~ 95% of PV patients and by different mutations within exon 12 of the JAK2 gene (4% of PV patients), which are responsible for the pathogenesis of PV 3,4 . The presence of JAK2V617F or a higher allele burden is not directly associated with PV survival or transformation rates 5,6 , however, increased JAK2V617F allele burdens have been associated with fibrotic transformation 7 .# Background
Polycythemia vera (PV) is a clonal stem cell disorder characterized by erythrocytosis, with the majority of cases caused by constitutive activation of the JAK-STAT signal transduction pathway. The disease is associated with burdensome symptoms, reduced quality of life, thrombohemorrhagic complications and potential transformation to myelofibrosis (MF), myelodysplastic syndrome and/or acute myeloid leukemia (AML) 1,2 Guideline Questions 1. What diagnostic and baseline investigations are recommended for adult patients with suspected or confirmed PV? 2. What are the recommended treatment options for PV?
# Search Strategy
This guideline was generated using systematic literature searches of PubMed and MEDLINE databases, ASCO abstracts and proceedings, and ASH abstracts and proceedings. The search included practice guidelines, systematic reviews, meta-analyses, randomized controlled trials and clinical trials. The guidelines were also adapted from the Canadian MPN Group recommendations.
# Target Population
The following guidelines apply to adults over the age of 18 years. Different principles may apply to pediatric patients.
# Recommendations
- Polycythemia vera (PV) should be considered when there is persistent elevation of hemoglobin (>165 g/L in men and >160 g/L in women) or hematocrit (>49% in men and >48% in women).
- JAK2V617F mutation testing and erythropoietin levels should be performed when PV is suspected.
Bone marrow biopsy and aspiration may be necessary in some cases to confirm the diagnosis of PV and to distinguish PV from other myeloproliferative neoplasms.
PV is highly likely when JAK2V617F mutation is present and erythropoietin level is subnormal. When JAK2V617F mutation is seen with normal erythropoietin level, bone marrow biopsy is recommended to differentiate PV from other MPNs. When JAK2V617F is normal and erythropoietin is low, consider JAK2 exon 12 mutational analysis or alternative diagnosis of congenital polycythemia. JAK2 exon 12 testing may be performed via Next Generation Sequencing (NGS) which is currently only available through bone marrow biopsy in Calgary.
# Clinical Manifestations
The estimated incidence of PV is ~ 2.8 per 100,000 among men and ~1.3 per 100,000 in woman with a prevalence of 22 cases per 100,000.
(). The median age of presentation is in the 6 th decade of life with only 1/3 of patients diagnosed younger than 50 years of age 8 .
The symptoms of PV can be variable with a majority of patients diagnosed incidentally by bloodwork.
Splenomegaly is present in 30-40% of patients 9 . Non-specific symptoms such as headache, weakness, dizziness, and excessive sweating are present in 30% to 50% of PV patients and are often related to hyperviscosity resulting from erythrocytosis 10,11 . Fatigue is common and may be related to iron deficiency often found in PV patients at diagnosis, even before the onset of therapeutic phlebotomy.
Specific symptoms such as pruritus, especially after warm baths or showers (aquagenic pruritus) is reported in 70% of patients and suspected to be related to the degranulation of increased mast cells in the skin of PV patients, releasing histamine and other inflammatory mediators 12,13 . Erythromelalgia, described as burning pain in the feet and/or hands accompanied by erythema is seen in up to 28% of patients resulting from microvascular thrombosis and ischemia due to platelet activation and aggregation 14 . Both arterial and venous thrombotic events are a major cause of morbidity and mortality in PV. The incidence of thrombosis is approximately 18 x 1000 person years and accounts for 45% of all PV deaths 9 .
# Diagnostic Evaluation
In the setting of isolated erythrocytosis, it is important to distinguish between primary and secondary polycythemia. Secondary polycythemia is caused by various factors driving erythropoiesis and may include hypoxia-driven mechanisms such as smoking, sleep apnea/hypoventilation, cardiac or pulmonary disease, high altitude or renal artery stenosis. Alternatively, oxygen-independent mechanisms include: drugs (androgens, erythropoietin, tumors-hepatic, renal, hemanigioblastomas) or post renal transplant 2 . Relative polycythemia should also be ruled out and is characterized by an isolated decrease in plasma volume with resultant elevation of hemoglobin, hematocrit and red blood cell count without an increase in red cell mass. Gaisbock's disease, stress erythrocytosis or spurious polycythemia refer to states of chronically low plasma volumes. A careful history and physical exam with select investigations can help distinguish PV from secondary causes (Table 1).
# Diagnosis
The diagnosis of PV is based on World Health Organization (WHO) criteria utilizing a composite assessment of clinical and laboratory features as shown in Table 3. Recently, 2016 revisions of the WHO classification have been made that have modified diagnostic hemoglobin levels as well as the utility of BM morphology. A bone marrow biopsy is not uniformly required in all cases, in particular, if patients meet previously defined WHO 2008 hemoglobin requirements and there is low likelihood of masked PV. Figure 1 demonstrates an approach to diagnosis with indications for additional molecular testing and bone marrow biopsy. The rationale for the changes is based on recent observations that some JAK2 V617F-positive PV patients present with hemoglobin levels lower than the 2008 WHO threshold with characteristic bone marrow findings of PV. This would be classified as "masked PV" (mPV) and such patients may have increased risk of thrombosis, secondary to late diagnosis and resulting inadequate disease control . In PV, the classical BM features are increased cellularity with trilineage proliferation (panmyelosis). Megakaryocytes are pleomorphic with varying sizes without significant abnormalities in maturation and minimal reticulin fibrosis (grade1-2) is present 23 . 17 . This was validated in a population-based PV study of 327 patients whereby age >70, leukocyte count >13 x 10 9 /L and thrombosis at time of diagnosis resulted in poorer survival with 10-year survival rates of 84%, 59% or 26% with the presence of none, one or ≥ 2risk factors 26 . Overall, 45% of PV-related deaths are associated with cardiovascular disease 27 .
Approximately 10% of PV patients transform into post-polycythemia vera myelofibrosis (PPV-MF), with progressive splenomegaly, MF-related symptoms, and anemia 28 . The IWG criteria for PPV-MF is shown in Table 4. Disease duration (>10 years) and JAK2V617F allele burden (>50%) are associated with a higher risk of evolution to PPV-MF 27,29 . The risk of leukemic transformation has been reported at 2.3% at 10 years and 5.5% at 15 years and remains <10% at 20 years. Older age, abnormal karyotype, and leukocytes ≥15 X 10 9 /L are independent risk factors for leukemic transformation 30,31 . Post PV AML is an aggressive disease with very poor outcomes. Intensive chemotherapy followed by consolidated by allogeneic transplant is recommended in young fit patients. Hypomethylating agents and/or experimental therapies can be considered 32,33 .
# Treatment
The main goal of therapy in PV is to prevent thrombohemorrhagic complications and control symptoms. The currently available treatments are non-curative. All patients should be counselled regarding their disease course and associated complications with management of their vascular risk factors. Currently, there are no specific lipid or blood pressure target ranges for individuals with PV. However, with the increased risk of arterial thrombosis, it is important that patients control atherosclerotic risk factors such as hypertension, dyslipidemia, diabetes and obesity as well as smoking cessation. The Framingham Heart Study and the risk assessment tools incorporated in current Canadian Cardiovascular Society guidelines should be applied for general prevention of cardiovascular disease 36 .
The European Leukemia Net (ELN) guidelines for Philadelphia-Negative Classical Myeloproliferative neoplasms (MPNs) recommends that all patients with PV be managed with phlebotomy to maintain a hematocrit (HCT) below 45%, and low-dose Aspirin 35 . Current risk stratification in PV is based on an estimate of thrombosis risk (Table 5) and patients are treated according to their risk group (Figure 2). The ELN has also defined criteria for response which are mainly intended for standardization in clinical trials and are not typically applied as rigorously in clinical practice 37 .
# Low-risk patients:
Treatment options for low risk patients include phlebotomy and low-dose Aspirin (81 -100 mg/day) 35 (Figure 2)
Phlebotomy.
Phlebotomy is well tolerated and can be performed as an emergency therapy if patients are experiencing symptoms of hyperviscosity as well as an important treatment for long-term maintenance in PV 35,38 . Typically, initial phlebotomy involves removal of 500 mL of blood every other day until a hematocrit of <45% is achieved. Lower quantity (i.e 250 mL) and frequency of phlebotomy should be considered in the elderly or patients with multiple comorbidities such as cardiovascular disease. Once an optimal hematocrit has been obtained a CBC can be assessed every 4-8 weeks and phlebotomy maintenance can be arranged accordingly (i.e every 2-3 months) to maintain Hct levels. Frequent phlebotomies will lead to iron deficiency and eventually result in reactive thrombocytosis and microcytosis. As a result, phlebotomy-induced iron deficiency can lead to complications such as increasing fatigue and restless leg syndrome. Iron supplementation is generally avoided in the setting of PV 9 .
Based on several studies, the recommended HCT target in PV is < 45% 39,40 . The 2013 Italian Cytoreductive Therapy in Polycythemia Vera (CYTO-PV) was a multicenter, randomized controlled trial (n=365) that compared maintaining a HCT of ≤ 45% "low hematocrit" to a HCT between 45-50% ("high hematocrit") using phlebotomy and/or hydroxyurea. The primary composite end point was the time until death from cardiovascular causes or major thrombotic events. At a median follow-up of 31 months, the primary end point was 2.7% among those with a HCT of <45% compared to 9.8% in the "high hematocrit" group (HR 3.91; 95% CI, 1.45 to 10.53; P = 0.007). There was no significant between-group difference in the rate of adverse events 40 .
Low-dose Aspirin.
The randomized, placebo-controlled, European Collaboration on Low-Dose Aspirin in Polycythemia Vera (ECLAP) study (n=518) demonstrated a significant risk reduction (RR 0.40) in a combined endpoint of cardiovascular events and venous thrombotic events (nonfatal MI, nonfatal stroke, PE, major venous thrombosis or death from CV causes) with the use of low-dose Aspirin (100 mg daily) over placebo, with no significant increased risk of bleeding 39 . Based on this data, daily low-dose Aspirin is recommended for all PV patients in the absence of contraindications 35 . Low dose Aspirin is effective in alleviating vasomotor microvascular symptoms particularly erythromelagia, which are resulting from platelet-rich arteriolar microthrombi 41 .
# High-risk patients:
High risk patients as shown in Table 5 (≥ 60 years of age and/or prior history of thrombosis) should be on cytoreductive therapy 35 . Cytoreductive therapy can be considered on an individual case basis (irrespective of risk) in patients with any of the following features 9 : (Figure 2) i. Extreme thrombocytosis (platelet count ≥1500×10 9 /L) or if thrombocytosis is associated to bleeding or avWD ii. Progressive leukocytosis ≥20 -25×10 9 /L iii. Symptomatic splenomegaly iv. Severe disease-related symptoms v. Intolerance to phlebotomy
# Cytoreductive therapies.
The European Leukemia Net (ELN) guidelines recommend either hydroxyurea or interferon-α as firstline cytoreductive therapy 35 .
# Hydroxyurea.
Hydroxyurea (HU) is an oral antimetabolite that prevents DNA synthesis by inhibiting the enzyme ribonucleoside reductase. Hydroxyurea is typically started at a dose of 15-20mg/kg/day (~1000mg/day). After a response is attained, a maintenance dose is continued to ensure a CBC remains within a normal range with CBC initially performed monthly and every 3 months thereafter once in a steady state 9 . Hydroxyurea is well tolerated with side effects including skin and nail changes, gastrointestinal toxicities, oral and leg ulcers myelosuppression and development of macrocytosis 9 .
In the Polycythemia Vera Study Group (PVSG) trial, patients treated with HU had a lower incidence of thrombosis compared with historical controls treated with phlebotomy (9.8% vs. 32.8%) 42 . Long-term outcomes comparing hydroxyurea to pipobroman were reported in the French Polycythemia Study Group (FPSG) study, which randomly assigned HU versus pipobroman as first-line therapy in 285 patients < 65 years old. Median survivals were 20.3 and 15.4 years for the HU and pipobroman, respectively (P = .008). At 10, 15, and 20 years, cumulative incidence of acute myeloid leukemia/ myelodysplastic syndrome (AML/MDS) was 6.6%, 16.5%, and 24% in the HU arm and 13%, 34%, and 52% in the pipobroman arm (P = .004). Cumulative myelofibrosis incidence at 10, 15, and 20 years was 15%, 24%, and 32% with HU versus 5%, 10%, and 21% with pipobroman (P = .02). This illustrated the higher leukemogenic potential for pipobroman and its lack of suitability as first-line therapy in PV 43 . Hydroxyurea became a preferred first-line agent and although the incidence of evolution to AML with HU has been reported, it has been considered significantly lower than historical controls treated with chlorambucil or radiophosphorus (5.9% vs. 10.6% vs 8.3%, respectively) 42 . Studies have confirmed a low incidence of AML in PV patients treated with hydroxyurea and that exposure to P32, busulphan, and pipobroman (HR, 5.46; 95% CI, 1.84-16.25; P = .0023), but not to hydroxyurea (HU) alone (HR, 0.86; 95% CI, 0.26-2.88; P = .8021), increases the risk for progression to AML/MDS compared with treatment with phlebotomy or interferon 31 . The data for HU use in PV is also extrapolated from essential thrombocythemia (ET) studies. Cortelazzo et al. randomized 114 high-risk ET patients to HU versus no therapy. At a median follow-up of 27 months, 3.6% of patients on HU experienced a thrombotic event compared to 24% of those in the control group 44 . Likewise, in 809 high-risk ET patients, HU plus low dose Aspirin (100mg/day) was compared to Anagrelide plus low dose Aspirin. Hydroxyurea resulted in better reduction of arterial thrombosis, major bleeding and fibrotic progression. Anagrelide resulted in lower venous thrombosis rates however patients on this treatment were more likely to withdraw from their assigned treatment (P<0.001) 45 . The ANAHYDRET study, was a prospective randomized noninferiority phase 3 study of 259 high-risk ET patients. During the total observation time of 730 patient-years, there was no significant difference between the anagrelide and hydroxyurea group regarding incidences of arterial and venous thrombosis, bleeding events, or rates of discontinuation. Disease transformation into myelofibrosis or secondary leukemia was not reported in this study. Anagrelide was considered not inferior compared with hydroxyurea in the prevention of thrombotic complications in patients with ET however, is not considered a first line treatment option in PV 46 .
Although not a common problem in PV, the development of HU resistance or intolerance occurs and has been estimated as 11.5% in a median of 5.8 years from time of diagnosis. Hydroxyurea intolerance/resistance is associated with a 5.6 fold increase risk of death 47 . The ELN panel of experts has developed a standardized definition of resistance and intolerance to HU in PV 34 (Table 6). Younger patients with intolerance/resistance are alternatively treated with Interferonα therapy (IFN) or Ruxolitinib. Older patients can be treated with alternatives such as Ruxolitinib or select elderly patients may be considered for busulphan 35 . Any of the following criteria: 1. Need for phlebotomy to keep HCT 400 x 10 9 /L AND WBC >10 x 10 9 /L after 3 months of at least 2 g/day of HU 3. Failure to reduce massive splenomegaly- by more than 50% as measured clinically, OR failure to completely relieve symptoms related to splenomegaly, after 3 months of at least 2 g/day of HU 4. Persistent cytopenias: ANC <1 x 10 9 /L OR plt <100 x 10 9 /L OR Hgb <100 g/l at the lowest dose of HU required to achieve a complete or partial response § 5. Presence of leg ulcers or other unacceptable HU-related toxicities, such as mucocutaneous manifestations, GI symptoms, pneumonitis or fever *Spleen more than 10 cm from the costal margin.
§Complete response defined as: Hct <45% without phlebotomy, platelet count ≤400 x 10 9 /L, WBC ≤ 10 x 10 9/ Land no disease related symptoms. Partial response defined as: Hct <45% without phlebotomy, or response in three or more of the other criteria 37 .
# Interferon.
Both short-acting Interferon (IFN) and pegylated interferon (IFN)-α are effective in controlling blood counts as well as spleen size and symptoms (aquagenic pruritus) in PV, and is considered first-line therapy, particularly in younger patients (< 40 years) 35,48 . Unfortunately, side effects can limit therapy and include autoimmune disorders, flu-like manifestations, depression, heart and ocular disease which have led to permanent discontinuation in 20% to 40% of patients on conventional IFN and 20% to 25% on pegylated IFN 48 . It is contraindicated in patients with mental disorders. IFN is commonly administered subcutaneously at a starting dose of 3 million units daily until a response is achieved. Pegylated IFN is given at a starting dose of 45 µg weekly and if there is lack of response after 12 weeks, a dose increase is indicated (90 ug to 135 ug/weekly) The dose should be titrated individually based on efficacy and toxicity with CBC monitoring on a monthly basis.
Apart from the absence of leukemogenic risk, the other benefit of IFN may be its ability to attain molecular responses 48,49 . A phase II study of pegylated interferon alfa-2a (PEG-IFN-alpha-2a) in patients with ET (n=39) and PV (n=40) demonstrated that PEG-IFN-alpha-2a reduces the size of the malignant clones measured by JAK2 allele burden. Overall hematologic response rate was 80% in PV and 81% in ET (complete in 70% and 76% of patients, respectively). Molecular response rates were 38% in ET and 54% in PV, with complete (undetectable JAK2(V617F)) in 6% and 14%, respectively 49 . Two phase III studies comparing HU to pegylated forms of IFN-α are ongoing in the United States and Europe; PROUD-PV (NCT01949805) and MPD-RC 112 (NCT01259856), with aims of determining the efficacy of these two therapies as first line cytoreductive agents in high-risk PV and ET.
# Second line therapies:
Ruxolitinib.
Ruxolitinib is a JAK1/JAK2 inhibitor that has demonstrated clinical benefit and has been approved in patients with myelofibrosis 50,51 . A phase II study of PV patients (n=34) who were intolerant or refractory to HU received ruxolitinib for a median of 35 months. Achievement of a HCT <45% without phlebotomy occurred in 97% of patients by week 24. Patients with palpable splenomegaly at baseline, resulted in 44% and 63%, respectively, having a nonpalpable spleen at weeks 24 and 144. The RESPONSE study was a phase III open-label study evaluating the efficacy and safety of ruxolitinib versus investigator determined best available therapy (BAT) in patients with polycythemia vera who were intolerant or refractory to HU. The primary end point was both hematocrit control and ≥ 35% reduction in spleen volume at week 32, based on imaging. The primary end point was achieved in 21% of the patients in the ruxolitinib group versus 1% of those in the BAT group (OR 28.64; 95% CI 4.50-1206; P <0.0001). Hematocrit control was achieved in 60% of patients receiving ruxolitinib and 20% of those receiving BAT. Spleen volume reduction occurred in 38% and 1% of ruxolitinib versus BAT patients, respectively. Ruxolitinib achieved ≥ 50% reduction in the total symptom score at week 32 in 49% versus 5% of those with BAT. Thromboembolic events occurred in one patient receiving ruxolitinib and in six patients receiving standard therapy however, further investigations are needed to determine its role in reducing thrombotic risk among PV patients 23 . The most common hematologic adverse events (AEs) were anemia and thrombocytopenia; however, no patient in the RESPONSE trial discontinued treatment due to these cytopenias. Common non-hematologic AEs are headache, dizziness, diarrhea, and fatigue and there were herpes zoster infections noted in ~6% of patients.
Ruxolitinib is now approved by Health Canada for treatment of PV patients resistant to or intolerant of a cytoreductive agent.
# Symptom assessment
PV-related symptoms are troublesome to patients, and alleviation of this burden is an important treatment objective. It is important to carefully assess patients' symptoms and to have an objective means to monitor disease progression or response to treatment. The Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) is a validated objective tool for evaluating patient symptoms 11 . The MPN-SAF TSS, also known as MPN10, is a shorter questionnaire that includes 10 items: fatigue, concentration, early satiety, inactivity, night sweats, itching, bone pain, abdominal discomfort, weight loss, and fever. This score has been validated in a prospective study of 1433 patients and results correlated with other measures of disease burden and remains consistent between serial administrations 11 .
# Special Topics
# Pregnancy
Typically, only 10% of PV patients are diagnosed at <40 years of age 52 . PV increases risks for both fetus and mother with less than 60% of pregnancies occurring in PV patients being successful.
Patients are at risk of miscarriages with first trimester losses being most common. Maternal complications include preeclampsia, postpartum hemorrhage and thrombosis 45,53 . Phlebotomy should be used to keep the hematocrit at less than 45% but of note, the physiological changes of pregnancy often can reduce hematocrit levels. Female patients should be advised that HU is contraindicated in pregnancy and, therefore, appropriate contraceptive precautions should be taken while on this therapy and HU should be discontinued in setting of pregnancy. Interferon alfa-2b is recommended for those requiring cytoreductive therapy during pregnancy since all other cytoreductive agents are contraindicated due to possible teratogenic effects. Indications for cytoreduction in pregnancy include if platelet count >1500 x 10 9 /L or related complications of bleeding. There is some evidence that the use of low-dose aspirin throughout pregnancy improves live birth rate. The ELN has published treatment recommendations for PV patients during pregnancy (Table 7). It is recommended that prophylactic low-molecular-weight heparin (LMWH) be used for 6 weeks postpartum in all patients with consideration for its use during pregnancy in high risk pregnancy 9,35 . *Recurrent (≥3) first-trimester pregnancy loss, intrauterine growth restriction (IUGR), unexplained intrauterine death or if secondary to placental dysfunction, severe preeclampsia necessitation preterm delivery before 34 weeks, significant ante-postpartum hemorrhage, placental abruption, or marked sustained increase of platelets >1500 x 109/L (Adapted from: Gerds A. Oncology 2017;92:179-189 54 ).
# Perioperative Management:
Surgery in patients with PV has a high risk of both peri-operative bleeding and postoperative thromboembolism. In a multicenter retrospective study of 255 PV and ET patients, a high proportion of patients experienced vascular occlusions (7.7%) and major hemorrhage (7.3%) 55 . Elective surgeries should be delayed until cytoreductive measures and/or phlebotomy can be used to achieve blood count control since risks may be lower with hematologic control prior to surgery 56 . It is recommended that hematocrit maintenance <45% and normalization of blood counts be achieved ≥ 3 months prior to surgery 57 . Aspirin should be held for 5-7 days before surgery to reduce the risk of hemorrhage. LMWH should be given after surgery to prevent deep venous thrombosis 57 . Mechanical compression stockings are an option for patients with bleeding that prevents the use of anticoagulation. Ruxolitinib has potential rebound effects with discontinuation therefore it is recommended it be continued through surgery. If discontinuations are needed, a taper is required whereby it is discontinued 1-2 weeks prior to surgery 54 . When thromboembolic events do occur, treatment should be according to current management guidelines. Indefinite anticoagulation should be considered because of the high risk of recurrent events.
# Development and Revision History
This guideline was reviewed and endorsed by the Alberta Hematology Tumour Team. Members include . Evidence was selected and reviewed by a working group comprised of members from the Alberta Tumour Teams, external participants identified by the Working Group Lead, and a knowledge management specialist from the Guideline Resource Unit. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook. This guideline was originally developed in 2020.
# Maintenance
A formal review of the guideline will be conducted in 2022. If critical new evidence is brought forward before that time, however, the guideline working group members will revise and update the document accordingly. | Wildtype JAK2V617F and normal or high erythropoietin level makes PV very unlikely, and patients should be investigated for secondary causes of polycythemia.Investigations for secondary polycythemia that may be indicated include: i. Chest x-ray ii. Pulse oximetry iii. Arterial blood gas including carboxyhemoglobin and methemoglobin levels iv. Kidney and liver function tests v. Abdominal imaging studies (ultrasound or CT scan) vi. Oxyhemoglobin dissociation curve vii. Sleep studies 7. All patients should be treated with phlebotomy to target hematocrit less than 45%. 8. Low-dose acetylsalicyclic acid (ASA) should be used in all patients without a contraindication.In high-risk PV patients (age ≥60 years and/or history of thrombosis), cytoreductive therapy should be used with or without phlebotomy in combination with low dose ASA.Conventional cardiovascular risk factors (diabetes, hypertension, hyperlipidemia) should be aggressively managed, and cigarette smoking should be discouraged. 11. Thromboembolic events should be managed according to accepted management guidelines. 12. Thromboprophylaxis should be used after surgery and in other high-risk situations.Polycythemia vera (PV) is a BCR-ABL1-negative myeloproliferative neoplasm (MPN) characterized by erthryocytosis (with increased red cell mass) that is often accompanied by leukocytosis and thrombocytosis. Constitutive JAK-STAT signaling caused by the JAK2V617F mutation within exon 14 is present in ~ 95% of PV patients and by different mutations within exon 12 of the JAK2 gene (4% of PV patients), which are responsible for the pathogenesis of PV 3,4 . The presence of JAK2V617F or a higher allele burden is not directly associated with PV survival or transformation rates 5,6 , however, increased JAK2V617F allele burdens have been associated with fibrotic transformation 7 .# Background
Polycythemia vera (PV) is a clonal stem cell disorder characterized by erythrocytosis, with the majority of cases caused by constitutive activation of the JAK-STAT signal transduction pathway. The disease is associated with burdensome symptoms, reduced quality of life, thrombohemorrhagic complications and potential transformation to myelofibrosis (MF), myelodysplastic syndrome and/or acute myeloid leukemia (AML) 1,2 Guideline Questions 1. What diagnostic and baseline investigations are recommended for adult patients with suspected or confirmed PV? 2. What are the recommended treatment options for PV?
# Search Strategy
This guideline was generated using systematic literature searches of PubMed and MEDLINE databases, ASCO abstracts and proceedings, and ASH abstracts and proceedings. The search included practice guidelines, systematic reviews, meta-analyses, randomized controlled trials and clinical trials. The guidelines were also adapted from the Canadian MPN Group recommendations.
# Target Population
The following guidelines apply to adults over the age of 18 years. Different principles may apply to pediatric patients.
# Recommendations
1. Polycythemia vera (PV) should be considered when there is persistent elevation of hemoglobin (>165 g/L in men and >160 g/L in women) or hematocrit (>49% in men and >48% in women).
2. JAK2V617F mutation testing and erythropoietin levels should be performed when PV is suspected.
# 3.
Bone marrow biopsy and aspiration may be necessary in some cases to confirm the diagnosis of PV and to distinguish PV from other myeloproliferative neoplasms.
# 4.
PV is highly likely when JAK2V617F mutation is present and erythropoietin level is subnormal. When JAK2V617F mutation is seen with normal erythropoietin level, bone marrow biopsy is recommended to differentiate PV from other MPNs. When JAK2V617F is normal and erythropoietin is low, consider JAK2 exon 12 mutational analysis or alternative diagnosis of congenital polycythemia. JAK2 exon 12 testing may be performed via Next Generation Sequencing (NGS) which is currently only available through bone marrow biopsy in Calgary.
# Clinical Manifestations
The estimated incidence of PV is ~ 2.8 per 100,000 among men and ~1.3 per 100,000 in woman with a prevalence of 22 cases per 100,000.
(http://www.lls.org/sites/default/files/file_assets/FS13_PolycythemiaVera_FactSheet.pdf). The median age of presentation is in the 6 th decade of life with only 1/3 of patients diagnosed younger than 50 years of age 8 .
The symptoms of PV can be variable with a majority of patients diagnosed incidentally by bloodwork.
Splenomegaly is present in 30-40% of patients 9 . Non-specific symptoms such as headache, weakness, dizziness, and excessive sweating are present in 30% to 50% of PV patients and are often related to hyperviscosity resulting from erythrocytosis 10,11 . Fatigue is common and may be related to iron deficiency often found in PV patients at diagnosis, even before the onset of therapeutic phlebotomy.
Specific symptoms such as pruritus, especially after warm baths or showers (aquagenic pruritus) is reported in 70% of patients and suspected to be related to the degranulation of increased mast cells in the skin of PV patients, releasing histamine and other inflammatory mediators 12,13 . Erythromelalgia, described as burning pain in the feet and/or hands accompanied by erythema is seen in up to 28% of patients resulting from microvascular thrombosis and ischemia due to platelet activation and aggregation 14 . Both arterial and venous thrombotic events are a major cause of morbidity and mortality in PV. The incidence of thrombosis is approximately 18 x 1000 person years and accounts for 45% of all PV deaths 9 .
# Diagnostic Evaluation
In the setting of isolated erythrocytosis, it is important to distinguish between primary and secondary polycythemia. Secondary polycythemia is caused by various factors driving erythropoiesis and may include hypoxia-driven mechanisms such as smoking, sleep apnea/hypoventilation, cardiac or pulmonary disease, high altitude or renal artery stenosis. Alternatively, oxygen-independent mechanisms include: drugs (androgens, erythropoietin, tumors-hepatic, renal, hemanigioblastomas) or post renal transplant 2 . Relative polycythemia should also be ruled out and is characterized by an isolated decrease in plasma volume with resultant elevation of hemoglobin, hematocrit and red blood cell count without an increase in red cell mass. Gaisbock's disease, stress erythrocytosis or spurious polycythemia refer to states of chronically low plasma volumes. A careful history and physical exam with select investigations can help distinguish PV from secondary causes (Table 1).
# Diagnosis
The diagnosis of PV is based on World Health Organization (WHO) criteria utilizing a composite assessment of clinical and laboratory features as shown in Table 3. Recently, 2016 revisions of the WHO classification have been made that have modified diagnostic hemoglobin levels as well as the utility of BM morphology. A bone marrow biopsy is not uniformly required in all cases, in particular, if patients meet previously defined WHO 2008 hemoglobin requirements and there is low likelihood of masked PV. Figure 1 demonstrates an approach to diagnosis with indications for additional molecular testing and bone marrow biopsy. The rationale for the changes is based on recent observations that some JAK2 V617F-positive PV patients present with hemoglobin levels lower than the 2008 WHO threshold with characteristic bone marrow findings of PV. This would be classified as "masked PV" (mPV) and such patients may have increased risk of thrombosis, secondary to late diagnosis and resulting inadequate disease control [20][21][22] . In PV, the classical BM features are increased cellularity with trilineage proliferation (panmyelosis). Megakaryocytes are pleomorphic with varying sizes without significant abnormalities in maturation and minimal reticulin fibrosis (grade1-2) is present 23 . 17 . This was validated in a population-based PV study of 327 patients whereby age >70, leukocyte count >13 x 10 9 /L and thrombosis at time of diagnosis resulted in poorer survival with 10-year survival rates of 84%, 59% or 26% with the presence of none, one or ≥ 2risk factors 26 . Overall, 45% of PV-related deaths are associated with cardiovascular disease 27 .
Approximately 10% of PV patients transform into post-polycythemia vera myelofibrosis (PPV-MF), with progressive splenomegaly, MF-related symptoms, and anemia 28 . The IWG criteria for PPV-MF is shown in Table 4. Disease duration (>10 years) and JAK2V617F allele burden (>50%) are associated with a higher risk of evolution to PPV-MF 27,29 . The risk of leukemic transformation has been reported at 2.3% at 10 years and 5.5% at 15 years and remains <10% at 20 years. Older age, abnormal karyotype, and leukocytes ≥15 X 10 9 /L are independent risk factors for leukemic transformation 30,31 . Post PV AML is an aggressive disease with very poor outcomes. Intensive chemotherapy followed by consolidated by allogeneic transplant is recommended in young fit patients. Hypomethylating agents and/or experimental therapies can be considered 32,33 .
# Treatment
The main goal of therapy in PV is to prevent thrombohemorrhagic complications and control symptoms. The currently available treatments are non-curative. All patients should be counselled regarding their disease course and associated complications with management of their vascular risk factors. Currently, there are no specific lipid or blood pressure target ranges for individuals with PV. However, with the increased risk of arterial thrombosis, it is important that patients control atherosclerotic risk factors such as hypertension, dyslipidemia, diabetes and obesity as well as smoking cessation. The Framingham Heart Study and the risk assessment tools incorporated in current Canadian Cardiovascular Society guidelines should be applied for general prevention of cardiovascular disease 36 .
The European Leukemia Net (ELN) guidelines for Philadelphia-Negative Classical Myeloproliferative neoplasms (MPNs) recommends that all patients with PV be managed with phlebotomy to maintain a hematocrit (HCT) below 45%, and low-dose Aspirin 35 . Current risk stratification in PV is based on an estimate of thrombosis risk (Table 5) and patients are treated according to their risk group (Figure 2). The ELN has also defined criteria for response which are mainly intended for standardization in clinical trials and are not typically applied as rigorously in clinical practice 37 .
# Low-risk patients:
Treatment options for low risk patients include phlebotomy and low-dose Aspirin (81 -100 mg/day) 35 (Figure 2)
Phlebotomy.
Phlebotomy is well tolerated and can be performed as an emergency therapy if patients are experiencing symptoms of hyperviscosity as well as an important treatment for long-term maintenance in PV 35,38 . Typically, initial phlebotomy involves removal of 500 mL of blood every other day until a hematocrit of <45% is achieved. Lower quantity (i.e 250 mL) and frequency of phlebotomy should be considered in the elderly or patients with multiple comorbidities such as cardiovascular disease. Once an optimal hematocrit has been obtained a CBC can be assessed every 4-8 weeks and phlebotomy maintenance can be arranged accordingly (i.e every 2-3 months) to maintain Hct levels. Frequent phlebotomies will lead to iron deficiency and eventually result in reactive thrombocytosis and microcytosis. As a result, phlebotomy-induced iron deficiency can lead to complications such as increasing fatigue and restless leg syndrome. Iron supplementation is generally avoided in the setting of PV 9 .
Based on several studies, the recommended HCT target in PV is < 45% 39,40 . The 2013 Italian Cytoreductive Therapy in Polycythemia Vera (CYTO-PV) was a multicenter, randomized controlled trial (n=365) that compared maintaining a HCT of ≤ 45% "low hematocrit" to a HCT between 45-50% ("high hematocrit") using phlebotomy and/or hydroxyurea. The primary composite end point was the time until death from cardiovascular causes or major thrombotic events. At a median follow-up of 31 months, the primary end point was 2.7% among those with a HCT of <45% compared to 9.8% in the "high hematocrit" group (HR 3.91; 95% CI, 1.45 to 10.53; P = 0.007). There was no significant between-group difference in the rate of adverse events 40 .
Low-dose Aspirin.
The randomized, placebo-controlled, European Collaboration on Low-Dose Aspirin in Polycythemia Vera (ECLAP) study (n=518) demonstrated a significant risk reduction (RR 0.40) in a combined endpoint of cardiovascular events and venous thrombotic events (nonfatal MI, nonfatal stroke, PE, major venous thrombosis or death from CV causes) with the use of low-dose Aspirin (100 mg daily) over placebo, with no significant increased risk of bleeding 39 . Based on this data, daily low-dose Aspirin is recommended for all PV patients in the absence of contraindications 35 . Low dose Aspirin is effective in alleviating vasomotor microvascular symptoms particularly erythromelagia, which are resulting from platelet-rich arteriolar microthrombi 41 .
# High-risk patients:
High risk patients as shown in Table 5 (≥ 60 years of age and/or prior history of thrombosis) should be on cytoreductive therapy 35 . Cytoreductive therapy can be considered on an individual case basis (irrespective of risk) in patients with any of the following features 9 : (Figure 2) i. Extreme thrombocytosis (platelet count ≥1500×10 9 /L) or if thrombocytosis is associated to bleeding or avWD ii. Progressive leukocytosis ≥20 -25×10 9 /L iii. Symptomatic splenomegaly iv. Severe disease-related symptoms v. Intolerance to phlebotomy
# Cytoreductive therapies.
The European Leukemia Net (ELN) guidelines recommend either hydroxyurea or interferon-α as firstline cytoreductive therapy 35 .
# Hydroxyurea.
Hydroxyurea (HU) is an oral antimetabolite that prevents DNA synthesis by inhibiting the enzyme ribonucleoside reductase. Hydroxyurea is typically started at a dose of 15-20mg/kg/day (~1000mg/day). After a response is attained, a maintenance dose is continued to ensure a CBC remains within a normal range with CBC initially performed monthly and every 3 months thereafter once in a steady state 9 . Hydroxyurea is well tolerated with side effects including skin and nail changes, gastrointestinal toxicities, oral and leg ulcers myelosuppression and development of macrocytosis 9 .
In the Polycythemia Vera Study Group (PVSG) trial, patients treated with HU had a lower incidence of thrombosis compared with historical controls treated with phlebotomy (9.8% vs. 32.8%) 42 . Long-term outcomes comparing hydroxyurea to pipobroman were reported in the French Polycythemia Study Group (FPSG) study, which randomly assigned HU versus pipobroman as first-line therapy in 285 patients < 65 years old. Median survivals were 20.3 and 15.4 years for the HU and pipobroman, respectively (P = .008). At 10, 15, and 20 years, cumulative incidence of acute myeloid leukemia/ myelodysplastic syndrome (AML/MDS) was 6.6%, 16.5%, and 24% in the HU arm and 13%, 34%, and 52% in the pipobroman arm (P = .004). Cumulative myelofibrosis incidence at 10, 15, and 20 years was 15%, 24%, and 32% with HU versus 5%, 10%, and 21% with pipobroman (P = .02). This illustrated the higher leukemogenic potential for pipobroman and its lack of suitability as first-line therapy in PV 43 . Hydroxyurea became a preferred first-line agent and although the incidence of evolution to AML with HU has been reported, it has been considered significantly lower than historical controls treated with chlorambucil or radiophosphorus (5.9% vs. 10.6% vs 8.3%, respectively) 42 . Studies have confirmed a low incidence of AML in PV patients treated with hydroxyurea and that exposure to P32, busulphan, and pipobroman (HR, 5.46; 95% CI, 1.84-16.25; P = .0023), but not to hydroxyurea (HU) alone (HR, 0.86; 95% CI, 0.26-2.88; P = .8021), increases the risk for progression to AML/MDS compared with treatment with phlebotomy or interferon 31 . The data for HU use in PV is also extrapolated from essential thrombocythemia (ET) studies. Cortelazzo et al. randomized 114 high-risk ET patients to HU versus no therapy. At a median follow-up of 27 months, 3.6% of patients on HU experienced a thrombotic event compared to 24% of those in the control group 44 . Likewise, in 809 high-risk ET patients, HU plus low dose Aspirin (100mg/day) was compared to Anagrelide plus low dose Aspirin. Hydroxyurea resulted in better reduction of arterial thrombosis, major bleeding and fibrotic progression. Anagrelide resulted in lower venous thrombosis rates however patients on this treatment were more likely to withdraw from their assigned treatment (P<0.001) 45 . The ANAHYDRET study, was a prospective randomized noninferiority phase 3 study of 259 high-risk ET patients. During the total observation time of 730 patient-years, there was no significant difference between the anagrelide and hydroxyurea group regarding incidences of arterial and venous thrombosis, bleeding events, or rates of discontinuation. Disease transformation into myelofibrosis or secondary leukemia was not reported in this study. Anagrelide was considered not inferior compared with hydroxyurea in the prevention of thrombotic complications in patients with ET however, is not considered a first line treatment option in PV 46 .
Although not a common problem in PV, the development of HU resistance or intolerance occurs and has been estimated as 11.5% in a median of 5.8 years from time of diagnosis. Hydroxyurea intolerance/resistance is associated with a 5.6 fold increase risk of death 47 . The ELN panel of experts has developed a standardized definition of resistance and intolerance to HU in PV 34 (Table 6). Younger patients with intolerance/resistance are alternatively treated with Interferonα therapy (IFN) or Ruxolitinib. Older patients can be treated with alternatives such as Ruxolitinib or select elderly patients may be considered for busulphan 35 . Any of the following criteria: 1. Need for phlebotomy to keep HCT <45% after 3 months of at least 2 g/day of HU 2. Uncontrolled myeloproliferation: plt >400 x 10 9 /L AND WBC >10 x 10 9 /L after 3 months of at least 2 g/day of HU 3. Failure to reduce massive splenomegaly* by more than 50% as measured clinically, OR failure to completely relieve symptoms related to splenomegaly, after 3 months of at least 2 g/day of HU 4. Persistent cytopenias: ANC <1 x 10 9 /L OR plt <100 x 10 9 /L OR Hgb <100 g/l at the lowest dose of HU required to achieve a complete or partial response § 5. Presence of leg ulcers or other unacceptable HU-related toxicities, such as mucocutaneous manifestations, GI symptoms, pneumonitis or fever *Spleen more than 10 cm from the costal margin.
§Complete response defined as: Hct <45% without phlebotomy, platelet count ≤400 x 10 9 /L, WBC ≤ 10 x 10 9/ Land no disease related symptoms. Partial response defined as: Hct <45% without phlebotomy, or response in three or more of the other criteria 37 .
# Interferon.
Both short-acting Interferon (IFN) and pegylated interferon (IFN)-α are effective in controlling blood counts as well as spleen size and symptoms (aquagenic pruritus) in PV, and is considered first-line therapy, particularly in younger patients (< 40 years) 35,48 . Unfortunately, side effects can limit therapy and include autoimmune disorders, flu-like manifestations, depression, heart and ocular disease which have led to permanent discontinuation in 20% to 40% of patients on conventional IFN and 20% to 25% on pegylated IFN 48 . It is contraindicated in patients with mental disorders. IFN is commonly administered subcutaneously at a starting dose of 3 million units daily until a response is achieved. Pegylated IFN is given at a starting dose of 45 µg weekly and if there is lack of response after 12 weeks, a dose increase is indicated (90 ug to 135 ug/weekly) The dose should be titrated individually based on efficacy and toxicity with CBC monitoring on a monthly basis.
Apart from the absence of leukemogenic risk, the other benefit of IFN may be its ability to attain molecular responses 48,49 . A phase II study of pegylated interferon alfa-2a (PEG-IFN-alpha-2a) in patients with ET (n=39) and PV (n=40) demonstrated that PEG-IFN-alpha-2a reduces the size of the malignant clones measured by JAK2 allele burden. Overall hematologic response rate was 80% in PV and 81% in ET (complete in 70% and 76% of patients, respectively). Molecular response rates were 38% in ET and 54% in PV, with complete (undetectable JAK2(V617F)) in 6% and 14%, respectively 49 . Two phase III studies comparing HU to pegylated forms of IFN-α are ongoing in the United States and Europe; PROUD-PV (NCT01949805) and MPD-RC 112 (NCT01259856), with aims of determining the efficacy of these two therapies as first line cytoreductive agents in high-risk PV and ET.
# Second line therapies:
Ruxolitinib.
Ruxolitinib is a JAK1/JAK2 inhibitor that has demonstrated clinical benefit and has been approved in patients with myelofibrosis 50,51 . A phase II study of PV patients (n=34) who were intolerant or refractory to HU received ruxolitinib for a median of 35 months. Achievement of a HCT <45% without phlebotomy occurred in 97% of patients by week 24. Patients with palpable splenomegaly at baseline, resulted in 44% and 63%, respectively, having a nonpalpable spleen at weeks 24 and 144. The RESPONSE study was a phase III open-label study evaluating the efficacy and safety of ruxolitinib versus investigator determined best available therapy (BAT) in patients with polycythemia vera who were intolerant or refractory to HU. The primary end point was both hematocrit control and ≥ 35% reduction in spleen volume at week 32, based on imaging. The primary end point was achieved in 21% of the patients in the ruxolitinib group versus 1% of those in the BAT group (OR 28.64; 95% CI 4.50-1206; P <0.0001). Hematocrit control was achieved in 60% of patients receiving ruxolitinib and 20% of those receiving BAT. Spleen volume reduction occurred in 38% and 1% of ruxolitinib versus BAT patients, respectively. Ruxolitinib achieved ≥ 50% reduction in the total symptom score at week 32 in 49% versus 5% of those with BAT. Thromboembolic events occurred in one patient receiving ruxolitinib and in six patients receiving standard therapy however, further investigations are needed to determine its role in reducing thrombotic risk among PV patients 23 . The most common hematologic adverse events (AEs) were anemia and thrombocytopenia; however, no patient in the RESPONSE trial discontinued treatment due to these cytopenias. Common non-hematologic AEs are headache, dizziness, diarrhea, and fatigue and there were herpes zoster infections noted in ~6% of patients.
Ruxolitinib is now approved by Health Canada for treatment of PV patients resistant to or intolerant of a cytoreductive agent.
# Symptom assessment
PV-related symptoms are troublesome to patients, and alleviation of this burden is an important treatment objective. It is important to carefully assess patients' symptoms and to have an objective means to monitor disease progression or response to treatment. The Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) is a validated objective tool for evaluating patient symptoms 11 . The MPN-SAF TSS, also known as MPN10, is a shorter questionnaire that includes 10 items: fatigue, concentration, early satiety, inactivity, night sweats, itching, bone pain, abdominal discomfort, weight loss, and fever. This score has been validated in a prospective study of 1433 patients and results correlated with other measures of disease burden and remains consistent between serial administrations 11 .
# Special Topics
# Pregnancy
Typically, only 10% of PV patients are diagnosed at <40 years of age 52 . PV increases risks for both fetus and mother with less than 60% of pregnancies occurring in PV patients being successful.
Patients are at risk of miscarriages with first trimester losses being most common. Maternal complications include preeclampsia, postpartum hemorrhage and thrombosis 45,53 . Phlebotomy should be used to keep the hematocrit at less than 45% but of note, the physiological changes of pregnancy often can reduce hematocrit levels. Female patients should be advised that HU is contraindicated in pregnancy and, therefore, appropriate contraceptive precautions should be taken while on this therapy and HU should be discontinued in setting of pregnancy. Interferon alfa-2b is recommended for those requiring cytoreductive therapy during pregnancy since all other cytoreductive agents are contraindicated due to possible teratogenic effects. Indications for cytoreduction in pregnancy include if platelet count >1500 x 10 9 /L or related complications of bleeding. There is some evidence that the use of low-dose aspirin throughout pregnancy improves live birth rate. The ELN has published treatment recommendations for PV patients during pregnancy (Table 7). It is recommended that prophylactic low-molecular-weight heparin (LMWH) be used for 6 weeks postpartum in all patients with consideration for its use during pregnancy in high risk pregnancy 9,35 . *Recurrent (≥3) first-trimester pregnancy loss, intrauterine growth restriction (IUGR), unexplained intrauterine death or if secondary to placental dysfunction, severe preeclampsia necessitation preterm delivery before 34 weeks, significant ante-postpartum hemorrhage, placental abruption, or marked sustained increase of platelets >1500 x 109/L (Adapted from: Gerds A. Oncology 2017;92:179-189 54 ).
# Perioperative Management:
Surgery in patients with PV has a high risk of both peri-operative bleeding and postoperative thromboembolism. In a multicenter retrospective study of 255 PV and ET patients, a high proportion of patients experienced vascular occlusions (7.7%) and major hemorrhage (7.3%) 55 . Elective surgeries should be delayed until cytoreductive measures and/or phlebotomy can be used to achieve blood count control since risks may be lower with hematologic control prior to surgery 56 . It is recommended that hematocrit maintenance <45% and normalization of blood counts be achieved ≥ 3 months prior to surgery 57 . Aspirin should be held for 5-7 days before surgery to reduce the risk of hemorrhage. LMWH should be given after surgery to prevent deep venous thrombosis 57 . Mechanical compression stockings are an option for patients with bleeding that prevents the use of anticoagulation. Ruxolitinib has potential rebound effects with discontinuation therefore it is recommended it be continued through surgery. If discontinuations are needed, a taper is required whereby it is discontinued 1-2 weeks prior to surgery 54 . When thromboembolic events do occur, treatment should be according to current management guidelines. Indefinite anticoagulation should be considered because of the high risk of recurrent events.
# Development and Revision History
This guideline was reviewed and endorsed by the Alberta Hematology Tumour Team. Members include [surgical oncologists, radiation oncologists, medical oncologists, dermatologists, nurses, pathologists, and pharmacists]. Evidence was selected and reviewed by a working group comprised of members from the Alberta Tumour Teams, external participants identified by the Working Group Lead, and a knowledge management specialist from the Guideline Resource Unit. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook. This guideline was originally developed in 2020.
# Maintenance
A formal review of the guideline will be conducted in 2022. If critical new evidence is brought forward before that time, however, the guideline working group members will revise and update the document accordingly.
# Disclaimer
The recommendations contained in this guideline are a consensus of the Alberta Provincial Hematology Tumour Team and are a synthesis of currently accepted approaches to management, derived from a review of relevant scientific literature. Clinicians applying these guidelines should, in consultation with the patient, use independent medical judgment in the context of individual clinical circumstances to direct care.
# Copyright © (2020) Alberta Health Services
This copyright work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivative 4.0 International license. You are free to copy and distribute the work including in other media and formats for non-commercial purposes, as long as you attribute the work to Alberta Health Services, do not adapt the work, and abide by the other license terms. To view a copy of this license, see https://creativecommons.org/licenses/by-nc-nd/4.0/. The license does not apply to AHS trademarks, logos or content for which Alberta Health Services is not the copyright owner.
# Funding Source
Financial support for the development of CancerControl Alberta's evidence-based clinical practice guidelines and supporting materials comes from the CancerControl Alberta operating budget; no outside commercial funding was received to support the development of this document.
All cancer drugs described in the guidelines are funded in accordance with the Outpatient Cancer Drug Benefit Program, at no charge, to eligible residents of Alberta, unless otherwise explicitly stated. For a complete list of funded drugs, specific indications, and approved prescribers, please refer to the Outpatient Cancer Drug Benefit Program Master List.
# Conflict of Interest Statements
Generated using the standard COI form.
Dr. Sonia Cerquozzi reports personal fees, non-financial support and other from Novartis, personal fees, non-financial support and other from Celgene, personal fees from Pfizer, outside the submitted work. | None | None |
8c347db92fbebacf90d2a907dfce232c909e5d65 | cma | None | # LIST OF ABBREVIATIONS AND DEFINITIONS
# Individuals of childbearing potential
People with the anatomy and physiology to bear children (regardless of gender) who are 45 years of age and younger.
# Individuals with no childbearing potential
Individuals who are unable to conceive a child due to advanced age (over 45) or because they do not have the anatomy/physiology to bear children.
# Neonate
An infant less than 120 days old.
# RBC
# Red blood cell
# SUMMARY OF REVISIONS February 2022
Included definitions: Neonate, Individuals of childbearing potential, Individuals with no childbearing potential Gender neutral language adopted Added as likely unacceptable indication: RhD positive individuals awaiting ABO confirmation results
Best practices recommendations updated to include: redistribution of O RhD negative RBCs and consider using O RhD positive RBCs for pre-hospital transfusion.
Recommendations for hospital transfusion services updated to include: develop a policy for RBC transfusion of patients undergoing HSCT and consider using group O RhD positive RBCs in pre-hospital settings such as air and/or ground ambulance.
# KEY TAKE AWAY POINTS O-Negative red blood cells (RBC) are a scarce resource
Use appropriately to ensure they are available for those patients for whom there is no alternative.
Use appropriately to reduce impact on health of O RhD negative donors.
Optimal utilization of O RhD negative red cells ensures equitable use and access to a valuable and finite resource.
# PURPOSE
The purpose of this statement is to provide recommendations or examples of best practices for the use of Group O RhD negative red blood cell (RBC) units in order to ensure their availability for those patients for whom there is no alternative.
# BACKGROUND
While the total number of RBCs issued by the Canadian Blood Services has decreased over the past 10 years, the demand for O RhD negative RBCs continues to increase in Canada.
# WHO SHOULD RECEIVE O RhD NEGATIVE RED BLOOD CELLS?
Group O RhD negative individuals 1 of child-bearing potential should receive only RhD negative components to prevent the development of alloantibodies directed at the RhD antigen which could result in hemolytic disease of the fetus and/or newborn in the case of a future RhD positive pregnancy.
Group O individuals alloimmunized against RhD antigen must receive RhD negative RBCs to avoid a hemolytic transfusion reaction.
Other group O RhD negative individuals should receive O RhD negative RBCs but consideration should be given to the use of O RhD positive RBCs when large volumes are needed as described in the chart. - Any O RhD negative individuals without allo anti-D and no childbearing potential requiring a large volume transfusion (defined as greater than 4-6 units) 2
- Non-O RhD negative individuals to avoid expiry, when an ABO/Rh identical unit is available in the local inventory.
- RhD positive individuals awaiting ABO confirmation results
1 Includes individuals who have discrepant or indeterminate RhD typing results, while awaiting genotyping to confirm RhD type.
2 For O RhD negative individuals with no child-bearing potential, who do not have anti-D AND are under-going large volume transfusion (greater than 4 to 6 units), hospitals are strongly encouraged to have a policy on switching to O RhD positive RBCs after 4 to 6 units have been transfused.
# BEST PRACTICES
- Change to group-specific units immediately once the patient's ABO group is determined.
- Establish policies which detail the acceptable and unacceptable indications for utilization of O RhD negative RBCs. Examples of such indications are listed in Table 1. In general, use O RhD positive RBCs in emergency situations for individuals of non-childbearing potential and any other patient groups who meet hospital indications.
- Use group-specific phenotypically matched or antigen negative red cells when available instead of using O RhD negative RBCs.
- Collect and monitor usage data to confirm the appropriate use of O RhD negative RBCs. Ensure that the emergency use of O RhD negative RBCs is reviewed by the Hospital Transfusion Services and/or Transfusion Committee. This review may identify cases where the switch to groupspecific RBCs could have been made earlier, where determination of patient blood group took longer than acceptable or was not performed, or patients for whom O RhD negative RBCs were not indicated.
- Review hospital outdate rates of O RhD negative RBCs and the transfusion of older O RhD negative RBCs to non-O RhD negative individuals to avoid the unit outdating. High outdate rates or rates of transfusion to avoid outdating suggest that greater than necessary inventory of O RhD negative RBCs may be held.
- Review hospital inventory levels of O RhD negative RBCs compared to the total number RBCs.
Although this varies by institution, and depends on the patient population served and distance from the blood centre, in general, the percentage of O RhD negative RBCs should not exceed 10% of the total RBC inventory.
- Establish protocols for redistribution of O RhD negative RBCs to avoid expiry.
- Review hospital redistribution rates of O RhD negative RBCs. High redistribution rates suggest that greater than necessary inventory of O RhD negative RBCs may be held.
# WHAT CAN HOSPITAL TRANSFUSION SERVICES DO?
Develop and implement a policy for emergency release of RBCs.
- Immediately determine ABO/Rh on patients who are bleeding or have severe anemia upon presentation.
- Transfuse all bleeding individuals of non-childbearing potential with group O RhD positive RBCs until their blood group is determined, unless have historical allogeneic anti-D.
- Determine the optimal child-bearing age restriction for individuals served by your hospital and transfuse individuals above that age with group O RhD positive RBCs until their blood group can be determined, unless known to have anti-D.
- Have a policy and procedure to switch patients to their own blood group as soon as determined.
- Have a policy and procedure for switching known O RhD negative hemorrhaging patients to O RhD positive RBCs unless known to have anti-D. Define patients who can be switched, number of units at which point the patient will be switched, and whether medical director approval is required each time.
- Develop a policy for RBC transfusion of patients undergoing HSCT.
Develop and implement policies for optimal inventory management.
- Small rural hospitals should consider stocking a mix of O RhD positive and O RhD negative RBCs
- Consider using group O RhD positive RBCs in pre-hospital settings such as air and/or ground ambulance.
- Reevaluate optimal inventory levels on a regular basis, or after hospital organizational or clinical program changes, especially those that will reduce red cell demand. Promptly notify your local Canadian Blood Services of any adjustments.
- Transfuse oldest units first unless there are other clinical considerations.
- Always request group specific units for patients with RBC antibodies. Only use RhD negative substitutions if group specific is not available for the scheduled transfusion date. Notify your local Canadian Blood Services immediately for any antigen negative blood requests, especially those that will be potentially difficult to fill or for those patients who will require ongoing transfusions.
- Reduce crossmatched RBC inventory by using strategies such as just in time (crossmatch on demand), electronic crossmatch, and implementing a maximum surgical blood order schedule (MSBOS). Review and, if appropriate, cancel RBC inventory tagged for specific patients 24 hours after surgery or immediately after imminent need has passed, while making allowances for patients with RBC antibodies.
- Share inventory between affiliated hospital sites to ensure appropriate use and preventing outdating.
- Track O RhD negative RBC transfusions to O RhD positive patients as a quality indicator.
- Monitor soon to outdate O RhD negative RBC units and redistribute to larger nearby hospitals where they are less likely to expire.
- Track and review redistribution data and data about transfusions of O RhD negative RBC to non-O RhD negative patients to avoid expiry and adjust ordering practices from Canadian Blood Services if frequency is excessive. | # LIST OF ABBREVIATIONS AND DEFINITIONS
# Individuals of childbearing potential
People with the anatomy and physiology to bear children (regardless of gender) who are 45 years of age and younger.
# Individuals with no childbearing potential
Individuals who are unable to conceive a child due to advanced age (over 45) or because they do not have the anatomy/physiology to bear children.
# Neonate
An infant less than 120 days old.
# RBC
# Red blood cell
# SUMMARY OF REVISIONS February 2022
Included definitions: Neonate, Individuals of childbearing potential, Individuals with no childbearing potential Gender neutral language adopted Added as likely unacceptable indication: RhD positive individuals awaiting ABO confirmation results
Best practices recommendations updated to include: redistribution of O RhD negative RBCs and consider using O RhD positive RBCs for pre-hospital transfusion.
Recommendations for hospital transfusion services updated to include: develop a policy for RBC transfusion of patients undergoing HSCT and consider using group O RhD positive RBCs in pre-hospital settings such as air and/or ground ambulance.
# KEY TAKE AWAY POINTS O-Negative red blood cells (RBC) are a scarce resource
Use appropriately to ensure they are available for those patients for whom there is no alternative.
Use appropriately to reduce impact on health of O RhD negative donors.
Optimal utilization of O RhD negative red cells ensures equitable use and access to a valuable and finite resource.
# PURPOSE
The purpose of this statement is to provide recommendations or examples of best practices for the use of Group O RhD negative red blood cell (RBC) units in order to ensure their availability for those patients for whom there is no alternative.
# BACKGROUND
While the total number of RBCs issued by the Canadian Blood Services has decreased over the past 10 years, the demand for O RhD negative RBCs continues to increase in Canada.
# WHO SHOULD RECEIVE O RhD NEGATIVE RED BLOOD CELLS?
Group O RhD negative individuals 1 of child-bearing potential should receive only RhD negative components to prevent the development of alloantibodies directed at the RhD antigen which could result in hemolytic disease of the fetus and/or newborn in the case of a future RhD positive pregnancy.
Group O individuals alloimmunized against RhD antigen must receive RhD negative RBCs to avoid a hemolytic transfusion reaction.
Other group O RhD negative individuals should receive O RhD negative RBCs but consideration should be given to the use of O RhD positive RBCs when large volumes are needed as described in the chart. • Any O RhD negative individuals without allo anti-D and no childbearing potential requiring a large volume transfusion (defined as greater than 4-6 units) 2
• Non-O RhD negative individuals to avoid expiry, when an ABO/Rh identical unit is available in the local inventory.
• RhD positive individuals awaiting ABO confirmation results
1 Includes individuals who have discrepant or indeterminate RhD typing results, while awaiting genotyping to confirm RhD type.
2 For O RhD negative individuals with no child-bearing potential, who do not have anti-D AND are under-going large volume transfusion (greater than 4 to 6 units), hospitals are strongly encouraged to have a policy on switching to O RhD positive RBCs after 4 to 6 units have been transfused.
# BEST PRACTICES
• Change to group-specific units immediately once the patient's ABO group is determined.
• Establish policies which detail the acceptable and unacceptable indications for utilization of O RhD negative RBCs. Examples of such indications are listed in Table 1. In general, use O RhD positive RBCs in emergency situations for individuals of non-childbearing potential and any other patient groups who meet hospital indications.
• Use group-specific phenotypically matched or antigen negative red cells when available instead of using O RhD negative RBCs.
• Collect and monitor usage data to confirm the appropriate use of O RhD negative RBCs. Ensure that the emergency use of O RhD negative RBCs is reviewed by the Hospital Transfusion Services and/or Transfusion Committee. This review may identify cases where the switch to groupspecific RBCs could have been made earlier, where determination of patient blood group took longer than acceptable or was not performed, or patients for whom O RhD negative RBCs were not indicated.
• Review hospital outdate rates of O RhD negative RBCs and the transfusion of older O RhD negative RBCs to non-O RhD negative individuals to avoid the unit outdating. High outdate rates or rates of transfusion to avoid outdating suggest that greater than necessary inventory of O RhD negative RBCs may be held.
• Review hospital inventory levels of O RhD negative RBCs compared to the total number RBCs.
Although this varies by institution, and depends on the patient population served and distance from the blood centre, in general, the percentage of O RhD negative RBCs should not exceed 10% of the total RBC inventory.
• Establish protocols for redistribution of O RhD negative RBCs to avoid expiry.
• Review hospital redistribution rates of O RhD negative RBCs. High redistribution rates suggest that greater than necessary inventory of O RhD negative RBCs may be held.
# WHAT CAN HOSPITAL TRANSFUSION SERVICES DO?
Develop and implement a policy for emergency release of RBCs.
• Immediately determine ABO/Rh on patients who are bleeding or have severe anemia upon presentation.
• Transfuse all bleeding individuals of non-childbearing potential with group O RhD positive RBCs until their blood group is determined, unless have historical allogeneic anti-D.
• Determine the optimal child-bearing age restriction for individuals served by your hospital and transfuse individuals above that age with group O RhD positive RBCs until their blood group can be determined, unless known to have anti-D.
• Have a policy and procedure to switch patients to their own blood group as soon as determined.
• Have a policy and procedure for switching known O RhD negative hemorrhaging patients to O RhD positive RBCs unless known to have anti-D. Define patients who can be switched, number of units at which point the patient will be switched, and whether medical director approval is required each time.
• Develop a policy for RBC transfusion of patients undergoing HSCT.
Develop and implement policies for optimal inventory management.
• Small rural hospitals should consider stocking a mix of O RhD positive and O RhD negative RBCs
• Consider using group O RhD positive RBCs in pre-hospital settings such as air and/or ground ambulance.
• Reevaluate optimal inventory levels on a regular basis, or after hospital organizational or clinical program changes, especially those that will reduce red cell demand. Promptly notify your local Canadian Blood Services of any adjustments.
• Transfuse oldest units first unless there are other clinical considerations.
• Always request group specific units for patients with RBC antibodies. Only use RhD negative substitutions if group specific is not available for the scheduled transfusion date. Notify your local Canadian Blood Services immediately for any antigen negative blood requests, especially those that will be potentially difficult to fill or for those patients who will require ongoing transfusions.
• Reduce crossmatched RBC inventory by using strategies such as just in time (crossmatch on demand), electronic crossmatch, and implementing a maximum surgical blood order schedule (MSBOS). Review and, if appropriate, cancel RBC inventory tagged for specific patients 24 hours after surgery or immediately after imminent need has passed, while making allowances for patients with RBC antibodies.
• Share inventory between affiliated hospital sites to ensure appropriate use and preventing outdating.
• Track O RhD negative RBC transfusions to O RhD positive patients as a quality indicator.
• Monitor soon to outdate O RhD negative RBC units and redistribute to larger nearby hospitals where they are less likely to expire.
• Track and review redistribution data and data about transfusions of O RhD negative RBC to non-O RhD negative patients to avoid expiry and adjust ordering practices from Canadian Blood Services if frequency is excessive. | None | None |
bd817f39befe5b675fa36d184edf35a0b77ff988 | cma | None | # Recommendations
Chemotherapy for Non-Metastatic Breast Cancer 1. The decision for adjuvant/neoadjuvant chemotherapy should be guided by the subtype of breast cancer (hormone receptor -positive/human epidermal growth factor receptor 2 negative, HER2-positive, and triple negative (TN)], prognosis, benefits (absolute gains in disease free survival and overall survival ), toxicity risks, overall health of patient, and preference of patient. 1,2 (Level of Evidence: I, Strength of Recommendation: A) 2. Individualized prognosis and expected benefit from systemic treatments, including chemotherapy, can be estimated using an online calculator such as NHS Predict which considers: patient age and menopausal status, presentation (screen detected versus symptomatic), tumour size, axillary lymph node status, and the status of estrogen receptor (ER), HER2 and Ki67 if known. 3 In some patients with ER-positive/HER2-negative early breast cancer, prognosis +/-benefit of chemotherapy can be estimated from gene expression profile (GEP) testing. 4,5 Figure 1 outlines OncotypeDX testing eligibility in Alberta. 3. Figure 2 outlines an approach to chemotherapy decision-making for HR-positive/HER2-negative breast cancer, Figure 3 for HER2-positive, and Figure 4 for TN. 1,2, (Level of Evidence: I, Strength of Recommendation: A) 4. As for the decision to use chemotherapy, the choice of regimen should also be guided by prognosis, benefits (absolute gains in DFS and OS where applicable), toxicity risks, overall health of patient, and preference of patient. In addition to the listed adjuvant chemotherapy regimens, other evidence-based options exist, and may be used based on clinical discretion and in review with multidisciplinary breast cancer tumour board. 5. Delays in initiating adjuvant chemotherapy should be avoided. 10 Adjuvant chemotherapy should be started, as soon as surgical healing has been completed and ideally not later than 12 weeks following surgery. 1 (Level of Evidence: I, Strength of Recommendation: A) 6. In patients with known cardiac dysfunction or significant cardiac risk, a non-anthracycline adjuvant chemotherapy regimen is preferred. (Level of Evidence: I, Strength of Recommendation: A) If trastuzumab is required, consider upfront referral to cardiology. (Level of Evidence: V, Strength of Recommendation: A) 7. Offer young women referral to a fertility clinic prior to initiation of adjuvant systemic therapies if future pregnancies are potentially desired. 14 (Level of Evidence: V, Strength of Recommendation: A) In addition to standard fertility preservation methods or if standard fertility preservation methods are not feasible, use of a luteinizing hormone-releasing hormone (LHRH) agonist during chemotherapy can be discussed with the goal of reducing the likelihood of chemotherapy-induced ovarian insufficiency. 14,15 (Level of Evidence: II, Strength of Recommendation: B) 8. Use primary granulocyte colony-stimulating factor (GCSF) prophylaxis with dose dense regimens and regimens in which the risk of febrile neutropenia is greater than or equal to 20%. 16 Use secondary GCSF prophylaxis if there was a neutropenic complication in previous chemotherapy cycle and if dose-reduction is expected to compromise oncologic outcomes. 16 (Level of Evidence: I, Strength of Recommendation: A)
# Chemotherapy for Hormone Receptor-Positive/HER2-Negative Breast Cancer
- Decision-making about chemotherapy in this group is complex as there is a wide range for prognosis, stage for stage, driven by underlying tumour biology. The American Joint Committee on Cancer (AJCC) 8 th Edition incorporates prognostic stage grouping for hormone receptorpositive breast cancer that not only considers T-stage and N-stage, but also grade, ER-status, progesterone receptor (PR)-status, and the OncotypeDX Recurrence Score (RS) (if less than 11) when available. 17 2. Favourable tumour biology is suggested by a luminal A molecular signature or luminal A-like characteristics (high ER & PR expression AND grade 1-2 and/or low Ki67 score). 1, 2 3. Less favourable tumour biology is suggested by a luminal B molecular signature or luminal B-like characteristics (high or low ER expression AND low PR expression or PR-negative AND grade 2-3 and/or higher Ki67 score). 1, 2 4. The predicted absolute overall survival benefit of chemotherapy is low for most patients with favourable tumour biology. However, the predicted absolute overall survival benefit of chemotherapy can be quite variable for patients with less favourable tumour biology. NHS Predict, and in eligible patients, OncotypeDX testing, can aid with prognostication and chemotherapy decision-making. 5,18
# Lower risk
T1a/b and node negative or Luminal A-like 1 or OncotypeDX lower risk 3 Higher risk T >3cm &/or node positive and Luminal B-like 2 or OncotypeDX higher risk 4 Neoadjuvant chemotherapy 6 DC, FEC-D, ddAC-P
# Development and Revision History
This guideline was reviewed and endorsed by the Alberta Provincial Breast Tumour Team. Members include surgical oncologists, radiation oncologists, medical oncologists, nurses, pathologists, and pharmacists. Evidence was selected and reviewed by a working group comprised of members from the Alberta Provincial Breast Tumour Team, external participants identified by the Working Group Lead, and a methodologist from the Guideline Resource Unit. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook.
This guideline was originally developed in April 2014 and updated in April 2021.
# Levels of Evidence
# I
Evidence | # Recommendations
Chemotherapy for Non-Metastatic Breast Cancer 1. The decision for adjuvant/neoadjuvant chemotherapy should be guided by the subtype of breast cancer (hormone receptor [HR]-positive/human epidermal growth factor receptor 2 [HER2]negative, HER2-positive, and triple negative (TN)], prognosis, benefits (absolute gains in disease free survival [DFS] and overall survival [OS]), toxicity risks, overall health of patient, and preference of patient. 1,2 (Level of Evidence: I, Strength of Recommendation: A) 2. Individualized prognosis and expected benefit from systemic treatments, including chemotherapy, can be estimated using an online calculator such as NHS Predict which considers: patient age and menopausal status, presentation (screen detected versus symptomatic), tumour size, axillary lymph node status, and the status of estrogen receptor (ER), HER2 and Ki67 if known. 3 In some patients with ER-positive/HER2-negative early breast cancer, prognosis +/-benefit of chemotherapy can be estimated from gene expression profile (GEP) testing. 4,5 Figure 1 outlines OncotypeDX testing eligibility in Alberta. 3. Figure 2 outlines an approach to chemotherapy decision-making for HR-positive/HER2-negative breast cancer, Figure 3 for HER2-positive, and Figure 4 for TN. 1,2,[6][7][8][9] (Level of Evidence: I, Strength of Recommendation: A) 4. As for the decision to use chemotherapy, the choice of regimen should also be guided by prognosis, benefits (absolute gains in DFS and OS where applicable), toxicity risks, overall health of patient, and preference of patient. In addition to the listed adjuvant chemotherapy regimens, other evidence-based options exist, and may be used based on clinical discretion and in review with multidisciplinary breast cancer tumour board. 5. Delays in initiating adjuvant chemotherapy should be avoided. 10 Adjuvant chemotherapy should be started, as soon as surgical healing has been completed and ideally not later than 12 weeks following surgery. 1 (Level of Evidence: I, Strength of Recommendation: A) 6. In patients with known cardiac dysfunction or significant cardiac risk, a non-anthracycline adjuvant chemotherapy regimen is preferred. (Level of Evidence: I, Strength of Recommendation: A) If trastuzumab is required, consider upfront referral to cardiology. [11][12][13] (Level of Evidence: V, Strength of Recommendation: A) 7. Offer young women referral to a fertility clinic prior to initiation of adjuvant systemic therapies if future pregnancies are potentially desired. 14 (Level of Evidence: V, Strength of Recommendation: A) In addition to standard fertility preservation methods or if standard fertility preservation methods are not feasible, use of a luteinizing hormone-releasing hormone (LHRH) agonist during chemotherapy can be discussed with the goal of reducing the likelihood of chemotherapy-induced ovarian insufficiency. 14,15 (Level of Evidence: II, Strength of Recommendation: B) 8. Use primary granulocyte colony-stimulating factor (GCSF) prophylaxis with dose dense regimens and regimens in which the risk of febrile neutropenia is greater than or equal to 20%. 16 Use secondary GCSF prophylaxis if there was a neutropenic complication in previous chemotherapy cycle and if dose-reduction is expected to compromise oncologic outcomes. 16 (Level of Evidence: I, Strength of Recommendation: A)
# Chemotherapy for Hormone Receptor-Positive/HER2-Negative Breast Cancer
1. Decision-making about chemotherapy in this group is complex as there is a wide range for prognosis, stage for stage, driven by underlying tumour biology. The American Joint Committee on Cancer (AJCC) 8 th Edition incorporates prognostic stage grouping for hormone receptorpositive breast cancer that not only considers T-stage and N-stage, but also grade, ER-status, progesterone receptor (PR)-status, and the OncotypeDX Recurrence Score (RS) (if less than 11) when available. 17 2. Favourable tumour biology is suggested by a luminal A molecular signature or luminal A-like characteristics (high ER & PR expression AND grade 1-2 and/or low Ki67 score). 1, 2 3. Less favourable tumour biology is suggested by a luminal B molecular signature or luminal B-like characteristics (high or low ER expression AND low PR expression or PR-negative AND grade 2-3 and/or higher Ki67 score). 1, 2 4. The predicted absolute overall survival benefit of chemotherapy is low for most patients with favourable tumour biology. However, the predicted absolute overall survival benefit of chemotherapy can be quite variable for patients with less favourable tumour biology. NHS Predict, and in eligible patients, OncotypeDX testing, can aid with prognostication and chemotherapy decision-making. 5,18
# Lower risk
T1a/b and node negative or Luminal A-like 1 or OncotypeDX lower risk 3 Higher risk T >3cm &/or node positive and Luminal B-like 2 or OncotypeDX higher risk 4 Neoadjuvant chemotherapy 6 DC, FEC-D, ddAC-P
# Development and Revision History
This guideline was reviewed and endorsed by the Alberta Provincial Breast Tumour Team. Members include surgical oncologists, radiation oncologists, medical oncologists, nurses, pathologists, and pharmacists. Evidence was selected and reviewed by a working group comprised of members from the Alberta Provincial Breast Tumour Team, external participants identified by the Working Group Lead, and a methodologist from the Guideline Resource Unit. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook.
This guideline was originally developed in April 2014 and updated in April 2021.
# Levels of Evidence
# I
Evidence | None | None |
278efb57b12c2ecdf80ae29429de250783218442 | cma | None | Adults 18 years of age and olderPrimary Series: Tw o doses of 0.5 mL (0.5 x 10 8 Infectious Units), 28 days apart Booster dose (2 years after primary series): One dose of 0.5 mL (0.5 x 10 8 Inf.U)# PREAMBLE
The National Advisory Committee on Immunization (NACI) is an External Advisory Body that provides the Public Health Agency of Canada (PHAC) with independent, ongoing and timely medical, scientific, and public health advice in response to questions from PHAC relating to immunization.
In addition to burden of disease and vaccine characteristics, PHAC has expanded the mandate of NACI to include the systematic consideration of programmatic factors in developing evidence based recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels.
The additional factors to be systematically considered by NACI include: economics, ethics, equity, feasibility, and acceptability. Not all NACI statements will require in-depth analyses of all programmatic factors. While systematic consideration of programmatic factors will be conducted using evidence-informed tools to identify distinct issues that could impact decision -making for recommendation development, only distinct issues identified as being specific to the vaccine or vaccine-preventable disease will be included.
This statement contains NACI's independent advice and recommendations, which are based upon the best current available scientific knowledge. T his document is being disseminated for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph. Recommendations for use and other information set out herein may differ from that set out in the product monographs of the Canadian manufacturers of the vaccines. Manufacturer(s) have sought approval of the vaccines and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of PHAC's Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.
# BACKGROUND
Monkeypox virus is a member of the Orthopoxvirus genus, which also includes variola virus (smallpox virus), vaccinia virus, cowpox, and other poxviruses. Monkeypox viruses are zoonotic, therefore infection may occur in contexts where there is contact with wild species that are susceptible to monkeypox viruses. Human-to-human transmission of monkeypox virus also occurs amongst close contacts of people infected with monkeypox. Monkeypox is endemic in Central and West Africa, but there have been cases and outbreaks in non-endemic countries due to international travel or the importation of infected animals from affected areas. There are two distinct clades of monkeypox virus: the Congo Basin (Central African) clade and the West African clade. The Congo Basin clade has caused more severe illness.
Based on historical data, monkeypox has a typical incubation period of 6-13 days from exposure but can range from 5-21 days (1) . The disease is usually self-limiting and resolves within 14 to 28 days. Symptoms include fever, headache, back pain, myalgia, asthenia, lymphadenopathy and skin lesions/rash which typically tend to be more concentrated on the face, extremities, and oral mucous membranes, but can also appear in the genital area. Rash lesions begin as macules and further develop to papules, vesicles, pustules, and then form crusts. The duration of communicability for monkeypox virus may be up to 2-4 weeks, based on limited evidence of PCR detection of monkeypox in the upper respiratory tract (2) . Potential complications of monkeypox include secondary bacterial infections, pneumonia, sepsis, encephalitis, and vision loss from corneal inflammation. Monkeypox virus may cause severe disease in young children, individuals who are immunocompromised (3) , and those who are pregnant. Information about monkeypox in people who are pregnant is sparse but cases of first trimester miscarriage and stillbirths have been reported (4) .
In the current 2022 multi-country outbreak, monkeypox cases may have an atypical presentation including oral, genital, and/or anal lesions with or without fever, or systemic symptoms. Personto-person transmission can occur through direct contact with a person who is infected, including intimate sexual activity, or through shared contaminated objects. The potential for respiratory transmission is unknown at this time but may also be possible.
The 2022 multi-country monkeypox outbreak represents the first incidence of broader community transmission in a number of countries outside of certain regions of Africa. Initial detection in early May 2022 was a family cluster of three cases in the United Kingdom, with one case having recent travel history to an endemic region. On May 15, the World Health Organization (WHO) was notified of four additional confirmed cases, unlinked to travel, and this suggested more extensive community transmission of the virus. Since then, additional cases have been reported in the United Kingdom and internationally, including Canada. By June 7, at least 1,060 confirmed cases from 30 non-endemic countries and territories have been reported in official and media sources according to monitoring by the Global Public Health Intelligence Network (GPHIN). Ten , the United States , Italy , and Belgium ).
As of June 7, 81 cases of monkeypox had been confirmed in Canada (71 in Quebec, 8 in Ontario, 1 in Alberta, and 1 in British Columbia). According to open-source information, the Quebec cases are mainly men between 30-55 years of age, and they presented to Sexually Transmitted and Blood-Borne Infection clinics in the Montreal area. The infections were suspected to have been acquired in Montreal. Some of the individuals with infection reported links to travel in Belgium and Mexico.
Smallpox vaccines used during the global smallpox eradication programs may provide some protection against monkeypox (1) . However, global smallpox vaccination programs ended in 1980 when smallpox was declared eradicated. Discontinuation of smallpox vaccination for travel was recommended by the WHO in 1980 and was no longer required by any country by 1982 Canadians born in 1972 or later have not been routinely immunized against smallpox (unless immunized for other purposes such as travel or work-related risks). For those who have been previously vaccinated for smallpox (i.e., eligible for vaccine in 1980 or earlier), the degree of protection conferred from the smallpox vaccine against monkeypox infection may be up to 85% (5) , however the durability of protection and the degree of protection against the current strain of monkeypox remains unknown.
# OBJECTIVE
In the context of the rapidly evolving multi-country monkeypox outbreak, this rapid response was undertaken to provide guidance on the use of an orthopoxvirus (Imvamune ® ) vaccine with potential efficacy against monkeypox. Imvamune ® is stockpiled within Canada's National Emergency Strategic Stockpile for the purposes of national security due to its potential efficacy against variola, the virus that causes smallpox. Due to the unique epidemiology and supply considerations, the planned task for this rapid response was to consider the use of Imvamune ® for post-exposure prophylaxis and to summarize the available evidence in support of Imvamune ® use in this specific current context. Unrelated to the current monkeypox outbreak, NACI was also asked to consider use of Imvamune ® in laboratory research settings where replicating orthopoxviruses are studied.
NACI and PHAC continue to monitor the evolving scientific data recognizing that the trajectory of the current monkeypox outbreak remains unclear, the situation is rapidly evolving and there may be additional considerations in the coming weeks.
# METHODS
On May 26 and May 27, 2022, monkeypox data were discussed and reviewed by the NACI High Consequence Infectious Disease working group (HCID WG), along with input from the Public Health Ethics Consultative Group (PHECG), Canadian Immunization Committee (CIC) NACI's Vaccine Safety Working Group (VSWG) and two LGBTQ2S+ groups from Ontario and BC. The HCID WG reviewed data on the current status of the monkeypox outbreak, along with additional evidence included in published scientific literature and from the manufacturer, regarding the safety, immunogenicity and protection offered by Imvamune ® . NACI approved these HCID WG recommendations on June 8, 2022.
# VACCINE
Imvamune ® (also called Modified Vaccinia Ankara-Bavarian Nordic (MVA-BN), Jynneos ® , Imvanex ® ) is a non-replicating, third-generation smallpox vaccine manufactured by Bavarian Nordic. Imvamune ® was initially authorized for use in Canada on November 21, 2013, as an Extraordinary Use New Drug Submission (EUNDS) for use by the Canadian Government in an emergency situation for active immunization against smallpox infection and disease in persons 18 years of age and older who have a contraindication to the first or second generation smallpox vaccines. It was subsequently approved under a supplement to the EUNDS on November 5, 2020 for active immunization against smallpox, monkeypox and related Orthopoxvirus infections and disease in adults 18 years of age and older determined to be at high risk for exposure (6) .
Imvamune ® contains trace amounts of host cell DNA and protein, benzonase, ciprofloxacin and gentamicin. No preservative or adjuvant is added to the formulation. The MVA virus is also being developed as a vector vaccine platform against other viruses, including tuberculosis, respiratory syncytial virus, Ebola virus and others.
Imvamune differs from previous generations of smallpox vaccines as it is a non-replicating vaccine virus in humans, meaning based on preclinical studies, it is not able to produce more copies of itself (7) . While Imvamune is capable of replicating to high titers in avian cell lines such as chicken embryo fibroblasts, it is attenuated and has limited replication capability in human cells (8) .
Preclinical data from previous generation smallpox vaccines showed decreased immune responses when tecovirimat (TPOXX, an antiviral drug from SIGA technologies) was administered concurrently with earlier generation smallpox vaccines (9) . Due to the differences between previous generation smallpox vaccines and Imvamune ® , it is unclear if antivirals could impact protection offered by Imvamune ® .
# Adjuvant / Preservatives
The vaccine contains no adjuvant or preservatives
# Contraindications
- Patients w ho are hypersensitive to this vaccine or to any ingredient in the formulation or component of the container. Individuals w ho show hypersensitivity reactions after receiving the first dose of the vaccine should not be given the second dose. As w ith other vaccines, vaccination w ith IMVAMUNE ® must be postponed in persons w ith acute febrile conditions if used for non-emergency (pre-event) prophylaxis.
# Storage
- Store frozen at -20°C ± 5°C or -50°C ±10°C or -80°C ±10°C. After thaw ing, the vaccine should be used immediately or can be stored at 2°C -8°C for up to 2 w eeks prior to use. Do not refreeze a vial once it has been thaw ed. Protect from light.
Handling Thaw at room temperature. The drug product should appear as a pale milky colored homogeneous suspension. The single-dose vial should be sw irled gently (not shaken) for at least 30 seconds to ensure homogeneity upon thaw ing, The vaccine must not be used if any foreign particulate matter are visible.
# Reconstitution No
Route of adm inistration 0.5 mL subcutaneous injection, at any site
# Syringe and needle selection
- Withdraw w ith a syringe and needle long enough to reach the bottom of the vial.
- For injection, needle should be changed to a subcutaneous injection needle a In Canada, there are several vaccines manufactured by processes involving hens' eggs or their derivatives, such as chicken cell cultures b Tromethamine (trometamol, Tris) may very rarely cause allergic reactions and is found in some medications injected to do tests (contrast media) as w ell as other medications taken by mouth or injection, and some creams and lotions. Note that this is not a complete list. c Benzonase is used for purification of viral vaccines, viral vectors for vaccine, cell and gene therapy, and oncolytic viruses, removing DNA/RNA from proteins and other biologicals; reduction of viscosity caused by nucleic acids; sample preparation in electrophoresis and chromatography and prevention of cell clumping. d Gentamicin and ciprofloxacin are used as antibiotics in the treatment of some bacterial infections.
# RECOMMENDATIONS
Please see Table 2 for an explanation of strong versus discretionary NACI recommendations. Please see Appendix A which summarizes the clinical and preclinical data for Imvamune ® .
For those without a contraindication to the vaccine: For individuals who had received a live replicating 1st or 2nd generation smallpox vaccine in the past and who sustain a high risk exposure to a probable or confirmed case of monkeypox, a single dose of Imvamune ® PEP may be offered (i.e., as a booster dose).
The benefit of protection against infection should be discussed with a healthcare provider and weighed against the potential risk of recurrent myocarditis for individuals with a history of myocarditis/pericarditis linked to a previous dose of live replicating 1st and 2nd generation smallpox vaccine and/or Imvamune ® ; a precautionary approach is warranted at this time until more information is available. For immunocompetent individuals who have received a live replicating 1 st or 2 nd generation smallpox vaccine in the past and who are at high risk for occupational exposure, a single dose of Imvamune ® may be offered (i.e., as a booster dose), rather than the two dose primary vaccine series). This single Imvamune ® dose should be given at least two years after the latest live replicating smallpox vaccine dose.
In consultation with a physician, the benefit of protection against infection should be weighed against the risk of recurrent myocarditis for individuals with a history of myocarditis/pericarditis linked to a previous dose of live replicating 1 st and 2 nd generation smallpox vaccine and/or Imvamune ® ; a precautionary approach is warranted at this time until more information is available. Immunocompromised populations (including people living with HIV) may particularly benefit from vaccination as these populations may be at risk for more severe outcomes if infected depending on the nature and degree of the immunosuppression. Although data on the use of Imvamune ® in immunocompromised populations are limited, Imvamune ® has been tested clinically in people living with HIV (CD4 ≥100 cells/µL) and hematopoietic stem transplant patients (studied two years post-HSCT) and safety was comparable to healthy controls in these populations. There are limited data overall on VE/immunogenicity or safety in immunocompromised populations, but immunosuppression increases risk of negative outcomes due to infection. Live vaccines are usually contraindicated for immunocompromised populations; however, Imvamune ® may be safely used in this group as it is considered a non-replicating vaccine (8) . When using Imvamune ® as PrEP in immunocompromised individuals, 2 doses are recommended regardless of previous smallpox vaccine history.
If at risk for infection, pregnant populations may particularly benefit from vaccination as these populations may be at risk for severe outcomes from disease. Imvamune ® has never been tested in persons who are pregnant. Though limited, safety and toxicity studies have identified no concerning safety signals. There is a lack of evidence of safety and efficacy of Imvamune ® PEP or PrEP in this group, though at this time there is no reason to believe that vaccination would have any adverse impact on the person who is pregnant or the fetus. Live vaccines are usually contraindicated for pregnant populations; however, Imvamune ® may be used in this group as it is considered a non-replicating vaccine. The risks due to monkeypox infection should be weighed against the lack of evidence of vaccine safety.
Lactating populations are not at higher risk for negative outcomes due to monkeypox infection. There are no Imvamune ® studies in this population. There is a lack of evidence of safety and efficacy of Imvamune ® PEP or PrEP in this group, though at this time there is no reason to believe that vaccination would have any adverse impact on the person who is lactating or the child. There is no information on excretion of vaccine components or antigens into breastmilk; however, this is unlikely as Imvamune ® is a non-replicating vaccine.
Although Imvamune ® is not authorized for children, this population may be at higher risk of severe outcomes from monkeypox infection and may benefit from vaccination. Indirect evidence of clinical testing of the MVA vector as a viral vector vaccine platform for other vaccines in development, including for RSV, TB and Ebola, indicates that out of almost 2000 vaccine recipients, Imvamune ® components are well tolerated in recipients under 18 years of age. There is a lack of evidence of safety and efficacy of Imvamune ® PEP or PrEP in this group.
People with atopic dermatitis were a risk group with severe adverse outcomes for earlier generations of smallpox vaccines. From limited clinical testing of Imvamune ® , solicited AEs were more frequent in this group including transient worsening of atopic dermatitis symptoms. Historically, previous generations of orthopoxvirus vaccines carried a risk of diffuse vaccinia virus infection for individuals with atopic dermatitis. The Imvamune ® vaccine was developed to overcome those adverse effects through the use of a non-replicating virus.
# NACI recommendation for concurrent administration:
Imvamune ® given as PEP or PrEP should not be delayed due to recent receipt of an mRNA COVID-19 vaccine. If vaccine timing can be planned (i.e., prior to employment within a research laboratory), NACI recommends that Imvamune ® be given at least 4 weeks after or before an mRNA vaccine for COVID-19 .
First generation orthopoxvirus vaccines and mRNA COVID-19 vaccines both have a potential risk of cardiac adverse events (myocarditis). Risk for myo-or pericarditis with the newer generation non-replicating attenuated virus vaccine Imvamune ® is still unknown. . It would be prudent to wait for a period of at least 4 weeks before or after the administration of mRNA COVID-19 vaccine in order to prevent erroneous attribution of an AEFI to one particular vaccine or the other. This suggested minimum waiting period between vaccines is precautionary at this time. Protection from monkeypox exposure should be prioritized and recent mRNA vaccine receipt should not delay Imvamune ® PEP or PrEP if protection is urgent.
# Summary of Evidence and Considerations for the Vaccine:
- There continue to be many unknowns about the outbreak of monkeypox virus, including symptoms, modes of transmission and groups at high risk for severe outcomes. There is very limited evidence available upon which to base guidance for Imvamune ® use for pre-or post-exposure recommendations in any population. Data on the pre-exposure use of vaccine are limited to clinical trial settings where data for safety, immunogenicity and efficacy against vaccinia are available. o Safety data from clinical testing do not identify any safety signals of concern; however, these data are limited and not predictive of very rare events occurring at a rate below 1/ 10 000. o Data for cardiac adverse events of special interest are available from limited clinical testing. o Limited immunological data are available to inform the durability of immune responses and the ability for Imvamune ® to boost previous anti-orthopoxvirus immune responses. Data to inform post-exposure use of vaccine are limited to indirect evidence either from preclinical studies in animal models or from smallpox vaccination in the pre -eradication era. Data for populations either at risk for more severe outcomes due to monkeypox infection, or who may be at higher risk for adverse events due to vaccination, are even more limited. o Small clinical trials of Imvamune ® in people living with HIV and in people with atopic dermatitis offer limited safety and immunogenicity data. o Imvamune ® has never been tested in children (<18y), people who are pregnant or people who are lactating. Limited indirect data for these groups have been used to make recommendations. Informed consent when administering Imvamune ® PEP or PrEP should include a discussion of the limited data available on monkeypox infection and disease as well as limited data available for the safety and efficacy of Imvamune ® . NACI continues to monitor and assess the evidence as it emerges and will update its recommendations as needed.
# ADDITIONAL INFORMATION
NACI continues to endeavour to make ethical, equitable and evidence -informed recommendations. Given the paucity of data on benefits and risks of Imvamune ® in the context of a monkeypox outbreak setting, the use of Imvamune ® must balance the benefits and risks of what is known and unknown about the vaccine and the disease.
It is important to obtain informed consent when offering the vaccine, and to clearly explain to potential recipients what is unknown (in addition to what is known) about the vaccine, when discussing potential risks and benefits. This is particularly important for individuals identified by NACI as special populations and for any off-label use in individuals <18 years of age.
Additionally, there is an ethical obligation to conduct close monitoring and surveillance of the use of the vaccine, in order to collect information to inform the response going forward. Both informed consent and post-market safety surveillance will be vital for the ethical implementation of an Imvamune ® vaccination program, especially in pediatric populations <18 years of age when the vaccine is being used off-label.
It will be important to closely monitor who is at risk of monkeypox and provide rationale for when vaccination is needed. Additionally, to prevent stigmatization of specific populations and potentially increase vaccine acceptability, the primary focus should be identifying risk f actors for transmission of monkeypox (e.g., proximity of contact, sexual activities, specific behaviours) whenever possible, rather than identifying populations perceived to be at a higher risk.
Given the limited clinical evidence on the use of Imvamune ® for monkeypox PEP or PrEP, understanding of the need for, and benefit of Imvamune ® in the context of a monkeypox outbreak setting is evolving.
Certain behaviours place individuals at increased risk of exposure to the monkeypox virus (e.g., proximity of contact, sexual activities, household member or behaviours that cause exposure to body fluids or fomites). Some populations are at increased risk of severe monkeypox disease due to various biological factors (e.g. individuals who are immunocompromised, pregnant, and/or, young children) and social factors that may intersect. Risk factors of severe disease and risk of exposure may overlap, further increasing risk. Any combination of these factors, as well as varying access to health care services, has the potential for disproportionate consequences for specific populations characterized by increased rates of infection, disease, and severe illness. Program planning should ensure equitable access to vaccination information and services and minimize differences in vaccine acceptance and uptake based on socioeconomic status and other socioeconomic determinants of health that may intersect.
# RESEARCH PRIORITIES
- Further study of the protection offered by Imvamune ® vaccine against monkeypox infection and disease (in PrEP and PEP scenarios), including: a. Understanding which immune responses are protective against infection and disease and defining protective thresholds b. Understanding how the impact of previous orthopox infection or vaccination impacts the protection offered by Imvamune ® c. Real-world evidence on the vaccine effectiveness of Imvamune against monkeypox and for the use of single dose PrEP and PEP. 2. Further studies to further inform on the safety of Imvamune ® vaccine including both clinical trials and post-market safety surveillance. 3. Safety in special populations, including people who are pregnant or breastfeeding, children <18 years of age, and people who are immunocompromised should also be assessed by targeted clinical trials. 4. Further study into the epidemiology of the disease to better understand the modes of transmission, the disease presentation, and to identify the populations at highest risk for severe disease in order to inform and optimize disease prevention strategies.
# Implication
A strong recommendation applies to most populations/individuals and should be followed unless a clear and compelling rationale for an alternative approach is present.
A discretionary recommendation may be considered for some populations/individuals in some circumstances. Alternative approaches may be reasonable. The safety of Imvamune was assessed in the limited context of clinical trials and Imvamune ® has not been administered at the scale needed to predict low frequency adverse effects. In the limited safety assessments that have been done, no signals of concern for Imvamune ® have been identified.
- Imvamune ® 's safety has been assessed in 20 completed clinical trials where approximately 13,700 vaccine doses were given to 7,414 subjects (10) . The most common local adverse events following immunization (AEFI) were pain, erythema, induration and swelling. The most common systemic AEFI were fatigue, headache, myalgia, and nausea. Most of the reported AEFIs were of mild to moderate intensity and resolved within the first seven days following vaccination. Cardiac adverse events of special interest were reported to occur in 1.4% (91/6,640) of Imvamune ® recipients, 0.2% (3/1,206) of placebo recipients who were smallpox vaccinenaïve and 2.1% (16/762) of Imvamune ® recipients who were smallpox vaccineexperienced. Age was likely not adjusted for between vaccinated groups. Among the cardiac AEFIs reported, 28 were asymptomatic post-vaccination elevation of troponin-I, 6 cases were considered to be causally related to Imvamune ® vaccination and included tachycardia, electrocardiogram T wave inversion, abnormal electrocardiogram, electrocardiogram ST segment elevation, abnormal electrocardiogram T wave, and palpitations. None of the 6 events considered vaccine-related were considered serious. Despite close cardiac monitoring, no confirmed case of myocarditis, pericarditis, endocarditis or any other type of cardiac inflammatory disease (or related syndromes) was recorded.
# Clinical Immunogenicity and Indirect Evidence of Protection by Imvamune ®
There are no data indicating the efficacy or effectiveness of Imvamune ® vaccination against monkeypox infection or disease in the context of PrEP or PEP. Clinical data for Imvamune ® PrEP are limited to clinical immunogenicity or indirect protection from vaccinia (the virus used for 1 st or 2 nd generation smallpox vaccines). There is no established threshold above which immune responses to any orthopoxviruses are considered protective therefore the interpretation of the decline or boosting of immune responses remains unclear. Clinical protection from symptoms of vaccinia infection may not be indicative of protection against monkeypox.
- In a Phase 3 (11) randomized, open-label active-controlled non-inferiority trial, 440 smallpox vaccine naïve adults were randomly assigned to receive 2 doses of Imvamune ® 4 weeks apart followed by one dose of the second generation replicating smallpox vaccine (to observe for effect of Imvamune ® on vaccinia vaccine cutaneous reaction) or one dose of the second generation replicating smallpox vaccine alone. o Imvamune ® immune responses (binding and neutralization) were detectable by week 2. At week 6 after dose 2, immune responses peaked at or beyond responses to 1-dose of previous generation, replicating vaccine. o At the time of peak titres, all participants in the Imvamune ® group had seroconverted and 97.3% of participants in the previous generation group had seroconverted. At time points when previous generation has historically been considered to be protective (weeks 2 and 4), seroconversion rates were similar between both groups. o Previous vaccination with Imvamune ® prevented the formation of a full major cutaneous reaction in the majority of participants (77.0%) after vaccinia vaccination/infection at week 8 in the MVA group, as compared with a rate of full major cutaneous reaction of 92.5% in the vaccinia-only group. The maximum lesion area of the major cutaneous reaction was significantly re duced (by 97.9%) when vaccinia vaccination was preceded by Imvamune ® vaccination. In Phase 2 clinical testing (12,13) , immune responses after one or two doses of Imvamune ® declined after 2 years. One or two doses of Imvamune ® were able to boost previously generated immune responses within 7 days to the level of those achieved after the 2 dose primary series. Small studies have demonstrated that Imvamune ® is able to boost pre-existing immunological memory from previous orthopoxvirus vaccines. o A small study of 18 participants who received previous generation, replicating smallpox vaccines showed that at baseline, 22% of previous vaccinees had detectable immune responses to orthopox antigens and by day 28 after Imvamune ® vaccination, 100% of previous vaccinees had seroconverted (14) . o Another study included 200 vaccinia-experienced subjects. By day 14 following a single dose of Imvamune ® 95.5% seroconverted (15) . o In additional study vaccinia-experienced subjects received either 1 (n=58) or 2 doses (n=62) of Imvamune ® . Seroconversion rates in neutralizing antibody titers two weeks following the final dose were 77.6% and 90.0%, respectively (16) .
# Preclinical Immunogenicity and Efficacy Data for Imvamune ®
Given the limited clinical data available to demonstrate Imvamune ® efficacy and effectiveness against monkeypox infection and disease, insight may be gained from preclinical data for MVA -BN (the non-replicating virus in Imvamune ® vaccines). Immune responses and protection from disease outcomes have been demonstrated across different animal models however it remains unclear the degree to which preclinical results will predict outcomes in humans.
- In murine models, a single pre-exposure dose of MVA-BN induced a comparable immune response (antibody levels and T cell response) and survival to a lethal challenge with vaccinia and mousepox as vaccination with previous generation replicating smallpox vaccines. This was observed both with immunocompetent as well as immunosuppressed animals (17)(18)(19)(20) . In non-human primate models, the efficacy of MVA-BN was tested in comparison against lethal monkeypox challenge. Across all studies, 80-100% of MVA-BN-vaccinated animals survived compared to 0-40% of control animals (21)(22)(23) .
- Animal testing was also conducted on black-tailed prairie dogs. Vaccination with Imvamune ® protected the animals from death and modified the severity of rash illness (23) .
# Data for Post-Exposure Prophylaxis (PEP)
Safety Data for Imvamune ® There are no safety data available to demonstrate the safety of Imvamune ® in the context of PEP. However, the safety of Imvamune ® in a PEP context can be inferred from studies in a PrEP context. It is unclear how previous orthopoxvirus exposure could affect Imvamune ® safety.
# Clinical Immunogenicity and Indirect Evidence of Protection by Imvamune ®
There are no data indicating the efficacy or effectiveness of Imvamune ® vaccination against monkeypox infection or disease in the context of PrEP or PEP. Clinical data for Imvamune ® PEP can be inferred from clinical pre-exposure testing where immunological responses were detected within 2 weeks of vaccination (24) . Timing of PEP could be inferred from studies of early generation smallpox vaccines; however, it is unknown how these smallpox studies directly relate to protection from monkeypox by Imvamune ® .
- From historical study of previous generation smallpox vaccines, the median effectiveness in preventing smallpox disease with vaccination at 0-6 h, 6-24 h, and 1-3 days after exposure was estimated as 93%, 90%, and 80%, respectively, and effectiveness in modifying disease among those who develop illness was estimated as 80%, 80%, and 75%, respectively (25) .
# Preclinical Immunogenicity and Efficacy Data for Imvamune ®
Given the limited clinical data available to demonstrate Imvamune ® efficacy and effectiveness against monkeypox infection and disease, insight may be gained fro m preclinical data for MVA-BN (the non-replicating virus in Imvamune ® vaccines). Immune responses and protection from disease outcomes have been demonstrated across different animal models however it remains unclear the degree to which preclinical results will predict outcomes in humans.
- In murine models, a single post-exposure dose of MVA-BN induced a comparable immune response (antibody levels and T cell response) and survival to a lethal challenge with vaccinia and mousepox as vaccination with replicating smallpox vaccines. This was observed both with immunocompetent as well as immunosuppressed animals (26,27) . After a lethal dose of monkeypox in prairie dogs, vaccination with MVA-BN one day after exposure conferred a survival rate of 80% compared to 25% for unvaccinated animals (28) . Vaccination three days after exposure conferred a survival rate of 38% with MVA-BN.
# Imvamune in Special Populations
Data are even more limited for populations either at risk for more severe outcomes due to monkeypox infection, or who may be at higher risk for adverse events due to vaccination. Small clinical trials of Imvamune ® in people infected with HIV and in people with atopic dermatitis offer limited safety and immunogenicity data. Imvamune ® has never been tested in children (<18y), people who are pregnant or people who are lactating, though limited data may be available from testing the MVA vaccine platform for other viruses. Limited indirect data for these groups have been used to make recommendations.
# Immunocompromised individuals:
- Immunocompromised individuals, including those receiving immunosuppressive therapy, are a very heterogeneous population some of whom may respond differently to vaccines and thus require unique considerations regarding immunization The use of Imvamune ® in immunocompromised patients is supported by clinical trials which include more than 690 individuals living with human immunodeficiency virus (HIV) (CD4 ≥ 100 cells/µL). o Phase 2 non-randomized trial POX-MVA-011 included 482 individuals living with HIV (CD4+ count 200-750 cells/µL) in the US (29) . o Phase 1/2 non-randomized trial POX-MVA-010 included 91 individuals living with HIV (CD4+ count ≥350 cells/mm 3 ) in the US (30) . Compared to people without HIV, individuals with HIV may have lower immune responses to one dose of Imvamune ® and may have decreased durability of immune responses (38) . o However, one paper explored a 3-dose schedules and double standard dose in a small number of subjects. Phase 2 randomized trial POX-MVA-037 included 87 individuals with a history of AIDS (had a documented CD4 cell nadir of <200 cells/µL any time prior to screening) in the US (31) . Imvamune ® was well tolerated in 20 individuals who received hematopoietic stem cell transplant at least two years prior to study enrollment and were not exposed to immunosuppressive medication for at least 30 days prior to enrollment, with no serious adverse events. Self-limited local discomfort was the most frequent reactogenicity (32) . The safety profile of Imvamune ® in individuals who are immunocompromised has been shown to be comparable to that recorded for healthy individuals. There were no instances of progressive vaccinia (30) .
# Pregnant and lactating people:
- The safety and efficacy of Imvamune ® has not been formally evaluated in pregnancy, and there are limited data on the use of Imvamune ® in pregnancy. During the clinical trial program, 29 pregnancies were reported and no safety signals were identified. No congenital abnormalities were observed and complication rates were in line with expected background rates (8) . Developmental and Reproductive Toxicology (DART) studies in rats and rabbits indicated no evidence of vaccine-related fetal malformations or variations, and no adverse effects on female fertility or pre-weaning development (6,33,34) . Data on Imvamune ® in people who are pregnant or lactating is very limited, however, at least one other vaccine using MVA as a vector is being tested in people who are pregnant: o A Phase 3 Ebola vaccine trial of 2853 in pregnant women to assess the safety, reactogenicity and immunogenicity of a 2-dose regimen: an adenovirus-based viral vector vaccine followed by MVA-Filo vaccine. No data are yet available for this study (35) .
# Children (< 18 years old):
- Although Imvamune ® is not licensed in, and has not been studied in children, several paediatric studies of other vaccines using MVA as a vector (often at a considerably higher dose than used in Imvamune ® ) have been undertaken with a reassuring side effect profile. o A Phase 3 Ebola vaccine trial of an MVA-based vaccine containing antigens from the Ebola virus (MVA-BN-Filo) included children (age 1-17 years) from Sierra Leone. In total, 432 children received the active product MVA-BN-Filo 1x10 8 InfU. This is double the MVA dose compared to the Imvamune ® product monograph. The most frequent solicited local AE was injection site pain in all age groups. The percentage of participants with at least one solicited systemic event was 4.9-15.4% after MVA-BN-Filo, 4.2-10.4% after MenACWY and 0-10.4% after placebo. The most frequent solicited systemic AEs in children 4-17 years were headache, fatigue and chills, while in children 1-3 years of age, they were decreased appetite, decreased activity and pyrexia. The percentage of participants with at least one solicited systemic event was 16.1-18.9% after MVA-BN-Filo, 25-31% after MenACWY comparator and 13-29% after placebo (36) . o A Phase 2 measles vaccine (MVA-mBN85B) partially randomized, controlled trial included 90 healthy children aged 6 months to 6 years in South Africa. The three treatment arms were: half-dose compared to Imvamune ® , double dose compared to Imvamune ® versus Rouvax control (37,38) . There were no serious adverse events. The incidence was low for Grade 3 solicited local AEs (after 1 st vaccination: 13.3% and 46.7%, for Low dose and Normal dose, respectively; after 2 nd vaccination: 11.1% and 21.4%, respectively) and general AEs (after 1 st vaccination: 13.3% and 10%, respectively; after 2 nd vaccination: 7.4% and 3.6%, respectively). Local reactogenicity with the Normal dose was higher than with the Lower dose, suggesting dose-effect.
# Individuals with atopic dermatitis:
- Evidence on the safety and immunogenicity of Imvamune ® in individuals with atopic dermatitis (AD) or eczema is available from Phase 1 (39) and Phase 2 (40) clinical trials. Overall, Imvamune ® is well tolerated in individuals with AD, though individuals with AD may experience a higher frequency of local and systemic reactogenicity compared to those without AD.
- In a Phase 2 study in adults receiving 2 doses of Imvamune ® 4 weeks apart, solicited AEs (erythema, swelling, and systemic AEs) were more frequent in participants with AD compared to those without AD (61.2% vs 49.3%, 52.2% vs 40.8%, and 70.1% vs 56.4%, respectively), with the difference mostly due to events of mild to moderate severity. o In a Phase 1 study in adults receiving 2 doses of Imvamune ® 4 weeks apart, 7% of participants with active AD or a history of AD experienced a transient worsening of AD symptoms, but there was no indication or trend that could be detected that indicated that vaccination worsened the intensity of AD. o No deaths, cases of eczema vaccinatum (EV) or myopericarditis were observed.
- Immune responses (binding antibodies, neutralizing antibodies, seroconversion rates and CD8 T cell responses) were comparable between individuals with and without AD. | Adults 18 years of age and olderPrimary Series: Tw o doses of 0.5 mL (0.5 x 10 8 Infectious Units), 28 days apart Booster dose (2 years after primary series): One dose of 0.5 mL (0.5 x 10 8 Inf.U)# PREAMBLE
The National Advisory Committee on Immunization (NACI) is an External Advisory Body that provides the Public Health Agency of Canada (PHAC) with independent, ongoing and timely medical, scientific, and public health advice in response to questions from PHAC relating to immunization.
In addition to burden of disease and vaccine characteristics, PHAC has expanded the mandate of NACI to include the systematic consideration of programmatic factors in developing evidence based recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels.
The additional factors to be systematically considered by NACI include: economics, ethics, equity, feasibility, and acceptability. Not all NACI statements will require in-depth analyses of all programmatic factors. While systematic consideration of programmatic factors will be conducted using evidence-informed tools to identify distinct issues that could impact decision -making for recommendation development, only distinct issues identified as being specific to the vaccine or vaccine-preventable disease will be included.
This statement contains NACI's independent advice and recommendations, which are based upon the best current available scientific knowledge. T his document is being disseminated for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph. Recommendations for use and other information set out herein may differ from that set out in the product monographs of the Canadian manufacturers of the vaccines. Manufacturer(s) have sought approval of the vaccines and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of PHAC's Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.
# BACKGROUND
Monkeypox virus is a member of the Orthopoxvirus genus, which also includes variola virus (smallpox virus), vaccinia virus, cowpox, and other poxviruses. Monkeypox viruses are zoonotic, therefore infection may occur in contexts where there is contact with wild species that are susceptible to monkeypox viruses. Human-to-human transmission of monkeypox virus also occurs amongst close contacts of people infected with monkeypox. Monkeypox is endemic in Central and West Africa, but there have been cases and outbreaks in non-endemic countries due to international travel or the importation of infected animals from affected areas. There are two distinct clades of monkeypox virus: the Congo Basin (Central African) clade and the West African clade. The Congo Basin clade has caused more severe illness.
Based on historical data, monkeypox has a typical incubation period of 6-13 days from exposure but can range from 5-21 days (1) . The disease is usually self-limiting and resolves within 14 to 28 days. Symptoms include fever, headache, back pain, myalgia, asthenia, lymphadenopathy and skin lesions/rash which typically tend to be more concentrated on the face, extremities, and oral mucous membranes, but can also appear in the genital area. Rash lesions begin as macules and further develop to papules, vesicles, pustules, and then form crusts. The duration of communicability for monkeypox virus may be up to 2-4 weeks, based on limited evidence of PCR detection of monkeypox in the upper respiratory tract (2) . Potential complications of monkeypox include secondary bacterial infections, pneumonia, sepsis, encephalitis, and vision loss from corneal inflammation. Monkeypox virus may cause severe disease in young children, individuals who are immunocompromised (3) , and those who are pregnant. Information about monkeypox in people who are pregnant is sparse but cases of first trimester miscarriage and stillbirths have been reported (4) .
In the current 2022 multi-country outbreak, monkeypox cases may have an atypical presentation including oral, genital, and/or anal lesions with or without fever, or systemic symptoms. Personto-person transmission can occur through direct contact with a person who is infected, including intimate sexual activity, or through shared contaminated objects. The potential for respiratory transmission is unknown at this time but may also be possible.
The 2022 multi-country monkeypox outbreak represents the first incidence of broader community transmission in a number of countries outside of certain regions of Africa. Initial detection in early May 2022 was a family cluster of three cases in the United Kingdom, with one case having recent travel history to an endemic region. On May 15, the World Health Organization (WHO) was notified of four additional confirmed cases, unlinked to travel, and this suggested more extensive community transmission of the virus. Since then, additional cases have been reported in the United Kingdom and internationally, including Canada. By June 7, at least 1,060 confirmed cases from 30 non-endemic countries and territories have been reported in official and media sources according to monitoring by the Global Public Health Intelligence Network (GPHIN). Ten [40], the United States [31], Italy [20], and Belgium [17]).
As of June 7, 81 cases of monkeypox had been confirmed in Canada (71 in Quebec, 8 in Ontario, 1 in Alberta, and 1 in British Columbia). According to open-source information, the Quebec cases are mainly men between 30-55 years of age, and they presented to Sexually Transmitted and Blood-Borne Infection clinics in the Montreal area. The infections were suspected to have been acquired in Montreal. Some of the individuals with infection reported links to travel in Belgium and Mexico.
Smallpox vaccines used during the global smallpox eradication programs may provide some protection against monkeypox (1) . However, global smallpox vaccination programs ended in 1980 when smallpox was declared eradicated. Discontinuation of smallpox vaccination for travel was recommended by the WHO in 1980 and was no longer required by any country by 1982 Canadians born in 1972 or later have not been routinely immunized against smallpox (unless immunized for other purposes such as travel or work-related risks). For those who have been previously vaccinated for smallpox (i.e., eligible for vaccine in 1980 or earlier), the degree of protection conferred from the smallpox vaccine against monkeypox infection may be up to 85% (5) , however the durability of protection and the degree of protection against the current strain of monkeypox remains unknown.
# OBJECTIVE
In the context of the rapidly evolving multi-country monkeypox outbreak, this rapid response was undertaken to provide guidance on the use of an orthopoxvirus (Imvamune ® ) vaccine with potential efficacy against monkeypox. Imvamune ® is stockpiled within Canada's National Emergency Strategic Stockpile for the purposes of national security due to its potential efficacy against variola, the virus that causes smallpox. Due to the unique epidemiology and supply considerations, the planned task for this rapid response was to consider the use of Imvamune ® for post-exposure prophylaxis and to summarize the available evidence in support of Imvamune ® use in this specific current context. Unrelated to the current monkeypox outbreak, NACI was also asked to consider use of Imvamune ® in laboratory research settings where replicating orthopoxviruses are studied.
NACI and PHAC continue to monitor the evolving scientific data recognizing that the trajectory of the current monkeypox outbreak remains unclear, the situation is rapidly evolving and there may be additional considerations in the coming weeks.
# METHODS
On May 26 and May 27, 2022, monkeypox data were discussed and reviewed by the NACI High Consequence Infectious Disease working group (HCID WG), along with input from the Public Health Ethics Consultative Group (PHECG), Canadian Immunization Committee (CIC) NACI's Vaccine Safety Working Group (VSWG) and two LGBTQ2S+ groups from Ontario and BC. The HCID WG reviewed data on the current status of the monkeypox outbreak, along with additional evidence included in published scientific literature and from the manufacturer, regarding the safety, immunogenicity and protection offered by Imvamune ® . NACI approved these HCID WG recommendations on June 8, 2022.
# VACCINE
Imvamune ® (also called Modified Vaccinia Ankara-Bavarian Nordic (MVA-BN), Jynneos ® , Imvanex ® ) is a non-replicating, third-generation smallpox vaccine manufactured by Bavarian Nordic. Imvamune ® was initially authorized for use in Canada on November 21, 2013, as an Extraordinary Use New Drug Submission (EUNDS) for use by the Canadian Government in an emergency situation for active immunization against smallpox infection and disease in persons 18 years of age and older who have a contraindication to the first or second generation smallpox vaccines. It was subsequently approved under a supplement to the EUNDS on November 5, 2020 for active immunization against smallpox, monkeypox and related Orthopoxvirus infections and disease in adults 18 years of age and older determined to be at high risk for exposure (6) .
Imvamune ® contains trace amounts of host cell DNA and protein, benzonase, ciprofloxacin and gentamicin. No preservative or adjuvant is added to the formulation. The MVA virus is also being developed as a vector vaccine platform against other viruses, including tuberculosis, respiratory syncytial virus, Ebola virus and others.
Imvamune differs from previous generations of smallpox vaccines as it is a non-replicating vaccine virus in humans, meaning based on preclinical studies, it is not able to produce more copies of itself (7) . While Imvamune is capable of replicating to high titers in avian cell lines such as chicken embryo fibroblasts, it is attenuated and has limited replication capability in human cells (8) .
Preclinical data from previous generation smallpox vaccines showed decreased immune responses when tecovirimat (TPOXX, an antiviral drug from SIGA technologies) was administered concurrently with earlier generation smallpox vaccines (9) . Due to the differences between previous generation smallpox vaccines and Imvamune ® , it is unclear if antivirals could impact protection offered by Imvamune ® .
# Adjuvant / Preservatives
The vaccine contains no adjuvant or preservatives
# Contraindications
Patients w ho are hypersensitive to this vaccine or to any ingredient in the formulation or component of the container. Individuals w ho show hypersensitivity reactions after receiving the first dose of the vaccine should not be given the second dose. As w ith other vaccines, vaccination w ith IMVAMUNE ® must be postponed in persons w ith acute febrile conditions if used for non-emergency (pre-event) prophylaxis.
# Storage
Store frozen at -20°C ± 5°C or -50°C ±10°C or -80°C ±10°C. After thaw ing, the vaccine should be used immediately or can be stored at 2°C -8°C for up to 2 w eeks prior to use. Do not refreeze a vial once it has been thaw ed. Protect from light.
Handling Thaw at room temperature. The drug product should appear as a pale milky colored homogeneous suspension. The single-dose vial should be sw irled gently (not shaken) for at least 30 seconds to ensure homogeneity upon thaw ing, The vaccine must not be used if any foreign particulate matter are visible.
# Reconstitution No
Route of adm inistration 0.5 mL subcutaneous injection, at any site
# Syringe and needle selection
Withdraw w ith a syringe and needle long enough to reach the bottom of the vial.
For injection, needle should be changed to a subcutaneous injection needle a In Canada, there are several vaccines manufactured by processes involving hens' eggs or their derivatives, such as chicken cell cultures b Tromethamine (trometamol, Tris) may very rarely cause allergic reactions and is found in some medications injected to do tests (contrast media) as w ell as other medications taken by mouth or injection, and some creams and lotions. Note that this is not a complete list. c Benzonase is used for purification of viral vaccines, viral vectors for vaccine, cell and gene therapy, and oncolytic viruses, removing DNA/RNA from proteins and other biologicals; reduction of viscosity caused by nucleic acids; sample preparation in electrophoresis and chromatography and prevention of cell clumping. d Gentamicin and ciprofloxacin are used as antibiotics in the treatment of some bacterial infections.
# RECOMMENDATIONS
Please see Table 2 for an explanation of strong versus discretionary NACI recommendations. Please see Appendix A which summarizes the clinical and preclinical data for Imvamune ® .
For those without a contraindication to the vaccine: For individuals who had received a live replicating 1st or 2nd generation smallpox vaccine in the past and who sustain a high risk exposure to a probable or confirmed case of monkeypox, a single dose of Imvamune ® PEP may be offered (i.e., as a booster dose).
The benefit of protection against infection should be discussed with a healthcare provider and weighed against the potential risk of recurrent myocarditis for individuals with a history of myocarditis/pericarditis linked to a previous dose of live replicating 1st and 2nd generation smallpox vaccine and/or Imvamune ® ; a precautionary approach is warranted at this time until more information is available. For immunocompetent individuals who have received a live replicating 1 st or 2 nd generation smallpox vaccine in the past and who are at high risk for occupational exposure, a single dose of Imvamune ® may be offered (i.e., as a booster dose), rather than the two dose primary vaccine series). This single Imvamune ® dose should be given at least two years after the latest live replicating smallpox vaccine dose.
In consultation with a physician, the benefit of protection against infection should be weighed against the risk of recurrent myocarditis for individuals with a history of myocarditis/pericarditis linked to a previous dose of live replicating 1 st and 2 nd generation smallpox vaccine and/or Imvamune ® ; a precautionary approach is warranted at this time until more information is available. Immunocompromised populations (including people living with HIV) may particularly benefit from vaccination as these populations may be at risk for more severe outcomes if infected depending on the nature and degree of the immunosuppression. Although data on the use of Imvamune ® in immunocompromised populations are limited, Imvamune ® has been tested clinically in people living with HIV (CD4 ≥100 cells/µL) and hematopoietic stem transplant patients (studied two years post-HSCT) and safety was comparable to healthy controls in these populations. There are limited data overall on VE/immunogenicity or safety in immunocompromised populations, but immunosuppression increases risk of negative outcomes due to infection. Live vaccines are usually contraindicated for immunocompromised populations; however, Imvamune ® may be safely used in this group as it is considered a non-replicating vaccine (8) . When using Imvamune ® as PrEP in immunocompromised individuals, 2 doses are recommended regardless of previous smallpox vaccine history.
If at risk for infection, pregnant populations may particularly benefit from vaccination as these populations may be at risk for severe outcomes from disease. Imvamune ® has never been tested in persons who are pregnant. Though limited, safety and toxicity studies have identified no concerning safety signals. There is a lack of evidence of safety and efficacy of Imvamune ® PEP or PrEP in this group, though at this time there is no reason to believe that vaccination would have any adverse impact on the person who is pregnant or the fetus. Live vaccines are usually contraindicated for pregnant populations; however, Imvamune ® may be used in this group as it is considered a non-replicating vaccine. The risks due to monkeypox infection should be weighed against the lack of evidence of vaccine safety.
Lactating populations are not at higher risk for negative outcomes due to monkeypox infection. There are no Imvamune ® studies in this population. There is a lack of evidence of safety and efficacy of Imvamune ® PEP or PrEP in this group, though at this time there is no reason to believe that vaccination would have any adverse impact on the person who is lactating or the child. There is no information on excretion of vaccine components or antigens into breastmilk; however, this is unlikely as Imvamune ® is a non-replicating vaccine.
Although Imvamune ® is not authorized for children, this population may be at higher risk of severe outcomes from monkeypox infection and may benefit from vaccination. Indirect evidence of clinical testing of the MVA vector as a viral vector vaccine platform for other vaccines in development, including for RSV, TB and Ebola, indicates that out of almost 2000 vaccine recipients, Imvamune ® components are well tolerated in recipients under 18 years of age. There is a lack of evidence of safety and efficacy of Imvamune ® PEP or PrEP in this group.
People with atopic dermatitis were a risk group with severe adverse outcomes for earlier generations of smallpox vaccines. From limited clinical testing of Imvamune ® , solicited AEs were more frequent in this group including transient worsening of atopic dermatitis symptoms. Historically, previous generations of orthopoxvirus vaccines carried a risk of diffuse vaccinia virus infection for individuals with atopic dermatitis. The Imvamune ® vaccine was developed to overcome those adverse effects through the use of a non-replicating virus.
# NACI recommendation for concurrent administration:
Imvamune ® given as PEP or PrEP should not be delayed due to recent receipt of an mRNA COVID-19 vaccine. If vaccine timing can be planned (i.e., prior to employment within a research laboratory), NACI recommends that Imvamune ® be given at least 4 weeks after or before an mRNA vaccine for COVID-19 .
First generation orthopoxvirus vaccines and mRNA COVID-19 vaccines both have a potential risk of cardiac adverse events (myocarditis). Risk for myo-or pericarditis with the newer generation non-replicating attenuated virus vaccine Imvamune ® is still unknown. . It would be prudent to wait for a period of at least 4 weeks before or after the administration of mRNA COVID-19 vaccine in order to prevent erroneous attribution of an AEFI to one particular vaccine or the other. This suggested minimum waiting period between vaccines is precautionary at this time. Protection from monkeypox exposure should be prioritized and recent mRNA vaccine receipt should not delay Imvamune ® PEP or PrEP if protection is urgent.
# Summary of Evidence and Considerations for the Vaccine:
There continue to be many unknowns about the outbreak of monkeypox virus, including symptoms, modes of transmission and groups at high risk for severe outcomes. There is very limited evidence available upon which to base guidance for Imvamune ® use for pre-or post-exposure recommendations in any population. Data on the pre-exposure use of vaccine are limited to clinical trial settings where data for safety, immunogenicity and efficacy against vaccinia are available. o Safety data from clinical testing do not identify any safety signals of concern; however, these data are limited and not predictive of very rare events occurring at a rate below 1/ 10 000. o Data for cardiac adverse events of special interest are available from limited clinical testing. o Limited immunological data are available to inform the durability of immune responses and the ability for Imvamune ® to boost previous anti-orthopoxvirus immune responses. Data to inform post-exposure use of vaccine are limited to indirect evidence either from preclinical studies in animal models or from smallpox vaccination in the pre -eradication era. Data for populations either at risk for more severe outcomes due to monkeypox infection, or who may be at higher risk for adverse events due to vaccination, are even more limited. o Small clinical trials of Imvamune ® in people living with HIV and in people with atopic dermatitis offer limited safety and immunogenicity data. o Imvamune ® has never been tested in children (<18y), people who are pregnant or people who are lactating. Limited indirect data for these groups have been used to make recommendations. Informed consent when administering Imvamune ® PEP or PrEP should include a discussion of the limited data available on monkeypox infection and disease as well as limited data available for the safety and efficacy of Imvamune ® . NACI continues to monitor and assess the evidence as it emerges and will update its recommendations as needed.
# ADDITIONAL INFORMATION
NACI continues to endeavour to make ethical, equitable and evidence -informed recommendations. Given the paucity of data on benefits and risks of Imvamune ® in the context of a monkeypox outbreak setting, the use of Imvamune ® must balance the benefits and risks of what is known and unknown about the vaccine and the disease.
It is important to obtain informed consent when offering the vaccine, and to clearly explain to potential recipients what is unknown (in addition to what is known) about the vaccine, when discussing potential risks and benefits. This is particularly important for individuals identified by NACI as special populations and for any off-label use in individuals <18 years of age.
Additionally, there is an ethical obligation to conduct close monitoring and surveillance of the use of the vaccine, in order to collect information to inform the response going forward. Both informed consent and post-market safety surveillance will be vital for the ethical implementation of an Imvamune ® vaccination program, especially in pediatric populations <18 years of age when the vaccine is being used off-label.
It will be important to closely monitor who is at risk of monkeypox and provide rationale for when vaccination is needed. Additionally, to prevent stigmatization of specific populations and potentially increase vaccine acceptability, the primary focus should be identifying risk f actors for transmission of monkeypox (e.g., proximity of contact, sexual activities, specific behaviours) whenever possible, rather than identifying populations perceived to be at a higher risk.
Given the limited clinical evidence on the use of Imvamune ® for monkeypox PEP or PrEP, understanding of the need for, and benefit of Imvamune ® in the context of a monkeypox outbreak setting is evolving.
Certain behaviours place individuals at increased risk of exposure to the monkeypox virus (e.g., proximity of contact, sexual activities, household member or behaviours that cause exposure to body fluids or fomites). Some populations are at increased risk of severe monkeypox disease due to various biological factors (e.g. individuals who are immunocompromised, pregnant, and/or, young children) and social factors that may intersect. Risk factors of severe disease and risk of exposure may overlap, further increasing risk. Any combination of these factors, as well as varying access to health care services, has the potential for disproportionate consequences for specific populations characterized by increased rates of infection, disease, and severe illness. Program planning should ensure equitable access to vaccination information and services and minimize differences in vaccine acceptance and uptake based on socioeconomic status and other socioeconomic determinants of health that may intersect.
# RESEARCH PRIORITIES
1. Further study of the protection offered by Imvamune ® vaccine against monkeypox infection and disease (in PrEP and PEP scenarios), including: a. Understanding which immune responses are protective against infection and disease and defining protective thresholds b. Understanding how the impact of previous orthopox infection or vaccination impacts the protection offered by Imvamune ® c. Real-world evidence on the vaccine effectiveness of Imvamune against monkeypox and for the use of single dose PrEP and PEP. 2. Further studies to further inform on the safety of Imvamune ® vaccine including both clinical trials and post-market safety surveillance. 3. Safety in special populations, including people who are pregnant or breastfeeding, children <18 years of age, and people who are immunocompromised should also be assessed by targeted clinical trials. 4. Further study into the epidemiology of the disease to better understand the modes of transmission, the disease presentation, and to identify the populations at highest risk for severe disease in order to inform and optimize disease prevention strategies.
# Implication
A strong recommendation applies to most populations/individuals and should be followed unless a clear and compelling rationale for an alternative approach is present.
A discretionary recommendation may be considered for some populations/individuals in some circumstances. Alternative approaches may be reasonable. The safety of Imvamune was assessed in the limited context of clinical trials and Imvamune ® has not been administered at the scale needed to predict low frequency adverse effects. In the limited safety assessments that have been done, no signals of concern for Imvamune ® have been identified.
Imvamune ® 's safety has been assessed in 20 completed clinical trials where approximately 13,700 vaccine doses were given to 7,414 subjects (10) . The most common local adverse events following immunization (AEFI) were pain, erythema, induration and swelling. The most common systemic AEFI were fatigue, headache, myalgia, and nausea. Most of the reported AEFIs were of mild to moderate intensity and resolved within the first seven days following vaccination. Cardiac adverse events of special interest were reported to occur in 1.4% (91/6,640) of Imvamune ® recipients, 0.2% (3/1,206) of placebo recipients who were smallpox vaccinenaïve and 2.1% (16/762) of Imvamune ® recipients who were smallpox vaccineexperienced. Age was likely not adjusted for between vaccinated groups. Among the cardiac AEFIs reported, 28 were asymptomatic post-vaccination elevation of troponin-I, 6 cases were considered to be causally related to Imvamune ® vaccination and included tachycardia, electrocardiogram T wave inversion, abnormal electrocardiogram, electrocardiogram ST segment elevation, abnormal electrocardiogram T wave, and palpitations. None of the 6 events considered vaccine-related were considered serious. Despite close cardiac monitoring, no confirmed case of myocarditis, pericarditis, endocarditis or any other type of cardiac inflammatory disease (or related syndromes) was recorded.
# Clinical Immunogenicity and Indirect Evidence of Protection by Imvamune ®
There are no data indicating the efficacy or effectiveness of Imvamune ® vaccination against monkeypox infection or disease in the context of PrEP or PEP. Clinical data for Imvamune ® PrEP are limited to clinical immunogenicity or indirect protection from vaccinia (the virus used for 1 st or 2 nd generation smallpox vaccines). There is no established threshold above which immune responses to any orthopoxviruses are considered protective therefore the interpretation of the decline or boosting of immune responses remains unclear. Clinical protection from symptoms of vaccinia infection may not be indicative of protection against monkeypox.
In a Phase 3 (11) randomized, open-label active-controlled non-inferiority trial, 440 smallpox vaccine naïve adults were randomly assigned to receive 2 doses of Imvamune ® 4 weeks apart followed by one dose of the second generation replicating smallpox vaccine (to observe for effect of Imvamune ® on vaccinia vaccine cutaneous reaction) or one dose of the second generation replicating smallpox vaccine alone. o Imvamune ® immune responses (binding and neutralization) were detectable by week 2. At week 6 after dose 2, immune responses peaked at or beyond responses to 1-dose of previous generation, replicating vaccine. o At the time of peak titres, all participants in the Imvamune ® group had seroconverted and 97.3% of participants in the previous generation group had seroconverted. At time points when previous generation has historically been considered to be protective (weeks 2 and 4), seroconversion rates were similar between both groups. o Previous vaccination with Imvamune ® prevented the formation of a full major cutaneous reaction in the majority of participants (77.0%) after vaccinia vaccination/infection at week 8 in the MVA group, as compared with a rate of full major cutaneous reaction of 92.5% in the vaccinia-only group. The maximum lesion area of the major cutaneous reaction was significantly re duced (by 97.9%) when vaccinia vaccination was preceded by Imvamune ® vaccination. In Phase 2 clinical testing (12,13) , immune responses after one or two doses of Imvamune ® declined after 2 years. One or two doses of Imvamune ® were able to boost previously generated immune responses within 7 days to the level of those achieved after the 2 dose primary series. Small studies have demonstrated that Imvamune ® is able to boost pre-existing immunological memory from previous orthopoxvirus vaccines. o A small study of 18 participants who received previous generation, replicating smallpox vaccines showed that at baseline, 22% of previous vaccinees had detectable immune responses to orthopox antigens and by day 28 after Imvamune ® vaccination, 100% of previous vaccinees had seroconverted (14) . o Another study included 200 vaccinia-experienced subjects. By day 14 following a single dose of Imvamune ® 95.5% seroconverted (15) . o In additional study vaccinia-experienced subjects received either 1 (n=58) or 2 doses (n=62) of Imvamune ® . Seroconversion rates in neutralizing antibody titers two weeks following the final dose were 77.6% and 90.0%, respectively (16) .
# Preclinical Immunogenicity and Efficacy Data for Imvamune ®
Given the limited clinical data available to demonstrate Imvamune ® efficacy and effectiveness against monkeypox infection and disease, insight may be gained from preclinical data for MVA -BN (the non-replicating virus in Imvamune ® vaccines). Immune responses and protection from disease outcomes have been demonstrated across different animal models however it remains unclear the degree to which preclinical results will predict outcomes in humans.
In murine models, a single pre-exposure dose of MVA-BN induced a comparable immune response (antibody levels and T cell response) and survival to a lethal challenge with vaccinia and mousepox as vaccination with previous generation replicating smallpox vaccines. This was observed both with immunocompetent as well as immunosuppressed animals (17)(18)(19)(20) . In non-human primate models, the efficacy of MVA-BN was tested in comparison against lethal monkeypox challenge. Across all studies, 80-100% of MVA-BN-vaccinated animals survived compared to 0-40% of control animals (21)(22)(23) .
Animal testing was also conducted on black-tailed prairie dogs. Vaccination with Imvamune ® protected the animals from death and modified the severity of rash illness (23) .
# Data for Post-Exposure Prophylaxis (PEP)
Safety Data for Imvamune ® There are no safety data available to demonstrate the safety of Imvamune ® in the context of PEP. However, the safety of Imvamune ® in a PEP context can be inferred from studies in a PrEP context. It is unclear how previous orthopoxvirus exposure could affect Imvamune ® safety.
# Clinical Immunogenicity and Indirect Evidence of Protection by Imvamune ®
There are no data indicating the efficacy or effectiveness of Imvamune ® vaccination against monkeypox infection or disease in the context of PrEP or PEP. Clinical data for Imvamune ® PEP can be inferred from clinical pre-exposure testing where immunological responses were detected within 2 weeks of vaccination (24) . Timing of PEP could be inferred from studies of early generation smallpox vaccines; however, it is unknown how these smallpox studies directly relate to protection from monkeypox by Imvamune ® .
From historical study of previous generation smallpox vaccines, the median effectiveness in preventing smallpox disease with vaccination at 0-6 h, 6-24 h, and 1-3 days after exposure was estimated as 93%, 90%, and 80%, respectively, and effectiveness in modifying disease among those who develop illness was estimated as 80%, 80%, and 75%, respectively (25) .
# Preclinical Immunogenicity and Efficacy Data for Imvamune ®
Given the limited clinical data available to demonstrate Imvamune ® efficacy and effectiveness against monkeypox infection and disease, insight may be gained fro m preclinical data for MVA-BN (the non-replicating virus in Imvamune ® vaccines). Immune responses and protection from disease outcomes have been demonstrated across different animal models however it remains unclear the degree to which preclinical results will predict outcomes in humans.
In murine models, a single post-exposure dose of MVA-BN induced a comparable immune response (antibody levels and T cell response) and survival to a lethal challenge with vaccinia and mousepox as vaccination with replicating smallpox vaccines. This was observed both with immunocompetent as well as immunosuppressed animals (26,27) . After a lethal dose of monkeypox in prairie dogs, vaccination with MVA-BN one day after exposure conferred a survival rate of 80% compared to 25% for unvaccinated animals (28) . Vaccination three days after exposure conferred a survival rate of 38% with MVA-BN.
# Imvamune in Special Populations
Data are even more limited for populations either at risk for more severe outcomes due to monkeypox infection, or who may be at higher risk for adverse events due to vaccination. Small clinical trials of Imvamune ® in people infected with HIV and in people with atopic dermatitis offer limited safety and immunogenicity data. Imvamune ® has never been tested in children (<18y), people who are pregnant or people who are lactating, though limited data may be available from testing the MVA vaccine platform for other viruses. Limited indirect data for these groups have been used to make recommendations.
# Immunocompromised individuals:
Immunocompromised individuals, including those receiving immunosuppressive therapy, are a very heterogeneous population some of whom may respond differently to vaccines and thus require unique considerations regarding immunization The use of Imvamune ® in immunocompromised patients is supported by clinical trials which include more than 690 individuals living with human immunodeficiency virus (HIV) (CD4 ≥ 100 cells/µL). o Phase 2 non-randomized trial POX-MVA-011 included 482 individuals living with HIV (CD4+ count 200-750 cells/µL) in the US (29) . o Phase 1/2 non-randomized trial POX-MVA-010 included 91 individuals living with HIV (CD4+ count ≥350 cells/mm 3 ) in the US (30) . Compared to people without HIV, individuals with HIV may have lower immune responses to one dose of Imvamune ® and may have decreased durability of immune responses (38) . o However, one paper explored a 3-dose schedules and double standard dose in a small number of subjects. Phase 2 randomized trial POX-MVA-037 included 87 individuals with a history of AIDS (had a documented CD4 cell nadir of <200 cells/µL any time prior to screening) in the US (31) . Imvamune ® was well tolerated in 20 individuals who received hematopoietic stem cell transplant at least two years prior to study enrollment and were not exposed to immunosuppressive medication for at least 30 days prior to enrollment, with no serious adverse events. Self-limited local discomfort was the most frequent reactogenicity (32) . The safety profile of Imvamune ® in individuals who are immunocompromised has been shown to be comparable to that recorded for healthy individuals. There were no instances of progressive vaccinia (30) .
# Pregnant and lactating people:
The safety and efficacy of Imvamune ® has not been formally evaluated in pregnancy, and there are limited data on the use of Imvamune ® in pregnancy. During the clinical trial program, 29 pregnancies were reported and no safety signals were identified. No congenital abnormalities were observed and complication rates were in line with expected background rates (8) . Developmental and Reproductive Toxicology (DART) studies in rats and rabbits indicated no evidence of vaccine-related fetal malformations or variations, and no adverse effects on female fertility or pre-weaning development (6,33,34) . Data on Imvamune ® in people who are pregnant or lactating is very limited, however, at least one other vaccine using MVA as a vector is being tested in people who are pregnant: o A Phase 3 Ebola vaccine trial of 2853 in pregnant women to assess the safety, reactogenicity and immunogenicity of a 2-dose regimen: an adenovirus-based viral vector vaccine followed by MVA-Filo vaccine. No data are yet available for this study (35) .
# Children (< 18 years old):
Although Imvamune ® is not licensed in, and has not been studied in children, several paediatric studies of other vaccines using MVA as a vector (often at a considerably higher dose than used in Imvamune ® ) have been undertaken with a reassuring side effect profile. o A Phase 3 Ebola vaccine trial of an MVA-based vaccine containing antigens from the Ebola virus (MVA-BN-Filo) included children (age 1-17 years) from Sierra Leone. In total, 432 children received the active product MVA-BN-Filo 1x10 8 InfU. This is double the MVA dose compared to the Imvamune ® product monograph. The most frequent solicited local AE was injection site pain in all age groups. The percentage of participants with at least one solicited systemic event was 4.9-15.4% after MVA-BN-Filo, 4.2-10.4% after MenACWY and 0-10.4% after placebo. The most frequent solicited systemic AEs in children 4-17 years were headache, fatigue and chills, while in children 1-3 years of age, they were decreased appetite, decreased activity and pyrexia. The percentage of participants with at least one solicited systemic event was 16.1-18.9% after MVA-BN-Filo, 25-31% after MenACWY comparator and 13-29% after placebo (36) . o A Phase 2 measles vaccine (MVA-mBN85B) partially randomized, controlled trial included 90 healthy children aged 6 months to 6 years in South Africa. The three treatment arms were: half-dose compared to Imvamune ® , double dose compared to Imvamune ® versus Rouvax control (37,38) . There were no serious adverse events. The incidence was low for Grade 3 solicited local AEs (after 1 st vaccination: 13.3% and 46.7%, for Low dose and Normal dose, respectively; after 2 nd vaccination: 11.1% and 21.4%, respectively) and general AEs (after 1 st vaccination: 13.3% and 10%, respectively; after 2 nd vaccination: 7.4% and 3.6%, respectively). Local reactogenicity with the Normal dose was higher than with the Lower dose, suggesting dose-effect.
# Individuals with atopic dermatitis:
Evidence on the safety and immunogenicity of Imvamune ® in individuals with atopic dermatitis (AD) or eczema is available from Phase 1 (39) and Phase 2 (40) clinical trials. Overall, Imvamune ® is well tolerated in individuals with AD, though individuals with AD may experience a higher frequency of local and systemic reactogenicity compared to those without AD.
o In a Phase 2 study in adults receiving 2 doses of Imvamune ® 4 weeks apart, solicited AEs (erythema, swelling, and systemic AEs) were more frequent in participants with AD compared to those without AD (61.2% vs 49.3%, 52.2% vs 40.8%, and 70.1% vs 56.4%, respectively), with the difference mostly due to events of mild to moderate severity. o In a Phase 1 study in adults receiving 2 doses of Imvamune ® 4 weeks apart, 7% of participants with active AD or a history of AD experienced a transient worsening of AD symptoms, but there was no indication or trend that could be detected that indicated that vaccination worsened the intensity of AD. o No deaths, cases of eczema vaccinatum (EV) or myopericarditis were observed.
o Immune responses (binding antibodies, neutralizing antibodies, seroconversion rates and CD8 T cell responses) were comparable between individuals with and without AD.
# ACKNOWLEDGEMENTS
This statement was prepared by: A Killikelly, N Brousseau, M Plamondon, R Krishnan, MY Yeung, N Forbes, R Harrison, S Deeks, MC Tunis, on behalf of NACI. | None | None |
2de8844c530680e5dc5f065f23821f64b70776df | cma | None | To provide a diagnostic approach to the evaluation of pregnant patients with a clinical suspicion of deep vein thrombosis (DVT) or pulmonary embolism (PE).Pregnancy is a well-established risk factor for venous thromboembolism (VTE). DVT complicates approximately 1 per 1,000 pregnancies, while PE complicates 0.5 per 1,000 pregnancies. VTE occurs in all trimesters of pregnancy and the postpartum period. The daily risk of VTE is increased 5-to 10-fold during pregnancy and 15-to 35-fold early after delivery compared to non-pregnant women of similar age. Although most studies have reported that the elevated risk of VTE returns to baseline by the end of the sixth postpartum week, there is evidence that a small residual increase in risk may persist for 12 weeks after delivery.The presentation of DVT in pregnancy differs from that in non-pregnant patients. The left leg is affected in >80% of cases and pregnant patients are much more likely to present with isolated iliac and/or femoral vein thrombosis, i.e. not arising by contiguous extension of a thrombus in the calf. These isolated iliofemoral thrombi often present with swelling of the entire leg with flank, buttock, or back pain rather than symptoms lower in the leg and carry a greater risk of post-thrombotic syndrome.#
Symptoms that mimic VTE, such as leg swelling, groin discomfort, and dyspnea are common in normal pregnancy. Therefore, the majority of pregnant women investigated for VTE (>90%) will not have VTE. However, the suspicion of VTE must be increased in patients with unilateral leg swelling (particularly of the left leg), previous history of VTE, family history of VTE, high risk thrombophilia, bedrest for 7 days (especially with increased body mass index) or medical illness. Since the consequences of failing to diagnose VTE in pregnancy are significant, the threshold for investigating pregnant women with suspected DVT or PE must be low. In addition, the consequences of assuming VTE is present when it is not are also significant because: 1) prolonged anticoagulation throughout pregnancy is costly, requires daily subcutaneous injection, and complicates delivery, 2) VTE prophylaxis with LMWH would be recommended in subsequent pregnancies, and 3) combined oral contraceptives would be subsequently contraindicated. Therefore, the investigation of DVT and PE in pregnancy must be safe both for mother and fetus and should accurately diagnose (or exclude) clinically significant VTE.
# INVESTIGATIVE STRATEGIES for DVT:
Although it has been shown that physicians are able to risk stratify pregnant women with suspected DVT using the LEFt rule (in which 1 point is provided for each of left leg symptoms, edema of affected leg with more than a 2 cm difference (between legs), and presentation in the first trimester of pregnancy), there have been no published management studies demonstrating the safety of using this rule alone or with D-dimer testing to exclude DVT in this patient population. A prospective validation of a diagnostic strategy to diagnose DVT during pregnancy using the LEFt rule is ongoing (NCT01708239). As a result, compression ultrasound is the first choice for investigation of DVT, as it is safe for mother and fetus and is readily available. Compression ultrasound should visualize the entire proximal venous system, including the iliac veins, to rule out DVT. However, good visualization of the iliac veins with compression ultrasound can be limited in many pregnant women. A recent metaanalysis found the false-negative frequency of a single leg ultrasound with iliac imaging in pregnant women with suspected DVT to be low, at less than 2%. However, the safety of performing only a single test has not been well validated in patient management studies so additional testing (as outlined in Figure 1) is generally recommended if the intial ultrasound is negative. In patients in whom the iliac system cannot be visualized and in whom symptoms are suggestive of isolated iliac vein thrombosis -such as whole leg swelling, buttock, back, or flank pain -magnetic resonance imaging (MRI) should be considered, if available. Direct thrombus imaging (MRDTI), if available, eliminates the need for gadolinium. Alternatively, if MRI is not available, anticoagulation should be started and compression ultrasound repeated in 2 to 3 days; at that time, if the iliac veins are visualized and there is no evidence of DVT, anticoagulants can be stopped. MRI can be safely carried out in pregnant patients although the exact specificity and sensitivity of this technique is unclear.
# INVESTIGATIVE STRATEGIES for PE:
Two prospective diagnostic management outcome studies investigating diagnostic algorithms for diagnosis of PE in during pregnancy were recently published. Taken together, these studies suggest Ddimer measurement and pretest probability calculation can be used to safely direct investigation of pregnant patients with suspected PE. The most recent study, the pregnancy-adapted YEARS protocol (see Figure 2), which was evaluated in 498 pregnant women with suspected PE, is the best validated method for diagnosing and excluding PE in pregnancy. The algorithm starts with performance of a sensitive D-dimer test and calculation of the YEARS score (3 items with one point assigned for each: clinical signs of DVT, hemoptysis, PE as most likely diagnosis). All women with clinical signs of DVT (the first criterion on the YEARS score) should undergo a single leg ultrasound. If DVT is diagnosed, therapeutic anticoagulation is started and testing stopped. Patients with a negative ultrasound and those not requiring ultrasound are evaluated according to their YEARS criteria. The D-dimer threshold for excluding PE is dependent on the number of YEARS criteria satisfied. For patients with one or more positive criteria, the threshold for performance of radiologic testing is 500 ng/mL, while for those with no positive criteria, the threshold is 1000 ng/mL. In the validation study, the 3-month false negative rate for this protocol was 0.21% (95% confidence interval, 0.04 -1.2%) and pulmonary diagnostic imaging was avoided in 39% of patients.
Use of D-dimers in pregnancy has been discouraged as D-dimers increase through normal pregnancy with highest levels in the 3 rd trimester. However, a systematic review and meta-analysis found Ddimers are highly sensitive to rule out VTE with a very high negative predictive value of 100% (95% confidence interval, 99.1 -100.0%). This further supports its use in diagnostic algorithm as described above. Options for diagnostic imaging include ventilation/perfusion (V/Q) lung scan and computed tomographic pulmonary angiography (CTPA). The calculated radiation risk to the fetus with V/Q scan is 0.5 mGy and for CTPA is 0.1 mGy, well below the threshold of 50 mGy associated with increased risk of fetal health problems. However, the calculated minimum radiation dose to each breast for an average 60 kg woman is significantly higher for CTPA (10 to 70 mGy, although that number can be reduced by approximately 20% with the use of bismuth breast shields) than for V/Q scan (<1.5 mGy, depending on technique), raising concerns of increased breast cancer risk in pregnant women exposed to CTPA. As a result, some physicians prefer V/Q scanning (especially in women with normal chest radiography), if available. In some centres, additional modifications of V/Q or CT techniques are available that can further reduce radiation exposure, so discussing with radiology and nuclear medicine can be helpful.
Investigation of suspected PE in pregnancy often creates anxiety in patients and physicians because of the radiation exposure to the mother and fetus. Clinical likelihood of PE, availability of timely imaging modalities, and patient preference should all be taken into consideration. It is essential that patients and physicians understand the risks and consequences of not pursuing imaging and that patients and physicians are accurately informed of the potential radiation risks to mother and fetus before decisions are made.
# SPECIAL CONSIDERATIONS:
If DVT or PE is suspected in the postpartum period, the patient should be investigated as in nonpregnant patients, remembering that the pretest probability will be higher as this is the highest risk time for VTE in pregnant patients. CT scan is safe in breastfeeding; however, radioisotopes used in V/Q scanning may contaminate breastmilk for 24-48 hrs.
# OTHER RELEVANT THROMBOSIS CANADA GUIDES:
- Deep Vein Thrombosis: Diagnosis - Pregnancy: Thromboprophylaxis - Pregnancy: Venous Thromboembolism Treatment - Pulmonary Embolism: Diagnosis
# Date of version: 14Sept2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein. | To provide a diagnostic approach to the evaluation of pregnant patients with a clinical suspicion of deep vein thrombosis (DVT) or pulmonary embolism (PE).Pregnancy is a well-established risk factor for venous thromboembolism (VTE). DVT complicates approximately 1 per 1,000 pregnancies, while PE complicates 0.5 per 1,000 pregnancies. VTE occurs in all trimesters of pregnancy and the postpartum period. The daily risk of VTE is increased 5-to 10-fold during pregnancy and 15-to 35-fold early after delivery compared to non-pregnant women of similar age. Although most studies have reported that the elevated risk of VTE returns to baseline by the end of the sixth postpartum week, there is evidence that a small residual increase in risk may persist for 12 weeks after delivery.The presentation of DVT in pregnancy differs from that in non-pregnant patients. The left leg is affected in >80% of cases and pregnant patients are much more likely to present with isolated iliac and/or femoral vein thrombosis, i.e. not arising by contiguous extension of a thrombus in the calf. These isolated iliofemoral thrombi often present with swelling of the entire leg with flank, buttock, or back pain rather than symptoms lower in the leg and carry a greater risk of post-thrombotic syndrome.#
Symptoms that mimic VTE, such as leg swelling, groin discomfort, and dyspnea are common in normal pregnancy. Therefore, the majority of pregnant women investigated for VTE (>90%) will not have VTE. However, the suspicion of VTE must be increased in patients with unilateral leg swelling (particularly of the left leg), previous history of VTE, family history of VTE, high risk thrombophilia, bedrest for 7 days (especially with increased body mass index) or medical illness. Since the consequences of failing to diagnose VTE in pregnancy are significant, the threshold for investigating pregnant women with suspected DVT or PE must be low. In addition, the consequences of assuming VTE is present when it is not are also significant because: 1) prolonged anticoagulation throughout pregnancy is costly, requires daily subcutaneous injection, and complicates delivery, 2) VTE prophylaxis with LMWH would be recommended in subsequent pregnancies, and 3) combined oral contraceptives would be subsequently contraindicated. Therefore, the investigation of DVT and PE in pregnancy must be safe both for mother and fetus and should accurately diagnose (or exclude) clinically significant VTE.
# INVESTIGATIVE STRATEGIES for DVT:
Although it has been shown that physicians are able to risk stratify pregnant women with suspected DVT using the LEFt rule (in which 1 point is provided for each of left leg symptoms, edema of affected leg with more than a 2 cm difference (between legs), and presentation in the first trimester of pregnancy), there have been no published management studies demonstrating the safety of using this rule alone or with D-dimer testing to exclude DVT in this patient population. A prospective validation of a diagnostic strategy to diagnose DVT during pregnancy using the LEFt rule is ongoing (NCT01708239). As a result, compression ultrasound is the first choice for investigation of DVT, as it is safe for mother and fetus and is readily available. Compression ultrasound should visualize the entire proximal venous system, including the iliac veins, to rule out DVT. However, good visualization of the iliac veins with compression ultrasound can be limited in many pregnant women. A recent metaanalysis found the false-negative frequency of a single leg ultrasound with iliac imaging in pregnant women with suspected DVT to be low, at less than 2%. However, the safety of performing only a single test has not been well validated in patient management studies so additional testing (as outlined in Figure 1) is generally recommended if the intial ultrasound is negative. In patients in whom the iliac system cannot be visualized and in whom symptoms are suggestive of isolated iliac vein thrombosis -such as whole leg swelling, buttock, back, or flank pain -magnetic resonance imaging (MRI) should be considered, if available. Direct thrombus imaging (MRDTI), if available, eliminates the need for gadolinium. Alternatively, if MRI is not available, anticoagulation should be started and compression ultrasound repeated in 2 to 3 days; at that time, if the iliac veins are visualized and there is no evidence of DVT, anticoagulants can be stopped. MRI can be safely carried out in pregnant patients although the exact specificity and sensitivity of this technique is unclear.
# INVESTIGATIVE STRATEGIES for PE:
Two prospective diagnostic management outcome studies investigating diagnostic algorithms for diagnosis of PE in during pregnancy were recently published. Taken together, these studies suggest Ddimer measurement and pretest probability calculation can be used to safely direct investigation of pregnant patients with suspected PE. The most recent study, the pregnancy-adapted YEARS protocol (see Figure 2), which was evaluated in 498 pregnant women with suspected PE, is the best validated method for diagnosing and excluding PE in pregnancy. The algorithm starts with performance of a sensitive D-dimer test and calculation of the YEARS score (3 items with one point assigned for each: clinical signs of DVT, hemoptysis, PE as most likely diagnosis). All women with clinical signs of DVT (the first criterion on the YEARS score) should undergo a single leg ultrasound. If DVT is diagnosed, therapeutic anticoagulation is started and testing stopped. Patients with a negative ultrasound and those not requiring ultrasound are evaluated according to their YEARS criteria. The D-dimer threshold for excluding PE is dependent on the number of YEARS criteria satisfied. For patients with one or more positive criteria, the threshold for performance of radiologic testing is 500 ng/mL, while for those with no positive criteria, the threshold is 1000 ng/mL. In the validation study, the 3-month false negative rate for this protocol was 0.21% (95% confidence interval, 0.04 -1.2%) and pulmonary diagnostic imaging was avoided in 39% of patients.
Use of D-dimers in pregnancy has been discouraged as D-dimers increase through normal pregnancy with highest levels in the 3 rd trimester. However, a systematic review and meta-analysis found Ddimers are highly sensitive to rule out VTE with a very high negative predictive value of 100% (95% confidence interval, 99.1 -100.0%). This further supports its use in diagnostic algorithm as described above. Options for diagnostic imaging include ventilation/perfusion (V/Q) lung scan and computed tomographic pulmonary angiography (CTPA). The calculated radiation risk to the fetus with V/Q scan is 0.5 mGy and for CTPA is 0.1 mGy, well below the threshold of 50 mGy associated with increased risk of fetal health problems. However, the calculated minimum radiation dose to each breast for an average 60 kg woman is significantly higher for CTPA (10 to 70 mGy, although that number can be reduced by approximately 20% with the use of bismuth breast shields) than for V/Q scan (<1.5 mGy, depending on technique), raising concerns of increased breast cancer risk in pregnant women exposed to CTPA. As a result, some physicians prefer V/Q scanning (especially in women with normal chest radiography), if available. In some centres, additional modifications of V/Q or CT techniques are available that can further reduce radiation exposure, so discussing with radiology and nuclear medicine can be helpful.
Investigation of suspected PE in pregnancy often creates anxiety in patients and physicians because of the radiation exposure to the mother and fetus. Clinical likelihood of PE, availability of timely imaging modalities, and patient preference should all be taken into consideration. It is essential that patients and physicians understand the risks and consequences of not pursuing imaging and that patients and physicians are accurately informed of the potential radiation risks to mother and fetus before decisions are made.
# SPECIAL CONSIDERATIONS:
If DVT or PE is suspected in the postpartum period, the patient should be investigated as in nonpregnant patients, remembering that the pretest probability will be higher as this is the highest risk time for VTE in pregnant patients. CT scan is safe in breastfeeding; however, radioisotopes used in V/Q scanning may contaminate breastmilk for 24-48 hrs.
# OTHER RELEVANT THROMBOSIS CANADA GUIDES:
• Deep Vein Thrombosis: Diagnosis • Pregnancy: Thromboprophylaxis • Pregnancy: Venous Thromboembolism Treatment • Pulmonary Embolism: Diagnosis
# Date of version: 14Sept2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein. | None | None |
7cbedaaa8fbfd90fc8dd7ea73c451c34ea512161 | cma | None | To describe the indication for a vena cava filter (VCF), the most common and important associated complications, and the practical management of patients who have a VCF placed.Appropriately placed VCFs are designed to reduce the frequency of significant pulmonary embolism (PE) by trapping thromboemboli arising in the deep veins of the lower extremities before they reach the lungs.Use of a VCF should be considered judiciously given the lack of high-quality evidence that they prevent clinically important PE.#
VCFs are indicated in patients with a recently diagnosed (usually within 4 weeks) acute proximal DVT or acute PE in whom there is a contraindication to anticoagulation. If acute proximal DVT is not present, then a decision on the need for VCF should be taken on a case-by-case basis in consultation with a physician with thrombosis medicine expertise.
VCF placement can also be considered in select hemodynamically unstable patients with acute DVT (in shock or ventilatory support) in addition to other advanced therapies (thrombolysis, thrombectomy, embolectomy) particularly where there is a concern that endovenous intervention may lead to iatrogenic PE.
# WE DO NOT SUPPORT PLACING
# POST-VCF INSERTION MANAGEMENT:
1) Anticoagulation should be initiated to prevent extension of the DVT as soon as it is safe to do so.
2) Virtually all VCFs should be removed shortly after the patient is able to tolerate appropriate anticoagulation. The longer a filter is left in situ, the lower the success of retrieval and the higher the risk of long-term complications. 3) Retrieval may be most successful if attempted within 9-12 weeks post insertion. More recent filters can be retrieved six or more months after placement.
4) A documented plan for retrieval of the VCF should be made at the time of filter insertion. If a VCF is not removed, the patient requires regular, long-term monitoring of clinical status and filter integrity, in addition to possibly long-term anticoagulation (see below). 5) Maintenance of patients on therapeutic anticoagulation should be considered at the time of retrieval and at experienced centers this has not been associated with increased risk of retrieval complications.
# SPECIAL CONSIDERATIONS:
- Very limited evidence supports the use of VCFs and there is no evidence that filters prevent fatal PE. They are also associated with an increased risk of DVT. - The duration of anticoagulation is generally not affected by the presence of a VCF. Patients require anticoagulation for the appropriate duration for the DVT and not just because they have a filter in place. However, this area is controversial and there is no consensus -some clinicians continue anticoagulation long-term in patients with a VCF while others stop anticoagulants once the patients have completed the appropriate duration of anticoagulation for the DVT. - There are few studies of VCFs in children.
# Date of Version: 06July2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein. | To describe the indication for a vena cava filter (VCF), the most common and important associated complications, and the practical management of patients who have a VCF placed.Appropriately placed VCFs are designed to reduce the frequency of significant pulmonary embolism (PE) by trapping thromboemboli arising in the deep veins of the lower extremities before they reach the lungs.Use of a VCF should be considered judiciously given the lack of high-quality evidence that they prevent clinically important PE.#
VCFs are indicated in patients with a recently diagnosed (usually within 4 weeks) acute proximal DVT or acute PE in whom there is a contraindication to anticoagulation. If acute proximal DVT is not present, then a decision on the need for VCF should be taken on a case-by-case basis in consultation with a physician with thrombosis medicine expertise.
VCF placement can also be considered in select hemodynamically unstable patients with acute DVT (in shock or ventilatory support) in addition to other advanced therapies (thrombolysis, thrombectomy, embolectomy) particularly where there is a concern that endovenous intervention may lead to iatrogenic PE.
# WE DO NOT SUPPORT PLACING
# POST-VCF INSERTION MANAGEMENT:
1) Anticoagulation should be initiated to prevent extension of the DVT as soon as it is safe to do so.
2) Virtually all VCFs should be removed shortly after the patient is able to tolerate appropriate anticoagulation. The longer a filter is left in situ, the lower the success of retrieval and the higher the risk of long-term complications. 3) Retrieval may be most successful if attempted within 9-12 weeks post insertion. More recent filters can be retrieved six or more months after placement.
4) A documented plan for retrieval of the VCF should be made at the time of filter insertion. If a VCF is not removed, the patient requires regular, long-term monitoring of clinical status and filter integrity, in addition to possibly long-term anticoagulation (see below). 5) Maintenance of patients on therapeutic anticoagulation should be considered at the time of retrieval and at experienced centers this has not been associated with increased risk of retrieval complications.
# SPECIAL CONSIDERATIONS:
• Very limited evidence supports the use of VCFs and there is no evidence that filters prevent fatal PE. They are also associated with an increased risk of DVT. • The duration of anticoagulation is generally not affected by the presence of a VCF. Patients require anticoagulation for the appropriate duration for the DVT and not just because they have a filter in place. However, this area is controversial and there is no consensus -some clinicians continue anticoagulation long-term in patients with a VCF while others stop anticoagulants once the patients have completed the appropriate duration of anticoagulation for the DVT. • There are few studies of VCFs in children.
# Date of Version: 06July2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein. | None | None |
d5eb64985e6c3b0d9562c18198e7752ef0fe14c4 | cma | None | A position statement developed by the Canadian Psychiatric Association's (CPA) Research Committee and approved by the CPA's Board of Directors on May 13, 2020.#
The Canadian Psychiatric Association (CPA; www.cpaapc.org) is the professional association for over 4,700 psychiatrists and 900 psychiatry residents in Canada. In addressing its mission, the CPA uses evidence-based methods to not only educate and inform the public and its own membership but also to develop mental health programs, services and policies.
In response to the federal government legalizing and regulating access to cannabis in 2017, the CPA published a position statement with respect to cannabis use and adverse health consequences in youth and young adults 1 based on the accumulating evidence of negative consequences of early sustained use (e.g., National Academies of Sciences and Medicine, 2017). 2 However, psychiatrists and other mental health professionals are also being asked about the potential therapeutic uses of cannabis and cannabinoid products for mental illnesses; information is widely distributed on cannabis use being associated with mental wellness and suggesting cannabis use as a treatment for a variety of mental health concerns. As the CPA is evidence based, it is prudent to examine the existing research in this area to inform our membership needs and thus the public.
In Canada, before a new medication can be approved (or, an existing medication can be prescribed to treat a previously unrecognized condition), it must pass through Health Canada's regulatory approval process. As part of this process, clinical trial data must show a positive therapeutic effect on symptoms and that this effect is not associated with significant risks (e.g., potential side effects). For therapeutic indications and clinical decision making, Level 1 evidence is usually required. Level 1 evidence includes systematic reviews of randomized control trials (RCTs) or high-quality individual RCTs (see Centre for Evidence-based Medicine for details, http:// www.cebm.net.)
The CPA has systematically reviewed the existing literature on RCTs examining potential beneficial uses of cannabis and cannabinoid products to treat mental illness. This review incorporated studies in adults only (greater than 18 years old). Of the 1,982 papers identified, 29 RCTs were available to review (see Figure 1 for systematic review flow diagram). Methodological quality for each study was assessed using Cochrane Collaboration guidelines. 3 The 29 publications were in the following clinical areas: anxiety disorders (three RCTs), posttraumatic stress disorder (one RCT), 7 psychotic disorders (six RCTs), anorexia nervosa (two RCTs), 14,15 cannabis dependence management (nine RCTs), The Canadian Psychiatric Association-Position Statement nicotine/opioid dependence (five RCTs), attentiondeficit hyperactivity disorder (one RCT) 30 and Tourette's disorder (two RCTs). 31,32 The clinical trials identified followed accepted designs (parallel or crossover design methodology); however, sample sizes were relatively small in most of the RCTs, which weakens the conclusions, and they evaluated a variety of naturally derived and synthetic tetrahydrocannabinol (THC; e.g., nabilone, dronabinol, nabiximols) and cannabidiol products at varying doses across studies, making comparisons difficult. Results were often not specific to the primary psychiatric symptoms that the trial was designed to address. Of note, no studies used combustible dried cannabis or cannabis edibles. Results of some studies showed atypical doseresponse effects. Also, there were no RCTs investigating the potential benefits of cannabinoid products in major depressive disorder (i.e., clinical level depression) or bipolar disorders. While different inclusion and exclusion criteria were used for manuscript selection, the results discussed here are comparable to another recent systematic review and meta-analysis on this topic. 33 With respect to the use of cannabis and cannabinoid products in mental illness, based on the current evidence, the CPA: | A position statement developed by the Canadian Psychiatric Association's (CPA) Research Committee and approved by the CPA's Board of Directors on May 13, 2020.#
The Canadian Psychiatric Association (CPA; www.cpaapc.org) is the professional association for over 4,700 psychiatrists and 900 psychiatry residents in Canada. In addressing its mission, the CPA uses evidence-based methods to not only educate and inform the public and its own membership but also to develop mental health programs, services and policies.
In response to the federal government legalizing and regulating access to cannabis in 2017, the CPA published a position statement with respect to cannabis use and adverse health consequences in youth and young adults 1 based on the accumulating evidence of negative consequences of early sustained use (e.g., National Academies of Sciences and Medicine, 2017). 2 However, psychiatrists and other mental health professionals are also being asked about the potential therapeutic uses of cannabis and cannabinoid products for mental illnesses; information is widely distributed on cannabis use being associated with mental wellness and suggesting cannabis use as a treatment for a variety of mental health concerns. As the CPA is evidence based, it is prudent to examine the existing research in this area to inform our membership needs and thus the public.
In Canada, before a new medication can be approved (or, an existing medication can be prescribed to treat a previously unrecognized condition), it must pass through Health Canada's regulatory approval process. As part of this process, clinical trial data must show a positive therapeutic effect on symptoms and that this effect is not associated with significant risks (e.g., potential side effects). For therapeutic indications and clinical decision making, Level 1 evidence is usually required. Level 1 evidence includes systematic reviews of randomized control trials (RCTs) or high-quality individual RCTs (see Centre for Evidence-based Medicine for details, http:// www.cebm.net.)
The CPA has systematically reviewed the existing literature on RCTs examining potential beneficial uses of cannabis and cannabinoid products to treat mental illness. This review incorporated studies in adults only (greater than 18 years old). Of the 1,982 papers identified, 29 RCTs were available to review (see Figure 1 for systematic review flow diagram). Methodological quality for each study was assessed using Cochrane Collaboration guidelines. 3 The 29 publications were in the following clinical areas: anxiety disorders (three RCTs), [4][5][6] posttraumatic stress disorder (one RCT), 7 psychotic disorders (six RCTs), [8][9][10][11][12][13] anorexia nervosa (two RCTs), 14,15 cannabis dependence management (nine RCTs), [16][17][18][19][20][21][22][23][24] The Canadian Psychiatric Association-Position Statement nicotine/opioid dependence (five RCTs), [25][26][27][28][29] attentiondeficit hyperactivity disorder (one RCT) 30 and Tourette's disorder (two RCTs). 31,32 The clinical trials identified followed accepted designs (parallel or crossover design methodology); however, sample sizes were relatively small in most of the RCTs, which weakens the conclusions, and they evaluated a variety of naturally derived and synthetic tetrahydrocannabinol (THC; e.g., nabilone, dronabinol, nabiximols) and cannabidiol products at varying doses across studies, making comparisons difficult. Results were often not specific to the primary psychiatric symptoms that the trial was designed to address. Of note, no studies used combustible dried cannabis or cannabis edibles. Results of some studies showed atypical doseresponse effects. Also, there were no RCTs investigating the potential benefits of cannabinoid products in major depressive disorder (i.e., clinical level depression) or bipolar disorders. While different inclusion and exclusion criteria were used for manuscript selection, the results discussed here are comparable to another recent systematic review and meta-analysis on this topic. 33 With respect to the use of cannabis and cannabinoid products in mental illness, based on the current evidence, the CPA:
Acknowledges there are no current Health Canadaapproved indications for use of cannabis or cannabinoid products for the treatment of mental illness.
Acknowledges there is some limited evidence for use of cannabinoid products (excluding combustible dried cannabis and cannabis edibles) for the treatment of mental illness, but the evidence base is currently of low-quality and below that required to meet Level 1 evidence. Strongly discourages cannabis and cannabinoid product use by anyone experiencing mental illness. Use of cannabis or a cannabinoid product should never delay (or replace) more evidence-based forms of treatment. We encourage patients to discuss potential harms of use with their treating physician.
Recommends that mental health care professionals should approach counselling around cannabinoidbased treatments with appropriate caution given the known side effects and lack of positive RCTs.
Recommends that any discussion of the potential therapeutic benefit of cannabinoid products be balanced with the risk for adverse outcomes (e.g., worsening of the underlying illness, addiction, cognitive impairment) and should be within the context of the methodology of the current RCTs, which includes carefully chosen cannabinoid products, dosing, side effect monitoring and regimented drug administration.
To better assess whether cannabinoid-based products have any therapeutic value, larger neuroscience-based, hypothesis-driven RCTs are needed and should include varying lower risk products (e.g., low THC concentration), dose ranges and routes of administration. Narrowing the knowledge gap with high-quality RCTs should be a priority for all stakeholders.
Recommends that agencies (e.g., provincial/federal governments, nonprofit organizations) address the apparent disconnect between popular public opinion and the lack of available high-level research evidence supporting the therapeutic uses of cannabinoid products in mental illness.
# Reconnaissance
Les auteurs remercient D re Annie Trépannier pour ses suggestions et son aide dans la préparation de la version française de cette déclaration de principe. | None | None |
93e54bd508ee1f355d03e6caf68db383c119f5d3 | cma | None | The Canadian Rheumatology Association (CRA) is committed to supporting its members in their efforts to continue to deliver optimal care for their patients with rheumatic diseases. At the same time, the CRA acknowledges the gravity of the situation with the COVID-19 pandemic and the importance of identifying effective treatments in a timely and scientific manner. The identification of hydroxychloroquine (HCQ) as a possible treatment for COVID-19 has led to significant off-label use, which now threatens access for patients with lupus and other types of inflammatory rheumatic disease who are reliant on this medication for disease control.#
Although the CRA supports ongoing study for effective treatment for COVID-19, it calls for priority access to HCQ for patients with rheumatic conditions (including lupus and certain types of inflammatory arthritis) to treat these chronic diseases. The CRA further urges policy makers, regulators, and industry to work together to increase Canada's supply of HCQ to meet the higher demand.
# Recent Related Statements:
- Joint Statement on Use of HCQ and Azithromycin for COVID-19 from OMA, OPA and RNAO" The purpose of this position statement is to advocate for priority access of hydroxychloroquine for patients with rheumatic conditions while at the same time encouraging continued study and increased production of hydroxychloroquine to address the current higher demands for the drug due to the COVID-19 pandemic.
# What is the CRA's position regarding the use of hydroxychloroquine as a possible treatment for COVID-19?
The CRA's position statement on COVID-19 and hydroxychloroquine supply is available in full on our website. To summarize:
- Rheumatologists need to be able to continue to provide the best care possible for individual patients while also considering the well-being of society as a whole. As such, decisions about the ongoing allocation of hydroxychloroquine supply should also incorporate recommendations from rheumatologists who are experts in treatment with hydroxychloroquine for rheumatologic diseases, for which the medication is approved by Health Canada.
- It is imperative that every effort is made to ensure an adequate supply of hydroxychloroquine for all patients and that there is no interruption in patient care for people living with lupus or other types of inflammatory rheumatic disease.
- The Canadian Rheumatology Association continues to monitor the data available regarding the safety and efficacy of hydroxychloroquine as a possible treatment for COVID-19, and will provide further updates to this position statement as needed.
# Why is/was there a concern regarding the use of hydroxychloroquine?
Hydroxychloroquine has demonstrated antiviral activity against SARS-CoV-2 in tissue culture. These findings, as well as its relative tolerability in patients taking the drug for
# RHEUM.CA
Health Canada-approved indications, have raised interest in these agents as potential therapeutic options in the current COVID-19 pandemic. 1 2 3
Although the CRA supports ongoing study for effective treatment for COVID-19, it calls for priority access to hydroxychloroquine for patients with rheumatic conditions (including lupus and certain types of inflammatory arthritis) to treat these chronic diseases. The CRA further urges policy makers, regulators, and industry to work together to increase Canada's supply of hydroxychloroquine to meet the higher demand and to ensure an adequate supply of hydroxychloroquine for all patients who need it.
# What role does the CRA play in the advocacy for additional supply?
In providing this position statement, the CRA is advocating for increased supply to meet the higher demands of hydroxychloroquine during the COVID-19 pandemic. We hope that this can influence stakeholders including policy makers, regulators and the pharmaceutical industry to work together to increase Canada's supply of hydroxychloroquine.
The CRA's mission is to promote the pursuit of excellence in arthritis and rheumatic disease care. One of the ways it does this is by ensuring that CRA members and their patients are in possession of up-to-date guidance regarding access to medications so informed and appropriate treatment decisions may be made. Furthermore, the CRA works closely with key stakeholders including government officials, disease and patient groups and other national and provincial medical associations to both inform their decision making and to help guide our approach.
# Who was involved in the development of the position statement?
The position statement was developed by the CRA Therapeutics Committee and reviewed and approved by the CRA Board of Directors so that they can offer up-to-date guidance regarding access to hydroxychloroquine during these exceptional times.
# How exactly is hydroxychloroquine used in rheumatology?
Hydroxychloroquine is a disease-modifying anti-rheumatic drug (DMARD). This drug, either as monotherapy or in combination therapy, is used to suppress or control rheumatic disease. Hydroxychloroquine is an essential medicine for patients with lupus. It is also a mainstay of therapy for many patients with rheumatoid arthritis. In addition, it is used to RHEUM.CA treat other connective tissue diseases such as Sjogren's syndrome and dermatomyositis. It is the only medication shown to increase survival in patients with systemic lupus erythematosus (SLE) and has been shown to reduce SLE flares and prevent organ damage including cardiovascular events. 1. In SLE, it was demonstrated that stopping hydroxychloroquine resulted in over twice the risk of disease flare in patients 4 .
The use of hydroxychloroquine in SLE and RA is supported by many guidelines worldwide.
# What is the difference between a guideline, a consensus statement and a position statement?
The CRA classifies its guidance into clinical practice guidelines and position statements. Clinical practice guidelines follow international standards for best practice and provide recommendations for best practice based on the latest evidence. A position statement is a document that outlines CRA's stance on a topic relevant to its membership. They are generally developed as a quick response to emerging or controversial issues. Although there is usually insufficient time to adopt the same rigorous approach as clinical practice guidelines, position statements still refer to appropriate evidence-based literature and must be approved by the CRA prior to being released.
- Will this position statement be included in new CRA guidelines when they are developed?
As our guidelines are updated, new information will always be considered as part of the review process.
# How often will you update this position statement?
The position statement will be updated when new information or clinical evidence becomes available. | The Canadian Rheumatology Association (CRA) is committed to supporting its members in their efforts to continue to deliver optimal care for their patients with rheumatic diseases. At the same time, the CRA acknowledges the gravity of the situation with the COVID-19 pandemic and the importance of identifying effective treatments in a timely and scientific manner. The identification of hydroxychloroquine (HCQ) as a possible treatment for COVID-19 has led to significant off-label use, which now threatens access for patients with lupus and other types of inflammatory rheumatic disease who are reliant on this medication for disease control.#
Although the CRA supports ongoing study for effective treatment for COVID-19, it calls for priority access to HCQ for patients with rheumatic conditions (including lupus and certain types of inflammatory arthritis) to treat these chronic diseases. The CRA further urges policy makers, regulators, and industry to work together to increase Canada's supply of HCQ to meet the higher demand.
# Recent Related Statements:
• Joint Statement on Use of HCQ and Azithromycin for COVID-19 from OMA, OPA and RNAO" The purpose of this position statement is to advocate for priority access of hydroxychloroquine for patients with rheumatic conditions while at the same time encouraging continued study and increased production of hydroxychloroquine to address the current higher demands for the drug due to the COVID-19 pandemic.
# What is the CRA's position regarding the use of hydroxychloroquine as a possible treatment for COVID-19?
The CRA's position statement on COVID-19 and hydroxychloroquine supply is available in full on our website. To summarize:
• Rheumatologists need to be able to continue to provide the best care possible for individual patients while also considering the well-being of society as a whole. As such, decisions about the ongoing allocation of hydroxychloroquine supply should also incorporate recommendations from rheumatologists who are experts in treatment with hydroxychloroquine for rheumatologic diseases, for which the medication is approved by Health Canada.
• It is imperative that every effort is made to ensure an adequate supply of hydroxychloroquine for all patients and that there is no interruption in patient care for people living with lupus or other types of inflammatory rheumatic disease.
• The Canadian Rheumatology Association continues to monitor the data available regarding the safety and efficacy of hydroxychloroquine as a possible treatment for COVID-19, and will provide further updates to this position statement as needed.
# Why is/was there a concern regarding the use of hydroxychloroquine?
Hydroxychloroquine has demonstrated antiviral activity against SARS-CoV-2 in tissue culture. These findings, as well as its relative tolerability in patients taking the drug for
# RHEUM.CA
Health Canada-approved indications, have raised interest in these agents as potential therapeutic options in the current COVID-19 pandemic. 1 2 3
Although the CRA supports ongoing study for effective treatment for COVID-19, it calls for priority access to hydroxychloroquine for patients with rheumatic conditions (including lupus and certain types of inflammatory arthritis) to treat these chronic diseases. The CRA further urges policy makers, regulators, and industry to work together to increase Canada's supply of hydroxychloroquine to meet the higher demand and to ensure an adequate supply of hydroxychloroquine for all patients who need it.
# What role does the CRA play in the advocacy for additional supply?
In providing this position statement, the CRA is advocating for increased supply to meet the higher demands of hydroxychloroquine during the COVID-19 pandemic. We hope that this can influence stakeholders including policy makers, regulators and the pharmaceutical industry to work together to increase Canada's supply of hydroxychloroquine.
The CRA's mission is to promote the pursuit of excellence in arthritis and rheumatic disease care. One of the ways it does this is by ensuring that CRA members and their patients are in possession of up-to-date guidance regarding access to medications so informed and appropriate treatment decisions may be made. Furthermore, the CRA works closely with key stakeholders including government officials, disease and patient groups and other national and provincial medical associations to both inform their decision making and to help guide our approach.
# Who was involved in the development of the position statement?
The position statement was developed by the CRA Therapeutics Committee and reviewed and approved by the CRA Board of Directors so that they can offer up-to-date guidance regarding access to hydroxychloroquine during these exceptional times.
# How exactly is hydroxychloroquine used in rheumatology?
Hydroxychloroquine is a disease-modifying anti-rheumatic drug (DMARD). This drug, either as monotherapy or in combination therapy, is used to suppress or control rheumatic disease. Hydroxychloroquine is an essential medicine for patients with lupus. It is also a mainstay of therapy for many patients with rheumatoid arthritis. In addition, it is used to RHEUM.CA treat other connective tissue diseases such as Sjogren's syndrome and dermatomyositis. It is the only medication shown to increase survival in patients with systemic lupus erythematosus (SLE) and has been shown to reduce SLE flares and prevent organ damage including cardiovascular events. 1. In SLE, it was demonstrated that stopping hydroxychloroquine resulted in over twice the risk of disease flare in patients 4 .
The use of hydroxychloroquine in SLE and RA is supported by many guidelines worldwide.
# What is the difference between a guideline, a consensus statement and a position statement?
The CRA classifies its guidance into clinical practice guidelines and position statements. Clinical practice guidelines follow international standards for best practice and provide recommendations for best practice based on the latest evidence. A position statement is a document that outlines CRA's stance on a topic relevant to its membership. They are generally developed as a quick response to emerging or controversial issues. Although there is usually insufficient time to adopt the same rigorous approach as clinical practice guidelines, position statements still refer to appropriate evidence-based literature and must be approved by the CRA prior to being released.
8. Will this position statement be included in new CRA guidelines when they are developed?
As our guidelines are updated, new information will always be considered as part of the review process.
# How often will you update this position statement?
The position statement will be updated when new information or clinical evidence becomes available. | None | None |
88b5b9059fbe1b726c3d66add3728239f70b35f8 | cma | None | To describe the effect of the newer direct oral anticoagulants (DOACs) on routine laboratory coagulation tests: prothrombin time (PT), international normalized ratio (INR), activated partial thromboplastin time (aPTT), and thrombin clotting time (TCT). - To describe tests used to accurately quantify DOAC levels. - To discuss how clinicians should use and interpret coagulation tests in patients taking a DOAC who are bleeding or require elective surgery or an invasive procedure.Four DOACs, a direct thrombin inhibitor (dabigatran) and three direct factor Xa inhibitors (apixaban, edoxaban, and rivaroxaban) are approved for clinical use in Canada for various indications, based on findings from large randomized trials.The effects of DOACs on routine laboratory coagulation tests are summarized in Table 1. The international normalized ratio (INR) and the international sensitivity index (ISI) used in the INR calculation are based on vitamin K antagonist sensitivity not DOAC sensitivity, laboratories may consider reporting the PT (seconds) in addition to the INR.#
No effect ¶ Results will vary according to the PT or aPTT reagent used and its sensitivity to the DOAC. A doseresponse curve of PT and aPTT using dabigatran, apixaban, edoxaban, and rivaroxaban calibrators may assist in the local interpretation of these assays. † Drug overdose or bioaccumulation may elevate the PT and aPTT. ‡ TCT is very sensitive to presence of dabigatran and even low (potentially negligible) plasma levels may lead to elevated TCT results. - Reagent and dose dependent
# EFFECT OF DABIGATRAN ON COAGULATION TESTS:
There is currently no routinely available laboratory test that can reliably assess the anticoagulant effect of dabigatran in a manner similar to how the INR is used to assess adequacy of warfarin therapy or how the aPTT is used to monitor intravenous (IV) unfractionated heparin (UFH) therapy. Therefore, these laboratory tests should NOT be used to monitor the anticoagulant effect of dabigatran.
- Dabigatran is a direct thrombin inhibitor. It has a peak effect 1-3 hours after oral intake and, if testing is done within this time period, it often leads to an elevated PT/INR, aPTT and TCT. For example, soon after dabigatran intake, the INR may be slightly elevated to ~1.5-1.8 (normal: 0.8-1.2), the aPTT may be elevated to greater than twice the upper limit of the laboratory's reference range and the TCT will usually be markedly elevated above the laboratory reference range. After this peak effect period, the effect of dabigatran on the PT/INR and aPTT diminishes, although there will be a prolonged effect on the TCT, which is the most sensitive test to detect the anticoagulant effect of dabigatran. - The relationship between dabigatran anticoagulant effect and any of the routine laboratory tests of coagulation is variable, depending on the reagent sensitivity. - Commercially available dilute thrombin time (dTT) assays, Ecarin-based assays or chromogenic anti-Factor IIa assays can be used to quantify the anticoagulant effect of dabigatran and may be considered for patients. However, these assays are not widely available and there are not yet established therapeutic reference intervals for interpreting test results.
# WHAT DO NORMAL COAGULATION TESTS MEAN IN DABIGATRAN-TREATED PATIENTS?
- In some dabigatran-treated patients, the aPTT remains normal in the presence of dabigatran in the on-therapy range. - A normal TCT excludes the presence of significant dabigatran concentrations and is the most sensitive way to completely exclude residual effect of dabigatran; however, the TCT may be elevated in the presence of clinically insignificant levels of dabigatran, sometimes for a prolonged period of time following last dose of dabigatran. Moreover, the TCT is not a widely available test.
# EFFECT OF APIXABAN, EDOXABAN, AND RIVAROXABAN ON COAGULATION TESTS:
There is currently no routinely available laboratory test that can reliably assess the anticoagulant effect of apixaban, edoxaban, and rivaroxaban in a manner similar to how the INR is used to assess the adequacy of warfarin therapy or how the aPTT is used to monitor IV UFH therapy. Therefore, these laboratory tests should NOT be used to monitor the anticoagulant effect of apixaban, edoxaban, or rivaroxaban.
- Apixaban, edoxaban, and rivaroxaban are factor Xa inhibitors. Edoxaban and rivaroxaban may affect the PT/INR and aPTT but have no effect on the TCT. Apixaban has a minimal effect on PT/INR and aPTT and no effect on the TCT. However, the effect on the PT/INR is variable, depending on the sensitivity of the PT or aPTT reagent used. - Apixaban achieves peak plasma concentration approximately 3 hours after ingestion. Even if testing is done at this time, the effect of apixaban on PT/INR and aPTT is much less pronounced than for edoxaban and rivaroxaban and these tests are not useful to assess the intensity of apixaban's anticoagulant effect. TCT is not affected. - Edoxaban has a peak effect approximately 1-2 hours after ingestion. It prolongs PT/INR and aPTT in a dose dependent manner but both assays are insufficiently sensitive at low therapeutic levels and edoxaban effect is reagent-dependent. Therefore, a normal PT/INR or aPTT does not exclude the presence of on therapy or greater edoxaban concentrations. TCT is not affected. - Rivaroxaban has a peak effect 1-3 hours after oral intake and, if testing is done within this time, it often leads to an elevated PT/INR and aPTT. For example, soon after oral intake, the PT may be elevated to greater than twice the upper limit of the laboratory's reference range and the aPTT may be slightly elevated. After this peak effect, the effect of rivaroxaban on PT/INR and aPTT diminishes but there may be a residual effect on these tests even at trough levels (24 hours after last intake). A normal PT/INR or aPTT does not exclude the presence of on therapy or greater rivaroxaban concentrations. TCT is not affected. - Specific anti-Xa assays with drug-specific calibrators (different than those used to assess low molecular weight heparin activity) can be used to quantify the anticoagulant effect of apixaban, edoxaban, and rivaroxaban. However, these tests are not widely available and there are no established therapeutic reference intervals for interpreting test results. Anti-Xa assays calibrated for LMWHs or UFH should NOT be used to assess for the anticoagulant effect of apixaban, edoxaban, or rivaroxaban. In addition, antithrombin supplemented anti-factor Xa methods should not be used as these methods tend to overestimate DOAC levels and are not validated by the manufacturers.
# WHAT DO NORMAL COAGULATION TESTS MEAN IN APIXABAN, EDOXABAN, OR RIVAROXABAN-TREATED PATIENTS?
- In apixaban, edoxaban, and rivaroxaban-treated patients, a normal PT/INR and aPTT may be found despite the presence of therapeutic levels of the drug. No routine coagulation test can reliably exclude a residual anticoagulant effect.
# LABORATORY TESTING IN PATIENTS RECEIVING A DOAC WHO ARE BLEEDING:
Laboratory testing may help in the management of patients who are bleeding, especially if it is lifethreatening. The timing of the last dose of the anticoagulant and assessment of renal function should be obtained to help interpret laboratory results. Patients with moderate or severe bleeding should urgently have the following laboratory tests: CBC, PT/INR, aPTT, creatinine.
# Dabigatran-treated patients who are bleeding:
- In bleeding patients with a highly elevated aPTT (e.g. greater than 80 sec) and/or an unmeasurable TCT (i.e. value greater than the critical limit of the laboratory's reference range), a significant anticoagulant effect of dabigatran is likely. - If the aPTT is normal in a dabigatran-treated patient, it excludes above on-therapy levels of dabigatran but does not exclude on therapy levels. As discussed in the Clinical Guide: NOACs/DOACs: Peri-operative Management, there is no need for routine laboratory testing outside of what would be done prior to any surgery/procedure.
# Dabigatran-treated patients:
- For most elective surgery/procedures, dabigatran should be stopped prior to surgery based on a calculated creatinine clearance and the bleeding risk associated with the procedure. See the Clinical Guide: NOACs/DOACs: Perioperative Management. No coagulation testing prior to surgery is recommended.
Apixaban, edoxaban, and rivaroxaban-treated patients:
- For most elective surgery/procedures, apixaban, edoxaban, or rivaroxaban, should be stopped prior to surgery based on a calculated creatinine clearance and the bleeding risk associated with the procedure. See the Clinical Guide: NOACs/DOACs: Perioperative Management. No coagulation testing prior to surgery is recommended.
# OTHER CONSIDERATIONS:
- For each of the DOACs, serum creatinine and estimated creatinine clearance (e.g. using the
Cockroft-Gault equation) should be done at baseline, at least yearly, and in clinical situations when renal function may deteriorate because these drugs are at least partially renally cleared and will accumulate in renal insufficiency. - If specific assays for quantifying DOAC activity are available in your center and you feel there is a benefit in determining this activity in a specific patient, discussion with the coagulation laboratory director is recommended in order to evaluate the relevance of the indication and guidance as to the interpretation of the results. - While new assays are being offered, such as TEG and ROTEM and other point-of-care testing, the utility of these assays in the measurement of DOACs is limited and should be interpreted with caution.
OTHER RELEVANT THROMBOSIS CANADA CLINICAL GUIDES: Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein. | To describe the effect of the newer direct oral anticoagulants (DOACs) on routine laboratory coagulation tests: prothrombin time (PT), international normalized ratio (INR), activated partial thromboplastin time (aPTT), and thrombin clotting time (TCT). • To describe tests used to accurately quantify DOAC levels. • To discuss how clinicians should use and interpret coagulation tests in patients taking a DOAC who are bleeding or require elective surgery or an invasive procedure.Four DOACs, a direct thrombin inhibitor (dabigatran) and three direct factor Xa inhibitors (apixaban, edoxaban, and rivaroxaban) are approved for clinical use in Canada for various indications, based on findings from large randomized trials.The effects of DOACs on routine laboratory coagulation tests are summarized in Table 1. The international normalized ratio (INR) and the international sensitivity index (ISI) used in the INR calculation are based on vitamin K antagonist sensitivity not DOAC sensitivity, laboratories may consider reporting the PT (seconds) in addition to the INR.#
No effect ¶ Results will vary according to the PT or aPTT reagent used and its sensitivity to the DOAC. A doseresponse curve of PT and aPTT using dabigatran, apixaban, edoxaban, and rivaroxaban calibrators may assist in the local interpretation of these assays. † Drug overdose or bioaccumulation may elevate the PT and aPTT. ‡ TCT is very sensitive to presence of dabigatran and even low (potentially negligible) plasma levels may lead to elevated TCT results. * Reagent and dose dependent
# EFFECT OF DABIGATRAN ON COAGULATION TESTS:
There is currently no routinely available laboratory test that can reliably assess the anticoagulant effect of dabigatran in a manner similar to how the INR is used to assess adequacy of warfarin therapy or how the aPTT is used to monitor intravenous (IV) unfractionated heparin (UFH) therapy. Therefore, these laboratory tests should NOT be used to monitor the anticoagulant effect of dabigatran.
• Dabigatran is a direct thrombin inhibitor. It has a peak effect 1-3 hours after oral intake and, if testing is done within this time period, it often leads to an elevated PT/INR, aPTT and TCT. For example, soon after dabigatran intake, the INR may be slightly elevated to ~1.5-1.8 (normal: 0.8-1.2), the aPTT may be elevated to greater than twice the upper limit of the laboratory's reference range and the TCT will usually be markedly elevated above the laboratory reference range. After this peak effect period, the effect of dabigatran on the PT/INR and aPTT diminishes, although there will be a prolonged effect on the TCT, which is the most sensitive test to detect the anticoagulant effect of dabigatran. • The relationship between dabigatran anticoagulant effect and any of the routine laboratory tests of coagulation is variable, depending on the reagent sensitivity. • Commercially available dilute thrombin time (dTT) assays, Ecarin-based assays or chromogenic anti-Factor IIa assays can be used to quantify the anticoagulant effect of dabigatran and may be considered for patients. However, these assays are not widely available and there are not yet established therapeutic reference intervals for interpreting test results.
# WHAT DO NORMAL COAGULATION TESTS MEAN IN DABIGATRAN-TREATED PATIENTS?
• In some dabigatran-treated patients, the aPTT remains normal in the presence of dabigatran in the on-therapy range. • A normal TCT excludes the presence of significant dabigatran concentrations and is the most sensitive way to completely exclude residual effect of dabigatran; however, the TCT may be elevated in the presence of clinically insignificant levels of dabigatran, sometimes for a prolonged period of time following last dose of dabigatran. Moreover, the TCT is not a widely available test.
# EFFECT OF APIXABAN, EDOXABAN, AND RIVAROXABAN ON COAGULATION TESTS:
There is currently no routinely available laboratory test that can reliably assess the anticoagulant effect of apixaban, edoxaban, and rivaroxaban in a manner similar to how the INR is used to assess the adequacy of warfarin therapy or how the aPTT is used to monitor IV UFH therapy. Therefore, these laboratory tests should NOT be used to monitor the anticoagulant effect of apixaban, edoxaban, or rivaroxaban.
• Apixaban, edoxaban, and rivaroxaban are factor Xa inhibitors. Edoxaban and rivaroxaban may affect the PT/INR and aPTT but have no effect on the TCT. Apixaban has a minimal effect on PT/INR and aPTT and no effect on the TCT. However, the effect on the PT/INR is variable, depending on the sensitivity of the PT or aPTT reagent used. • Apixaban achieves peak plasma concentration approximately 3 hours after ingestion. Even if testing is done at this time, the effect of apixaban on PT/INR and aPTT is much less pronounced than for edoxaban and rivaroxaban and these tests are not useful to assess the intensity of apixaban's anticoagulant effect. TCT is not affected. • Edoxaban has a peak effect approximately 1-2 hours after ingestion. It prolongs PT/INR and aPTT in a dose dependent manner but both assays are insufficiently sensitive at low therapeutic levels and edoxaban effect is reagent-dependent. Therefore, a normal PT/INR or aPTT does not exclude the presence of on therapy or greater edoxaban concentrations. TCT is not affected. • Rivaroxaban has a peak effect 1-3 hours after oral intake and, if testing is done within this time, it often leads to an elevated PT/INR and aPTT. For example, soon after oral intake, the PT may be elevated to greater than twice the upper limit of the laboratory's reference range and the aPTT may be slightly elevated. After this peak effect, the effect of rivaroxaban on PT/INR and aPTT diminishes but there may be a residual effect on these tests even at trough levels (24 hours after last intake). A normal PT/INR or aPTT does not exclude the presence of on therapy or greater rivaroxaban concentrations. TCT is not affected. • Specific anti-Xa assays with drug-specific calibrators (different than those used to assess low molecular weight heparin [LMWH] activity) can be used to quantify the anticoagulant effect of apixaban, edoxaban, and rivaroxaban. However, these tests are not widely available and there are no established therapeutic reference intervals for interpreting test results. Anti-Xa assays calibrated for LMWHs or UFH should NOT be used to assess for the anticoagulant effect of apixaban, edoxaban, or rivaroxaban. In addition, antithrombin supplemented anti-factor Xa methods should not be used as these methods tend to overestimate DOAC levels and are not validated by the manufacturers.
# WHAT DO NORMAL COAGULATION TESTS MEAN IN APIXABAN, EDOXABAN, OR RIVAROXABAN-TREATED PATIENTS?
• In apixaban, edoxaban, and rivaroxaban-treated patients, a normal PT/INR and aPTT may be found despite the presence of therapeutic levels of the drug. No routine coagulation test can reliably exclude a residual anticoagulant effect.
# LABORATORY TESTING IN PATIENTS RECEIVING A DOAC WHO ARE BLEEDING:
Laboratory testing may help in the management of patients who are bleeding, especially if it is lifethreatening. The timing of the last dose of the anticoagulant and assessment of renal function should be obtained to help interpret laboratory results. Patients with moderate or severe bleeding should urgently have the following laboratory tests: CBC, PT/INR, aPTT, creatinine.
# Dabigatran-treated patients who are bleeding:
• In bleeding patients with a highly elevated aPTT (e.g. greater than 80 sec) and/or an unmeasurable TCT (i.e. value greater than the critical limit of the laboratory's reference range), a significant anticoagulant effect of dabigatran is likely. • If the aPTT is normal in a dabigatran-treated patient, it excludes above on-therapy levels of dabigatran but does not exclude on therapy levels. As discussed in the Clinical Guide: NOACs/DOACs: Peri-operative Management, there is no need for routine laboratory testing outside of what would be done prior to any surgery/procedure.
# Dabigatran-treated patients:
• For most elective surgery/procedures, dabigatran should be stopped prior to surgery based on a calculated creatinine clearance and the bleeding risk associated with the procedure. See the Clinical Guide: NOACs/DOACs: Perioperative Management. No coagulation testing prior to surgery is recommended.
Apixaban, edoxaban, and rivaroxaban-treated patients:
• For most elective surgery/procedures, apixaban, edoxaban, or rivaroxaban, should be stopped prior to surgery based on a calculated creatinine clearance and the bleeding risk associated with the procedure. See the Clinical Guide: NOACs/DOACs: Perioperative Management. No coagulation testing prior to surgery is recommended.
# OTHER CONSIDERATIONS:
• For each of the DOACs, serum creatinine and estimated creatinine clearance (e.g. using the
Cockroft-Gault equation) should be done at baseline, at least yearly, and in clinical situations when renal function may deteriorate because these drugs are at least partially renally cleared and will accumulate in renal insufficiency. • If specific assays for quantifying DOAC activity are available in your center and you feel there is a benefit in determining this activity in a specific patient, discussion with the coagulation laboratory director is recommended in order to evaluate the relevance of the indication and guidance as to the interpretation of the results. • While new assays are being offered, such as TEG and ROTEM and other point-of-care testing, the utility of these assays in the measurement of DOACs is limited and should be interpreted with caution.
OTHER RELEVANT THROMBOSIS CANADA CLINICAL GUIDES: Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein. | None | None |
04eec77745181fd5e911f22800d4d55a182c3acb | cma | None | The recommendations contained in this guideline are a consensus of the Alberta Provincial GI Tumour Team and are a synthesis of currently accepted approaches to management, derived from a review of relevant scientific literature. Clinicians applying these guidelines should, in consultation with the patient, use independent medical judgment in the context of individual clinical circumstances to direct care. All cancer drugs described in the guidelines are funded in accordance with the Outpatient Cancer Drug Benefit Program, at no charge, to eligible residents of Alberta, unless otherwise explicitly stated. For a complete list of funded drugs, specific indications, and approved prescribers, please refer to the Outpatient Cancer Drug Benefit Program Master List.#
Participation of members of the Alberta Provincial GI Tumour Team in the development of this guideline has been voluntary and the authors have not been remunerated for their contributions. There was no direct industry involvement in the development or dissemination of this guideline. CancerControl Alberta recognizes that although industry support of research, education and other areas is necessary in order to advance patient care, such support may lead to potential conflicts of interest. Some members of the Alberta Provincial GI Tumour Team are involved in research funded by industry or have other such potential conflicts of interest. However the developers of this guideline are satisfied it was developed in an unbiased manner.
# BACKGROUND
Colorectal cancer (CRC) is the second most commonly diagnosed cancer in Canada, and is the second leading cause of cancer deaths in Canadian men and the third leading cause of cancer deaths in Canadian women. 1 There were approximately 27,000 new diagnoses in Canada in 2017 (incidence rate: 79.6 per 100,000 in men, 54.9 per 100,000 in women); Alberta patients with newly diagnosed CRC are most commonly diagnosed with stage III disease, accounting for 28.6% of all new CRC cases in 2018. 2 There were 9,400 deaths associated with CRC in Canada in 2017, and the 5-year overall survival rate is 63% in men and 65% in women. 1 Rates of CRC continue to increase among adults younger than 50 years of age in Canada. 3,4 Surgical resection is the primary treatment for 80% of CRC patients with non-metastatic disease. Despite potentially curative surgery and the use of chemotherapy and/or radiotherapy, more than 40% of stage II/III patients will experience disease recurrence following primary therapy. The majority of recurrences occur within the first five years, predominantly in the liver, but also the lungs in patients with distal rectal tumours; a large (N=83,000) SEER analysis reported 5-year disease-specific conditional survival probability ≥80% for stage I/II/III CRC patients. 5 The rate of recurrence in years 5-10 may be higher in men (8.3%) than women (5.3%). 6 The optimal surveillance protocol for non-metastatic CRC patients post-treatment remains controversial, in part due to wide variation in surveillance protocols in randomized trials. 7 Variable surveillance strategies have been published from different jurisdictions with no clear consensus, and are summarized in Appendix A.
# GUIDELINE QUESTION
What is the appropriate posttreatment surveillance protocol for adult patients who have completed treatment for stage I, II, or III colorectal cancer?
# DEVELOPMENT AND REVISION HISTORY
This guideline was reviewed and endorsed by the Alberta Gastrointestinal (GI) Tumour Team. Members of the Alberta GI Tumour Team include surgeons, radiation oncologists, medical oncologists, gastroenterologists, nurses, pathologists, and pharmacists. Evidence was selected and reviewed by a working group comprised of members from the Alberta GI Tumour Team, and a Knowledge Management Specialist from the Guideline Resource Unit. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook. This guideline was originally developed in Feb. 2008Feb. , and was updated in 2009Feb. , 2010Feb. , 2011Feb. , 2013Feb. , 2014Feb. , and 2019. The 2019 updated expanded the scope to include patients with stage I CRC.
# SEARCH STRATEGY
The original literature search for this guideline spanned from 1990-2008, and included primary literature and guidelines from other jurisdictions. The 2019 update expanded the literature search to July 1, 2018, and included primary literature and guidelines from other jurisdictions. The detailed search criteria and resulting evidence tables can be found in Appendix A.
# TARGET POPULATION
The recommendations outlined in this guideline apply to adults over the age of 18 years who have completed treatment for stage I, II, or III CRC. CEA is an oncofetal protein that is elevated in patients with a variety of cancers including CRC. 9 Elevated preoperative CEA levels should return to baseline postoperatively, if they do not then residual disease should be suspected. 10 In patients with successfully resected primary CRC, the sensitivity and specificity of CEA is dependent on the threshold used. A cutoff value of 2.5 µg/mL results in pooled sensitivity of 82% but specificity of 80%; 11 a cutoff value of 10.0 µg/mL results in lower sensitivity (68%) but higher specificity (97%), reflecting fewer false positives. Serial measurement of CEA can detect disease recurrence in patients with initially normal CEA levels, although the sensitivity is low (27-50%). 12-15 A postoperative CEA elevation indicates recurrence with relatively high probability, however, normal postoperative CEA levels (even if initially elevated) are not useful in excluding disease recurrence. The use of serial CEA surveillance has been criticized because 30-40% of CRC recurrences are not associated with a measurable elevation in serum CEA. 16 In addition, some studies have failed to show CEA testing improves survival or quality of life, 17,18 and cost-effectiveness has been reported to be relatively poor ($22,963 -$4,888,208 per quality adjusted life year saved). 19 The optimal frequency of CEA measurements during posttreatment surveillance is also unclear, and is largely based on consensus. One study has shown more frequent (every 1-2 months) CEA testing is superior, 20 however others have not. Most published clinical practice guidelines recommend testing every 3-6 months for 3-5 years posttreatment (refer to Appendix B for a complete review).
# SUMMARY OF RECOMMENDATIONS
# Investigation
- CT of the chest, abdomen, and pelvis is recommend at years 1 and 2 posttreatment, with an option for year 3, for all non-metastatic patients who would potentially be considered a candidate for additional treatment.
The primary issue in forming CT recommendations is inconsistent protocols reported in randomized controlled trials. 21 In some cases, CT was performed for only the liver or pelvis, and frequency varied. One meta-analysis did report a survival benefit for CRC patients who received posttreatment CT imaging (every 3-12 months) and frequent CEA measurements, 22 and two others reported a survival benefit associated with liver imaging. 17,23 Other data in support of posttreatment CT surveillance comes from adjuvant chemotherapy trials. While the US Intergroup studies did not mandate CT in the follow-up protocol, two European trials reported that 32% and 44% of relapses were detected by imaging, and 38% and 46% of these patients proceeded to potentially curative resection, respectively. 24,25 The utility of CT imaging should be balanced by concerns about radiation exposure and the risk for second malignancies, particularly in younger patients.
Colonoscopy is recommended at 1 year post-surgery and every 3-5 years thereafter, based on findings, for all non-metastatic patients who would potentially be considered a candidate for additional treatment. Patients with high risk hereditary genetic features (i.e., HNPCC, FAP) may require more frequent colonoscopies, at the discretion of their surgeon or oncologist. 26,27 The primary goal of surveillance colonoscopy is to detect metachronous CRCs, polyps, and anastomotic recurrences of the initial primary to allow for potentially curative treatment. Metachronous lesions develop in 1.5% to 3% of patients in the first 3-5 years postoperatively. Greater than 50% of these lesions arise within 24 months of the initial resection and may represent synchronous cancers that were missed initially. 28,31,32 Anastomotic recurrences occur in 2% to 4% of patients with colon cancer. Rates are higher in patients with rectal cancer, particularly in patients who did not undergo total mesorectal excision and/or pelvic radiation. 28,33,34 At least 80% of anastomotic recurrences occur within 2.5 years of the primary resection. 31,35 Fecal occult blood testing (FOBT) and/or fecal immunochemical test (FIT) should not be used for surveillance for new primary lesions or polyps. Meta-analyses of randomized trials have shown that patients who undergo surveillance colonoscopy after CRC resection have higher overall, but non disease-specific survival. 8,40 Neither randomized trials nor meta-analyses have shown a survival benefit in performing colonoscopy at shorter than 3-5 year intervals. 17,28,33,41
# Consider periodic clinical assessment.
Patient history and physical examination (H&P) may be performed at the discretion of the responsible physician. The utility of H&P in this setting is unclear, and there is not strong evidence to suggest that routine H&P increases detection of recurrence or impacts outcomes.
# Patient posttreatment surveillance can be led by their general practitioner (GP), a nurse practitioner, surgeon, or their medical/radiation oncologist.
A randomized trial comparing GP-led vs. surgeon-led surveillance for colon cancer found no difference in patient quality of life, anxiety, depression, or satisfaction, with similar time to recurrence detection, and similar survival rates in each group. 42 A systematic review evaluating which provider patients preferred for CRC posttreatment surveillance found 5 studies that supported specialist-led care, and 9 studies that indicated patient willingness to have follow-up by non-specialist providers (primary care or nursing). 43 7. Information about the late effects of CRC treatment, risk reduction strategies, and health promotion recommendations, should be provided to patients completing treatment, as well as their primary healthcare providers. 27 There is a growing body of literature supporting associations between obesity, physical activity, nutrition, and tobacco use on CRC outcomes such as disease progression, recurrence, and mortality. In Alberta, patients and primary healthcare providers are given resources both at the end of active treatment and when the patients is transferred to their primary healthcare provider, including letters and booklets. These tools facilitate further discussions with the patient and presents an opportunity to improve care coordination by clarifying roles. The After Treatment -Information and Resources to Help You Set Priorities and Take Action booklet and sample letters are accessible on the external website.
# GLOSSARY OF ABBREVIATIONS
Acronym
# DISSEMINATION
- Present the guideline at the local and provincial tumour team meetings and weekly rounds.
- Post the guideline on the Alberta Health Services website.
- Send an electronic notification of the new guideline to all members of CancerControl Alberta.
# MAINTENANCE
A formal review of the guideline will be conducted at the Annual Provincial Meeting in 2020. If critical new evidence is brought forward before that time, however, the guideline working group members will revise and update the document accordingly. It takes into consideration related information presented at local, national, and international meetings, similar guidelines published by the American Society for Clinical Oncology (ASCO), the National Comprehensive Cancer Network (NCCN), and Cancer Care Ontario (CCO), as well as the Alberta Provincial Gastrointestinal Tumour Team's interpretation of the data.
# Search:
Grey Literature: Guidelines related to CRC surveillance published between January 1, 2013 and July 1, 2018 were identified using Google Advanced Search and the National Guidelines Clearinghouse database.
Results: 9 guidelines from other jurisdictions were identified and included (Table 1). Results: 23 articles found, 13 included: 8 relevant trials (Table 2), 5 systematic reviews/ meta-analyses (Table 3) were identified and included o CEA is insufficiently sensitive to be used alone, even with a low threshold; essential to augment CEA monitoring with another diagnostic modality in order to avoid missed cases o trying to improve sensitivity by adopting a low threshold is a poor strategy because of the high numbers of false alarms generated - Recommendation: monitoring for colorectal cancer recurrence with more than one diagnostic modality but applying the highest CEA cut-off assessed (10 µg/L) | The recommendations contained in this guideline are a consensus of the Alberta Provincial GI Tumour Team and are a synthesis of currently accepted approaches to management, derived from a review of relevant scientific literature. Clinicians applying these guidelines should, in consultation with the patient, use independent medical judgment in the context of individual clinical circumstances to direct care. All cancer drugs described in the guidelines are funded in accordance with the Outpatient Cancer Drug Benefit Program, at no charge, to eligible residents of Alberta, unless otherwise explicitly stated. For a complete list of funded drugs, specific indications, and approved prescribers, please refer to the Outpatient Cancer Drug Benefit Program Master List.#
Participation of members of the Alberta Provincial GI Tumour Team in the development of this guideline has been voluntary and the authors have not been remunerated for their contributions. There was no direct industry involvement in the development or dissemination of this guideline. CancerControl Alberta recognizes that although industry support of research, education and other areas is necessary in order to advance patient care, such support may lead to potential conflicts of interest. Some members of the Alberta Provincial GI Tumour Team are involved in research funded by industry or have other such potential conflicts of interest. However the developers of this guideline are satisfied it was developed in an unbiased manner.
# BACKGROUND
Colorectal cancer (CRC) is the second most commonly diagnosed cancer in Canada, and is the second leading cause of cancer deaths in Canadian men and the third leading cause of cancer deaths in Canadian women. 1 There were approximately 27,000 new diagnoses in Canada in 2017 (incidence rate: 79.6 per 100,000 in men, 54.9 per 100,000 in women); Alberta patients with newly diagnosed CRC are most commonly diagnosed with stage III disease, accounting for 28.6% of all new CRC cases in 2018. 2 There were 9,400 deaths associated with CRC in Canada in 2017, and the 5-year overall survival rate is 63% in men and 65% in women. 1 Rates of CRC continue to increase among adults younger than 50 years of age in Canada. 3,4 Surgical resection is the primary treatment for 80% of CRC patients with non-metastatic disease. Despite potentially curative surgery and the use of chemotherapy and/or radiotherapy, more than 40% of stage II/III patients will experience disease recurrence following primary therapy. The majority of recurrences occur within the first five years, predominantly in the liver, but also the lungs in patients with distal rectal tumours; a large (N=83,000) SEER analysis reported 5-year disease-specific conditional survival probability ≥80% for stage I/II/III CRC patients. 5 The rate of recurrence in years 5-10 may be higher in men (8.3%) than women (5.3%). 6 The optimal surveillance protocol for non-metastatic CRC patients post-treatment remains controversial, in part due to wide variation in surveillance protocols in randomized trials. 7 Variable surveillance strategies have been published from different jurisdictions with no clear consensus, and are summarized in Appendix A.
# GUIDELINE QUESTION
What is the appropriate posttreatment surveillance protocol for adult patients who have completed treatment for stage I, II, or III colorectal cancer?
# DEVELOPMENT AND REVISION HISTORY
This guideline was reviewed and endorsed by the Alberta Gastrointestinal (GI) Tumour Team. Members of the Alberta GI Tumour Team include surgeons, radiation oncologists, medical oncologists, gastroenterologists, nurses, pathologists, and pharmacists. Evidence was selected and reviewed by a working group comprised of members from the Alberta GI Tumour Team, and a Knowledge Management Specialist from the Guideline Resource Unit. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook. This guideline was originally developed in Feb. 2008Feb. , and was updated in 2009Feb. , 2010Feb. , 2011Feb. , 2013Feb. , 2014Feb. , and 2019. The 2019 updated expanded the scope to include patients with stage I CRC.
# SEARCH STRATEGY
The original literature search for this guideline spanned from 1990-2008, and included primary literature and guidelines from other jurisdictions. The 2019 update expanded the literature search to July 1, 2018, and included primary literature and guidelines from other jurisdictions. The detailed search criteria and resulting evidence tables can be found in Appendix A.
# TARGET POPULATION
The recommendations outlined in this guideline apply to adults over the age of 18 years who have completed treatment for stage I, II, or III CRC. CEA is an oncofetal protein that is elevated in patients with a variety of cancers including CRC. 9 Elevated preoperative CEA levels should return to baseline postoperatively, if they do not then residual disease should be suspected. 10 In patients with successfully resected primary CRC, the sensitivity and specificity of CEA is dependent on the threshold used. A cutoff value of 2.5 µg/mL results in pooled sensitivity of 82% but specificity of 80%; 11 a cutoff value of 10.0 µg/mL results in lower sensitivity (68%) but higher specificity (97%), reflecting fewer false positives. Serial measurement of CEA can detect disease recurrence in patients with initially normal CEA levels, although the sensitivity is low (27-50%). 12-15 A postoperative CEA elevation indicates recurrence with relatively high probability, however, normal postoperative CEA levels (even if initially elevated) are not useful in excluding disease recurrence. The use of serial CEA surveillance has been criticized because 30-40% of CRC recurrences are not associated with a measurable elevation in serum CEA. 16 In addition, some studies have failed to show CEA testing improves survival or quality of life, 17,18 and cost-effectiveness has been reported to be relatively poor ($22,963 -$4,888,208 per quality adjusted life year saved). 19 The optimal frequency of CEA measurements during posttreatment surveillance is also unclear, and is largely based on consensus. One study has shown more frequent (every 1-2 months) CEA testing is superior, 20 however others have not. Most published clinical practice guidelines recommend testing every 3-6 months for 3-5 years posttreatment (refer to Appendix B for a complete review).
# SUMMARY OF RECOMMENDATIONS
# Investigation
3. CT of the chest, abdomen, and pelvis is recommend at years 1 and 2 posttreatment, with an option for year 3, for all non-metastatic patients who would potentially be considered a candidate for additional treatment.
The primary issue in forming CT recommendations is inconsistent protocols reported in randomized controlled trials. 21 In some cases, CT was performed for only the liver or pelvis, and frequency varied. One meta-analysis did report a survival benefit for CRC patients who received posttreatment CT imaging (every 3-12 months) and frequent CEA measurements, 22 and two others reported a survival benefit associated with liver imaging. 17,23 Other data in support of posttreatment CT surveillance comes from adjuvant chemotherapy trials. While the US Intergroup studies did not mandate CT in the follow-up protocol, two European trials reported that 32% and 44% of relapses were detected by imaging, and 38% and 46% of these patients proceeded to potentially curative resection, respectively. 24,25 The utility of CT imaging should be balanced by concerns about radiation exposure and the risk for second malignancies, particularly in younger patients.
# 4.
Colonoscopy is recommended at 1 year post-surgery and every 3-5 years thereafter, based on findings, for all non-metastatic patients who would potentially be considered a candidate for additional treatment. Patients with high risk hereditary genetic features (i.e., HNPCC, FAP) may require more frequent colonoscopies, at the discretion of their surgeon or oncologist. 26,27 The primary goal of surveillance colonoscopy is to detect metachronous CRCs, polyps, and anastomotic recurrences of the initial primary to allow for potentially curative treatment. Metachronous lesions develop in 1.5% to 3% of patients in the first 3-5 years postoperatively. [28][29][30] Greater than 50% of these lesions arise within 24 months of the initial resection and may represent synchronous cancers that were missed initially. 28,31,32 Anastomotic recurrences occur in 2% to 4% of patients with colon cancer. Rates are higher in patients with rectal cancer, particularly in patients who did not undergo total mesorectal excision and/or pelvic radiation. 28,33,34 At least 80% of anastomotic recurrences occur within 2.5 years of the primary resection. 31,35 Fecal occult blood testing (FOBT) and/or fecal immunochemical test (FIT) should not be used for surveillance for new primary lesions or polyps. [36][37][38][39] Meta-analyses of randomized trials have shown that patients who undergo surveillance colonoscopy after CRC resection have higher overall, but non disease-specific survival. 8,40 Neither randomized trials nor meta-analyses have shown a survival benefit in performing colonoscopy at shorter than 3-5 year intervals. 17,28,33,41
# Consider periodic clinical assessment.
Patient history and physical examination (H&P) may be performed at the discretion of the responsible physician. The utility of H&P in this setting is unclear, and there is not strong evidence to suggest that routine H&P increases detection of recurrence or impacts outcomes.
# Patient posttreatment surveillance can be led by their general practitioner (GP), a nurse practitioner, surgeon, or their medical/radiation oncologist.
A randomized trial comparing GP-led vs. surgeon-led surveillance for colon cancer found no difference in patient quality of life, anxiety, depression, or satisfaction, with similar time to recurrence detection, and similar survival rates in each group. 42 A systematic review evaluating which provider patients preferred for CRC posttreatment surveillance found 5 studies that supported specialist-led care, and 9 studies that indicated patient willingness to have follow-up by non-specialist providers (primary care or nursing). 43 7. Information about the late effects of CRC treatment, risk reduction strategies, and health promotion recommendations, should be provided to patients completing treatment, as well as their primary healthcare providers. 27 There is a growing body of literature supporting associations between obesity, physical activity, nutrition, and tobacco use on CRC outcomes such as disease progression, recurrence, and mortality. In Alberta, patients and primary healthcare providers are given resources both at the end of active treatment and when the patients is transferred to their primary healthcare provider, including letters and booklets. These tools facilitate further discussions with the patient and presents an opportunity to improve care coordination by clarifying roles. The After Treatment -Information and Resources to Help You Set Priorities and Take Action booklet and sample letters are accessible on the external website.
# GLOSSARY OF ABBREVIATIONS
Acronym
# DISSEMINATION
• Present the guideline at the local and provincial tumour team meetings and weekly rounds.
• Post the guideline on the Alberta Health Services website.
• Send an electronic notification of the new guideline to all members of CancerControl Alberta.
# MAINTENANCE
A formal review of the guideline will be conducted at the Annual Provincial Meeting in 2020. If critical new evidence is brought forward before that time, however, the guideline working group members will revise and update the document accordingly. It takes into consideration related information presented at local, national, and international meetings, similar guidelines published by the American Society for Clinical Oncology (ASCO), the National Comprehensive Cancer Network (NCCN), and Cancer Care Ontario (CCO), as well as the Alberta Provincial Gastrointestinal Tumour Team's interpretation of the data.
# Search:
Grey Literature: Guidelines related to CRC surveillance published between January 1, 2013 and July 1, 2018 were identified using Google Advanced Search and the National Guidelines Clearinghouse database.
Results: 9 guidelines from other jurisdictions were identified and included (Table 1). Results: 23 articles found, 13 included: 8 relevant trials (Table 2), 5 systematic reviews/ meta-analyses (Table 3) were identified and included o CEA is insufficiently sensitive to be used alone, even with a low threshold; essential to augment CEA monitoring with another diagnostic modality in order to avoid missed cases o trying to improve sensitivity by adopting a low threshold is a poor strategy because of the high numbers of false alarms generated • Recommendation: monitoring for colorectal cancer recurrence with more than one diagnostic modality but applying the highest CEA cut-off assessed (10 µg/L) | None | None |
3ecb1909bd54119955b14658c3ee521442642788 | cma | None | The Canadian Cardiovascular Society (CCS) Atrial Fibrillation Guidelines Committee provides periodic reviews of new data to produce focused updates that address clinically important advances in atrial fibrillation (AF) management. This 2018 Focused Update addresses: (1) anticoagulation in the context of cardioversion of AF; (2) the management of antithrombotic therapy for patients with AF in the context of coronary artery disease; (3) investigation and management of subclinical AF; (4) the use of antidotes for the reversal of nonvitamin K antagonist oral anticoagulants; (5) acute pharmacological cardioversion of AF; (6) catheter ablation for AF, including patients with concomitant AF and heart failure; and (7) an integrated approach toLe comit e des lignes directrices en matière de fibrillation auriculaire de la Soci et e canadienne de cardiologie (SCC) procède à des examens p eriodiques des nouvelles donn ees pour produire des mises à jour th ematiques portant sur des avanc ees cliniquement importantes de la prise en charge de la fibrillation auriculaire (FA). La mise à jour cibl ee 2018 porte sur les aspects suivants : 1) l'anticoagulation dans le contexte de la cardioversion de la FA; 2) la prise en charge du traitement antithrombotique des patients atteints de FA dans le contexte d'une coronaropathie; 3) la recherche et la prise en charge de la FA sub-clinique; 4) les antidotes aux anticoagulants oraux non-vitamine K; 5) cardioversion pharmacologique aiguë de la FA; 6) l'ablation par#
The contemporary management of atrial fibrillation (AF) is centred on a reduction in the morbidity and mortality associated with AF, as well as on symptomatic improvement with consequent reduction in AF-related emergency room visits or hospitalizations. 1 The Canadian Cardiovascular Society (CCS) Atrial Fibrillation Guidelines committee provides periodic reviews of new data to produce focused updates that address clinically important advances in AF management. The committee reviewed data published since the 2016 Focused Update for the management of AF. This 2018 Focused Update addresses:
- Anticoagulation in the context of cardioversion of AF; 2. The management of antithrombotic therapy for patients with AF in the context of coronary artery disease (CAD); 3. Investigation and management of subclinical AF (SCAF); 4. The use of antidotes for the reversal of non-vitamin K antagonist oral anticoagulants (NOACs); 5. Acute pharmacological cardioversion of AF; 6. Catheter ablation for AF, including patients with concomitant AF and heart failure (HF); 7. Integrated approach to the patient with AF and modifiable cardiovascular risk factors.
The recommendations were developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) standards with strength of recommendations now classified as "strong" or "weak." Details of the updated recommendations are presented, along with their background and rationale. The literature review process and evidence tables are included as Supplementary Material, along with an updated summary of all CCS AF Guidelines Recommendations on the CCS Web site.
# I. Anticoagulation in the Context of Cardioversion
There have been no randomized clinical trials of oral anticoagulation (OAC) therapy vs placebo for prevention of thromboembolic events at the time of cardioversion. Because of the stroke risk associated with cardioversion in the absence of anticoagulation, it is unlikely that such a study will be done. Contemporary estimates of the risk of thromboembolic events around the time of cardioversion can be obtained from analysis of the results of the pivotal randomized trials of adjusted-dose warfarin vs NOACs, reports of outcomes of cardioversions performed during these pivotal trials, and reports of randomized trials of adjusted-dose warfarin therapy vs NOAC therapy before cardioversion. Using these sources, the 1-month risk of stroke or systemic embolism (SSE) after cardioversion is estimated to be 0.46% for those treated with adjusted-dose warfarin and 0.31% for those treated with a NOAC. These risks are approximately twofold greater for a thromboembolic event in the month after cardioversion compared with the background risk (0.14% and 0.12% per month baseline stroke risk in those treated with adjusted-dose warfarin and with a NOAC, respectively). For those not receiving anticoagulant therapy the risk of a thromboembolic event is increased approximately fourfold (1.9% for the month after cardioversion vs 0.5% per month baseline risk). The thromboembolic risk in the pericardioversion period can be conceptually separated into 2 mechanistic phenomena. The first is the generation of thrombi during persistent AF, with subsequent embolization after restoration of an organized atrial contraction. 15 The second relates to a period of transient atrial mechanical dysfunction after the restoration of sinus rhythm. This "atrial stunning" is responsible for the development of new thromboembolism post cardioversion despite the restoration of sinus rhythm. 19,20 This atrial mechanical dysfunction has been reported with all modes of conversion (pharmacologic, electrical, and spontaneous) and is at maximal in the period immediately after cardioversion. The duration and severity of atrial stunning varies depending on the duration of the atrial arrhythmia, the atrial size, as well as the presence of comorbid structural heart disease.
# OAC use before and after cardioversion
Patients who present with acute (episode duration < 48 hours) nonvalvular AF (NVAF; ie, AF in the absence of rheumatic mitral stenosis, moderate-severe nonrheumatic mitral stenosis, or a mechanical heart valve) have long been considered to have a low risk of thromboembolic events after cardioversion on the basis of the rationale that left atrial thrombi have not yet had time to form. This practice has been supported by observational reports of short-term outcomes after cardioversion in patients with acute AF/atrial flutter (AFL). In these reports the post cardioversion the patient with AF and modifiable cardiovascular risk factors. The recommendations were developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) standards. Individual studies and literature were reviewed for quality and bias; the literature review process and evidence tables are included as Supplementary Material and are available on the CCS Web site. Details of the updated recommendations are presented, along with their background and rationale. This document is linked to an updated summary of all CCS AF guidelines recommendations, from 2010 to the present 2018 Focused Update, which is provided in the Supplementary Material.
cath eter de la FA, y compris chez les patients atteints d'insuffisance cardiaque; 7) une approche int egr ee du patient pr esentant une FA et des facteurs de risque cardiovasculaire modifiables. Les recommandations ont et e elabor ees à l'aide du système GRADE (Grading of Recommendations, Assessment, Development, and Evaluation). Chaque etude et chaque publication ont et e soumises à un examen visant à evaluer leur qualit e et leurs biais; le processus d'examen des publications et les tableaux de donn ees probantes sont pr esent es sous la forme d'un suppl ement accessible sur le site Web de la SCC. Les d etails des recommandations mises à jour sont pr esent es, ainsi que leur contexte et leur justification. Ce document comporte un lien vers un sommaire mis à jour de toutes les lignes directrices en matière de FA de la SCC, de 2010 à la pr esente mise à jour cibl ee 2018, qui est offerte dans le suppl ement en ligne.
30-day risk of SSE was reported to be 0.19% (4047 patients who underwent 4503 spontaneous, pharmacologic, or electrical cardioversions). Although this risk is comparable with that of elective cardioversion in more persistent AF/AFL patients who receive anticoagulation therapy, it is important to recognize that these reports describe cohorts of stable patients at low risk of thromboembolism for whom cardioversion was considered to be an appropriate therapeutic option by their treating physician. Specifically, these patients had a low baseline stroke risk (69% of patients with a Congestive Heart Failure, Hypertension, Age, Diabetes, Stroke/Transient Ischemic Attack score of 0-1; 28% receiving chronic OAC therapy) and presented early in the 48-hour window (mean duration of acute AF/AFL of 8.0 hours). Nevertheless, these data suggest that it might be possible to identify a population of patients with acute AF/ AFL who are at low risk of a thromboembolic event associated with cardioversion.
Conversely, previous CCS AF guidelines have suggested that it is might be possible to identify a population of patients with acute AF/AFL in whom immediate cardioversion without preprocedural anticoagulant therapy presents an unacceptably high risk of thromboembolic complication. Such patients were considered, in previous CCS AF guidelines, to include those with a stroke or transient ischemic attack within the previous 6 months, those with moderate to severe rheumatic mitral stenosis, and those with a mechanical heart valve. 37 The Finnish Cardioversion (FinCV) study was a retrospective, observational study that determined outcomes in consecutive patients who underwent cardioversion of acute AF (duration 12 hours (OR, 3.89; 95% CI, 1.76-8.60; P ¼ 0.001), HF (OR, 3.37; 95% CI, 1.39-8.19; P ¼ 0.007), diabetes mellitus (OR, 2.66; 95% CI, 1.25-5.69; P ¼ 0.012), and female sex (OR, 2.11; 95% CI, 1.04-4.28; P ¼ 0.038). 39,40 A recent report from the Swedish National Patient Registry 42 described outcomes in 10,722 patients who underwent direct current (DC) cardioversion of AF (the duration of AF being unavailable) between January 1, 2006 and December 1, 2010. The 30-day incidence of thromboembolic complication in patients not receiving periprocedural anticoagulation therapy was significantly higher than those receiving anticoagulation therapy (0.9% vs 0.3%; OR, 2.54; 95% CI, 1.70-3.79; P 65 Years), Drugs/Alcohol Concomitantly (HAS-BLED) scores (OR, 2.51; 95% CI, 1.69-3.75; P 75 years, previous SSE, and rehospitalization for AF were significant risk factors for thromboembolism, the CHADS 2 and CHA 2 DS 2 -VASc scores offered no discriminative ability in those not receiving OAC therapy (hazard ratio , 2.21; 95% CI, 0.79-6.77 and 2.40; 95% CI, 1.46-3.95 with CHA2DS2-VASc score 0-1 and CHA2DS2-VASc score 2 or more). Conversely, the risk of thromboembolism was low in patients who initiated OAC therapy only after cardioversion and was comparable with those who received OAC therapy before and after cardioversion (HR, 0.97 for those with only post cardioversion OAC therapy vs those who received OAC therapy pre/post cardioversion; 95% CI, 0.33-2.86).
Overall, the available evidence suggests that the incidence of a definite SSE in the month after cardioversion from acute AF/AFL (< 48 hours) in patients who were not receiving anticoagulation is approximately 0.7%, 40 which is above the thromboembolic risk threshold that the CCS uses to recommend anticoagulation therapy.
The comprehensive recommendations regarding cardioversion follow and are summarized in Figure 1.
Practical tip. NVAF is defined as AF in the absence of mechanical heart valves, rheumatic mitral stenosis, or moderate to severe nonrheumatic mitral stenosis.
Practical tip. When oral anticoagulation is to be used for only a short period (< 2 months) current evidence does not substantiate either an efficacy or safety advantage for use of a NOAC over adjusted-dose warfarin. Nevertheless, the convenience of use of a NOAC over adjusted-dose warfarin in the pericardioversion period is substantial and the onset of therapeutic anticoagulation is nearly immediate with a NOAC whereas it is delayed in the case of adjusted-dose warfarin. Accordingly, it is reasonable to use NOAC therapy in the pericardioversion period.
# The use of TEE to exclude left atrial thrombus
When early cardioversion is desired (ie, without a preceding period of therapeutic OAC treatment) TEE can be performed to exclude left atrial thrombi. The utility of this approach was shown by Klein et al., who randomized 1222 patients with AF of > 48-hour duration and assigned them to TEE-guided cardioversion, or conventional treatment (eg, pretreatment with warfarin for 3 weeks before cardioversion). 43 Although there was no significant difference in the rate of embolic events (0.8% in the TEE group vs 0.5% in the conventional group; P ¼ 0.50), the TEE group had a significantly lower rate of hemorrhagic events (2.9% vs 5.5%; P ¼ 0.03), a significantly shorter time to cardioversion (3.0 AE 5.6 vs 30.6 AE 10.6 days, P < 0.001), and a greater success rate (sinus rhythm restoration of 71.1% vs 65.2%; P ¼ 0.03).
# NOACs vs warfarin for cardioversion
Each of the pivotal trials that compared NOACs with adjusted-dose warfarin reported short-term, prospective, nonrandomized efficacy and safety outcomes after DC cardioversion in study participants with persistent AF/AFL. Similarly, prospective, randomized trials have been completed that compared 3 of the currently available NOACs with adjusted-dose warfarin in the setting of planned cardioversion. 7,8 The data of the Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY), 10 Values and preferences. This recommendation places a high value on immediately addressing instability by attempting cardioversion, and a lower value on reducing the risk of cardioversion-associated stroke with a period of anticoagulation before cardioversion. Therapeutic anticoagulation therapy should be initiated as soon as possible.
- When a decision has been reached that a patient will be undergoing unplanned cardioversion of AF/AFL, we suggest that therapeutic anticoagulation therapy be initiated immediately (preferably before cardioversion) with either a NOAC, or with heparin followed by adjusted-dose warfarin (Weak Recommendation, Low-Quality Evidence).
- We suggest that, in the absence of a strong contraindication, all patients who undergo cardioversion of AF/ AFL receive at least 4 weeks of therapeutic anticoagulation (adjusted-dose warfarin or a NOAC) after cardioversion. (Weak Recommendation, Low-Quality Evidence). Thereafter, we recommend that the need for ongoing antithrombotic therapy should be on the basis of the risk of stroke as determined by the CCS Algorithm ("CHADS-65"; Strong Recommendation, Moderate-Quality Evidence).
Values and preferences. This approach places relatively greater emphasis on the benefits of stroke prevention compared with the risks of bleeding with a short course of anticoagulation therapy. Although it might be possible to parse these risks either on the basis of patient characteristics or the duration of acute AF/AFL, the CCS AF Guidelines Committee at this point has chosen to simplify by recommending anticoagulation for 1 month after cardioversion for all such patients in the absence of a strong contraindication.
Inhibition Compared With Vitamin K Antagonist for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF), 11 Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARIS-TOTLE), 12 Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48), 13 Explore the Efficacy and Safety of Once-Daily Oral Rivaroxaban for the Prevention of Cardiovascular Events in Patients With Non-Valvular Atrial Fibrillation Scheduled for Cardioversion (X-VeRT), 6 and Edoxaban vs Warfarin in Subjects Undergoing Cardioversion of Atrial Fibrillation (ENSURE-AF) 7 trials formed the basis of a comparative meta-analysis reported by Renda et al. 44 In these trials, 6148 patients underwent 6854 cardioversions for AF and were followed for a mean of 42 days. Collectively, there were no significant differences between NOACs and adjusted-dose warfarin with respect to either efficacy (RR, 0.82; 95% CI, 0.38-1.75 for SSE) or safety (RR, 0.98; 95% CI, 0.51-1.87 for major bleeding).
Published after the meta-analysis by Renda et al., Eliquis Evaluated in Acute Cardioversion Compared to Usual Treatments for Anticoagulation in Subjects With Atrial Fibrillation (EMANATE) 8 randomized 1500 patients who were not receiving OAC therapy to receive apixaban (753 patients) or heparin followed by VKA (747 patients) before DC cardioversion of persistent AF/AFL. Mean time to cardioversion was 3.4 days in the apixaban loading dose group, 25.7 days in the apixaban (no loading dose) group, and 17.8 days in the VKA group. In an intention-to-treat analysis, no patient randomized to receive apixaban had a SSE (0%) whereas 6 patients randomized to receive heparin/VKA therapy (0.8%) had a stroke (log rank P ¼ 0.016). In patients who had received at least 1 dose of their assigned anticoagulant therapy there were 3 major bleeding events and 11 clinically relevant nonmajor bleeding events in 735 patients (total of 1.9%) in the apixaban group and 6 major bleeding events and 13 clinically relevant nonmajor bleeding events in 721 patients (2.6%) in the heparin/VKA group (P ¼ not significant).
It should be noted that these trials, individually and in their aggregate, were not sufficiently powered to exclude a clinically meaningful difference in either safety or efficacy. In the absence of a signal suggesting inferiority in safety or efficacy outcomes, the committee considered that NOAC therapy has advantages over dose-adjusted warfarin therapy (rapidity of onset and offset, standard dosages, and lack of need for therapeutic monitoring). Accordingly, NOAC therapy is preferred over adjusted-dose warfarin in the pericardioversion period in anticoagulation-naive patients.
# II. Management of Antithrombotic Therapy in Patients With AF and CAD
Up to 20%-30% of AF patients also have concomitant CAD, with a significant proportion requiring percutaneous coronary intervention (PCI). 45,46 An OAC is indicated for the prevention of AF-related SSE, whereas antiplatelet therapy is required for the prevention of coronary events after ACS or PCI. Each offers a relative efficacy benefit (eg, dual antiplatelet therapy is more effective than an OAC alone in reducing ischemic coronary events in an ACS population, but is inferior to an OAC for the prevention of SSE in an AF/AFL population at increased risk of AF-related stroke). 47 As such, management requires a careful and balanced assessment of the individual risks of bleeding against the anticipated effect on thrombotic outcomes.
The extensive evidence for antithrombotic therapy for the prevention of SSE among patients with AF/AFL has been thoroughly reviewed in previous CCS guidelines and is not reviewed in depth herein. This section specifically focuses on antithrombotic regimens for AF patients with coronary or peripheral arterial disease, with an emphasis on the evidence published since the previous AF guideline update in 2016. 49 The recommendations for patients who undergo PCI with AF are consistent with the 2018 CCS/Canadian Association of Interventional Cardiology (CAIC) focused update of the guidelines for the use of antiplatelet therapy. 52 To clarify potentially confusing terminology in this area, single-agent antiplatelet therapy (SAPT) refers to the use of a single antiplatelet drug (eg, acetylsalicylic acid ), DAPT refers to the concomitant use of 2 antiplatelet agents (eg, ASA with clopidogrel), dual pathway therapy refers to the concomitant use of a SAPT with an OAC agent (eg, VKA with clopidogrel), and triple antithrombotic therapy (TT) the combination of DAPT with an OAC (eg, VKA with ASA and clopidogrel).
Practical tip. For patients who require combinations of antiplatelet and OAC agents for concomitant AF and coronary/arterial vascular disease, we suggest that measures be used to reduce the risk of bleeding, including careful consideration of modifiable bleeding risk factors with vigorous efforts to mitigate them; consideration of proton pump inhibitor use; avoidance of prasugrel and ticagrelor in conjunction with OACs; the use of warfarin in the lower target international normalized ratio (INR) range (eg, 2.0-2.5); consideration of the lower effective doses of NOACs in selected patients (Fig. 3); specific measures during coronary invasive procedures (radial access, small-diameter sheaths, early sheath removal from femoral site, and minimized use of acute procedural antithrombotic therapies); delaying nonurgent procedures until dual pathway therapy is no longer required; use of walking aids for those with gait or balance disorders; avoidance of nonsteroidal anti-inflammatory drugs or other drugs that might increase bleeding risk; and, strict blood pressure control.
# Stable vascular disease and AF in patients at low risk of SSE
SAPT (eg, ASA 81 mg/d) is recommended for patients with AF who are at low risk of SSE (age < 65 years and CHADS 2 score of 0) if vascular disease is present (CAD, peripheral arterial disease, or aortic plaque). This is on the basis of the efficacy of ASA therapy for the prevention of coronary events among patients with stable CAD (RR reduction of 18% for primary prevention and 20% for secondary prevention of MI), rather than the small reduction in stroke observed in AF patients (RR reduction, 22% vs placebo). 9,53 Although there is extensive evidence for the efficacy of OAC therapy for prevention of ischemic coronary events in patients with stable CAD (eg, VKA), the CCS AF guidelines recommend SAPT in preference to OACs in those at low risk of SSE because of its safety profile and ease of use.
More recently, in a non-AF population, the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial showed that dual pathway therapy with ASA and "vascular dose" rivaroxaban (2.5 mg twice per day ) was associated with a significant reduction in cardiovascular mortality and ischemic stroke, albeit with a significantly increased risk of major bleeding. 54 As such the combination of ASA and very low dose rivaroxaban might be a reasonable alternative to ASA alone for NVAF patients at low risk of stroke (age < 65 years and CHADS 2 score of 0) who also have coronary or arterial vascular disease.
Practical tip. For patients with NVAF/AFL aged < 65 years with no CHADS-65 risk factors, the risk of stroke associated with AF is not sufficiently elevated to justify OAC therapy. For this group treatment should be directed at the underlying coronary/peripheral arterial disease as outlined in
# RECOMMENDATION
- For patients with NVAF/AFL aged < 65 years with no CHADS 2 risk factors, we suggest no antithrombotic therapy for stroke prevention (Weak Recommendation, Moderate-Quality Evidence), with management of their coronary or arterial vascular disease as directed by the 2018 CCS/CAIC focused update of the guidelines for the use of antiplatelet therapy. 52 the 2018 CCS/CAIC focused update of the guidelines for the use of antiplatelet therapy. 52 Therapeutic options include ASA 81 mg daily alone; or ASA in combination with either clopidogrel 75 mg daily, ticagrelor 60 mg BID, or rivaroxaban 2.5 mg BID.
# Stable vascular disease and AF in patients at high risk of SSE
In patients with AF who are aged ! 65 years or with CHADS 2 score ! 1, an OAC is indicated for stroke prevention (Fig. 4). When such a patient also has stable CAD (defined by the absence of ACS for the preceding 12 months), OAC therapy provides protection against stroke and ischemic coronary events. The Warfarin-Aspirin Reinfarction Study (WARIS)-II indicates that the additional use of antiplatelet therapy with an OAC offers minimal beneficial effect on ischemic or thrombotic coronary outcomes (eg, combined end point of death, myocardial infarction , and stroke, 16.7% with an OAC vs 15.0% with combination OAC and ASA treatment; P ¼ 0.18), while conferring an increased risk of adverse bleeding outcomes (overall bleeding 2.82% per year with an OAC alone vs 3.27% per year with combination OAC and ASA treatment). 59,60 The comprehensive recommendations regarding antithrombotic treatment in AF patients indicated for an OAC with concomitant coronary/peripheral arterial disease are summarized in Figure 3.
Practical tip. For patients with high-risk clinical or angiographic features for ischemic coronary outcomes (Fig. 2) who are at low risk of bleeding, some clinicians prefer a combination of an OAC and single antiplatelet therapy (either aspirin or clopidogrel) in preference to OAC therapy alone. 52
# PCI or ACS in patients with AF
Patients who undergo PCI are generally prescribed DAPT for a period that varies from 4 weeks with bare metal stent (BMS) to more than 12 months after drug-eluting stent (DES) implantation. Shorter durations of DAPT decrease the risk of major bleeding, whereas premature DAPT discontinuation might increase the risk of stent thrombosis and MI. There has been a trend to shorten DAPT duration as secondgeneration DESs with sustained antiproliferative action and reduced thrombogenicity have become available.
For patients with AF and low stroke risk (age < 65 years and CHADS 2 score of 0), the post-PCI therapeutic DAPT regimen should be provided as outlined in the 2018 CCS/CAIC antiplatelet guidelines, because an OAC is not recommended for stroke prevention in these patients. 52 Values and preferences. For patients with AF and stable coronary or arterial vascular disease, the CCS AF Guidelines Committee believed that routine use of combination therapy (an OAC with a single antiplatelet agent) was not justified because of the increased risk of bleeding without a significant reduction in ischemic coronary and cerebrovascular thrombotic events. RECOMMENDATION 10. When an OAC is indicated in the presence of coronary or arterial vascular disease, we suggest a NOAC in preference to warfarin (Weak Recommendation, Moderate-Quality Evidence).
Values and preferences. The suggestion for use of a NOAC rather than warfarin places relatively greater weight on the ease of use of NOACs vs warfarin, as well as the data from randomized controlled trials of NOACs vs warfarin for NVAF (eg, equal or greater reduction of stroke, equal or greater reduction in all-cause mortality, equal or less major bleeding, less intracranial bleeding, and no net increase in CAD outcomes).
For a patient at higher risk of AF-related stroke (age ! 65 years or with CHADS 2 score ! 1) combination OAC and antiplatelet therapy is required. In these patients the optimal therapeutic regimen should be individualized on the basis of a balanced assessment of their risk of AF-related stroke, ischemic coronary event, and clinically relevant bleeding. The risk of AF-related SSE can be estimated from the CHADS-65 illustrated in Figure 4. 48,49 The risk of ischemic coronary events is modulated by the clinical presentation (eg, ACS being higher risk than elective PCI), clinical characteristics (higher risk with comorbid diabetes mellitus or chronic kidney disease, current tobacco use, or previous stent thrombosis), as well as PCI-related factors (higher risk with multivessel disease, multiple stent implantation, total stent length > 60 mm, bifurcation lesion, chronic total occlusion intervention, and stent type; Fig. 2). 52,61 The risk of bleeding can be estimated from clinical risk scores such as HAS-BLED, Predicting Bleeding Complications in Patients Undergoing Stent Implantation and Subsequent Dual Anti Platelet Therapy (PRECISE-DAPT), and Cardiovascular Disease Research Using Linked Bespoke Studies and Electronic Health Records (CALIBER), with the former validated in a VKA-treated population, and the latter two in a population with CAD treated with PCI and DAPT. 52 The population of patients with ACS who do not undergo revascularization (PCI or coronary artery bypass grafting), represents a heterogenous group. This population includes patients with thrombotic plaque rupture (type I MI) as well as those with supply-demand mismatch due to tachycardia, infection, sepsis, etc (type II MI). For patients with type II MI it is unclear if there is an advantage to routine use of combined OAC and antiplatelet therapy. For patients who have true ACS (type I MI) and are not revascularized, the management should take into consideration the relative risks and benefits of combination therapy.
# Key trials of dual pathway therapy vs triple therapy in AF with ACS/PCI
The Open-Label, Randomized, Controlled, Multicenter Study Exploring Two Treatment Strategies of Rivaroxaban and a Dose-Adjusted Oral Vitamin K Antagonist Treatment Strategy in Subjects with Atrial Fibrillation who Undergo Percutaneous Coronary Intervention (PIONEER AF-PCI) randomized 2124 patients with NVAF who underwent PCI for ACS (51%) or for stable CAD to receive, in a 1:1:1 ratio: (1) A P2Y12 inhibitor (94% clopidogrel) with rivaroxaban 15 mg/d (dual pathway) for 12 months; (2) DAPT with rivaroxaban 2.5 mg BID (reduced-dose TT) for 1, 6, or 12 months; or, (3) TT with warfarin (target INR, 2-3) with DAPT for 1, 6, or 12 months. 62 The primary safety end point of clinically significant bleeding (eg, Thrombolysis in Myocardial Infarction major bleeding and minor bleeding), was lower in the dual pathway and reduced-dose TT groups compared with TT with warfarin (16.8% in patients treated with dual pathway therapy, 18% in patients treated with reduced-dose TT, and 26.7% in patients treated with traditional TT ). For the 2 TT groups the relative reduction in bleeding with reduced-dose TT persisted across all 3 durations of DAPT use ( 1 In a post hoc analysis, there was a reduction in the composite of all-cause death and rehospitalizations with rivaroxaban-based strategies compared with traditional TT with warfarin. 63 The There are several notable limitations to these trials. First, a large proportion of patients underwent elective PCI (44%-72%), meaning the relative risk of coronary outcomes might be underestimated. Second, measures to decrease bleeding risk were underutilized, suggesting that the bleeding rate might have been increased in the TT arm relative to contemporary practice. Third, these trials compared dual pathway therapy using a NOAC with TT using warfarin. It is unknown whether the results would have been similar had the dual pathway therapy groups used a VKA, or the TT group used a therapeutic-dose NOAC. Last, each of the trials was powered to address safety outcomes (ie, bleeding). Although each of these trials were individually underpowered to assess efficacy outcomes (eg, mortality, stroke, and coronary outcomes) a limited metaanalysis of the What Is the Optimal Antiplatelet and Anticoagulation Therapy in Patients With Oral Anticoagulation and Coronary Stenting (WOEST), PIONEER AF-PCI, and RE-DUAL PCI trials showed that the use of dual pathway therapy was associated with a significant reduction in major bleeding events, without an excess in the occurrence of MI, definite stent thrombosis, and stroke. 65
# Duration of TT
The benefit of TT (reduction of recurrent MI and stent thrombosis) must be balanced against the increased bleeding risk with this therapeutic regimen. Importantly, the rate of bleeding with TT peaks within the first month of treatment, and thereafter the risk of bleeding is relatively stable for the duration of TT.
In the AF population, it is possible that shorter durations of DAPT might be reasonable when concomitant OAC therapy will be used for the prevention of SSE. This concept was demonstrated in the Intracoronary Stenting and Antithrombotic Regimen: Triple Therapy in Patients on Oral Anticoagulation After Drug Eluting Stent Implantation (ISAR-TRIPLE) study, which showed no significant difference in the primary end point of "net clinical benefit" (combination of death, MI, stent thrombosis, stroke, or TIMI major bleeding) between those who received 6 weeks vs 6 months of TT. A post hoc landmark analysis from 6 weeks to 9 months (ie, excluding the period in which both groups had received TT) showed a significant reduction in any Bleeding Academic Research Consortium (BARC) bleeding in the abbreviated TT group. 66 Likewise, the PIONEER AF-PCI and RE-DUAL PCI trials showed no relationship between major adverse cardiovascular events and TT duration or clinical presentation (ACS vs stable CAD). 62,64 On balance, these findings suggest that shortening the TT course to 6 months and thereafter continuing therapy with an OAC and a single antiplatelet agent, might be reasonable in the context of elevated bleeding risk.
AF patients at higher risk of stroke who undergo PCI without high-risk features AF patients at higher risk of stroke who undergo PCI for ACS or elective PCI with high-risk features Practical tip. For some patients < 65 years of age with CHADS 2 score of 1 at the lower end of the stroke risk spectrum (eg, isolated hypertension), some clinicians prefer DAPT (eg, aspirin and ticagrelor or prasugrel) in preference to triple therapy (an OAC with DAPT).
Practical tip. A PCI is considered high risk for ischemic coronary outcomes on the basis of the clinical presentation (eg, ACS), patient characteristics (comorbid diabetes mellitus treated with oral hypoglycemics or insulin, chronic kidney disease (estimated glomerular filtration rate 60 mm, complex bifurcation lesion, chronic total occlusion intervention, and stent type (eg, bioabsorbable vascular scaffold; Fig. 2).
Practical tip. All patients should receive ASA 81 mg (or a minimum of 160 mg if ASA-naive) on the day of the PCI procedure. ASA may be continued as part of TT for up to 6 months for patients with a high risk of thrombotic coronary events and low risk of bleeding. ASA can be discontinued as early as the day after PCI for patients with a low risk of thrombotic coronary events and a high risk of bleeding. For patients at intermediate risk of thrombotic coronary events and intermediate risk of bleeding ASA can be continued as part of TT for 1-3 months.
AF patients at higher risk of stroke in association with medically managed type 1 MI
# III. Investigation and Management of SCAF
The Values and preferences. For patients with AF and type 1 MI who do not undergo revascularization, the CCS AF Guidelines Committee places relatively greater emphasis on the reduction in ischemic coronary and cerebrovascular thrombotic events, rather than the increase in bleeding observed with combination therapy. When combination therapy is used the preference for clopidogrel rather than ASA is on the basis of the findings from the Clopidogrel vs Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) study, in which clopidogrel was shown to be superior to ASA (0.5% absolute reduction in composite of vascular death, MI, or ischemic stroke; P ¼ 0.043), well as the substantial efficacy and safety data for combination therapy using clopidogrel and an OAC (clopidogrel used in 88% of patients in RE-DUAL PCI and 95% in PIONEER AF-PCI). 62,64,67 studies showed that episodes of SCAF as short as 5-6 minutes occur in 30%-40% of patients with implanted devices, and is associated with a 2-to 2.5-fold increased risk of stroke. 68,69 Although clinical risk factors influence the stroke risk among patients with SCAF, this risk appeared lower than among patients with clinical AF. 70 Because patients with SCAF tend to be older and at higher risk of OAC-associated bleeding, 71 the risk-benefit ratio of using an OAC is uncertain.
It appears that an increasing duration or burden of SCAF is associated with an increase in the absolute risk of stroke. 69,72 One study suggested that there was no increased risk of stroke among patients with SCAF when their longest daily burden in the past 30 days was < 5.5 hours. 69 A more recent analysis from the ASSERT trial suggests that the increased risk of stroke with SCAF is driven by patients whose episodes exceed 24 continuous hours. 72 There is also uncertainty about the temporal relationship between SCAF and stroke, because TRENDS and ASSERT showed no temporal association between SCAF and stroke in most patients. 73,74 The only randomized evaluation of an OAC in this setting is the Combined Use of BIOTRONIK Home Monitoring and Predefined Anticoagulation to Reduce Stroke Risk (IMPACT) study. 75 IMPACT did not show any benefit from remote monitoring for SCAF with protocol-driven initiation and cessation of OAC therapy. 75 There are currently 2 randomized trials ongoing, which are randomizing patients with SCAF to treatment with an OAC vs either aspirin or placebo: Non-Vitamin K Antagonist Oral Anticoagulants in Patients With Atrial High Rate Episodes (NOAH-AF-NET-6) trial 76 and the Apixaban for the Reduction of Thrombo-Embolism Due to Sub-Clinical Atrial Fibrillation (ARTESiA) trial. 77 These 2 trials, due to complete in 2019 and 2021, respectively, will determine if and when patients with SCAF should be treated with an OAC.
# IV. Antidotes for NOACs/NOAC Reversal Agents
NOACs are the preferred agents for stroke prevention in NVAF patients who merit anticoagulation. Although there was less life-threatening bleeding with NOACs than with warfarin in the randomized controlled trials, bleeding remains an important risk. The availability of specific reversal agents has the potential to mitigate the risks associated with major bleeding events (eg, severe active hemorrhage, or bleeding in the context of emergent surgery) and, with it, patient and physician acceptance of OAC therapy.
The CCS AF Guidelines Committee recommendation for idarucizumab, the dabigatran-specific reversal agent, in patients with active bleeding or those requiring surgery, remains unchanged from the 2016 guidelines update. That recommendation was on the basis of the interim publication of the Reversal Effects of Idarucizumab on Active Dabigatran (REVERSE-AD) trial, 78 now further supported by the data from the full cohort analysis of 301 patients with uncontrollable or life-threatening bleeding (group A) and 202 patients who required urgent surgery (group B). 79 The median maximum percent reversal of the anticoagulant effect of dabigatran within 4 hours of idarucizumab administration was 100% in those who had a prolonged dilute thrombin time (DTT) or ecarin clotting time (ECT) at baseline. The reversal was rapid and occurred independently of age, sex, renal function, and dabigatran concentration at baseline. Reappearance of dabigatran levels > 20 mg/mL (below which impairment of hemostasis is unlikely) was observed in 23% of patients. This was likely due to redistribution of unbound dabigatran from the extravascular to the intravascular space, and was associated with recurrent or continued bleeding in 10 of the patients in the "life-threatening bleeding" group but none of the patients in the "urgent surgery" group. It was possible to assess time to cessation of bleeding in 134 patients in group A; median time to hemostasis was 2.5 hours after idarucizumab administration and all had confirmed bleeding cessation within 24 hours. Of the 197 patients in group B, periprocedural hemostasis was assessed as normal or mildly abnormal in 98.5%. At 30 days, thrombotic events occurred in 4.8% of all patients, with a mortality rate of 13.5% in group A, and 12.6% in group B.
Another specific reversal agent is andexanet alfa. Andexanet is a recombinant modified human factor Xa decoy protein that binds to the active site of factor Xa inhibitors and sequesters them within the vascular space. 80 The pharmacodynamic halflife is approximately 1 hour. In the Andexanet Alfa -a Novel Antidote to the Anticoagulation Effects of FXA Inhibitors (ANNEXA-4) study, patients with acute major bleeding who had received 1 of 4 factor Xa inhibitors (apixaban, rivaroxaban, edoxaban, or enoxaparin) within the previous 18 hours were treated with a bolus and 2-hour infusion of andexanet, the dose of which was dependent on the timing of the last dose of factor Xa inhibitor. 81 In the published interim analysis of 67 patients the median anti-factor Xa activity decreased by 89% (95% CI, 58%-94%) among the 26 patients who received rivaroxaban and by 93% (95% CI, 87%-94%) among the 20 patients who received apixaban. 81 Four hours after the end of the infusion, there was a relative decrease in anti-factor Xa activity from baseline of 30%-39%. Clinical hemostasis was adjudicated as excellent or good in 37 of 47 patients (78%) at the 12-hour postinfusion mark. At 30 days, the overall mortality rate was 15% (10 patients died) and thrombotic event rate was 18% (12 patients). The US prescribing information provides safety data for 185 patients, citing a 30-day thrombotic event rate of 18% (33 patients) and a mortality rate of 14% (25 deaths). 82 Although promising, there are insufficient data to recommend andexanet for RECOMMENDATION 14. We suggest that it is reasonable to prescribe OAC therapy for patients who are aged 65 years or older or with a CHADS 2 score of ! 1 (CHADS-65) who have episodes of SCAF lasting > 24 continuous hours in duration. Additionally, high-risk patients (such as those with a recent embolic stroke of unknown source) with shorter-lasting episodes might also be considered for OAC therapy (Weak Recommendation, Low-Quality Evidence).
reversal of life-threatening bleeding associated with factor Xa inhibitors at this time.
Practical tip. In acute, life-threatening bleeding situations in which standard resuscitation (such as local measures, transfusion, etc) is anticipated to be insufficient (eg, intracranial hemorrhage), or in situations in which standard resuscitation has not stabilized the patient, 5 g of intravenous (I.V.) idarucizumab should be administered as soon as possible. Activated partial thromboplastin time (aPTT) and thrombin time may be used to qualitatively identify the presence of active dabigatran at baseline in a patient, although they are less sensitive than DTT and ECT; 92% of patients in the REVERSE-AD trial had an elevated DTT or ECT, whereas only 74% had an elevated aPTT. However, obtaining these measures should not delay the administration of idarucizumab. In many instances of life-threatening bleeding, clinicians have to make a treatment decision on the basis of a history of dabigatran use rather than laboratory evidence. Renal function and timing of the last dose of dabigatran provide key information regarding the likely extent of remaining dabigatran effect.
Practical tip. "Urgent" surgery as defined in the REVERSE-AD trial is surgery that cannot be delayed beyond 8 hours (amended from 4 hours in the initial version of the protocol). The timing of surgery should be on the basis of the clinical indication and stability of the patient. In instances in which delayed surgery is appropriate, clinicians may obtain coagulation parameters (eg, thrombin time or aPTT) to identify patients who would be unlikely to benefit from idarucizumab (see the previous "practical tip").
Practical tip. Reversing dabigatran therapy exposes patients to the thrombotic risk of their underlying disease. Oral anticoagulation should be reintroduced as soon as medically appropriate.
# V. Acute Pharmacological Rhythm Control
For patients with acute AF/AFL who are eligible for cardioversion, acute rhythm control can be established via either pharmacological or electrical cardioversion. In general, DC electrical cardioversion is more effective, with immediate restoration of sinus rhythm, however, it requires the use of general anaesthesia. Pharmacological cardioversion is less effective, but avoids the risks associated with procedural sedation, and does not require a preceding period of fasting. 24,28,33,83,84 Antiarrhythmic medication selection is typically dictated by the patient's comorbidities (eg, structural heart disease), as well as physician preference. Characteristics of antiarrhythmic medications used for acute pharmacological cardioversion are shown in Table 1.
A commonly used I.V. medication for cardioversion of acute AF/AFL in the emergency department setting is the class RECOMMENDATION 15. We recommend administering idarucizumab for emergency reversal of dabigatran's anticoagulant effect in patients with uncontrollable or potentially lifethreatening bleeding and/or in patients who require urgent surgery for which normal hemostasis is necessary (Strong Recommendation, Moderate-Quality Evidence).
Values and preferences. This recommendation places relatively greater value on the ability of idarucizumab to reverse coagulation parameters indicative of dabigatran's effect, its potential to decrease bleeding-related outcomes, and risks of urgent surgery, and its safety and tolerability profile, and less value on the absence of a control group in the REVERSE-AD trial and on the cost of the drug. z Vernakalant should be avoided in patients with hypotension, recent ACS, or significant structural heart disease.
Ia agent, procainamide. 85 Procainamide is usually administered over 60 minutes at a dose of 15-18 mg/kg, although a significant amount of the clinical evidence has been on the basis of the infusion of 1 g over 60 minutes. 24,33,86 Procainamide is more effective for the conversion of acute AF (50% conversion) than for AFL (30% conversion). 86 Time to cardioversion is approximately 1 hour. 86 The most common side effect is hypotension (approximately 5%), although QRS widening, premature ventricular contractions, and Torsade de Pointes (TdP) might occur. This medication, like all drugs with class I (Na þ channel-blocking) action, should be avoided in patients with Brugada syndrome. 87 Ibutilide is an I.V. class III agent that has been shown to effectively terminate AFL (50%-75%) and AF (30%-50%), with cardioversion typically occurring within 30-60 minutes. 84 However, widespread clinical uptake has been limited by a significant risk of TdP, which occurs in approximately 2%-3% of patients. Consequently, ibutilide should not be used in patients with prolonged QTc on electrocardiogram, those with a history of HF or reduced ejection fraction, or those with electrolyte disturbances (low serum potassium or magnesium levels). Pretreatment with high-dose magnesium (! 4 g I.V.) might improve ibutilide cardioversion rates and might reduce the risk of TdP. Patients must be observed with continuous electrocardiogram monitoring for a minimum of 4 hours after ibutilide administration.
The atrial-selective antiarrhythmic drug vernakalant was recently approved by Health Canada. In an emergency department-based study of acute AF, the conversion rate was 59% and the median time to cardioversion was 12 minutes. 83 The major potential adverse effects are hypotension, along with bradycardia after cardioversion. Transient but fairly common side effects include dysgeusia (abnormal taste), paraesthesia, and nausea. Vernakalant should not be used in patients with hypotension, severe HF (New York Heart Association classification III/IV), recent ACS, or severe aortic stenosis. It is less effective in the conversion of typical AFL. 91 With the exception of patients with structural heart disease, amiodarone is not recommended for acute rhythm control because of the delayed action in conversion (approximately 8 hours). The most common adverse drug reactions with I.V. administration are phlebitis, hypotension, and bradycardia. Although there is potential for prolongation of the QT interval the incidence of TdP is rare. 95 An alternate approach is to consider oral administration of flecainide or propafenone in combination with an atrioventricular node-blocking agent (b-blockers or calcium channel inhibitors; Table 2). Although the time to cardioversion (2-6 hours) is longer than with I.V. medications, the major clinical benefit is that patients are able to treat their subsequent AF episodes using the "pill-in-the-pocket" approach, which reduces the need to visit the emergency department. A key (1) AF persistence > 6 hours after PIP-AAD administration or electrical cardioversion required for termination (2) Adverse events including symptomatic hypotension (systolic BP 90 mm Hg), symptomatic conversion pauses (> 5 seconds), symptomatic bradycardia after sinus rhythm restoration, proarrhythmia (conversion to atrial flutter/tachycardia, or episodes of ventricular tachycardia), severe symptoms (dyspnea, presyncope, syncope), or a > 50% increase in QRS interval duration from baseline Instructions for subsequent out-of-hospital use Patients should take the AV nodal agent 30 minutes after the perceived arrhythmia onset, followed by the class Ic AAD 30 minutes after the AV nodal agent. After AAD administration patients should rest in a supine or seated position for the next 4 hours, or until the episode resolves Patients should present to the ED in the event that:
(1) The AF episode did not terminate within 6-8 hours (2) They felt unwell after taking the medication at home (eg, a subjective worsening of the arrhythmia after AAD ingestion, or if they developed new or severe symptoms such as dyspnea, presyncope, or syncope) (3) More than one episode occurred in a 24-hour period (patients were advised not to take a second PIP-AAD dose within 24 hours) (4) If the AF episode was associated with severe symptoms at baseline (eg, significant dyspnea, chest pain, presyncope, or symptoms of stroke), even in the absence of PIP-AAD use AAD, antiarrhythmic drug; AF, atrial fibrillation; AV, atrioventricular; BP, blood pressure; ECG, electrocardiogram; ED, emergency department; PIP, "pill-inthe-pocket." caveat to this approach is that the first dose must be administered in a monitored environment to exclude treatmentrelated adverse reactions. 96,97 Indications, contraindications, and monitoring details are presented in Table 2.
# VI. Catheter Ablation of AF
The section on catheter ablation of AF was last updated in 2014. Since that time, there have been significant developments in periablation management and clinical trial evidence.
Uninterrupted OAC therapy with a VKA has been the standard of care periablation since clinical trials showed less bleeding and reduced thromboembolic complications compared with VKA interruption with low molecular-weight heparin bridging. 98 The safety and efficacy of uninterrupted NOAC therapy periablation, was recently explored in 3 randomized trials that compared uninterrupted NOAC with uninterrupted VKA treatment periablation. The Active-Controlled Multi-Center Study With Blind-Adjudication Designed to Evaluate the Safety of Uninterrupted Rivaroxaban and Uninterrupted Vitamin K Antagonists in Subjects Undergoing Catheter Ablation for Non-Valvular Atrial Fibrillation (VENTURE-AF) trial was the smallest (n ¼ 248) of these trials, which randomized patients to uninterrupted rivaroxaban vs uninterrupted VKA treatment. 99 The trial showed that there was no difference in major bleeding or thromboembolic events. In contrast, the Randomized Evaluation of Dabigatran Etexilate Compared to Warfarin in Pulmonary Vein Ablation: Assessment of an Uninterrupted Peri-Procedural Anticoagulation Strategy trial (RE-CIR-CUIT; n ¼ 635) showed a significant reduction in ISTH bleeding with uninterrupted dabigatran 150 mg BID compared with uninterrupted VKA (1.6% vs 6.9%, P ¼ 0.0009). 100 Of note, the number of patients with cardiac tamponade and with groin hematoma was higher in the VKA arm. There was no difference in the number of patients with a thromboembolic event, with only 1 in the VKA arm. Finally, the recently published Anticoagulation Using the Direct Factor Xa Inhibitor Apixaban During Atrial Fibrillation Catheter Ablation (AXAFA) trial (n ¼ 674) showed no difference between uninterrupted apixaban and uninterrupted VKA treatment for either bleeding or thromboembolic events. 101 This trial also performed a substudy of post-ablation cerebral magnetic resonance images to look for subclinical cerebral microemboli and again, there was no difference between strategies. The ongoing Evaluation of Edoxaban Compared With VKA in Subjects Undergoing Catheter Ablation of Nonvalvular Atrial Fibrillation (ELIMINATE-AF) trial will report on uninterrupted edoxaban vs uninterrupted VKA treatment (ClinicalTrials.gov NCT02942576). On the basis of these data we make the following recommendation.
Other important clinical trials included Substrate and Trigger Ablation for Reduction of Atrial Fibrillation (STAR AF II), which compared 3 techniques for ablation of persistent AF. 102 Although guidelines had made the assumption that more extensive ablation was required for treating these patients, the trial showed that strategies of additional use of empiric linear ablation or targeted electrogram ablation in addition to pulmonary vein isolation did not improve freedom from AF over pulmonary vein isolation alone.
Previous iterations of the CCS AF guidelines recommend a trial of antiarrhythmic drugs (AADs) before considering an ablation procedure for most patients, with first-line ablation therapy reserved for highly selected symptomatic patients with paroxysmal AF. These recommendations are on the basis of the results of several randomized controlled studies that showed superior freedom from recurrent arrhythmia, a reduction in the overall AF burden, and improvement in symptoms, exercise capacity, and quality of life with catheter ablation relative to AAD therapy. The Catheter Ablation vs Anti-Arrhythmic Drug Therapy for Atrial Fibrillation (CABANA) trial was designed to evaluate the effect of ablation on mortality, stroke, and bleeding end points. 112 This study randomized older, higher-risk patients to ablation (n ¼ 1108) or drug therapy (n ¼ 1096). At the time of this guideline update, the study had not been published, but the presented results showed no difference in the primary composite outcome (death, disabling stroke, serious bleeding, or cardiac arrest) at 5 years in an intention to treat analysis (HR, 0.86; 95% CI, 0.65-1.15). Despite a high rate of crossover (9.2% not receiving ablation in the intervention arm and 27.5% of drug therapy patients receiving ablation) a significant reduction in the secondary end point of death and cardiovascular hospitalization was observed (HR, 0.83; 95% CI, 0.74-0.93). Moreover, the "on treatment" analysis, which evaluated the patients who received ablation showed a significant reduction in the primary end point (HR, 0.67; 95% CI, 0.50-0.89) with associated significant reductions in all-cause mortality (HR, 0.60; 95% CI, 0.42-0.86) and death and cardiovascular hospitalization (HR, 0.83; 95% CI, 0.74-0.94) compared with drug therapy. Until the full publication is available, however, the Guideline Committee has not changed its recommendation that AF ablation should be second-line therapy for most patients and first-line therapy only for highly selected patients.
# Ablation in patients with AF and HF
AF and HF frequently coexist, with AF representing an independent predictor of progression, hospitalization, and death in the HF population. Although restoring and maintaining sinus rhythm has been considered as a therapeutic target to improve clinical outcomes, large randomized controlled trials of AADs have failed to support this hypothesis. It is postulated that the attenuated benefit observed with AAD therapy is related to cardiac and noncardiac toxicities (eg, proarrhythmia or negative inotropy). As such, ablation has been proposed as a more efficacious means to improve outcomes.
To date, 7 randomized trials have been performed (Table 3). Collectively these randomized studies have shown a single-procedure success (eg, elimination of any AF episodes > 30 seconds) in the range of 40%-69%, with RECOMMENDATION 16. We suggest that catheter ablation may be performed using uninterrupted therapeutic oral anticoagulation with either a NOAC or adjusted-dose warfarin (Weak Recommendation, Moderate-Quality Evidence). However, a more substantial quantification of the utility of catheter ablation in patients with AF and HF with reduced systolic function is the objective outcomes, such as mortality and hospitalization. Although CABANA failed to show significant mortality benefit in unselected populations, recent randomized trials have shown that catheter ablation of AF in HF patients with reduced LVEF results in significant improvement in allcause mortality as well as fewer HF hospitalizations. 128,131,132 The first of these studies was the Ablation vs Amiodarone for Treatment of Persistent Atrial Fibrillation in Patients With Congestive Heart Failure and an Implanted Device (AATAC) study, which randomized 203 patients with New York Heart Association functional class II-III HF and an LVEF < 40% to catheter ablation (n ¼ 102) or amiodarone rhythm control (n ¼ 101). 128 After 24-27 months of follow-up, patients in the ablation group had a significantly greater freedom from recurrent AF (70% vs 34%; P < 0.001). In addition, the secondary end points of unplanned hospitalization and all-cause mortality were both significantly reduced (45% and 56%, respectively), corresponding to number needed to treat of 3.8 for unplanned hospitalization and 10 for all-cause mortality. The second study, Catheter Ablation vs Standard Conventional Therapy in Patients with Left Ventricular Dysfunction and Atrial Fibrillation (CASTLE-AF), randomized patients with symptomatic paroxysmal or persistent AF, New York Heart Association class II-IV HF, and an LVEF 35% to catheter ablation (179 patients) or medical therapy (184 patients). 131 All patients had a cardiac implantable device (implantable cardioverter defibrillator or cardiac resynchronization therapy-implantable cardioverter defibrillator). After a median follow-up of 37.8 months, patients in the ablation group were significantly less likely to meet the primary composite end point of all-cause mortality or HF admission (16.1% absolute reduction; HR, 0.62; 95% CI, 0.43-0.87; P ¼ 0.006). Similar to AATAC, there was a 47% relative reduction in all-cause mortality (HR, 0.53; 95% CI, 0.32-0.86) and a 44% reduction in HF hospitalization (HR, 0.56; 95% CI, 0.37-0.83).
Taken together, these studies show that catheter ablation is associated with an improvement in all-cause mortality (8.1% vs 15.9%; RR, 0.52; 95% CI, 0.35-0.76; P < 0.01), a reduction in HF hospitalization (17.7% vs 31.3%; RR, 0.57; 95% CI, 0.45-0.72; P < 0.01) and ejection fraction, compared with medical therapy. Ongoing randomized controlled trials in the AF and HF population will assess the effect of AF ablation on all-cause mortality (Rhythm Control -Catheter Ablation With or Without Anti-arrhythmic Drug Control of Maintaining Sinus Rhythm Versus Rate Control With Medical Therapy Although these results are compelling, the committee decided not to add a new recommendation for ablation in HF patients. Instead, we believe that the existing recommendation to pursue catheter ablation as a second-line treatment for symptomatic patients applies to this group. Despite the lack of a new recommendation specifically for patients with HF and a reduced LVEF, it is important to recognize that the consideration of patients with structural heart disease as an appropriate ablation candidate does represent a philosophical shift in practice because these patients were previously discouraged from ablation because of concerns regarding potential inefficacy and harm.
# VII. Integrated Approach to AF and Modifiable Cardiovascular Risk Factors
There are several care gaps in AF management, specifically in the domains of stroke prevention, in the timing/appropriateness of transitions between rate and rhythm control, as well in the assessment for ablation procedure candidacy. 133,134 Dedicated multidisciplinary clinics specifically focused on AF care have recently been developed as a means to facilitate patient and provider education, as well as to provide evidence-based care centred on chronic disease management principles. Previous studies have suggested that a combined specialist and nursebased AF clinic is associated with improved adherence to guideline-based care, enhanced transitions of care (from the emergency room to the specialty clinic and back to community care), and significant improvement in quality of life. 51, In addition, systematic multidisciplinary AF clinics have been shown to reduce cardiovascular death (HR, 0.28 vs usual care) and cardiovascular hospitalization (HR, 0.66 vs usual care). 135 Analogous multidisciplinary models of care, such as HF clinics, have shown similar benefits in cardiovascular outcomes as well as cost-effectiveness. 139,140 Greater coordination of care with nursing interventions has been shown to result in more efficient use of resources, 141 better coordination of heart rhythm procedures, 142,143 and better implementation of other cardiac therapies for patients with HF. 144,145 In the Canadian context, reduced wait times, improved implementation of recommendations, and more effective use of tertiary care resources has been shown. 146 Although the genesis of AF clinics in Canada arises from the Calgary model, similar programs now exist across the country. 147 Although individually tailored to the needs of their communities, these Canadian AF clinics are broadly on the basis of the principles of: (1) timely access to specialist care, to reduce adverse outcomes (eg, stroke or rehospitalization) imposed by delays in treatment initiation; (2) knowledge translation, because improved understanding of AF facilitates active participation by the patient in their treatment pathway, with secondary benefits in treatment adherence and persistence; and (3) guideline adherence, in particular in the domains of stroke prevention and comorbidity management (eg, hypertension, obesity, and sleep apnea). 70,147,148 This last point is especially relevant as a systematic approach to patient care, including protocol-driven management on the basis of contemporary guidelines, and offers an opportunity for holistic management of the patient beyond the heart rhythm.
Recently, there has been a renewed focus on the contribution of modifiable cardiovascular risk factors to the causation and persistence of AF. Although the precise mechanistic links between risk factors and AF occurrence remain somewhat uncertain, information available from the literature provides many potential insights. Hypertension, the most significant population-attributable modifiable risk factor for AF, causes activation of the sympathetic and renin-angiotensin-aldosterone systems, as well as structural and electrophysiological atrial remodelling that enhances AF susceptibility. Diabetes mellitus promotes AF via structural remodelling (possibly mediated by advanced glycosylation end-products) and autonomic remodelling. Tobacco use promotes AF through a combination of the direct effects of nicotine on the atrium (eg, altered atrial conduction and refractoriness), as well as structural remodelling, inflammation, and oxidative stress. Alcohol, when consumed in excess, promotes AF through the induction of arrhythmia triggers (increased sympathetic activity/impairment of vagal tone) as well as atrial fibrosis (from the direct toxic effects of alcohol metabolites). Obesity promotes AF through weight-related structural remodelling (changes in atrial dimensions and interstitial fibrosis), weight-related electrophysiological remodelling (conduction slowing and shortening of the effective refractory period), autonomic dysfunction, and inflammation. Obstructive sleep apnea promotes AF acutely through strongly negative intrathoracic pressures leading to increased venous return (AF-promoting left atrial volume loading) and hypoxia-induced pulmonary vasoconstriction. Chronic obstructive sleep apnea induces electrical and structural remodelling of the atria, autonomic dysregulation, oxidative stress, and inflammation.
Previous studies have shown that intensive risk factor management has beneficial effects on AF. 152,153 Rienstra et al. reported improved maintenance of sinus rhythm at 1 year with a strategy of cardiac rehabilitation, HF medication optimization, and aggressive blood pressure control (75% maintenance of sinus rhythm on a 7-day Holter vs 63% in the control group; OR, 1.77; P ¼ 0.042). 153 The Long-Term Effect of Goal-Directed Weight Management on Atrial Fibrillation Cohort: A Long-Term Follow-Up Study (LEGACY) cohort study showed that patients with a weight loss of > 10% was associated with a 6-fold increase in the likelihood of being arrhythmia-free over a 5-year follow-up period compared with those with lesser degrees of weight loss ( 2 peak metabolic equivalents (METs) improvement in cardiorespiratory fitness was associated with a significantly reduced AF burden compared with a gain of < 2 METs over long-term follow-up. 155 This response was proportional to the increase in cardiorespiratory fitness, with an adjusted reduction in AF recurrence of 10% for each MET gained (HR, 0.90; 95% CI, 0.83-1.00). 155 These data suggest that a comprehensive management strategy that includes suppression of triggers (targeted by risk factor modification, AADs, and/or catheter ablation) and amelioration of arrhythmogenic substrate (risk factor modification) might lead to improved outcomes. Further research is required to determine whether these interventions will effectively alter the occurrence or progression of AF, when it is present.
It is the opinion of the AF Guidelines Committee that, for now, the emphasis of risk factor modification should focus on cardiovascular event reduction with the optimal management of risk factors and concomitant disorders (Table 4), following the recommendations of the 2018 Canadian dyslipidemia, 156 hypertension, 157 and diabetes 158 guidelines.
Practical tip. The detection and optimal management of risk factors and concomitant disorders together with appropriate rate/rhythm control and stroke prevention might contribute to a reduction in cardiovascular-related emergency department visits and hospitalizations. Addressing such risk factors might be most comprehensively and efficiently accomplished through a specialized clinic or other multidisciplinary management approach, and through use of a standardized, systematic protocol-based approach. RECOMMENDATION 17. We recommend systematic and strict guideline-adherent management of traditional modifiable cardiovascular risk factors and/or conditions associated with AF, to reduce cardiovascular events (eg, stroke, MI, etc; Strong Recommendation, High-Quality Evidence).
Values and preferences. This recommendation places a high value on a systematic approach to providing guideline-directed therapy for any cardiovascular risk factors and/or conditions associated with AF.
# RECOMMENDATION
- We suggest that, in addition to implementing appropriate rate or rhythm control measures, an approach targeting modifiable risk markers and conditions associated with AF should be applied to prevent recurrence of the arrhythmia and/or decrease its symptom burden (Weak Recommendation, Low-Quality Evidence).
Values and preferences. The aggressive treatment of obesity and cardiometabolic risk markers/conditions (including hypertension, HF, diabetes, and sleep apnea) has been shown to reduce AF burden and improve quality of life. This recommendation places a high value on the recognized association between these potential risk markers and conditions that are known to aggravate AF and the possibility that treatment of these might result in prevention and/or regression of the substrate that causes AF as well as improvement of patient symptoms. | The Canadian Cardiovascular Society (CCS) Atrial Fibrillation Guidelines Committee provides periodic reviews of new data to produce focused updates that address clinically important advances in atrial fibrillation (AF) management. This 2018 Focused Update addresses: (1) anticoagulation in the context of cardioversion of AF; (2) the management of antithrombotic therapy for patients with AF in the context of coronary artery disease; (3) investigation and management of subclinical AF; (4) the use of antidotes for the reversal of nonvitamin K antagonist oral anticoagulants; (5) acute pharmacological cardioversion of AF; (6) catheter ablation for AF, including patients with concomitant AF and heart failure; and (7) an integrated approach toLe comit e des lignes directrices en matière de fibrillation auriculaire de la Soci et e canadienne de cardiologie (SCC) procède à des examens p eriodiques des nouvelles donn ees pour produire des mises à jour th ematiques portant sur des avanc ees cliniquement importantes de la prise en charge de la fibrillation auriculaire (FA). La mise à jour cibl ee 2018 porte sur les aspects suivants : 1) l'anticoagulation dans le contexte de la cardioversion de la FA; 2) la prise en charge du traitement antithrombotique des patients atteints de FA dans le contexte d'une coronaropathie; 3) la recherche et la prise en charge de la FA sub-clinique; 4) les antidotes aux anticoagulants oraux non-vitamine K; 5) cardioversion pharmacologique aiguë de la FA; 6) l'ablation par#
The contemporary management of atrial fibrillation (AF) is centred on a reduction in the morbidity and mortality associated with AF, as well as on symptomatic improvement with consequent reduction in AF-related emergency room visits or hospitalizations. 1 The Canadian Cardiovascular Society (CCS) Atrial Fibrillation Guidelines committee provides periodic reviews of new data to produce focused updates that address clinically important advances in AF management. The committee reviewed data published since the 2016 Focused Update for the management of AF. This 2018 Focused Update addresses:
1. Anticoagulation in the context of cardioversion of AF; 2. The management of antithrombotic therapy for patients with AF in the context of coronary artery disease (CAD); 3. Investigation and management of subclinical AF (SCAF); 4. The use of antidotes for the reversal of non-vitamin K antagonist oral anticoagulants (NOACs); 5. Acute pharmacological cardioversion of AF; 6. Catheter ablation for AF, including patients with concomitant AF and heart failure (HF); 7. Integrated approach to the patient with AF and modifiable cardiovascular risk factors.
The recommendations were developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) standards with strength of recommendations now classified as "strong" or "weak." Details of the updated recommendations are presented, along with their background and rationale. The literature review process and evidence tables are included as Supplementary Material, along with an updated summary of all CCS AF Guidelines Recommendations on the CCS Web site.
# I. Anticoagulation in the Context of Cardioversion
There have been no randomized clinical trials of oral anticoagulation (OAC) therapy vs placebo for prevention of thromboembolic events at the time of cardioversion. Because of the stroke risk associated with cardioversion in the absence of anticoagulation, it is unlikely that such a study will be done. [2][3][4][5][6][7][8][9][10][11][12][13][14] Contemporary estimates of the risk of thromboembolic events around the time of cardioversion can be obtained from analysis of the results of the pivotal randomized trials of adjusted-dose warfarin vs NOACs, [10][11][12][13] reports of outcomes of cardioversions performed during these pivotal trials, [2][3][4][5] and reports of randomized trials of adjusted-dose warfarin therapy vs NOAC therapy before cardioversion. [6][7][8] Using these sources, the 1-month risk of stroke or systemic embolism (SSE) after cardioversion is estimated to be 0.46% for those treated with adjusted-dose warfarin and 0.31% for those treated with a NOAC. These risks are approximately twofold greater for a thromboembolic event in the month after cardioversion compared with the background risk (0.14% and 0.12% per month baseline stroke risk in those treated with adjusted-dose warfarin and with a NOAC, respectively). For those not receiving anticoagulant therapy the risk of a thromboembolic event is increased approximately fourfold (1.9% for the month after cardioversion vs 0.5% per month baseline risk). [9][10][11][12][13] The thromboembolic risk in the pericardioversion period can be conceptually separated into 2 mechanistic phenomena. The first is the generation of thrombi during persistent AF, with subsequent embolization after restoration of an organized atrial contraction. 15 The second relates to a period of transient atrial mechanical dysfunction after the restoration of sinus rhythm. [16][17][18] This "atrial stunning" is responsible for the development of new thromboembolism post cardioversion despite the restoration of sinus rhythm. 19,20 This atrial mechanical dysfunction has been reported with all modes of conversion (pharmacologic, electrical, and spontaneous) and is at maximal in the period immediately after cardioversion. [19][20][21][22] The duration and severity of atrial stunning varies depending on the duration of the atrial arrhythmia, the atrial size, as well as the presence of comorbid structural heart disease. [19][20][21][22]
# OAC use before and after cardioversion
Patients who present with acute (episode duration < 48 hours) nonvalvular AF (NVAF; ie, AF in the absence of rheumatic mitral stenosis, moderate-severe nonrheumatic mitral stenosis, or a mechanical heart valve) have long been considered to have a low risk of thromboembolic events after cardioversion on the basis of the rationale that left atrial thrombi have not yet had time to form. This practice has been supported by observational reports of short-term outcomes after cardioversion in patients with acute AF/atrial flutter (AFL). [23][24][25][26][27][28][29][30][31][32][33][34][35][36] In these reports the post cardioversion the patient with AF and modifiable cardiovascular risk factors. The recommendations were developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) standards. Individual studies and literature were reviewed for quality and bias; the literature review process and evidence tables are included as Supplementary Material and are available on the CCS Web site. Details of the updated recommendations are presented, along with their background and rationale. This document is linked to an updated summary of all CCS AF guidelines recommendations, from 2010 to the present 2018 Focused Update, which is provided in the Supplementary Material.
cath eter de la FA, y compris chez les patients atteints d'insuffisance cardiaque; 7) une approche int egr ee du patient pr esentant une FA et des facteurs de risque cardiovasculaire modifiables. Les recommandations ont et e elabor ees à l'aide du système GRADE (Grading of Recommendations, Assessment, Development, and Evaluation). Chaque etude et chaque publication ont et e soumises à un examen visant à evaluer leur qualit e et leurs biais; le processus d'examen des publications et les tableaux de donn ees probantes sont pr esent es sous la forme d'un suppl ement accessible sur le site Web de la SCC. Les d etails des recommandations mises à jour sont pr esent es, ainsi que leur contexte et leur justification. Ce document comporte un lien vers un sommaire mis à jour de toutes les lignes directrices en matière de FA de la SCC, de 2010 à la pr esente mise à jour cibl ee 2018, qui est offerte dans le suppl ement en ligne.
30-day risk of SSE was reported to be 0.19% (4047 patients who underwent 4503 spontaneous, pharmacologic, or electrical cardioversions). Although this risk is comparable with that of elective cardioversion in more persistent AF/AFL patients who receive anticoagulation therapy, it is important to recognize that these reports describe cohorts of stable patients at low risk of thromboembolism for whom cardioversion was considered to be an appropriate therapeutic option by their treating physician. Specifically, these patients had a low baseline stroke risk (69% of patients with a Congestive Heart Failure, Hypertension, Age, Diabetes, Stroke/Transient Ischemic Attack [CHADS 2 ] score of 0-1; 28% receiving chronic OAC therapy) and presented early in the 48-hour window (mean duration of acute AF/AFL of 8.0 hours). Nevertheless, these data suggest that it might be possible to identify a population of patients with acute AF/ AFL who are at low risk of a thromboembolic event associated with cardioversion.
Conversely, previous CCS AF guidelines have suggested that it is might be possible to identify a population of patients with acute AF/AFL in whom immediate cardioversion without preprocedural anticoagulant therapy presents an unacceptably high risk of thromboembolic complication. Such patients were considered, in previous CCS AF guidelines, to include those with a stroke or transient ischemic attack within the previous 6 months, those with moderate to severe rheumatic mitral stenosis, and those with a mechanical heart valve. 37 The Finnish Cardioversion (FinCV) study was a retrospective, observational study that determined outcomes in consecutive patients who underwent cardioversion of acute AF (duration < 48 hours). This study included 7660 [38][39][40][41] To date, several analyses have been performed and showed the following key findings. First, the incidence of definite SSE was lower in patients receiving anticoagulation therapy. 40 In an analysis of the total patient population, the incidence of SSE in patients who were receiving anticoagulation therapy at the time of their cardioversion attempt (0.1% in 2298 encounters) was significantly lower than in patients not receiving anticoagulation therapy (0.7% in 5362 encounters; 82% relative risk [RR] reduction; P ¼ 0.001). 40 In patients with a CHA 2 DS 2 -VASc score ! 2, the risk of SSE after a cardioversion attempt was significantly lower in patients receiving anticoagulation therapy (3 of 1708 encounters; 0.2%) than in patients not receiving anticoagulation therapy (28 of 2590 encounters; 1.1%; P ¼ 0.001). In patients with a CHA 2 DS 2 -VASc score of 0-1, the risk of SSE after a cardioversion attempt was quantitatively lower in patients receiving anticoagulation therapy (0 of 509 encounters; 0.0%) than in patients not receiving anticoagulation therapy (10 of 2772 encounters; 0.4%), but this trend was not statistically significant despite the relatively large number of subjects. 40 Second, longer durations of AF before cardioversion, even in the 48-hour window of acute AF, were associated with a significantly increased risk of SEE. 38,41 In a cohort restricted to the 5116 successful cardioversions performed in the absence of periprocedural or postprocedural anticoagulation in 2481 patients, multivariable logistic regression analysis showed an increased incidence of SSE in patients cardioverted in the time window after AF onset of 12-24 hours (21 of 1840 encounters; 1.1%; odds ratio [OR], 3.3; 95% confidence interval [CI], 1.3-8.9; P ¼ 0.001) or in the time window after AF onset of 24-48 hours (9 of 836 encounters; 1.1%; OR, 4.0; 95% CI, 1.7-9.1; P ¼ 0.02) compared with those cardioverted in < 12 hours after AF onset (8 of 2400 encounters; 0.3%). 38 Third, the statistically significant independent predictors of an increased incidence of SSE in the month after cardioversion of acute AF in the complete cohort were increasing age (per year; OR, 1.05; 95% CI, 1.02-1.09; P < 0.001), AF episode duration > 12 hours (OR, 3.89; 95% CI, 1.76-8.60; P ¼ 0.001), HF (OR, 3.37; 95% CI, 1.39-8.19; P ¼ 0.007), diabetes mellitus (OR, 2.66; 95% CI, 1.25-5.69; P ¼ 0.012), and female sex (OR, 2.11; 95% CI, 1.04-4.28; P ¼ 0.038). 39,40 A recent report from the Swedish National Patient Registry 42 described outcomes in 10,722 patients who underwent direct current (DC) cardioversion of AF (the duration of AF being unavailable) between January 1, 2006 and December 1, 2010. The 30-day incidence of thromboembolic complication in patients not receiving periprocedural anticoagulation therapy was significantly higher than those receiving anticoagulation therapy (0.9% vs 0.3%; OR, 2.54; 95% CI, 1.70-3.79; P < 0.001); the increased OR persisted even after matching patients on the basis of the components of the CHA 2 DS 2 -VASc and Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly (> 65 Years), Drugs/Alcohol Concomitantly (HAS-BLED) scores (OR, 2.51; 95% CI, 1.69-3.75; P < 0.001). Similar findings were observed in a recent observational analysis of the Danish National Patient Registry. 14 This analysis included 16,274 patients discharged from hospital after a first-time DC cardioversion for AF between 2000 and 2008. The 30-day incidence of a thromboembolic event after DC cardioversion was 0.29% (32 of 11,190 patients) in those who received a preprocedure OAC compared with 1.1% (54 of 5084) in patients who did not receive a preprocedure OAC. 14 Although age > 75 years, previous SSE, and rehospitalization for AF were significant risk factors for thromboembolism, the CHADS 2 and CHA 2 DS 2 -VASc scores offered no discriminative ability in those not receiving OAC therapy (hazard ratio [HR], 2.21; 95% CI, 0.79-6.77 and 2.40; 95% CI, 1.46-3.95 with CHA2DS2-VASc score 0-1 and CHA2DS2-VASc score 2 or more). Conversely, the risk of thromboembolism was low in patients who initiated OAC therapy only after cardioversion and was comparable with those who received OAC therapy before and after cardioversion (HR, 0.97 for those with only post cardioversion OAC therapy vs those who received OAC therapy pre/post cardioversion; 95% CI, 0.33-2.86).
Overall, the available evidence suggests that the incidence of a definite SSE in the month after cardioversion from acute AF/AFL (< 48 hours) in patients who were not receiving anticoagulation is approximately 0.7%, 40 which is above the thromboembolic risk threshold that the CCS uses to recommend anticoagulation therapy.
The comprehensive recommendations regarding cardioversion follow and are summarized in Figure 1.
Practical tip. NVAF is defined as AF in the absence of mechanical heart valves, rheumatic mitral stenosis, or moderate to severe nonrheumatic mitral stenosis.
Practical tip. When oral anticoagulation is to be used for only a short period (< 2 months) current evidence does not substantiate either an efficacy or safety advantage for use of a NOAC over adjusted-dose warfarin. Nevertheless, the convenience of use of a NOAC over adjusted-dose warfarin in the pericardioversion period is substantial and the onset of therapeutic anticoagulation is nearly immediate with a NOAC whereas it is delayed in the case of adjusted-dose warfarin. Accordingly, it is reasonable to use NOAC therapy in the pericardioversion period.
# The use of TEE to exclude left atrial thrombus
When early cardioversion is desired (ie, without a preceding period of therapeutic OAC treatment) TEE can be performed to exclude left atrial thrombi. The utility of this approach was shown by Klein et al., who randomized 1222 patients with AF of > 48-hour duration and assigned them to TEE-guided cardioversion, or conventional treatment (eg, pretreatment with warfarin for 3 weeks before cardioversion). 43 Although there was no significant difference in the rate of embolic events (0.8% in the TEE group vs 0.5% in the conventional group; P ¼ 0.50), the TEE group had a significantly lower rate of hemorrhagic events (2.9% vs 5.5%; P ¼ 0.03), a significantly shorter time to cardioversion (3.0 AE 5.6 vs 30.6 AE 10.6 days, P < 0.001), and a greater success rate (sinus rhythm restoration of 71.1% vs 65.2%; P ¼ 0.03).
# NOACs vs warfarin for cardioversion
Each of the pivotal trials that compared NOACs with adjusted-dose warfarin reported short-term, prospective, nonrandomized efficacy and safety outcomes after DC cardioversion in study participants with persistent AF/AFL. [2][3][4][5] Similarly, prospective, randomized trials have been completed that compared 3 of the currently available NOACs with adjusted-dose warfarin in the setting of planned cardioversion. 7,8 The data of the Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY), 10 Values and preferences. This recommendation places a high value on immediately addressing instability by attempting cardioversion, and a lower value on reducing the risk of cardioversion-associated stroke with a period of anticoagulation before cardioversion. Therapeutic anticoagulation therapy should be initiated as soon as possible.
5. When a decision has been reached that a patient will be undergoing unplanned cardioversion of AF/AFL, we suggest that therapeutic anticoagulation therapy be initiated immediately (preferably before cardioversion) with either a NOAC, or with heparin followed by adjusted-dose warfarin (Weak Recommendation, Low-Quality Evidence).
6. We suggest that, in the absence of a strong contraindication, all patients who undergo cardioversion of AF/ AFL receive at least 4 weeks of therapeutic anticoagulation (adjusted-dose warfarin or a NOAC) after cardioversion. (Weak Recommendation, Low-Quality Evidence). Thereafter, we recommend that the need for ongoing antithrombotic therapy should be on the basis of the risk of stroke as determined by the CCS Algorithm ("CHADS-65"; Strong Recommendation, Moderate-Quality Evidence).
Values and preferences. This approach places relatively greater emphasis on the benefits of stroke prevention compared with the risks of bleeding with a short course of anticoagulation therapy. Although it might be possible to parse these risks either on the basis of patient characteristics or the duration of acute AF/AFL, the CCS AF Guidelines Committee at this point has chosen to simplify by recommending anticoagulation for 1 month after cardioversion for all such patients in the absence of a strong contraindication.
Inhibition Compared With Vitamin K Antagonist for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF), 11 Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARIS-TOTLE), 12 Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48), 13 Explore the Efficacy and Safety of Once-Daily Oral Rivaroxaban for the Prevention of Cardiovascular Events in Patients With Non-Valvular Atrial Fibrillation Scheduled for Cardioversion (X-VeRT), 6 and Edoxaban vs Warfarin in Subjects Undergoing Cardioversion of Atrial Fibrillation (ENSURE-AF) 7 trials formed the basis of a comparative meta-analysis reported by Renda et al. 44 In these trials, 6148 patients underwent 6854 cardioversions for AF and were followed for a mean of 42 days. Collectively, there were no significant differences between NOACs and adjusted-dose warfarin with respect to either efficacy (RR, 0.82; 95% CI, 0.38-1.75 for SSE) or safety (RR, 0.98; 95% CI, 0.51-1.87 for major bleeding).
Published after the meta-analysis by Renda et al., Eliquis Evaluated in Acute Cardioversion Compared to Usual Treatments for Anticoagulation in Subjects With Atrial Fibrillation (EMANATE) 8 randomized 1500 patients who were not receiving OAC therapy to receive apixaban (753 patients) or heparin followed by VKA (747 patients) before DC cardioversion of persistent AF/AFL. Mean time to cardioversion was 3.4 days in the apixaban loading dose group, 25.7 days in the apixaban (no loading dose) group, and 17.8 days in the VKA group. In an intention-to-treat analysis, no patient randomized to receive apixaban had a SSE (0%) whereas 6 patients randomized to receive heparin/VKA therapy (0.8%) had a stroke (log rank P ¼ 0.016). In patients who had received at least 1 dose of their assigned anticoagulant therapy there were 3 major bleeding events and 11 clinically relevant nonmajor bleeding events in 735 patients (total of 1.9%) in the apixaban group and 6 major bleeding events and 13 clinically relevant nonmajor bleeding events in 721 patients (2.6%) in the heparin/VKA group (P ¼ not significant).
It should be noted that these trials, individually and in their aggregate, were not sufficiently powered to exclude a clinically meaningful difference in either safety or efficacy. In the absence of a signal suggesting inferiority in safety or efficacy outcomes, the committee considered that NOAC therapy has advantages over dose-adjusted warfarin therapy (rapidity of onset and offset, standard dosages, and lack of need for therapeutic monitoring). Accordingly, NOAC therapy is preferred over adjusted-dose warfarin in the pericardioversion period in anticoagulation-naive patients.
# II. Management of Antithrombotic Therapy in Patients With AF and CAD
Up to 20%-30% of AF patients also have concomitant CAD, with a significant proportion requiring percutaneous coronary intervention (PCI). 45,46 An OAC is indicated for the prevention of AF-related SSE, whereas antiplatelet therapy is required for the prevention of coronary events after ACS or PCI. Each offers a relative efficacy benefit (eg, dual antiplatelet therapy [DAPT] is more effective than an OAC alone in reducing ischemic coronary events in an ACS population, but is inferior to an OAC for the prevention of SSE in an AF/AFL population at increased risk of AF-related stroke). 47 As such, management requires a careful and balanced assessment of the individual risks of bleeding against the anticipated effect on thrombotic outcomes.
The extensive evidence for antithrombotic therapy for the prevention of SSE among patients with AF/AFL has been thoroughly reviewed in previous CCS guidelines and is not reviewed in depth herein. [48][49][50][51][52] This section specifically focuses on antithrombotic regimens for AF patients with coronary or peripheral arterial disease, with an emphasis on the evidence published since the previous AF guideline update in 2016. 49 The recommendations for patients who undergo PCI with AF are consistent with the 2018 CCS/Canadian Association of Interventional Cardiology (CAIC) focused update of the guidelines for the use of antiplatelet therapy. 52 To clarify potentially confusing terminology in this area, single-agent antiplatelet therapy (SAPT) refers to the use of a single antiplatelet drug (eg, acetylsalicylic acid [ASA]), DAPT refers to the concomitant use of 2 antiplatelet agents (eg, ASA with clopidogrel), dual pathway therapy refers to the concomitant use of a SAPT with an OAC agent (eg, VKA with clopidogrel), and triple antithrombotic therapy (TT) the combination of DAPT with an OAC (eg, VKA with ASA and clopidogrel).
Practical tip. For patients who require combinations of antiplatelet and OAC agents for concomitant AF and coronary/arterial vascular disease, we suggest that measures be used to reduce the risk of bleeding, including careful consideration of modifiable bleeding risk factors with vigorous efforts to mitigate them; consideration of proton pump inhibitor use; avoidance of prasugrel and ticagrelor in conjunction with OACs; the use of warfarin in the lower target international normalized ratio (INR) range (eg, 2.0-2.5); consideration of the lower effective doses of NOACs in selected patients (Fig. 3); specific measures during coronary invasive procedures (radial access, small-diameter sheaths, early sheath removal from femoral site, and minimized use of acute procedural antithrombotic therapies); delaying nonurgent procedures until dual pathway therapy is no longer required; use of walking aids for those with gait or balance disorders; avoidance of nonsteroidal anti-inflammatory drugs or other drugs that might increase bleeding risk; and, strict blood pressure control.
# Stable vascular disease and AF in patients at low risk of SSE
SAPT (eg, ASA 81 mg/d) is recommended for patients with AF who are at low risk of SSE (age < 65 years and CHADS 2 score of 0) if vascular disease is present (CAD, peripheral arterial disease, or aortic plaque). This is on the basis of the efficacy of ASA therapy for the prevention of coronary events among patients with stable CAD (RR reduction of 18% for primary prevention and 20% for secondary prevention of MI), rather than the small reduction in stroke observed in AF patients (RR reduction, 22% vs placebo). 9,53 Although there is extensive evidence for the efficacy of OAC therapy for prevention of ischemic coronary events in patients with stable CAD (eg, VKA), the CCS AF guidelines recommend SAPT in preference to OACs in those at low risk of SSE because of its safety profile and ease of use.
More recently, in a non-AF population, the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial showed that dual pathway therapy with ASA and "vascular dose" rivaroxaban (2.5 mg twice per day [BID]) was associated with a significant reduction in cardiovascular mortality and ischemic stroke, albeit with a significantly increased risk of major bleeding. 54 As such the combination of ASA and very low dose rivaroxaban might be a reasonable alternative to ASA alone for NVAF patients at low risk of stroke (age < 65 years and CHADS 2 score of 0) who also have coronary or arterial vascular disease.
Practical tip. For patients with NVAF/AFL aged < 65 years with no CHADS-65 risk factors, the risk of stroke associated with AF is not sufficiently elevated to justify OAC therapy. For this group treatment should be directed at the underlying coronary/peripheral arterial disease as outlined in
# RECOMMENDATION
8. For patients with NVAF/AFL aged < 65 years with no CHADS 2 risk factors, we suggest no antithrombotic therapy for stroke prevention (Weak Recommendation, Moderate-Quality Evidence), with management of their coronary or arterial vascular disease as directed by the 2018 CCS/CAIC focused update of the guidelines for the use of antiplatelet therapy. 52 the 2018 CCS/CAIC focused update of the guidelines for the use of antiplatelet therapy. 52 Therapeutic options include ASA 81 mg daily alone; or ASA in combination with either clopidogrel 75 mg daily, ticagrelor 60 mg BID, or rivaroxaban 2.5 mg BID.
# Stable vascular disease and AF in patients at high risk of SSE
In patients with AF who are aged ! 65 years or with CHADS 2 score ! 1, an OAC is indicated for stroke prevention (Fig. 4). When such a patient also has stable CAD (defined by the absence of ACS for the preceding 12 months), OAC therapy provides protection against stroke and ischemic coronary events. [55][56][57][58][59][60] The Warfarin-Aspirin Reinfarction Study (WARIS)-II indicates that the additional use of antiplatelet therapy with an OAC offers minimal beneficial effect on ischemic or thrombotic coronary outcomes (eg, combined end point of death, myocardial infarction [MI], and stroke, 16.7% with an OAC vs 15.0% with combination OAC and ASA treatment; P ¼ 0.18), while conferring an increased risk of adverse bleeding outcomes (overall bleeding 2.82% per year with an OAC alone vs 3.27% per year with combination OAC and ASA treatment). 59,60 The comprehensive recommendations regarding antithrombotic treatment in AF patients indicated for an OAC with concomitant coronary/peripheral arterial disease are summarized in Figure 3.
Practical tip. For patients with high-risk clinical or angiographic features for ischemic coronary outcomes (Fig. 2) who are at low risk of bleeding, some clinicians prefer a combination of an OAC and single antiplatelet therapy (either aspirin or clopidogrel) in preference to OAC therapy alone. 52
# PCI or ACS in patients with AF
Patients who undergo PCI are generally prescribed DAPT for a period that varies from 4 weeks with bare metal stent (BMS) to more than 12 months after drug-eluting stent (DES) implantation. Shorter durations of DAPT decrease the risk of major bleeding, whereas premature DAPT discontinuation might increase the risk of stent thrombosis and MI. There has been a trend to shorten DAPT duration as secondgeneration DESs with sustained antiproliferative action and reduced thrombogenicity have become available.
For patients with AF and low stroke risk (age < 65 years and CHADS 2 score of 0), the post-PCI therapeutic DAPT regimen should be provided as outlined in the 2018 CCS/CAIC antiplatelet guidelines, because an OAC is not recommended for stroke prevention in these patients. 52 Values and preferences. For patients with AF and stable coronary or arterial vascular disease, the CCS AF Guidelines Committee believed that routine use of combination therapy (an OAC with a single antiplatelet agent) was not justified because of the increased risk of bleeding without a significant reduction in ischemic coronary and cerebrovascular thrombotic events. RECOMMENDATION 10. When an OAC is indicated in the presence of coronary or arterial vascular disease, we suggest a NOAC in preference to warfarin (Weak Recommendation, Moderate-Quality Evidence).
Values and preferences. The suggestion for use of a NOAC rather than warfarin places relatively greater weight on the ease of use of NOACs vs warfarin, as well as the data from randomized controlled trials of NOACs vs warfarin for NVAF (eg, equal or greater reduction of stroke, equal or greater reduction in all-cause mortality, equal or less major bleeding, less intracranial bleeding, and no net increase in CAD outcomes).
For a patient at higher risk of AF-related stroke (age ! 65 years or with CHADS 2 score ! 1) combination OAC and antiplatelet therapy is required. In these patients the optimal therapeutic regimen should be individualized on the basis of a balanced assessment of their risk of AF-related stroke, ischemic coronary event, and clinically relevant bleeding. The risk of AF-related SSE can be estimated from the CHADS-65 illustrated in Figure 4. 48,49 The risk of ischemic coronary events is modulated by the clinical presentation (eg, ACS being higher risk than elective PCI), clinical characteristics (higher risk with comorbid diabetes mellitus or chronic kidney disease, current tobacco use, or previous stent thrombosis), as well as PCI-related factors (higher risk with multivessel disease, multiple stent implantation, total stent length > 60 mm, bifurcation lesion, chronic total occlusion intervention, and stent type; Fig. 2). 52,61 The risk of bleeding can be estimated from clinical risk scores such as HAS-BLED, Predicting Bleeding Complications in Patients Undergoing Stent Implantation and Subsequent Dual Anti Platelet Therapy (PRECISE-DAPT), and Cardiovascular Disease Research Using Linked Bespoke Studies and Electronic Health Records (CALIBER), with the former validated in a VKA-treated population, and the latter two in a population with CAD treated with PCI and DAPT. 52 The population of patients with ACS who do not undergo revascularization (PCI or coronary artery bypass grafting), represents a heterogenous group. This population includes patients with thrombotic plaque rupture (type I MI) as well as those with supply-demand mismatch due to tachycardia, infection, sepsis, etc (type II MI). For patients with type II MI it is unclear if there is an advantage to routine use of combined OAC and antiplatelet therapy. For patients who have true ACS (type I MI) and are not revascularized, the management should take into consideration the relative risks and benefits of combination therapy.
# Key trials of dual pathway therapy vs triple therapy in AF with ACS/PCI
The Open-Label, Randomized, Controlled, Multicenter Study Exploring Two Treatment Strategies of Rivaroxaban and a Dose-Adjusted Oral Vitamin K Antagonist Treatment Strategy in Subjects with Atrial Fibrillation who Undergo Percutaneous Coronary Intervention (PIONEER AF-PCI) randomized 2124 patients with NVAF who underwent PCI for ACS (51%) or for stable CAD to receive, in a 1:1:1 ratio: (1) A P2Y12 inhibitor (94% clopidogrel) with rivaroxaban 15 mg/d (dual pathway) for 12 months; (2) DAPT with rivaroxaban 2.5 mg BID (reduced-dose TT) for 1, 6, or 12 months; or, (3) TT with warfarin (target INR, 2-3) with DAPT for 1, 6, or 12 months. 62 The primary safety end point of clinically significant bleeding (eg, Thrombolysis in Myocardial Infarction [TIMI] major bleeding and minor bleeding), was lower in the dual pathway and reduced-dose TT groups compared with TT with warfarin (16.8% in patients treated with dual pathway therapy, 18% in patients treated with reduced-dose TT, and 26.7% in patients treated with traditional TT [HR, 0.59 (95% CI, 0.47-0.76); and HR, 0.63 (95% CI, 0.50-0.80, respectively)]). For the 2 TT groups the relative reduction in bleeding with reduced-dose TT persisted across all 3 durations of DAPT use ( 1 In a post hoc analysis, there was a reduction in the composite of all-cause death and rehospitalizations with rivaroxaban-based strategies compared with traditional TT with warfarin. 63 The There are several notable limitations to these trials. First, a large proportion of patients underwent elective PCI (44%-72%), meaning the relative risk of coronary outcomes might be underestimated. Second, measures to decrease bleeding risk were underutilized, suggesting that the bleeding rate might have been increased in the TT arm relative to contemporary practice. Third, these trials compared dual pathway therapy using a NOAC with TT using warfarin. It is unknown whether the results would have been similar had the dual pathway therapy groups used a VKA, or the TT group used a therapeutic-dose NOAC. Last, each of the trials was powered to address safety outcomes (ie, bleeding). Although each of these trials were individually underpowered to assess efficacy outcomes (eg, mortality, stroke, and coronary outcomes) a limited metaanalysis of the What Is the Optimal Antiplatelet and Anticoagulation Therapy in Patients With Oral Anticoagulation and Coronary Stenting (WOEST), PIONEER AF-PCI, and RE-DUAL PCI trials showed that the use of dual pathway therapy was associated with a significant reduction in major bleeding events, without an excess in the occurrence of MI, definite stent thrombosis, and stroke. 65
# Duration of TT
The benefit of TT (reduction of recurrent MI and stent thrombosis) must be balanced against the increased bleeding risk with this therapeutic regimen. Importantly, the rate of bleeding with TT peaks within the first month of treatment, and thereafter the risk of bleeding is relatively stable for the duration of TT.
In the AF population, it is possible that shorter durations of DAPT might be reasonable when concomitant OAC therapy will be used for the prevention of SSE. This concept was demonstrated in the Intracoronary Stenting and Antithrombotic Regimen: Triple Therapy in Patients on Oral Anticoagulation After Drug Eluting Stent Implantation (ISAR-TRIPLE) study, which showed no significant difference in the primary end point of "net clinical benefit" (combination of death, MI, stent thrombosis, stroke, or TIMI major bleeding) between those who received 6 weeks vs 6 months of TT. A post hoc landmark analysis from 6 weeks to 9 months (ie, excluding the period in which both groups had received TT) showed a significant reduction in any Bleeding Academic Research Consortium (BARC) bleeding in the abbreviated TT group. 66 Likewise, the PIONEER AF-PCI and RE-DUAL PCI trials showed no relationship between major adverse cardiovascular events and TT duration or clinical presentation (ACS vs stable CAD). 62,64 On balance, these findings suggest that shortening the TT course to 6 months and thereafter continuing therapy with an OAC and a single antiplatelet agent, might be reasonable in the context of elevated bleeding risk.
AF patients at higher risk of stroke who undergo PCI without high-risk features AF patients at higher risk of stroke who undergo PCI for ACS or elective PCI with high-risk features Practical tip. For some patients < 65 years of age with CHADS 2 score of 1 at the lower end of the stroke risk spectrum (eg, isolated hypertension), some clinicians prefer DAPT (eg, aspirin and ticagrelor or prasugrel) in preference to triple therapy (an OAC with DAPT).
Practical tip. A PCI is considered high risk for ischemic coronary outcomes on the basis of the clinical presentation (eg, ACS), patient characteristics (comorbid diabetes mellitus treated with oral hypoglycemics or insulin, chronic kidney disease (estimated glomerular filtration rate < 60 mL/min), current tobacco use, previous ACS, or previous stent thrombosis), as well as PCI-related factors (multivessel PCI, multiple [! 3] stents implanted, total stent length > 60 mm, complex bifurcation lesion, chronic total occlusion intervention, and stent type (eg, bioabsorbable vascular scaffold; Fig. 2).
Practical tip. All patients should receive ASA 81 mg (or a minimum of 160 mg if ASA-naive) on the day of the PCI procedure. ASA may be continued as part of TT for up to 6 months for patients with a high risk of thrombotic coronary events and low risk of bleeding. ASA can be discontinued as early as the day after PCI for patients with a low risk of thrombotic coronary events and a high risk of bleeding. For patients at intermediate risk of thrombotic coronary events and intermediate risk of bleeding ASA can be continued as part of TT for 1-3 months.
AF patients at higher risk of stroke in association with medically managed type 1 MI
# III. Investigation and Management of SCAF
The Values and preferences. For patients with AF and type 1 MI who do not undergo revascularization, the CCS AF Guidelines Committee places relatively greater emphasis on the reduction in ischemic coronary and cerebrovascular thrombotic events, rather than the increase in bleeding observed with combination therapy. When combination therapy is used the preference for clopidogrel rather than ASA is on the basis of the findings from the Clopidogrel vs Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) study, in which clopidogrel was shown to be superior to ASA (0.5% absolute reduction in composite of vascular death, MI, or ischemic stroke; P ¼ 0.043), well as the substantial efficacy and safety data for combination therapy using clopidogrel and an OAC (clopidogrel used in 88% of patients in RE-DUAL PCI and 95% in PIONEER AF-PCI). 62,64,67 studies showed that episodes of SCAF as short as 5-6 minutes occur in 30%-40% of patients with implanted devices, and is associated with a 2-to 2.5-fold increased risk of stroke. 68,69 Although clinical risk factors influence the stroke risk among patients with SCAF, this risk appeared lower than among patients with clinical AF. 70 Because patients with SCAF tend to be older and at higher risk of OAC-associated bleeding, 71 the risk-benefit ratio of using an OAC is uncertain.
It appears that an increasing duration or burden of SCAF is associated with an increase in the absolute risk of stroke. 69,72 One study suggested that there was no increased risk of stroke among patients with SCAF when their longest daily burden in the past 30 days was < 5.5 hours. 69 A more recent analysis from the ASSERT trial suggests that the increased risk of stroke with SCAF is driven by patients whose episodes exceed 24 continuous hours. 72 There is also uncertainty about the temporal relationship between SCAF and stroke, because TRENDS and ASSERT showed no temporal association between SCAF and stroke in most patients. 73,74 The only randomized evaluation of an OAC in this setting is the Combined Use of BIOTRONIK Home Monitoring and Predefined Anticoagulation to Reduce Stroke Risk (IMPACT) study. 75 IMPACT did not show any benefit from remote monitoring for SCAF with protocol-driven initiation and cessation of OAC therapy. 75 There are currently 2 randomized trials ongoing, which are randomizing patients with SCAF to treatment with an OAC vs either aspirin or placebo: Non-Vitamin K Antagonist Oral Anticoagulants in Patients With Atrial High Rate Episodes (NOAH-AF-NET-6) trial 76 and the Apixaban for the Reduction of Thrombo-Embolism Due to Sub-Clinical Atrial Fibrillation (ARTESiA) trial. 77 These 2 trials, due to complete in 2019 and 2021, respectively, will determine if and when patients with SCAF should be treated with an OAC.
# IV. Antidotes for NOACs/NOAC Reversal Agents
NOACs are the preferred agents for stroke prevention in NVAF patients who merit anticoagulation. Although there was less life-threatening bleeding with NOACs than with warfarin in the randomized controlled trials, [10][11][12][13] bleeding remains an important risk. The availability of specific reversal agents has the potential to mitigate the risks associated with major bleeding events (eg, severe active hemorrhage, or bleeding in the context of emergent surgery) and, with it, patient and physician acceptance of OAC therapy.
The CCS AF Guidelines Committee recommendation for idarucizumab, the dabigatran-specific reversal agent, in patients with active bleeding or those requiring surgery, remains unchanged from the 2016 guidelines update. That recommendation was on the basis of the interim publication of the Reversal Effects of Idarucizumab on Active Dabigatran (REVERSE-AD) trial, 78 now further supported by the data from the full cohort analysis of 301 patients with uncontrollable or life-threatening bleeding (group A) and 202 patients who required urgent surgery (group B). 79 The median maximum percent reversal of the anticoagulant effect of dabigatran within 4 hours of idarucizumab administration was 100% in those who had a prolonged dilute thrombin time (DTT) or ecarin clotting time (ECT) at baseline. The reversal was rapid and occurred independently of age, sex, renal function, and dabigatran concentration at baseline. Reappearance of dabigatran levels > 20 mg/mL (below which impairment of hemostasis is unlikely) was observed in 23% of patients. This was likely due to redistribution of unbound dabigatran from the extravascular to the intravascular space, and was associated with recurrent or continued bleeding in 10 of the patients in the "life-threatening bleeding" group but none of the patients in the "urgent surgery" group. It was possible to assess time to cessation of bleeding in 134 patients in group A; median time to hemostasis was 2.5 hours after idarucizumab administration and all had confirmed bleeding cessation within 24 hours. Of the 197 patients in group B, periprocedural hemostasis was assessed as normal or mildly abnormal in 98.5%. At 30 days, thrombotic events occurred in 4.8% of all patients, with a mortality rate of 13.5% in group A, and 12.6% in group B.
Another specific reversal agent is andexanet alfa. Andexanet is a recombinant modified human factor Xa decoy protein that binds to the active site of factor Xa inhibitors and sequesters them within the vascular space. 80 The pharmacodynamic halflife is approximately 1 hour. In the Andexanet Alfa -a Novel Antidote to the Anticoagulation Effects of FXA Inhibitors (ANNEXA-4) study, patients with acute major bleeding who had received 1 of 4 factor Xa inhibitors (apixaban, rivaroxaban, edoxaban, or enoxaparin) within the previous 18 hours were treated with a bolus and 2-hour infusion of andexanet, the dose of which was dependent on the timing of the last dose of factor Xa inhibitor. 81 In the published interim analysis of 67 patients the median anti-factor Xa activity decreased by 89% (95% CI, 58%-94%) among the 26 patients who received rivaroxaban and by 93% (95% CI, 87%-94%) among the 20 patients who received apixaban. 81 Four hours after the end of the infusion, there was a relative decrease in anti-factor Xa activity from baseline of 30%-39%. Clinical hemostasis was adjudicated as excellent or good in 37 of 47 patients (78%) at the 12-hour postinfusion mark. At 30 days, the overall mortality rate was 15% (10 patients died) and thrombotic event rate was 18% (12 patients). The US prescribing information provides safety data for 185 patients, citing a 30-day thrombotic event rate of 18% (33 patients) and a mortality rate of 14% (25 deaths). 82 Although promising, there are insufficient data to recommend andexanet for RECOMMENDATION 14. We suggest that it is reasonable to prescribe OAC therapy for patients who are aged 65 years or older or with a CHADS 2 score of ! 1 (CHADS-65) who have episodes of SCAF lasting > 24 continuous hours in duration. Additionally, high-risk patients (such as those with a recent embolic stroke of unknown source) with shorter-lasting episodes might also be considered for OAC therapy (Weak Recommendation, Low-Quality Evidence).
reversal of life-threatening bleeding associated with factor Xa inhibitors at this time.
Practical tip. In acute, life-threatening bleeding situations in which standard resuscitation (such as local measures, transfusion, etc) is anticipated to be insufficient (eg, intracranial hemorrhage), or in situations in which standard resuscitation has not stabilized the patient, 5 g of intravenous (I.V.) idarucizumab should be administered as soon as possible. Activated partial thromboplastin time (aPTT) and thrombin time may be used to qualitatively identify the presence of active dabigatran at baseline in a patient, although they are less sensitive than DTT and ECT; 92% of patients in the REVERSE-AD trial had an elevated DTT or ECT, whereas only 74% had an elevated aPTT. However, obtaining these measures should not delay the administration of idarucizumab. In many instances of life-threatening bleeding, clinicians have to make a treatment decision on the basis of a history of dabigatran use rather than laboratory evidence. Renal function and timing of the last dose of dabigatran provide key information regarding the likely extent of remaining dabigatran effect.
Practical tip. "Urgent" surgery as defined in the REVERSE-AD trial is surgery that cannot be delayed beyond 8 hours (amended from 4 hours in the initial version of the protocol). The timing of surgery should be on the basis of the clinical indication and stability of the patient. In instances in which delayed surgery is appropriate, clinicians may obtain coagulation parameters (eg, thrombin time or aPTT) to identify patients who would be unlikely to benefit from idarucizumab (see the previous "practical tip").
Practical tip. Reversing dabigatran therapy exposes patients to the thrombotic risk of their underlying disease. Oral anticoagulation should be reintroduced as soon as medically appropriate.
# V. Acute Pharmacological Rhythm Control
For patients with acute AF/AFL who are eligible for cardioversion, acute rhythm control can be established via either pharmacological or electrical cardioversion. In general, DC electrical cardioversion is more effective, with immediate restoration of sinus rhythm, however, it requires the use of general anaesthesia. Pharmacological cardioversion is less effective, but avoids the risks associated with procedural sedation, and does not require a preceding period of fasting. 24,28,33,83,84 Antiarrhythmic medication selection is typically dictated by the patient's comorbidities (eg, structural heart disease), as well as physician preference. Characteristics of antiarrhythmic medications used for acute pharmacological cardioversion are shown in Table 1.
A commonly used I.V. medication for cardioversion of acute AF/AFL in the emergency department setting is the class RECOMMENDATION 15. We recommend administering idarucizumab for emergency reversal of dabigatran's anticoagulant effect in patients with uncontrollable or potentially lifethreatening bleeding and/or in patients who require urgent surgery for which normal hemostasis is necessary (Strong Recommendation, Moderate-Quality Evidence).
Values and preferences. This recommendation places relatively greater value on the ability of idarucizumab to reverse coagulation parameters indicative of dabigatran's effect, its potential to decrease bleeding-related outcomes, and risks of urgent surgery, and its safety and tolerability profile, and less value on the absence of a control group in the REVERSE-AD trial and on the cost of the drug. z Vernakalant should be avoided in patients with hypotension, recent ACS, or significant structural heart disease.
Ia agent, procainamide. 85 Procainamide is usually administered over 60 minutes at a dose of 15-18 mg/kg, although a significant amount of the clinical evidence has been on the basis of the infusion of 1 g over 60 minutes. 24,33,86 Procainamide is more effective for the conversion of acute AF (50% conversion) than for AFL (30% conversion). 86 Time to cardioversion is approximately 1 hour. 86 The most common side effect is hypotension (approximately 5%), although QRS widening, premature ventricular contractions, and Torsade de Pointes (TdP) might occur. This medication, like all drugs with class I (Na þ channel-blocking) action, should be avoided in patients with Brugada syndrome. 87 Ibutilide is an I.V. class III agent that has been shown to effectively terminate AFL (50%-75%) and AF (30%-50%), with cardioversion typically occurring within 30-60 minutes. 84 However, widespread clinical uptake has been limited by a significant risk of TdP, which occurs in approximately 2%-3% of patients. Consequently, ibutilide should not be used in patients with prolonged QTc on electrocardiogram, those with a history of HF or reduced ejection fraction, or those with electrolyte disturbances (low serum potassium or magnesium levels). Pretreatment with high-dose magnesium (! 4 g I.V.) might improve ibutilide cardioversion rates and might reduce the risk of TdP. [88][89][90] Patients must be observed with continuous electrocardiogram monitoring for a minimum of 4 hours after ibutilide administration.
The atrial-selective antiarrhythmic drug vernakalant was recently approved by Health Canada. In an emergency department-based study of acute AF, the conversion rate was 59% and the median time to cardioversion was 12 minutes. 83 The major potential adverse effects are hypotension, along with bradycardia after cardioversion. Transient but fairly common side effects include dysgeusia (abnormal taste), paraesthesia, and nausea. Vernakalant should not be used in patients with hypotension, severe HF (New York Heart Association classification III/IV), recent ACS, or severe aortic stenosis. It is less effective in the conversion of typical AFL. 91 With the exception of patients with structural heart disease, amiodarone is not recommended for acute rhythm control because of the delayed action in conversion (approximately 8 hours). [92][93][94] The most common adverse drug reactions with I.V. administration are phlebitis, hypotension, and bradycardia. Although there is potential for prolongation of the QT interval the incidence of TdP is rare. 95 An alternate approach is to consider oral administration of flecainide or propafenone in combination with an atrioventricular node-blocking agent (b-blockers or calcium channel inhibitors; Table 2). Although the time to cardioversion (2-6 hours) is longer than with I.V. medications, the major clinical benefit is that patients are able to treat their subsequent AF episodes using the "pill-in-the-pocket" approach, which reduces the need to visit the emergency department. A key (1) AF persistence > 6 hours after PIP-AAD administration or electrical cardioversion required for termination (2) Adverse events including symptomatic hypotension (systolic BP 90 mm Hg), symptomatic conversion pauses (> 5 seconds), symptomatic bradycardia after sinus rhythm restoration, proarrhythmia (conversion to atrial flutter/tachycardia, or episodes of ventricular tachycardia), severe symptoms (dyspnea, presyncope, syncope), or a > 50% increase in QRS interval duration from baseline Instructions for subsequent out-of-hospital use Patients should take the AV nodal agent 30 minutes after the perceived arrhythmia onset, followed by the class Ic AAD 30 minutes after the AV nodal agent. After AAD administration patients should rest in a supine or seated position for the next 4 hours, or until the episode resolves Patients should present to the ED in the event that:
(1) The AF episode did not terminate within 6-8 hours (2) They felt unwell after taking the medication at home (eg, a subjective worsening of the arrhythmia after AAD ingestion, or if they developed new or severe symptoms such as dyspnea, presyncope, or syncope) (3) More than one episode occurred in a 24-hour period (patients were advised not to take a second PIP-AAD dose within 24 hours) (4) If the AF episode was associated with severe symptoms at baseline (eg, significant dyspnea, chest pain, presyncope, or symptoms of stroke), even in the absence of PIP-AAD use AAD, antiarrhythmic drug; AF, atrial fibrillation; AV, atrioventricular; BP, blood pressure; ECG, electrocardiogram; ED, emergency department; PIP, "pill-inthe-pocket." caveat to this approach is that the first dose must be administered in a monitored environment to exclude treatmentrelated adverse reactions. 96,97 Indications, contraindications, and monitoring details are presented in Table 2.
# VI. Catheter Ablation of AF
The section on catheter ablation of AF was last updated in 2014. Since that time, there have been significant developments in periablation management and clinical trial evidence.
Uninterrupted OAC therapy with a VKA has been the standard of care periablation since clinical trials showed less bleeding and reduced thromboembolic complications compared with VKA interruption with low molecular-weight heparin bridging. 98 The safety and efficacy of uninterrupted NOAC therapy periablation, was recently explored in 3 randomized trials that compared uninterrupted NOAC with uninterrupted VKA treatment periablation. The Active-Controlled Multi-Center Study With Blind-Adjudication Designed to Evaluate the Safety of Uninterrupted Rivaroxaban and Uninterrupted Vitamin K Antagonists in Subjects Undergoing Catheter Ablation for Non-Valvular Atrial Fibrillation (VENTURE-AF) trial was the smallest (n ¼ 248) of these trials, which randomized patients to uninterrupted rivaroxaban vs uninterrupted VKA treatment. 99 The trial showed that there was no difference in major bleeding or thromboembolic events. In contrast, the Randomized Evaluation of Dabigatran Etexilate Compared to Warfarin in Pulmonary Vein Ablation: Assessment of an Uninterrupted Peri-Procedural Anticoagulation Strategy trial (RE-CIR-CUIT; n ¼ 635) showed a significant reduction in ISTH bleeding with uninterrupted dabigatran 150 mg BID compared with uninterrupted VKA (1.6% vs 6.9%, P ¼ 0.0009). 100 Of note, the number of patients with cardiac tamponade and with groin hematoma was higher in the VKA arm. There was no difference in the number of patients with a thromboembolic event, with only 1 in the VKA arm. Finally, the recently published Anticoagulation Using the Direct Factor Xa Inhibitor Apixaban During Atrial Fibrillation Catheter Ablation (AXAFA) trial (n ¼ 674) showed no difference between uninterrupted apixaban and uninterrupted VKA treatment for either bleeding or thromboembolic events. 101 This trial also performed a substudy of post-ablation cerebral magnetic resonance images to look for subclinical cerebral microemboli and again, there was no difference between strategies. The ongoing Evaluation of Edoxaban Compared With VKA in Subjects Undergoing Catheter Ablation of Nonvalvular Atrial Fibrillation (ELIMINATE-AF) trial will report on uninterrupted edoxaban vs uninterrupted VKA treatment (ClinicalTrials.gov NCT02942576). On the basis of these data we make the following recommendation.
Other important clinical trials included Substrate and Trigger Ablation for Reduction of Atrial Fibrillation (STAR AF II), which compared 3 techniques for ablation of persistent AF. 102 Although guidelines had made the assumption that more extensive ablation was required for treating these patients, the trial showed that strategies of additional use of empiric linear ablation or targeted electrogram ablation in addition to pulmonary vein isolation did not improve freedom from AF over pulmonary vein isolation alone.
Previous iterations of the CCS AF guidelines recommend a trial of antiarrhythmic drugs (AADs) before considering an ablation procedure for most patients, with first-line ablation therapy reserved for highly selected symptomatic patients with paroxysmal AF. These recommendations are on the basis of the results of several randomized controlled studies that showed superior freedom from recurrent arrhythmia, a reduction in the overall AF burden, and improvement in symptoms, exercise capacity, and quality of life with catheter ablation relative to AAD therapy. [103][104][105][106][107][108][109][110][111] The Catheter Ablation vs Anti-Arrhythmic Drug Therapy for Atrial Fibrillation (CABANA) trial was designed to evaluate the effect of ablation on mortality, stroke, and bleeding end points. 112 This study randomized older, higher-risk patients to ablation (n ¼ 1108) or drug therapy (n ¼ 1096). At the time of this guideline update, the study had not been published, but the presented results showed no difference in the primary composite outcome (death, disabling stroke, serious bleeding, or cardiac arrest) at 5 years in an intention to treat analysis (HR, 0.86; 95% CI, 0.65-1.15). Despite a high rate of crossover (9.2% not receiving ablation in the intervention arm and 27.5% of drug therapy patients receiving ablation) a significant reduction in the secondary end point of death and cardiovascular hospitalization was observed (HR, 0.83; 95% CI, 0.74-0.93). Moreover, the "on treatment" analysis, which evaluated the patients who received ablation showed a significant reduction in the primary end point (HR, 0.67; 95% CI, 0.50-0.89) with associated significant reductions in all-cause mortality (HR, 0.60; 95% CI, 0.42-0.86) and death and cardiovascular hospitalization (HR, 0.83; 95% CI, 0.74-0.94) compared with drug therapy. Until the full publication is available, however, the Guideline Committee has not changed its recommendation that AF ablation should be second-line therapy for most patients and first-line therapy only for highly selected patients.
# Ablation in patients with AF and HF
AF and HF frequently coexist, with AF representing an independent predictor of progression, hospitalization, and death in the HF population. [113][114][115][116][117][118][119] Although restoring and maintaining sinus rhythm has been considered as a therapeutic target to improve clinical outcomes, large randomized controlled trials of AADs have failed to support this hypothesis. [120][121][122][123][124] It is postulated that the attenuated benefit observed with AAD therapy is related to cardiac and noncardiac toxicities (eg, proarrhythmia or negative inotropy). As such, ablation has been proposed as a more efficacious means to improve outcomes.
To date, 7 randomized trials have been performed (Table 3). [125][126][127][128][129][130][131] Collectively these randomized studies have shown a single-procedure success (eg, elimination of any AF episodes > 30 seconds) in the range of 40%-69%, with RECOMMENDATION 16. We suggest that catheter ablation may be performed using uninterrupted therapeutic oral anticoagulation with either a NOAC or adjusted-dose warfarin (Weak Recommendation, Moderate-Quality Evidence). [125][126][127][128][129][130][131] However, a more substantial quantification of the utility of catheter ablation in patients with AF and HF with reduced systolic function is the objective outcomes, such as mortality and hospitalization. Although CABANA failed to show significant mortality benefit in unselected populations, recent randomized trials have shown that catheter ablation of AF in HF patients with reduced LVEF results in significant improvement in allcause mortality as well as fewer HF hospitalizations. 128,131,132 The first of these studies was the Ablation vs Amiodarone for Treatment of Persistent Atrial Fibrillation in Patients With Congestive Heart Failure and an Implanted Device (AATAC) study, which randomized 203 patients with New York Heart Association functional class II-III HF and an LVEF < 40% to catheter ablation (n ¼ 102) or amiodarone rhythm control (n ¼ 101). 128 After 24-27 months of follow-up, patients in the ablation group had a significantly greater freedom from recurrent AF (70% vs 34%; P < 0.001). In addition, the secondary end points of unplanned hospitalization and all-cause mortality were both significantly reduced (45% and 56%, respectively), corresponding to number needed to treat of 3.8 for unplanned hospitalization and 10 for all-cause mortality. The second study, Catheter Ablation vs Standard Conventional Therapy in Patients with Left Ventricular Dysfunction and Atrial Fibrillation (CASTLE-AF), randomized patients with symptomatic paroxysmal or persistent AF, New York Heart Association class II-IV HF, and an LVEF 35% to catheter ablation (179 patients) or medical therapy (184 patients). 131 All patients had a cardiac implantable device (implantable cardioverter defibrillator or cardiac resynchronization therapy-implantable cardioverter defibrillator). After a median follow-up of 37.8 months, patients in the ablation group were significantly less likely to meet the primary composite end point of all-cause mortality or HF admission (16.1% absolute reduction; HR, 0.62; 95% CI, 0.43-0.87; P ¼ 0.006). Similar to AATAC, there was a 47% relative reduction in all-cause mortality (HR, 0.53; 95% CI, 0.32-0.86) and a 44% reduction in HF hospitalization (HR, 0.56; 95% CI, 0.37-0.83).
Taken together, these studies show that catheter ablation is associated with an improvement in all-cause mortality (8.1% vs 15.9%; RR, 0.52; 95% CI, 0.35-0.76; P < 0.01), a reduction in HF hospitalization (17.7% vs 31.3%; RR, 0.57; 95% CI, 0.45-0.72; P < 0.01) and ejection fraction, compared with medical therapy. Ongoing randomized controlled trials in the AF and HF population will assess the effect of AF ablation on all-cause mortality (Rhythm Control -Catheter Ablation With or Without Anti-arrhythmic Drug Control of Maintaining Sinus Rhythm Versus Rate Control With Medical Therapy Although these results are compelling, the committee decided not to add a new recommendation for ablation in HF patients. Instead, we believe that the existing recommendation to pursue catheter ablation as a second-line treatment for symptomatic patients applies to this group. Despite the lack of a new recommendation specifically for patients with HF and a reduced LVEF, it is important to recognize that the consideration of patients with structural heart disease as an appropriate ablation candidate does represent a philosophical shift in practice because these patients were previously discouraged from ablation because of concerns regarding potential inefficacy and harm.
# VII. Integrated Approach to AF and Modifiable Cardiovascular Risk Factors
There are several care gaps in AF management, specifically in the domains of stroke prevention, in the timing/appropriateness of transitions between rate and rhythm control, as well in the assessment for ablation procedure candidacy. 133,134 Dedicated multidisciplinary clinics specifically focused on AF care have recently been developed as a means to facilitate patient and provider education, as well as to provide evidence-based care centred on chronic disease management principles. Previous studies have suggested that a combined specialist and nursebased AF clinic is associated with improved adherence to guideline-based care, enhanced transitions of care (from the emergency room to the specialty clinic and back to community care), and significant improvement in quality of life. 51,[135][136][137][138] In addition, systematic multidisciplinary AF clinics have been shown to reduce cardiovascular death (HR, 0.28 vs usual care) and cardiovascular hospitalization (HR, 0.66 vs usual care). 135 Analogous multidisciplinary models of care, such as HF clinics, have shown similar benefits in cardiovascular outcomes as well as cost-effectiveness. 139,140 Greater coordination of care with nursing interventions has been shown to result in more efficient use of resources, 141 better coordination of heart rhythm procedures, 142,143 and better implementation of other cardiac therapies for patients with HF. 144,145 In the Canadian context, reduced wait times, improved implementation of recommendations, and more effective use of tertiary care resources has been shown. 146 Although the genesis of AF clinics in Canada arises from the Calgary model, similar programs now exist across the country. 147 Although individually tailored to the needs of their communities, these Canadian AF clinics are broadly on the basis of the principles of: (1) timely access to specialist care, to reduce adverse outcomes (eg, stroke or rehospitalization) imposed by delays in treatment initiation; (2) knowledge translation, because improved understanding of AF facilitates active participation by the patient in their treatment pathway, with secondary benefits in treatment adherence and persistence; and (3) guideline adherence, in particular in the domains of stroke prevention and comorbidity management (eg, hypertension, obesity, and sleep apnea). 70,147,148 This last point is especially relevant as a systematic approach to patient care, including protocol-driven management on the basis of contemporary guidelines, and offers an opportunity for holistic management of the patient beyond the heart rhythm.
Recently, there has been a renewed focus on the contribution of modifiable cardiovascular risk factors to the causation and persistence of AF. [149][150][151] Although the precise mechanistic links between risk factors and AF occurrence remain somewhat uncertain, information available from the literature provides many potential insights. Hypertension, the most significant population-attributable modifiable risk factor for AF, causes activation of the sympathetic and renin-angiotensin-aldosterone systems, as well as structural and electrophysiological atrial remodelling that enhances AF susceptibility. Diabetes mellitus promotes AF via structural remodelling (possibly mediated by advanced glycosylation end-products) and autonomic remodelling. Tobacco use promotes AF through a combination of the direct effects of nicotine on the atrium (eg, altered atrial conduction and refractoriness), as well as structural remodelling, inflammation, and oxidative stress. Alcohol, when consumed in excess, promotes AF through the induction of arrhythmia triggers (increased sympathetic activity/impairment of vagal tone) as well as atrial fibrosis (from the direct toxic effects of alcohol metabolites). Obesity promotes AF through weight-related structural remodelling (changes in atrial dimensions and interstitial fibrosis), weight-related electrophysiological remodelling (conduction slowing and shortening of the effective refractory period), autonomic dysfunction, and inflammation. Obstructive sleep apnea promotes AF acutely through strongly negative intrathoracic pressures leading to increased venous return (AF-promoting left atrial volume loading) and hypoxia-induced pulmonary vasoconstriction. Chronic obstructive sleep apnea induces electrical and structural remodelling of the atria, autonomic dysregulation, oxidative stress, and inflammation.
Previous studies have shown that intensive risk factor management has beneficial effects on AF. 152,153 Rienstra et al. reported improved maintenance of sinus rhythm at 1 year with a strategy of cardiac rehabilitation, HF medication optimization, and aggressive blood pressure control (75% maintenance of sinus rhythm on a 7-day Holter vs 63% in the control group; OR, 1.77; P ¼ 0.042). 153 The Long-Term Effect of Goal-Directed Weight Management on Atrial Fibrillation Cohort: A Long-Term Follow-Up Study (LEGACY) cohort study showed that patients with a weight loss of > 10% was associated with a 6-fold increase in the likelihood of being arrhythmia-free over a 5-year follow-up period compared with those with lesser degrees of weight loss (< 10%). 154 Abed et al. reported that weight reduction with intensive risk factor management resulted in a significant improvement in AF-related quality of life and symptom scores, as well as AF burden (episode frequency and duration). 152 Aggressive Risk Factor Reduction Study for Atrial Fibrillation and Implications for the Outcome of Ablation (ARREST-AF) was a single-centre cohort study that showed that patients who chose to undergo aggressive risk factor modification had better quality of life and symptom control, a significant reduction in AF burden, and greater arrhythmia-free survival after catheter ablation compared with those who did not (OR, 4.8; 95% CI, 2.04-11.4). 150 The Impact of Cardiorespiratory Fitness on Arrhythmia Recurrence in Obese Individuals With Atrial Fibrillation (CARDIO-FIT) study showed that a > 2 peak metabolic equivalents (METs) improvement in cardiorespiratory fitness was associated with a significantly reduced AF burden compared with a gain of < 2 METs over long-term follow-up. 155 This response was proportional to the increase in cardiorespiratory fitness, with an adjusted reduction in AF recurrence of 10% for each MET gained (HR, 0.90; 95% CI, 0.83-1.00). 155 These data suggest that a comprehensive management strategy that includes suppression of triggers (targeted by risk factor modification, AADs, and/or catheter ablation) and amelioration of arrhythmogenic substrate (risk factor modification) might lead to improved outcomes. Further research is required to determine whether these interventions will effectively alter the occurrence or progression of AF, when it is present.
It is the opinion of the AF Guidelines Committee that, for now, the emphasis of risk factor modification should focus on cardiovascular event reduction with the optimal management of risk factors and concomitant disorders (Table 4), following the recommendations of the 2018 Canadian dyslipidemia, 156 hypertension, 157 and diabetes 158 guidelines.
Practical tip. The detection and optimal management of risk factors and concomitant disorders together with appropriate rate/rhythm control and stroke prevention might contribute to a reduction in cardiovascular-related emergency department visits and hospitalizations. Addressing such risk factors might be most comprehensively and efficiently accomplished through a specialized clinic or other multidisciplinary management approach, and through use of a standardized, systematic protocol-based approach. RECOMMENDATION 17. We recommend systematic and strict guideline-adherent management of traditional modifiable cardiovascular risk factors and/or conditions associated with AF, to reduce cardiovascular events (eg, stroke, MI, etc; Strong Recommendation, High-Quality Evidence).
Values and preferences. This recommendation places a high value on a systematic approach to providing guideline-directed therapy for any cardiovascular risk factors and/or conditions associated with AF.
# RECOMMENDATION
18. We suggest that, in addition to implementing appropriate rate or rhythm control measures, an approach targeting modifiable risk markers and conditions associated with AF should be applied to prevent recurrence of the arrhythmia and/or decrease its symptom burden (Weak Recommendation, Low-Quality Evidence).
Values and preferences. The aggressive treatment of obesity and cardiometabolic risk markers/conditions (including hypertension, HF, diabetes, and sleep apnea) has been shown to reduce AF burden and improve quality of life. This recommendation places a high value on the recognized association between these potential risk markers and conditions that are known to aggravate AF and the possibility that treatment of these might result in prevention and/or regression of the substrate that causes AF as well as improvement of patient symptoms.
# Acknowledgements
The authors thank Ms Christianna Brooks (CCS staff) for her assistance and outstanding contribution throughout the guideline writing process.
Secondary Panel Members: David Bewick, MD, Vidal Essebag, MD, PhD, Peter Guerra, MD, Milan Gupta, MD, Brett Heilbron, MBChB, Paul Khairy, MD, Bob Kiaii, MD, George Klein, MD, Simon Kouz, MD, Daniel Ngui, MD, Pierre Pag e, MD, Calum Redpath, MD, Jan Surkes, MD, and Richard Whitlock, MD.
# Supplementary Material
To access the supplementary material accompanying this article, visit the online version of the Canadian Journal of Cardiology at www.onlinecjc.ca and at https://doi.org/10. 1016/j.cjca.2018.08.026. | None | None |
161329152651881e43467c583b6929e6fc30e4ef | cma | None | The CAEP Acute Atrial Fibrillation/Flutter Best Practices Checklist was created to assist emergency physicians in Canada and elsewhere manage patients who present to the emergency department (ED) with acute/recentonset atrial fibrillation or flutter. The checklist focuses on symptomatic patients with acute atrial fibrillation (AAF) or flutter (AAFL), i.e. those with recent-onset episodes (either first detected, recurrent paroxysmal or recurrent persistent episodes) where the onset is generally less than 48 hours but may be as much as seven days. These are the most common acute arrhythmia cases requiring care in the ED. 1,2 Canadian emergency physicians are known for publishing widely on this topic and for managing these patients quickly and efficiently in the ED. This project was funded by a research grant from the Canadian Arrhythmia Network and the resultant guidelines have been formally recommended by the Canadian Association of Emergency Physicians (CAEP). We chose to adapt, for use by emergency physicians, existing high-quality clinical practice guidelines (CPG) previously developed by the Canadian Cardiovascular Society (CCS). These CPGs were developed and revised using a rigorous process that is based on the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system of evaluation. 9,10 With the assistance of our PhD methodologist (IG), we used the recently developed Canadian CAN-IMPLEMENT © process adapted from the ADAPTE Collaboration. We created an Advisory Committee consisting of ten academic emergency physicians (one also expert in thrombosis medicine), four community emergency physicians, three cardiologists, one PhD methodologist, and two patients. Our focus was four key elements of ED care: assessment and risk stratification, rhythm and rate control, short-term and long-term stroke prevention, and disposition and follow-up. The Advisory Committee communicated by a two-day faceto-face meeting in March 2017, teleconferences,#
and email. The checklist was prepared and revised through a process of feedback and discussions on all issues by all panel members. These revisions went through ten iterations until consensus was achieved. We then circulated the draft checklist for comment to approximately 300 emergency medicine and cardiology colleagues; their email written feedback was further incorporated and the final version created and approved by the panel.
During the consensus and feedback processes, we addressed a number of issues and concerns, some of which required extensive discussion. We spent considerable time defining what is meant by "unstable" and highlighting the issue that many unstable patients are actually suffering from underlying medical problems rather than a primary arrhythmia. Where possible we chose to simplify the checklist, for example listing only procainamide for pharmacological cardioversion. Other drugs were considered including vernakalant, ibutilide, propafenone, flecainide, and amiodarone. We also tried to give specific drug dosage recommendations, recognizing that physicians are free to consult any number of excellent pharmaceutical references. The panel believes that, overall, a strategy of ED cardioversion and discharge home from the ED is preferable from both the patient and the healthcare system perspective, for most patients. One controversial recommendation is to consider rate control or transesophageal echocardiography (TEE)-guided CV if the duration of symptoms is 24-48 hours and the patient has two or more CHADS-65 criteria. This is based on some recent data from Finland. 14,15 We emphasize the importance of evaluating long-term stroke risk by use of the CHADS-65 algorithm and encourage ED physicians to prescribe anticoagulants where indicated.
Our hope is that the CAEP Acute Atrial Fibrillation/ Flutter Best Practices Checklist will standardize and improve care of AAF and AAFL in large and small EDs alike. We believe that these patients can be managed rapidly and safely, with early ED discharge and return to normal activities.
# APPENDICES | The CAEP Acute Atrial Fibrillation/Flutter Best Practices Checklist was created to assist emergency physicians in Canada and elsewhere manage patients who present to the emergency department (ED) with acute/recentonset atrial fibrillation or flutter. The checklist focuses on symptomatic patients with acute atrial fibrillation (AAF) or flutter (AAFL), i.e. those with recent-onset episodes (either first detected, recurrent paroxysmal or recurrent persistent episodes) where the onset is generally less than 48 hours but may be as much as seven days. These are the most common acute arrhythmia cases requiring care in the ED. 1,2 Canadian emergency physicians are known for publishing widely on this topic and for managing these patients quickly and efficiently in the ED. [3][4][5] This project was funded by a research grant from the Canadian Arrhythmia Network and the resultant guidelines have been formally recommended by the Canadian Association of Emergency Physicians (CAEP). We chose to adapt, for use by emergency physicians, existing high-quality clinical practice guidelines (CPG) previously developed by the Canadian Cardiovascular Society (CCS). [6][7][8] These CPGs were developed and revised using a rigorous process that is based on the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system of evaluation. 9,10 With the assistance of our PhD methodologist (IG), we used the recently developed Canadian CAN-IMPLEMENT © process adapted from the ADAPTE Collaboration. [11][12][13] We created an Advisory Committee consisting of ten academic emergency physicians (one also expert in thrombosis medicine), four community emergency physicians, three cardiologists, one PhD methodologist, and two patients. Our focus was four key elements of ED care: assessment and risk stratification, rhythm and rate control, short-term and long-term stroke prevention, and disposition and follow-up. The Advisory Committee communicated by a two-day faceto-face meeting in March 2017, teleconferences,#
and email. The checklist was prepared and revised through a process of feedback and discussions on all issues by all panel members. These revisions went through ten iterations until consensus was achieved. We then circulated the draft checklist for comment to approximately 300 emergency medicine and cardiology colleagues; their email written feedback was further incorporated and the final version created and approved by the panel.
During the consensus and feedback processes, we addressed a number of issues and concerns, some of which required extensive discussion. We spent considerable time defining what is meant by "unstable" and highlighting the issue that many unstable patients are actually suffering from underlying medical problems rather than a primary arrhythmia. Where possible we chose to simplify the checklist, for example listing only procainamide for pharmacological cardioversion. Other drugs were considered including vernakalant, ibutilide, propafenone, flecainide, and amiodarone. We also tried to give specific drug dosage recommendations, recognizing that physicians are free to consult any number of excellent pharmaceutical references. The panel believes that, overall, a strategy of ED cardioversion and discharge home from the ED is preferable from both the patient and the healthcare system perspective, for most patients. One controversial recommendation is to consider rate control or transesophageal echocardiography (TEE)-guided CV if the duration of symptoms is 24-48 hours and the patient has two or more CHADS-65 criteria. This is based on some recent data from Finland. 14,15 We emphasize the importance of evaluating long-term stroke risk by use of the CHADS-65 algorithm and encourage ED physicians to prescribe anticoagulants where indicated.
Our hope is that the CAEP Acute Atrial Fibrillation/ Flutter Best Practices Checklist will standardize and improve care of AAF and AAFL in large and small EDs alike. We believe that these patients can be managed rapidly and safely, with early ED discharge and return to normal activities.
# APPENDICES
| None | None |
5482760844d0c0da756de38709d23d1ee368f95f | cma | None | The disclosure information of the authors and reviewers is available from the CCS on their guidelines library at www.ccs.ca. This statement was developed following a thorough consideration of medical literature and the best available evidence and clinical experience. It represents the consensus of a Canadian panel comprised of multidisciplinary experts on this topic with a mandate to formulate disease-specific recommendations. These recommendations are aimed to provide a reasonable and practical approach to care for specialists and allied health professionals obliged with the duty of bestowing optimal care to patients and families, and can be subject to change as scientific knowledge and technology advance and as practice patterns evolve. The statement is not intended to be a substitute for physicians using their individual judgement in managing clinical care in consultation with the patient, with appropriate regard to all the individual circumstances of the patient, diagnostic and treatment options available and available resources. Adherence to these recommendations will not necessarily produce successful outcomes in every case.# ABSTRACT
Familial hypercholesterolemia (FH) is the most common monogenic disorder causing premature atherosclerotic cardiovascular disease. It affects 1 in 250 individuals worldwide, and of the approximately 145,000 Canadians estimated to have FH, most are undiagnosed. Herein, we provide an update of the 2014 Canadian Cardiovascular Society position statement on FH addressing the need for case identification, prompt recognition, and treatment with statins and ezetimibe, and cascade family screening. We provide a new Canadian definition for FH and tools for clinicians to make a diagnosis. The risk of atherosclerotic cardiovascular disease in patients with "definite" FH is 10-to 20-fold that of a normolipidemic individual and initiating treatment in youth or young adulthood can normalize life expectancy. Target levels for low-density lipoprotein cholesterol are proposed and are aligned with the Canadian Cardiovascular Society guidelines on dyslipidemia. Recommendation for the use of inhibitors of proprotein convertase kexin/subtilisin type 9 are made in patients who cannot achieve therapeutic low-density lipoprotein cholesterol targets on maximally tolerated statins and ezetimibe. The writing committee used the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology in the preparation of the present document, which offers guidance for practical evaluation and management of patients with FH. This position statement also aims to raise awareness of FH nationally, and to mobilize patient support, promote knowledge translation, and availability of treatment and health care resources for this under-recognized, but important medical condition.
# R ESUM E
L'hypercholest erol emie familiale (HF) est la maladie monog enique la plus courante à l'origine d'une pathologie cardiovasculaire ath eroscl ereuse pr ecoce. Elle touche 1 personne sur 250 dans le monde et, chez la plupart des quelque 145 000 Canadiens atteints selon les estimations, demeure non diagnostiqu ee. Dans cet article, nous pr esentons une mise à jour de l' enonc e de position de la Soci et e canadienne de cardiologie de 2014 sur la HF soulignant la n ecessit e du diagnostic rapide, du traitement par des statines et de l' ez etimibe et du d epistage familial en cascade. Nous proposons une nouvelle d efinition canadienne de la HF et des outils diagnostiques à l'intention des cliniciens. Le risque de maladie cardiovasculaire ath eroscl ereuse chez les patients ayant reçu un diagnostic de HF est de 10 à 20 fois sup erieur à celui d'une personne normolipid emique, et l'instauration d'un traitement chez les jeunes ou les jeunes adultes peut normaliser leur esp erance de vie. Des valeurs cibles du taux de cholest erol à lipoprot eines de basse densit e conformes aux lignes directrices sur la dyslipid emie de la Soci et e canadienne de cardiologie sont propos ees. L'administration d'inhibiteurs de la proprot eine convertase kexine/ subtilisine de type 9 est recommand ee chez les patients qui ne parviennent pas à atteindre les cibles th erapeutiques en matière de cholest erol à lipoprot eines de basse densit e aux doses maximales tol er ees de statine et d' ez etimibe. Le comit e de r edaction a utilis e la m ethodologie GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) pour elaborer le pr esent document, qui contient des recommandations pratiques pour l' evaluation et la prise en charge des patients atteints de HF. Cet enonc e de position a egalement pour objectifs de promouvoir la sensibilisation à la HF à l' echelle nationale, l'offre de mesures de soutien aux patients, l'application des connaissances et la disponibilit e des ressources en matière de traitement et de soins de sant e pour cette affection dont l'importance a et e longtemps n eglig ee.
Heterozygous familial hypercholesterolemia (FH) is the most common monogenic disorder encountered in clinical practice and affects 1 in 250 individuals. 1 It is transmitted as an autosomal codominant disorder and causes elevated lowdensity lipoprotein cholesterol (LDL-C) levels across the lifespan. Affected patients are at markedly increased risk of premature atherosclerotic cardiovascular disease (ASCVD). Prompt recognition and initiation of therapy with statins in youth or young adulthood has been shown to markedly decrease the risk of ASCVD and to normalize life expectancy. 2 Nonetheless, many patients with FH remain unrecognized and undertreated in countries that have not enacted a national registry, as has been done in the Netherlands, Norway, the United Kingdom, and Spain. 2 There is a considerable challenge to raise awareness among health care professionals and patients and an opportunity to identify patients with FH in a cost-effective way through cascade screening of first-degree relatives, and to treat affected individuals. Herein, we provide an update to the 2014 Canadian Cardiovascular Society (CCS) position statement on FH, 3 with the following additions:
A Web site (www.FHCanada.net), which provides information and resources for patients and health care professionals; Better estimates of the prevalence of FH in Canada and the world 1 ;
A new, simplified definition of FH specific to the Canadian context 4 ; A validated tool to calculate the baseline LDL-C during treatment with statins or ezetimibe 5 ; Diagnostic tools () for health care professionals to make a precise diagnosis of FH; Initial data from the FH Canada registry 6 ; and Genetic testing for FH in a Clinical Laboratory Improvement Amendments-certified laboratory.
# Diagnosis of FH
It is estimated that only approximately 10% of patients with FH in Canada have been diagnosed. 2 The most commonly used diagnostic criteria for FH include the Dutch Lipid Clinic Network Criteria (DLCNC), the Simon Broome Registry criteria, and the Make Early Diagnosis Prevent Early Death criteria. 3 In the United States, many physicians report using a "clinical diagnosis" of FH on the basis of clinical judgement alone or in combination with the formal diagnostic criteria. 7 In a large population in Denmark, the DLCNC ("probable" or "definite" diagnosis) offered the best predictive value for identifying an FH-causing DNA variant compared with the Simon Broome Registry or Make Early Diagnosis Prevent Early Death criteria. 8 Limitations of the existing diagnostic criteria for FH include their complexity and heavy weighting toward the classic physical stigmata of FH (premature corneal arcus, tendon xanthomas, and xanthelasmas), which are infrequently observed in contemporary populations. The current algorithms are difficult to use in clinical practice and will miss some patients at high risk for ASCVD. It is often difficult to obtain the family history and the baseline LDL-C levels. The Familial Hypercholesterolemia Canada network (www. FHCanada.net) has proposed a new set of simplified, Canadian diagnostic criteria for FH (Fig. 1) on the basis of the 95th percentile LDL-C cut points determined for a large Canadian population (n ¼ 3.3 million subjects), the presence of a DNA diagnosis, cutaneous manifestations, and family history. 4 The new Canadian definition shows excellent agreement with the DLCNC or Simon Broome Registry criteria. 4 Additional validation of these criteria against the "gold standard" genetic diagnosis of FH will provide further insight into their performance. These new, simplified criteria for FH are anticipated to enable health care providers in Canada and other jurisdictions to recognize FH more easily, and thus improve earlier treatment and better outcomes for these patients.
# Screening for FH
Universal screening of lipid levels is recommended for Canadian men 40 years of age and older and women 50 years of age or older, or earlier if other ASCVD risk factors are present. 9 There remains controversy as to whether screening in childhood (ie, around age 10 years) for FH should be implemented. This approach would be expected to identify some cases of FH. The initial screening should include a fasting or nonfasting lipid profile and the LDL-C calculated with the Friedewald formula. When the patient is taking statins with or without ezetimibe, the baseline LDL-C (ie, before treatment) can be reliably imputed 5 and this value should then be used in the FH diagnostic criteria. Cascade screening for FH 10 (lipid screening of first-degree relatives of individuals with FH and consideration of genetic testing) is recommended and has been shown to be effective in the Netherlands for the identification and treatment of new cases. 11 Opportunistic genetic screening of young individuals who present with an acute coronary syndrome has also been shown to be effective in diagnosing FH. 12 Genetic screening of FH can aid in the identification of individuals with FH who might not have been previously diagnosed. 13 Genetic testing can be requested by the treating physician to confirm the diagnosis in "probable" and "definite" FH. The yield of genetic screening all patients with an LDL-C > 5 mmol/Ldwithout further diagnostic criteria for FHeis in the range of 2%-3%. 13,14 Child and parent screening using cholesterol levels and presence of FHcausing DNA variants has also been proposed as a method to screen for the condition. 15 Where available, genetic counselling should be provided. Affected children should be referred to a pediatric specialist.
# Genetics
FH is caused most commonly by DNA variants in the LDLR, APOB, or PCSK9 genes. A pathogenic variant in 1 of these genes can be identified in 30%-80% of individuals with clinical FH. 16,17 Most of these pathogenic variants are in the LDLR gene, whereas 1%-5% and up to 3% are found in APOB and PCSK9 genes, respectively. Some cases of FH result from the combined effects of several allelic variations in these and other genes that influence LDL-C levels. This polygenic form of clinical FH can be ascertained using a "polygenic risk score." 18 The reasons that a pathogenic variant is not identified in some individuals with clinical FH include: a genetic variant of uncertain significance in 1 of these genes (ie, with insufficient evidence to classify it as disease-causing); a polygenic cause of FH 16 ; the presence of variants not detected by current sequencing or genotyping technologies (eg, complex rearrangements or noncoding variants); the presence of a disease-causing variant in rare genes (STAP1, LDLRAP1, APOE, LIPA); or a causative variant in an (as of yet) unidentified gene.
Genetic testing can aid in the diagnosis of FH, 13 and can greatly facilitate cascade screening of family members. 10 Data from SAFEHEART (Spanish Familial Hypercholesterolemia Cohort Study) in Spain have shown that a positive genetic test result for FH is associated with increased use of lipid-lowering therapy and improved control of lipid levels. 19 Genetic testing might also help to identify a subgroup of patients with clinical FH who are at particularly elevated risk for cardiovascular events, making early diagnosis and treatment imperative for improved prognosis. Adult subjects with an LDL-C > 5 mmol/L (corresponding approximately to a nonehigh-density lipoprotein cholesterol (HDL-C) > 6.5 mmol/L) with no FH-causing variant have a 6-fold increased risk for ASCVD relative to normolipidemic individuals; whereas in individuals with LDL-C > 5 mmol/L and an FHcausing variant, a 22-fold excess risk was observed. 14 Similarly, in a cohort of Japanese patients with LDL-C > 4.7 mmol/L, the presence of clinical signs of FH (xanthomas or family history) increased the risk of ASCVD by 4.6-fold, whereas the presence of clinical signs and a pathogenic variant increased risk by 11.6-fold. 20 In a study of a single-payer health RECOMMENDATION 1. We recommend that FH be defined using the DLCNC, Simon Broome Registry, or FH Canada definition (Strong Recommendation, High-Quality Evidence).
Values and preferences. There is no "gold standard" for the diagnosis of FH. Currently available definitions rely on a scoring system to increase diagnostic confidence.
# RECOMMENDATION
- We recommend that cascade screening (lipid profile) protocols be implemented at the local, provincial, and national level in Canada and offered to first-degree relatives of patients with FH (Strong Recommendation, Moderate-Quality Evidence).
insurance provider in the United States, > 50,000 participants underwent DNA sequencing for the LDLR, APOB, and PCSK9 genes. Carriers of a pathogenic LDLR variant had a 10-fold higher risk of premature ASCVD, compared with the general population. 13 These findings imply that knowledge of a patient's genotype can improve risk assessment for ASCVD in patients with FH. Nonetheless, it is important to emphasize that individuals with hypercholesterolemia without an FHcausing variant are also at significantly and sufficiently elevated risk of ASCVD to warrant therapy, 9 and the inability to detect an FH-causing variant, or inability to access genetic testing, should not be used as a basis to withhold treatment in such individuals. Genetic testing for FH is recommended by the US Centers for Disease Control Office of Public Health Genomics, 21 the International Atherosclerosis Society, 22 and by the United Kingdom National Institutes for Clinical Excellence (NICE). 23 An international expert panel convened by the Familial Hypercholesterolemia Foundation has also recommended that genetic testing for FH should be offered to individuals strongly clinically suspected to have FH, and that cascade genetic screening be offered to first-degree relatives of affected probands. 24 LDLR, APOB and PCSK9 are also considered medically actionable genes for which the diagnostic information leads to changes in treatment, as stated by the American College of Medical Genetics and Genomics. 25 Despite these recommendations, genetic testing for FH is currently not routinely available as part of clinical care in Canada, outside of Quebec. Thus, genetic testing for FH cannot be mandated as a prerequisite to provide patient access to appropriate therapy.
# ASCVD Risk and FH
# ASCVD risk stratification in patients with FH: Genetics
As described previously, individuals with FH-causing variants in the LDLR, APOB, or PCSK9 genes are at a 5-to 22fold increased risk of ASCVD compared with normolipidemic
# RECOMMENDATION
- We recommend that genetic testing be offered, when available, to complement a diagnosis of FH and enable cascade screening (Strong Recommendation, High-Quality Evidence).
The decision to request genetic screening should be made by the treating physician after discussion with the patient. A downloadable form is available at www. FHCanada.net.
Values and preferences. Patient preferences and confidentiality must be considered. Genetic testing is currently not available in most provinces. individuals, because of lifelong exposure to elevated LDL-C. 13,14 This risk is further increased by conventional cardiovascular risk factors.
# ASCVD risk stratification in patients with FH: Clinical variables
Studies from large FH cohorts have identified independent clinical predictors of ASCVD risk. These include LDL-C, HDL-C, age, sex, diabetes, lipoprotein(a), body mass index, smoking, and hypertension. 26 Existing risk calculators developed in the general (non-FH) population, such as the Framingham Risk Score, the Pooled Cohort Equation, or the European SCORE were developed to predict the ASCVD risk in non-FH populations and are not designed to assess the risk in FH subjects. 3,27 Consequently, these scores and algorithms underestimate the risk of ASCVD in patients with FH, which results from lifelong extreme elevation in LDL-C level. These scores should thus not be used in FH. Attempts have been made to improve risk stratification in FH. The Montreal-FH-SCORE was specifically created to stratify cardiovascular risk in adults with FH. 27 This score was developed in a cohort of 670 Canadian adults with FH carrying a pathogenic variant in the LDLR gene. Age, HDL-C, male sex, hypertension, and smoking were independent predictors of ASCVD risk, and were combined to create the Montreal-FH-SCORE. The SAFEHEART registry also provides a similar risk estimation tool for patients with FH, on the basis of the Spanish experience. 19 A large study of 14,000 individuals with FH showed that patients with FH with diabetes are at an especially higher risk of ASCVD. 28 ASCVD risk stratification in patients with FH: Imaging Detection of subclinical atherosclerosis might be warranted in a patient suspected of having FH. 9 Additionally, among individuals who meet "probable FH" criteria using the Canadian, the Simon Broome Registry, or the DLCNC algorithms, detection of premature atheroma using carotid ultrasound or coronary artery calcium scoring might promote more intensive treatment. It must be emphasized, however, that because of the effectiveness of long-term statin therapy, serial imaging using, for example, sonography of the carotid arteries during follow-up of statin-treated patients with FH, is of limited value. 29 Individuals with FH develop aortic calcifications in a gene-dosage and age-dependent manner. Assessment of the aortic valve and root using echocardiography is warranted in patients with severe FH to examine aortic valve calcification and stenosis. Stress testing, including stress imaging studies, might be warranted to rule out silent ischemia in patients who engage in rigourous exercise.
# Management of FH in Adults
# Overall goals of treatment
Although several prospective studies have shown that lifetime exposure to high levels of atherogenic apolipoprotein (apo) B-containing lipoproteins dramatically increases ASCVD risk in patients with FH, no randomized trials exist to support that reducing LDL-C should be the primary target in patients with FH, nor is there evidence for a specific LDL-C goal. Extrapolating from the general population, the therapeutic goal for patients with FH without ASCVD is a 50% reduction from baseline (untreated LDL-C) and LDL-C < 3.5 mmol/L. 23 Some suggest that a reasonable therapeutic goal for primary prevention in adults with FH is to reach a goal of LDL-C < 2.5 mmol/L. 2 In patients with FH with established ASCVD, the CCS guideline currently recommends a goal of LDL-C < 2.0 mmol/L or noneHDL-C < 2.6 mmol/L. 9 Accordingly, as discussed in the Pharmacologic Therapies section below, LDL-C goals will require individualization.
# Lifestyle factors
Increasing evidence suggests that lifestyle-related risk factors such as smoking, a low-quality diet, physical inactivity, suboptimal fitness levels, abdominal obesity, insulin resistance, and type 2 diabetes are associated with accelerated atherosclerosis and long-term cardiovascular risk in patients with FH. Thus, patients with FH and their families would benefit from lifestyle management education, including advice regarding diet, exercise, and correction of sedentary behaviours, weight control, blood pressure control, diabetes control, and smoking cessation. However, conclusive data regarding the effectiveness of dietary interventions in FH are unavailable. 3 Values and preferences. If adult patients with FH require further stratification of their ASCVD risk, we suggest using the Montreal-FH-SCORE. Patients must be involved in healthy choices and preventive measures.
# Pharmacologic therapies
Randomized controlled trials on the reduction in cardiovascular events with the use of lipid-lowering agents for FH do not exist. Historical cohort data from the Netherlands FH registry shows that statin-treated patients with FH had cardiovascular outcomes similar to an age-and sex-matched population without FH. 30 In addition, several prospective cohort studies have shown that initiation of statin therapy in patients with FH is associated with a reduction in carotid intima-media thickness in adults and children. 29,31 Thus, despite the limited evidentiary basis, statins are the drug class of choice for FH, on the basis of landmark trials in the non-FH population that have shown that statins are the best treatment available for lowering LDL-C in patients with increased ASCVD risk. A recent analysis from the Dutch screening program for FH revealed that treatment with moderate-or high-intensity statins conferred a 44% relative risk reduction in ASCVD and mortality, compared with patients who did not use statins. 30 The addition of adjunctive agents is recommended on an individualized basis to reach the desired LDL-C levels. In patients with FH in whom the target LDL-C level cannot be achieved with statin monotherapy, or when high doses of statins are not tolerated because of adverse effects, the combination of a lower dose of statins with ezetimibe can be an alternative. The combination of a statin with a bile acid sequestrant can also be used to achieve LDL-C target levels in patients with FH. Bile acid sequestrants can have adverse gastrointestinal effects, increase triglyceride levels, and reduce the intestinal absorption of many drugs, limiting their clinical use.
Inhibitors of proprotein convertase kexin/subtilisin type 9 (PCSK9) have emerged as a promising target for lowering LDL-C levels to reduce the risk of ASCVD in patients with FH. Health Canada has approved 2 PCSK9 monoclonal antibodies administered subcutaneously (alirocumab 75 or 150 mg every 2 weeks or 300 mg every month and evolocumab 140 mg every 2 weeks or 420 mg every month) for reducing LDL-C levels in patients with FH who have not achieved target LDL-C levels despite maximally tolerated doses of statins. In studies of patients with FH (n ¼ 735), alirocumab decreased LDL-C by approximately 50%-60% from baseline and was well tolerated, with a safety profile similar to that of placebo. 32 Similarly, evolocumab decreased LDL-C by a mean of 53.6% compared with standard of care in 440 patients with FH from 2 clinical trials. 33 Similar effectiveness has been observed with real-world use of PCSK9 inhibitors in Canadian patients with FH. 34 Two large cardiovascular outcome trials in patients with established ASCVD showed that PCSK9 inhibitors reduced cardiovascular risk and were safe and well tolerated. The Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial examined 27,564 patients randomized to placebo (standard of care) or evolocumab 140 mg subcutaneously every 2 weeks. On a background of statin therapy (99% of patients), evolocumab lowered LDL-C levels to a median of 0.78 mmol/L and reduced the risk of cardiovascular events (15% relative risk reduction in the primary composite end point of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization). 35 The Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab (ODYSSEY Outcomes) trial tested the hypothesis that alirocumab, 75 or 150 mg subcutaneously every 2 weeks, would reduce cardiovascular events in patients with an acute coronary syndrome 1-12 months before randomization. The trial randomized 18,924 patients to standard of care alone or standard of care and alirocumab, on the background of statin use. There was a 15% reduction in the primary end point of coronary heart disease death, nonfatal myocardial infarction, stroke, or unstable angina requiring hospitalization. 36 Both drugs were well tolerated with an adverse event profile similar to that of placebo. Subgroup analyses of patients with FH from these outcome trials are pending. A third group of trials, the Studies of PCSK9 Inhibition and the Reduction of Vascular Events (SPIRE) program, used the drug bococizumab, the development of which has been terminated because of an attenuation of its LDL-C-lowering effect because of frequent development of antidrug antibodies. Notwithstanding this limitation, a subgroup analysis in 1578 patients with FH in SPIRE showed that these patients had a similar benefit from bococizumab compared with placebo, with a 17% relative risk reduction in major adverse cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death), with no statistical difference in benefit between patients with or without FH. 37 On the basis of these results, monoclonal antibodies inhibitors of PCSK9 should be considered in patients with FH who have not achieved their therapeutic goals, after use of maximally tolerated statin therapy with ezetimibe. RECOMMENDATION 7. We suggest that patients with FH adopt a healthy lifestyle as recommended by the CCS guidelines on the diagnosis and treatment of dyslipidemias 9 (Weak Recommendation, Low-Quality Evidence).
Values and preferences. Non-lipid cardiovascular disease risk factors amplify the already high risk in patients with FH and should be managed.
# Lipoprotein apheresis
Extracorporeal removal of apolipoprotein B-containing lipoproteinsdlipoprotein apheresisdis currently recommended in adults with homozygous FH (HoFH) and in children (> 15 kg in weight for LDL-C apheresis 38 ) with refractory LDL-C > 5.0 mmol/L during maximally tolerated medical therapy. Plasmapheresis or plasma exchange, a nonselective extracorporeal method, is an alternative, but less preferred treatment in jurisdictions where LDL-C apheresis is not available. Patients with HoFH are at extremely high risk of ASCVD and should be referred to a lipid specialist centre for cholesterol-lowering therapy (see the HoFH section). Although clinical evidence has suggested that long-term lipoprotein apheresis can contribute to atherosclerotic plaque regression and stabilization, no hard efficacy data from a double-blind, randomized trial has ever shown its clinical benefit. A recent study underscores the importance of screening for the LDLR mutation in HoFH and the relevance of adapting lipoprotein apheresis therapy to the severity of the disease and the benefits associated with more frequent lipoprotein apheresis treatments. 39
# Specific groups
Pregnancy in FH. Statins are the most commonly used class of drug to treat adolescents and women with FH of childbearing potential. Because of the potential teratogenicity risk, it is recommended to interrupt statin and ezetimibe therapy at least 1 month before stopping contraception. A recent meta-analysis of controlled observational studies has failed to corroborate this risk. 40 In addition, a cohort study of 886,996 completed pregnancies linked to live-born infants that included 1152 women who had used a statin during the first trimester did not find a significant teratogenic effect. 41 Although these new safety data are reassuring, suspension of statin treatment prior to pregnancy in women with FH is still advisable. For pregnant women with FH, bile acid sequestrants can be safely prescribed and in those with ASCVD (or those with HoFH) therapeutic apheresis can be considered.
Studies in primates showed that evolocumab crosses the placental barrier but reproduction studies have not shown an effect on embryo-fetal or early postnatal development. No studies have been conducted with PCSK9 inhibitors in pregnant women and there are no data on fetal harm when administrated to pregnant women with FH. Therefore, PCSK9 inhibitors should also be discontinued before conception.
# RECOMMENDATION
- We recommend that statins should not be used during pregnancy (Strong Recommendation, Low-Quality Evidence).
Values and preferences. Women should be advised to stop statins at least 1 month before stopping contraceptives or before attempting conception, or immediately at the time of diagnosis of pregnancy. agents as required, including ezetimibe and PCSK9 inhibitors according to the CCS guidelines on the diagnosis and treatment of dyslipidemias 9 (Strong Recommendation, Low-Quality Evidence).
Values and preferences. Because the primary target of therapy is LDL-C (with noneHDL-C or apolipoprotein B as alternate targets), the goal of therapy should conform to national dyslipidemia guidelines for children and for adults who require primary or secondary prevention. We recognize that guidelines preceding this one have diverse consensus goals such as an LDL-C target of < 2.5 mmol/L (European Society of Atherosclerosis, and in the United States, the National Lipid Association, the US FH Foundation, and the American Heart Association) for adult patients with FH because they are considered to be at high, lifetime cardiovascular risk. The NICE (United Kingdom) recommends an LDL-C target of < 3.5 mmol/L in adult patients with FH. In the absence of randomized controlled trial data of relevance to FH in the current therapeutic era, the general principle should be to attain the lowest level of LDL-C agreed upon between the patient and practitioner with the understanding that randomized controlled trial data from primary and secondary prevention trials suggest that low levels of LDL-C < 1.5 mmol/L are safe and associated with lower residual ASCVD risk. 9. In patients with FH and ASCVD, we suggest that targets should follow the recommendations of the CCS guidelines on the diagnosis and treatment of dyslipidemias 9 (LDL-C < 2.0 mmol/L and non eHDL-C < 2.6 mmol/L) (Weak Recommendation, Moderate-Quality Evidence). 10. We recommend that statins be used as the primary line of therapy (Strong Recommendation, High-Quality Evidence).
Cost. The yearly cost of generic statins is approximately CAD $300. 11. We suggest that ezetimibe be used as second-line agent to achieve unmet LDL-C goals (Weak Recommendation, Low-Quality Evidence). 12. We recommend that monoclonal antibody inhibitors of PCSK9 be considered in adult FH individuals without ASCVD if they have not achieved a 50% reduction in LDL-C from baseline level and reached an LDL-C level of at least < 3.5 mmol/L or lower (as determined by the shared decision process between physician and patient) on maximally tolerated statin therapy with or without ezetimibe, as per recommendation 8 (Strong Recommendation, High-Quality of Evidence).
Values and preferences. In a patient with FH, the decision to treat an asymptomatic condition (severe hypercholesterolemia) must balance the patient's perceived overall risk with actual risk of ASCVD.
Cost. Alirocumab and evolocumab are costly medications and must be used judiciously in a cost-constrained medical system.
Type 2 diabetes mellitus in patients with FH. Statins increase the risk for new-onset diabetes mellitus in high cardiovascular risk patients, although the risk is modest and outweighed markedly by the reduction in cardiovascular events by taking a statin. Interestingly, patients with FH with mutations in the LDLR gene show a lower prevalence of type 2 diabetes mellitus than unaffected relatives and lower than observed in the general population despite exposure to long-term high-dose statin therapy. 42 Although the mechanism for lowered risk of diabetes is uncertain, it might relate to reduced LDLR-mediated uptake of cholesterol in pancreatic b cells. Patients with FH who also have type 2 diabetes represent an extraordinarily high-risk group for ASCVD and should be managed aggressively.
HoFH. HoFH, although rare (1 in 250,000 to 1 in 1,000,000 individuals), results in severe LDL-C elevations and manifest ASCVD in the first 2 decades of life. 38 Cutaneous and tendon xanthomata are present from a very young age and, together with family history of heterozygous FH in both parents, and an untreated LDL-C > 13 mmol/L, can lead to the diagnosis. Genetic testing of patients and their family members might reveal concordant or discordant (compound heterozygote) FH-causing mutations. Patients with 2 null mutations have higher LDL-C levels, and are more resistant to treatment and develop earlier ASCVD. 38 Cardiovascular disease in patients with HoFH is characterized by aggressive atherosclerosis of the aortic root, primarily affecting the aortic valve and supravalvular region, although other vascular beds might be affected. Patients should be urgently referred to specialized care at the time of diagnosis and have a complete cardiovascular evaluation, because fatal coronary artery occlusions have been reported before 2 years of age. Lifestyle management and initiation of high-potency statin and ezetimibe with titration should be started as soon as the diagnosis is made. Nearly all patients with HoFH will require extracorporeal LDL-C removal, particularly if the LDL-C, with treatment, remains > 5 mmol/L or if ASCVD is present. Either plasmapheresis or preferably LDL-C apheresis should be started as soon as technically feasible, usually before 5 and at least by 8 years of age. Newer therapies, such as lomitapide, mipomersen, and PCSK9 inhibitors, have been advocated as adjunctive treatments. Frequent surveillance with cardiovascular imaging and stress testing is necessary to detect and monitor progression of atherosclerosis.
# Pediatric aspects
As a genetic condition, FH causes a lifetime of elevated LDL-C, evident even in umbilical cord blood of affected individuals. This lifetime exposure is associated with high risk of accelerated atherosclerosis, and increased markers of early atherosclerosis are evident in affected youth. The atherosclerosis process is not uniform across the lifespan and is more readily reversible in its earliest stages. This has led some experts to advocate for a strategy aimed at reducing atherosclerosis early in the course of the disease with the goal of preventing ASCVD events. However, although the case is becoming more solid for FH, accrual of evidence to support such a strategy has many important and perhaps unsolvable challenges. 15 Screening and diagnosis. Screening strategies targeted toward the children of parents with dyslipidemia or a positive family history of premature ASCVD are no more likely to identify children with elevated LDL-C than random screening, 43 although it is unclear if this is true for FH. Cascade screening depends on the effective identification of index cases and the willingness of family members to be screened; both have been problematic. 10 Parents have been more likely to desire that their children be tested than test themselves. These factors have led some organizations to recommend universal screening of children at specific ages. 21 Children with elevated LDL-C are more likely to have FH than adults with similar levels. Thus, universal lipid screening of children, with additional genetic testing when indicated, might result in a higher yield of confirmed cases. In addition, the identification of children with FH affords the opportunity for reverse cascade screening (ie, screening of the parents, who are usually of an age at which they have little contact with the health care system). A recent study by Wald et al. showed the effectiveness of incorporating such a universal screening strategy for infants in the setting of visits for routine vaccinations and health maintenance. 15 Nonetheless, lipid screening remains controversial depending on what level of evidence one views as sufficient. The diagnosis of FH in children, on the basis of criteria defined for adults, remains problematic unless a genetic mutation is confirmed, because physical findings are usually absent, and the family history is less contributory. In a study of 1034 Dutch children from families with FH, an LDL-C > 3.5 mmol/L predicted the presence of genetically confirmed FH with a 98% post-test probability. 11 Thus, lower LDL-C cut points for diagnosis of FH are needed for children.
# RECOMMENDATION
- We recommend that patients with HoFH be referred to a specialized lipid clinic and undergo complete evaluation for genetic analysis, presence of ASCVD, and aggressive lipid-lowering therapies, including consideration for extracorporeal LDL-C removal, lomitapide, and PCSK9 inhibitors (Strong Recommendation, Moderate-Quality Evidence).
# RECOMMENDATION
- We suggest that universal cholesterol level screening be considered for detection of FH in children with reverse cascade screening of parents when warranted (Weak Recommendation, Moderate-Quality Evidence).
Values and preferences. Patient confidentiality must be protected. Potential psychosocial implications of "labelling" children with the diagnosis are unclear.
Cost. Screening should be supported by provincial health agencies.
Management. Although optimizing lifestyle behaviours is paramount, it does not cause sufficient reductions in LDL-C in children with FH, and its effect is mainly in preventing or managing other cardiovascular risk factors. Statin therapy is recommended, and algorithms to guide decision-making have been defined. 21 The age at statin initiation requires clinical judgement in conjunction with the family's wishes. The usual age at initiation is 8-10 years, and the LDL-C threshold is informed by the presence of other risk factors or risk conditions. There have been pediatric trials in patients with FH with all of the available statins, and they have shown safety and efficacy similar to that in adults. 44 Although data regarding lifetime safety are likely to remain unavailable, it is reassuring that no safety concerns have been identified in longer-term pediatric studies. In recent pediatric trials that have incorporated vascular measures as outcomes, slowing or regression of carotid intima media thickness was seen, despite failure to reach optimal LDL-C targets in all. 31 If the goal is to reduce atherosclerosis with the aim of preventing adult ASCVD (for which a lifelong trial is not feasible or ethical, particularly for FH), then effective treatment starting in youth seems reasonable.
# Cascade Screening, FH Registry, Knowledge Translation
# Cascade screening
Despite the very high risk of premature ASCVD with prolonged exposure to elevated LDL-C, and the proven benefits of treatment in improving clinical outcomes, it is estimated that fewer than 5% of individuals with FH are identified worldwide. 2 In Canada, regional discrepancies in FH diagnosis might be related to the prevalence and awareness of the disease. 6 Unfortunately, because of the asymptomatic nature of severe hypercholesterolemia, the clinical presentation is often an acute coronary syndrome. Potential models to identify cases include universal cholesterol screening at a particular age, such as at the time of immunization as mentioned previously, opportunistic screening in primary care, screening of people admitted to hospital with premature myocardial infarction, or cascade screening of family members of affected patients. Among the potential options, cascade screening of family members of affected individuals is considered the most cost-effective and practical strategy 10 and has been implemented in many countries globally as the basis for developing FH registries. With 50% of first-degree relatives being affected, this strategy of screening yields high results for case identification in the adult population.
# FH registries
FH registries of individuals identified by cascade screening have been established in several European countries, of which the Dutch registry is the most successful. 2 The United Kingdom NICE registry also uses cascade screening with genetic testing and LDL-C measurement to identify affected relatives of FH index cases. 23 This approach: (1) reduced the average age at which the patients are diagnosed and treated;
(2) increased the proportion of patients with FH receiving statin therapy, and significantly decreasing their lipid levels;
(3) reduced morbidity and mortality from ASCVD when statin treatment was initiated; (4) improved lipid levels in RECOMMENDATION 16. We suggest that statin therapy be considered usually between 8 and 10 years of age if LDL-C remains ! 4.9 mmol/L, or ! 4.1 mmol/L with a family history of premature ASCVD or other cardiovascular risk factors or risk conditions (Weak Recommendation, Moderate-Quality Evidence).
Values and preferences. The age at which statin treatment is started in children with FH should incorporate the preferences of the patient and family.
Cost. Low to moderate doses of all statins are generic. children with FH; and (5) yielded cost-effective interventions. Additional benefits of FH registries include the ability to monitor effectiveness of therapy over time, to provide jurisdictional prevalence data, and to create a database for clinical trials and research. The first FH registry in Canada was initiated in British Columbia in 2012, and has recently been expanded to become a pan-Canadian FH registry. 6 The registry is Web-based, password-secured, and allows data entry from member sites without the requirement for specific software. The intended outcomes include an increased diagnosis of FH, data on jurisdictional prevalence of FH, and availability of a clinical trial database.
# Knowledge translation
The existence of cascade screening programs and FH registries will help with the identification of susceptible individuals and their family members at an early age and will serve to increase awareness of the prevalence of the condition, the high risk of premature ASCVD, and the importance of treatment starting from a young age in patients with FH. The persistent perception among the public and physicians that very elevated LDL-C is most often on the basis of poor diet, excess weight, or other secondary factors as opposed to genetic predisposition needs to be overcome, as part of an overall effort to identify and treat patients with FH more frequently and effectively.
# Conclusions
Herein, we provide an update of the 2014 Canadian Cardiovascular Society position statement on FH, which should be updated in accordance with an evolving evidence base (Fig. 2). The provision of optimal care to patients with FH presents many challenges to the patient, their family or caregivers, the physician, other health care providers, and the health care system as a whole. It represents the unique opportunity to make an accurate diagnosis using a simplified definition for FH, 4 and to provide early treatment, thus modifying the natural course of a disease that was once devastating for patients and their family. | The disclosure information of the authors and reviewers is available from the CCS on their guidelines library at www.ccs.ca. This statement was developed following a thorough consideration of medical literature and the best available evidence and clinical experience. It represents the consensus of a Canadian panel comprised of multidisciplinary experts on this topic with a mandate to formulate disease-specific recommendations. These recommendations are aimed to provide a reasonable and practical approach to care for specialists and allied health professionals obliged with the duty of bestowing optimal care to patients and families, and can be subject to change as scientific knowledge and technology advance and as practice patterns evolve. The statement is not intended to be a substitute for physicians using their individual judgement in managing clinical care in consultation with the patient, with appropriate regard to all the individual circumstances of the patient, diagnostic and treatment options available and available resources. Adherence to these recommendations will not necessarily produce successful outcomes in every case.# ABSTRACT
Familial hypercholesterolemia (FH) is the most common monogenic disorder causing premature atherosclerotic cardiovascular disease. It affects 1 in 250 individuals worldwide, and of the approximately 145,000 Canadians estimated to have FH, most are undiagnosed. Herein, we provide an update of the 2014 Canadian Cardiovascular Society position statement on FH addressing the need for case identification, prompt recognition, and treatment with statins and ezetimibe, and cascade family screening. We provide a new Canadian definition for FH and tools for clinicians to make a diagnosis. The risk of atherosclerotic cardiovascular disease in patients with "definite" FH is 10-to 20-fold that of a normolipidemic individual and initiating treatment in youth or young adulthood can normalize life expectancy. Target levels for low-density lipoprotein cholesterol are proposed and are aligned with the Canadian Cardiovascular Society guidelines on dyslipidemia. Recommendation for the use of inhibitors of proprotein convertase kexin/subtilisin type 9 are made in patients who cannot achieve therapeutic low-density lipoprotein cholesterol targets on maximally tolerated statins and ezetimibe. The writing committee used the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology in the preparation of the present document, which offers guidance for practical evaluation and management of patients with FH. This position statement also aims to raise awareness of FH nationally, and to mobilize patient support, promote knowledge translation, and availability of treatment and health care resources for this under-recognized, but important medical condition.
# R ESUM E
L'hypercholest erol emie familiale (HF) est la maladie monog enique la plus courante à l'origine d'une pathologie cardiovasculaire ath eroscl ereuse pr ecoce. Elle touche 1 personne sur 250 dans le monde et, chez la plupart des quelque 145 000 Canadiens atteints selon les estimations, demeure non diagnostiqu ee. Dans cet article, nous pr esentons une mise à jour de l' enonc e de position de la Soci et e canadienne de cardiologie de 2014 sur la HF soulignant la n ecessit e du diagnostic rapide, du traitement par des statines et de l' ez etimibe et du d epistage familial en cascade. Nous proposons une nouvelle d efinition canadienne de la HF et des outils diagnostiques à l'intention des cliniciens. Le risque de maladie cardiovasculaire ath eroscl ereuse chez les patients ayant reçu un diagnostic de HF est de 10 à 20 fois sup erieur à celui d'une personne normolipid emique, et l'instauration d'un traitement chez les jeunes ou les jeunes adultes peut normaliser leur esp erance de vie. Des valeurs cibles du taux de cholest erol à lipoprot eines de basse densit e conformes aux lignes directrices sur la dyslipid emie de la Soci et e canadienne de cardiologie sont propos ees. L'administration d'inhibiteurs de la proprot eine convertase kexine/ subtilisine de type 9 est recommand ee chez les patients qui ne parviennent pas à atteindre les cibles th erapeutiques en matière de cholest erol à lipoprot eines de basse densit e aux doses maximales tol er ees de statine et d' ez etimibe. Le comit e de r edaction a utilis e la m ethodologie GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) pour elaborer le pr esent document, qui contient des recommandations pratiques pour l' evaluation et la prise en charge des patients atteints de HF. Cet enonc e de position a egalement pour objectifs de promouvoir la sensibilisation à la HF à l' echelle nationale, l'offre de mesures de soutien aux patients, l'application des connaissances et la disponibilit e des ressources en matière de traitement et de soins de sant e pour cette affection dont l'importance a et e longtemps n eglig ee.
Heterozygous familial hypercholesterolemia (FH) is the most common monogenic disorder encountered in clinical practice and affects 1 in 250 individuals. 1 It is transmitted as an autosomal codominant disorder and causes elevated lowdensity lipoprotein cholesterol (LDL-C) levels across the lifespan. Affected patients are at markedly increased risk of premature atherosclerotic cardiovascular disease (ASCVD). Prompt recognition and initiation of therapy with statins in youth or young adulthood has been shown to markedly decrease the risk of ASCVD and to normalize life expectancy. 2 Nonetheless, many patients with FH remain unrecognized and undertreated in countries that have not enacted a national registry, as has been done in the Netherlands, Norway, the United Kingdom, and Spain. 2 There is a considerable challenge to raise awareness among health care professionals and patients and an opportunity to identify patients with FH in a cost-effective way through cascade screening of first-degree relatives, and to treat affected individuals. Herein, we provide an update to the 2014 Canadian Cardiovascular Society (CCS) position statement on FH, 3 with the following additions:
A Web site (www.FHCanada.net), which provides information and resources for patients and health care professionals; Better estimates of the prevalence of FH in Canada and the world 1 ;
A new, simplified definition of FH specific to the Canadian context 4 ; A validated tool to calculate the baseline LDL-C during treatment with statins or ezetimibe 5 ; Diagnostic tools (http://www.circl.ubc.ca/cardioriskcalculator.html) for health care professionals to make a precise diagnosis of FH; Initial data from the FH Canada registry 6 ; and Genetic testing for FH in a Clinical Laboratory Improvement Amendments-certified laboratory.
# Diagnosis of FH
It is estimated that only approximately 10% of patients with FH in Canada have been diagnosed. 2 The most commonly used diagnostic criteria for FH include the Dutch Lipid Clinic Network Criteria (DLCNC), the Simon Broome Registry criteria, and the Make Early Diagnosis Prevent Early Death criteria. 3 In the United States, many physicians report using a "clinical diagnosis" of FH on the basis of clinical judgement alone or in combination with the formal diagnostic criteria. 7 In a large population in Denmark, the DLCNC ("probable" or "definite" diagnosis) offered the best predictive value for identifying an FH-causing DNA variant compared with the Simon Broome Registry or Make Early Diagnosis Prevent Early Death criteria. 8 Limitations of the existing diagnostic criteria for FH include their complexity and heavy weighting toward the classic physical stigmata of FH (premature corneal arcus, tendon xanthomas, and xanthelasmas), which are infrequently observed in contemporary populations. The current algorithms are difficult to use in clinical practice and will miss some patients at high risk for ASCVD. It is often difficult to obtain the family history and the baseline LDL-C levels. The Familial Hypercholesterolemia Canada network (www. FHCanada.net) has proposed a new set of simplified, Canadian diagnostic criteria for FH (Fig. 1) on the basis of the 95th percentile LDL-C cut points determined for a large Canadian population (n ¼ 3.3 million subjects), the presence of a DNA diagnosis, cutaneous manifestations, and family history. 4 The new Canadian definition shows excellent agreement with the DLCNC or Simon Broome Registry criteria. 4 Additional validation of these criteria against the "gold standard" genetic diagnosis of FH will provide further insight into their performance. These new, simplified criteria for FH are anticipated to enable health care providers in Canada and other jurisdictions to recognize FH more easily, and thus improve earlier treatment and better outcomes for these patients.
# Screening for FH
Universal screening of lipid levels is recommended for Canadian men 40 years of age and older and women 50 years of age or older, or earlier if other ASCVD risk factors are present. 9 There remains controversy as to whether screening in childhood (ie, around age 10 years) for FH should be implemented. This approach would be expected to identify some cases of FH. The initial screening should include a fasting or nonfasting lipid profile and the LDL-C calculated with the Friedewald formula. When the patient is taking statins with or without ezetimibe, the baseline LDL-C (ie, before treatment) can be reliably imputed 5 and this value should then be used in the FH diagnostic criteria. Cascade screening for FH 10 (lipid screening of first-degree relatives of individuals with FH and consideration of genetic testing) is recommended and has been shown to be effective in the Netherlands for the identification and treatment of new cases. 11 Opportunistic genetic screening of young individuals who present with an acute coronary syndrome has also been shown to be effective in diagnosing FH. 12 Genetic screening of FH can aid in the identification of individuals with FH who might not have been previously diagnosed. 13 Genetic testing can be requested by the treating physician to confirm the diagnosis in "probable" and "definite" FH. The yield of genetic screening all patients with an LDL-C > 5 mmol/Ldwithout further diagnostic criteria for FHeis in the range of 2%-3%. 13,14 Child and parent screening using cholesterol levels and presence of FHcausing DNA variants has also been proposed as a method to screen for the condition. 15 Where available, genetic counselling should be provided. Affected children should be referred to a pediatric specialist.
# Genetics
FH is caused most commonly by DNA variants in the LDLR, APOB, or PCSK9 genes. A pathogenic variant in 1 of these genes can be identified in 30%-80% of individuals with clinical FH. 16,17 Most of these pathogenic variants are in the LDLR gene, whereas 1%-5% and up to 3% are found in APOB and PCSK9 genes, respectively. Some cases of FH result from the combined effects of several allelic variations in these and other genes that influence LDL-C levels. This polygenic form of clinical FH can be ascertained using a "polygenic risk score." 18 The reasons that a pathogenic variant is not identified in some individuals with clinical FH include: a genetic variant of uncertain significance in 1 of these genes (ie, with insufficient evidence to classify it as disease-causing); a polygenic cause of FH 16 ; the presence of variants not detected by current sequencing or genotyping technologies (eg, complex rearrangements or noncoding variants); the presence of a disease-causing variant in rare genes (STAP1, LDLRAP1, APOE, LIPA); or a causative variant in an (as of yet) unidentified gene.
Genetic testing can aid in the diagnosis of FH, 13 and can greatly facilitate cascade screening of family members. 10 Data from SAFEHEART (Spanish Familial Hypercholesterolemia Cohort Study) in Spain have shown that a positive genetic test result for FH is associated with increased use of lipid-lowering therapy and improved control of lipid levels. 19 Genetic testing might also help to identify a subgroup of patients with clinical FH who are at particularly elevated risk for cardiovascular events, making early diagnosis and treatment imperative for improved prognosis. Adult subjects with an LDL-C > 5 mmol/L (corresponding approximately to a nonehigh-density lipoprotein cholesterol (HDL-C) > 6.5 mmol/L) with no FH-causing variant have a 6-fold increased risk for ASCVD relative to normolipidemic individuals; whereas in individuals with LDL-C > 5 mmol/L and an FHcausing variant, a 22-fold excess risk was observed. 14 Similarly, in a cohort of Japanese patients with LDL-C > 4.7 mmol/L, the presence of clinical signs of FH (xanthomas or family history) increased the risk of ASCVD by 4.6-fold, whereas the presence of clinical signs and a pathogenic variant increased risk by 11.6-fold. 20 In a study of a single-payer health RECOMMENDATION 1. We recommend that FH be defined using the DLCNC, Simon Broome Registry, or FH Canada definition (Strong Recommendation, High-Quality Evidence).
Values and preferences. There is no "gold standard" for the diagnosis of FH. Currently available definitions rely on a scoring system to increase diagnostic confidence.
# RECOMMENDATION
2. We recommend that cascade screening (lipid profile) protocols be implemented at the local, provincial, and national level in Canada and offered to first-degree relatives of patients with FH (Strong Recommendation, Moderate-Quality Evidence).
insurance provider in the United States, > 50,000 participants underwent DNA sequencing for the LDLR, APOB, and PCSK9 genes. Carriers of a pathogenic LDLR variant had a 10-fold higher risk of premature ASCVD, compared with the general population. 13 These findings imply that knowledge of a patient's genotype can improve risk assessment for ASCVD in patients with FH. Nonetheless, it is important to emphasize that individuals with hypercholesterolemia without an FHcausing variant are also at significantly and sufficiently elevated risk of ASCVD to warrant therapy, 9 and the inability to detect an FH-causing variant, or inability to access genetic testing, should not be used as a basis to withhold treatment in such individuals. Genetic testing for FH is recommended by the US Centers for Disease Control Office of Public Health Genomics, 21 the International Atherosclerosis Society, 22 and by the United Kingdom National Institutes for Clinical Excellence (NICE). 23 An international expert panel convened by the Familial Hypercholesterolemia Foundation has also recommended that genetic testing for FH should be offered to individuals strongly clinically suspected to have FH, and that cascade genetic screening be offered to first-degree relatives of affected probands. 24 LDLR, APOB and PCSK9 are also considered medically actionable genes for which the diagnostic information leads to changes in treatment, as stated by the American College of Medical Genetics and Genomics. 25 Despite these recommendations, genetic testing for FH is currently not routinely available as part of clinical care in Canada, outside of Quebec. Thus, genetic testing for FH cannot be mandated as a prerequisite to provide patient access to appropriate therapy.
# ASCVD Risk and FH
# ASCVD risk stratification in patients with FH: Genetics
As described previously, individuals with FH-causing variants in the LDLR, APOB, or PCSK9 genes are at a 5-to 22fold increased risk of ASCVD compared with normolipidemic
# RECOMMENDATION
3. We recommend that genetic testing be offered, when available, to complement a diagnosis of FH and enable cascade screening (Strong Recommendation, High-Quality Evidence).
The decision to request genetic screening should be made by the treating physician after discussion with the patient. A downloadable form is available at www. FHCanada.net.
Values and preferences. Patient preferences and confidentiality must be considered. Genetic testing is currently not available in most provinces. individuals, because of lifelong exposure to elevated LDL-C. 13,14 This risk is further increased by conventional cardiovascular risk factors.
# ASCVD risk stratification in patients with FH: Clinical variables
Studies from large FH cohorts have identified independent clinical predictors of ASCVD risk. These include LDL-C, HDL-C, age, sex, diabetes, lipoprotein(a), body mass index, smoking, and hypertension. 26 Existing risk calculators developed in the general (non-FH) population, such as the Framingham Risk Score, the Pooled Cohort Equation, or the European SCORE were developed to predict the ASCVD risk in non-FH populations and are not designed to assess the risk in FH subjects. 3,27 Consequently, these scores and algorithms underestimate the risk of ASCVD in patients with FH, which results from lifelong extreme elevation in LDL-C level. These scores should thus not be used in FH. Attempts have been made to improve risk stratification in FH. The Montreal-FH-SCORE was specifically created to stratify cardiovascular risk in adults with FH. 27 This score was developed in a cohort of 670 Canadian adults with FH carrying a pathogenic variant in the LDLR gene. Age, HDL-C, male sex, hypertension, and smoking were independent predictors of ASCVD risk, and were combined to create the Montreal-FH-SCORE. The SAFEHEART registry also provides a similar risk estimation tool for patients with FH, on the basis of the Spanish experience. 19 A large study of 14,000 individuals with FH showed that patients with FH with diabetes are at an especially higher risk of ASCVD. 28 ASCVD risk stratification in patients with FH: Imaging Detection of subclinical atherosclerosis might be warranted in a patient suspected of having FH. 9 Additionally, among individuals who meet "probable FH" criteria using the Canadian, the Simon Broome Registry, or the DLCNC algorithms, detection of premature atheroma using carotid ultrasound or coronary artery calcium scoring might promote more intensive treatment. It must be emphasized, however, that because of the effectiveness of long-term statin therapy, serial imaging using, for example, sonography of the carotid arteries during follow-up of statin-treated patients with FH, is of limited value. 29 Individuals with FH develop aortic calcifications in a gene-dosage and age-dependent manner. Assessment of the aortic valve and root using echocardiography is warranted in patients with severe FH to examine aortic valve calcification and stenosis. Stress testing, including stress imaging studies, might be warranted to rule out silent ischemia in patients who engage in rigourous exercise.
# Management of FH in Adults
# Overall goals of treatment
Although several prospective studies have shown that lifetime exposure to high levels of atherogenic apolipoprotein (apo) B-containing lipoproteins dramatically increases ASCVD risk in patients with FH, no randomized trials exist to support that reducing LDL-C should be the primary target in patients with FH, nor is there evidence for a specific LDL-C goal. Extrapolating from the general population, the therapeutic goal for patients with FH without ASCVD is a 50% reduction from baseline (untreated LDL-C) and LDL-C < 3.5 mmol/L. 23 Some suggest that a reasonable therapeutic goal for primary prevention in adults with FH is to reach a goal of LDL-C < 2.5 mmol/L. 2 In patients with FH with established ASCVD, the CCS guideline currently recommends a goal of LDL-C < 2.0 mmol/L or noneHDL-C < 2.6 mmol/L. 9 Accordingly, as discussed in the Pharmacologic Therapies section below, LDL-C goals will require individualization.
# Lifestyle factors
Increasing evidence suggests that lifestyle-related risk factors such as smoking, a low-quality diet, physical inactivity, suboptimal fitness levels, abdominal obesity, insulin resistance, and type 2 diabetes are associated with accelerated atherosclerosis and long-term cardiovascular risk in patients with FH. Thus, patients with FH and their families would benefit from lifestyle management education, including advice regarding diet, exercise, and correction of sedentary behaviours, weight control, blood pressure control, diabetes control, and smoking cessation. However, conclusive data regarding the effectiveness of dietary interventions in FH are unavailable. 3 Values and preferences. If adult patients with FH require further stratification of their ASCVD risk, we suggest using the Montreal-FH-SCORE. Patients must be involved in healthy choices and preventive measures.
# Pharmacologic therapies
Randomized controlled trials on the reduction in cardiovascular events with the use of lipid-lowering agents for FH do not exist. Historical cohort data from the Netherlands FH registry shows that statin-treated patients with FH had cardiovascular outcomes similar to an age-and sex-matched population without FH. 30 In addition, several prospective cohort studies have shown that initiation of statin therapy in patients with FH is associated with a reduction in carotid intima-media thickness in adults and children. 29,31 Thus, despite the limited evidentiary basis, statins are the drug class of choice for FH, on the basis of landmark trials in the non-FH population that have shown that statins are the best treatment available for lowering LDL-C in patients with increased ASCVD risk. A recent analysis from the Dutch screening program for FH revealed that treatment with moderate-or high-intensity statins conferred a 44% relative risk reduction in ASCVD and mortality, compared with patients who did not use statins. 30 The addition of adjunctive agents is recommended on an individualized basis to reach the desired LDL-C levels. In patients with FH in whom the target LDL-C level cannot be achieved with statin monotherapy, or when high doses of statins are not tolerated because of adverse effects, the combination of a lower dose of statins with ezetimibe can be an alternative. The combination of a statin with a bile acid sequestrant can also be used to achieve LDL-C target levels in patients with FH. Bile acid sequestrants can have adverse gastrointestinal effects, increase triglyceride levels, and reduce the intestinal absorption of many drugs, limiting their clinical use.
Inhibitors of proprotein convertase kexin/subtilisin type 9 (PCSK9) have emerged as a promising target for lowering LDL-C levels to reduce the risk of ASCVD in patients with FH. Health Canada has approved 2 PCSK9 monoclonal antibodies administered subcutaneously (alirocumab 75 or 150 mg every 2 weeks or 300 mg every month and evolocumab 140 mg every 2 weeks or 420 mg every month) for reducing LDL-C levels in patients with FH who have not achieved target LDL-C levels despite maximally tolerated doses of statins. In studies of patients with FH (n ¼ 735), alirocumab decreased LDL-C by approximately 50%-60% from baseline and was well tolerated, with a safety profile similar to that of placebo. 32 Similarly, evolocumab decreased LDL-C by a mean of 53.6% compared with standard of care in 440 patients with FH from 2 clinical trials. 33 Similar effectiveness has been observed with real-world use of PCSK9 inhibitors in Canadian patients with FH. 34 Two large cardiovascular outcome trials in patients with established ASCVD showed that PCSK9 inhibitors reduced cardiovascular risk and were safe and well tolerated. The Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial examined 27,564 patients randomized to placebo (standard of care) or evolocumab 140 mg subcutaneously every 2 weeks. On a background of statin therapy (99% of patients), evolocumab lowered LDL-C levels to a median of 0.78 mmol/L and reduced the risk of cardiovascular events (15% relative risk reduction in the primary composite end point of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization). 35 The Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab (ODYSSEY Outcomes) trial tested the hypothesis that alirocumab, 75 or 150 mg subcutaneously every 2 weeks, would reduce cardiovascular events in patients with an acute coronary syndrome 1-12 months before randomization. The trial randomized 18,924 patients to standard of care alone or standard of care and alirocumab, on the background of statin use. There was a 15% reduction in the primary end point of coronary heart disease death, nonfatal myocardial infarction, stroke, or unstable angina requiring hospitalization. 36 Both drugs were well tolerated with an adverse event profile similar to that of placebo. Subgroup analyses of patients with FH from these outcome trials are pending. A third group of trials, the Studies of PCSK9 Inhibition and the Reduction of Vascular Events (SPIRE) program, used the drug bococizumab, the development of which has been terminated because of an attenuation of its LDL-C-lowering effect because of frequent development of antidrug antibodies. Notwithstanding this limitation, a subgroup analysis in 1578 patients with FH in SPIRE showed that these patients had a similar benefit from bococizumab compared with placebo, with a 17% relative risk reduction in major adverse cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death), with no statistical difference in benefit between patients with or without FH. 37 On the basis of these results, monoclonal antibodies inhibitors of PCSK9 should be considered in patients with FH who have not achieved their therapeutic goals, after use of maximally tolerated statin therapy with ezetimibe. RECOMMENDATION 7. We suggest that patients with FH adopt a healthy lifestyle as recommended by the CCS guidelines on the diagnosis and treatment of dyslipidemias 9 (Weak Recommendation, Low-Quality Evidence).
Values and preferences. Non-lipid cardiovascular disease risk factors amplify the already high risk in patients with FH and should be managed.
# Lipoprotein apheresis
Extracorporeal removal of apolipoprotein B-containing lipoproteinsdlipoprotein apheresisdis currently recommended in adults with homozygous FH (HoFH) and in children (> 15 kg in weight for LDL-C apheresis 38 ) with refractory LDL-C > 5.0 mmol/L during maximally tolerated medical therapy. Plasmapheresis or plasma exchange, a nonselective extracorporeal method, is an alternative, but less preferred treatment in jurisdictions where LDL-C apheresis is not available. Patients with HoFH are at extremely high risk of ASCVD and should be referred to a lipid specialist centre for cholesterol-lowering therapy (see the HoFH section). Although clinical evidence has suggested that long-term lipoprotein apheresis can contribute to atherosclerotic plaque regression and stabilization, no hard efficacy data from a double-blind, randomized trial has ever shown its clinical benefit. A recent study underscores the importance of screening for the LDLR mutation in HoFH and the relevance of adapting lipoprotein apheresis therapy to the severity of the disease and the benefits associated with more frequent lipoprotein apheresis treatments. 39
# Specific groups
Pregnancy in FH. Statins are the most commonly used class of drug to treat adolescents and women with FH of childbearing potential. Because of the potential teratogenicity risk, it is recommended to interrupt statin and ezetimibe therapy at least 1 month before stopping contraception. A recent meta-analysis of controlled observational studies has failed to corroborate this risk. 40 In addition, a cohort study of 886,996 completed pregnancies linked to live-born infants that included 1152 women who had used a statin during the first trimester did not find a significant teratogenic effect. 41 Although these new safety data are reassuring, suspension of statin treatment prior to pregnancy in women with FH is still advisable. For pregnant women with FH, bile acid sequestrants can be safely prescribed and in those with ASCVD (or those with HoFH) therapeutic apheresis can be considered.
Studies in primates showed that evolocumab crosses the placental barrier but reproduction studies have not shown an effect on embryo-fetal or early postnatal development. No studies have been conducted with PCSK9 inhibitors in pregnant women and there are no data on fetal harm when administrated to pregnant women with FH. Therefore, PCSK9 inhibitors should also be discontinued before conception.
# RECOMMENDATION
13. We recommend that statins should not be used during pregnancy (Strong Recommendation, Low-Quality Evidence).
Values and preferences. Women should be advised to stop statins at least 1 month before stopping contraceptives or before attempting conception, or immediately at the time of diagnosis of pregnancy. agents as required, including ezetimibe and PCSK9 inhibitors according to the CCS guidelines on the diagnosis and treatment of dyslipidemias 9 (Strong Recommendation, Low-Quality Evidence).
Values and preferences. Because the primary target of therapy is LDL-C (with noneHDL-C or apolipoprotein B as alternate targets), the goal of therapy should conform to national dyslipidemia guidelines for children and for adults who require primary or secondary prevention. We recognize that guidelines preceding this one have diverse consensus goals such as an LDL-C target of < 2.5 mmol/L (European Society of Atherosclerosis, and in the United States, the National Lipid Association, the US FH Foundation, and the American Heart Association) for adult patients with FH because they are considered to be at high, lifetime cardiovascular risk. The NICE (United Kingdom) recommends an LDL-C target of < 3.5 mmol/L in adult patients with FH. In the absence of randomized controlled trial data of relevance to FH in the current therapeutic era, the general principle should be to attain the lowest level of LDL-C agreed upon between the patient and practitioner with the understanding that randomized controlled trial data from primary and secondary prevention trials suggest that low levels of LDL-C < 1.5 mmol/L are safe and associated with lower residual ASCVD risk. 9. In patients with FH and ASCVD, we suggest that targets should follow the recommendations of the CCS guidelines on the diagnosis and treatment of dyslipidemias 9 (LDL-C < 2.0 mmol/L and non eHDL-C < 2.6 mmol/L) (Weak Recommendation, Moderate-Quality Evidence). 10. We recommend that statins be used as the primary line of therapy (Strong Recommendation, High-Quality Evidence).
Cost. The yearly cost of generic statins is approximately CAD $300. 11. We suggest that ezetimibe be used as second-line agent to achieve unmet LDL-C goals (Weak Recommendation, Low-Quality Evidence). 12. We recommend that monoclonal antibody inhibitors of PCSK9 be considered in adult FH individuals without ASCVD if they have not achieved a 50% reduction in LDL-C from baseline level and reached an LDL-C level of at least < 3.5 mmol/L or lower (as determined by the shared decision process between physician and patient) on maximally tolerated statin therapy with or without ezetimibe, as per recommendation 8 (Strong Recommendation, High-Quality of Evidence).
Values and preferences. In a patient with FH, the decision to treat an asymptomatic condition (severe hypercholesterolemia) must balance the patient's perceived overall risk with actual risk of ASCVD.
Cost. Alirocumab and evolocumab are costly medications and must be used judiciously in a cost-constrained medical system.
Type 2 diabetes mellitus in patients with FH. Statins increase the risk for new-onset diabetes mellitus in high cardiovascular risk patients, although the risk is modest and outweighed markedly by the reduction in cardiovascular events by taking a statin. Interestingly, patients with FH with mutations in the LDLR gene show a lower prevalence of type 2 diabetes mellitus than unaffected relatives and lower than observed in the general population despite exposure to long-term high-dose statin therapy. 42 Although the mechanism for lowered risk of diabetes is uncertain, it might relate to reduced LDLR-mediated uptake of cholesterol in pancreatic b cells. Patients with FH who also have type 2 diabetes represent an extraordinarily high-risk group for ASCVD and should be managed aggressively.
HoFH. HoFH, although rare (1 in 250,000 to 1 in 1,000,000 individuals), results in severe LDL-C elevations and manifest ASCVD in the first 2 decades of life. 38 Cutaneous and tendon xanthomata are present from a very young age and, together with family history of heterozygous FH in both parents, and an untreated LDL-C > 13 mmol/L, can lead to the diagnosis. Genetic testing of patients and their family members might reveal concordant or discordant (compound heterozygote) FH-causing mutations. Patients with 2 null mutations have higher LDL-C levels, and are more resistant to treatment and develop earlier ASCVD. 38 Cardiovascular disease in patients with HoFH is characterized by aggressive atherosclerosis of the aortic root, primarily affecting the aortic valve and supravalvular region, although other vascular beds might be affected. Patients should be urgently referred to specialized care at the time of diagnosis and have a complete cardiovascular evaluation, because fatal coronary artery occlusions have been reported before 2 years of age. Lifestyle management and initiation of high-potency statin and ezetimibe with titration should be started as soon as the diagnosis is made. Nearly all patients with HoFH will require extracorporeal LDL-C removal, particularly if the LDL-C, with treatment, remains > 5 mmol/L or if ASCVD is present. Either plasmapheresis or preferably LDL-C apheresis should be started as soon as technically feasible, usually before 5 and at least by 8 years of age. Newer therapies, such as lomitapide, mipomersen, and PCSK9 inhibitors, have been advocated as adjunctive treatments. Frequent surveillance with cardiovascular imaging and stress testing is necessary to detect and monitor progression of atherosclerosis.
# Pediatric aspects
As a genetic condition, FH causes a lifetime of elevated LDL-C, evident even in umbilical cord blood of affected individuals. This lifetime exposure is associated with high risk of accelerated atherosclerosis, and increased markers of early atherosclerosis are evident in affected youth. The atherosclerosis process is not uniform across the lifespan and is more readily reversible in its earliest stages. This has led some experts to advocate for a strategy aimed at reducing atherosclerosis early in the course of the disease with the goal of preventing ASCVD events. However, although the case is becoming more solid for FH, accrual of evidence to support such a strategy has many important and perhaps unsolvable challenges. 15 Screening and diagnosis. Screening strategies targeted toward the children of parents with dyslipidemia or a positive family history of premature ASCVD are no more likely to identify children with elevated LDL-C than random screening, 43 although it is unclear if this is true for FH. Cascade screening depends on the effective identification of index cases and the willingness of family members to be screened; both have been problematic. 10 Parents have been more likely to desire that their children be tested than test themselves. These factors have led some organizations to recommend universal screening of children at specific ages. 21 Children with elevated LDL-C are more likely to have FH than adults with similar levels. Thus, universal lipid screening of children, with additional genetic testing when indicated, might result in a higher yield of confirmed cases. In addition, the identification of children with FH affords the opportunity for reverse cascade screening (ie, screening of the parents, who are usually of an age at which they have little contact with the health care system). A recent study by Wald et al. showed the effectiveness of incorporating such a universal screening strategy for infants in the setting of visits for routine vaccinations and health maintenance. 15 Nonetheless, lipid screening remains controversial depending on what level of evidence one views as sufficient. The diagnosis of FH in children, on the basis of criteria defined for adults, remains problematic unless a genetic mutation is confirmed, because physical findings are usually absent, and the family history is less contributory. In a study of 1034 Dutch children from families with FH, an LDL-C > 3.5 mmol/L predicted the presence of genetically confirmed FH with a 98% post-test probability. 11 Thus, lower LDL-C cut points for diagnosis of FH are needed for children.
# RECOMMENDATION
14. We recommend that patients with HoFH be referred to a specialized lipid clinic and undergo complete evaluation for genetic analysis, presence of ASCVD, and aggressive lipid-lowering therapies, including consideration for extracorporeal LDL-C removal, lomitapide, and PCSK9 inhibitors (Strong Recommendation, Moderate-Quality Evidence).
# RECOMMENDATION
15. We suggest that universal cholesterol level screening be considered for detection of FH in children with reverse cascade screening of parents when warranted (Weak Recommendation, Moderate-Quality Evidence).
Values and preferences. Patient confidentiality must be protected. Potential psychosocial implications of "labelling" children with the diagnosis are unclear.
Cost. Screening should be supported by provincial health agencies.
Management. Although optimizing lifestyle behaviours is paramount, it does not cause sufficient reductions in LDL-C in children with FH, and its effect is mainly in preventing or managing other cardiovascular risk factors. Statin therapy is recommended, and algorithms to guide decision-making have been defined. 21 The age at statin initiation requires clinical judgement in conjunction with the family's wishes. The usual age at initiation is 8-10 years, and the LDL-C threshold is informed by the presence of other risk factors or risk conditions. There have been pediatric trials in patients with FH with all of the available statins, and they have shown safety and efficacy similar to that in adults. 44 Although data regarding lifetime safety are likely to remain unavailable, it is reassuring that no safety concerns have been identified in longer-term pediatric studies. In recent pediatric trials that have incorporated vascular measures as outcomes, slowing or regression of carotid intima media thickness was seen, despite failure to reach optimal LDL-C targets in all. 31 If the goal is to reduce atherosclerosis with the aim of preventing adult ASCVD (for which a lifelong trial is not feasible or ethical, particularly for FH), then effective treatment starting in youth seems reasonable.
# Cascade Screening, FH Registry, Knowledge Translation
# Cascade screening
Despite the very high risk of premature ASCVD with prolonged exposure to elevated LDL-C, and the proven benefits of treatment in improving clinical outcomes, it is estimated that fewer than 5% of individuals with FH are identified worldwide. 2 In Canada, regional discrepancies in FH diagnosis might be related to the prevalence and awareness of the disease. 6 Unfortunately, because of the asymptomatic nature of severe hypercholesterolemia, the clinical presentation is often an acute coronary syndrome. Potential models to identify cases include universal cholesterol screening at a particular age, such as at the time of immunization as mentioned previously, opportunistic screening in primary care, screening of people admitted to hospital with premature myocardial infarction, or cascade screening of family members of affected patients. Among the potential options, cascade screening of family members of affected individuals is considered the most cost-effective and practical strategy 10 and has been implemented in many countries globally as the basis for developing FH registries. With 50% of first-degree relatives being affected, this strategy of screening yields high results for case identification in the adult population.
# FH registries
FH registries of individuals identified by cascade screening have been established in several European countries, of which the Dutch registry is the most successful. 2 The United Kingdom NICE registry also uses cascade screening with genetic testing and LDL-C measurement to identify affected relatives of FH index cases. 23 This approach: (1) reduced the average age at which the patients are diagnosed and treated;
(2) increased the proportion of patients with FH receiving statin therapy, and significantly decreasing their lipid levels;
(3) reduced morbidity and mortality from ASCVD when statin treatment was initiated; (4) improved lipid levels in RECOMMENDATION 16. We suggest that statin therapy be considered usually between 8 and 10 years of age if LDL-C remains ! 4.9 mmol/L, or ! 4.1 mmol/L with a family history of premature ASCVD or other cardiovascular risk factors or risk conditions (Weak Recommendation, Moderate-Quality Evidence).
Values and preferences. The age at which statin treatment is started in children with FH should incorporate the preferences of the patient and family.
Cost. Low to moderate doses of all statins are generic. children with FH; and (5) yielded cost-effective interventions. Additional benefits of FH registries include the ability to monitor effectiveness of therapy over time, to provide jurisdictional prevalence data, and to create a database for clinical trials and research. The first FH registry in Canada was initiated in British Columbia in 2012, and has recently been expanded to become a pan-Canadian FH registry. 6 The registry is Web-based, password-secured, and allows data entry from member sites without the requirement for specific software. The intended outcomes include an increased diagnosis of FH, data on jurisdictional prevalence of FH, and availability of a clinical trial database.
# Knowledge translation
The existence of cascade screening programs and FH registries will help with the identification of susceptible individuals and their family members at an early age and will serve to increase awareness of the prevalence of the condition, the high risk of premature ASCVD, and the importance of treatment starting from a young age in patients with FH. The persistent perception among the public and physicians that very elevated LDL-C is most often on the basis of poor diet, excess weight, or other secondary factors as opposed to genetic predisposition needs to be overcome, as part of an overall effort to identify and treat patients with FH more frequently and effectively.
# Conclusions
Herein, we provide an update of the 2014 Canadian Cardiovascular Society position statement on FH, which should be updated in accordance with an evolving evidence base (Fig. 2). The provision of optimal care to patients with FH presents many challenges to the patient, their family or caregivers, the physician, other health care providers, and the health care system as a whole. It represents the unique opportunity to make an accurate diagnosis using a simplified definition for FH, 4 and to provide early treatment, thus modifying the natural course of a disease that was once devastating for patients and their family.
# Acknowledgements
The authors acknowledge the support of Christianna Brooks (CCS staff) for her help during the position statement
#
writing process. The authors also acknowledge the volunteer contributions of panel members, organizations, and individuals involved in the establishment and dissemination of best practices resulting from this position statement development (for further details see the Supplementary Material online).
All members of the primary panel participated in the writing process and have reviewed and agree with the content of the article; all members of the secondary panel read and reviewed the manuscript and agree with the content of the article.
# RECOMMENDATION
17. We recommend that a national registry for FH be implemented to raise awareness among patients and health care professionals and to provide advocacy to ensure access to effective therapies (Strong Recommendation, Moderate-Quality Evidence).
Values and preferences. Patient confidentiality must be protected.
Cost. Maintaining an FH registry should be supported as an assured provincial health service.
# Supplementary Material
To access the supplementary material accompanying this article, visit the online version of the Canadian Journal of Cardiology at www.onlinecjc.ca and at https://doi.org/10. 1016/j.cjca.2018.09.005. | None | None |
43d58e5103f84206852e8094040c760fde3f9e9f | cma | None | riteria and reporting 4. Other considerations pediatric population and during pregnancy Chronic PE SPECT-CT CANM Endorsement of the 2009 EAN Guidelines for Ventilation / Perfusion Scin 1) Diagnostic approach to pulmonary embolism (P Key Points: 1. Predictive models for PE are generally inaccurate 2. D-dimer has high sensitivity but low specificity for PE 3. Negative D-dimer has a high NPV 4. High quantitative value of D-Dimer increases likeliho# INTRODUCTION
Amyloidosis is a group of diseases in which normal or abnormal proteins breakdowns, known as amyloid fibrils, build up in tissue. Physicians have known about the anatomic and clinical effects of these proteins deposition for many centuries. Such have been described since at least 1639 when Nicolao Fontano reported a case of sago spleen in the journal Responsionum & Curationum Medicinalium. The term "amyloid" was coined in 1838 by Matthias Schleiden, a German botanist, to describe a normal amylaceous constituent of plants. There are about 30 different known types of amyloidosis related to genetic or acquired specific protein misfoldings. They are grouped into localized and systemic forms and their symptomatology depends on which organs are affected. The four most common systemic amyloidosis are the light chain (AL), inflammatory (AA), dialysis (Aβ2M), and hereditary and old age (ATTRwt) types.
The incidence of AL amyloidosis is about 3-13 per million people per year and of AA amyloidosis about 2 per million people per year with the majority onsetting between 55 and 60 years old. Diagnosis may be suspected when protein is found in the urine, organ enlargement is present, or polyneuropathy develops and is confirmed by tissue biopsy. Treatment is geared towards decreasing the amount of the involved protein. Without treatment the prognosis is quite bleak and the average life expectancy between 6 to 48 months.
# CARDIAC AMYLOIDOSIS
Cardiac amyloidosis also known as stiff heart syndrome is a form of restrictive infiltrative cardiomyopathy that confers significant mortality. It can be inherited or familial. It is rare before the age of 40. While its incidence is similar in men and women, its prevalence is higher in men than in women. Accurate estimates of the incidence and prevalence of cardiac amyloidosis are lacking. Improved awareness and advances in imaging over the past 3 decades have shown that it is substantially underdiagnosed.
The vast majority of cardiac amyloidosis are of the acquired monoclonal immunoglobulin light chain (AL) type or the familial or mutation transthyretin (ATTR) type. Light chain (AL) amyloidosis refers to the misfolding of monoclonal light chains produced by plasma cells that deposit in organs. In transthyretin amyloidosis, the transthyretin protein produced by the liver which transport thyroxine and retinol dissociates into monomers and misfolds with monomers and dimers and protofilaments depositing in various organs. The heart might be affected in up to 50 percent of patients with systemic light chain (AL) amyloidosis and ATTRwt might account for as many as 30% of patients with heart failure. The accumulation of amyloid fibrils in the myocardial interstitium increases the thickness and mass of the ventricular wall and results in progressive diastolic and systolic dysfunction. Amyloid deposition in the heart may occur in the atria, ventricles, perivascular space, valves and conduction system.
# DIAGNOSIS OF CARDIAC AMYLOID
Cardiac symptomatology is nonspecific, and patients often present with heart failure such as dyspnea and leg edema. The key clinical features which heighten the suspicion of cardiac amyloid include without being limited to: established AL or ATTR diagnosis in non-cardiac organ, carpal tunnel syndrome, nephrotic syndrome, peripheral sensorimotor neuropathy and/or neuronal autonomic dysfunction, unexplained increased left ventricular wall thickness, preserved left ventricular ejection fraction with low flow aortic gradient aortic stenosis.
Challenges for the clinical diagnosis of cardiac amyloidosis are related to the relative rarity of the disease, the different potential origins of myocardial hypertrophy, the unfamiliarity with proper diagnostic algorithms, and the absence of definitive treatment.
The formal diagnosis of cardiac amyloid requires histological confirmation with an endomyocardial biopsy that demonstrates apple-green birefringence when stained with sulfate Alcian Blue or Congo Red and viewed with a polarizing microscope. Myocardial biopsy is invasive and although the risks of serious complications is limited it is performed in few centers. A combination of clinical, laboratory, electrocardiographic and imaging methods is commonly used instead.
In a patient with a known plasma cell dyscrasia and AL amyloidosis the combination of serum BNP (B-type natriuretic peptide) and troponin can be useful to stratify prognosis and guide treatment strategies. Low voltage, axis deviation, left ventricular hypertrophy criteria, pseudo infarction pattern T waves abnormalities, atrial fibrillation and other rhythm disturbances can be seen on the ECG Albeit not necessarily specific, the echocardiographic hallmarks of cardiac amyloid include ventricular wall thickness, small left ventricular chamber volume, valve thickening, atrial enlargement and signs of elevated filling pressures with a restrictive diastolic filling. Speckle-tracking echocardiography and left ventricular longitudinal strain measurement by tissue Doppler have emerged as useful clinical tools for the identification of cardiac amyloidosis to differentiate the different forms of ventricular wall thickening. The relative preservation of apical strain and the segmental strain bulls-eye pattern can be a good indicator of cardiac amyloidosis.
Cardiovascular Magnetic Resonance has the intrinsic ability to characterize tissue particularly when enhance with gadolinium-based contrast agents. Late gadolinium enhancement of thickened left ventricular walls and documentation of expansion of the extracellular space can contribute to the diagnosis, monitor the amyloid fibrils load and treatment response.
Molecular Imaging of cardiac amyloid with PET amyloid tracers such as 18F-florbetapir, 18Fflorbetaben and 11C-Pittsburgh B radiophar-maceuticals has been used to image and quantitate amyloid deposits in the heart. They appear to have high sensitivity and specificity. They are not widely available and expensive. Sympathetic denervation in cardiac amyloidosis has been demonstrated with Metaiodobenzylguanidine (MIBG) SPECT in patients with ATTR. It is an indirect nonspecific imaging marker and it is not recommended for clinical use.
# CARDIAC AMYLOID IMAGING WITH BONES TRACERS -PYROPHOSPHATE
Pyrophosphate is a ubiquitous metabolic byproduct of many intracellular processes found in most cells. Pyrophosphate acts as a potent inhibitor of calcification; it antagonizes the ability of inorganic phosphate to crystallize with calcium to form hydroxyapatite by occupying some of the inorganic phosphate sites on the surface of nascent growing hydroxyapatite crystals.
Radiolabeled biphosphonate derivatives such as 99m Tc-bisphosphonate complexes, 99m Tcmethylenediphosphonate ( 99m Tc-MDP), and 99m Tc-hydroxymethylenediphosphonate ( 99m Tc-HMDP, are among avid bone seeking radiopharmaceuticals that have been used for many decades in nuclear medicine. They are all related to pyrophosphate binding to nascent hydroxyapatite crystals and reflecting calcium deposits and bone turnover. In soft tissues, their accumulation is thought to result from absorption on calcium salt surface.
Over the past decades, different bone tracers including 99mTcpyrophosphate ( 99m Tc-PYP), 99m Tc-HMDP) , and 99m Tc-3,3-diphosphono-1,2-propanodicarboxylic acid ( 99m Tc-DPD), have been used for the imaging of cardiac amyloidosis with 99m TC PYP being the only compound approved by Health Canada for clinical use.
In a seminal article published in 1982 already, Wizenberg et al described the value of positive myocardial technetium-99m-pyrophosphate scintigraphy in the noninvasive diagnosis of cardiac amyloidosis. Falling into desuetude largely because of the absence of therapies cardiac nuclear imaging with PYP has witnessed a true renaissance with the emergence of new therapies.
In cardiac amyloidosis, Tc-99m pyrophosphate binds to microcalcifications associated with amyloid deposits in ATTR with high affinity, allowing early diagnosis of ATTR cardiac amyloidosis. Because it shows minimal affinity for amyloid deposits in AL cardiac amyloidosis, it allows distinction between the two types.
In addition to its high sensitivity and specificity above 90%, quantitative assessment of Tc-99mpyrrophospate uptake in ATTR cardiac amyloid disease uptake provides additional prognostic information on major adverse cardiac event (MACE)-free survival, increased acute heart failure, and mortality
# PATIENTS SELECTION
Nuclear cardiac imaging with Tc-99m pyrophosphate is currently indicated in the following groups of patients:
- Individuals with heart failure and unexplained increase in left ventricular wall thickness.
- African-Americans/Canadians over the age of 60 years with heart failure, unexplained or with increased left ventricular wall thickness (>12 mm).
- Individuals over the age of 60 years with unexplained heart failure and preserved left ventricular ejection fraction.
- Individuals, especially elderly males, with unexplained neuropathy, bilateral carpal tunnel syndrome or atrial arrhythmias and signs/symptoms of heart failure.
- Evaluation of cardiac involvement in individuals with known or suspected familial amyloidosis.
- Individuals whose findings are suspicious for cardiac amyloidosis on cardiac magnetic resonance or echocardiography.
# SCINTIGRAPHIC PROCEDURE
# Considerations
Planar pyrophosphate imaging is simple and rapid to perform. Visual interpretation and quantitation of tracer uptake is straightforward. It has been proven useful for the identification of ATTR cardiac amyloidosis with sensitivity and specificity above 90%.
However planar images for the diagnosis of cardiac amyloidosis have limitations. Notably: a. They only allow a visual assessment and quantitative planar quantification of tracer uptake b. They do not define regional differences in myocardial tracer deposition. c. They do not account for tracer uptake unrelated to amyloidosis: calcified valves, mitral annulus calcification, calcified thrombus, pericardial calcification. d. They may be impacted by tracer uptake in skeleton and blood pool activity.
SPECT imaging, particularly with CT attenuation and anatomic mapping, overcomes these limitations and determines the exact localization of tracer uptake. SPECT and particularly SPECT/CT images allow a more quantitative tracer uptake evaluation, the generation of polar maps of raw counts and the determination of relative tracer intensity. Apical sparing is important to detect as it impacts prognosis. Higher apical sparing ratios have been shown to be associated with a significantly better survival.
Based on our personal experience and the expert consensus recommendation for currently available guidelines (ASNC, EANM, SNMMI) we recommend the following, acquisition, processing and interpretation for the performance of Tc-99m-pyrrophosphate scintigraphic studies
# Acquisition Procedure
# Images Processing-Interpretation
On planar or spect images, a visual semiquantitative analysis assess the cardiac uptake relative to the ribs with a grade 0 exhibiting no uptake, a grade 1 showing uptake less than bone, a grade 2 where cardiac uptake is equal to bone uptake and a grade 3 with cardiac uptake greater than bone uptake.
Visual score 0: absent myocardial uptake 1: myocardial uptake bone
Using this scoring system, the sensitivity for ATTR amyloid has been reported to be as high as >99%, while the specificity was 86%. Grade 2 or 3 tracer uptake on imaging, coupled with the absence of a monoclonal protein, had a specificity and positive predictive value for ATTR amyloidosis of 100%.
The Quantitative analysis of planar images involved the drawing of a region of interest (ROI) over the heart, copying and mirroring the region on the contralateral chest and the calculation of the heart-to-contralateral ratio mean counts per pixel. ----------------------------------------------------Contralateral ROI Total Counts
# Heart/Controlateral Ratio (H/CL) = Heart ROI Total Counts
Cardiac AL amyloidosis have a ratio that is consistently less than 1.5 while patients with clinical cardiac amyloid disease have a ratio of 1.5 or above on 1hr. post injection planar images.
Attention should be paid not to include extracardiac uptake in the cardiac ROI and the right ventricle on the contralateral chest when uptake is also present in that cavity. The greater the ratio the poorer the 5-year patient's survival.
# Reporting
# PROGNOSIS-TREATMENT
The presence and severity of amyloid cardiomyopathy is the major factor influencing prognosis of affected subjects. Management of cardiac amyloidosis is best performed in specialized centers, or at least in consultation with such a center. Treatment requires a twofold approach: management of cardiac-related complications due to amyloid deposition (which is similar regardless of the specific type of amyloid) and treatment of the underlying disease to suppress new amyloid formation (which is targeted for each specific form).
In ATTR, disease progression can be slowed or prevented by novel TTR-targeted therapies. Inotersen and patisiran are TTR RNA silencing agents that prevent the hepatic production of TTR protein.
-6 - Inotersen is an antisense oligonucleotide and patisiran is a small interfering RNA molecule. Both agents have been studied in phase III clinical trials involving ambulatory patients with hATTR and polyneuropathy symptoms. Tafamidis is an oral TTR stabilizer that binds to TTR tetramers in circulation and prevents their breakdown into unstable amyloidogenic monomers.
In the Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT), Over 30 months, tafamidis was associated with a 32% reduction in mortality and a 30% reduction in cardiovascular hospitalization.
# FIGURES | riteria and reporting 4. Other considerations pediatric population and during pregnancy Chronic PE SPECT-CT CANM Endorsement of the 2009 EAN Guidelines for Ventilation / Perfusion Scin 1) Diagnostic approach to pulmonary embolism (P Key Points: 1. Predictive models for PE are generally inaccurate 2. D-dimer has high sensitivity but low specificity for PE 3. Negative D-dimer has a high NPV 4. High quantitative value of D-Dimer increases likeliho# INTRODUCTION
Amyloidosis is a group of diseases in which normal or abnormal proteins breakdowns, known as amyloid fibrils, build up in tissue. Physicians have known about the anatomic and clinical effects of these proteins deposition for many centuries. Such have been described since at least 1639 when Nicolao Fontano reported a case of sago spleen in the journal Responsionum & Curationum Medicinalium. The term "amyloid" was coined in 1838 by Matthias Schleiden, a German botanist, to describe a normal amylaceous constituent of plants. There are about 30 different known types of amyloidosis related to genetic or acquired specific protein misfoldings. They are grouped into localized and systemic forms and their symptomatology depends on which organs are affected. The four most common systemic amyloidosis are the light chain (AL), inflammatory (AA), dialysis (Aβ2M), and hereditary and old age (ATTRwt) types.
The incidence of AL amyloidosis is about 3-13 per million people per year and of AA amyloidosis about 2 per million people per year with the majority onsetting between 55 and 60 years old. Diagnosis may be suspected when protein is found in the urine, organ enlargement is present, or polyneuropathy develops and is confirmed by tissue biopsy. Treatment is geared towards decreasing the amount of the involved protein. Without treatment the prognosis is quite bleak and the average life expectancy between 6 to 48 months.
# CARDIAC AMYLOIDOSIS
Cardiac amyloidosis also known as stiff heart syndrome is a form of restrictive infiltrative cardiomyopathy that confers significant mortality. It can be inherited or familial. It is rare before the age of 40. While its incidence is similar in men and women, its prevalence is higher in men than in women. Accurate estimates of the incidence and prevalence of cardiac amyloidosis are lacking. Improved awareness and advances in imaging over the past 3 decades have shown that it is substantially underdiagnosed.
The vast majority of cardiac amyloidosis are of the acquired monoclonal immunoglobulin light chain (AL) type or the familial or mutation transthyretin (ATTR) type. Light chain (AL) amyloidosis refers to the misfolding of monoclonal light chains produced by plasma cells that deposit in organs. In transthyretin amyloidosis, the transthyretin protein produced by the liver which transport thyroxine and retinol dissociates into monomers and misfolds with monomers and dimers and protofilaments depositing in various organs. The heart might be affected in up to 50 percent of patients with systemic light chain (AL) amyloidosis and ATTRwt might account for as many as 30% of patients with heart failure. The accumulation of amyloid fibrils in the myocardial interstitium increases the thickness and mass of the ventricular wall and results in progressive diastolic and systolic dysfunction. Amyloid deposition in the heart may occur in the atria, ventricles, perivascular space, valves and conduction system.
# DIAGNOSIS OF CARDIAC AMYLOID
Cardiac symptomatology is nonspecific, and patients often present with heart failure such as dyspnea and leg edema. The key clinical features which heighten the suspicion of cardiac amyloid include without being limited to: established AL or ATTR diagnosis in non-cardiac organ, carpal tunnel syndrome, nephrotic syndrome, peripheral sensorimotor neuropathy and/or neuronal autonomic dysfunction, unexplained increased left ventricular wall thickness, preserved left ventricular ejection fraction with low flow aortic gradient aortic stenosis.
Challenges for the clinical diagnosis of cardiac amyloidosis are related to the relative rarity of the disease, the different potential origins of myocardial hypertrophy, the unfamiliarity with proper diagnostic algorithms, and the absence of definitive treatment.
The formal diagnosis of cardiac amyloid requires histological confirmation with an endomyocardial biopsy that demonstrates apple-green birefringence when stained with sulfate Alcian Blue or Congo Red and viewed with a polarizing microscope. Myocardial biopsy is invasive and although the risks of serious complications is limited it is performed in few centers. A combination of clinical, laboratory, electrocardiographic and imaging methods is commonly used instead.
In a patient with a known plasma cell dyscrasia and AL amyloidosis the combination of serum BNP (B-type natriuretic peptide) and troponin can be useful to stratify prognosis and guide treatment strategies. Low voltage, axis deviation, left ventricular hypertrophy criteria, pseudo infarction pattern T waves abnormalities, atrial fibrillation and other rhythm disturbances can be seen on the ECG Albeit not necessarily specific, the echocardiographic hallmarks of cardiac amyloid include ventricular wall thickness, small left ventricular chamber volume, valve thickening, atrial enlargement and signs of elevated filling pressures with a restrictive diastolic filling. Speckle-tracking echocardiography and left ventricular longitudinal strain measurement by tissue Doppler have emerged as useful clinical tools for the identification of cardiac amyloidosis to differentiate the different forms of ventricular wall thickening. The relative preservation of apical strain and the segmental strain bulls-eye pattern can be a good indicator of cardiac amyloidosis.
Cardiovascular Magnetic Resonance has the intrinsic ability to characterize tissue particularly when enhance with gadolinium-based contrast agents. Late gadolinium enhancement of thickened left ventricular walls and documentation of expansion of the extracellular space can contribute to the diagnosis, monitor the amyloid fibrils load and treatment response.
Molecular Imaging of cardiac amyloid with PET amyloid tracers such as 18F-florbetapir, 18Fflorbetaben and 11C-Pittsburgh B radiophar-maceuticals has been used to image and quantitate amyloid deposits in the heart. They appear to have high sensitivity and specificity. They are not widely available and expensive. Sympathetic denervation in cardiac amyloidosis has been demonstrated with Metaiodobenzylguanidine (MIBG) SPECT in patients with ATTR. It is an indirect nonspecific imaging marker and it is not recommended for clinical use.
# CARDIAC AMYLOID IMAGING WITH BONES TRACERS -PYROPHOSPHATE
Pyrophosphate is a ubiquitous metabolic byproduct of many intracellular processes found in most cells. Pyrophosphate acts as a potent inhibitor of calcification; it antagonizes the ability of inorganic phosphate to crystallize with calcium to form hydroxyapatite by occupying some of the inorganic phosphate sites on the surface of nascent growing hydroxyapatite crystals.
Radiolabeled biphosphonate derivatives such as 99m Tc-bisphosphonate complexes, 99m Tcmethylenediphosphonate ( 99m Tc-MDP), and 99m Tc-hydroxymethylenediphosphonate ( 99m Tc-HMDP, are among avid bone seeking radiopharmaceuticals that have been used for many decades in nuclear medicine. They are all related to pyrophosphate binding to nascent hydroxyapatite crystals and reflecting calcium deposits and bone turnover. In soft tissues, their accumulation is thought to result from absorption on calcium salt surface.
Over the past decades, different bone tracers including 99mTcpyrophosphate ( 99m Tc-PYP), 99m Tc-HMDP) , and 99m Tc-3,3-diphosphono-1,2-propanodicarboxylic acid ( 99m Tc-DPD), have been used for the imaging of cardiac amyloidosis with 99m TC PYP being the only compound approved by Health Canada for clinical use.
In a seminal article published in 1982 already, Wizenberg et al described the value of positive myocardial technetium-99m-pyrophosphate scintigraphy in the noninvasive diagnosis of cardiac amyloidosis. Falling into desuetude largely because of the absence of therapies cardiac nuclear imaging with PYP has witnessed a true renaissance with the emergence of new therapies.
In cardiac amyloidosis, Tc-99m pyrophosphate binds to microcalcifications associated with amyloid deposits in ATTR with high affinity, allowing early diagnosis of ATTR cardiac amyloidosis. Because it shows minimal affinity for amyloid deposits in AL cardiac amyloidosis, it allows distinction between the two types.
In addition to its high sensitivity and specificity above 90%, quantitative assessment of Tc-99mpyrrophospate uptake in ATTR cardiac amyloid disease uptake provides additional prognostic information on major adverse cardiac event (MACE)-free survival, increased acute heart failure, and mortality
# PATIENTS SELECTION
Nuclear cardiac imaging with Tc-99m pyrophosphate is currently indicated in the following groups of patients:
• Individuals with heart failure and unexplained increase in left ventricular wall thickness.
• African-Americans/Canadians over the age of 60 years with heart failure, unexplained or with increased left ventricular wall thickness (>12 mm).
• Individuals over the age of 60 years with unexplained heart failure and preserved left ventricular ejection fraction.
• Individuals, especially elderly males, with unexplained neuropathy, bilateral carpal tunnel syndrome or atrial arrhythmias and signs/symptoms of heart failure.
• Evaluation of cardiac involvement in individuals with known or suspected familial amyloidosis.
• Individuals whose findings are suspicious for cardiac amyloidosis on cardiac magnetic resonance or echocardiography.
# SCINTIGRAPHIC PROCEDURE
# Considerations
Planar pyrophosphate imaging is simple and rapid to perform. Visual interpretation and quantitation of tracer uptake is straightforward. It has been proven useful for the identification of ATTR cardiac amyloidosis with sensitivity and specificity above 90%.
However planar images for the diagnosis of cardiac amyloidosis have limitations. Notably: a. They only allow a visual assessment and quantitative planar quantification of tracer uptake b. They do not define regional differences in myocardial tracer deposition. c. They do not account for tracer uptake unrelated to amyloidosis: calcified valves, mitral annulus calcification, calcified thrombus, pericardial calcification. d. They may be impacted by tracer uptake in skeleton and blood pool activity.
SPECT imaging, particularly with CT attenuation and anatomic mapping, overcomes these limitations and determines the exact localization of tracer uptake. SPECT and particularly SPECT/CT images allow a more quantitative tracer uptake evaluation, the generation of polar maps of raw counts and the determination of relative tracer intensity. Apical sparing is important to detect as it impacts prognosis. Higher apical sparing ratios have been shown to be associated with a significantly better survival.
Based on our personal experience and the expert consensus recommendation for currently available guidelines (ASNC, EANM, SNMMI) we recommend the following, acquisition, processing and interpretation for the performance of Tc-99m-pyrrophosphate scintigraphic studies
# Acquisition Procedure
# Images Processing-Interpretation
On planar or spect images, a visual semiquantitative analysis assess the cardiac uptake relative to the ribs with a grade 0 exhibiting no uptake, a grade 1 showing uptake less than bone, a grade 2 where cardiac uptake is equal to bone uptake and a grade 3 with cardiac uptake greater than bone uptake.
Visual score 0: absent myocardial uptake 1: myocardial uptake < bone 2: myocardial uptake = bone 3: myocardial uptake > bone
#
Using this scoring system, the sensitivity for ATTR amyloid has been reported to be as high as >99%, while the specificity was 86%. Grade 2 or 3 tracer uptake on imaging, coupled with the absence of a monoclonal protein, had a specificity and positive predictive value for ATTR amyloidosis of 100%.
The Quantitative analysis of planar images involved the drawing of a region of interest (ROI) over the heart, copying and mirroring the region on the contralateral chest and the calculation of the heart-to-contralateral ratio mean counts per pixel. ----------------------------------------------------Contralateral ROI Total Counts
# Heart/Controlateral Ratio (H/CL) = Heart ROI Total Counts
Cardiac AL amyloidosis have a ratio that is consistently less than 1.5 while patients with clinical cardiac amyloid disease have a ratio of 1.5 or above on 1hr. post injection planar images.
Attention should be paid not to include extracardiac uptake in the cardiac ROI and the right ventricle on the contralateral chest when uptake is also present in that cavity. The greater the ratio the poorer the 5-year patient's survival.
# Reporting
# PROGNOSIS-TREATMENT
The presence and severity of amyloid cardiomyopathy is the major factor influencing prognosis of affected subjects. Management of cardiac amyloidosis is best performed in specialized centers, or at least in consultation with such a center. Treatment requires a twofold approach: management of cardiac-related complications due to amyloid deposition (which is similar regardless of the specific type of amyloid) and treatment of the underlying disease to suppress new amyloid formation (which is targeted for each specific form).
In ATTR, disease progression can be slowed or prevented by novel TTR-targeted therapies. Inotersen and patisiran are TTR RNA silencing agents that prevent the hepatic production of TTR protein.
-6 - Inotersen is an antisense oligonucleotide and patisiran is a small interfering RNA molecule. Both agents have been studied in phase III clinical trials involving ambulatory patients with hATTR and polyneuropathy symptoms. Tafamidis is an oral TTR stabilizer that binds to TTR tetramers in circulation and prevents their breakdown into unstable amyloidogenic monomers.
In the Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT), Over 30 months, tafamidis was associated with a 32% reduction in mortality and a 30% reduction in cardiovascular hospitalization.
# FIGURES
| None | None |
1faa8cbd06c7abbdd2f0dafa5611e7be84d8be0c | cma | None | # Introduction
In 2020, the COVID-19 Pandemic has created rapid and significant social disruption, both through illness and social distancing practices. In order to create healthcare capacity, most clinical services have been reduced and many scheduled surgeries have been indefinitely postponed. Furthermore, supply chain disruptions and medication shortages are anticipated.
Preventing unintended pregnancy and accessing abortion may become more difficult during the COVID-19 pandemic, and the need for such services may, in fact, surpass normal demand. Therefore, contraception and abortion care remain essential and time-sensitive.
We wish to provide interim guidance to affirm best practices and, where evidence is limited, provide expert consensus on strategies to maintain abortion access during the COVID-19 pandemic or other periods of major social disruption such as natural disaster, wartime conflict, or significant supply-chain disruption.
# Recommendations and Summary Statements
Induced Abortion 1. Induced abortion is an essential and time-sensitive medical service that must be maintained in any pandemic or during periods of social disruption.
Induced abortion is both a medical service and a human right 1 . The personal cost of experiencing unintended pregnancy is high, as are the costs borne by the healthcare system to manage people with unintended pregnancy 2 . However, any reduction of abortion services would magnify risk and place additional burden on the healthcare system 3 . Abortion is safer when performed at earlier gestational ages, therefore delays in abortion access increase risk to patients 4,5 . Abortion is also safer than childbirth, increasing risk to those who cannot access induced abortion when desired 6,7 . In countries where safe abortion is not available, unsafe abortion is a major contributor of maternal mortality 1 . The current pandemic impairs access to both contraception and abortion health care services. The result is increased demand on existing services, which must not only be maintained but must adapt to meet local need.
# Clinicians and patients should select the most appropriate method of abortion. Clinicians should balance the risks and benefits of in-person procedural abortion with those of medical abortion, which can be provided in a virtual setting.
In early pregnancy, medical abortion (MA) and procedural (surgical) abortion are both first-line options for pregnancy termination 8,9 . While procedural abortion is slightly more effective with lower complication rates than medical abortion, it requires at least one in-person assessment in a healthcare facility . As healthcare resources change, it may be difficult to obtain tests that are typically performed prior to MA in keeping with previous guidelines.
All clinicians providing abortion services should exercise resource stewardship regardless of the method of abortion chosen. MA can safely be provided by telemedicine or virtual visits 11 . Several "no-touch" or "no-test" medical abortion regimens have recently been developed, which guide clinicians in the provision of abortion care without testing (or when testing is unavailable) 12 .
It is critical that patients have 24/7 access to a knowledgeable provider who can provide the appropriate care for those undergoing medical abortion. Because many emergency department visits can be avoided through telephone triage, clinicians able to support abortion patients (directly or through an on-call coverage model) should be the first point of contact for patient questions or concerns.
# Patients and clinicians should adhere to local infection control regulations and strategies, including deferring appointments if a patient has influenza-like illness, or is suspected or confirmed to be COVID-19 positive.
While abortion is an urgent medical issue, the safety of other patients and healthcare workers is also important. Because most patients can defer an abortion for a two-week isolation period without significant risk of adverse outcomes, local infection control policies should be followed. If a patient is ill and is suspected or confirmed to have COVID-19, and the abortion cannot be delayed, a hospital-based procedural abortion is recommended. This option will limit the required exposure to a single visit and should be performed by healthcare workers with adequate training and personal protective equipment to manage patients with SARS-CoV2 infection. Ultimately, an individualized approach is needed for such scenarios.
# Where equipment and competent providers are available, hospitals and abortion facilities should extend gestational age limits by two weeks to ensure continued access to first and second-trimester abortion.
Most hospitals have a policy on whether abortions are permitted and stating their upper gestational age limit. Gestational age limits should be based on provider competence and available resources whenever possible. Therefore, if resources permit, hospitals should extend gestational age limits by two weeks to ensure continued access to patients whose care has been deferred due to the COVID-19 pandemic. Hospitals with skilled providers should increase the gestational age limit to 24 weeks as some second trimester services may be limited due to hospital constraints.
# Procedural (Surgical) Abortion
- Procedural abortion with a paracervical block and procedural sedation is NOT an aerosol-generating medical procedure. Procedural sedation should be strongly considered over general anaesthesia for surgical abortion.
When compared to general anaesthesia, local anaesthesia with procedural sedation is associated with lower pain and complication rates 9 . Furthermore, light procedural sedation with spontaneous respiration and avoidance of bag-mask ventilation is NOT considered an aerosol generating medical procedure, and therefore does not require the use of N95 respirators. Procedural sedation may permit fewer personnel and/or greater physical distancing than a traditional operating room 13 . It is inappropriate for hospitals to limit abortion access based on aerosolization risk or respirator conservation as an anaesthesia machine and ventilation should not be required.
# Nitrous Oxide should NOT be used during procedural abortion, owing to the possible risk of contamination with SARS-CoV2.
Given emerging evidence of asymptomatic carriers, and uncertainty about the integrity of nitrous oxide/oxygen circuits, the use of Entonox may pose a health hazard to patients and healthcare workers. Furthermore, given that nitrous oxide is minimally effective for pain relief during procedural abortion, its use should be discontinued 9 .
# Repeat Rhesus Factor (Rh) testing is NOT required prior to procedural abortion.
Given the low probability of Rhesus alloimmunization, repeat Rh testing is not needed. The decision to administer Immune Globulin (RhIG) may be based on previous results.
# Induction abortion should be considered for patients who are unable to access second-trimester surgical services.
If patients cannot access second-trimester (Dilation and Evacuation) programs, induction abortion remains an option for patients. Pre-treatment with mifepristone 200 mg PO 24-48 hours prior to misoprostol reduces time in hospital. A misoprostol regimen is described in the SOGC Induced Abortion guideline 9 . To minimize time in hospital, the first dose of misoprostol (which is provided with combination mifepristone/misoprostol) can be taken at home and the patient is admitted when contractions start, or a second dose is required.
# Medical Abortion (MA)
# Medical abortion with mifepristone and misoprostol should be offered as a first-line method of induced abortion for pregnancies up to 70 days.
Combination mifepristone/misoprostol is indicated for 63 days, and the existing SOGC guideline states that it can be used up to 70 days8. We continue to recommend these gestational age limits for the majority of MA providers.
# For experienced providers where close surveillance is possible, medical abortion with mifepristone and misoprostol can be offered as an alternative to procedural abortion up to 77 days.
Emerging evidence and consensus opinion support the use of mifepristone medical abortion to 77 days (11 weeks) with repeated doses of misoprostol 10 . However, this should be reserved for experienced providers who can provide adequate coverage and backup should urgent care be needed. Patients should be informed that mifepristone use beyond 63 days is off-label, that they will likely expel and see an intact fetus, and that there is a higher risk of complication. For these reasons, and the possible higher risk of Emergency Department visits, we continue to recommend procedural abortion beyond 70 days in most cases.
As the proportion of induced abortions that are medical abortions increase, surgical services are decreasing in many jurisdictions. In the event of shortages of mifepristone, surgical services must be restored and/or expanded to ensure access to abortion on humanitarian grounds.
Clinicians should prescribe an additional dose of misoprostol 800 mcg (buccal or vaginal) to be used on direction of a healthcare provider in the event of suspected incomplete or failed abortion.
To minimize patient visits to pharmacies, and to reduce complications, MA prescriptions should include an additional dose of misoprostol 800 mcg so that patients have medication on hand if an additional dose is required. Typically, a second dose of misoprostol is given at higher gestational ages, if by history a failed MA is suspected (minimal bleeding or expulsion), or to manage an incomplete abortion or ongoing pregnancy 8 .
Affirming best practice, the initial prescription should also include any contraception to be initiated at the time of medical abortion. Additional analgesics and STI prophylaxis can be prescribed based on clinician judgement and patient request.
# Medical abortion can be provided based on a home pregnancy test and Last Menstrual Period (LMP) dating alone if the patient has no risk factors for ectopic pregnancy, is reasonably certain of her LMP, is not using hormonal contraception, has regular menstrual cycles, and has no other contraindications.
This statement affirms the current MA guideline 8 . Patients who are reasonably certain of their LMP and have regular menstrual cycles are very likely to accurately predict being within the gestational age limit for MA. No further testing is required.
# All patients with uncertain pregnancy dating, risk factors for ectopic pregnancy, or symptoms consistent with ectopic pregnancy, should undergo ultrasound evaluation prior to medical abortion.
Ultrasound remains the gold standard for pregnancy assessment, regardless of pregnancy intention. Because unrecognized ectopic pregnancy is a rare but serious risk in periods of limited healthcare resources, it is important to remember that patients with risk factors (such as previous ectopic pregnancy or tubal surgery) or signs/symptoms of ectopic pregnancy should have an ultrasound. Those patients who are uncertain of their gestational age (by LMP or conception dating) should have further assessment of gestational age 8 .
# If ultrasound is not used prior to medical abortion, close surveillance and follow-up is required until completion.
All MAs performed without ultrasound are, by definition, pregnancies of unknown location (PULs). Though the risk of unrecognized ectopic pregnancy is low, close follow-up is required to ensure completion of the MA 8 . Clinicians should not initiate an MA if they are not reasonably certain that they will be available (directly or through an on-call service) to provide rapid assessment until confirmed completion of the abortion.
# Rh testing and Immune Globulin (RhIG) administration may be withheld for medical abortion prior to 70 days.
Current evidence supports withholding Rh testing and RhIG for medical abortions up to 56 days (8 weeks) gestational age given the very low probability of Rh-antigen expression on fetal cells. There is only expert opinion evidence to guide Rh management for MA between 56 and 70 days 14, 15 . In keeping with other national guidelines, the low probability of alloimmunization, and whereas testing and RhIG administration requires one or two additional patient visits, we recommend that Rh testing and RhIG may be withheld for MA during the COVID-19 pandemic.
We recommend a return to the current MA guidelines following resolution of the COVID-19 pandemic 8 , and further guidance will be provided when this guideline is due for renewal.
# Medical abortion can be provided a tiered approach (minimal resource, limited resource, and onlabel provision with full resource utilization). The decision to offer medical abortion should be made based on clinician competence, resource availability, and patient preference.
"On label" provision of mifepristone medical abortion requires the most resources when compared to other evidence-based protocols 8 . However, resources such as imaging and laboratory testing may vary widely and in an unpredictable manner during a pandemic or period of social disruption. Clinicians should exercise resource stewardship when possible and recognize when a lack of resources or clinician comfort precludes the safe provision of MA.
Several new MA guidelines have been published to provide experienced providers with protocols to manage MA at higher gestational ages and using a "no-touch" or "no-test" approach 12 . Striking a balance, this interim guidance identifies tests that can be safely excluded while maintaining a high degree of safety. Providers must consider their own competence and experience with MA prior to using these protocols, must inform patients that these are new protocols based on low-resource availability and that this is an off-label indication. If a clinician does not feel that resources permit safe medical abortion, a procedural abortion or referral to a more experienced clinician is advised. | # Introduction
In 2020, the COVID-19 Pandemic has created rapid and significant social disruption, both through illness and social distancing practices. In order to create healthcare capacity, most clinical services have been reduced and many scheduled surgeries have been indefinitely postponed. Furthermore, supply chain disruptions and medication shortages are anticipated.
Preventing unintended pregnancy and accessing abortion may become more difficult during the COVID-19 pandemic, and the need for such services may, in fact, surpass normal demand. Therefore, contraception and abortion care remain essential and time-sensitive.
We wish to provide interim guidance to affirm best practices and, where evidence is limited, provide expert consensus on strategies to maintain abortion access during the COVID-19 pandemic or other periods of major social disruption such as natural disaster, wartime conflict, or significant supply-chain disruption.
# Recommendations and Summary Statements
Induced Abortion 1. Induced abortion is an essential and time-sensitive medical service that must be maintained in any pandemic or during periods of social disruption.
Induced abortion is both a medical service and a human right 1 . The personal cost of experiencing unintended pregnancy is high, as are the costs borne by the healthcare system to manage people with unintended pregnancy 2 . However, any reduction of abortion services would magnify risk and place additional burden on the healthcare system 3 . Abortion is safer when performed at earlier gestational ages, therefore delays in abortion access increase risk to patients 4,5 . Abortion is also safer than childbirth, increasing risk to those who cannot access induced abortion when desired 6,7 . In countries where safe abortion is not available, unsafe abortion is a major contributor of maternal mortality 1 . The current pandemic impairs access to both contraception and abortion health care services. The result is increased demand on existing services, which must not only be maintained but must adapt to meet local need.
# Clinicians and patients should select the most appropriate method of abortion. Clinicians should balance the risks and benefits of in-person procedural abortion with those of medical abortion, which can be provided in a virtual setting.
In early pregnancy, medical abortion (MA) and procedural (surgical) abortion are both first-line options for pregnancy termination 8,9 . While procedural abortion is slightly more effective with lower complication rates than medical abortion, it requires at least one in-person assessment in a healthcare facility [8][9][10] . As healthcare resources change, it may be difficult to obtain tests that are typically performed prior to MA in keeping with previous guidelines.
All clinicians providing abortion services should exercise resource stewardship regardless of the method of abortion chosen. MA can safely be provided by telemedicine or virtual visits 11 . Several "no-touch" or "no-test" medical abortion regimens have recently been developed, which guide clinicians in the provision of abortion care without testing (or when testing is unavailable) 12 .
It is critical that patients have 24/7 access to a knowledgeable provider who can provide the appropriate care for those undergoing medical abortion. Because many emergency department visits can be avoided through telephone triage, clinicians able to support abortion patients (directly or through an on-call coverage model) should be the first point of contact for patient questions or concerns.
# Patients and clinicians should adhere to local infection control regulations and strategies, including deferring appointments if a patient has influenza-like illness, or is suspected or confirmed to be COVID-19 positive.
While abortion is an urgent medical issue, the safety of other patients and healthcare workers is also important. Because most patients can defer an abortion for a two-week isolation period without significant risk of adverse outcomes, local infection control policies should be followed. If a patient is ill and is suspected or confirmed to have COVID-19, and the abortion cannot be delayed, a hospital-based procedural abortion is recommended. This option will limit the required exposure to a single visit and should be performed by healthcare workers with adequate training and personal protective equipment to manage patients with SARS-CoV2 infection. Ultimately, an individualized approach is needed for such scenarios.
# Where equipment and competent providers are available, hospitals and abortion facilities should extend gestational age limits by two weeks to ensure continued access to first and second-trimester abortion.
Most hospitals have a policy on whether abortions are permitted and stating their upper gestational age limit. Gestational age limits should be based on provider competence and available resources whenever possible. Therefore, if resources permit, hospitals should extend gestational age limits by two weeks to ensure continued access to patients whose care has been deferred due to the COVID-19 pandemic. Hospitals with skilled providers should increase the gestational age limit to 24 weeks as some second trimester services may be limited due to hospital constraints.
# Procedural (Surgical) Abortion
1. Procedural abortion with a paracervical block and procedural sedation is NOT an aerosol-generating medical procedure. Procedural sedation should be strongly considered over general anaesthesia for surgical abortion.
When compared to general anaesthesia, local anaesthesia with procedural sedation is associated with lower pain and complication rates 9 . Furthermore, light procedural sedation with spontaneous respiration and avoidance of bag-mask ventilation is NOT considered an aerosol generating medical procedure, and therefore does not require the use of N95 respirators. Procedural sedation may permit fewer personnel and/or greater physical distancing than a traditional operating room 13 . It is inappropriate for hospitals to limit abortion access based on aerosolization risk or respirator conservation as an anaesthesia machine and ventilation should not be required.
# Nitrous Oxide should NOT be used during procedural abortion, owing to the possible risk of contamination with SARS-CoV2.
Given emerging evidence of asymptomatic carriers, and uncertainty about the integrity of nitrous oxide/oxygen circuits, the use of Entonox may pose a health hazard to patients and healthcare workers. Furthermore, given that nitrous oxide is minimally effective for pain relief during procedural abortion, its use should be discontinued 9 .
# Repeat Rhesus Factor (Rh) testing is NOT required prior to procedural abortion.
Given the low probability of Rhesus alloimmunization, repeat Rh testing is not needed. The decision to administer Immune Globulin (RhIG) may be based on previous results.
# Induction abortion should be considered for patients who are unable to access second-trimester surgical services.
If patients cannot access second-trimester (Dilation and Evacuation) programs, induction abortion remains an option for patients. Pre-treatment with mifepristone 200 mg PO 24-48 hours prior to misoprostol reduces time in hospital. A misoprostol regimen is described in the SOGC Induced Abortion guideline 9 . To minimize time in hospital, the first dose of misoprostol (which is provided with combination mifepristone/misoprostol) can be taken at home and the patient is admitted when contractions start, or a second dose is required.
# Medical Abortion (MA)
# Medical abortion with mifepristone and misoprostol should be offered as a first-line method of induced abortion for pregnancies up to 70 days.
Combination mifepristone/misoprostol is indicated for 63 days, and the existing SOGC guideline states that it can be used up to 70 days8. We continue to recommend these gestational age limits for the majority of MA providers.
# For experienced providers where close surveillance is possible, medical abortion with mifepristone and misoprostol can be offered as an alternative to procedural abortion up to 77 days.
Emerging evidence and consensus opinion support the use of mifepristone medical abortion to 77 days (11 weeks) with repeated doses of misoprostol 10 . However, this should be reserved for experienced providers who can provide adequate coverage and backup should urgent care be needed. Patients should be informed that mifepristone use beyond 63 days is off-label, that they will likely expel and see an intact fetus, and that there is a higher risk of complication. For these reasons, and the possible higher risk of Emergency Department visits, we continue to recommend procedural abortion beyond 70 days in most cases.
As the proportion of induced abortions that are medical abortions increase, surgical services are decreasing in many jurisdictions. In the event of shortages of mifepristone, surgical services must be restored and/or expanded to ensure access to abortion on humanitarian grounds.
# 4.
Clinicians should prescribe an additional dose of misoprostol 800 mcg (buccal or vaginal) to be used on direction of a healthcare provider in the event of suspected incomplete or failed abortion.
To minimize patient visits to pharmacies, and to reduce complications, MA prescriptions should include an additional dose of misoprostol 800 mcg so that patients have medication on hand if an additional dose is required. Typically, a second dose of misoprostol is given at higher gestational ages, if by history a failed MA is suspected (minimal bleeding or expulsion), or to manage an incomplete abortion or ongoing pregnancy 8 .
Affirming best practice, the initial prescription should also include any contraception to be initiated at the time of medical abortion. Additional analgesics and STI prophylaxis can be prescribed based on clinician judgement and patient request.
# Medical abortion can be provided based on a home pregnancy test and Last Menstrual Period (LMP) dating alone if the patient has no risk factors for ectopic pregnancy, is reasonably certain of her LMP, is not using hormonal contraception, has regular menstrual cycles, and has no other contraindications.
This statement affirms the current MA guideline 8 . Patients who are reasonably certain of their LMP and have regular menstrual cycles are very likely to accurately predict being within the gestational age limit for MA. No further testing is required.
# All patients with uncertain pregnancy dating, risk factors for ectopic pregnancy, or symptoms consistent with ectopic pregnancy, should undergo ultrasound evaluation prior to medical abortion.
Ultrasound remains the gold standard for pregnancy assessment, regardless of pregnancy intention. Because unrecognized ectopic pregnancy is a rare but serious risk in periods of limited healthcare resources, it is important to remember that patients with risk factors (such as previous ectopic pregnancy or tubal surgery) or signs/symptoms of ectopic pregnancy should have an ultrasound. Those patients who are uncertain of their gestational age (by LMP or conception dating) should have further assessment of gestational age 8 .
# If ultrasound is not used prior to medical abortion, close surveillance and follow-up is required until completion.
All MAs performed without ultrasound are, by definition, pregnancies of unknown location (PULs). Though the risk of unrecognized ectopic pregnancy is low, close follow-up is required to ensure completion of the MA 8 . Clinicians should not initiate an MA if they are not reasonably certain that they will be available (directly or through an on-call service) to provide rapid assessment until confirmed completion of the abortion.
# Rh testing and Immune Globulin (RhIG) administration may be withheld for medical abortion prior to 70 days.
Current evidence supports withholding Rh testing and RhIG for medical abortions up to 56 days (8 weeks) gestational age given the very low probability of Rh-antigen expression on fetal cells. There is only expert opinion evidence to guide Rh management for MA between 56 and 70 days 14, 15 . In keeping with other national guidelines, the low probability of alloimmunization, and whereas testing and RhIG administration requires one or two additional patient visits, we recommend that Rh testing and RhIG may be withheld for MA during the COVID-19 pandemic.
We recommend a return to the current MA guidelines following resolution of the COVID-19 pandemic 8 , and further guidance will be provided when this guideline is due for renewal.
# Medical abortion can be provided a tiered approach (minimal resource, limited resource, and onlabel provision with full resource utilization). The decision to offer medical abortion should be made based on clinician competence, resource availability, and patient preference.
"On label" provision of mifepristone medical abortion requires the most resources when compared to other evidence-based protocols 8 . However, resources such as imaging and laboratory testing may vary widely and in an unpredictable manner during a pandemic or period of social disruption. Clinicians should exercise resource stewardship when possible and recognize when a lack of resources or clinician comfort precludes the safe provision of MA.
Several new MA guidelines have been published to provide experienced providers with protocols to manage MA at higher gestational ages and using a "no-touch" or "no-test" approach 12 . Striking a balance, this interim guidance identifies tests that can be safely excluded while maintaining a high degree of safety. Providers must consider their own competence and experience with MA prior to using these protocols, must inform patients that these are new protocols based on low-resource availability and that this is an off-label indication. If a clinician does not feel that resources permit safe medical abortion, a procedural abortion or referral to a more experienced clinician is advised. | None | None |
0ba41800315541cf6c65fa0716a80c7ddd65bbce | cma | None | The Canadian Anesthesiologists' Society (CAS) promotes safe anesthesia care to the highest possible standard. Traditionally, this care was provided in operating rooms by anesthesiologists. Contemporary practice, however, includes many other care locations and providers. Nevertheless, requirements for assessing the patient and managing the medical intervention are independent of provider or location. Procedural sedation is defined as the technique of safely administering short-acting sedative or dissociative agents, with or without analgesics, to reduce discomfort, apprehension, and potentially unpleasant memories while minimizing cardiorespiratory depression of patients during diagnostic and therapeutic procedures. These effects are distinct from both general anesthesia, which provides a state of total unconsciousness, and analgesia alone, which delivers a reduction in or insensibility to pain, not necessarily with a reduction in or a loss of consciousness. Some use of analgesic medication is common for procedural sedation. The larger doses necessary for very painful procedures may be hazardous, however, and other options may need to be considered, such as general anesthesia. Recognizing that adverse events are not uncommon with procedural sedation, the sedation provider must practice careful patient selection and complete a thorough preprocedural assessment. These providers must also be vigilant and prepared to deal with potential complications, such as respiratory depression, airway obstruction, and hypoxemia. Importantly, outside the This article is accompanied by an editorial.#
-perating room, these complications may be associated with a higher risk of morbidity and mortality. Although high quality studies comparing outcomes in the operating room with those in locations outside of the operating room are lacking, 1 US closed claims data have shown that complication rates and adverse outcomes are higher when anesthesia care, including procedural sedation, is delivered in remote locations. 2 This position paper describes best practices and establishes guidelines applicable to anesthesiologists and anesthesia care teams for administering safe procedural sedation both within and outside the operating room, including out-of-hospital facilities. It also recognizes that many medical and dental professionals are presently providing sedation services. Recent Canadian closed claims data for all sedation providers have identified that serious adverse events and patient harm related to procedural sedation do occur, even in the hands of experienced anesthesiologists. 3 Contributing factors include inadequate assessment, medication selection, lack of situational awareness, and deficiencies in procedural and post-procedural monitoring with failure to recognize airway and respiratory compromise. Formal curricula with a demonstration of competency in procedural sedation have been recommended as an essential component of anesthesia training programs. 4 The principles outlined in this document can also be applied by non-anesthesia sedation providers, although such professionals may wish to evaluate their compliance in accordance with their own professional guidelines or those of the healthcare facility. The CAS strongly advocates that all sedation providers be held to a comparably rigorous and prudent set of guidelines but also acknowledges that some differences in practice may exist between anesthesia and non-anesthesia sedation providers. We strongly recommend that, within a specific institution, consideration be given to developing procedural sedation guidelines or policies, ideally through a multidisciplinary committee representative of all sedation providers and stakeholders, including anesthesiologists. 5 Anesthesiologists are experts in delivering safe procedural sedation, and anesthesia departments should therefore, to the extent that their resources permit, endeavor to provide planned and emergency sedation services to the facility. Anesthesiologists should encourage upholding the highest possible institutional sedation standards and, again, as resources permit, support the education of sedation providers and sedation assistants throughout their facility. The concept of facility sedation teams, often led by anesthesiology, is growing in popularity, particularly for the delivery of pediatric sedation services, 6 as they have the benefit of increasing the availability and mobility of sedation services as well as promoting ongoing education and skill acquisition of team members.
# Levels of sedation
The American Society of Anesthesiologists' (ASA) Continuum of Depth of Sedation has become widely accepted as a useful tool to standardize the definition of levels of sedation and the American Academy of Pediatrics and the Joint Commission on Accreditation of Healthcare Organizations have together sanctioned the use of the ASA Continuum. 7 The continuum defines three distinct levels of sedation, described as minimal, moderate, and deep. It also acknowledges that a patient may readily pass from a state of minimal sedation to deep sedation and even to a fourth level (i.e., general anesthesia). Good clinical correlates are required to enhance the precision and reproducibility of any level of sedation measurement system.
The ASA sedation continuum describes in very specific terms the characteristics of each level of sedation as summarized in Table 1. 8 The term ''conscious sedation,'' which was often used in the past, roughly correlates with moderate sedation. The term is no longer recommended. The transition between having and then losing constant verbal contact with the patient occurs between moderate and deep sedation. This transition point is an important observation to monitor that is not specifically mentioned in the ASA continuum. Reflex withdrawal from a painful stimulus should not be considered ''purposeful''. Many other sedation ''scales'' (e.g., Ramsay) exist and are more commonly used by non-anesthesiologist providers. 7 These scales are useful but must take these definitions into account when assigning a number to the depth of sedation.
# Pre-procedural assessment
Providing potent medications by parenteral routes requires assessment of the patient and administration by a physician or other health professional, such as a delegated anesthesia assistant or registered nurse with specific training and experience in providing procedural sedation. The assessment must include documenting an appropriate medical and surgical history, identifying relevant medical co-morbidities, patient medications and allergies, and the indications for the procedure. A focused physical examination and any relevant investigations must also be performed. The nature of the procedural sedation, any significant risks, and possible alternatives must be discussed with the patient and must be documented in the health record. Screening for obstructive sleep apnea (OSA) using validated screening tools, such as the STOP-Bang Questionnaire, 9 is recommended. If the patient is at risk of, or confirmed to have, moderate to severe OSA, procedural sedation may carry with it an increased risk and should be modified accordingly. 10
# Physical examination
The physical examination must be appropriate to the medical co-morbidities of the patient. It must include a thorough assessment of the patient's airway, including predictors of difficult bag-mask ventilation and endotracheal intubation, in view of the potential for respiratory depression and compromised airway maintenance during procedural sedation. The airway assessment must be formally documented in the health record.
# Management of sedation and patient monitoring
General guidelines for procedural sedation are the same as those for other forms of anesthesia and are consistent with those outlined in the CAS Guidelines to the Practice of Anesthesia. 11 The CAS practice guidelines state that it is unacceptable for a single physician to administer an anesthetic, including deep procedural sedation, and simultaneously perform a diagnostic or therapeutic procedure, except for procedures done with only infiltration of local anesthetic and/or minimal sedation.
Heart rate, blood pressure, respiratory rate, oxygen saturation, and the level of sedation/consciousness must be monitored and documented for all patients undergoing procedural sedation. Oxygen saturation monitoring (i.e., pulse oximetry) must be continuous and recorded at regular intervals along with other vital signs. For minimally invasive procedures in suitable patients without significant cardiorespiratory disease, the usual CAS Guidelines requirement for electrocardiographic monitoring may be waived if continuous pulse oximetry is used and only minimal to moderate sedation is employed.
Waveform capnography is required for patients expected to require moderate or deep procedural sedation (see Capnography section). It is strongly recommended that, in addition to the continuous observation of clinical signs, the rate and quality of ventilation be monitored and documented routinely with waveform capnography for all patients during procedural sedation.
Routine administration of supplemental oxygen by nasal cannula or high-flow face mask is strongly recommended for all patients undergoing procedural sedation and is required for deep sedation. Appropriate precautions should be taken to minimize the risk of fire in the procedure room due to the enriched atmosphere that may be created by using supplemental oxygen, particularly for procedures around the head and neck.
Clinical studies have shown that the level of sedation may become deeper than intended. 12 Therefore, appropriate equipment must be readily available and functioning to manage patients who develop significant cardiorespiratory depression. The following equipment (in various sizes according to the patient population served by the institution) should be available: The precise requirements for pre-procedural fasting are evolving. In general, patients provided with moderate or deep sedation should fast in accordance with the general CAS Guidelines:
- Eight hours after a meal that includes meat, fried, or fatty foods. - Six hours after a light meal, infant formula, or nonhuman milk. - Four hours after ingestion of unfortified breast milk.
- Two hours after clear fluids.
More liberal guidelines may be appropriate for minimal sedation (e.g., cataract surgery). Nevertheless, they should be individualized, and providers should exercise caution in view of the patient's specific co-morbidities and risk factors for pulmonary aspiration of gastric contents.
Any health professional employing sedative-hypnotic agents to provide sedation must have the expertise, experience, equipment, and other resources available to resuscitate patients. Accordingly, ACLS certification is strongly recommended. They must be able to provide advanced airway management and to ''rescue'' patients who become more deeply sedated than intended and develop respiratory depression or apnea. 13 Failure to respond quickly and appropriately in such circumstances may result in life-threatening complications, such as hypoxic brain injury, pulmonary aspiration of gastric contents, and cardiac arrest.
# Capnography
The CAS Guidelines state that continuous monitoring of end-tidal carbon dioxide (waveform capnography) is mandatory during general anesthesia and for moderate or deep procedural sedation. Several studies have shown that the ability to detect respiratory depression during procedural sedation is significantly enhanced when capnography monitoring is utilized. 14 For minimal sedation, capnography may be a useful adjunct to detect progression to an unintended deeper level of sedation with associated respiratory depression and is therefore recommended. Capnography is useful in monitoring patient ventilation when it cannot be directly observed (e.g., during magnetic resonance imaging), when multiple sedative agents are utilized, and when the pre-procedural assessment identifies an increased clinical risk for respiratory depression or airway obstruction (e.g., morbid obesity, OSA).
# Provision of sedation and delegation
Sedation may be provided by a team that includes a sedation supervisor (typically the anesthesiologist/ physician) and an approved and credentialed sedation assistant(s) (e.g., registered nurse, respiratory therapist, anesthesia assistant, or other appropriately trained health professional). The department of anesthesiology must define the specific qualifications, roles, and responsibilities of the sedation assistant. The sedation team may work together to conduct the sedation by performing the discrete tasks of 1) assessing the patient, 2) providing the sedation, and 3) monitoring the patient.
For minimal to moderate levels of sedation in a stable patient:
- The sedation supervisor may delegate administration of sedation and patient monitoring to the sedation assistant. - The sedation assistant must remain in constant attendance with the patient, providing continuous monitoring and immediately informing the sedation supervisor of any concerns.
- A member of the sedation team must monitor the patient continuously. - The sedation supervisor must remain immediately available to support the sedation assistant as necessary. - The sedation supervisor (anesthesiologist/physician) retains responsibility for the patient.
For deep sedation:
- The CAS Guidelines state that it is unacceptable for one anesthesiologist to conduct or supervise the administration of deep procedural sedation simultaneously for concurrent diagnostic or therapeutic procedures on more than one patient at a time.
# Supervision ratios
In specific circumstances where minimal or moderate sedation is administered, it may be appropriate for an anesthesiologist to supervise more than one patient concurrently while strictly adhering to the principles outlined above. It is essential to re-emphasize that an appropriately trained and credentialed individual must be in constant attendance with each patient receiving care.
The attending anesthesiologist must assume medical responsibility for the care of all patients involved in this care model and must be immediately available to attend to any patient when required. Each department of anesthesiology must establish the acceptable number of concurrent patients. Important factors to consider include the intensity and complexity of the caseload, the physical status of the patients, sedation assistant staffing and experience, and any institutional policies and procedures.
# Medications used for procedural sedation
This document does not provide a detailed review of the specific benefits or properties of all available medications used for procedural sedation. Anesthesiologists and anesthesia assistants are familiar with the pharmacology and properties of these agents and are experienced in their use. The CAS does support several fundamental principles that should be applied by all sedation providers in any setting. The overarching principle of procedural sedation is that one should use the minimum intervention possible with due consideration given to the specific procedure and patient. In general, medication should be administered in small divided doses or by continuous infusion titrated to clinical effect, allowing sufficient time to appreciate the peak depth of sedation achieved and accounting for variations in the amount of pain and procedural stimulation. Knowledge of each medication's time of onset, peak effect, and duration of effect is essential. When multiple medications are utilized, particularly with opioids, it is essential to consider the potential synergistic effects on the level of sedation and the increased risk for respiratory depression.
Where feasible, local or regional anesthesia should be strongly considered in addition to sedation for particularly painful procedures. Various combinations of medication can be used to administer procedural sedation and they should ideally be short acting and titratable. Increasingly, the potent sedative-hypnotic agents, specifically propofol, have become popular with both anesthesiologists and non-anesthesiologists to provide excellent moderate or deep procedural sedation with high patient satisfaction rates and a more rapid recovery profile than some other combinations of medication.
When anesthetic agents such as propofol are used for procedural sedation, however, they have a greater potential to produce unintentional general anesthesia, even when carefully administered. All sedation providers using agents such as propofol must have specific training and experience with their use, take all necessary monitoring precautions, and have the equipment and skills immediately available to manage the airway and provide ventilation and cardiovascular support associated with even brief periods of general anesthesia. 15,16
# Recovery and discharge
Post-procedural care of the sedated patient may be delegated to appropriately trained and qualified individuals. Post-procedural monitoring during the early recovery period is required, as stated in the CAS Guidelines, and should include level of consciousness, ventilation, oxygen saturation, heart rate, and blood pressure. The appropriate frequency and duration of monitoring should be determined by the facility's standards, taking into account the length and complexity of the specific procedure, the patient's complexity, and the level of sedation provided. Discharge readiness should be assessed by validated discharge criteria, such as the modified Aldrete score 17 for Phase 1 recovery when discharging a patient from the recovery room to another healthcare institutional location, or the postanesthetic discharge scoring system for Phase 2 recovery 18 when discharging the patient home (Table 2). If the patient is to be discharged home, the most responsible physician or delegated alternate physician must be available to attend to the patient until the institutionally set standards for discharge are met. Regardless of the level of procedural sedation performed, the discharge procedures for the postanesthetic period should conform to the CAS Guidelines to the Practice of Anesthesia.
# Quality assurance
The practice of procedural sedation must undergo the same rigorous scrutiny regarding patient outcomes as is applied for other forms of anesthesia care. A specific mechanism must be established for auditing procedural sedation and documenting any major complications, adverse events, or critical incidents. All critical incidents should be systematically reviewed and include appropriate recommendations for improvement where indicated.
# Sédation procédurale : exposé de principe de la Société canadienne des anesthésiologistes
La Société canadienne des anesthésiologistes (SCA) promeut des soins anesthésiques sécuritaires selon les normes les plus élevées possibles. Traditionnellement, ces soins étaient assurés par les anesthésiologistes dans les salles d'opération. Cependant, la pratique actuelle inclut de nombreux autres environnements et prestataires de soins. Les exigences d'évaluation du patient et de gestion de l'intervention médicale sont néanmoins indépendantes du prestataire ou du site.
La sédation procédurale est définie comme étant la technique permettant d'administrer de manière sécuritaire un sédatif ou des agents dissociatifs à courte durée d'action, avec ou sans analgésiques, dans le but de réduire l'inconfort, l'appréhension et les souvenirs potentiellement déplaisants, tout en minimisant la Able to move no extremities = 0 Severe or more than three dressing changes required = 0
Maximum scores = 10. A modified Aldrete score of C 9 is considered acceptable for discharge from Phase 1 to Phase 2 recovery and a PADSS score of C 9 is considered acceptable for discharge from Phase 2 or directly home following only one phase of recovery. The numerical analogue pain scale (0-10) is recommended for assessing post-procedural pain. BP = blood pressure; HR = heart rate.
Adapted from: Aldrete JA. The post-anesthesia recovery score revisited. J Clin Anesth 1995; 7: 89-91; 17 and Chung F, Chan VW, Ong D. A postanesthetic discharge scoring system for home readiness after ambulatory surgery. J Clin Anesth 1995; 7: 500-6. 18 dépression cardiorespiratoire chez des patients subissant des procédures diagnostiques ou thérapeutiques. Ces effets sont différents à la fois de l'anesthésie générale qui entraîne un état de perte de conscience totale et de l'analgésie pure qui assure une diminution ou une absence de sensibilité à la douleur sans nécessairement s'accompagner d'une réduction ou d'une perte de la conscience. L'utilisation limitée de médicaments antalgiques est fréquente au cours de la sédation procédurale. Les plus fortes doses nécessaires pour des procédures très douloureuses peuvent être dangereuses et dans ce cas il y a sans doute lieu d'envisager d'autres options, telles que l'anesthésie générale. Sachant que les effets secondaires ne sont pas rares avec la sédation procédurale, la personne en charge de la sédation doit sélectionner les patients de manière scrupuleuse et effectuer une évaluation complète de ces derniers avant la procédure. Ces prestataires doivent être vigilants et prêts à faire face à des complications potentielles, telles qu'une dépression respiratoire, une obstruction des voies respiratoires et une hypoxémie. Il est important de rappeler qu'en dehors d'une salle d'opération, ces complications peuvent être associées à un risque plus élevé de morbidité et de mortalité. Bien que l'on manque d'études de grande qualité comparant les résultats en salle d'opération à ceux obtenus dans d'autres environnements, 1 des données américaines (É tats-Unis) sur des cas des plaintes judiciaires résolues ont montré que les taux de complications et d'effets indésirables sont plus élevés quand les soins anesthésiques, y compris la sédation procédurale, sont délivrés dans des environnements isolés. 2 Cet exposé de principe décrit les meilleures pratiques et établit des lignes directrices s'appliquant aux anesthésiologistes et aux équipes de soins anesthésiques pour l'administration d'une sédation procédurale sécuritaire à la fois dans et en-dehors de la salle d'opération, y compris dans des établissements extérieurs à l'hôpital. Il reconnaît également que de nombreux professionnels médicaux et dentaires fournissent actuellement des services de sédation. Des données canadiennes récentes sur des plaintes judiciaires résolues concernant les différents prestataires de sédation ont identifié que des événements indésirables et des lésions graves des patients en rapport avec une sédation procédurale arrivent effectivement, même entre les mains d'anesthésiologistes expérimentés. 3 Les facteurs contributifs sont, notamment, une évaluation insuffisante, le choix du médicament, l'absence de prise de conscience de la gravité de la situation et les insuffisances de suivi pendant et après la procédure, avec la non-reconnaissance de la détérioration de la ventilation et de l'état des voies respiratoires. Des programmes d'études formelles avec une démonstration de la compétence en matière de sédation procédurale ont été recommandés comme une composante essentielle des programmes de formation en anesthésie. 4 Les principes décrits dans ce document peuvent également s'appliquer à des prestataires de sédation non-anesthésiologistes, bien que ces professionnels puissent souhaiter évaluer leur conformité avec leurs propres lignes directrices professionnelles ou celles de leur établissement de soins de santé. La SCA encourage fortement tous les prestataires de sédation à s'en tenir à un ensemble comparablement prudent et rigoureux de recommandations, mais reconnaît aussi qu'il peut exister des différences de pratiques entre les prestataires de sédation anesthésiologistes et non-anesthésiologistes. Nous préconisons fortement qu'au sein d'un établissement donné, il soit sérieusement envisagé d'élaborer des lignes directrices ou des règles pour la sédation procédurale, idéalement par un comité multidisciplinaire représentant tous les prestataires de sédations et les acteurs, y compris les anesthésiologistes. 5 Les anesthésiologistes sont les experts pour ce qui est de délivrer une sédation procédurale sécuritaire et les départements d'anesthésie devraient donc, dans la mesure où leurs ressources le permettent, s'efforcer de fournir des services de sédation élective et d'urgence dans leur établissement. Les anesthésiologistes doivent encourager le maintien de normes de sédation le plus élevé possible dans leurs établissements et, encore une fois, dans la mesure de leurs ressources, soutenir l'éducation des prestataires et assistants de sédation dans l'ensemble de leur établissement. Le concept d'équipes institutionnelles de sédation, souvent menées par un anesthésiologiste, gagne en popularité notamment pour la prestation de services de sédation en pédiatrie, 6 car elles ont l'avantage d'augmenter la disponibilité et la mobilité des services de sédation, et aussi de promouvoir l'éducation continue et l'acquisition d'habiletés pour les membres de l'équipe.
# Niveaux de sédation
Le Continuum de profondeur de la sédation de l'American Society of Anesthesiologists (ASA) est devenu un outil utile largement accepté pour standardiser la définition des niveaux de sédation; l'American Academy of Pediatrics et la JCAHO (Joint Commission on Accreditation of Healthcare Organizations) ont approuvé ensemble l'utilisation du Continuum de l'ASA. 7 Le continuum définit trois niveaux distincts de sédation : minimale, modérée et profonde. Il reconnaît aussi qu'un patient peut facilement passer du stade de sédation minimale au stade de sédation profonde et même à un quatrième niveau (c'est-à-dire une anesthésie générale). De bonnes corrélations cliniques sont requises pour améliorer la précision et la reproductibilité d'un quelconque niveau du système de mesure de la sédation.
Le continuum de sédation de l'ASA décrit en termes très précis les caractéristiques de chaque niveau de sédation, résumés dans le Tableau 1. 8 Le terme « sédation consciente » qui a souvent été utilisé par le passé correspond globalement à une sédation modérée. Ce terme n'est plus recommandé. La transition entre la persistance puis la perte du contact verbal constant avec le patient a lieu entre la sédation modérée et la sédation profonde. Ce point de transition est une observation importante à surveiller, mais qui n'est pas mentionné de manière spécifique dans le continuum de l'ASA. Le signe du retrait réflexe à une stimulation douloureuse ne doit pas être vu comme « intentionnelle ». Il existe de nombreuses autres « échelles » de sédation (p. ex., Ramsay) qui sont plus souvent utilisées par les prestataires de soins nonanesthésiologistes. 7 Ces échelles sont utiles, mais elles doivent prendre ces définitions en compte quand un chiffre est attribué à la profondeur de la sédation.
# É valuation préprocédurale
Administrer des médicaments puissants par voie parentérale exige une évaluation du patient et leur administration par un médecin ou un autre professionnel de la santé tel qu'un assistant en anesthésie délégué ou une infirmière autorisée avec une formation spécifique et expérience de sédation procédurale. L'évaluation doit inclure la documentation des antécédents médicaux et chirurgicaux appropriés, l'identification des comorbidités médicales pertinentes, les médicaments pris par le patient et ses allergies, ainsi que les indications de la procédure. Un examen physique orienté et toutes les investigations pertinentes doivent aussi être pratiqués. La nature de la sédation procédurale, tous ses risques significatifs et les autres options doivent être discutés avec le patient et documentés dans le dossier de santé.
La recherche d'un syndrome d'apnée-hypopnée du sommeil (SAHS) au moyen d'outils de dépistage validés, tels que le questionnaire STOP-Bang, 9 est recommandée. Si le patient présente un risque de SAHS ou a une forme modérée à sévère de SAHS confirmé, la sédation procédurale peut entraîner de plus grands risques et devrait être modifiée en conséquence. 10 Examen physique L'examen physique doit être approprié et adapté aux comorbidités médicales du patient. Il doit inclure une évaluation rigoureuse des voies respiratoires du patient, incluant les facteurs prédictifs de difficultés pour la ventilation au masque et l'intubation endotrachéale, en cas de risque de dépression respiratoire et de perte de la perméabilité des voies respiratoires au cours de la sédation procédurale. L'évaluation des voies respiratoires doit être documentée de façon formelle dans le dossier médical.
# Gestion de la sédation et surveillance des patients
Les recommandations générales pour la sédation procédurale sont identiques à celles des autres formes d'anesthésie et concordent avec celles qui sont décrites dans le Guide d'exercice de l'anesthésie de la SCA. 11 Le Guide d'exercice de la SCA indique qu'il n'est pas acceptable qu'un seul médecin administre une anesthésie (y compris dans le cas d'une sédation procédurale) et réalise en même temps la procédure diagnostique ou Tableau 1 Le Continuum de profondeur de la sédation de l'American Society of Anesthesiologists thérapeutique, hormis le cas de procédures effectuées avec seulement une infiltration d'anesthésique local et/ou une sédation minimale. La fréquence cardiaque, la pression artérielle, la fréquence respiratoire, la saturation en oxygène et le niveau de sédation/conscience doivent être suivis et documentés pour tous les patients subissant une sédation procédurale. La surveillance de la saturation en oxygène (c'est-à-dire, l'oxymétrie de pouls) doit être continue et consignée à intervalles réguliers en même temps que les autres constantes vitales. Pour les procédures peu invasives chez des patients sélectionnés sans maladie cardiorespiratoire significative, les recommandations habituelles de la SCA concernant la surveillance électrocardiographique peuvent être ignorées si une mesure continue de l'oxymétrie de pouls est utilisée et que la sédation appliquée est seulement minimale à modérée.
Un suivi de capnographie continue est requis pour les patients devant subir une sédation procédurale modérée à profonde (voir la rubrique « Capnographie »). Il est fortement recommandé qu'en plus de l'observation constante des signes cliniques, la fréquence et la qualité de la ventilation soient surveillées et documentées de manière régulière avec un suivi de capnographie pour tous les patients subissant une sédation procédurale.
L'administration systématique d'oxygène par lunette nasale ou masque facial à haut débit est fortement recommandée pour tous les patients subissant une sédation procédurale et est requise en cas de sédation profonde. Les précautions appropriées doivent être prises pour limiter le risque d'incendie dans la salle de procédure en raison de l'atmosphère enrichie qui pourrait être créée par l'utilisation d'un supplément d'oxygène, en particulier pour les procédures concernant les zones céphaliques et cervicales.
Les études cliniques ont montré que le niveau de sédation peut devenir plus profond que ce qui était recherché. 12 En conséquence, l'équipement approprié doit être facilement disponible et en état de fonctionner pour gérer les patients présentant une dépression cardiorespiratoire significative. L'équipement suivant (en différentes tailles en fonction de la population de patients servis par l'établissement) doit être disponible : Les demandes précises concernant le jeûne précédant la procédure évoluent. D'une manière générale, les patients recevant une sédation modérée ou profonde doivent être à jeun conformément aux recommandations générales de la SCA :
- Huit heures après un repas incluant viande, friture ou aliments gras. - Six heures après un repas léger, un biberon de lait maternisé ou de lait non humain.
- Quatre heures après l'ingestion de lait maternel non enrichi. - Deux heures après l'absorption de liquide translucide.
Des recommandations plus libérales peuvent être appropriées pour une sédation minimale (p. ex., chirurgie pour cataracte). Néanmoins, elles doivent être personnalisées et les prestataires de soins doivent faire preuve de prudence en tenant compte des comorbidités propres aux patients et des facteurs de risque spécifiques d'aspiration pulmonaire du contenu gastrique.
Tout professionnel de la santé utilisant des agents sédatifs-hypnotiques pour obtenir une sédation doit avoir l'expertise, l'expérience, l'équipement et les autres ressources disponibles pour la ressuscitation des patients. En conséquence, un certificat en technique spécialisée de réanimation cardiorespiratoire est fortement recommandé. Ils doivent être capables d'assurer une gestion avancée des voies respiratoires et de « sauver » les patients dont la sédation devient plus profonde que prévu et développe une dépression respiratoire ou des apnées. 13 L'absence de réponse rapide et appropriée à de telles circonstances peut déboucher sur des complications engageant le pronostic vital tel qu'une lésion hypoxique du cerveau, l'aspiration pulmonaire du contenu gastrique et un arrêt cardiaque.
# Capnographie
Le Guide d'exercice de la SCA indique que la surveillance continue du dioxyde de carbone en fin de respiration (tracé de capnographie) est obligatoire au cours d'une anesthésie générale et pendant une sédation procédurale modérée à profonde. Quelques études ont montré que les capacités de détection d'une dépression respiratoire au cours de la sédation procédurale sont significativement améliorées avec le suivi de la capnographie. 14 En cas de sédation minime, la capnographie peut être un apport utile pour détecter la progression vers un niveau de sédation avec dépression respiratoire associée non souhaité; elle est donc recommandée. La capnographie est utile pour le suivi de la ventilation des patients quand celle-ci ne peut pas être directement observée (p. ex., au cours d'une imagerie par résonance magnétique), quand plusieurs agents sédatifs sont utilisés et quand l'évaluation avant procédure a identifié un risque clinique accru de dépression respiratoire ou d'obstruction des voies respiratoires (p. ex., obésité morbide, SAHS).
# Réalisation de la sédation et délégation
La sédation peut être assurée par une équipe incluant un superviseur de sédation (habituellement l'anesthésiologiste ou un autre médecin) et un ou plusieurs assistants de sédation approuvés et dûment accrédités (p. ex., infirmière autorisée, inhalothérapeute, assistant d'anesthésie ou tout autre professionnel de la santé dûment formé). Il incombe au département d'anesthésiologie de définir les qualifications, fonctions et responsabilités spécifiques des assistants de sédation. L'équipe de sédation doit travailler ensemble à sa réalisation en effectuant des tâches spécifiques 1) d'évaluation du patient, 2) de sédation proprement dite et 3) de surveillance du patient.
En cas de sédation minimale à modérée chez des patients stables :
- Le superviseur de sédation pourra déléguer l'administration de la sédation et la surveillance du patient à un assistant de sédation. - L'assistant de sédation doit rester en permanence auprès du patient, assurant une surveillance continue et informant immédiatement le superviseur de sédation à la moindre préoccupation. - Un membre de l'équipe de sédation doit surveiller le patient en permanence. - Le superviseur de sédation doit rester immédiatement disponible pour seconder l'assistant de sédation si nécessaire. - Le superviseur de sédation (anesthésiologiste/médecin) conserve la responsabilité du patient.
En cas de sédation profonde :
- Le Guide d'exercice de la SCA indique qu'il n'est pas acceptable qu'un anesthésiologiste réalise ou supervise l'administration d'une sédation procédurale profonde en même temps que des procédures diagnostiques ou thérapeutiques chez plus d'un patient au même moment.
# Ratios de surveillance
Dans les circonstances spécifiques où une sédation minime à modérée est administrée, un anesthésiologiste pourrait superviser plus d'un patient à la fois tout en respectant strictement les principes décrits plus haut. Cependant, quand des agents anesthésiques tels que le propofol sont utilisés pour une sédation procédurale, il y a un plus grand risque de provoquer une anesthésie générale involontaire, même quand ils sont administrés avec prudence. Tous les prestataires de sédation utilisant des produits tels que le propofol doivent avoir reçu une formation spécifique et avoir l'expérience de leur utilisation, prendre toutes les précautions de monitorage nécessaires et disposer immédiatement de l'équipement et des habiletés requises pour gérer les voies aériennes et fournir la ventilation/le soutien cardiovasculaire associés à des périodes d'anesthésie générale, même brèves. 15,16
# Récupération et congé
Les soins post procédure d'un patient ayant subi une sédation peuvent être délégués à des personnes qualifiées et correctement formées. Un monitorage est requis au cours de la première période de récupération post procédure, comme l'indique le Guide d'exercice de la SCA, et doit porter sur le niveau de conscience, la ventilation, la saturation en oxygène, la fréquence cardiaque et la pression artérielle. La fréquence et la durée appropriées du monitorage doivent être déterminées par les normes de l'établissement en tenant compte la durée et la complexité de la procédure en question, la complexité du cas du patient et le niveau de sédation atteint. Le congé peut être donné au patient après une évaluation avec des critères validés, tel que le score modifié d'Aldrete 17 pour la récupération de Phase 1 quand le patient est renvoyé d'une salle de réveil vers un autre service de l'établissement de soin, ou le système de cotation de congé post anesthésique pour la récupération de Phase 2 18 quand le patient retourne à son domicile (Tableau 2). Si le patient doit rentrer chez lui, le médecin responsable ou le médecin délégué le remplaçant doit être disponible pour s'occuper du patient jusqu'à ce que les normes établies par l'établissement pour le congé soient remplies. Indépendamment du niveau de sédation procédurale réalisé, les procédures de congé pour la période postanesthésique doivent être conformes au Guide d'exercice de l'anesthésie de la SCA.
# Suivi de qualité
La pratique de la sédation procédurale doit suivre la même attention rigoureuse concernant l'évolution des patients que celle qui s'applique aux autres formes de soins anesthésiques. Un mécanisme spécifique doit être mis en place pour la vérification de la sédation procédurale et la documentation de toutes les complications majeures, événements indésirables ou incidents critiques. Tous les incidents critiques doivent être systématiquement analysés et déboucher sur les recommandations appropriées pour des améliorations quand il y a lieu.
Responsabilité édiroriale Cet article a été traité par le Dr Hilary P. Grocott, Rédacteur en chef, Journal canadien d'anesthésie. | The Canadian Anesthesiologists' Society (CAS) promotes safe anesthesia care to the highest possible standard. Traditionally, this care was provided in operating rooms by anesthesiologists. Contemporary practice, however, includes many other care locations and providers. Nevertheless, requirements for assessing the patient and managing the medical intervention are independent of provider or location. Procedural sedation is defined as the technique of safely administering short-acting sedative or dissociative agents, with or without analgesics, to reduce discomfort, apprehension, and potentially unpleasant memories while minimizing cardiorespiratory depression of patients during diagnostic and therapeutic procedures. These effects are distinct from both general anesthesia, which provides a state of total unconsciousness, and analgesia alone, which delivers a reduction in or insensibility to pain, not necessarily with a reduction in or a loss of consciousness. Some use of analgesic medication is common for procedural sedation. The larger doses necessary for very painful procedures may be hazardous, however, and other options may need to be considered, such as general anesthesia. Recognizing that adverse events are not uncommon with procedural sedation, the sedation provider must practice careful patient selection and complete a thorough preprocedural assessment. These providers must also be vigilant and prepared to deal with potential complications, such as respiratory depression, airway obstruction, and hypoxemia. Importantly, outside the This article is accompanied by an editorial.#
operating room, these complications may be associated with a higher risk of morbidity and mortality. Although high quality studies comparing outcomes in the operating room with those in locations outside of the operating room are lacking, 1 US closed claims data have shown that complication rates and adverse outcomes are higher when anesthesia care, including procedural sedation, is delivered in remote locations. 2 This position paper describes best practices and establishes guidelines applicable to anesthesiologists and anesthesia care teams for administering safe procedural sedation both within and outside the operating room, including out-of-hospital facilities. It also recognizes that many medical and dental professionals are presently providing sedation services. Recent Canadian closed claims data for all sedation providers have identified that serious adverse events and patient harm related to procedural sedation do occur, even in the hands of experienced anesthesiologists. 3 Contributing factors include inadequate assessment, medication selection, lack of situational awareness, and deficiencies in procedural and post-procedural monitoring with failure to recognize airway and respiratory compromise. Formal curricula with a demonstration of competency in procedural sedation have been recommended as an essential component of anesthesia training programs. 4 The principles outlined in this document can also be applied by non-anesthesia sedation providers, although such professionals may wish to evaluate their compliance in accordance with their own professional guidelines or those of the healthcare facility. The CAS strongly advocates that all sedation providers be held to a comparably rigorous and prudent set of guidelines but also acknowledges that some differences in practice may exist between anesthesia and non-anesthesia sedation providers. We strongly recommend that, within a specific institution, consideration be given to developing procedural sedation guidelines or policies, ideally through a multidisciplinary committee representative of all sedation providers and stakeholders, including anesthesiologists. 5 Anesthesiologists are experts in delivering safe procedural sedation, and anesthesia departments should therefore, to the extent that their resources permit, endeavor to provide planned and emergency sedation services to the facility. Anesthesiologists should encourage upholding the highest possible institutional sedation standards and, again, as resources permit, support the education of sedation providers and sedation assistants throughout their facility. The concept of facility sedation teams, often led by anesthesiology, is growing in popularity, particularly for the delivery of pediatric sedation services, 6 as they have the benefit of increasing the availability and mobility of sedation services as well as promoting ongoing education and skill acquisition of team members.
# Levels of sedation
The American Society of Anesthesiologists' (ASA) Continuum of Depth of Sedation has become widely accepted as a useful tool to standardize the definition of levels of sedation and the American Academy of Pediatrics and the Joint Commission on Accreditation of Healthcare Organizations have together sanctioned the use of the ASA Continuum. 7 The continuum defines three distinct levels of sedation, described as minimal, moderate, and deep. It also acknowledges that a patient may readily pass from a state of minimal sedation to deep sedation and even to a fourth level (i.e., general anesthesia). Good clinical correlates are required to enhance the precision and reproducibility of any level of sedation measurement system.
The ASA sedation continuum describes in very specific terms the characteristics of each level of sedation as summarized in Table 1. 8 The term ''conscious sedation,'' which was often used in the past, roughly correlates with moderate sedation. The term is no longer recommended. The transition between having and then losing constant verbal contact with the patient occurs between moderate and deep sedation. This transition point is an important observation to monitor that is not specifically mentioned in the ASA continuum. Reflex withdrawal from a painful stimulus should not be considered ''purposeful''. Many other sedation ''scales'' (e.g., Ramsay) exist and are more commonly used by non-anesthesiologist providers. 7 These scales are useful but must take these definitions into account when assigning a number to the depth of sedation.
# Pre-procedural assessment
Providing potent medications by parenteral routes requires assessment of the patient and administration by a physician or other health professional, such as a delegated anesthesia assistant or registered nurse with specific training and experience in providing procedural sedation. The assessment must include documenting an appropriate medical and surgical history, identifying relevant medical co-morbidities, patient medications and allergies, and the indications for the procedure. A focused physical examination and any relevant investigations must also be performed. The nature of the procedural sedation, any significant risks, and possible alternatives must be discussed with the patient and must be documented in the health record. Screening for obstructive sleep apnea (OSA) using validated screening tools, such as the STOP-Bang Questionnaire, 9 is recommended. If the patient is at risk of, or confirmed to have, moderate to severe OSA, procedural sedation may carry with it an increased risk and should be modified accordingly. 10
# Physical examination
The physical examination must be appropriate to the medical co-morbidities of the patient. It must include a thorough assessment of the patient's airway, including predictors of difficult bag-mask ventilation and endotracheal intubation, in view of the potential for respiratory depression and compromised airway maintenance during procedural sedation. The airway assessment must be formally documented in the health record.
# Management of sedation and patient monitoring
General guidelines for procedural sedation are the same as those for other forms of anesthesia and are consistent with those outlined in the CAS Guidelines to the Practice of Anesthesia. 11 The CAS practice guidelines state that it is unacceptable for a single physician to administer an anesthetic, including deep procedural sedation, and simultaneously perform a diagnostic or therapeutic procedure, except for procedures done with only infiltration of local anesthetic and/or minimal sedation.
Heart rate, blood pressure, respiratory rate, oxygen saturation, and the level of sedation/consciousness must be monitored and documented for all patients undergoing procedural sedation. Oxygen saturation monitoring (i.e., pulse oximetry) must be continuous and recorded at regular intervals along with other vital signs. For minimally invasive procedures in suitable patients without significant cardiorespiratory disease, the usual CAS Guidelines requirement for electrocardiographic monitoring may be waived if continuous pulse oximetry is used and only minimal to moderate sedation is employed.
Waveform capnography is required for patients expected to require moderate or deep procedural sedation (see Capnography section). It is strongly recommended that, in addition to the continuous observation of clinical signs, the rate and quality of ventilation be monitored and documented routinely with waveform capnography for all patients during procedural sedation.
Routine administration of supplemental oxygen by nasal cannula or high-flow face mask is strongly recommended for all patients undergoing procedural sedation and is required for deep sedation. Appropriate precautions should be taken to minimize the risk of fire in the procedure room due to the enriched atmosphere that may be created by using supplemental oxygen, particularly for procedures around the head and neck.
Clinical studies have shown that the level of sedation may become deeper than intended. 12 Therefore, appropriate equipment must be readily available and functioning to manage patients who develop significant cardiorespiratory depression. The following equipment (in various sizes according to the patient population served by the institution) should be available: The precise requirements for pre-procedural fasting are evolving. In general, patients provided with moderate or deep sedation should fast in accordance with the general CAS Guidelines:
•
• Eight hours after a meal that includes meat, fried, or fatty foods. • Six hours after a light meal, infant formula, or nonhuman milk. • Four hours after ingestion of unfortified breast milk.
• Two hours after clear fluids.
More liberal guidelines may be appropriate for minimal sedation (e.g., cataract surgery). Nevertheless, they should be individualized, and providers should exercise caution in view of the patient's specific co-morbidities and risk factors for pulmonary aspiration of gastric contents.
Any health professional employing sedative-hypnotic agents to provide sedation must have the expertise, experience, equipment, and other resources available to resuscitate patients. Accordingly, ACLS certification is strongly recommended. They must be able to provide advanced airway management and to ''rescue'' patients who become more deeply sedated than intended and develop respiratory depression or apnea. 13 Failure to respond quickly and appropriately in such circumstances may result in life-threatening complications, such as hypoxic brain injury, pulmonary aspiration of gastric contents, and cardiac arrest.
# Capnography
The CAS Guidelines state that continuous monitoring of end-tidal carbon dioxide (waveform capnography) is mandatory during general anesthesia and for moderate or deep procedural sedation. Several studies have shown that the ability to detect respiratory depression during procedural sedation is significantly enhanced when capnography monitoring is utilized. 14 For minimal sedation, capnography may be a useful adjunct to detect progression to an unintended deeper level of sedation with associated respiratory depression and is therefore recommended. Capnography is useful in monitoring patient ventilation when it cannot be directly observed (e.g., during magnetic resonance imaging), when multiple sedative agents are utilized, and when the pre-procedural assessment identifies an increased clinical risk for respiratory depression or airway obstruction (e.g., morbid obesity, OSA).
# Provision of sedation and delegation
Sedation may be provided by a team that includes a sedation supervisor (typically the anesthesiologist/ physician) and an approved and credentialed sedation assistant(s) (e.g., registered nurse, respiratory therapist, anesthesia assistant, or other appropriately trained health professional). The department of anesthesiology must define the specific qualifications, roles, and responsibilities of the sedation assistant. The sedation team may work together to conduct the sedation by performing the discrete tasks of 1) assessing the patient, 2) providing the sedation, and 3) monitoring the patient.
For minimal to moderate levels of sedation in a stable patient:
• The sedation supervisor may delegate administration of sedation and patient monitoring to the sedation assistant. • The sedation assistant must remain in constant attendance with the patient, providing continuous monitoring and immediately informing the sedation supervisor of any concerns.
• A member of the sedation team must monitor the patient continuously. • The sedation supervisor must remain immediately available to support the sedation assistant as necessary. • The sedation supervisor (anesthesiologist/physician) retains responsibility for the patient.
For deep sedation:
• The CAS Guidelines state that it is unacceptable for one anesthesiologist to conduct or supervise the administration of deep procedural sedation simultaneously for concurrent diagnostic or therapeutic procedures on more than one patient at a time.
# Supervision ratios
In specific circumstances where minimal or moderate sedation is administered, it may be appropriate for an anesthesiologist to supervise more than one patient concurrently while strictly adhering to the principles outlined above. It is essential to re-emphasize that an appropriately trained and credentialed individual must be in constant attendance with each patient receiving care.
The attending anesthesiologist must assume medical responsibility for the care of all patients involved in this care model and must be immediately available to attend to any patient when required. Each department of anesthesiology must establish the acceptable number of concurrent patients. Important factors to consider include the intensity and complexity of the caseload, the physical status of the patients, sedation assistant staffing and experience, and any institutional policies and procedures.
# Medications used for procedural sedation
This document does not provide a detailed review of the specific benefits or properties of all available medications used for procedural sedation. Anesthesiologists and anesthesia assistants are familiar with the pharmacology and properties of these agents and are experienced in their use. The CAS does support several fundamental principles that should be applied by all sedation providers in any setting. The overarching principle of procedural sedation is that one should use the minimum intervention possible with due consideration given to the specific procedure and patient. In general, medication should be administered in small divided doses or by continuous infusion titrated to clinical effect, allowing sufficient time to appreciate the peak depth of sedation achieved and accounting for variations in the amount of pain and procedural stimulation. Knowledge of each medication's time of onset, peak effect, and duration of effect is essential. When multiple medications are utilized, particularly with opioids, it is essential to consider the potential synergistic effects on the level of sedation and the increased risk for respiratory depression.
Where feasible, local or regional anesthesia should be strongly considered in addition to sedation for particularly painful procedures. Various combinations of medication can be used to administer procedural sedation and they should ideally be short acting and titratable. Increasingly, the potent sedative-hypnotic agents, specifically propofol, have become popular with both anesthesiologists and non-anesthesiologists to provide excellent moderate or deep procedural sedation with high patient satisfaction rates and a more rapid recovery profile than some other combinations of medication.
When anesthetic agents such as propofol are used for procedural sedation, however, they have a greater potential to produce unintentional general anesthesia, even when carefully administered. All sedation providers using agents such as propofol must have specific training and experience with their use, take all necessary monitoring precautions, and have the equipment and skills immediately available to manage the airway and provide ventilation and cardiovascular support associated with even brief periods of general anesthesia. 15,16
# Recovery and discharge
Post-procedural care of the sedated patient may be delegated to appropriately trained and qualified individuals. Post-procedural monitoring during the early recovery period is required, as stated in the CAS Guidelines, and should include level of consciousness, ventilation, oxygen saturation, heart rate, and blood pressure. The appropriate frequency and duration of monitoring should be determined by the facility's standards, taking into account the length and complexity of the specific procedure, the patient's complexity, and the level of sedation provided. Discharge readiness should be assessed by validated discharge criteria, such as the modified Aldrete score 17 for Phase 1 recovery when discharging a patient from the recovery room to another healthcare institutional location, or the postanesthetic discharge scoring system for Phase 2 recovery 18 when discharging the patient home (Table 2). If the patient is to be discharged home, the most responsible physician or delegated alternate physician must be available to attend to the patient until the institutionally set standards for discharge are met. Regardless of the level of procedural sedation performed, the discharge procedures for the postanesthetic period should conform to the CAS Guidelines to the Practice of Anesthesia.
# Quality assurance
The practice of procedural sedation must undergo the same rigorous scrutiny regarding patient outcomes as is applied for other forms of anesthesia care. A specific mechanism must be established for auditing procedural sedation and documenting any major complications, adverse events, or critical incidents. All critical incidents should be systematically reviewed and include appropriate recommendations for improvement where indicated.
# Sédation procédurale : exposé de principe de la Société canadienne des anesthésiologistes
La Société canadienne des anesthésiologistes (SCA) promeut des soins anesthésiques sécuritaires selon les normes les plus élevées possibles. Traditionnellement, ces soins étaient assurés par les anesthésiologistes dans les salles d'opération. Cependant, la pratique actuelle inclut de nombreux autres environnements et prestataires de soins. Les exigences d'évaluation du patient et de gestion de l'intervention médicale sont néanmoins indépendantes du prestataire ou du site.
La sédation procédurale est définie comme étant la technique permettant d'administrer de manière sécuritaire un sédatif ou des agents dissociatifs à courte durée d'action, avec ou sans analgésiques, dans le but de réduire l'inconfort, l'appréhension et les souvenirs potentiellement déplaisants, tout en minimisant la Able to move no extremities = 0 Severe or more than three dressing changes required = 0
Maximum scores = 10. A modified Aldrete score of C 9 is considered acceptable for discharge from Phase 1 to Phase 2 recovery and a PADSS score of C 9 is considered acceptable for discharge from Phase 2 or directly home following only one phase of recovery. The numerical analogue pain scale (0-10) is recommended for assessing post-procedural pain. BP = blood pressure; HR = heart rate.
Adapted from: Aldrete JA. The post-anesthesia recovery score revisited. J Clin Anesth 1995; 7: 89-91; 17 and Chung F, Chan VW, Ong D. A postanesthetic discharge scoring system for home readiness after ambulatory surgery. J Clin Anesth 1995; 7: 500-6. 18 dépression cardiorespiratoire chez des patients subissant des procédures diagnostiques ou thérapeutiques. Ces effets sont différents à la fois de l'anesthésie générale qui entraîne un état de perte de conscience totale et de l'analgésie pure qui assure une diminution ou une absence de sensibilité à la douleur sans nécessairement s'accompagner d'une réduction ou d'une perte de la conscience. L'utilisation limitée de médicaments antalgiques est fréquente au cours de la sédation procédurale. Les plus fortes doses nécessaires pour des procédures très douloureuses peuvent être dangereuses et dans ce cas il y a sans doute lieu d'envisager d'autres options, telles que l'anesthésie générale. Sachant que les effets secondaires ne sont pas rares avec la sédation procédurale, la personne en charge de la sédation doit sélectionner les patients de manière scrupuleuse et effectuer une évaluation complète de ces derniers avant la procédure. Ces prestataires doivent être vigilants et prêts à faire face à des complications potentielles, telles qu'une dépression respiratoire, une obstruction des voies respiratoires et une hypoxémie. Il est important de rappeler qu'en dehors d'une salle d'opération, ces complications peuvent être associées à un risque plus élevé de morbidité et de mortalité. Bien que l'on manque d'études de grande qualité comparant les résultats en salle d'opération à ceux obtenus dans d'autres environnements, 1 des données américaines (É tats-Unis) sur des cas des plaintes judiciaires résolues ont montré que les taux de complications et d'effets indésirables sont plus élevés quand les soins anesthésiques, y compris la sédation procédurale, sont délivrés dans des environnements isolés. 2 Cet exposé de principe décrit les meilleures pratiques et établit des lignes directrices s'appliquant aux anesthésiologistes et aux équipes de soins anesthésiques pour l'administration d'une sédation procédurale sécuritaire à la fois dans et en-dehors de la salle d'opération, y compris dans des établissements extérieurs à l'hôpital. Il reconnaît également que de nombreux professionnels médicaux et dentaires fournissent actuellement des services de sédation. Des données canadiennes récentes sur des plaintes judiciaires résolues concernant les différents prestataires de sédation ont identifié que des événements indésirables et des lésions graves des patients en rapport avec une sédation procédurale arrivent effectivement, même entre les mains d'anesthésiologistes expérimentés. 3 Les facteurs contributifs sont, notamment, une évaluation insuffisante, le choix du médicament, l'absence de prise de conscience de la gravité de la situation et les insuffisances de suivi pendant et après la procédure, avec la non-reconnaissance de la détérioration de la ventilation et de l'état des voies respiratoires. Des programmes d'études formelles avec une démonstration de la compétence en matière de sédation procédurale ont été recommandés comme une composante essentielle des programmes de formation en anesthésie. 4 Les principes décrits dans ce document peuvent également s'appliquer à des prestataires de sédation non-anesthésiologistes, bien que ces professionnels puissent souhaiter évaluer leur conformité avec leurs propres lignes directrices professionnelles ou celles de leur établissement de soins de santé. La SCA encourage fortement tous les prestataires de sédation à s'en tenir à un ensemble comparablement prudent et rigoureux de recommandations, mais reconnaît aussi qu'il peut exister des différences de pratiques entre les prestataires de sédation anesthésiologistes et non-anesthésiologistes. Nous préconisons fortement qu'au sein d'un établissement donné, il soit sérieusement envisagé d'élaborer des lignes directrices ou des règles pour la sédation procédurale, idéalement par un comité multidisciplinaire représentant tous les prestataires de sédations et les acteurs, y compris les anesthésiologistes. 5 Les anesthésiologistes sont les experts pour ce qui est de délivrer une sédation procédurale sécuritaire et les départements d'anesthésie devraient donc, dans la mesure où leurs ressources le permettent, s'efforcer de fournir des services de sédation élective et d'urgence dans leur établissement. Les anesthésiologistes doivent encourager le maintien de normes de sédation le plus élevé possible dans leurs établissements et, encore une fois, dans la mesure de leurs ressources, soutenir l'éducation des prestataires et assistants de sédation dans l'ensemble de leur établissement. Le concept d'équipes institutionnelles de sédation, souvent menées par un anesthésiologiste, gagne en popularité notamment pour la prestation de services de sédation en pédiatrie, 6 car elles ont l'avantage d'augmenter la disponibilité et la mobilité des services de sédation, et aussi de promouvoir l'éducation continue et l'acquisition d'habiletés pour les membres de l'équipe.
# Niveaux de sédation
Le Continuum de profondeur de la sédation de l'American Society of Anesthesiologists (ASA) est devenu un outil utile largement accepté pour standardiser la définition des niveaux de sédation; l'American Academy of Pediatrics et la JCAHO (Joint Commission on Accreditation of Healthcare Organizations) ont approuvé ensemble l'utilisation du Continuum de l'ASA. 7 Le continuum définit trois niveaux distincts de sédation : minimale, modérée et profonde. Il reconnaît aussi qu'un patient peut facilement passer du stade de sédation minimale au stade de sédation profonde et même à un quatrième niveau (c'est-à-dire une anesthésie générale). De bonnes corrélations cliniques sont requises pour améliorer la précision et la reproductibilité d'un quelconque niveau du système de mesure de la sédation.
Le continuum de sédation de l'ASA décrit en termes très précis les caractéristiques de chaque niveau de sédation, résumés dans le Tableau 1. 8 Le terme « sédation consciente » qui a souvent été utilisé par le passé correspond globalement à une sédation modérée. Ce terme n'est plus recommandé. La transition entre la persistance puis la perte du contact verbal constant avec le patient a lieu entre la sédation modérée et la sédation profonde. Ce point de transition est une observation importante à surveiller, mais qui n'est pas mentionné de manière spécifique dans le continuum de l'ASA. Le signe du retrait réflexe à une stimulation douloureuse ne doit pas être vu comme « intentionnelle ». Il existe de nombreuses autres « échelles » de sédation (p. ex., Ramsay) qui sont plus souvent utilisées par les prestataires de soins nonanesthésiologistes. 7 Ces échelles sont utiles, mais elles doivent prendre ces définitions en compte quand un chiffre est attribué à la profondeur de la sédation.
# É valuation préprocédurale
Administrer des médicaments puissants par voie parentérale exige une évaluation du patient et leur administration par un médecin ou un autre professionnel de la santé tel qu'un assistant en anesthésie délégué ou une infirmière autorisée avec une formation spécifique et expérience de sédation procédurale. L'évaluation doit inclure la documentation des antécédents médicaux et chirurgicaux appropriés, l'identification des comorbidités médicales pertinentes, les médicaments pris par le patient et ses allergies, ainsi que les indications de la procédure. Un examen physique orienté et toutes les investigations pertinentes doivent aussi être pratiqués. La nature de la sédation procédurale, tous ses risques significatifs et les autres options doivent être discutés avec le patient et documentés dans le dossier de santé.
La recherche d'un syndrome d'apnée-hypopnée du sommeil (SAHS) au moyen d'outils de dépistage validés, tels que le questionnaire STOP-Bang, 9 est recommandée. Si le patient présente un risque de SAHS ou a une forme modérée à sévère de SAHS confirmé, la sédation procédurale peut entraîner de plus grands risques et devrait être modifiée en conséquence. 10 Examen physique L'examen physique doit être approprié et adapté aux comorbidités médicales du patient. Il doit inclure une évaluation rigoureuse des voies respiratoires du patient, incluant les facteurs prédictifs de difficultés pour la ventilation au masque et l'intubation endotrachéale, en cas de risque de dépression respiratoire et de perte de la perméabilité des voies respiratoires au cours de la sédation procédurale. L'évaluation des voies respiratoires doit être documentée de façon formelle dans le dossier médical.
# Gestion de la sédation et surveillance des patients
Les recommandations générales pour la sédation procédurale sont identiques à celles des autres formes d'anesthésie et concordent avec celles qui sont décrites dans le Guide d'exercice de l'anesthésie de la SCA. 11 Le Guide d'exercice de la SCA indique qu'il n'est pas acceptable qu'un seul médecin administre une anesthésie (y compris dans le cas d'une sédation procédurale) et réalise en même temps la procédure diagnostique ou Tableau 1 Le Continuum de profondeur de la sédation de l'American Society of Anesthesiologists thérapeutique, hormis le cas de procédures effectuées avec seulement une infiltration d'anesthésique local et/ou une sédation minimale. La fréquence cardiaque, la pression artérielle, la fréquence respiratoire, la saturation en oxygène et le niveau de sédation/conscience doivent être suivis et documentés pour tous les patients subissant une sédation procédurale. La surveillance de la saturation en oxygène (c'est-à-dire, l'oxymétrie de pouls) doit être continue et consignée à intervalles réguliers en même temps que les autres constantes vitales. Pour les procédures peu invasives chez des patients sélectionnés sans maladie cardiorespiratoire significative, les recommandations habituelles de la SCA concernant la surveillance électrocardiographique peuvent être ignorées si une mesure continue de l'oxymétrie de pouls est utilisée et que la sédation appliquée est seulement minimale à modérée.
Un suivi de capnographie continue est requis pour les patients devant subir une sédation procédurale modérée à profonde (voir la rubrique « Capnographie »). Il est fortement recommandé qu'en plus de l'observation constante des signes cliniques, la fréquence et la qualité de la ventilation soient surveillées et documentées de manière régulière avec un suivi de capnographie pour tous les patients subissant une sédation procédurale.
L'administration systématique d'oxygène par lunette nasale ou masque facial à haut débit est fortement recommandée pour tous les patients subissant une sédation procédurale et est requise en cas de sédation profonde. Les précautions appropriées doivent être prises pour limiter le risque d'incendie dans la salle de procédure en raison de l'atmosphère enrichie qui pourrait être créée par l'utilisation d'un supplément d'oxygène, en particulier pour les procédures concernant les zones céphaliques et cervicales.
Les études cliniques ont montré que le niveau de sédation peut devenir plus profond que ce qui était recherché. 12 En conséquence, l'équipement approprié doit être facilement disponible et en état de fonctionner pour gérer les patients présentant une dépression cardiorespiratoire significative. L'équipement suivant (en différentes tailles en fonction de la population de patients servis par l'établissement) doit être disponible : Les demandes précises concernant le jeûne précédant la procédure évoluent. D'une manière générale, les patients recevant une sédation modérée ou profonde doivent être à jeun conformément aux recommandations générales de la SCA :
• É
• Huit heures après un repas incluant viande, friture ou aliments gras. • Six heures après un repas léger, un biberon de lait maternisé ou de lait non humain.
• Quatre heures après l'ingestion de lait maternel non enrichi. • Deux heures après l'absorption de liquide translucide.
Des recommandations plus libérales peuvent être appropriées pour une sédation minimale (p. ex., chirurgie pour cataracte). Néanmoins, elles doivent être personnalisées et les prestataires de soins doivent faire preuve de prudence en tenant compte des comorbidités propres aux patients et des facteurs de risque spécifiques d'aspiration pulmonaire du contenu gastrique.
Tout professionnel de la santé utilisant des agents sédatifs-hypnotiques pour obtenir une sédation doit avoir l'expertise, l'expérience, l'équipement et les autres ressources disponibles pour la ressuscitation des patients. En conséquence, un certificat en technique spécialisée de réanimation cardiorespiratoire est fortement recommandé. Ils doivent être capables d'assurer une gestion avancée des voies respiratoires et de « sauver » les patients dont la sédation devient plus profonde que prévu et développe une dépression respiratoire ou des apnées. 13 L'absence de réponse rapide et appropriée à de telles circonstances peut déboucher sur des complications engageant le pronostic vital tel qu'une lésion hypoxique du cerveau, l'aspiration pulmonaire du contenu gastrique et un arrêt cardiaque.
# Capnographie
Le Guide d'exercice de la SCA indique que la surveillance continue du dioxyde de carbone en fin de respiration (tracé de capnographie) est obligatoire au cours d'une anesthésie générale et pendant une sédation procédurale modérée à profonde. Quelques études ont montré que les capacités de détection d'une dépression respiratoire au cours de la sédation procédurale sont significativement améliorées avec le suivi de la capnographie. 14 En cas de sédation minime, la capnographie peut être un apport utile pour détecter la progression vers un niveau de sédation avec dépression respiratoire associée non souhaité; elle est donc recommandée. La capnographie est utile pour le suivi de la ventilation des patients quand celle-ci ne peut pas être directement observée (p. ex., au cours d'une imagerie par résonance magnétique), quand plusieurs agents sédatifs sont utilisés et quand l'évaluation avant procédure a identifié un risque clinique accru de dépression respiratoire ou d'obstruction des voies respiratoires (p. ex., obésité morbide, SAHS).
# Réalisation de la sédation et délégation
La sédation peut être assurée par une équipe incluant un superviseur de sédation (habituellement l'anesthésiologiste ou un autre médecin) et un ou plusieurs assistants de sédation approuvés et dûment accrédités (p. ex., infirmière autorisée, inhalothérapeute, assistant d'anesthésie ou tout autre professionnel de la santé dûment formé). Il incombe au département d'anesthésiologie de définir les qualifications, fonctions et responsabilités spécifiques des assistants de sédation. L'équipe de sédation doit travailler ensemble à sa réalisation en effectuant des tâches spécifiques 1) d'évaluation du patient, 2) de sédation proprement dite et 3) de surveillance du patient.
En cas de sédation minimale à modérée chez des patients stables :
• Le superviseur de sédation pourra déléguer l'administration de la sédation et la surveillance du patient à un assistant de sédation. • L'assistant de sédation doit rester en permanence auprès du patient, assurant une surveillance continue et informant immédiatement le superviseur de sédation à la moindre préoccupation. • Un membre de l'équipe de sédation doit surveiller le patient en permanence. • Le superviseur de sédation doit rester immédiatement disponible pour seconder l'assistant de sédation si nécessaire. • Le superviseur de sédation (anesthésiologiste/médecin) conserve la responsabilité du patient.
En cas de sédation profonde :
• Le Guide d'exercice de la SCA indique qu'il n'est pas acceptable qu'un anesthésiologiste réalise ou supervise l'administration d'une sédation procédurale profonde en même temps que des procédures diagnostiques ou thérapeutiques chez plus d'un patient au même moment.
# Ratios de surveillance
Dans les circonstances spécifiques où une sédation minime à modérée est administrée, un anesthésiologiste pourrait superviser plus d'un patient à la fois tout en respectant strictement les principes décrits plus haut. Cependant, quand des agents anesthésiques tels que le propofol sont utilisés pour une sédation procédurale, il y a un plus grand risque de provoquer une anesthésie générale involontaire, même quand ils sont administrés avec prudence. Tous les prestataires de sédation utilisant des produits tels que le propofol doivent avoir reçu une formation spécifique et avoir l'expérience de leur utilisation, prendre toutes les précautions de monitorage nécessaires et disposer immédiatement de l'équipement et des habiletés requises pour gérer les voies aériennes et fournir la ventilation/le soutien cardiovasculaire associés à des périodes d'anesthésie générale, même brèves. 15,16
# Récupération et congé
Les soins post procédure d'un patient ayant subi une sédation peuvent être délégués à des personnes qualifiées et correctement formées. Un monitorage est requis au cours de la première période de récupération post procédure, comme l'indique le Guide d'exercice de la SCA, et doit porter sur le niveau de conscience, la ventilation, la saturation en oxygène, la fréquence cardiaque et la pression artérielle. La fréquence et la durée appropriées du monitorage doivent être déterminées par les normes de l'établissement en tenant compte la durée et la complexité de la procédure en question, la complexité du cas du patient et le niveau de sédation atteint. Le congé peut être donné au patient après une évaluation avec des critères validés, tel que le score modifié d'Aldrete 17 pour la récupération de Phase 1 quand le patient est renvoyé d'une salle de réveil vers un autre service de l'établissement de soin, ou le système de cotation de congé post anesthésique pour la récupération de Phase 2 18 quand le patient retourne à son domicile (Tableau 2). Si le patient doit rentrer chez lui, le médecin responsable ou le médecin délégué le remplaçant doit être disponible pour s'occuper du patient jusqu'à ce que les normes établies par l'établissement pour le congé soient remplies. Indépendamment du niveau de sédation procédurale réalisé, les procédures de congé pour la période postanesthésique doivent être conformes au Guide d'exercice de l'anesthésie de la SCA.
# Suivi de qualité
La pratique de la sédation procédurale doit suivre la même attention rigoureuse concernant l'évolution des patients que celle qui s'applique aux autres formes de soins anesthésiques. Un mécanisme spécifique doit être mis en place pour la vérification de la sédation procédurale et la documentation de toutes les complications majeures, événements indésirables ou incidents critiques. Tous les incidents critiques doivent être systématiquement analysés et déboucher sur les recommandations appropriées pour des améliorations quand il y a lieu.
Responsabilité édiroriale Cet article a été traité par le Dr Hilary P. Grocott, Rédacteur en chef, Journal canadien d'anesthésie.
#
Acknowledgements Contributions to the earlier version of this position paper from former members of the CAS Committee on Standards to the Practice of Anesthesia are gratefully acknowledged.
#
Competing interests All authors of this article are members of the Standards Committee of the Canadian Anesthesiologists' Society (CAS). None of the authors have any financial or commercial interests relating to any companies or manufacturers of equipment or medications referenced in this article. Dr. Gregory Dobson is the Chair of the Committee on Standards of the CAS.
Editorial responsibility This submission was handled by Dr. Hilary P. Grocott, Editor-in-Chief, Canadian Journal of Anesthesia.
Remerciements Les auteurs sont très reconnaissants envers les anciens membres du Comité des normes de l'exercice de l'anesthésie de la SCA pour leurs contributions à la version précédente de cet exposé de principe.
# Conflits d'intérêts Tous les auteurs de cet article sont membres du
Comité des normes de la Société canadienne des anesthésiologistes (SCA). Aucun auteur n'a de lien financier ou commercial avec les sociétés pharmaceutiques ou fabricants d'équipements mentionnés dans cet article. Le D r Gregory Dobson est le président du Comité des normes de la SCA. | None | None |
a9bb4dd11865f48b16bacdeb98dda15c78e0a61d | cma | None | Recommendations apply to patients >18 years of age. Recommendations are based on the best available data and may change as additional data becomes available. Science Briefs can be found on the Ontario COVID-19 Science Advisory Table website.Dexamethasone 6 mg PO/IV daily for 10 days (or until discharge if sooner) is recommended.n Reassurance and information for self-monitoring of symptoms (including self-monitoring of oxygen saturation) are recommended. p Fluvoxamine 50 mg PO daily titrated up to 100 mg PO twice daily for a total of 15 days may be considered for these patients if they present within 7 days of symptom onset. See fluvoxamine recommendation statement for higher risk mildly ill patients. p Budesonide 800 mcg inhaled twice daily for 14 days may be considered for these patients. See budesonide recommendation statement for higher risk mildly ill patients. g The following therapies are not recommended for these patients: nirmatrelvir/ritonavir (Paxlovid) and remdesivir. u There is currently insufficient evidence to make a recommendation around aspirin or anticoagulation for mildly ill patients. g The following therapies are not recommended for mildly ill patients: dexamethasone, tocilizumab, sarilumab, and baricitinib.#
Tocilizumab is recommended for patients who are on recommended doses of dexamethasone therapy (or a dose-equivalent corticosteroid) AND are within 14 days of hospital admission (or within 14 days of a new COVID-19 diagnosis if the infection was nosocomially acquired).
# RECOMMENDATIONS FOR DRUG SHORTAGE SITUATIONS
In drug shortage situations, a single dose of tocilizumab 400 mg IV or sarilumab 400 mg IV should be used for all eligible patients. A second dose of tocilizumab or sarilumab should not be given to any patient.
Baricitinib 4 mg PO/NG daily for 14 days (or until discharge if sooner) is recommended in patients who are on recommended doses of dexamethasone therapy (or a dose-equivalent corticosteroid) or who have a contraindication to corticosteroid treatment. The panel does not recommend combined use of baricitinib and IL-6 inhibitors due to absence of safety and efficacy evidence.
Dexamethasone 12 mg PO/IV daily for 10 days (or until discharge if sooner) may be considered in patients who are unable to receive IL-6 inhibitors (tocilizumab, sarilumab) or baricitinib. This recommendation is based on very low certainty evidence of reduction in days alive without life support, and the need for inpatient treatment options with a reasonable safety profile during an anticipated spike in COVID-19 cases due to the Omicron variant and widespread shortages of IL-6 inhibitors and baricitinib.
Prophylactic dose low molecular weight or unfractionated heparin is recommended. These patients should not receive therapeutic dose anticoagulation unless they have a separate indication for this treatment.
Remdesivir is not recommended for patients receiving mechanical ventilation. Remdesivir 200 mg IV on day 1, then 100 mg IV daily for 4 days may be considered in patients requiring high-flow oxygen (i.e., oxygen by mask, oxygen by high-flow nasal cannula, or non-invasive mechanical ventilation).
# SARS-CoV-2 neutralizing antibodies are not recommended.
Nirmatrelvir/ritonavir (Paxlovid) is not recommended.
Bacterial co-infection is uncommon in COVID-19 pneumonia at presentation. Do not add empiric antibiotics for bacterial pneumonia unless bacterial infection is strongly suspected. Continue empiric antibiotics for no more than 5 days, and de-escalate on the basis of microbiology results and clinical judgment.
n g g p g g g n n
Tocilizumab is recommended for patients who have evidence of systemic inflammation, defined as a serum CRP of 75 mg/L or higher, AND have evidence of disease progression (i.e., increasing oxygen or ventilatory requirements) despite 24-48 hours of recommended doses of dexamethasone therapy (or a dose-equivalent corticosteroid), AND are within 14 days of hospital admission (or within 14 days of a new COVID-19 diagnosis if the infection was nosocomially acquired).
# RECOMMENDATIONS FOR DRUG SHORTAGE SITUATIONS
In drug shortage situations, a single dose of tocilizumab 400 mg IV or sarilumab 400 mg IV should be used for all eligible patients. A second dose of tocilizumab or sarilumab should not be given to any patient. Baricitinib 4 mg PO/NG daily for 14 days (or until discharge if sooner) is recommended in patients who are on recommended doses of dexamethasone therapy (or a dose-equivalent corticosteroid) or who have a contraindication to corticosteroid treatment. The panel does not recommend combined use of baricitinib and IL-6 inhibitors due to absence of safety and efficacy evidence.
Dexamethasone 6 mg PO/IV daily for 10 days (or until discharge if sooner) is recommended. If patients are discharged with home-based oxygen therapy, dexamethasone 6 mg PO daily until oxygen is no longer required (for a maximum of 10 days) may be considered.
Remdesivir 200 mg IV on day 1, then 100 mg IV daily for 4 days is recommended.
Therapeutic dose anticoagulation may be considered over prophylactic dose anticoagulation in patients who are felt to be at low risk of bleeding. All other patients should receive prophylactic dose anticoagulation. STEP 1 u Determine the risk of disease progression.
# SARS-CoV
- Higher risk individuals are those who have a ≥5% risk of hospitalization if they develop COVID-19. Standard risk individuals are those who have a <5% of hospitalization.
- Indigenous people, Black people, and members of other racialized communities may be at increased risk of disease progression due to disparate rates of comorbidity, increased barriers to vaccination, and social determinants of health. They should be considered priority populations for access to COVID-19 drugs and therapeutics.
# AGE (years)
NUMBER
# STEP 2 u
Based on the risk level, refer to the corresponding recommendation statements below.
# RISK LEVEL RECOMMENDATIONS HIGHER RISK OF SEVERE DISEASE
Individuals who have a ≥5% risk of hospitalization or are immunocompromised u It is recommended that higher risk patients receive nirmatrelvir/ritonavir (Paxlovid) or remdesivir. The choice of drug depends on availability, contraindications, and ease of administration.
# These individuals should have a reasonable expectation for 1-year survival prior to SARS-CoV-2 infection.
n Nirmatrelvir/ritonavir (Paxlovid) at a dose of 300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet), with all three tablets taken together orally twice daily for 5 days, is recommended for these patients if they present within 5 days of symptom onset.
- In patients with moderate renal impairment (eGFR ≥30 to <60 mL/min), the dose should be reduced to 150 mg nirmatrelvir (one 150 mg tablet) and 100 mg ritonavir (one 100 mg tablet) taken together twice daily for 5 days. Paxlovid is not recommended in patients with severe renal impairment (eGFR <30 mL/min). - Specialized pharmacist consultation is important to mitigate any significant drug-drug interactions with other drugs. - Paxlovid should be preferentially deployed in regions and to populations where administration is a barrier to intravenous medication.
n Remdesivir 200 mg IV on day 1, then 100 mg IV daily for 2 days is recommended for these patients if they present within 7 days of symptom onset.
u If the above drugs are unavailable or contraindicated: p Fluvoxamine may be considered for patients with mild COVID-19 illness presenting within 7 days of symptom onset. The recommended starting dose is 50 mg PO daily, titrated up to 100 mg PO twice daily for a total of 15 days. Pharmacist consultation and outpatient provider follow-up is important to avoid any significant adverse drug interactions with fluvoxamine. This recommendation balances the very low certainty evidence of benefit for preventing hospitalization with the need for management options for mild illness with a reasonable safety profile during a surge in COVID-19 cases due to the Omicron variant.
p Budesonide 800 mcg inhaled twice daily for 14 days may be considered for these patients. This recommendation is based on very low certainty evidence of reduction in duration of symptoms, and the need for outpatient treatment options with a reasonable safety profile during an anticipated spike in COVID-19 cases due to the Omicron variant. Budesonide may have a role as an additional therapy in patients already on other therapies who have respiratory symptoms.
# STANDARD RISK | Recommendations apply to patients >18 years of age. Recommendations are based on the best available data and may change as additional data becomes available. Science Briefs can be found on the Ontario COVID-19 Science Advisory Table website.Dexamethasone 6 mg PO/IV daily for 10 days (or until discharge if sooner) is recommended.n Reassurance and information for self-monitoring of symptoms (including self-monitoring of oxygen saturation) are recommended. p Fluvoxamine 50 mg PO daily titrated up to 100 mg PO twice daily for a total of 15 days may be considered for these patients if they present within 7 days of symptom onset. See fluvoxamine recommendation statement for higher risk mildly ill patients. p Budesonide 800 mcg inhaled twice daily for 14 days may be considered for these patients. See budesonide recommendation statement for higher risk mildly ill patients. g The following therapies are not recommended for these patients: nirmatrelvir/ritonavir (Paxlovid) and remdesivir. u There is currently insufficient evidence to make a recommendation around aspirin or anticoagulation for mildly ill patients. g The following therapies are not recommended for mildly ill patients: dexamethasone, tocilizumab, sarilumab, and baricitinib.#
Tocilizumab is recommended for patients who are on recommended doses of dexamethasone therapy (or a dose-equivalent corticosteroid) AND are within 14 days of hospital admission (or within 14 days of a new COVID-19 diagnosis if the infection was nosocomially acquired).
# RECOMMENDATIONS FOR DRUG SHORTAGE SITUATIONS
In drug shortage situations, a single dose of tocilizumab 400 mg IV or sarilumab 400 mg IV should be used for all eligible patients. A second dose of tocilizumab or sarilumab should not be given to any patient.
Baricitinib 4 mg PO/NG daily for 14 days (or until discharge if sooner) is recommended in patients who are on recommended doses of dexamethasone therapy (or a dose-equivalent corticosteroid) or who have a contraindication to corticosteroid treatment. The panel does not recommend combined use of baricitinib and IL-6 inhibitors due to absence of safety and efficacy evidence.
Dexamethasone 12 mg PO/IV daily for 10 days (or until discharge if sooner) may be considered in patients who are unable to receive IL-6 inhibitors (tocilizumab, sarilumab) or baricitinib. This recommendation is based on very low certainty evidence of reduction in days alive without life support, and the need for inpatient treatment options with a reasonable safety profile during an anticipated spike in COVID-19 cases due to the Omicron variant and widespread shortages of IL-6 inhibitors and baricitinib.
Prophylactic dose low molecular weight or unfractionated heparin is recommended. These patients should not receive therapeutic dose anticoagulation unless they have a separate indication for this treatment.
Remdesivir is not recommended for patients receiving mechanical ventilation. Remdesivir 200 mg IV on day 1, then 100 mg IV daily for 4 days may be considered in patients requiring high-flow oxygen (i.e., oxygen by mask, oxygen by high-flow nasal cannula, or non-invasive mechanical ventilation).
# SARS-CoV-2 neutralizing antibodies are not recommended.
Nirmatrelvir/ritonavir (Paxlovid) is not recommended.
Bacterial co-infection is uncommon in COVID-19 pneumonia at presentation. Do not add empiric antibiotics for bacterial pneumonia unless bacterial infection is strongly suspected. Continue empiric antibiotics for no more than 5 days, and de-escalate on the basis of microbiology results and clinical judgment.
n g g p g g g n n
Tocilizumab is recommended for patients who have evidence of systemic inflammation, defined as a serum CRP of 75 mg/L or higher, AND have evidence of disease progression (i.e., increasing oxygen or ventilatory requirements) despite 24-48 hours of recommended doses of dexamethasone therapy (or a dose-equivalent corticosteroid), AND are within 14 days of hospital admission (or within 14 days of a new COVID-19 diagnosis if the infection was nosocomially acquired).
# RECOMMENDATIONS FOR DRUG SHORTAGE SITUATIONS
In drug shortage situations, a single dose of tocilizumab 400 mg IV or sarilumab 400 mg IV should be used for all eligible patients. A second dose of tocilizumab or sarilumab should not be given to any patient. Baricitinib 4 mg PO/NG daily for 14 days (or until discharge if sooner) is recommended in patients who are on recommended doses of dexamethasone therapy (or a dose-equivalent corticosteroid) or who have a contraindication to corticosteroid treatment. The panel does not recommend combined use of baricitinib and IL-6 inhibitors due to absence of safety and efficacy evidence.
Dexamethasone 6 mg PO/IV daily for 10 days (or until discharge if sooner) is recommended. If patients are discharged with home-based oxygen therapy, dexamethasone 6 mg PO daily until oxygen is no longer required (for a maximum of 10 days) may be considered.
Remdesivir 200 mg IV on day 1, then 100 mg IV daily for 4 days is recommended.
Therapeutic dose anticoagulation may be considered over prophylactic dose anticoagulation in patients who are felt to be at low risk of bleeding. All other patients should receive prophylactic dose anticoagulation. STEP 1 u Determine the risk of disease progression.
# SARS-CoV
• Higher risk individuals are those who have a ≥5% risk of hospitalization if they develop COVID-19. Standard risk individuals are those who have a <5% of hospitalization.
• Indigenous people, Black people, and members of other racialized communities may be at increased risk of disease progression due to disparate rates of comorbidity, increased barriers to vaccination, and social determinants of health. They should be considered priority populations for access to COVID-19 drugs and therapeutics.
# AGE (years)
NUMBER
# STEP 2 u
Based on the risk level, refer to the corresponding recommendation statements below.
# RISK LEVEL RECOMMENDATIONS HIGHER RISK OF SEVERE DISEASE
Individuals who have a ≥5% risk of hospitalization or are immunocompromised u It is recommended that higher risk patients receive nirmatrelvir/ritonavir (Paxlovid) or remdesivir. The choice of drug depends on availability, contraindications, and ease of administration.
# These individuals should have a reasonable expectation for 1-year survival prior to SARS-CoV-2 infection.
n Nirmatrelvir/ritonavir (Paxlovid) at a dose of 300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet), with all three tablets taken together orally twice daily for 5 days, is recommended for these patients if they present within 5 days of symptom onset.
• In patients with moderate renal impairment (eGFR ≥30 to <60 mL/min), the dose should be reduced to 150 mg nirmatrelvir (one 150 mg tablet) and 100 mg ritonavir (one 100 mg tablet) taken together twice daily for 5 days. Paxlovid is not recommended in patients with severe renal impairment (eGFR <30 mL/min). • Specialized pharmacist consultation is important to mitigate any significant drug-drug interactions with other drugs. • Paxlovid should be preferentially deployed in regions and to populations where administration is a barrier to intravenous medication.
n Remdesivir 200 mg IV on day 1, then 100 mg IV daily for 2 days is recommended for these patients if they present within 7 days of symptom onset.
u If the above drugs are unavailable or contraindicated: p Fluvoxamine may be considered for patients with mild COVID-19 illness presenting within 7 days of symptom onset. The recommended starting dose is 50 mg PO daily, titrated up to 100 mg PO twice daily for a total of 15 days. Pharmacist consultation and outpatient provider follow-up is important to avoid any significant adverse drug interactions with fluvoxamine. This recommendation balances the very low certainty evidence of benefit for preventing hospitalization with the need for management options for mild illness with a reasonable safety profile during a surge in COVID-19 cases due to the Omicron variant.
p Budesonide 800 mcg inhaled twice daily for 14 days may be considered for these patients. This recommendation is based on very low certainty evidence of reduction in duration of symptoms, and the need for outpatient treatment options with a reasonable safety profile during an anticipated spike in COVID-19 cases due to the Omicron variant. Budesonide may have a role as an additional therapy in patients already on other therapies who have respiratory symptoms.
# STANDARD RISK
| None | None |
78bc032080b13bd682cfc421586b7b1ae23787ba | cma | None | # Background
Cirrhosis represents a diffuse liver disease characterized by structurally abnormal nodules of liver cells surrounded by fibrosis. 1 It results from chronic liver injury and regeneration secondary to chronic viral hepatitis, alcoholic liver disease, metabolic liver diseases (e.g. hemochromatosis, Wilson's disease, α1-antitrypsin deficiency, non-alcoholic steatohepatitis), and autoimmune diseases (e.g. autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis). Cirrhosis is associated with an annual incidence of hepatocellular carcinoma of 3 to 5 percent.
Hepatocarcinogenesis represents a multi-step process in which both genetic abnormalities and epigenetic alterations encourage the malignant transformation of hepatocytes. Hepatocellular carcinomas are associated with up-regulated signal transduction through multiple pathways (e.g. mitogen-activated protein kinase, vascular endothelial growth factor receptor).
Prognosis depends upon the extent of hepatic replacement by the tumour, the α-fetoprotein (AFP) level, the patient's performance status (see Appendix B), the tumour's histologic subtype (e.g.: fibrolamellar variant), and the degree of liver dysfunction (as assessed by the Child-Pugh classification system, see Appendix C).
# Guideline Questions
- What are the goals of therapy and recommendations for the treatment of adult patients with: o very early stage hepatocellular carcinoma? o early stage hepatocellular carcinoma? o intermediate stage hepatocellular carcinoma? o advanced stage hepatocellular carcinoma? o terminal stage hepatocellular carcinoma?
# Search Strategy
This guideline was developed to promote evidence-based practice in Alberta. It was compiled from the results of randomized controlled trials and systematic reviews, derived from an English language and relevant term search of PubMed and MEDLINE from 1990 forward. It takes into consideration related information presented at local, national, and international meetings as well as the Alberta Provincial Gastrointestinal Tumour Team's interpretation of the data. The 2021 update did not necessitate a full literature review; recommendations were modified based on a consensus discussion at the 2020 Annual Gastrointestinal Tumour Team Meeting.
# Target Population
The recommendations outlined in this guideline apply to adults over the age of 18 years with hepatocellular carcinoma (HCC). Different principles may apply to pediatric patients.
The American Association for the Study of Liver Disease (AASLD) promotes routine HCC surveillance for all adult patients with Child-Pugh A or B cirrhosis. 2 Screening and surveillance using liver ultrasound, with or without α-fetoprotein (AFP), is recommended every six months. Patients with Child-Pugh C cirrhosis are not recommended for surveillance due to low anticipated survival unless these patients are on a liver transplant waiting list (see Appendix C for details on Child-Pugh score).
Patients with hepatitis B are also considered at risk; screening is recommended starting at age 40 for Asian males, age 50 for Asian females and age 20 for those of African descent. 2 The American College of Radiology (ACR) has created the Ultrasound Liver Imaging Reporting and Data System (US LI-RADS) algorithm for interpretation and reporting of ultrasound exam results. 3 The US LI-RADS is composed of 3 observational categories and 3 visualization scores, which are summarized in Table 1. An AFP value that exceeds 20 ng/mL is considered positive, while anything lower is considered negative. 3 Noninvasive diagnosis with a multiphase CT scan or a multiphase MRI is recommended by the AASLD. 2 The results should be interpreted and reported through the CT/MRI Liver Imaging Reporting and Data System (CT/MRI LI-RADS) algorithm developed by the ACR. This algorithm allows definitive diagnosis of HCC in high risk patients without pathologic confirmation. 5 The CT/MRI LI-RADS outlines eight diagnostic categories summarized in Table 2. The key imaging features include size ≥ 1 cm, arterial phase hyperenhancement (APHE), and a combination of washout, threshold growth and capsule appearance. 6 If these features are not present but HCC is suspected, then a liver biopsy should be considered. A biopsy should also be considered in patients with a liver mass that is atypical of HCC on contrast-enhanced imaging 2 . If high-grade dysplasia and HCC are not disguisable by routine histology alone, tumour markers glypican-3 (GPC3), heat-shock protein 70 (HSP70) and glutamine synthetase (GS) can be assessed.
# Goals and Recommendations
To define and provide optimal care to a patient with HCC, a multidisciplinary team (MDT) is required.
It should be composed of hepatobiliary surgeons, diagnostic and interventional radiologists, hepatologists/gastroenterologists, and oncologists. Consideration is given to patient factors (e.g. functional status, co-morbidities, liver function) and tumour factors (e.g. size, number, location, vascular invasion).
The Barcelona Clinic Liver Cancer (BCLC) staging system (Table 3) provides a system to define the care for patients with HCC. 7,8 It links the TNM staging system (see Appendix A), the patient's ECOG performance status (see Appendix B), and the patient's liver function (see Appendix C) to treatment options. An algorithm for management of HCC according to the updated AHS clinical practice guideline recommendations is provided (Figure 1).
Consider treatment on a clinical trial, if available. - Well-compensated liver function (Child-Pugh class A). Tumour Requirements: - Solitary tumour (< 2 cm) confined to one lobe of the liver.
- Absence of vascular invasion and extra-hepatic disease.
- Complete removal of the tumour with a margin of ≥ 1 cm anticipated.
# Goals:
- To render patient free of disease and to delay or prevent recurrence. Recommendation:
- Resection. 10 Resection: - In carefully selected patients, five-year survivals of 50 to 70% are anticipated.
- Comparative genomic hybridization reveals that 60 to 70% of recurrences are intra-hepatic metastases and that 30 to 40% are de novo tumour development. - Abnormal bilirubin and portal hypertension (as suggested by thrombocytopenia with platelet count under 100, varices, ascites, and/or splenomegaly) predict for failure to benefit from resection. 11 - If extra-hepatic disease is confirmed at laparotomy, resection is not pursued.
- Intra-operative ultrasound and bi-manual palpation assessment for other intra-hepatic lesions. Intraoperative or subsequent radiofrequency ablation or percutaneous ethanol injection 12,13 can be considered for multicentric disease. - No clear benefit has been established for adjuvant therapy post-resection. In fact, adjuvant chemotherapy may adversely affect the outcome, especially in cirrhotic patients. 14,15 Sorafenib was of no benefit as adjuvant therapy following curative intent resection or radiofrequency ablation (STORM study). 16 - In patients who are not candidates for surgical resection, radiofrequency ablation (see below) can offer a 97% complete response for tumours ≤ 2 cm with long-term survival similar to what has been reported in patients who have undergone resection. 17 - Three randomized controlled trials comparing surgical resection to RFA have been performed in China.
Although the studies had methodological flaws (cross-over between groups), similar outcomes were reported in two studies 18,19 whereas one study demonstrated improved recurrence-free and overall survival in the surgical resection group. 20 Follow-Up: To identify recurrence, obtain a contrast enhanced CT scan, MR, or ultrasound of the abdomen every three months for two years and then every six months thereafter. Obtain an AFP every three months for two years and then every six months thereafter. 21
# Early Stage HCC
Patient Requirements:
- Good performance status (ECOG 0).
- Well-compensated liver function (Child-Pugh class A). Tumour Requirements: - Solitary tumour confined to one lobe of liver or three nodules (all ≤ 3 cm)
- Absence of vascular invasion and extra-hepatic disease.
- Complete removal of the tumour(s) with a margin of ≥ 1 cm anticipated. Goals:
- To render patient free of disease and to delay or prevent recurrence. Recommendations:
- Resection (see above), liver transplantation (see below), or ablation 12 (see below). Liver Transplantation:
Removes the cancer and corrects the underlying "field defect" (cirrhosis) but subjects the patient to the potential complications of long-term immunosuppression. - Offers a five-year disease-free survival of up to 70% and a short-term mortality of up to 10%.
- In Alberta, transplantation is contraindicated if the total tumour volume (TTV) exceeds 115 cm 3 , the alphafetoprotein exceeds 400 ng/mL, vascular invasion and/or extra-hepatic disease exist, or significant comorbidities exist. - Patients may be considered for liver transplantation after being "down-staged" if their initial total tumour volume was under 250 cm 3 and both the total tumour volume and the AFP remain under 115 cm 3 and 400 ng/mL, respectively, for more than six months. 22,23
# Radiofrequency Ablation (RFA) or Percutaneous Ethanol Injection (PEI):
- Provides tumour control pending transplantation or as an adjunct or alternative to resection.
- Recent series of radiofrequency ablation report local recurrence rates under 5% and five-year survivals equal to resection. Radiofrequency ablation requires fewer sessions to ablate tumours and results in improved survival when compared to percutaneous ethanol injection. 24 - Survival rates with radiofrequency ablation may be similar to surgical resection; 18 however, two-year recurrence rates are higher following percutaneous ethanol injection and radiofrequency ablation than with resection. 25 - Best outcomes are achieved from radiofrequency ablation when tumours are centrally located, measure under 3 cm, and are distant from "heat sinks" (blood vessels). 11 Consider percutaneous ethanol injection or transarterial chemo-embolization (TACE) when tumours are in a subcapsular location, exceed 4 cm, or are located adjacent to blood vessels. - Hepatocellular carcinomas are considered "treated" only if the imaging study demonstrates complete tumour necrosis (without contrast enhancement to suggest residual disease).
# Intermediate Stage HCC
# Patient Requirements:
- Good performance status (ECOG 0-1).
- Well-compensated liver function (Child-Pugh class A) and only select patients with impaired liver function (Child-Pugh class B 7). Tumour Requirements:
- Multinodular disease.
- Absence of extra-hepatic disease.
- Patency of the main portal vein (as assessed by ultrasound Doppler or MR angiography) for TACE.
- Adequate renal function.
# Goals:
- To maintain or to improve the patient's quality of life (to control or to delay the onset of tumour-related symptoms, possibly while awaiting transplant).
- To prolong life, if possible. Recommendations:
- Transarterial chemo-embolization or transarterial radioembolization. Consider palliative care if not an LT candidate.
# Transarterial Chemo-Embolization (TACE):
- Blood supply to hepatocellular carcinomas is preferentially derived from the hepatic artery rather than the portal vein. - Involves placement of an intravascular catheter into the hepatic artery (inserted percutaneously in the femoral artery and advanced through the abdominal aorta and celiac trunk). Injection of chemotherapy (with or without the oily contrast agent, Lipiodol) followed by embolic agents (e.g.: gelatin-sponge particles, Embosphere ® ) occludes the relevant branch of the hepatic artery and localizes the chemotherapy. Metaanalyses of randomized controlled trials demonstrate a survival benefit of TACE. 35,36 Drug-eluting beads (DEBs) decrease the systemic exposure to doxorubicin. 37 Although DEBs have not been shown to be superior to conventional TACE, they offer a more standardized technique and are better tolerated with fewer complications. 29 Recent cohort studies are demonstrating median survival of 4 years after TACE with DEBs in carefully selected patients. 30 Transarterial Radioembolization (TARE):
- TARE or selective internal radiotherapy (SIRT) uses microspheres loaded with yttrium-90 (Y 90 ) to deliver radiation directly into the tumour via the hepatic artery. Unlike TACE it is done as an outpatient. Prior to the TARE, the patient requires a staging angiogram to calculate the liver-to-lung shunt fraction in Nuclear Medicine using technicium-99 macro-aggregated albumin (Tc 99 MAA). At the same time selective embolization of the gastroduodenal arteries is carried out to prevent delivery of radiation to the stomach and duodenum. The procedure may be repeated depending upon response.
- A meta-analysis 38 and large cohort studies from Europe 31 and the USA 32 have shown similar survival to TACE in BCLC stage B patients. However, a separate meta-analysis showed superior survival with TACE in unresectable patients. 39 - TARE, unlike TACE, can be performed safely in patients with portal vein thrombosis, as the microspheres used in TARE are smaller and less embolic. 31,32 - TARE may be considered for patients who have progressive disease after TACE, who cannot tolerate doxorubicin or who are likely to fail TACE (large HCC).
- TARE may also be more effective than TACE in bridging or down-staging patients to liver transplantation. 33,35
Outcomes following TARE are best in patients with preserved liver function (Child-Pugh score <8 or MELD score <13). 34 Patients should be selected for TARE at MDT meetings.
- As there remains uncertainty about TARE efficacy compared to TACE (intermediate stage) or sorafenib (advanced stage), clinical trials are encouraged.
# Advanced Stage HCC
Patient Requirements:
- Good performance status (ECOG 0 or 1).
- Well-compensated liver function (Child-Pugh class A). Tumour Requirements:
- Disease ineligible for, or that progressed after, surgical or locoregional therapy. Goals:
- To maintain or to improve the patient's quality of life (to control or to delay the onset of tumour-related symptoms). - To prolong life, if possible.
# Recommendations:
- First-line treatment: Atezolizumab-Bevacizumab , or participation in a clinical trial 36 First-Line Systemic Therapy:
Atezolizumab-Bevacizumab (Preferred, Type of recommendation: evidence based, benefits outweigh harms; Evidence quality: moderate to high; Strength of recommendation: strong) 42 - Atezolizumab-bevacizumab was compared to sorafenib in the open-label phase 3 IMbrave150 trial. 43 Hazard ratio for death was 0.58 (95%CI: 0.42-0.79; p<0.001) in favor of atezolizumab-bevacizumab. Last revision: August, 2021
Additionally, hazard ratio for disease progression or death was superior in the atezolizumab-bevacizumab arm (HR: 0.59; 95%CI: 0.47-0.76; p20 kPa or if the platelet count is <150. 46 Patients with incompletely treated varices should not be treated with this combination. - Atezolizumab-Bevacizumab is not currently funded in Alberta
In those patients where Atezolizumab-Bevacizumab is not appropriate/contraindicated: Lenvatinib (Type of recommendation: evidence based, benefits outweigh harms; Evidence quality: moderate to high; Strength of recommendation: strong) - Lenvatinib was shown to be non-inferior to sorafenib for overall survival in an open-label, phase 3, multicenter, non-inferiority trial in patients with unresectable hepatocellular carcinoma, who had not received treatment for advanced disease (median OS 13.6m lenvatinib vs 12.3m sorafenib, respectively, HR: 0.92, 95%CI: 0.79-1.06). Patients had Child Pugh A liver function, and ECOG 0-1. 47 - It is worth noting that lenvatinib was superior to sorafenib in terms of progression-free survival (7.4m vs 3.7m, respectively, HR: 0.66, 95%CI: 0.57-0.77, p<0.001). Objective response rates were also higher in the lenvatinib group (24.1% vs. 9.2%, respectively, p<0.001). - Treatment-related adverse events of grade 3 or higher occurred in 57% of patients treated with lenvatinib and 49% with sorafenib. Rates of hand-foot syndrome are lower in the lenvatinib arm compared to sorafenib arm. In the lenvatinib arm, the most common any-grade adverse events included hypertension (42%), diarrhea (39%), decreased appetite (34%), and decreased weight (31% - Hypothyroidism develops in 18% of patients within two to four months of starting Sorafenib. Obtain a baseline TSH and then monitor levels every six weeks. 35,50 - Increases the incidence of arterial thromboembolic events (1.4%, RR 3.03, p = 0.015). 36 Second-Line Systemic Therapy:
# Lenvatinib (if not received in the first-line)
- There is no level 1 evidence to inform the most effective treatment after atezolizumab plus bevacizumab.
The most common second line therapies received by patients in the IMbrave150 trial were sorafenib (n=31)
# Stereotactic Body Radiotherapy (SBRT)
- There is growing experience with providing ionizing radiotherapy to HCC using very conformal dose distribution, with image guidance and motion management to provide high doses of radiation to the HCC while minimizing exposure to the adjacent liver or other tissues. 53 - SBRT can provide good local control of HCC range (ranging from 43% to 100% at 1 year) which can depend on factors such as lesion size and number, and the delivered radiation dose. It has been used in patients with portal vein invasion 54 and to bridge patients to liver transplantation. 55 - Patients should be discussed at multidisciplinary rounds. SBRT can be considered when alternative therapies such as ablation/embolization techniques have failed or are contraindicated.
- Patients can experience worsening of liver function with SBRT 54 and tolerance to normal liver is the main dose limiting constraint. Most safety evidence is for patients with Child-Pugh class A disease. Evidence is more limited for Child-Pugh class B disease and in practice treatment dose is lowered to reduce the chance of treatment toxicities. Treatment of patients with Child-Pugh class C disease is not recommended as the safety of liver SBRT in this population has not been determined.
- Continued clinical trials in the use of liver SBRT are recommended. Studies evaluating SBRT in combination with sorafenib are currently underway. Enrollment of patients into clinical trials or investigational protocols should be encouraged.
# Terminal Stage HCC
# Patient Requirements:
- Poor performance status (ECOG > 2).
- Decompensated liver function (Child-Pugh class B and C). Goals:
- To maintain or to improve the patient's quality of life (to control tumour-related symptoms). Recommendations:
- Best supportive care .
- Palliative chemotherapy may adversely affect outcome. 56 Appendix A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook.
# This guideline was originally developed in 2009.
Maintenance A formal review of the guideline will be conducted in 2022. If critical new evidence is brought forward before that time, however, the guideline working group members will revise and update the document accordingly.
# Abbreviations | # Background
Cirrhosis represents a diffuse liver disease characterized by structurally abnormal nodules of liver cells surrounded by fibrosis. 1 It results from chronic liver injury and regeneration secondary to chronic viral hepatitis, alcoholic liver disease, metabolic liver diseases (e.g. hemochromatosis, Wilson's disease, α1-antitrypsin deficiency, non-alcoholic steatohepatitis), and autoimmune diseases (e.g. autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis). Cirrhosis is associated with an annual incidence of hepatocellular carcinoma of 3 to 5 percent.
Hepatocarcinogenesis represents a multi-step process in which both genetic abnormalities and epigenetic alterations encourage the malignant transformation of hepatocytes. Hepatocellular carcinomas are associated with up-regulated signal transduction through multiple pathways (e.g. mitogen-activated protein kinase, vascular endothelial growth factor receptor).
Prognosis depends upon the extent of hepatic replacement by the tumour, the α-fetoprotein (AFP) level, the patient's performance status (see Appendix B), the tumour's histologic subtype (e.g.: fibrolamellar variant), and the degree of liver dysfunction (as assessed by the Child-Pugh classification system, see Appendix C).
# Guideline Questions
• What are the goals of therapy and recommendations for the treatment of adult patients with: o very early stage hepatocellular carcinoma? o early stage hepatocellular carcinoma? o intermediate stage hepatocellular carcinoma? o advanced stage hepatocellular carcinoma? o terminal stage hepatocellular carcinoma?
# Search Strategy
This guideline was developed to promote evidence-based practice in Alberta. It was compiled from the results of randomized controlled trials and systematic reviews, derived from an English language and relevant term search of PubMed and MEDLINE from 1990 forward. It takes into consideration related information presented at local, national, and international meetings as well as the Alberta Provincial Gastrointestinal Tumour Team's interpretation of the data. The 2021 update did not necessitate a full literature review; recommendations were modified based on a consensus discussion at the 2020 Annual Gastrointestinal Tumour Team Meeting.
# Target Population
The recommendations outlined in this guideline apply to adults over the age of 18 years with hepatocellular carcinoma (HCC). Different principles may apply to pediatric patients.
The American Association for the Study of Liver Disease (AASLD) promotes routine HCC surveillance for all adult patients with Child-Pugh A or B cirrhosis. 2 Screening and surveillance using liver ultrasound, with or without α-fetoprotein (AFP), is recommended every six months. Patients with Child-Pugh C cirrhosis are not recommended for surveillance due to low anticipated survival unless these patients are on a liver transplant waiting list (see Appendix C for details on Child-Pugh score).
Patients with hepatitis B are also considered at risk; screening is recommended starting at age 40 for Asian males, age 50 for Asian females and age 20 for those of African descent. 2 The American College of Radiology (ACR) has created the Ultrasound Liver Imaging Reporting and Data System (US LI-RADS) algorithm for interpretation and reporting of ultrasound exam results. 3 The US LI-RADS is composed of 3 observational categories and 3 visualization scores, which are summarized in Table 1. An AFP value that exceeds 20 ng/mL is considered positive, while anything lower is considered negative. 3 Noninvasive diagnosis with a multiphase CT scan or a multiphase MRI is recommended by the AASLD. 2 The results should be interpreted and reported through the CT/MRI Liver Imaging Reporting and Data System (CT/MRI LI-RADS) algorithm developed by the ACR. This algorithm allows definitive diagnosis of HCC in high risk patients without pathologic confirmation. 5 The CT/MRI LI-RADS outlines eight diagnostic categories summarized in Table 2. The key imaging features include size ≥ 1 cm, arterial phase hyperenhancement (APHE), and a combination of washout, threshold growth and capsule appearance. 6 If these features are not present but HCC is suspected, then a liver biopsy should be considered. A biopsy should also be considered in patients with a liver mass that is atypical of HCC on contrast-enhanced imaging 2 . If high-grade dysplasia and HCC are not disguisable by routine histology alone, tumour markers glypican-3 (GPC3), heat-shock protein 70 (HSP70) and glutamine synthetase (GS) can be assessed.
# Goals and Recommendations
To define and provide optimal care to a patient with HCC, a multidisciplinary team (MDT) is required.
It should be composed of hepatobiliary surgeons, diagnostic and interventional radiologists, hepatologists/gastroenterologists, and oncologists. Consideration is given to patient factors (e.g. functional status, co-morbidities, liver function) and tumour factors (e.g. size, number, location, vascular invasion).
The Barcelona Clinic Liver Cancer (BCLC) staging system (Table 3) provides a system to define the care for patients with HCC. 7,8 It links the TNM staging system (see Appendix A), the patient's ECOG performance status (see Appendix B), and the patient's liver function (see Appendix C) to treatment options. An algorithm for management of HCC according to the updated AHS clinical practice guideline recommendations is provided (Figure 1).
Consider treatment on a clinical trial, if available. • Well-compensated liver function (Child-Pugh class A). Tumour Requirements: • Solitary tumour (< 2 cm) confined to one lobe of the liver.
• Absence of vascular invasion and extra-hepatic disease.
• Complete removal of the tumour with a margin of ≥ 1 cm anticipated.
# Goals:
• To render patient free of disease and to delay or prevent recurrence. Recommendation:
• Resection. 10 Resection: • In carefully selected patients, five-year survivals of 50 to 70% are anticipated.
• Comparative genomic hybridization reveals that 60 to 70% of recurrences are intra-hepatic metastases and that 30 to 40% are de novo tumour development. • Abnormal bilirubin and portal hypertension (as suggested by thrombocytopenia with platelet count under 100, varices, ascites, and/or splenomegaly) predict for failure to benefit from resection. 11 • If extra-hepatic disease is confirmed at laparotomy, resection is not pursued.
• Intra-operative ultrasound and bi-manual palpation assessment for other intra-hepatic lesions. Intraoperative or subsequent radiofrequency ablation or percutaneous ethanol injection 12,13 can be considered for multicentric disease. • No clear benefit has been established for adjuvant therapy post-resection. In fact, adjuvant chemotherapy may adversely affect the outcome, especially in cirrhotic patients. 14,15 Sorafenib was of no benefit as adjuvant therapy following curative intent resection or radiofrequency ablation (STORM study). 16 • In patients who are not candidates for surgical resection, radiofrequency ablation (see below) can offer a 97% complete response for tumours ≤ 2 cm with long-term survival similar to what has been reported in patients who have undergone resection. 17 • Three randomized controlled trials comparing surgical resection to RFA have been performed in China.
Although the studies had methodological flaws (cross-over between groups), similar outcomes were reported in two studies 18,19 whereas one study demonstrated improved recurrence-free and overall survival in the surgical resection group. 20 Follow-Up: To identify recurrence, obtain a contrast enhanced CT scan, MR, or ultrasound of the abdomen every three months for two years and then every six months thereafter. Obtain an AFP every three months for two years and then every six months thereafter. 21
# Early Stage HCC
Patient Requirements:
• Good performance status (ECOG 0).
• Well-compensated liver function (Child-Pugh class A). Tumour Requirements: • Solitary tumour confined to one lobe of liver or three nodules (all ≤ 3 cm)
• Absence of vascular invasion and extra-hepatic disease.
• Complete removal of the tumour(s) with a margin of ≥ 1 cm anticipated. Goals:
• To render patient free of disease and to delay or prevent recurrence. Recommendations:
• Resection (see above), liver transplantation (see below), or ablation 12 (see below). Liver Transplantation:
•
Removes the cancer and corrects the underlying "field defect" (cirrhosis) but subjects the patient to the potential complications of long-term immunosuppression. • Offers a five-year disease-free survival of up to 70% and a short-term mortality of up to 10%.
• In Alberta, transplantation is contraindicated if the total tumour volume (TTV) exceeds 115 cm 3 , the alphafetoprotein exceeds 400 ng/mL, vascular invasion and/or extra-hepatic disease exist, or significant comorbidities exist. • Patients may be considered for liver transplantation after being "down-staged" if their initial total tumour volume was under 250 cm 3 and both the total tumour volume and the AFP remain under 115 cm 3 and 400 ng/mL, respectively, for more than six months. 22,23
# Radiofrequency Ablation (RFA) or Percutaneous Ethanol Injection (PEI):
• Provides tumour control pending transplantation or as an adjunct or alternative to resection.
• Recent series of radiofrequency ablation report local recurrence rates under 5% and five-year survivals equal to resection. Radiofrequency ablation requires fewer sessions to ablate tumours and results in improved survival when compared to percutaneous ethanol injection. 24 • Survival rates with radiofrequency ablation may be similar to surgical resection; 18 however, two-year recurrence rates are higher following percutaneous ethanol injection and radiofrequency ablation than with resection. 25 • Best outcomes are achieved from radiofrequency ablation when tumours are centrally located, measure under 3 cm, and are distant from "heat sinks" (blood vessels). 11 Consider percutaneous ethanol injection or transarterial chemo-embolization (TACE) when tumours are in a subcapsular location, exceed 4 cm, or are located adjacent to blood vessels. • Hepatocellular carcinomas are considered "treated" only if the imaging study demonstrates complete tumour necrosis (without contrast enhancement to suggest residual disease).
# Intermediate Stage HCC
# Patient Requirements:
• Good performance status (ECOG 0-1).
• Well-compensated liver function (Child-Pugh class A) and only select patients with impaired liver function (Child-Pugh class B 7). Tumour Requirements:
• Multinodular disease.
• Absence of extra-hepatic disease.
• Patency of the main portal vein (as assessed by ultrasound Doppler or MR angiography) for TACE.
• Adequate renal function.
# Goals:
• To maintain or to improve the patient's quality of life (to control or to delay the onset of tumour-related symptoms, possibly while awaiting transplant).
• To prolong life, if possible. Recommendations:
• Transarterial chemo-embolization [26][27][28][29][30] or transarterial radioembolization. [31][32][33][34] Consider palliative care if not an LT candidate.
# Transarterial Chemo-Embolization (TACE):
• Blood supply to hepatocellular carcinomas is preferentially derived from the hepatic artery rather than the portal vein. • Involves placement of an intravascular catheter into the hepatic artery (inserted percutaneously in the femoral artery and advanced through the abdominal aorta and celiac trunk). Injection of chemotherapy (with or without the oily contrast agent, Lipiodol) followed by embolic agents (e.g.: gelatin-sponge particles, Embosphere ® ) occludes the relevant branch of the hepatic artery and localizes the chemotherapy. Metaanalyses of randomized controlled trials demonstrate a survival benefit of TACE. 35,36 Drug-eluting beads (DEBs) decrease the systemic exposure to doxorubicin. 37 Although DEBs have not been shown to be superior to conventional TACE, they offer a more standardized technique and are better tolerated with fewer complications. 29 Recent cohort studies are demonstrating median survival of 4 years after TACE with DEBs in carefully selected patients. 30 Transarterial Radioembolization (TARE):
• TARE or selective internal radiotherapy (SIRT) uses microspheres loaded with yttrium-90 (Y 90 ) to deliver radiation directly into the tumour via the hepatic artery. Unlike TACE it is done as an outpatient. Prior to the TARE, the patient requires a staging angiogram to calculate the liver-to-lung shunt fraction in Nuclear Medicine using technicium-99 macro-aggregated albumin (Tc 99 MAA). At the same time selective embolization of the gastroduodenal arteries is carried out to prevent delivery of radiation to the stomach and duodenum. The procedure may be repeated depending upon response.
• A meta-analysis 38 and large cohort studies from Europe 31 and the USA 32 have shown similar survival to TACE in BCLC stage B patients. However, a separate meta-analysis showed superior survival with TACE in unresectable patients. 39 • TARE, unlike TACE, can be performed safely in patients with portal vein thrombosis, as the microspheres used in TARE are smaller and less embolic. 31,32 • TARE may be considered for patients who have progressive disease after TACE, who cannot tolerate doxorubicin or who are likely to fail TACE (large HCC).
• TARE may also be more effective than TACE in bridging or down-staging patients to liver transplantation. 33,35 •
Outcomes following TARE are best in patients with preserved liver function (Child-Pugh score <8 or MELD score <13). 34 Patients should be selected for TARE at MDT meetings.
• As there remains uncertainty about TARE efficacy compared to TACE (intermediate stage) or sorafenib (advanced stage), clinical trials are encouraged.
# Advanced Stage HCC
Patient Requirements:
• Good performance status (ECOG 0 or 1).
• Well-compensated liver function (Child-Pugh class A). Tumour Requirements:
• Disease ineligible for, or that progressed after, surgical or locoregional therapy. Goals:
• To maintain or to improve the patient's quality of life (to control or to delay the onset of tumour-related symptoms). • To prolong life, if possible.
# Recommendations:
• First-line treatment: Atezolizumab-Bevacizumab , or participation in a clinical trial 36 First-Line Systemic Therapy:
Atezolizumab-Bevacizumab (Preferred, Type of recommendation: evidence based, benefits outweigh harms; Evidence quality: moderate to high; Strength of recommendation: strong) 42 • Atezolizumab-bevacizumab was compared to sorafenib in the open-label phase 3 IMbrave150 trial. 43 Hazard ratio for death was 0.58 (95%CI: 0.42-0.79; p<0.001) in favor of atezolizumab-bevacizumab. Last revision: August, 2021
Additionally, hazard ratio for disease progression or death was superior in the atezolizumab-bevacizumab arm (HR: 0.59; 95%CI: 0.47-0.76; p<0.001). Overall survival at 12 months was 67% (95%CI: 61.3 to 73.1%) in the atezolizumab-bevacizumab arm compared to 54.6% (95%CI: 45.2-64.0%) in the sorafenib arm. An updated survival analysis showed median overall survival was 19.2 mo with atezolizumab-bevacizumab vs 13.4 months with sorafenib (HR, 0.66 [95% CI, 0.52, 0.85]; P=0.0009) 44 • Grade 3 or 4 adverse events occurred in 56.5% of atezolizumab-bevacizumab patients (n=329) and 55.1% of the sorafenib patients (n=156). Grade 3 or 4 hypertension occurred in 15.2% of atezolizumabbevacizumab group, however, other high-grade toxic effects were infrequent. • Treatment with Atezolizumab-Bevacizumab reduced the risk of deterioration in quality of life compared to sorafenib. 45 • Patients had an ECOG of 0-1, no contraindications to immunotherapy and were not at risk for bleeding. An EGD is strongly recommended within 6 months prior to starting therapy and any varices should be treated (especially if the transient elastography (FibroScan®) >20 kPa or if the platelet count is <150. 46 Patients with incompletely treated varices should not be treated with this combination. • Atezolizumab-Bevacizumab is not currently funded in Alberta
In those patients where Atezolizumab-Bevacizumab is not appropriate/contraindicated: Lenvatinib (Type of recommendation: evidence based, benefits outweigh harms; Evidence quality: moderate to high; Strength of recommendation: strong) • Lenvatinib was shown to be non-inferior to sorafenib for overall survival in an open-label, phase 3, multicenter, non-inferiority trial in patients with unresectable hepatocellular carcinoma, who had not received treatment for advanced disease (median OS 13.6m lenvatinib vs 12.3m sorafenib, respectively, HR: 0.92, 95%CI: 0.79-1.06). Patients had Child Pugh A liver function, and ECOG 0-1. 47 • It is worth noting that lenvatinib was superior to sorafenib in terms of progression-free survival (7.4m vs 3.7m, respectively, HR: 0.66, 95%CI: 0.57-0.77, p<0.001). Objective response rates were also higher in the lenvatinib group (24.1% vs. 9.2%, respectively, p<0.001). • Treatment-related adverse events of grade 3 or higher occurred in 57% of patients treated with lenvatinib and 49% with sorafenib. Rates of hand-foot syndrome are lower in the lenvatinib arm compared to sorafenib arm. In the lenvatinib arm, the most common any-grade adverse events included hypertension (42%), diarrhea (39%), decreased appetite (34%), and decreased weight (31% • Hypothyroidism develops in 18% of patients within two to four months of starting Sorafenib. Obtain a baseline TSH and then monitor levels every six weeks. 35,50 • Increases the incidence of arterial thromboembolic events (1.4%, RR 3.03, p = 0.015). 36 Second-Line Systemic Therapy:
# Lenvatinib (if not received in the first-line)
• There is no level 1 evidence to inform the most effective treatment after atezolizumab plus bevacizumab.
The most common second line therapies received by patients in the IMbrave150 trial were sorafenib (n=31)
# Stereotactic Body Radiotherapy (SBRT)
• There is growing experience with providing ionizing radiotherapy to HCC using very conformal dose distribution, with image guidance and motion management to provide high doses of radiation to the HCC while minimizing exposure to the adjacent liver or other tissues. 53 • SBRT can provide good local control of HCC range (ranging from 43% to 100% at 1 year) which can depend on factors such as lesion size and number, and the delivered radiation dose. It has been used in patients with portal vein invasion 54 and to bridge patients to liver transplantation. 55 • Patients should be discussed at multidisciplinary rounds. SBRT can be considered when alternative therapies such as ablation/embolization techniques have failed or are contraindicated.
• Patients can experience worsening of liver function with SBRT 54 and tolerance to normal liver is the main dose limiting constraint. Most safety evidence is for patients with Child-Pugh class A disease. Evidence is more limited for Child-Pugh class B disease and in practice treatment dose is lowered to reduce the chance of treatment toxicities. Treatment of patients with Child-Pugh class C disease is not recommended as the safety of liver SBRT in this population has not been determined.
• Continued clinical trials in the use of liver SBRT are recommended. Studies evaluating SBRT in combination with sorafenib are currently underway. Enrollment of patients into clinical trials or investigational protocols should be encouraged.
# Terminal Stage HCC
# Patient Requirements:
• Poor performance status (ECOG > 2).
• Decompensated liver function (Child-Pugh class B and C). Goals:
• To maintain or to improve the patient's quality of life (to control tumour-related symptoms). Recommendations:
• Best supportive care [Link].
• Palliative chemotherapy may adversely affect outcome. 56 Appendix A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook.
# This guideline was originally developed in 2009.
Maintenance A formal review of the guideline will be conducted in 2022. If critical new evidence is brought forward before that time, however, the guideline working group members will revise and update the document accordingly.
# Abbreviations
| None | None |
5d072b204f46d05165f40da31c898e6b0e5e5b2b | cma | None | This document was developed by Ontario Health's COVID-19 Therapeutics Interim Working Group based on best available evidence and expert consensus. There are limitations to the evidence that is currently available. Prescribers must determine whether adopting suggested information is clinically appropriate for individual patients through a risk-benefit assessment.# Background
During the COVID-19 pandemic in Ontario, the Ontario COVID-19 Science Advisory Table prepared and maintained guidance on the therapeutic management of adult patients with COVID-19. Health care providers have used this guidance, along with criteria from the Ministry of Health, to determine which patients would benefit from receiving nirmatrelvir/ritonavir (Paxlovid) to prevent severe illness due to COVID-19. As of fall 2022, the Ontario COVID-19 Science Advisory Table has been dissolved, and their guidance on the therapeutic management of COVID-19 will no longer be updated.
In fall 2022, Ontario Health established a COVID-19 Therapeutics Interim Working Group (Appendix A) to provide guidance and advice to Ontario Health and the Ministry of Health on priority issues regarding the appropriate use of therapeutics for COVID-19 infection. The first priority issue to be addressed by the Working Group relates to updating the recommendations on which patients would benefit from receiving nirmatrelvir/ritonavir (Paxlovid).
The following consensus-based recommendation was informed by a primary literature review and jurisdictional scan (Appendix B). Prescribers must determine whether adopting suggested information is clinically appropriate for individual patients through a risk-benefit assessment.
# Recommendation
Paxlovid should be strongly considered for individuals who have a confirmed COVID-19 diagnosis (based on positive PCR, rapid molecular, or rapid antigen test result), present within 5 days of symptom onset, and meet one or more of the following criteria:
- The individual is 60 years of age or older;
- The individual is 18 years of age or older and is immunocompromised;
- The individual is 18-59 years old and is at higher risk of severe COVID-19. Patients at higher risk of severe COVID-19 include:
- Those who have one or more comorbidity that puts them at higher risk of severe COVID-19 disease OR
- Those with inadequate immunity, i.e.:
- Unvaccinated or incomplete primary series OR o Completed primary series AND last COVID-19 vaccine dose was more than 6 months ago AND last SARS-CoV-2 infection was more than 6 months ago Social determinants of health may confer an increased risk of disease progression. Individuals who are at a higher risk of poor outcomes from COVID-19 infection based on social determinants of health should be considered priority populations for access to Paxlovid. Individuals at higher risk include Indigenous people, Black people, other members of racialized communities, individuals with intellectual, developmental, or cognitive disability, people who use substances regularly (e.g. alcohol), people who live with mental health conditions, and people who are underhoused.
Note: Combinations of risk factors are associated with higher risk of severe COVID-19.
# Additional resources
Visit the Ontario Health COVID-19 treatment website for the latest resources on Paxlovid and other COVID-19 therapeutics.
# Appendix B: References
The following resources informed these recommendations: | This document was developed by Ontario Health's COVID-19 Therapeutics Interim Working Group based on best available evidence and expert consensus. There are limitations to the evidence that is currently available. Prescribers must determine whether adopting suggested information is clinically appropriate for individual patients through a risk-benefit assessment.# Background
During the COVID-19 pandemic in Ontario, the Ontario COVID-19 Science Advisory Table prepared and maintained guidance on the therapeutic management of adult patients with COVID-19. Health care providers have used this guidance, along with criteria from the Ministry of Health, to determine which patients would benefit from receiving nirmatrelvir/ritonavir (Paxlovid) to prevent severe illness due to COVID-19. As of fall 2022, the Ontario COVID-19 Science Advisory Table has been dissolved, and their guidance on the therapeutic management of COVID-19 will no longer be updated.
In fall 2022, Ontario Health established a COVID-19 Therapeutics Interim Working Group (Appendix A) to provide guidance and advice to Ontario Health and the Ministry of Health on priority issues regarding the appropriate use of therapeutics for COVID-19 infection. The first priority issue to be addressed by the Working Group relates to updating the recommendations on which patients would benefit from receiving nirmatrelvir/ritonavir (Paxlovid).
The following consensus-based recommendation was informed by a primary literature review and jurisdictional scan (Appendix B). Prescribers must determine whether adopting suggested information is clinically appropriate for individual patients through a risk-benefit assessment.
( )
# Recommendation
Paxlovid should be strongly considered for individuals who have a confirmed COVID-19 diagnosis (based on positive PCR, rapid molecular, or rapid antigen test result), present within 5 days of symptom onset, and meet one or more of the following criteria:
• The individual is 60 years of age or older;
• The individual is 18 years of age or older and is immunocompromised;
• The individual is 18-59 years old and is at higher risk of severe COVID-19. Patients at higher risk of severe COVID-19 include:
• Those who have one or more comorbidity that puts them at higher risk of severe COVID-19 disease OR
• Those with inadequate immunity, i.e.:
o Unvaccinated or incomplete primary series OR o Completed primary series AND last COVID-19 vaccine dose was more than 6 months ago AND last SARS-CoV-2 infection was more than 6 months ago Social determinants of health may confer an increased risk of disease progression. Individuals who are at a higher risk of poor outcomes from COVID-19 infection based on social determinants of health should be considered priority populations for access to Paxlovid. Individuals at higher risk include Indigenous people, Black people, other members of racialized communities, individuals with intellectual, developmental, or cognitive disability, people who use substances regularly (e.g. alcohol), people who live with mental health conditions, and people who are underhoused.
Note: Combinations of risk factors are associated with higher risk of severe COVID-19.
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# Additional resources
Visit the Ontario Health COVID-19 treatment website for the latest resources on Paxlovid and other COVID-19 therapeutics.
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# Appendix B: References
The following resources informed these recommendations: | None | None |
8b2f754803d50bea3f879d2317d7ae39c0a6f04d | cma | None | Clinical practice guideline: evidence, recommendations and algorithm for the preoperative optimization of anemia, hyperglycemia and smoking F or most of the 20th century, the focus of research in surgery was improvements in intraoperative technique, which led to major technical paradigm shifts exemplified by the evolution of transurethral resection of the prostate, 1 laparoscopic cholecystectomy, 2 endovascular aneurysm repair 3 and total mesorectal excision for rectal cancer, 4 among many others. The late 1990s and early 2000s marked a shift in surgical research toward the evidencebased management of patients in the perioperative period, beginning with the Enhanced Recovery After Surgery Group's systematic review of patients undergoing colorectal surgery. 5 That publication introduced a new paradigm focused on the impact that standardized perioperative care could have on patient outcomes such as length of stay, postoperative pain and overall complication rates. 6,7 Although a large body of literature now exists to help guide the intraoperative and perioperative management of surgical patients, our working group believes that the preoperative period, which we define as the 8 weeks#
Preoperative optimization has not been explored comprehensively in the sur gic al literature, as this responsibility has often been divided among surgery, anesthesia and medicine. We developed an evidence-based clinical practice guideline to summarize existing evidence and present diagnostic and treatment algorithms for use by surgeons caring for patients scheduled to undergo major elective surgery. We focus on 3 common comorbid conditions seen across surgical specialties -anemia, hyperglycemia and smoking -as these conditions increase complication rates in patients undergoing major surgery and can be optimized successfully as soon as 6-8 weeks before surgery. With the ability to address these conditions earlier in the patient journey, surgeons can positively affect patient outcomes. The aim of this guideline is to bring optimization in the preoperative period under the existing umbrella of evidence-based surgical care. L'optimisation préopératoire n'a pas été explorée de manière exhaustive dans la littérature chirurgicale, car cette responsabilité a souvent été divisée entre la chirurgie, l'anesthésie et la médecine. Cette ligne directrice de pratique clinique fondée sur des données probantes a été conçue pour résumer les données existantes et présenter des algorithmes diagnostics et thérapeutiques relatifs à des comorbidités fréquentes chez les patients vus dans toutes les spécialités chirur gicales. L'accent a été placé sur l'optimisation préopératoire de l'anémie, de l'hyperglycémie et du tabagisme, étant donné que ces problèmes de santé accroissent le risque de complications chez les patients qui doivent subir une chi rur gie majeure et qu'il est possible de les corriger en bonne partie dans les 6-8 semaines précédant la chirurgie. Or, si les chirurgiens arrivent à corriger ces problèmes de santé plus tôt dans le parcours des patients, ils pourraient améliorer leurs résultats. Le but de cette ligne directrice est que l'optimisation préopératoire soit intégrée à l'ensemble actuel des soins chirurgicaux fondés sur des données probantes. preceding elective surgical procedures, is an area of inquiry that remains under explored in surgical literature. This "orphan" period in the care of a surgical patient exists for many reasons. The preoperative period has not traditionally been the responsibility of any single clinical specialty, with care often divided among surgeons, anesthetists and internists. As a result, there is little in the way of a standardized, evidence-based approach to the identification and treatment of comorbid conditions that could be effectively optimized in the preoperative period to improve patient outcomes.
In this evidence-based clinical practice guideline, we summarize existing evidence and present diagnostic and treatment algorithms for use by surgeons caring for patients undergoing major elective surgery. We focus on 3 common comorbid conditions seen across surgical specialties -anemia, hyperglycemia and smoking -and present evidence of improved patient outcomes with optimization strategies started as soon as 6-8 weeks before surgery.
The evidence presented here points to a new paradigm shift in the way multidisciplinary teams care for patients undergoing elective surgery, bringing the preoperative period under the existing umbrella of evidence-based surgical care.
# Literature search
Our search strategy for anemia is presented in Appendix 1 (available at canjsurg.ca). A similar search strategy was used for hyperglycemia and for smoking, with lines 1 and 3 changed to reflect the different components. We determined the strength of recommendations and the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. 8 Recommendations were developed by 2 reviewers for each subject area (anemia and diabetes: J.A.G. and T.M.Z., smoking: J.S. and J.A.G.). Disagreements were resolved by a third reviewer (H.M.).
# anemia
The prevalence of preoperative anemia is high. In 2 large studies of patients undergoing noncardiac surgery (n = 319 703), preoperative anemia was identified in 28%-30% of patients across multiple specialties. 9,10 In certain surgical specialties, the prevalence approaches half of all patients, as seen in colorectal surgery (40.4%-47.4%), 11,12 orthopedic surgery (25%-44%) and urology (8%-45%). 16 According to the World Health Organization (WHO), a prevalence of anemia greater than 40% in a population has severe health consequences, and, therefore, anemia should be an essential consideration in most surgical patients. 17 The WHO defines anemia as a hemoglobin level less than 120 g/L in women and less than 130 g/L in men. 18,19 These definitions have been validated by large population studies examining mean hemoglobin values by age, race and sex. 20 A second definition of anemia is a hematocrit value less than 0.39 for both sexes, which has also been vali dated in large database studies. 9,11 The WHO estimates a prevalence of anemia of 29.4% among all women of reproductive age, 18 which makes anemia an underrecognized condition warranting consideration even in young, healthy populations.
Anemia may be caused by chronic inflammatory conditions, kidney disease, malnutrition, ongoing small-volume blood loss and iron deficiency. Iron-deficiency anemia (IDA) is widely accepted to be the most common cause, and, in a recent study of 3342 patients undergoing gynecologic, urologic, colorectal, cardiac or orthopedic surgery, almost two-thirds (62%) of patients with preoperative anemia had some component of IDA. 21 In patients with cancer, chronic bleeding from gastrointestinal tumours can also contribute to preoperative anemia. Given the increased incidence of most surgical conditions with increasing age, the mean age of surgical patients is older than that of other cohorts and is associated with an increased prevalence of anemia. 20,22 Unlike in the general population, the cause of anemia in older patients is multifactorial in almost two-thirds of cases. 25 Several centres have reported improved postsurgical outcomes through preoperative diagnosis of anemia and treatment plans. These outcomes include shorter length of hospital stay, 15,26 decreased rates of postoperative nosocomial infections, 26 decreased 90-day readmission rates 15 and lower rates of blood transfusion. 15, The following clinical practice guideline summarizes the current evidence informing the recommendations within the proposed diagnostic and treatment algorithm for preoperative anemia (Figure 1).
# Recommendations
# Preoperative anemia is associated with adverse sur-
gical outcomes, and all patients undergoing major surgery should be screened for anemia at their first surgical clinic visit and investigated further, as appropriate (Table 1). Preoperative anemia was shown to be an independent risk factor associated with increased 1-year and overall mortality in 319 703 patients undergoing noncardiac surgery (adjusted hazard ratio 2.86, 95% confidence interval 2.56-3.20, and odds ratio 1.42, 95% CI 1.31-1.54, respectively). 9,10 In a propensity-matched cohort of 7759 patients undergoing noncardiac surgery, an independ ent association between preoperative anemia and increased 90-day mortality was shown (OR 2.29, 95% CI 1.45-3.63). 29 A National Surgical Quality Improvement Program (NSQIP) study of 5081 patients undergoing vascular surgery showed increased mortality for both moderate (OR 2.6, 95% CI 1.2-5.5) and severe (OR 2.8, 95% CI 1.3-6.3) anemia. 30 Preoperative anemia is independently associated with early postoperative complications such as increased overall 30-day postoperative morbidity in patients under going noncardiac surgery (OR 1.35, 95% CI 1.30-1.40), 9 increased rates of major cardiac events (5.1%-6.8% v. 2.6%; p = 0.001) and acute kidney injury (52.0%-63.2% v. 31.0%; p = 0.01) in patients undergoing vascular surgery, 30,31 and increased infectious complication rates in patients undergoing orthopedic surgery (57.1% v. 6.3%; p = 0.006) 32 and those with gastric cancer (OR 3.70, 95% CI 1.43-9.58). 33 In a large NSQIP database study, preoperative anemia in patients undergoing colorectal surgery was independently associated with a significantly increased frequency of composite outcome events (myocardial infarction, acute renal injury, stroke and death) that was proportional to anemia severity (mild: OR 1. 49 11 Preoperative anemia was independently associated with significant increases in length of postoperative hospital stay in a systematic review of orthopedic literature, 13 a retrospective analysis of 2394 patients who underwent total knee arthroplasty (OR 1.71-2.29; p < 0.001) 14 and an NSQIP study of 23 348 patients who underwent colorectal surgery (0.5-2.2 d longer; p < 0.01). 11 Unsurprisingly, preoperative anemia is independently associated with significantly increased rates of postoperative blood transfusion. This association has been shown after urologic (OR 6.28, 95% CI 3.43-11.51), 34 colorectal (24% v. 3%) 35 and orthopedic (OR 4.13-9.13; p < 0.001) 14 procedures. Compared to anemic values, a normal preoperative hemoglobin value was shown to significantly reduce the likelihood of transfusion after laparoscopic colorectal resection (HR 0.547, 95% CI 0.468-0.637). 36 Finally, preoperative anemia is independently associated with worse oncologic outcomes in patients with urologic, gastric, colorectal or mesenchymal cancer, with decreased disease-free survival, 37,38 cancer-specific survival 39,40 and overall survival, 39, and increased rates of cancer recurrence. 40,44 2. Complete blood count and ferritin are the most appropriate screening blood tests. Hemoglobin levels, as determined by a complete blood count, represent the gold standard diagnostic test for anemia. This was established through a series of reports published by the WHO between 1968 and 2015 in which the normal hemoglobin ranges for adult and pediatric popu lations (by sex) were determined and the definitions of anemia refined. Large population-based studies examining mean hemoglobin values by age, race and sex further validated the accepted normal ranges and the use of hemoglobin level to diagnose anemia. 20 The hematocrit, as determined by a complete blood count, has also been validated as an indicator of anemia in more recent large database studies, such as those using NSQIP data. 9,11,49 Iron-deficiency anemia is the most common cause of anemia in surgical patients and should be assessed as part of the initial investigation. 21, In a meta-analysis of 55 studies, Guyatt and colleagues 53 compared several blood tests to the gold standard for the diagnosis of IDA (absence of stainable iron in a bone marrow aspirate). They found the serum ferritin radioimmunoassay to be the most reliable test for the diagnosis of IDA, with an area under the ROC curve of 0.95. Although the radioimmunoassay is no longer commonplace, equivalence has been shown between this assay and the enzyme-linked immunoassays that are more common today, with an intraclass correlation coefficient of at least 0.98, which implies that the tests are interchangeable. 54 A serum ferritin level less than 30 μg/L has been shown to be both sensitive (92%) and specific (98%) for the diagnosis of IDA. The diagnostic utility of serum ferritin level as an effective first-line test for IDA was reaffirmed in more recent reviews on the topic. 47,55,58 3. Patients without evidence of anemia should not be treated with iron supplementation. Pratt and Khan 59 advocated consideration of iron supplementation for patients with nonanemic iron deficiency. However, currently there is insufficient evidence of clinical benefit to recommend treatment for patients with a preoperative hemoglobin level greater than 130 g/L for men or greater than 120 g/L for women. Although the rate of serious toxic effects related to oral iron supplementation is low, gastrointestinal adverse effects are common. 60 Therefore, given the low potential for benefit and high probability of adverse effects, this therapy should not be recommended for patients without evidence of anemia.
# For patients with anemia and a serum ferritin level
-f 30-100 ng/mL, transferrin saturation index and C-reactive protein tests should be ordered to better determine the presence of iron deficiency. In cases in which anemia is diagnosed but the serum ferritin level is nondiagnostic (30-100 ng/mL), 2 tests should be added to confirm IDA: measurement of the transferrin saturation index and the C-reactive protein level. 56,58 In the context of anemia with a serum ferritin level of 30-100 ng/mL, a transferrin saturation index less than 20% implies inadequate iron for normal erythropoiesis and is therefore strongly suggestive of IDA. 51,56,58 Serum ferritin is known to be an acute-phase reactant, 61,62 and the level can rise with increasing age. 20,62 Therefore, in the context of anemia with a serum ferritin level of 30-100 ng/mL, a C-reactive protein level greater than 5 mg/L is consistent with an inflammatory state and falsely elevated serum ferritin levels, and is therefore strongly suggestive of IDA. 51,56,58 5. Oral iron supplementation is the preferred treatment for patients with IDA and no contraindications (i.e., ≥ 8 wk until surgery, able to tolerate/ absorb oral iron formulation, hemoglobin level ≥ 100 g/L). A randomized controlled trial (RCT) involving 90 older inpatients with IDA showed significant increases in mean hemoglobin level after 60 days of treatment with low-, medium-or high-dose oral iron supplementation (increases of 13 g/L, 14 g/L and 14 g/L, respectively; p < 0.001 for all dosages). 63 In a multicentre RCT involving 46 patients with inflammatory bowel disease and IDA, an oral iron regimen administered for 6 weeks resulted in a mean increase in hemoglobin level of 21 g/L, which was not significantly different from that in patients receiving intravenous iron infusions. 64 In an RCT involving 45 patients awaiting resection for colon or rectal cancer, 2 weeks of oral iron treatment resulted in significantly higher hemoglobin levels at the time of surgery (mean 131 g/L v. 118 g/L; p = 0.04), 65 and a second prospective study in 58 similar patients showed a significant increase in preoperative hemoglobin level (+17.3 g/L; p < 0.001) after an average of 39 days of oral iron treatment. 66 Owing to the demonstrated effectiveness of oral iron therapy, and the lower cost and ease of administration for both the patient and the health care system, most blood management strategies recommend oral iron supplementation as first-line treatment for patients with IDA with no contraindications. 15,51,53,67 Although many dosages have been found to be effective, there is evidence to suggest that lower dosages (e.g., elemental iron equivalent of 40-60 mg orally daily or 80-100 mg orally every 2 d) are associated with fewer adverse effects such as abdominal discomfort, nausea, vomiting and changes in bowel habits. 51,63,68 A recent summary of evidence regarding the safety of oral iron supplementation did not identify any major safety concerns, although adverse effects such as nausea, heartburn, pain, and constipation or diarrhea are more common with oral formulations than with intravenous iron infusions. 69
# Intravenous iron infusions may be appropriate for
patients with IDA in certain circumstances (i.e., < 8 wk until surgery, unable to tolerate/absorb oral iron formulation, hemoglobin level < 100 g/L). In an RCT involving 76 patients with menorrhagia and severe IDA comparing 3 weeks of intravenous versus oral iron supplementation, intravenous iron supplementation was associated with a larger increase in posttreatment hemoglobin levels (mean +30 g/L v. +8 g/L; p < 0.001) and ferritin levels (mean +170.1 μg/L v. +4.1 μg/L; p < 0.001), and a higher frequency of reaching a target hemoglobin level of 100 g/L or greater (76.7% v. 11.5%; p < 0.001). 70 A prospective trial involving 266 patients with colon cancer receiving intravenous versus oral iron supplementation showed that intravenous iron supplementation was associated with a significantly shorter mean length of stay (8.4 d v. 10.9 d ; p < 0.001), lower frequency of transfusion (9.9% v. 38.7%, p < 0.001]), and larger increases in preoperative (+15 g/L v. +5 g/L; p < 0.001) and 30-day postoperative (+31 g/L v. +15 g/L; p < 0.001) hemoglobin levels. 71 In addition, patients receiving iron intravenously had a higher rate of normalized hemoglobin 30 days postoperatively (40% v. 26.7%; p < 0.05). In a multicentre RCT involving 116 patients undergoing elective surgery for colorectal cancer, the mean increase in total hemoglobin level was significantly greater with intravenous than oral iron therapy (+15.5 g/L v. +5.0 g/L; p < 0.001), and a smaller proportion of patients in the intravenous iron group were anemic at the time of surgery (75% v. 90%; p = 0.048). 72 These findings are consistent with those of a systematic review of 8 low-bias RCTs showing that patients with IDA preoperatively may have earlier and more robust recovery of the hemoglobin level with intravenous iron therapy than with oral supplementation. 73 In a prospective RCT, 72 patients with IDA were randomly allocated to receive intravenous iron supplementation versus usual care within 3 weeks before elective abdominal surgery. 74 Increases in hemoglobin level were significantly higher in the intravenous iron group preoperatively and 4 weeks after discharge (+8 g/L v. +1 g/L, p = 0.01; and 19 g/L v. 9 g/L, p = 0.01, respectively), with a significant associated reduction in postoperative allogenic blood transfusion (12.5% v. 53%; p < 0.001). Finally, a retrospective review of 318 patients with colorectal cancer and anemia who received intravenous iron treatment less than 6 weeks before surgery showed a significantly greater increase in hemoglobin level compared to no treatment (+10.5 g/L v. +1.6 g/L; p < 0.001). 75 Two studies have shown the utility of intravenous iron infusion for patients with anemia with minimal time until surgery. An RCT in 108 patients undergoing bilateral total knee replacement showed that, compared to no infusions, intraoperative intravenous infusions of iron and erythropoietin resulted in significantly higher hemoglobin levels in the first, second and sixth weeks postoperatively, and a significantly lower rate of blood transfusion (20.4% v. 53.7%; p = 0.01). 76 In a retrospective analysis of 2547 patients at risk for severe postoperative anemia who underwent major orthopedic surgery, compared to standard treatment, intravenous iron treatment at any time from 5 days preoperatively to 3 days postoperatively was associated with a sig-nificantly lower rate of postoperative nosocomial infections (10.7% v. 26.9%; p = 0.001) and shorter length of stay (11.9 d v. 13.4 d; p = 0.001), independent of transfusion status; the proportion who received transfusions was also lower (32.4% v. 48.8%; p = 0.001). 26 The safety of intravenous iron therapy is comparable to that of oral iron therapy, as shown in a systematic review of 8 low-bias RCTs and a prospective study of 266 patients that showed no deaths, hypersensitivity reactions or other serious drug reactions. 71,73 In addition to being safe, intravenous iron treatment is rarely associated with the adverse gastrointestinal effects seen with oral iron supplementation, which results in increased compliance with intravenous treatment. 28,70 7. For patients with anemia who have no evidence of IDA or IDA refractory to iron supplementation, referral to a hematologist should be considered for treatment with erythropoietin and intravenous iron infusions. In a systematic review of 8 low-bias RCTs, Lin and colleagues 73 concluded that a short preoperative course of erythropoietin or a single dose of erythropoietin plus intravenous iron infusion pre-or intraoperatively may reduce transfusion requirements significantly, with a number needed to treat to avoid allogenic blood transfusion of 3-6. In an RCT involving 201 patients with undifferentiated anemia scheduled to undergo hip arthroplasty, participants were randomly allocated to receive 4 weeks of high-dose erythropoietin with oral iron therapy, low-dose erythropoietin with oral iron therapy, or placebo; there was a significant dose-proportional reduction in the blood transfusion rate (11.4%, 22.8% and 44.9%, respectively; p < 0.003) and increase in the preoperative hemoglobin level (+19.5 g/L, +17.2 g/L and +1.2 g/L, respectively; p < 0.001). 77 In an RCT in which 74 patients with anemia undergoing valvular heart surgery were randomly allocated to receive erythropoietin and intravenous iron infusion or placebo 1 day before surgery, the intervention was associated with was a significant reduction in the rate of blood transfusion (59% v. 86%; p = 0.009), with a number needed to treat to avoid allogenic blood transfusion of 4, as well as a reduction in the mean number of units of packed red blood cells transfused per patient (3.3 78 In an RCT involving 108 iron-deficient patients undergoing bilateral total knee replacement, compared to standard care, administration of erythropoietin and intravenous iron infusion intraoperatively resulted in a significantly lower perioperative transfusion rate (20.4% v. 53.7%; p = 0.01), significantly fewer units of packed red blood cells transfused per patient (mean 0.2 v. 0.8 ; p = 0.005), and significantly higher hemoglobin levels 1, 2 and 3 days, and 2 and 6 weeks postoperatively. 76 Finally, in a retrospective study involving 412 patients with IDA who underwent elective orthopedic surgery, Basora and colleagues 79
v. 1.0 ; p = 0.001).
# E497
compared those who received intravenous iron treatment alone to those who received intravenous iron treatment and erythropoietin preoperatively and found a significantly greater increase in the preoperative hemoglobin level with the latter treatment (+15 g/L v. +8 g/L; p < 0.01).
A safety/noninferiority RCT involving 680 patients undergoing spinal surgery showed a significantly increased risk of deep vein thrombosis (DVT) in those who received erythropoietin compared with standard care (4.7% v. 2.1%, 97.5% CI exceeding the boundary for noninferiority); however, only mechanical (no pharmacologic) venous thromboembolism prophylaxis was used. 80 Importantly, neither the DVT rate, confirmed on Doppler imaging (4.1% v. 2.1%), nor the rate of all adverse events (76.5% v. 73.2%) was statistically significant.
The safety of treatment with erythropoietin-stimulating agents (ESAs) in patients undergoing active treatment for malignant disorders has been questioned owing to concerns regarding tumour progression. 81 Thus, the use of ESAs in this patient population should be considered with caution.
# Special considerations
# Inflammatory bowel disease
In a 2015 systematic review on the management of IDA in patients with inflammatory bowel disease that included 13 studies (2906 patients), Nielsen and colleagues 82 recommended oral iron therapy for patients with quiescent disease or mild anemia, and intravenous iron infusions for patients with moderate to severe anemia, active inflammatory bowel disease flare-ups or intolerance to oral supplementation.
# Severely impaired renal function
Owing to decreased or absent production of erythropoietin, anemia is a nearly universal complication in patients with severely impaired renal function. The mainstay of treatment for anemia in these patients is ESAs, often with the adjunct use of iron supplementation. The Canadian Society of Nephrology does not recommend targeting a hemoglobin level within the standard normal range for these patients but, rather, maintaining a level around 100 g/L. 83 Thus, patients with renal impairment who are already taking an ESA or who may have anemia requiring ESA therapy may not be candidates for treatment according to the algorithm (Figure 1). For this reason, management of perioperative anemia in patients with renal disease should be undertaken in collaboration with the patient's nephrologist.
# Conclusion
Preoperative anemia is a risk factor independently associated with a variety of postoperative complications. There is sufficient evidence from high-quality trials to inform recommendations for the diagnosis and management of pre-operative anemia. Routine screening, investigation and treatment for preoperative anemia in keeping with the evidence presented in this guideline is a cost-effective, highyield approach to optimizing anemia in any patient being assessed for major surgery. Coordinated preoperative assessment and treatment programs have proven effective in reducing rates of preoperative anemia and its associated complications, but they require collaboration among perioperative specialties including surgeons, anesthetists, internists, hematologists and perioperative nurses. 15,84 Given the potential for substantial benefit to patient outcomes, as well as the efficiencies to be gained by health care systems, development of such preoperative optimization programs is recommended for all centres with moderate-to high-volume surgical services, whether academic or community-based. To ensure the effectiveness of these programs, continuous quality-assurance projects should be carried out.
# hypergLycemia
Diabetes has been defined as a fasting blood glucose level of 7.0 mmol/L or greater, a glycated hemoglobin (HbA 1c ) value of 6.5% or greater, a 2-hour plasma glucose level in a 75-g oral glucose tolerance test of 11.1 mmol/L or greater, or a random plasma glucose level of 11.1 mmol/L or greater. 85,86 Prediabetes (fasting plasma glucose level of 6.1-6.9 mmol/L, a 2-hour plasma glucose level in an oral glucose tolerance test of 7.8-11.0 mmol/L, and an HbA 1c level of 6.0%-6.4%) places patients at very high risk for diabetes. The American Diabetes Association (ADA) expands the HbA 1c range for prediabetes to 5.7%-6.4%. 86 Screening guidelines for the general population vary by organization. 85,87,88 The prevalence of diabetes continues to rise, with the disease affecting an estimated 371 million people worldwide in 2012; this number is expected to increase to 552 million by 2030. 85 In the United States, the prevalence was 9.4% in 2015, and in Canada, the estimated prevalence was 6.8% in 2009. 85,89 Diabetes is even more common in surgical patients than in the general population: patients with diabetes account for an estimated 10%-20% of all surgical patients; a further 23%-60% of surgical patients have undiagnosed diabetes. Major surgical procedures produce a catabolic state and lead to transient hyperglycemia in patients without diabetes. This physiologic response is more pronounced in patients who have insulin resistance or no insulin production. 93 Diabetes-related complications include those from macrovascular and microvascular disease, such as myocardial infarction, stroke, retinopathy, nephropathy and neuropathy. 94 The appropriate management of hyperglycemia intraand postoperatively has been shown to improve outcomes. 95 The preoperative management of hyperglycemia is an area that can be improved. The following clinical practice guidelines summarize the evidence that we used to develop the recommendations in the proposed diagnostic and treatment algorithm for preoperative hyperglycemia (Figure 2).
# Recommendations
# Perioperative hyperglycemia increases the risk
-f postoperative complications, and all patients undergoing major surgery should be screened for diabetes. In its clinical practice guidelines, Diabetes Canada recommends admission screening with a random blood glucose test for all hospitalized patients owing to a high prevalence of undiagnosed and poorly controlled diabetes. 85 Diabetes Canada and the ADA also recommend measuring the HbA 1c level in all patients with diabetes or hyperglycemia if this has not been done in the previous 3 months. 96 In addition, an increased risk of postoperative complications has been well documented in the literature for patients with preoperative hyperglycemia in many different surgical specialties. An elevated HbA 1c level (≥ 6.5%) and perioperative hyperglycemia were associated with an increased risk of major complications (Clavien-Dindo grade III-V) in a prospective cohort of 478 patients undergoing abdominal sur-gery (OR 1.95, 95% CI 1.17-3.24). 97 Analysis of prospectively collected colorectal cancer data showed that diabetes was a risk factor for increased postoperative surgical complications such as surgical site infection (SSI), wound dehiscence, anastomotic leak, enterocutaneous fistula, ileus, hemorrhage, obstruction, urinary retention and ureteric injury (OR 1.44, 95% CI 1.02-2.04) but not mortality. 98 Patients with diabetes who had diabetic complications also had increased 30-day mortality (OR 13.7, 95% CI 3.4-54.7) and length of stay (3.8 d, 95% CI 0.7-7.1) compared to patients without complications. A systematic review showed that patients with diabetes who underwent carotid artery revascularization were at higher risk for perioperative stroke (OR 1.38, 95% CI 1.02-1.88), death (OR 1.94, 95% CI 1.36-2.75) and long-term mortality (OR 1.57, 95% CI 1.22-2.03). 99 In a large retrospective study, elevated HbA 1c levels in patients with peripheral vascular disease were associated with an increased risk of amputation and other complications. 100 Amputation was increasingly likely with HbA 1c levels of 6.1%-7.0% (HR 1.26, 95% CI 1.15-1.39), 7.1%-8.0% (HR 1.53, 95% CI 1.37-1.7) and greater than 8% (HR 2.05, 95% CI 1.87-2.26). The study also highlighted the increased risk of preoperative hyperglycemia in patients without diabetes compared to patients with diabetes with good control (HbA 1c level < 7.0%).
# E499
Preoperative hyperglycemia has also been shown to increase the rate of postoperative complications in patients undergoing cardiac surgery. A large retrospective study showed an increased risk of death or major cardiac event with an HbA 1c level of 8.1% or higher (8.1%-9.0%: HR 1.17, 95% CI 1.04-1.33; 9.1%-10.0%: HR 1.44, 95% CI 1.22-1.70; > 10.0%: HR 1.50, 95% CI 1.22-1.84). 101 Subramaniam and colleagues 102 conducted a prospective cohort study of patients undergoing coronary artery bypass grafting and found an increase in major adverse events including in-hospital death, myocardial infarction, tamponade, reoperation, SSI, renal failure, pneumonia and stroke in those with an HbA 1c level of 6.5% or higher (OR 1.6, 95% CI 1.1-2.3).
There is conflicting evidence in the orthopedic literature with regard to preoperative diabetes and HbA 1c levels. In a large NSQIP study, diabetes was found to be an in dependent predictor of postoperative complications (OR 1.67, 95% CI 2.217-1.253) and longer length of stay (OR 1.878, 95% CI 2.262-1.559). 103 Miller and colleagues 104 reported that an HbA 1c level greater than 6.4% was an independent risk factor for reoperation (HR 1.13, 95% CI 1.02-1.29) among patients who underwent spinal operations. However, 2 previous studies showed no difference in rates of postoperative joint infection, revision or DVT in patients with elevated HbA 1c levels. 105,106 Patients with previously undiagnosed diabetes (elevated HbA 1c level without a documented history of diabetes) have been shown to be at higher risk for postoperative complications than patients with known diabetes or patients with normal preoperative blood glucose levels. 92, A recent systematic review showed that patients with undiagnosed diabetes have an increased risk for overall postoperative complications after bariatric (OR 1.16, 95% CI 1.00-1.33), cardiac (OR 1.148, 95% CI 1.003-1.313), colorectal (OR 2.9, 95% CI 1.1-7.9) and vascular (risk ratio 7.0, 95% CI 2.8-17.2) surgery. 92 Patients with undiagnosed diabetes undergoing cardiac surgery also have an increased risk for 30-day mortality (OR 1.53, 95% CI 1.24-1.91). 110 Using NSQIP data for patients without known diabetes, Wang and colleagues 108 found that those with elevated preoperative random blood glucose levels (5.5-8 mmol/L and 8-10 mmol/L) had significantly higher postoperative infection rates than those with normal random blood glucose levels (9.33% and 10.16% v. 5.62%; p < 0.001).
A robust association exists between postoperative hyperglycemia and postoperative morbidity and mortality in general surgery patients, which makes preoperative identification of patients at risk essential for effective perioperative planning. Kwon A systematic review of papers published from 2001 to 2013 assessing preoperative testing identified a benefit in screening patients undergoing orthopedic and vascular procedures but not other procedures. 115 However, none of the studies in the review reported on changes in clinical management based on preoperative screening. Also, patients with diabetes and patients with undiagnosed diabetes were considered together. This review, therefore, has limited utility but is helpful in identifying some benefit of screening.
Although there is insufficient evidence to show that patients with hyperglycemia (both those with known diabetes and those with previously undiagnosed diabetes) benefit from preoperative treatment, screening identifies patients who would benefit from intra-and postoperative treatment of hyperglycemia, which has been proven to reduce postoperative morbidity and mortality. 95 With routine screening, the effect of treatment can also be studied properly.
# Measurement of the HbA 1c level is the most
appropriate screening test for hyperglycemia. Although there is debate regarding the ideal test to diagnose diabetes, an HbA 1c test is easier and more convenient for patients than a fasting blood glucose or oral glucose tolerance test, and the result is less affected by day-to-day variability. 85,86 An HbA 1c test will also show the level of control over the previous 2-3 months. 87 Care must be taken to ensure that an HbA 1c assay that has been standardized by the National Glycohemoglobin Standardization Program to the Diabetes Control and Complications Trial reference is used, as considerable variation may exist between different HbA 1c assays. 85,86 Existing guidelines vary in their recommendations for screening. The Strong for Surgery program (American College of Surgeons) recommends screening all patients without a previous diagnosis of diabetes by means of a fasting blood glucose test on the morning of surgery if their body mass index is greater than 30 or they are older than 45 years. Patients with diabetes who have an HbA 1c level greater than 7.0% should be referred for optimization. The National Institute for Health and Care Excellence recommends obtaining an HbA 1c level for patients with diabetes but not screening patients with no prior history of diabetes. 116 In their guidelines for primary care physicians evaluating patients preoperatively, Feely and colleagues 117 state that, in patients with known diabetes, the preoperative HbA 1c value is more likely to be useful if results would change perioperative management. Preoperative random glucose measurement could be considered in patients at very high risk for undiagnosed diabetes and in those with signs or symptoms of undiagnosed diabetes. 117
A preoperative HbA 1c level less than 6.0% does not require any further action or preoperative optimization. As per Diabetes Canada guidelines, an HbA 1c level less than 6.0% is generally considered to be normal and therefore does not require preoperative optimization. 85
A preoperative HbA 1c level of 6.0%-6.9% in a patient with no history of diabetes does not require preoperative optimization. However, it may represent pre diabetes or a new diagnosis of diabetes, and the patient should be referred to a family physician, internist or endocrinologist for follow-up and confirmation. Patients with a preoperative HbA 1c level of 6.0%-6.4% are at increased risk for diabetes (prediabetic). These patients are also at higher risk for postoperative complications and should have their blood glucose monitored while in hospital 100 (see recommendation 8).
Patients with confirmed or suspected diabetes (HbA 1c level ≥ 6.5%) are at increased risk for postoperative complications, even if their HbA 1c level is within the target range. 97,102,118 After identification of a preoperative HbA 1c level of 6.5% or higher, a second confirmation test is required to diagnose diabetes unless clear symptoms are present. 85,86 These patients should be referred to their family physician, an internist or an endocrinologist for confirmation. 85 In addition, they should be referred to a community diabetes education program for ongoing support. They should receive glycemic monitoring intra-and postoperatively, and should be treated as indicated (see recommendation 8).
A preoperative HbA 1c level of 7.0%-8.4% requires preoperative optimization, and these patients should be referred to their family physician, an internist or an endocrinologist for optimization to a target blood glucose level of 5-10 mmol/L. Patients with suboptimal glycemic control are at increased risk for postoperative complications. The ADA and Diabetes Canada recommend an HbA 1c target of less than 7% (blood glucose level < 8.5 mmol/L) for most nonpregnant patients with diabetes. 85,118 Diabetes Canada also recommends a postprandial glycemic target of 5-10 mmol/L for patients with diabetes. It has also been shown that an HbA 1c level higher than 8% increases hospital length of stay from 5.2 to 6.7 days (p = 0.02), 119 and a recent systematic review and meta-analysis showed a decrease in SSI rates (OR 0.43, 95% CI 0.29-0.64) with an intensive protocol aimed at strict intra-and postoperative blood glucose control (< 8.3 mmol/L), with no increase in rates of death or stroke related to hypoglycemia. 95 Patients with suboptimal glycemic control should receive optimization of their glycemic control regardless of whether or not they are having surgery. They should receive glycemic monitoring intra-and postoperatively, and should be treated as indicated (see recommendation 8).
A preoperative HbA 1c level of 8.5% or greater indicates poor glycemic control and requires preoperative optimization, and these patients should be referred to an internist or endocrinologist for preoperative optimization. An HbA 1c level of 8.5% or greater is substantially above target. Postoperative complication rates have been shown to increase with increasing HbA 1c levels. 100,101 Optimization may be expedited and enhanced by the involvement of an internist or endocrinologist, and preoperative involvement may be helpful for postoperative management. These patients should receive glycemic monitoring intra-and postoperatively, and should be treated as indicated (see recommendation 8).
# Patients with known diabetes with a preoperative
HbA 1c level less than 7.0% do not require preoperative optimization. Diabetes Canada and the ADA recommend a target HbA 1c level of less than 7.0% for most nonpregnant patients with diabetes in order to reduce the risk of microvascular complications. 85,118 Below 7.0%, it is a balance among smaller incremental benefits, polypharmacy and harm from hypoglycemia. These patients should receive glycemic monitoring intra-and postoperatively, and should be treated as indicated (see recommendation 8).
# All patients (both with and without diabetes) with a
preoperative HbA 1c level greater than 6.0% should undergo intra-and postoperative blood glucose monitoring, with a target blood glucose level of 6-10 mmol/L, to reduce the risk of postoperative complications. Hyperglycemia increases the risk of postoperative complications. A large NSQIP study of 55 408 patients with diabetes undergoing noncardiac surgery showed an increased risk of postoperative infections (incidence rate ratio 1.22, 95% CI 1.04-1.43). 120 Data from the Surgical Care and Outcomes Assessment Program also confirmed an increased risk of morbidity and mortality for patients with hyperglycemia. 114 There is conflicting evidence regarding intensive versus conventional glucose control postoperatively. A recent systematic review and meta-analysis showed a reduction in SSI rates (OR 0.43, 95% CI 0.29-0.64) with an intensive protocol aimed at stricter intra-and E501 postoperative blood glucose control (< 8.3 mmol/L), with no increase in mortality or strokes related to hypoglycemia. 95 However, a previous Cochrane review did not show any difference in infectious complications or mortality, but did show an increase in hypoglycemic episodes. 121 Diabetes Canada recommends a target blood glucose level of 6-10 mmol/L for critically ill patients and those undergoing major surgery. 85 To meet this target, it is recommended that a basal bolus insulin regimen be used rather than a correctional sliding scale. 85,96
# Preoperative management of diabetic medications
All patients with diabetes should be assessed in a preadmission clinic to help with the preoperative management of their medications. The ADA suggests holding all oral hypoglycemic agents the morning of surgery and giving 50% of the dosage of NPH insulin, or 60%-80% of the dosage of long-acting analogues or basal pump insulin. 96 Hypoglycemia is a serious preventable condition that patients may experience while they are fasting and are receiving insulin or other diabetic medications, such as sulphonylureas; these patients should be monitored for hypoglycemia and treated if it develops. 96 Sodium-glucose cotransporter-2 inhibitors should be avoided during fasting owing to an association with diabetic ketoacidosis. 96,122
# Special considerations
Diabetes Canada and the ADA recommend personalized HbA 1c targets, which may translate to less stringent HbA 1c targets for older or frail patients. 85,123 It is important to consider this when such patients are presenting for surgery, as they may have higher HbA 1c levels than expected. Regardless, it is still important to assess and treat them for hyperglycemia perioperatively to decrease the risk of associated complications.
# Conclusion
Surgical patients with preoperative hyperglycemia are at increased risk for postoperative complications regardless of surgical specialty. There is a lack of evidence regarding screening for hyperglycemia and optimization of preoperative hyperglycemia. In the absence of high-quality prospective studies assessing the benefits of preoperative management of hyperglycemia, it would be appropriate to treat patients undergoing major surgical procedures according to guidelines that address the management of diabetes in the general population. Given the high rate of undiagnosed diabetes and prediabetes in surgical patients, patients undergoing major surgery should be screened so that treatment may be initiated, as there is a clear benefit of proper intra-and postoperative control of hyperglycemia.
# smoking
Tobacco smoking remains highly prevalent in North America, and, despite decreased rates in recent decades, it remains the leading cause of preventable disease and death in Canada. 124 In 2016, 16.9% of Canadians aged 13 years or older (roughly 5.2 million people) were reported to be smokers. 125 The prevalence of smoking in clinical populations is even higher (> 20%). 126 Clinicians may not appreciate the adverse effect of smoking on postsurgical outcomes. 127 For example, a retrospective cohort study of more than 600 000 patients who underwent noncardiac surgery showed that preoperative smoking was associated with a 40% increase in 30-day mortality (OR 1.38, 95% CI 1.11-1.72) and a 70% increase in major morbidity (OR 1.72, 95% CI 1.67-1.78). 128 Several systematic reviews and meta-analyses have shown that interventions that help patients quit smoking before surgery lead to reductions in adverse surgical outcomes, including wound, pulmonary and overall complications. 129,130 The following clinical practice guideline summarizes the current evidence informing the recommendations within the proposed diagnostic and treatment algorithm for preoperative smoking (Figure 3).
# Recommendations
# Tobacco smoking is associated with increased
adverse postoperative outcomes, and all patients undergoing major surgery should have their smoking status identified and documented at every preoperative clinic visit. A retrospective review of 400 000 patients who underwent noncardiac surgery showed that, compared to nonsmokers, smokers had a 29% increase in 30-day mortality (OR 1.29, 95% CI 1.20-1.39) and a 55% increase in 1-year mortality (OR 1.55, 95% CI 1.50-1.61). 131 One-year postoperative mortality decreased significantly for prior smokers who had not smoked in the previous year (OR 1.14, 95% 1.10-1.19). 131 A meta-analysis of 107 studies published since 2000 showed preoperative smoking to be significantly associated with general morbidity (RR 1.52, 95% CI 1. 130 Smoking is a demonstrated risk factor in most surgical procedures, increasing rates of incisional hernia after laparotomy (OR 3.93, 95% CI 1.82-8.49), 132 spinal fusion nonunion (OR 2.01; p < 0.02), 133 disease recurrence (HR 1.25; p = 0.02) and metastasis (HR 2.64; p = 0.03) after radical prostatectomy, 134 anastamotic leakage after anterior resection for rectal cancer (OR 1.88, 95% CI 1.02-3.46) 135 and fracture after shoulder arthroplasty (HR 3.63; p = 0.02). 136 Smoking also leads to increased wound complication rates after both laparoscopic (OR 1.20; p = 0.02) and open (OR 1.28; p = 0.01) cholecystectomy, and results in a longer average postoperative length of stay, by 2-4 days (p < 0.001). 137 Although roughly 25% of surgical patients are smokers, 128 more than half of patients undergoing elective outpatient procedures report not having been informed about the adverse effects of smoking before surgery. 138 Of 116 consecutive patients surveyed after a surgical clinic appointment at a Canadian tertiary care centre, less than 10% had been asked about smoking status, and none had been asked about quitting or offered any form of intervention. 139 Smoking status should be documented systematically in all patients undergoing surgery. Combining clinician training with a charting system has been shown to increase the rates of assessing tobacco use, setting a quit date, providing materials and arranging for follow-up. 140 2. All surgical patients who smoke should be advised to quit smoking preoperatively and have their willingness to quit assessed to guide next steps. Because of the high risk of relapse, those who have quit within the previous 6 months should be treated as active smokers. More than 70% of all tobacco smokers report wanting to quit. 140 Half of Canadian smokers try to quit each year, 141 but patient-driven smoking cessation is ineffective: 80%-90% of self-quitters relapse within 3 months of cessation, and less than 5% achieve long-term success. 141 However, patients often view surgery as a "wake-up call" regarding their health and are more likely to be receptive to advice offered by health care professionals, particularly regarding the perioperative risks of smoking, at this time. A recent systematic review and meta-analysis suggested that cessation rates almost doubled (from 24.5% to 46.2%; effect size g = 0.56, 95% CI 0.32-0.80) before surgery with proactive, clinician-driven behavioural interventions. 145 The preoperative period is therefore an ideal time to intervene.
All patients who smoke should be advised to quit preoperatively in a clear, strong and personalized way, and have their willingness to quit assessed. 140 It is important to stratify patients by willingness to quit to determine the best management approach (see recommendations . Those who are willing to quit should set a quit date, and can choose between abrupt cessation or gradual reduction leading up to their quit date, which were shown to be equally effective in a meta-analysis of quit approaches (RR 0.94, 95% CI 0.79-1.13). 146 Among those who are unwilling to quit but willing to reduce the amount smoked per day, the use of pharmacotherapy should be encouraged to assist with smoking reduction. 147 Increased cessation rates have been reported after motivational
# E503
interviewing (a patient-centred approach focusing on the "5 Rs" strategy: relevance, risks, rewards, roadblocks and repetition at every visit 140 ) among patients who were in itially unwilling to quit. 140 Smoking relapse most frequently occurs early after quitting but can occur as late as months to years later. 148 A Cochrane review of 63 RCTs showed that multiple behavioural techniques used by patients to prevent relapse failed to show any benefit but that success rates may be improved with pharmacotherapy. 149 Given the high relapse rate, we recommend treating patients who have quit within the previous 6 months as active smokers. This provides them with the best available evidence-based cessation treatments to promote sustained abstinence.
A quit date should be set more than 8 weeks preoperatively to achieve the most substantial improvements in postoperative outcomes; however, outcome benefits may still be seen with cessation as late as the day of surgery. In a meta-analysis of 25 RCTs and cohort studies (combined n > 21 000), smoking cessation more than 8 weeks before surgery significantly reduced rates of postoperative pulmonary complications compared to active smoking (RR 0.53, 95% CI 0.37-0.76), with rates approaching those among nonsmokers (RR 1.16, 95% CI 0.76-1.77). 150 Cessation 4 weeks preoperatively had a smaller but significant effect on pulmonary complication rates (RR 0.77, 95% CI 0.61-0.96), but the risk remained higher than that among nonsmokers (RR 1.39, 95% CI 1.18-1.65). There was no significant pulmonary benefit to cessation 2-4 weeks or less than 2 weeks preoperatively (RR 1.14, p = 0.3; and RR 1.20, p = 0.1, respectively). 150 The same meta-analysis also showed that smoking cessation more than 3-4 weeks preoperatively reduced wound complication rates (RR 0.69, 95% CI 0.56-0.84), with rates approaching those among nonsmokers (RR 1.44, 95% CI 0.97-2.15). 150 A retrospective cohort study of 188 patients with head or neck cancer with flaps showed a similar reduction in wound failure rates among smokers who quit 3-6 weeks (RR 0.17, 95% CI 0.04-0.75) or more than 6 weeks (RR 0.17, 95% CI 0.05-0.60) before surgery. 151 Two landmark RCTs involving behavioural interventions and nicotine replacement therapy (NRT) showed improved postsurgical outcomes with smoking cessation programs 4 weeks or less before surgery. 152,153 Møller and colleagues 152 found that a program with a target quit date of 4 weeks before surgery led to significant reductions in rates of overall (18% v. 52%; p < 0.001) and wound-related (5% v. 31%; p = 0.001) complications. Lindström and colleagues 153 reported that a program with a target quit date of 3 weeks before surgery was associated with a significant reduction in any postoperative complication (21% v. 41%; RR 0.51; p = 0.03).
A recent observational nested matched case-control study showed benefit to quitting as late as the day of surgery, showing a significant decrease in SSI rates (OR 1.96, 95% CI 1.23-3.13). 154 However, 2 prior studies showed no significant reduction in wound complication rates with cessation less than 3 weeks before surgery. 150,151 4. In patients who are unwilling to quit smoking, motivational interviewing techniques can be used to increase motivation to quit, thereby increasing quit rates. An RCT involving 616 patients who were unmotivated to quit smoking showed that motivational interviewing based on the US Public Health Service 2008 smoking cessation guideline 140 led to a quit rate of 23% at 6 months and an average reduction of 30% in the amount smoked per day. 155 Motivational interviewing is a specialized skill, and interested clinicians can learn more 140 or consider referral to a specialist. Even patients unwilling to quit should be encouraged to abstain from smoking at least 24 hours before surgery, as this may reduce the occurrence of SSI. 154
# In patients who are unwilling to quit smoking but
willing to reduce, clinicians should offer full cessation treatment to support reduction goals. In a meta-analysis of RCTs involving smokers who did not intend to quit, smoking-reduction support with pharmacotherapy versus no intervention was found to be beneficial in achieving complete cessation (RR 1.93, 95% CI 1.41-2.64). 147 Of note, the authors used only long-term followup (> 6 mo) data, and, to our knowledge, no similar shorter-term data exist. Although the data are limited, pharmacotherapy is likely a major contributor to the success of smoking-reduction plans. Reduction counselling and support alone versus no intervention did not significantly increase abstinence (RR 1.49, 95% CI 0.56-3.93). Both reduction counselling and support with varenicline therapy (RR 2.66, 95% CI 2.10-3.36) and reduction counselling and support with NRT (RR 1.94, 95% CI 1.26-3.00) were far superior to reduction support with placebo.
Although there is currently no good evidence that preoperative smoking reduction without cessation improves surgical outcomes, 152 supporting surgical patients who are interested in smoking reduction preoperatively has no adverse consequences, improves long-term quit rates and may lead to preoperative cessation. 147 6. All surgical patients who smoke should be offered the combination of counselling and pharmacotherapy preoperatively. When this is not possible, they should still be offered either intervention individually. Both pharmacotherapy and cessation counselling are effective alone 145,156,157 and should be provided even if a patient is not interested in combined therapy. Whenever possible, patients who are willing to quit should be provided both interventions: a meta-analysis showed that combining therapies has increased efficacy compared to pharmacotherapy (OR 1.4, 95% CI 1.2-1.6) or behavioural therapy (OR 1.7, 95% CI 1.3-2.1) alone. 140 7. All surgical patients who smoke should be offered combination nicotine replacement therapy (NRT) preoperatively. Prescribers capable of follow-up may consider varen icline as a first-line agent. Second-line options include single-agent NRT and bupropion. Three therapies approved in Canada have been shown to increase smoking cessation rates in the general population: varenicline, NRT and bupropion. 158 156 Nicotine replacement therapy options are sold over the counter, whereas both varenicline and bupropion require a prescription. 156 We recommend combination NRT and varenicline as first-line treatments, as they are the most effective smokingcessation interventions (Appendix 1), with no significant difference between them in direct comparison (OR 1.06, 95% CI 0.75-1.48). 156 Combination NRT has no absolute contraindications 156 or required follow-up, and was associated with reduced postoperative complication rates in 2 RCTs. 152,153 It can easily be prescribed by surgeons, who can place patient concerns about the cost of patches ($20/ wk) and adjuncts ($15-$40/wk) in the context of savings from cigarette purchases 159 and overall health benefits.
Varenicline is the most effective monotherapy for smoking cessation (OR 2.89, 95% CI 2.40-3.48) 156 but has not been as well studied in the perioperative setting as NRT. Wong and colleagues 160 reported that 12 weeks of varenicline therapy initiated 1 week preoperatively significantly increased cessation rates 1 year after surgery (RR 1.45; p = 0.04). Given its efficacy, we consider varenicline a first-line treatment.
Bupropion is an atypical antidepressant that has been shown to improve smoking cessation rates versus placebo (OR 1.85, 95% CI 1.63-2.10). 156 It is contraindicated in patients with increased seizure risk. As it has not been well studied in the perioperative setting and is less effective than both combination NRT and varenicline, we consider it a second-line option.
Randomized controlled trials across 140 centres in 16 countries have shown no evidence that any of these 3 therapies are associated with an increased risk of adverse cardiovascular 161 or neuropsychiatric 162 events. A 2012 systematic review showed no clinical evidence of a detrimental effect of NRT on postoperative wound or tissue healing. 163 8. All surgical patients who smoke should be given brief counselling on the consequences of smoking and the benefits of smoking cessation preoperatively. When possible, counselling should be face to face, frequent and of sufficient duration, all of which increase cessation rates. Physician counselling to quit smoking has been shown to increase the likelihood of short-term abstinence by 30% (OR 1.3, 95% CI 1.1-1.6), and even interventions as brief as 3 minutes can increase cessation rates significantly (OR 1.3, 95% CI 1.01-1.60). 140 A meta-analysis of 22 studies in patients scheduled to undergo elective surgery showed 6 behaviour-change techniques leading to higher rates of smoking abstinence: provision of information on the consequences of smoking and smoking cessation; facilitation of goal setting; prompt review of cessation goals; regular monitoring by others (e.g., friends or family members); options for additional and later support; and provision of information on withdrawal symptoms. 145 Of these, providing information on the consequences of smoking and smoking cessation was the most significant predictor of quitting (β = 0.69, p = 0.01). Counselling interventions may be delivered (in order of most to least effective) face to face, by telephone, over the Internet 164 or in print. Higher cessation rates have been shown with increased duration (β = 0.01, p = 0.02) and frequency (β = 0.22, p = 0.002) of intervention sessions, 145 which is reflected in the US and Canadian guidelines. 140,165 Several other techniques have been attempted in perioperative RCTs, without evidence of increased preoperative cessation rates. These include a decision aid with laminated graphics to facilitate discussion, 166 a behavioral tapering regimen (scheduled reduced smoking) via handheld computer 167 and planned checks of carbon monoxide levels on the day of surgery. 168 9. All surgical patients who smoke should be offered clinical follow-up. Offering follow-up provides cessation support after the in itial intervention, and follow-up interventions with increased frequency are more effective. 140 Lindström and colleagues 153 reported that a weekly face-to-face or telephone intervention of smoking cessation therapy with individual counselling and NRT delivered by a trained nurse starting 4 weeks preoperatively led to both increased perioperative cessation rates (39.6% v. 1.9%) and decreased postoperative complication rates (21% v. 41%, p = 0.03) compared to standard care.
A meta-analysis of RCTs or quasi-randomised controlled trials in which telephone counselling was offered to smokers or recent quitters to assist smoking cessation showed an increase in smoking cessation rates when used as the primary intervention (RR 1.34, 95% CI 1.22-1.46), when following a face-to-face intervention (RR 1.41, 95% CI 1.20-1.66) and when used as an adjunct to NRT or varenicline (RR 1.14, 95% CI 1.03-1.27). 169 Having 3 or more follow-up telephone calls showed additional benefit (RR 1.32, 95% CI 1.23-1.42). In busy surgical clinics, repeat preoperative visits and follow-up with specialized nurses may not always be feasible or cost-effective. Lee and colleagues 170 conducted an RCT in which patients seen at least 3 weeks preoperatively received either no specific smoking-cessation intervention, or an intervention consisting of brief counselling by the preadmission nurse, brochures on smoking cessation, referral to a smokers helpline (available at no cost in all Canadian provinces) and a free 6-week supply of NRT. Significantly reduced smoking rates were observed in the intervention group at the time of surgery (14.3% v. 3.6%; p = 0.03).
# Conclusion
Smoking is the most important risk factor for postoperative complications and should be routinely identified, docu mented and treated preoperatively according to the patient's willingness to quit. By targeting a quit date of at least 8 weeks before surgery and offering a combination of brief counselling with pharmacotherapy and follow-up, clin icians can reduce perioperative smoking rates and postoperative complication rates. Given the minimal time and resources required, along with the substantial benefits of cessation, a preoperative smoking-cessation program should be offered in all surgical clinics. | Clinical practice guideline: evidence, recommendations and algorithm for the preoperative optimization of anemia, hyperglycemia and smoking F or most of the 20th century, the focus of research in surgery was improvements in intraoperative technique, which led to major technical paradigm shifts exemplified by the evolution of transurethral resection of the prostate, 1 laparoscopic cholecystectomy, 2 endovascular aneurysm repair 3 and total mesorectal excision for rectal cancer, 4 among many others. The late 1990s and early 2000s marked a shift in surgical research toward the evidencebased management of patients in the perioperative period, beginning with the Enhanced Recovery After Surgery Group's systematic review of patients undergoing colorectal surgery. 5 That publication introduced a new paradigm focused on the impact that standardized perioperative care could have on patient outcomes such as length of stay, postoperative pain and overall complication rates. 6,7 Although a large body of literature now exists to help guide the intraoperative and perioperative management of surgical patients, our working group believes that the preoperative period, which we define as the 8 weeks#
Preoperative optimization has not been explored comprehensively in the sur gic al literature, as this responsibility has often been divided among surgery, anesthesia and medicine. We developed an evidence-based clinical practice guideline to summarize existing evidence and present diagnostic and treatment algorithms for use by surgeons caring for patients scheduled to undergo major elective surgery. We focus on 3 common comorbid conditions seen across surgical specialties -anemia, hyperglycemia and smoking -as these conditions increase complication rates in patients undergoing major surgery and can be optimized successfully as soon as 6-8 weeks before surgery. With the ability to address these conditions earlier in the patient journey, surgeons can positively affect patient outcomes. The aim of this guideline is to bring optimization in the preoperative period under the existing umbrella of evidence-based surgical care. L'optimisation préopératoire n'a pas été explorée de manière exhaustive dans la littérature chirurgicale, car cette responsabilité a souvent été divisée entre la chirurgie, l'anesthésie et la médecine. Cette ligne directrice de pratique clinique fondée sur des données probantes a été conçue pour résumer les données existantes et présenter des algorithmes diagnostics et thérapeutiques relatifs à des comorbidités fréquentes chez les patients vus dans toutes les spécialités chirur gicales. L'accent a été placé sur l'optimisation préopératoire de l'anémie, de l'hyperglycémie et du tabagisme, étant donné que ces problèmes de santé accroissent le risque de complications chez les patients qui doivent subir une chi rur gie majeure et qu'il est possible de les corriger en bonne partie dans les 6-8 semaines précédant la chirurgie. Or, si les chirurgiens arrivent à corriger ces problèmes de santé plus tôt dans le parcours des patients, ils pourraient améliorer leurs résultats. Le but de cette ligne directrice est que l'optimisation préopératoire soit intégrée à l'ensemble actuel des soins chirurgicaux fondés sur des données probantes. preceding elective surgical procedures, is an area of inquiry that remains under explored in surgical literature. This "orphan" period in the care of a surgical patient exists for many reasons. The preoperative period has not traditionally been the responsibility of any single clinical specialty, with care often divided among surgeons, anesthetists and internists. As a result, there is little in the way of a standardized, evidence-based approach to the identification and treatment of comorbid conditions that could be effectively optimized in the preoperative period to improve patient outcomes.
In this evidence-based clinical practice guideline, we summarize existing evidence and present diagnostic and treatment algorithms for use by surgeons caring for patients undergoing major elective surgery. We focus on 3 common comorbid conditions seen across surgical specialties -anemia, hyperglycemia and smoking -and present evidence of improved patient outcomes with optimization strategies started as soon as 6-8 weeks before surgery.
The evidence presented here points to a new paradigm shift in the way multidisciplinary teams care for patients undergoing elective surgery, bringing the preoperative period under the existing umbrella of evidence-based surgical care.
# Literature search
Our search strategy for anemia is presented in Appendix 1 (available at canjsurg.ca). A similar search strategy was used for hyperglycemia and for smoking, with lines 1 and 3 changed to reflect the different components. We determined the strength of recommendations and the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. 8 Recommendations were developed by 2 reviewers for each subject area (anemia and diabetes: J.A.G. and T.M.Z., smoking: J.S. and J.A.G.). Disagreements were resolved by a third reviewer (H.M.).
# anemia
The prevalence of preoperative anemia is high. In 2 large studies of patients undergoing noncardiac surgery (n = 319 703), preoperative anemia was identified in 28%-30% of patients across multiple specialties. 9,10 In certain surgical specialties, the prevalence approaches half of all patients, as seen in colorectal surgery (40.4%-47.4%), 11,12 orthopedic surgery (25%-44%) [13][14][15] and urology (8%-45%). 16 According to the World Health Organization (WHO), a prevalence of anemia greater than 40% in a population has severe health consequences, and, therefore, anemia should be an essential consideration in most surgical patients. 17 The WHO defines anemia as a hemoglobin level less than 120 g/L in women and less than 130 g/L in men. 18,19 These definitions have been validated by large population studies examining mean hemoglobin values by age, race and sex. 20 A second definition of anemia is a hematocrit value less than 0.39 for both sexes, which has also been vali dated in large database studies. 9,11 The WHO estimates a prevalence of anemia of 29.4% among all women of reproductive age, 18 which makes anemia an underrecognized condition warranting consideration even in young, healthy populations.
Anemia may be caused by chronic inflammatory conditions, kidney disease, malnutrition, ongoing small-volume blood loss and iron deficiency. Iron-deficiency anemia (IDA) is widely accepted to be the most common cause, and, in a recent study of 3342 patients undergoing gynecologic, urologic, colorectal, cardiac or orthopedic surgery, almost two-thirds (62%) of patients with preoperative anemia had some component of IDA. 21 In patients with cancer, chronic bleeding from gastrointestinal tumours can also contribute to preoperative anemia. [22][23][24] Given the increased incidence of most surgical conditions with increasing age, the mean age of surgical patients is older than that of other cohorts and is associated with an increased prevalence of anemia. 20,22 Unlike in the general population, the cause of anemia in older patients is multifactorial in almost two-thirds of cases. 25 Several centres have reported improved postsurgical outcomes through preoperative diagnosis of anemia and treatment plans. These outcomes include shorter length of hospital stay, 15,26 decreased rates of postoperative nosocomial infections, 26 decreased 90-day readmission rates 15 and lower rates of blood transfusion. 15,[26][27][28] The following clinical practice guideline summarizes the current evidence informing the recommendations within the proposed diagnostic and treatment algorithm for preoperative anemia (Figure 1).
# Recommendations
# Preoperative anemia is associated with adverse sur-
gical outcomes, and all patients undergoing major surgery should be screened for anemia at their first surgical clinic visit and investigated further, as appropriate (Table 1). Preoperative anemia was shown to be an independent risk factor associated with increased 1-year and overall mortality in 319 703 patients undergoing noncardiac surgery (adjusted hazard ratio [HR] 2.86, 95% confidence interval [CI] 2.56-3.20, and odds ratio [OR] 1.42, 95% CI 1.31-1.54, respectively). 9,10 In a propensity-matched cohort of 7759 patients undergoing noncardiac surgery, an independ ent association between preoperative anemia and increased 90-day mortality was shown (OR 2.29, 95% CI 1.45-3.63). 29 A National Surgical Quality Improvement Program (NSQIP) study of 5081 patients undergoing vascular surgery showed increased mortality for both moderate (OR 2.6, 95% CI 1.2-5.5) and severe (OR 2.8, 95% CI 1.3-6.3) anemia. 30 Preoperative anemia is independently associated with early postoperative complications such as increased overall 30-day postoperative morbidity in patients under going noncardiac surgery (OR 1.35, 95% CI 1.30-1.40), 9 increased rates of major cardiac events (5.1%-6.8% v. 2.6%; p = 0.001) and acute kidney injury (52.0%-63.2% v. 31.0%; p = 0.01) in patients undergoing vascular surgery, 30,31 and increased infectious complication rates in patients undergoing orthopedic surgery (57.1% v. 6.3%; p = 0.006) 32 and those with gastric cancer (OR 3.70, 95% CI 1.43-9.58). 33 In a large NSQIP database study, preoperative anemia in patients undergoing colorectal surgery was independently associated with a significantly increased frequency of composite outcome events (myocardial infarction, acute renal injury, stroke and death) that was proportional to anemia severity (mild: OR 1. 49 11 Preoperative anemia was independently associated with significant increases in length of postoperative hospital stay in a systematic review of orthopedic literature, 13 a retrospective analysis of 2394 patients who underwent total knee arthroplasty (OR 1.71-2.29; p < 0.001) 14 and an NSQIP study of 23 348 patients who underwent colorectal surgery (0.5-2.2 d longer; p < 0.01). 11 Unsurprisingly, preoperative anemia is independently associated with significantly increased rates of postoperative blood transfusion. This association has been shown after urologic (OR 6.28, 95% CI 3.43-11.51), 34 colorectal (24% v. 3%) 35 and orthopedic (OR 4.13-9.13; p < 0.001) 14 procedures. Compared to anemic values, a normal preoperative hemoglobin value was shown to significantly reduce the likelihood of transfusion after laparoscopic colorectal resection (HR 0.547, 95% CI 0.468-0.637). 36 Finally, preoperative anemia is independently associated with worse oncologic outcomes in patients with urologic, gastric, colorectal or mesenchymal cancer, with decreased disease-free survival, 37,38 cancer-specific survival 39,40 and overall survival, 39,[41][42][43] and increased rates of cancer recurrence. 40,44 2. Complete blood count and ferritin are the most appropriate screening blood tests. Hemoglobin levels, as determined by a complete blood count, represent the gold standard diagnostic test for anemia. This was established through a series of reports published by the WHO between 1968 and 2015 in which the normal hemoglobin ranges for adult and pediatric popu lations (by sex) were determined and the definitions of anemia refined. [17][18][19][45][46][47][48] Large population-based studies examining mean hemoglobin values by age, race and sex further validated the accepted normal ranges and the use of hemoglobin level to diagnose anemia. 20 The hematocrit, as determined by a complete blood count, has also been validated as an indicator of anemia in more recent large database studies, such as those using NSQIP data. 9,11,49 Iron-deficiency anemia is the most common cause of anemia in surgical patients and should be assessed as part of the initial investigation. 21,[50][51][52] In a meta-analysis of 55 studies, Guyatt and colleagues 53 compared several blood tests to the gold standard for the diagnosis of IDA (absence of stainable iron in a bone marrow aspirate). They found the serum ferritin radioimmunoassay to be the most reliable test for the diagnosis of IDA, with an area under the ROC curve of 0.95. Although the radioimmunoassay is no longer commonplace, equivalence has been shown between this assay and the enzyme-linked immunoassays that are more common today, with an intraclass correlation coefficient of at least 0.98, which implies that the tests are interchangeable. 54 A serum ferritin level less than 30 μg/L has been shown to be both sensitive (92%) and specific (98%) for the diagnosis of IDA. [55][56][57] The diagnostic utility of serum ferritin level as an effective first-line test for IDA was reaffirmed in more recent reviews on the topic. 47,55,58 3. Patients without evidence of anemia should not be treated with iron supplementation. Pratt and Khan 59 advocated consideration of iron supplementation for patients with nonanemic iron deficiency. However, currently there is insufficient evidence of clinical benefit to recommend treatment for patients with a preoperative hemoglobin level greater than 130 g/L for men or greater than 120 g/L for women. Although the rate of serious toxic effects related to oral iron supplementation is low, gastrointestinal adverse effects are common. 60 Therefore, given the low potential for benefit and high probability of adverse effects, this therapy should not be recommended for patients without evidence of anemia.
# For patients with anemia and a serum ferritin level
of 30-100 ng/mL, transferrin saturation index and C-reactive protein tests should be ordered to better determine the presence of iron deficiency. In cases in which anemia is diagnosed but the serum ferritin level is nondiagnostic (30-100 ng/mL), 2 tests should be added to confirm IDA: measurement of the transferrin saturation index and the C-reactive protein level. 56,58 In the context of anemia with a serum ferritin level of 30-100 ng/mL, a transferrin saturation index less than 20% implies inadequate iron for normal erythropoiesis and is therefore strongly suggestive of IDA. 51,56,58 Serum ferritin is known to be an acute-phase reactant, 61,62 and the level can rise with increasing age. 20,62 Therefore, in the context of anemia with a serum ferritin level of 30-100 ng/mL, a C-reactive protein level greater than 5 mg/L is consistent with an inflammatory state and falsely elevated serum ferritin levels, and is therefore strongly suggestive of IDA. 51,56,58 5. Oral iron supplementation is the preferred treatment for patients with IDA and no contraindications (i.e., ≥ 8 wk until surgery, able to tolerate/ absorb oral iron formulation, hemoglobin level ≥ 100 g/L). A randomized controlled trial (RCT) involving 90 older inpatients with IDA showed significant increases in mean hemoglobin level after 60 days of treatment with low-, medium-or high-dose oral iron supplementation (increases of 13 g/L, 14 g/L and 14 g/L, respectively; p < 0.001 for all dosages). 63 In a multicentre RCT involving 46 patients with inflammatory bowel disease and IDA, an oral iron regimen administered for 6 weeks resulted in a mean increase in hemoglobin level of 21 g/L, which was not significantly different from that in patients receiving intravenous iron infusions. 64 In an RCT involving 45 patients awaiting resection for colon or rectal cancer, 2 weeks of oral iron treatment resulted in significantly higher hemoglobin levels at the time of surgery (mean 131 g/L v. 118 g/L; p = 0.04), 65 and a second prospective study in 58 similar patients showed a significant increase in preoperative hemoglobin level (+17.3 g/L; p < 0.001) after an average of 39 days of oral iron treatment. 66 Owing to the demonstrated effectiveness of oral iron therapy, and the lower cost and ease of administration for both the patient and the health care system, most blood management strategies recommend oral iron supplementation as first-line treatment for patients with IDA with no contraindications. 15,51,53,67 Although many dosages have been found to be effective, there is evidence to suggest that lower dosages (e.g., elemental iron equivalent of 40-60 mg orally daily or 80-100 mg orally every 2 d) are associated with fewer adverse effects such as abdominal discomfort, nausea, vomiting and changes in bowel habits. 51,63,68 A recent summary of evidence regarding the safety of oral iron supplementation did not identify any major safety concerns, although adverse effects such as nausea, heartburn, pain, and constipation or diarrhea are more common with oral formulations than with intravenous iron infusions. 69
# Intravenous iron infusions may be appropriate for
patients with IDA in certain circumstances (i.e., < 8 wk until surgery, unable to tolerate/absorb oral iron formulation, hemoglobin level < 100 g/L). In an RCT involving 76 patients with menorrhagia and severe IDA comparing 3 weeks of intravenous versus oral iron supplementation, intravenous iron supplementation was associated with a larger increase in posttreatment hemoglobin levels (mean +30 g/L v. +8 g/L; p < 0.001) and ferritin levels (mean +170.1 μg/L v. +4.1 μg/L; p < 0.001), and a higher frequency of reaching a target hemoglobin level of 100 g/L or greater (76.7% v. 11.5%; p < 0.001). 70 A prospective trial involving 266 patients with colon cancer receiving intravenous versus oral iron supplementation showed that intravenous iron supplementation was associated with a significantly shorter mean length of stay (8.4 d [standard deviation (SD) 6.8 d] v. 10.9 d [SD 12.4 d]; p < 0.001), lower frequency of transfusion (9.9% v. 38.7%, p < 0.001]), and larger increases in preoperative (+15 g/L v. +5 g/L; p < 0.001) and 30-day postoperative (+31 g/L v. +15 g/L; p < 0.001) hemoglobin levels. 71 In addition, patients receiving iron intravenously had a higher rate of normalized hemoglobin 30 days postoperatively (40% v. 26.7%; p < 0.05). In a multicentre RCT involving 116 patients undergoing elective surgery for colorectal cancer, the mean increase in total hemoglobin level was significantly greater with intravenous than oral iron therapy (+15.5 g/L v. +5.0 g/L; p < 0.001), and a smaller proportion of patients in the intravenous iron group were anemic at the time of surgery (75% v. 90%; p = 0.048). 72 These findings are consistent with those of a systematic review of 8 low-bias RCTs showing that patients with IDA preoperatively may have earlier and more robust recovery of the hemoglobin level with intravenous iron therapy than with oral supplementation. 73 In a prospective RCT, 72 patients with IDA were randomly allocated to receive intravenous iron supplementation versus usual care within 3 weeks before elective abdominal surgery. 74 Increases in hemoglobin level were significantly higher in the intravenous iron group preoperatively and 4 weeks after discharge (+8 g/L v. +1 g/L, p = 0.01; and 19 g/L v. 9 g/L, p = 0.01, respectively), with a significant associated reduction in postoperative allogenic blood transfusion (12.5% v. 53%; p < 0.001). Finally, a retrospective review of 318 patients with colorectal cancer and anemia who received intravenous iron treatment less than 6 weeks before surgery showed a significantly greater increase in hemoglobin level compared to no treatment (+10.5 g/L v. +1.6 g/L; p < 0.001). 75 Two studies have shown the utility of intravenous iron infusion for patients with anemia with minimal time until surgery. An RCT in 108 patients undergoing bilateral total knee replacement showed that, compared to no infusions, intraoperative intravenous infusions of iron and erythropoietin resulted in significantly higher hemoglobin levels in the first, second and sixth weeks postoperatively, and a significantly lower rate of blood transfusion (20.4% v. 53.7%; p = 0.01). 76 In a retrospective analysis of 2547 patients at risk for severe postoperative anemia who underwent major orthopedic surgery, compared to standard treatment, intravenous iron treatment at any time from 5 days preoperatively to 3 days postoperatively was associated with a sig-nificantly lower rate of postoperative nosocomial infections (10.7% v. 26.9%; p = 0.001) and shorter length of stay (11.9 d v. 13.4 d; p = 0.001), independent of transfusion status; the proportion who received transfusions was also lower (32.4% v. 48.8%; p = 0.001). 26 The safety of intravenous iron therapy is comparable to that of oral iron therapy, as shown in a systematic review of 8 low-bias RCTs and a prospective study of 266 patients that showed no deaths, hypersensitivity reactions or other serious drug reactions. 71,73 In addition to being safe, intravenous iron treatment is rarely associated with the adverse gastrointestinal effects seen with oral iron supplementation, which results in increased compliance with intravenous treatment. 28,70 7. For patients with anemia who have no evidence of IDA or IDA refractory to iron supplementation, referral to a hematologist should be considered for treatment with erythropoietin and intravenous iron infusions. In a systematic review of 8 low-bias RCTs, Lin and colleagues 73 concluded that a short preoperative course of erythropoietin or a single dose of erythropoietin plus intravenous iron infusion pre-or intraoperatively may reduce transfusion requirements significantly, with a number needed to treat to avoid allogenic blood transfusion of 3-6. In an RCT involving 201 patients with undifferentiated anemia scheduled to undergo hip arthroplasty, participants were randomly allocated to receive 4 weeks of high-dose erythropoietin with oral iron therapy, low-dose erythropoietin with oral iron therapy, or placebo; there was a significant dose-proportional reduction in the blood transfusion rate (11.4%, 22.8% and 44.9%, respectively; p < 0.003) and increase in the preoperative hemoglobin level (+19.5 g/L, +17.2 g/L and +1.2 g/L, respectively; p < 0.001). 77 In an RCT in which 74 patients with anemia undergoing valvular heart surgery were randomly allocated to receive erythropoietin and intravenous iron infusion or placebo 1 day before surgery, the intervention was associated with was a significant reduction in the rate of blood transfusion (59% v. 86%; p = 0.009), with a number needed to treat to avoid allogenic blood transfusion of 4, as well as a reduction in the mean number of units of packed red blood cells transfused per patient (3.3 78 In an RCT involving 108 iron-deficient patients undergoing bilateral total knee replacement, compared to standard care, administration of erythropoietin and intravenous iron infusion intraoperatively resulted in a significantly lower perioperative transfusion rate (20.4% v. 53.7%; p = 0.01), significantly fewer units of packed red blood cells transfused per patient (mean 0.2 [SD 0.5] v. 0.8 [SD 0.8]; p = 0.005), and significantly higher hemoglobin levels 1, 2 and 3 days, and 2 and 6 weeks postoperatively. 76 Finally, in a retrospective study involving 412 patients with IDA who underwent elective orthopedic surgery, Basora and colleagues 79
[SD 2.2] v. 1.0 [SD 1.1]; p = 0.001).
# E497
compared those who received intravenous iron treatment alone to those who received intravenous iron treatment and erythropoietin preoperatively and found a significantly greater increase in the preoperative hemoglobin level with the latter treatment (+15 g/L v. +8 g/L; p < 0.01).
A safety/noninferiority RCT involving 680 patients undergoing spinal surgery showed a significantly increased risk of deep vein thrombosis (DVT) in those who received erythropoietin compared with standard care (4.7% v. 2.1%, 97.5% CI exceeding the boundary for noninferiority); however, only mechanical (no pharmacologic) venous thromboembolism prophylaxis was used. 80 Importantly, neither the DVT rate, confirmed on Doppler imaging (4.1% v. 2.1%), nor the rate of all adverse events (76.5% v. 73.2%) was statistically significant.
The safety of treatment with erythropoietin-stimulating agents (ESAs) in patients undergoing active treatment for malignant disorders has been questioned owing to concerns regarding tumour progression. 81 Thus, the use of ESAs in this patient population should be considered with caution.
# Special considerations
# Inflammatory bowel disease
In a 2015 systematic review on the management of IDA in patients with inflammatory bowel disease that included 13 studies (2906 patients), Nielsen and colleagues 82 recommended oral iron therapy for patients with quiescent disease or mild anemia, and intravenous iron infusions for patients with moderate to severe anemia, active inflammatory bowel disease flare-ups or intolerance to oral supplementation.
# Severely impaired renal function
Owing to decreased or absent production of erythropoietin, anemia is a nearly universal complication in patients with severely impaired renal function. The mainstay of treatment for anemia in these patients is ESAs, often with the adjunct use of iron supplementation. The Canadian Society of Nephrology does not recommend targeting a hemoglobin level within the standard normal range for these patients but, rather, maintaining a level around 100 g/L. 83 Thus, patients with renal impairment who are already taking an ESA or who may have anemia requiring ESA therapy may not be candidates for treatment according to the algorithm (Figure 1). For this reason, management of perioperative anemia in patients with renal disease should be undertaken in collaboration with the patient's nephrologist.
# Conclusion
Preoperative anemia is a risk factor independently associated with a variety of postoperative complications. There is sufficient evidence from high-quality trials to inform recommendations for the diagnosis and management of pre-operative anemia. Routine screening, investigation and treatment for preoperative anemia in keeping with the evidence presented in this guideline is a cost-effective, highyield approach to optimizing anemia in any patient being assessed for major surgery. Coordinated preoperative assessment and treatment programs have proven effective in reducing rates of preoperative anemia and its associated complications, but they require collaboration among perioperative specialties including surgeons, anesthetists, internists, hematologists and perioperative nurses. 15,[26][27][28]84 Given the potential for substantial benefit to patient outcomes, as well as the efficiencies to be gained by health care systems, development of such preoperative optimization programs is recommended for all centres with moderate-to high-volume surgical services, whether academic or community-based. To ensure the effectiveness of these programs, continuous quality-assurance projects should be carried out.
# hypergLycemia
Diabetes has been defined as a fasting blood glucose level of 7.0 mmol/L or greater, a glycated hemoglobin (HbA 1c ) value of 6.5% or greater, a 2-hour plasma glucose level in a 75-g oral glucose tolerance test of 11.1 mmol/L or greater, or a random plasma glucose level of 11.1 mmol/L or greater. 85,86 Prediabetes (fasting plasma glucose level of 6.1-6.9 mmol/L, a 2-hour plasma glucose level in an oral glucose tolerance test of 7.8-11.0 mmol/L, and an HbA 1c level of 6.0%-6.4%) places patients at very high risk for diabetes. The American Diabetes Association (ADA) expands the HbA 1c range for prediabetes to 5.7%-6.4%. 86 Screening guidelines for the general population vary by organization. 85,87,88 The prevalence of diabetes continues to rise, with the disease affecting an estimated 371 million people worldwide in 2012; this number is expected to increase to 552 million by 2030. 85 In the United States, the prevalence was 9.4% in 2015, and in Canada, the estimated prevalence was 6.8% in 2009. 85,89 Diabetes is even more common in surgical patients than in the general population: patients with diabetes account for an estimated 10%-20% of all surgical patients; a further 23%-60% of surgical patients have undiagnosed diabetes. [90][91][92][93] Major surgical procedures produce a catabolic state and lead to transient hyperglycemia in patients without diabetes. This physiologic response is more pronounced in patients who have insulin resistance or no insulin production. 93 Diabetes-related complications include those from macrovascular and microvascular disease, such as myocardial infarction, stroke, retinopathy, nephropathy and neuropathy. 94 The appropriate management of hyperglycemia intraand postoperatively has been shown to improve outcomes. 95 The preoperative management of hyperglycemia is an area that can be improved. The following clinical practice guidelines summarize the evidence that we used to develop the recommendations in the proposed diagnostic and treatment algorithm for preoperative hyperglycemia (Figure 2).
# Recommendations
# Perioperative hyperglycemia increases the risk
of postoperative complications, and all patients undergoing major surgery should be screened for diabetes. In its clinical practice guidelines, Diabetes Canada recommends admission screening with a random blood glucose test for all hospitalized patients owing to a high prevalence of undiagnosed and poorly controlled diabetes. 85 Diabetes Canada and the ADA also recommend measuring the HbA 1c level in all patients with diabetes or hyperglycemia if this has not been done in the previous 3 months. 96 In addition, an increased risk of postoperative complications has been well documented in the literature for patients with preoperative hyperglycemia in many different surgical specialties. [97][98][99][100][101][102][103][104] An elevated HbA 1c level (≥ 6.5%) and perioperative hyperglycemia were associated with an increased risk of major complications (Clavien-Dindo grade III-V) in a prospective cohort of 478 patients undergoing abdominal sur-gery (OR 1.95, 95% CI 1.17-3.24). 97 Analysis of prospectively collected colorectal cancer data showed that diabetes was a risk factor for increased postoperative surgical complications such as surgical site infection (SSI), wound dehiscence, anastomotic leak, enterocutaneous fistula, ileus, hemorrhage, obstruction, urinary retention and ureteric injury (OR 1.44, 95% CI 1.02-2.04) but not mortality. 98 Patients with diabetes who had diabetic complications also had increased 30-day mortality (OR 13.7, 95% CI 3.4-54.7) and length of stay (3.8 d, 95% CI 0.7-7.1) compared to patients without complications. A systematic review showed that patients with diabetes who underwent carotid artery revascularization were at higher risk for perioperative stroke (OR 1.38, 95% CI 1.02-1.88), death (OR 1.94, 95% CI 1.36-2.75) and long-term mortality (OR 1.57, 95% CI 1.22-2.03). 99 In a large retrospective study, elevated HbA 1c levels in patients with peripheral vascular disease were associated with an increased risk of amputation and other complications. 100 Amputation was increasingly likely with HbA 1c levels of 6.1%-7.0% (HR 1.26, 95% CI 1.15-1.39), 7.1%-8.0% (HR 1.53, 95% CI 1.37-1.7) and greater than 8% (HR 2.05, 95% CI 1.87-2.26). The study also highlighted the increased risk of preoperative hyperglycemia in patients without diabetes compared to patients with diabetes with good control (HbA 1c level < 7.0%).
# E499
Preoperative hyperglycemia has also been shown to increase the rate of postoperative complications in patients undergoing cardiac surgery. A large retrospective study showed an increased risk of death or major cardiac event with an HbA 1c level of 8.1% or higher (8.1%-9.0%: HR 1.17, 95% CI 1.04-1.33; 9.1%-10.0%: HR 1.44, 95% CI 1.22-1.70; > 10.0%: HR 1.50, 95% CI 1.22-1.84). 101 Subramaniam and colleagues 102 conducted a prospective cohort study of patients undergoing coronary artery bypass grafting and found an increase in major adverse events including in-hospital death, myocardial infarction, tamponade, reoperation, SSI, renal failure, pneumonia and stroke in those with an HbA 1c level of 6.5% or higher (OR 1.6, 95% CI 1.1-2.3).
There is conflicting evidence in the orthopedic literature with regard to preoperative diabetes and HbA 1c levels. In a large NSQIP study, diabetes was found to be an in dependent predictor of postoperative complications (OR 1.67, 95% CI 2.217-1.253) and longer length of stay (OR 1.878, 95% CI 2.262-1.559). 103 Miller and colleagues 104 reported that an HbA 1c level greater than 6.4% was an independent risk factor for reoperation (HR 1.13, 95% CI 1.02-1.29) among patients who underwent spinal operations. However, 2 previous studies showed no difference in rates of postoperative joint infection, revision or DVT in patients with elevated HbA 1c levels. 105,106 Patients with previously undiagnosed diabetes (elevated HbA 1c level without a documented history of diabetes) have been shown to be at higher risk for postoperative complications than patients with known diabetes or patients with normal preoperative blood glucose levels. 92,[107][108][109] A recent systematic review showed that patients with undiagnosed diabetes have an increased risk for overall postoperative complications after bariatric (OR 1.16, 95% CI 1.00-1.33), cardiac (OR 1.148, 95% CI 1.003-1.313), colorectal (OR 2.9, 95% CI 1.1-7.9) and vascular (risk ratio [RR] 7.0, 95% CI 2.8-17.2) surgery. 92 Patients with undiagnosed diabetes undergoing cardiac surgery also have an increased risk for 30-day mortality (OR 1.53, 95% CI 1.24-1.91). 110 Using NSQIP data for patients without known diabetes, Wang and colleagues 108 found that those with elevated preoperative random blood glucose levels (5.5-8 mmol/L and 8-10 mmol/L) had significantly higher postoperative infection rates than those with normal random blood glucose levels (9.33% and 10.16% v. 5.62%; p < 0.001).
A robust association exists between postoperative hyperglycemia and postoperative morbidity and mortality in general surgery patients, which makes preoperative identification of patients at risk essential for effective perioperative planning. Kwon A systematic review of papers published from 2001 to 2013 assessing preoperative testing identified a benefit in screening patients undergoing orthopedic and vascular procedures but not other procedures. 115 However, none of the studies in the review reported on changes in clinical management based on preoperative screening. Also, patients with diabetes and patients with undiagnosed diabetes were considered together. This review, therefore, has limited utility but is helpful in identifying some benefit of screening.
Although there is insufficient evidence to show that patients with hyperglycemia (both those with known diabetes and those with previously undiagnosed diabetes) benefit from preoperative treatment, screening identifies patients who would benefit from intra-and postoperative treatment of hyperglycemia, which has been proven to reduce postoperative morbidity and mortality. 95 With routine screening, the effect of treatment can also be studied properly.
# Measurement of the HbA 1c level is the most
appropriate screening test for hyperglycemia. Although there is debate regarding the ideal test to diagnose diabetes, an HbA 1c test is easier and more convenient for patients than a fasting blood glucose or oral glucose tolerance test, and the result is less affected by day-to-day variability. 85,86 An HbA 1c test will also show the level of control over the previous 2-3 months. 87 Care must be taken to ensure that an HbA 1c assay that has been standardized by the National Glycohemoglobin Standardization Program to the Diabetes Control and Complications Trial reference is used, as considerable variation may exist between different HbA 1c assays. 85,86 Existing guidelines vary in their recommendations for screening. The Strong for Surgery program (American College of Surgeons) recommends screening all patients without a previous diagnosis of diabetes by means of a fasting blood glucose test on the morning of surgery if their body mass index is greater than 30 or they are older than 45 years. Patients with diabetes who have an HbA 1c level greater than 7.0% should be referred for optimization. The National Institute for Health and Care Excellence recommends obtaining an HbA 1c level for patients with diabetes but not screening patients with no prior history of diabetes. 116 In their guidelines for primary care physicians evaluating patients preoperatively, Feely and colleagues 117 state that, in patients with known diabetes, the preoperative HbA 1c value is more likely to be useful if results would change perioperative management. Preoperative random glucose measurement could be considered in patients at very high risk for undiagnosed diabetes and in those with signs or symptoms of undiagnosed diabetes. 117
# 3.
A preoperative HbA 1c level less than 6.0% does not require any further action or preoperative optimization. As per Diabetes Canada guidelines, an HbA 1c level less than 6.0% is generally considered to be normal and therefore does not require preoperative optimization. 85
# 4.
A preoperative HbA 1c level of 6.0%-6.9% in a patient with no history of diabetes does not require preoperative optimization. However, it may represent pre diabetes or a new diagnosis of diabetes, and the patient should be referred to a family physician, internist or endocrinologist for follow-up and confirmation. Patients with a preoperative HbA 1c level of 6.0%-6.4% are at increased risk for diabetes (prediabetic). These patients are also at higher risk for postoperative complications and should have their blood glucose monitored while in hospital 100 (see recommendation 8).
Patients with confirmed or suspected diabetes (HbA 1c level ≥ 6.5%) are at increased risk for postoperative complications, even if their HbA 1c level is within the target range. 97,102,118 After identification of a preoperative HbA 1c level of 6.5% or higher, a second confirmation test is required to diagnose diabetes unless clear symptoms are present. 85,86 These patients should be referred to their family physician, an internist or an endocrinologist for confirmation. 85 In addition, they should be referred to a community diabetes education program for ongoing support. They should receive glycemic monitoring intra-and postoperatively, and should be treated as indicated (see recommendation 8).
# 5.
A preoperative HbA 1c level of 7.0%-8.4% requires preoperative optimization, and these patients should be referred to their family physician, an internist or an endocrinologist for optimization to a target blood glucose level of 5-10 mmol/L. Patients with suboptimal glycemic control are at increased risk for postoperative complications. The ADA and Diabetes Canada recommend an HbA 1c target of less than 7% (blood glucose level < 8.5 mmol/L) for most nonpregnant patients with diabetes. 85,118 Diabetes Canada also recommends a postprandial glycemic target of 5-10 mmol/L for patients with diabetes. It has also been shown that an HbA 1c level higher than 8% increases hospital length of stay from 5.2 to 6.7 days (p = 0.02), 119 and a recent systematic review and meta-analysis showed a decrease in SSI rates (OR 0.43, 95% CI 0.29-0.64) with an intensive protocol aimed at strict intra-and postoperative blood glucose control (< 8.3 mmol/L), with no increase in rates of death or stroke related to hypoglycemia. 95 Patients with suboptimal glycemic control should receive optimization of their glycemic control regardless of whether or not they are having surgery. They should receive glycemic monitoring intra-and postoperatively, and should be treated as indicated (see recommendation 8).
# 6.
A preoperative HbA 1c level of 8.5% or greater indicates poor glycemic control and requires preoperative optimization, and these patients should be referred to an internist or endocrinologist for preoperative optimization. An HbA 1c level of 8.5% or greater is substantially above target. Postoperative complication rates have been shown to increase with increasing HbA 1c levels. 100,101 Optimization may be expedited and enhanced by the involvement of an internist or endocrinologist, and preoperative involvement may be helpful for postoperative management. These patients should receive glycemic monitoring intra-and postoperatively, and should be treated as indicated (see recommendation 8).
# Patients with known diabetes with a preoperative
HbA 1c level less than 7.0% do not require preoperative optimization. Diabetes Canada and the ADA recommend a target HbA 1c level of less than 7.0% for most nonpregnant patients with diabetes in order to reduce the risk of microvascular complications. 85,118 Below 7.0%, it is a balance among smaller incremental benefits, polypharmacy and harm from hypoglycemia. These patients should receive glycemic monitoring intra-and postoperatively, and should be treated as indicated (see recommendation 8).
# All patients (both with and without diabetes) with a
preoperative HbA 1c level greater than 6.0% should undergo intra-and postoperative blood glucose monitoring, with a target blood glucose level of 6-10 mmol/L, to reduce the risk of postoperative complications. Hyperglycemia increases the risk of postoperative complications. A large NSQIP study of 55 408 patients with diabetes undergoing noncardiac surgery showed an increased risk of postoperative infections (incidence rate ratio 1.22, 95% CI 1.04-1.43). 120 Data from the Surgical Care and Outcomes Assessment Program also confirmed an increased risk of morbidity and mortality for patients with hyperglycemia. 114 There is conflicting evidence regarding intensive versus conventional glucose control postoperatively. A recent systematic review and meta-analysis showed a reduction in SSI rates (OR 0.43, 95% CI 0.29-0.64) with an intensive protocol aimed at stricter intra-and E501 postoperative blood glucose control (< 8.3 mmol/L), with no increase in mortality or strokes related to hypoglycemia. 95 However, a previous Cochrane review did not show any difference in infectious complications or mortality, but did show an increase in hypoglycemic episodes. 121 Diabetes Canada recommends a target blood glucose level of 6-10 mmol/L for critically ill patients and those undergoing major surgery. 85 To meet this target, it is recommended that a basal bolus insulin regimen be used rather than a correctional sliding scale. 85,96
# Preoperative management of diabetic medications
All patients with diabetes should be assessed in a preadmission clinic to help with the preoperative management of their medications. The ADA suggests holding all oral hypoglycemic agents the morning of surgery and giving 50% of the dosage of NPH insulin, or 60%-80% of the dosage of long-acting analogues or basal pump insulin. 96 Hypoglycemia is a serious preventable condition that patients may experience while they are fasting and are receiving insulin or other diabetic medications, such as sulphonylureas; these patients should be monitored for hypoglycemia and treated if it develops. 96 Sodium-glucose cotransporter-2 inhibitors should be avoided during fasting owing to an association with diabetic ketoacidosis. 96,122
# Special considerations
Diabetes Canada and the ADA recommend personalized HbA 1c targets, which may translate to less stringent HbA 1c targets for older or frail patients. 85,123 It is important to consider this when such patients are presenting for surgery, as they may have higher HbA 1c levels than expected. Regardless, it is still important to assess and treat them for hyperglycemia perioperatively to decrease the risk of associated complications.
# Conclusion
Surgical patients with preoperative hyperglycemia are at increased risk for postoperative complications regardless of surgical specialty. There is a lack of evidence regarding screening for hyperglycemia and optimization of preoperative hyperglycemia. In the absence of high-quality prospective studies assessing the benefits of preoperative management of hyperglycemia, it would be appropriate to treat patients undergoing major surgical procedures according to guidelines that address the management of diabetes in the general population. Given the high rate of undiagnosed diabetes and prediabetes in surgical patients, patients undergoing major surgery should be screened so that treatment may be initiated, as there is a clear benefit of proper intra-and postoperative control of hyperglycemia.
# smoking
Tobacco smoking remains highly prevalent in North America, and, despite decreased rates in recent decades, it remains the leading cause of preventable disease and death in Canada. 124 In 2016, 16.9% of Canadians aged 13 years or older (roughly 5.2 million people) were reported to be smokers. 125 The prevalence of smoking in clinical populations is even higher (> 20%). 126 Clinicians may not appreciate the adverse effect of smoking on postsurgical outcomes. 127 For example, a retrospective cohort study of more than 600 000 patients who underwent noncardiac surgery showed that preoperative smoking was associated with a 40% increase in 30-day mortality (OR 1.38, 95% CI 1.11-1.72) and a 70% increase in major morbidity (OR 1.72, 95% CI 1.67-1.78). 128 Several systematic reviews and meta-analyses have shown that interventions that help patients quit smoking before surgery lead to reductions in adverse surgical outcomes, including wound, pulmonary and overall complications. 129,130 The following clinical practice guideline summarizes the current evidence informing the recommendations within the proposed diagnostic and treatment algorithm for preoperative smoking (Figure 3).
# Recommendations
# Tobacco smoking is associated with increased
adverse postoperative outcomes, and all patients undergoing major surgery should have their smoking status identified and documented at every preoperative clinic visit. A retrospective review of 400 000 patients who underwent noncardiac surgery showed that, compared to nonsmokers, smokers had a 29% increase in 30-day mortality (OR 1.29, 95% CI 1.20-1.39) and a 55% increase in 1-year mortality (OR 1.55, 95% CI 1.50-1.61). 131 One-year postoperative mortality decreased significantly for prior smokers who had not smoked in the previous year (OR 1.14, 95% 1.10-1.19). 131 A meta-analysis of 107 studies published since 2000 showed preoperative smoking to be significantly associated with general morbidity (RR 1.52, 95% CI 1. 130 Smoking is a demonstrated risk factor in most surgical procedures, increasing rates of incisional hernia after laparotomy (OR 3.93, 95% CI 1.82-8.49), 132 spinal fusion nonunion (OR 2.01; p < 0.02), 133 disease recurrence (HR 1.25; p = 0.02) and metastasis (HR 2.64; p = 0.03) after radical prostatectomy, 134 anastamotic leakage after anterior resection for rectal cancer (OR 1.88, 95% CI 1.02-3.46) 135 and fracture after shoulder arthroplasty (HR 3.63; p = 0.02). 136 Smoking also leads to increased wound complication rates after both laparoscopic (OR 1.20; p = 0.02) and open (OR 1.28; p = 0.01) cholecystectomy, and results in a longer average postoperative length of stay, by 2-4 days (p < 0.001). 137 Although roughly 25% of surgical patients are smokers, 128 more than half of patients undergoing elective outpatient procedures report not having been informed about the adverse effects of smoking before surgery. 138 Of 116 consecutive patients surveyed after a surgical clinic appointment at a Canadian tertiary care centre, less than 10% had been asked about smoking status, and none had been asked about quitting or offered any form of intervention. 139 Smoking status should be documented systematically in all patients undergoing surgery. Combining clinician training with a charting system has been shown to increase the rates of assessing tobacco use, setting a quit date, providing materials and arranging for follow-up. 140 2. All surgical patients who smoke should be advised to quit smoking preoperatively and have their willingness to quit assessed to guide next steps. Because of the high risk of relapse, those who have quit within the previous 6 months should be treated as active smokers. More than 70% of all tobacco smokers report wanting to quit. 140 Half of Canadian smokers try to quit each year, 141 but patient-driven smoking cessation is ineffective: 80%-90% of self-quitters relapse within 3 months of cessation, and less than 5% achieve long-term success. 141 However, patients often view surgery as a "wake-up call" regarding their health and are more likely to be receptive to advice offered by health care professionals, particularly regarding the perioperative risks of smoking, at this time. [142][143][144] A recent systematic review and meta-analysis suggested that cessation rates almost doubled (from 24.5% to 46.2%; effect size g = 0.56, 95% CI 0.32-0.80) before surgery with proactive, clinician-driven behavioural interventions. 145 The preoperative period is therefore an ideal time to intervene.
All patients who smoke should be advised to quit preoperatively in a clear, strong and personalized way, and have their willingness to quit assessed. 140 It is important to stratify patients by willingness to quit to determine the best management approach (see recommendations [3][4][5]. Those who are willing to quit should set a quit date, and can choose between abrupt cessation or gradual reduction leading up to their quit date, which were shown to be equally effective in a meta-analysis of quit approaches (RR 0.94, 95% CI 0.79-1.13). 146 Among those who are unwilling to quit but willing to reduce the amount smoked per day, the use of pharmacotherapy should be encouraged to assist with smoking reduction. 147 Increased cessation rates have been reported after motivational
# E503
interviewing (a patient-centred approach focusing on the "5 Rs" strategy: relevance, risks, rewards, roadblocks and repetition at every visit 140 ) among patients who were in itially unwilling to quit. 140 Smoking relapse most frequently occurs early after quitting but can occur as late as months to years later. 148 A Cochrane review of 63 RCTs showed that multiple behavioural techniques used by patients to prevent relapse failed to show any benefit but that success rates may be improved with pharmacotherapy. 149 Given the high relapse rate, we recommend treating patients who have quit within the previous 6 months as active smokers. This provides them with the best available evidence-based cessation treatments to promote sustained abstinence.
# 3.
A quit date should be set more than 8 weeks preoperatively to achieve the most substantial improvements in postoperative outcomes; however, outcome benefits may still be seen with cessation as late as the day of surgery. In a meta-analysis of 25 RCTs and cohort studies (combined n > 21 000), smoking cessation more than 8 weeks before surgery significantly reduced rates of postoperative pulmonary complications compared to active smoking (RR 0.53, 95% CI 0.37-0.76), with rates approaching those among nonsmokers (RR 1.16, 95% CI 0.76-1.77). 150 Cessation 4 weeks preoperatively had a smaller but significant effect on pulmonary complication rates (RR 0.77, 95% CI 0.61-0.96), but the risk remained higher than that among nonsmokers (RR 1.39, 95% CI 1.18-1.65). There was no significant pulmonary benefit to cessation 2-4 weeks or less than 2 weeks preoperatively (RR 1.14, p = 0.3; and RR 1.20, p = 0.1, respectively). 150 The same meta-analysis also showed that smoking cessation more than 3-4 weeks preoperatively reduced wound complication rates (RR 0.69, 95% CI 0.56-0.84), with rates approaching those among nonsmokers (RR 1.44, 95% CI 0.97-2.15). 150 A retrospective cohort study of 188 patients with head or neck cancer with flaps showed a similar reduction in wound failure rates among smokers who quit 3-6 weeks (RR 0.17, 95% CI 0.04-0.75) or more than 6 weeks (RR 0.17, 95% CI 0.05-0.60) before surgery. 151 Two landmark RCTs involving behavioural interventions and nicotine replacement therapy (NRT) showed improved postsurgical outcomes with smoking cessation programs 4 weeks or less before surgery. 152,153 Møller and colleagues 152 found that a program with a target quit date of 4 weeks before surgery led to significant reductions in rates of overall (18% v. 52%; p < 0.001) and wound-related (5% v. 31%; p = 0.001) complications. Lindström and colleagues 153 reported that a program with a target quit date of 3 weeks before surgery was associated with a significant reduction in any postoperative complication (21% v. 41%; RR 0.51; p = 0.03).
A recent observational nested matched case-control study showed benefit to quitting as late as the day of surgery, showing a significant decrease in SSI rates (OR 1.96, 95% CI 1.23-3.13). 154 However, 2 prior studies showed no significant reduction in wound complication rates with cessation less than 3 weeks before surgery. 150,151 4. In patients who are unwilling to quit smoking, motivational interviewing techniques can be used to increase motivation to quit, thereby increasing quit rates. An RCT involving 616 patients who were unmotivated to quit smoking showed that motivational interviewing based on the US Public Health Service 2008 smoking cessation guideline 140 led to a quit rate of 23% at 6 months and an average reduction of 30% in the amount smoked per day. 155 Motivational interviewing is a specialized skill, and interested clinicians can learn more 140 or consider referral to a specialist. Even patients unwilling to quit should be encouraged to abstain from smoking at least 24 hours before surgery, as this may reduce the occurrence of SSI. 154
# In patients who are unwilling to quit smoking but
willing to reduce, clinicians should offer full cessation treatment to support reduction goals. In a meta-analysis of RCTs involving smokers who did not intend to quit, smoking-reduction support with pharmacotherapy versus no intervention was found to be beneficial in achieving complete cessation (RR 1.93, 95% CI 1.41-2.64). 147 Of note, the authors used only long-term followup (> 6 mo) data, and, to our knowledge, no similar shorter-term data exist. Although the data are limited, pharmacotherapy is likely a major contributor to the success of smoking-reduction plans. Reduction counselling and support alone versus no intervention did not significantly increase abstinence (RR 1.49, 95% CI 0.56-3.93). Both reduction counselling and support with varenicline therapy (RR 2.66, 95% CI 2.10-3.36) and reduction counselling and support with NRT (RR 1.94, 95% CI 1.26-3.00) were far superior to reduction support with placebo.
Although there is currently no good evidence that preoperative smoking reduction without cessation improves surgical outcomes, 152 supporting surgical patients who are interested in smoking reduction preoperatively has no adverse consequences, improves long-term quit rates and may lead to preoperative cessation. 147 6. All surgical patients who smoke should be offered the combination of counselling and pharmacotherapy preoperatively. When this is not possible, they should still be offered either intervention individually. Both pharmacotherapy and cessation counselling are effective alone 145,156,157 and should be provided even if a patient is not interested in combined therapy. Whenever possible, patients who are willing to quit should be provided both interventions: a meta-analysis showed that combining therapies has increased efficacy compared to pharmacotherapy (OR 1.4, 95% CI 1.2-1.6) or behavioural therapy (OR 1.7, 95% CI 1.3-2.1) alone. 140 7. All surgical patients who smoke should be offered combination nicotine replacement therapy (NRT) preoperatively. Prescribers capable of follow-up may consider varen icline as a first-line agent. Second-line options include single-agent NRT and bupropion. Three therapies approved in Canada have been shown to increase smoking cessation rates in the general population: varenicline, NRT and bupropion. 158 156 Nicotine replacement therapy options are sold over the counter, whereas both varenicline and bupropion require a prescription. 156 We recommend combination NRT and varenicline as first-line treatments, as they are the most effective smokingcessation interventions (Appendix 1), with no significant difference between them in direct comparison (OR 1.06, 95% CI 0.75-1.48). 156 Combination NRT has no absolute contraindications 156 or required follow-up, and was associated with reduced postoperative complication rates in 2 RCTs. 152,153 It can easily be prescribed by surgeons, who can place patient concerns about the cost of patches ($20/ wk) and adjuncts ($15-$40/wk) in the context of savings from cigarette purchases 159 and overall health benefits.
Varenicline is the most effective monotherapy for smoking cessation (OR 2.89, 95% CI 2.40-3.48) 156 but has not been as well studied in the perioperative setting as NRT. Wong and colleagues 160 reported that 12 weeks of varenicline therapy initiated 1 week preoperatively significantly increased cessation rates 1 year after surgery (RR 1.45; p = 0.04). Given its efficacy, we consider varenicline a first-line treatment.
Bupropion is an atypical antidepressant that has been shown to improve smoking cessation rates versus placebo (OR 1.85, 95% CI 1.63-2.10). 156 It is contraindicated in patients with increased seizure risk. As it has not been well studied in the perioperative setting and is less effective than both combination NRT and varenicline, we consider it a second-line option.
Randomized controlled trials across 140 centres in 16 countries have shown no evidence that any of these 3 therapies are associated with an increased risk of adverse cardiovascular 161 or neuropsychiatric 162 events. A 2012 systematic review showed no clinical evidence of a detrimental effect of NRT on postoperative wound or tissue healing. 163 8. All surgical patients who smoke should be given brief counselling on the consequences of smoking and the benefits of smoking cessation preoperatively. When possible, counselling should be face to face, frequent and of sufficient duration, all of which increase cessation rates. Physician counselling to quit smoking has been shown to increase the likelihood of short-term abstinence by 30% (OR 1.3, 95% CI 1.1-1.6), and even interventions as brief as 3 minutes can increase cessation rates significantly (OR 1.3, 95% CI 1.01-1.60). 140 A meta-analysis of 22 studies in patients scheduled to undergo elective surgery showed 6 behaviour-change techniques leading to higher rates of smoking abstinence: provision of information on the consequences of smoking and smoking cessation; facilitation of goal setting; prompt review of cessation goals; regular monitoring by others (e.g., friends or family members); options for additional and later support; and provision of information on withdrawal symptoms. 145 Of these, providing information on the consequences of smoking and smoking cessation was the most significant predictor of quitting (β = 0.69, p = 0.01). Counselling interventions may be delivered (in order of most to least effective) face to face, by telephone, over the Internet 164 or in print. Higher cessation rates have been shown with increased duration (β = 0.01, p = 0.02) and frequency (β = 0.22, p = 0.002) of intervention sessions, 145 which is reflected in the US and Canadian guidelines. 140,165 Several other techniques have been attempted in perioperative RCTs, without evidence of increased preoperative cessation rates. These include a decision aid with laminated graphics to facilitate discussion, 166 a behavioral tapering regimen (scheduled reduced smoking) via handheld computer 167 and planned checks of carbon monoxide levels on the day of surgery. 168 9. All surgical patients who smoke should be offered clinical follow-up. Offering follow-up provides cessation support after the in itial intervention, and follow-up interventions with increased frequency are more effective. 140 Lindström and colleagues 153 reported that a weekly face-to-face or telephone intervention of smoking cessation therapy with individual counselling and NRT delivered by a trained nurse starting 4 weeks preoperatively led to both increased perioperative cessation rates (39.6% v. 1.9%) and decreased postoperative complication rates (21% v. 41%, p = 0.03) compared to standard care.
A meta-analysis of RCTs or quasi-randomised controlled trials in which telephone counselling was offered to smokers or recent quitters to assist smoking cessation showed an increase in smoking cessation rates when used as the primary intervention (RR 1.34, 95% CI 1.22-1.46), when following a face-to-face intervention (RR 1.41, 95% CI 1.20-1.66) and when used as an adjunct to NRT or varenicline (RR 1.14, 95% CI 1.03-1.27). 169 Having 3 or more follow-up telephone calls showed additional benefit (RR 1.32, 95% CI 1.23-1.42). In busy surgical clinics, repeat preoperative visits and follow-up with specialized nurses may not always be feasible or cost-effective. Lee and colleagues 170 conducted an RCT in which patients seen at least 3 weeks preoperatively received either no specific smoking-cessation intervention, or an intervention consisting of brief counselling by the preadmission nurse, brochures on smoking cessation, referral to a smokers helpline (available at no cost in all Canadian provinces) and a free 6-week supply of NRT. Significantly reduced smoking rates were observed in the intervention group at the time of surgery (14.3% v. 3.6%; p = 0.03).
# Conclusion
Smoking is the most important risk factor for postoperative complications and should be routinely identified, docu mented and treated preoperatively according to the patient's willingness to quit. By targeting a quit date of at least 8 weeks before surgery and offering a combination of brief counselling with pharmacotherapy and follow-up, clin icians can reduce perioperative smoking rates and postoperative complication rates. Given the minimal time and resources required, along with the substantial benefits of cessation, a preoperative smoking-cessation program should be offered in all surgical clinics.
# Acknowledgement:
The authors acknowledge the contributions of
#
Content licence: This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY-NC-ND 4.0) licence, which permits use, distribution and reproduction in any medium, provided that the original publication is properly cited, the use is noncommercial (i.e., research or educational use), and no modifications or adaptations are made. See: https://creativecommons. org/licenses/by-nc-nd/4.0/. | None | None |
c52a4787e82346ebeea894034e6bf6cc39808ce9 | cma | None | This guideline deals with investigation of blood on dipstick urine testing and proven microscopic hematuria in outpatient adults (age 19 and over). Gross hematuria workup is outside of the scope of this guideline. This guideline has been updated in order to limit the unnecessary evaluation (cytology, imaging, & referral) of patients without true microscopic hematuria.- Significant microscopic hematuria is defined as 3 or more RBC/hpf (≥ 3 RBC/hpf) on urine microscopy o Positive dipstick for hemoglobinuria requires confirmation with urine microscopy testing o Insignificant microscopic hematuria (0-2 RBC/hpf) does not require further investigation - Urine microscopy should be collected at the laboratory as the sample must be analysed within 2-3 hours. - Urine cytology is no longer recommended for routine workup of asymptomatic microscopic hematuria. 1 - A single positive urine microscopy (≥ 3 RBC/hpf) should initiate workup as microscopic hematuria is known to be highly intermittent, even in the setting of significant underlying pathology. 1 - Significant microscopic hematuria (≥ 3 RBC/hpf) should be investigated with renal function testing (urine albumin-to creatinine ratio (ACR), creatinine/eGFR), blood pressure, imaging and possible referral to urology (as per algorithm below). - The first line recommended imaging test in most circumstances for the investigation of significant microscopic hematuria is kidney/bladder ultrasound. - Cystoscopy is recommended for patients with significant microscopic hematuria over the age of 40 or at any age for those with risk factors for urologic malignancy or abnormality on imaging (see Table 1). 2,3 - Following a negative workup, urine microscopy, renal function (urine ACR, creatinine/eGFR), blood pressure and urine cytology (if risk factors for urothelial cancer are present) should be followed annually (follow-up can be discontinued after 3 years of negative testing). 2 - Indications for repeat investigation: o Repeat investigation should be undertaken for gross hematuria, new urinary symptoms, or increasing degree of microscopic hematuria, proteinuria, or declining renal function. o Consideration should be given to repeat investigation if microscopic hematuria persists 3-5 years after initial workup. 2 - Screening the general population for microscopic hematuria is not currently recommended.# Background
- The prevalence of microscopic hematuria in the general population ranges from 2.4 to 31.1%. 4 - Microscopic hematuria in adults is often an incidental finding but may be associated with urologic malignancy in up to 10% of cases. 5 - 33% of male patients ≥ 50 years with hemoglobinuria will ultimately be found to have urologic disease requiring intervention (among whom 25% will have malignancy). 6 - Smoking is the most important risk factor for bladder cancer.
- In those over 40 years with microscopic hematuria, the incidence of underlying renal or bladder malignancy increases with age. 2 - Bladder cancer is three times more common in men than in women. 4 - Microscopic hematuria is also frequently associated with renal parenchymal disease (e.g. glomerular disease). 1 - This guideline has been updated to limit the unnecessary evaluation (cytology, referral, imaging) of patients without true microscopic hematuria (≥ 3 RBC/hpf by urine microscopy). Only 14-18% of patients with a positive dipstick have ≥ 3 RBC/hpf by urine microscopy. 7
# Definition
- Microscopic hematuria is defined as the presence of 3 or more red blood cells (≥ 3 RBC) per high power field (hpf) on a urine microscopy evaluation. 1 o Hemoglobinuria on dipstick requires confirmation on urine microscopy before considering investigation.
# Risk Factors
Hematuria is the most common sign of bladder cancer. However, the incidence of bladder cancer in patients with microscopic hematuria is low. 4
# Screening for Microscopic Hematuria
- Although there is some evidence to support screening in the general population, 6,11 the balance of current evidence and expert opinion is such that screening for microscopic hematuria (with either dipstick or urine microscopy) is not currently recommended. See the Controversies in Care section below. - There is controversy around whether screening high-risk groups has value. See the Controversies in Care section below.
# Diagnosis/Investigation
- If hemoglobinuria is detected on urine dipstick testing (see algorithm below):
- Rule out possible contributing factors such as infection, menstruation, vigorous exercise, trauma to urethra, sexual activity, urological instrumentation, recent prostate exam, or viral illness. o If these factors are present, repeat the dipstick after resolution of this potentially contributing factor. o If the dipstick remains positive, confirm with laboratory urine microscopy.
- Further investigation as per the algorithm is warranted if significant microscopic hematuria (≥ 3 RBC/hpf) is present.
- Insignificant microscopic hematuria (≤ 2 RBC/hpf) does not require further investigation.
- Repeat testing may be considered based on clinician discretion and degree of suspicion of occult disease. o Causes of false positive results for blood on dipstick include: free hemoglobin or myoglobin, menstrual blood, recent exercise and dehydration. Therefore, a positive urine dipstick for blood with a negative urine microscopy (≤ 2 RBC/hpf) can occur. 12,13 Important considerations - Rule out infection prior to further workup/referral for microscopic hematuria. 1 Refer to the BC Guideline: Urinary Tract Infection in the Primary Care Setting -Investigation. o It cannot be assumed that isolated hematuria represents a urinary tract infection. 14
- The degree of hematuria does not correlate with the severity of the underlying disease. 5
- Anticoagulants, including aspirin, predispose patients to hematuria only in the presence of urinary tract disease. It is recommended that patients on anticoagulants with significant microscopic hematuria (≥ 3 RBC/hpf) be investigated.
# Microscopic evaluation to confirm positive dipstick results
Note: Cytology is a poor screening test and is not recommended in the initial workup *Please note that imaging does not completely assess the lower urinary tract. Patient may require referral to either or both urology or nephrology.
# Follow-up after Negative Workup
- No cause will be found for microscopic hematuria in many cases.
- When no specific cause for persistent microscopic hematuria is found, the patient should be followed annually with: 2,3 o Urine ACR o Urine microscopy o Creatinine/eGFR o Blood pressure o Urine cytology (only in patients with risk factors for urothelial cancer) 3
- If patients develop gross hematuria, new urinary symptoms, or increasing degree of microscopic hematuria, proteinuria, or declining renal function, reinvestigation as per algorithm should be undertaken. - If, after initial investigation, the degree of microscopic hematuria persists unchanged on annual follow-up, repeat investigation within 3-5 years should be considered. 1 - If three consecutive annual urine microscopies are negative, follow-up testing can be discontinued. 1
# Tests 1) Urine dipstick vs. urine microscopy
- Unexplained hemoglobinuria on dipstick requires investigation prior to referral.
- Urine dipstick lacks the ability to distinguish red blood cells from myoglobin or hemoglobin. o A positive dipstick test requires follow-up examination with urine microscopy to confirm the presence of red blood cells. 1
- Urine microscopy can distinguish between dysmorphic red cells (renal parenchyma) and isomorphic red cells (urinary collecting system) providing potential insight as to the source of hematuria and direction as to whether a nephrology referral is required in addition to referral to urology. 2 - Collection method for urine dipstick and urine microscopy:
- The specimen for urine microscopy must be examined while fresh (within 2-3 hours). This means the patient should go to the lab to give their specimen. o For any follow-up urine microscopy, sending the patient to the same lab helps with analytical consistency. o A midstream specimen collected in a clean container without prior cleansing of the genitalia provides a satisfactory sample. o If the specimen is likely to be contaminated by vaginal discharge or menstrual blood, repeat the sample after resolution.
# 2) Urine cytology studies:
- Urine cytology studies are no longer recommended for investigation of asymptomatic microscopic hematuria. 1 - Urine cytology is still recommended for gross hematuria and symptomatic microscopic hematuria (for which other modifiable etiologies have been ruled out). 3
3) Imaging:
- Patients who have evidence of renal parenchymal disease (glomerulopathy) may be appropriately investigated with kidney/bladder ultrasound.
# - In most cases, kidney/bladder ultrasound is the preferred initial investigation.
- Kidney/bladder ultrasound and computed tomography intravenous pyelogram (CTIVP) are often used to evaluate the upper urinary tract of patients with microscopic hematuria. o Traditional intravenous pyelogram (IVP) is still a valid test, however, it is no longer available at many institutions having been supplanted by CTIVP (which provides better detection of renal masses and stones). o Kidney/bladder ultrasound has comparable sensitivity and specificity, as well as lower morbidity and costs than CTIVP and traditional IVP.
- There is no imaging test (including kidney/bladder ultrasound, CTIVP, and traditional IVP) that completely assesses the lower urinary tract. For this, cystoscopy is required. a) Kidney/bladder ultrasound Strengths: inexpensive and safest detection of solid masses > 3cm in diameter and hydronephrosis, no ionizing radiation. Limitations: detection of solid tumors < 3cm in diameter. Kidney bladder ultrasound is preferred over IVP and CT as it has comparable sensitivity and specificity and lower morbidity and costs.
# b) Computed Tomography Intravenous Pyelogram (CTIVP)
Strengths: detection of renal calculi, small renal and pararenal abscesses, small renal tumors, upper tract urothelial tumors. Limitations: high cost and limited availability in some areas, equivalent to 2-3 years background radiation exposure. Note: CTKUB (non contrast CT) and single phase contrast enhanced CT (CT abdomen and pelvis) are not adequate investigations for hematuria.
# c) Traditional Intravenous Pyelogram (IVP)
Strengths: detecting transitional cell carcinoma of kidney/ureter or renal masses > 3cm in diameter.
Limitations: detecting renal masses < 3cm or lesions of the bladder or urethra, equivalent to 1 year background radiation exposure. Screening high-risk groups for microscopic hematuria to detect bladder cancer - There is conflicting evidence supporting screening high-risk groups for microscopic hematuria. o In 2017, the SIU-ICUD suggested that targeted screening in those with occupational exposure to potential carcinogens could remove challenges caused by testing the general population. 4 The SIU-ICUD considered targeted annual screening with cytology and dipstick of high-risk groups. o However, a study which included those at high-risk for bladder cancer based on age, smoking status or occupational exposure had a low rate of bladder cancer detection. 4,16
# Methodology
These guideline recommendations are tailored to support practice in British Columbia and are based on guidance by the American Urological Association, 1 Canadian Urological Association 2 and Canadian Consensus statement. 3 Where available, key references are provided. In situations where there is a lack of rigorous evidence, we provide best clinical opinion to support decision making and high-quality patient care. The guideline development process included significant engagement and consultation with primary care providers, specialists and key stakeholders, including with Provincial Laboratory Medicine Services. For more information about GPAC guideline development processes, refer to the GPAC handbook available at BCGuidelines.ca.
# Resources
Practitioner Resources
The principles of the Guidelines and Protocols Advisory Committee are to:
- encourage appropriate responses to common medical situations - recommend actions that are sufficient and efficient, neither excessive nor deficient - permit exceptions when justified by clinical circumstances | This guideline deals with investigation of blood on dipstick urine testing and proven microscopic hematuria in outpatient adults (age 19 and over). Gross hematuria workup is outside of the scope of this guideline. This guideline has been updated in order to limit the unnecessary evaluation (cytology, imaging, & referral) of patients without true microscopic hematuria.• Significant microscopic hematuria is defined as 3 or more RBC/hpf (≥ 3 RBC/hpf) on urine microscopy o Positive dipstick for hemoglobinuria requires confirmation with urine microscopy testing o Insignificant microscopic hematuria (0-2 RBC/hpf) does not require further investigation • Urine microscopy should be collected at the laboratory as the sample must be analysed within 2-3 hours. • Urine cytology is no longer recommended for routine workup of asymptomatic microscopic hematuria. 1 • A single positive urine microscopy (≥ 3 RBC/hpf) should initiate workup as microscopic hematuria is known to be highly intermittent, even in the setting of significant underlying pathology. 1 • Significant microscopic hematuria (≥ 3 RBC/hpf) should be investigated with renal function testing (urine albumin-to creatinine ratio (ACR), creatinine/eGFR), blood pressure, imaging and possible referral to urology (as per algorithm below). • The first line recommended imaging test in most circumstances for the investigation of significant microscopic hematuria is kidney/bladder ultrasound. • Cystoscopy is recommended for patients with significant microscopic hematuria over the age of 40 or at any age for those with risk factors for urologic malignancy or abnormality on imaging (see Table 1). 2,3 • Following a negative workup, urine microscopy, renal function (urine ACR, creatinine/eGFR), blood pressure and urine cytology (if risk factors for urothelial cancer are present) should be followed annually (follow-up can be discontinued after 3 years of negative testing). 2 • Indications for repeat investigation: o Repeat investigation should be undertaken for gross hematuria, new urinary symptoms, or increasing degree of microscopic hematuria, proteinuria, or declining renal function. o Consideration should be given to repeat investigation if microscopic hematuria persists 3-5 years after initial workup. 2 • Screening the general population for microscopic hematuria is not currently recommended.# Background
• The prevalence of microscopic hematuria in the general population ranges from 2.4 to 31.1%. 4 • Microscopic hematuria in adults is often an incidental finding but may be associated with urologic malignancy in up to 10% of cases. 5 • 33% of male patients ≥ 50 years with hemoglobinuria will ultimately be found to have urologic disease requiring intervention (among whom 25% will have malignancy). 6 • Smoking is the most important risk factor for bladder cancer.
• In those over 40 years with microscopic hematuria, the incidence of underlying renal or bladder malignancy increases with age. 2 • Bladder cancer is three times more common in men than in women. 4 • Microscopic hematuria is also frequently associated with renal parenchymal disease (e.g. glomerular disease). 1 • This guideline has been updated to limit the unnecessary evaluation (cytology, referral, imaging) of patients without true microscopic hematuria (≥ 3 RBC/hpf by urine microscopy). Only 14-18% of patients with a positive dipstick have ≥ 3 RBC/hpf by urine microscopy. 7
# Definition
• Microscopic hematuria is defined as the presence of 3 or more red blood cells (≥ 3 RBC) per high power field (hpf) on a urine microscopy evaluation. 1 o Hemoglobinuria on dipstick requires confirmation on urine microscopy before considering investigation.
# Risk Factors
Hematuria is the most common sign of bladder cancer. However, the incidence of bladder cancer in patients with microscopic hematuria is low. 4
# Screening for Microscopic Hematuria
• Although there is some evidence to support screening in the general population, 6,11 the balance of current evidence and expert opinion is such that screening for microscopic hematuria (with either dipstick or urine microscopy) is not currently recommended. See the Controversies in Care section below. • There is controversy around whether screening high-risk groups has value. See the Controversies in Care section below.
# Diagnosis/Investigation
• If hemoglobinuria is detected on urine dipstick testing (see algorithm below):
o Rule out possible contributing factors such as infection, menstruation, vigorous exercise, trauma to urethra, sexual activity, urological instrumentation, recent prostate exam, or viral illness. o If these factors are present, repeat the dipstick after resolution of this potentially contributing factor. o If the dipstick remains positive, confirm with laboratory urine microscopy.
• Further investigation as per the algorithm is warranted if significant microscopic hematuria (≥ 3 RBC/hpf) is present.
• Insignificant microscopic hematuria (≤ 2 RBC/hpf) does not require further investigation.
o Repeat testing may be considered based on clinician discretion and degree of suspicion of occult disease. o Causes of false positive results for blood on dipstick include: free hemoglobin or myoglobin, menstrual blood, recent exercise and dehydration. Therefore, a positive urine dipstick for blood with a negative urine microscopy (≤ 2 RBC/hpf) can occur. 12,13 Important considerations • Rule out infection prior to further workup/referral for microscopic hematuria. 1 Refer to the BC Guideline: Urinary Tract Infection in the Primary Care Setting -Investigation. o It cannot be assumed that isolated hematuria represents a urinary tract infection. 14
• The degree of hematuria does not correlate with the severity of the underlying disease. 5
• Anticoagulants, including aspirin, predispose patients to hematuria only in the presence of urinary tract disease. It is recommended that patients on anticoagulants with significant microscopic hematuria (≥ 3 RBC/hpf) be investigated.
# Microscopic evaluation to confirm positive dipstick results
Note: Cytology is a poor screening test and is not recommended in the initial workup *Please note that imaging does not completely assess the lower urinary tract. **Patient may require referral to either or both urology or nephrology.
# Follow-up after Negative Workup
• No cause will be found for microscopic hematuria in many cases.
• When no specific cause for persistent microscopic hematuria is found, the patient should be followed annually with: 2,3 o Urine ACR o Urine microscopy o Creatinine/eGFR o Blood pressure o Urine cytology (only in patients with risk factors for urothelial cancer) 3
• If patients develop gross hematuria, new urinary symptoms, or increasing degree of microscopic hematuria, proteinuria, or declining renal function, reinvestigation as per algorithm should be undertaken. • If, after initial investigation, the degree of microscopic hematuria persists unchanged on annual follow-up, repeat investigation within 3-5 years should be considered. 1 • If three consecutive annual urine microscopies are negative, follow-up testing can be discontinued. 1
# Tests 1) Urine dipstick vs. urine microscopy
• Unexplained hemoglobinuria on dipstick requires investigation prior to referral.
• Urine dipstick lacks the ability to distinguish red blood cells from myoglobin or hemoglobin. o A positive dipstick test requires follow-up examination with urine microscopy to confirm the presence of red blood cells. 1
• Urine microscopy can distinguish between dysmorphic red cells (renal parenchyma) and isomorphic red cells (urinary collecting system) providing potential insight as to the source of hematuria and direction as to whether a nephrology referral is required in addition to referral to urology. 2 • Collection method for urine dipstick and urine microscopy:
o The specimen for urine microscopy must be examined while fresh (within 2-3 hours). This means the patient should go to the lab to give their specimen. o For any follow-up urine microscopy, sending the patient to the same lab helps with analytical consistency. o A midstream specimen collected in a clean container without prior cleansing of the genitalia provides a satisfactory sample. o If the specimen is likely to be contaminated by vaginal discharge or menstrual blood, repeat the sample after resolution.
# 2) Urine cytology studies:
• Urine cytology studies are no longer recommended for investigation of asymptomatic microscopic hematuria. 1 • Urine cytology is still recommended for gross hematuria and symptomatic microscopic hematuria (for which other modifiable etiologies have been ruled out). 3
3) Imaging:
• Patients who have evidence of renal parenchymal disease (glomerulopathy) may be appropriately investigated with kidney/bladder ultrasound.
# • In most cases, kidney/bladder ultrasound is the preferred initial investigation.
o Kidney/bladder ultrasound and computed tomography intravenous pyelogram (CTIVP) are often used to evaluate the upper urinary tract of patients with microscopic hematuria. o Traditional intravenous pyelogram (IVP) is still a valid test, however, it is no longer available at many institutions having been supplanted by CTIVP (which provides better detection of renal masses and stones). o Kidney/bladder ultrasound has comparable sensitivity and specificity, as well as lower morbidity and costs than CTIVP and traditional IVP.
• There is no imaging test (including kidney/bladder ultrasound, CTIVP, and traditional IVP) that completely assesses the lower urinary tract. For this, cystoscopy is required. a) Kidney/bladder ultrasound Strengths: inexpensive and safest detection of solid masses > 3cm in diameter and hydronephrosis, no ionizing radiation. Limitations: detection of solid tumors < 3cm in diameter. Kidney bladder ultrasound is preferred over IVP and CT as it has comparable sensitivity and specificity and lower morbidity and costs.
# b) Computed Tomography Intravenous Pyelogram (CTIVP)
Strengths: detection of renal calculi, small renal and pararenal abscesses, small renal tumors, upper tract urothelial tumors. Limitations: high cost and limited availability in some areas, equivalent to 2-3 years background radiation exposure. Note: CTKUB (non contrast CT) and single phase contrast enhanced CT (CT abdomen and pelvis) are not adequate investigations for hematuria.
# c) Traditional Intravenous Pyelogram (IVP)
Strengths: detecting transitional cell carcinoma of kidney/ureter or renal masses > 3cm in diameter.
Limitations: detecting renal masses < 3cm or lesions of the bladder or urethra, equivalent to 1 year background radiation exposure. Screening high-risk groups for microscopic hematuria to detect bladder cancer • There is conflicting evidence supporting screening high-risk groups for microscopic hematuria. o In 2017, the SIU-ICUD suggested that targeted screening in those with occupational exposure to potential carcinogens could remove challenges caused by testing the general population. 4 The SIU-ICUD considered targeted annual screening with cytology and dipstick of high-risk groups. o However, a study which included those at high-risk for bladder cancer based on age, smoking status or occupational exposure had a low rate of bladder cancer detection. 4,16
# Methodology
These guideline recommendations are tailored to support practice in British Columbia and are based on guidance by the American Urological Association, 1 Canadian Urological Association 2 and Canadian Consensus statement. 3 Where available, key references are provided. In situations where there is a lack of rigorous evidence, we provide best clinical opinion to support decision making and high-quality patient care. The guideline development process included significant engagement and consultation with primary care providers, specialists and key stakeholders, including with Provincial Laboratory Medicine Services. For more information about GPAC guideline development processes, refer to the GPAC handbook available at BCGuidelines.ca.
# Resources
Practitioner Resources
#
The principles of the Guidelines and Protocols Advisory Committee are to:
• encourage appropriate responses to common medical situations • recommend actions that are sufficient and efficient, neither excessive nor deficient • permit exceptions when justified by clinical circumstances
# Disclaimer
The Clinical Practice Guidelines (the "Guidelines") have been developed by the Guidelines and Protocols Advisory Committee on behalf of the Medical Services Commission. The Guidelines are intended to give an understanding of a clinical problem, and outline one or more preferred approaches to the investigation and management of the problem. The Guidelines are not intended as a substitute for the advice or professional judgment of a health care professional, nor are they intended to be the only approach to the management of clinical problem. We cannot respond to patients or patient advocates requesting advice on issues related to medical conditions. If you need medical advice, please contact a health care professional.
# THE GUIDELINES AND PROTOCOLS ADVISORY COMMITTEE
This draft guideline is based on scientific evidence current as of February 2020.
The draft guideline was developed by the Guidelines and Protocols Advisory Committee in collaboration with Provincial Laboratory Medicine Services.
For more information about how BC Guidelines are developed, refer to the GPAC Handbook available at BCGuidelines.ca: GPAC Handbook. | None | None |
3aabd64f3f945298c42874912b181c1819002331 | cma | None | Screening for abdominal aortic aneurysms in Canada: 2020 review and position statement of the Canadian Society for Vascular Surgery A n abdominal aortic aneurysm (AAA) occurs when the abdominal aorta is more than 3 cm in maximal diameter, about 1.5 times larger than normal. The development of AAAs is associated with tradi tional cardiovascular risk factors, such as smoking, age, male sex, hypercho lesterolemia and family history. 1 The prevalence of AAAs in the general population aged 66 years or older ranges between 1% and 5%, 2 with a lower incidence in females, those with diabetes and those of African descent. 3 As the aorta expands beyond its normal size, the risk of aortic rupture increases. Rupture is often fatal, with more than 80% of all patients with ruptured AAAs dying, many before hospital admission or even after emergent surgery. These aneurysms are often asymptomatic and therefore underdiagnosed, with symptoms occurring only once the aneurysm has ruptured or immedi ately before rupture. Detecting AAAs before they pose a threat to life has proven to be an excellent way to decrease the devastating sequelae of untreated large aneur ysms. Screening with abdominal ultrasonography has proven highly effective and can be performed in a variety of settings, with high specificity and sensi tivity. 4 Detecting AAAs before they rupture has been shown to reduce aortic specific mortality, allcause mortality and rupture events, while proving to be costeffective. 4 In 2007, the Canadian Society for Vascular Surgery (CSVS) published a review and position statement for AAA screening in Canada. 5 Since that#
Abdominal aortic aneurysms (AAAs) remain a major risk to patients, despite level 1 evidence for screening to prevent rupture events and decrease mortality. In 2007, the Canadian Society for Vascular Surgery (CSVS) published a review and position statement for AAA screening in Canada. Since that publication, there have been a number of updates in the published literature affecting screen ing recommendations. In this paper, we present a review of some of the contro versies in the AAA screening literature to help elucidate differences in the vari ous published screening guidelines. This article represents a review of the data and updated recommendations for AAA screening in the Canadian population on behalf of the CSVS.
Les anévrismes de l'aorte abdominale (AAA) continuent de poser un risque majeur pour les patients, malgré des données probantes de niveau 1 à l'appui du dépistage pour prévenir les ruptures et réduire la mortalité. En 2007, la Société canadienne de chirurgie vasculaire (SCCV) a publié une revue et un énoncé de position sur le dépistage de l'AAA au Canada. Depuis lors, plu sieurs mises à jour ont paru dans la littérature et elles ont un impact sur les recommandations relatives au dépistage. Dans le présent article, nous présen tons une synthèse de quelques controverses soulevées dans la littérature sur le dépistage de l'AAA afin d'expliquer les différences entre les diverses lignes directrices publiées à ce sujet. Cet article propose au nom de la SCCV une revue des données probantes et des recommandations à jour sur le dépistage de l'AAA dans la population canadienne. publication, there have been updates to the published liter ature affecting screening recommendations. The CSVS enlisted a panel to review the literature and produce con sensus recommendations for AAA screening practices for CSVS members, primary care providers and patients.
# Current state of abdominal aortiC aneurysm sCreening
Despite the evidence supporting AAA screening, there are few structured national screening programs. The United Kingdom, Sweden and parts of Norway currently offer screening, with other countries currently evaluating the costeffectiveness of screening programs before imple menting them. 6 In the United States, the Screening Abdom inal Aortic Aneurysms Very Efficiently (SAAAVE) Act, effec tive as of Jan. 1, 2007, allows onetime free screening for patients at risk (men aged > 65 yr who have ever smoked, and men and women with a family history of AAA disease) as part of the "Welcome to Medicare" physical examina tion. In Canada, currently no national or provincial screen ing program exists.
The CSVS's position statement on AAA screening included screening for all men aged 65-75 and for women aged 66 or older with history of smoking, family history of AAA or cerebrovascular disease. 5 Since its publication, there have been updates from the 4 large populationbased AAA screening studies, 7-10 2 North American task force systematic reviews, 11 a recent US Society for Vascular Sur gery guidelines publication 12 and other studies reporting reallife experience of national screening studies. In addition, in 2017, the Canadian Task Force on Pre ventive Health Care published recommendations for AAA screening in Canada that included onetime screening in men aged 65-80 but no screening in women. 16 The recom mendations were a major departure from previous Can adian and other North American recommendations, espe cially regarding screening of women.
# development of 2020 Canadian soCiety for vasCular surgery position statement
The position statement panel consisted of members from the CSVS with experience in the full spectrum of care and therapies of AAA management. These members were highly selected by the executive of the CSVS. Any poten tial members who had any conflict of interest or disclosure were excluded.
The panel members reviewed the data from the 4 major randomized controlled trials (RCTs) 2,7,8,13 and the more recent publications describing their longterm follow up. In addition, the panel reviewed systematic reviews and observational studies including results from large national screening programs. A review of all the various published screening recommendations was also performed.
The strength of the panel's recommendations and the quality of evidence was determined with the Grading of Recommendations Assessment, Development and Evalua tion (GRADE) system. 17 The quality of evidence from ran domized trials has an initial rating of "high," which is fur ther modified based on consideration of risk of bias, inconsistency of the results across studies, indirectness of the evidence, imprecision of the estimates of effect and study limitations. Highquality evidence that an interven tion's desirable effects are clearly greater than its undesir able effects, or are clearly not, warrants a "strong" recom mendation, whereas uncertainty about the tradeoffs (because of lowquality evidence or because the desirable and undesirable effects are closely balanced) warrants a "weak" recommendation.
# Controversies in abdominal aortiC aneurysm sCreening
From the detailed review of the literature, the panel identified controversies that have likely contributed to some of the disparities in screening recommendations for AAAs. 5,12,16 By discussing these topics, the panel was ultimately able to provide more robust recommendations for screening.
# Decline in prevalence of abdominal aortic aneurysm at the population level
The Multicentre Aneurysm Screening Study (MASS), an RCT of screening for AAA in a large UK population, showed a prevalence of an aortic aneurysm of 4.9%. 2,9 This trial was considered the benchmark for screening recom mendations as it showed a significant reduction in aortic specific mortality and a modest reduction in overall mor tality associated with ultrasonography screening.
These benefits have been called into question with the publication of more recent populationlevel studies, which have shown a much lower prevalence of AAA. In a nationwide Swedish AAA screening program offered to all men older than 65 years, the prevalence of AAA was 1.5%. 13 Similarly, a study from Gloucestershire showed a decrease in AAA prevalence from 5% to 1.3% over 25 years in their screening program. 18 Among the first 700 000 men screened (2009-2013) in the Abdominal Aortic Aneurysm Screening Programme in the UK, the prevalence of AAA was 1.3%. 14 A reduction in smoking rates and better modification of cardiovascular risk factors have been cited as reasons for the decline in AAA preva lence. 19 This does result in having to screen a larger num ber of patients in order to prevent AAArelated events, which affects the potential costeffectiveness of the screening program and its expected gains in reduced overall mortality as AAArelated deaths become less common.
# E463
# Decline in mortality rates after abdominal aortic aneurysm repair
With the development of endovascular techniques for AAA repair (EVAR) and better perioperative care for patients undergoing open surgical AAA repair (OSR), the risks of operative intervention have decreased, which may further increase the benefits of screening. In the MASS, the mor tality rate after elective OSR was 6%. 2 More recent studies of aneurysm screening programs that include a mix of elec tive EVAR and OSR have shown substantially lower rates of postoperative mortality. In the Swedish nationwide screening program, the mortality rate after elective aneur ysm repair was 0.9%, 13 and in the UK Abdominal Aortic Aneurysm Screening Programme, the mortality rate was 0.8% in patients who had their aneurysm treated after it was detected by means of screening ultrasonography. 14 If modern surgical therapy can be provided in a safer and more minimally invasive fashion, the benefits of screening and, ultimately, intervention may be greater than traditionally reported. This has helped to balance the riskbenefit ratio of AAA screening in the face of lower AAA prevalence. In a simulation study, Svensjö and colleagues 20 estimated that AAA screening would still be costeffective even with an AAA prevalence rate of only 0.5%, given the improved postoperative outcomes seen with elective repair of aneurysms detected on screening.
# Uncertainties regarding risks and benefits of screening in women
In most AAA screening studies, women were either excluded or underrepresented. Only 1 of the 4 major RCTs included women, 10,15 and they accounted for only a small proportion (about 7%) of the patients in that trial. In the US, almost 40% of all AAArelated deaths and one third of hospital admissions for ruptured AAA occur in women. 21,22 The UK Small Aneurysm Trial showed a rup ture rate 3 times higher in women than in men, 23 and a more recent study indicates that this excess risk may be as high as fourfold. 24 The prevalence of AAA in women is relatively low, with one screening study indicating a prevalence of 1.3%, compared with 7.6% for men. 15 This lower prevalence is somewhat offset by the fact that AAAs in women tend to rupture more frequently and at lower aortic diameters. 23 In addition, women have higher mortality rates after both elective and emergent aneurysm repair. 25 Further more, the anatomy of AAAs in women is distinct, with a larger proportion not fulfilling the standard anatomic cri teria for EVAR compared to those in men. 26 The incon sistency between guidelines for AAA screening in women is understandable, as there is a paucity of evidence to guide recommendations. However, although AAA is less common in women, it is a much deadlier diagnosis than in men. Currently, national screening programs in Italy, New Zealand and the US include women. 6 reCommendations for abdominal aortiC aneurysm sCreening
# Men aged 65-80 years
The 4 major screening trials 2,7-10 showed a decrease in AAA related mortality in men who were screened. Screening is also associated with a decreased risk of AAA rupture and emergency procedures, including a decrease in mortality after any AAArelated procedure. 16 The number needed to screen to prevent an AAArelated death is estimated at 311, better than the benefit of breast cancer screening (number needed to screen = 1904 27 ) or fecal occult blood testing for colon cancer (number needed to screen = 1374 28 ).
Although the largest of the 4 major screening studies limited the upper age to 74 years, 2 the Chichester 10 and Western Australia 29 studies had higher upper age limits (80 yr and 83 yr, respectively) and showed benefit in these more inclusive cohorts. Given the aging population and excellent results of both OSR and EVAR in the modern era, we believe including patients aged 65-80 years will improve yield in AAA screening. Furthermore, a substantial propor tion of patients in populationbased aneurysm studies are within this inclusive age group at the time of aneurysm repair. 18, It is also important to note that there may have been a selection bias in the trial data, as in the Western Australia study, 29 in which those older than 75 were less likely than younger people to participate in AAA screening.
We recommend one-time screening ultrasonography for all men aged 65-80 years (grade 1a evidence).
# Women aged 65-80 years
The issue of AAA screening in women is important, given the discrepant recommendations between previous and current guidelines. In the Chichester study, women aged 65-80 were included. 15 The study did not identify a benefit to screening women but was significantly underpowered to determine differences in this subgroup.
A US screening study that included 10 012 women showed an overall prevalence of AAA of 0.7%, but the prev alence was higher in certain risk factor groups. 33 Women older than 65 with at least 1 risk factor for AAA were included. The prevalence of AAA among men was 3.9%. A history of smoking or cardiovascular disease (previous myo cardial infarction, coronary revascularization or other cardiac surgery), or increased age significantly increased the preva lence of AAA. The prevalence was 1.4% among women aged 75-85 and 2.7% among women older than age 85. Among patients with a history of tobacco use or heart dis ease, the prevalence rose to 3.4%, and the addition of family history increased the prevalence to 6.4%. Women with a history of tobacco use or cardiovascular disease had a three to fourfold increased prevalence with either risk factor. The Women's Health Initiative Cohort Study assessed a myriad of cardiovascular events, including AAA events, in more than 160 000 patients aged 50-79 over nearly 8 years. 30 Abdominal aortic aneurysm events were strongly associated with smoking and increased age. Current smokers were at higher risk than patients who had ever smoked (odds ratio 4.19 v. 1.94).
Many national screening studies have shown cost effectiveness in screening for AAA in men, despite a preva lence of 1%-2%. 2,34 It follows that women with a similar disease prevalence and known poorer longterm outcomes of AAA should be similarly screened and that screening should be beneficial and costeffective. In recent reports of AAA interventions, women accounted for about 20%-25% of AAAs treated. 35,36 We believe that the lack of screening data for women should not exclude this group from the possible benefits of ultrasonography screening.
We suggest one-time screening ultrasonography for all women aged 65-80 years with a history of smoking or cardiovascular disease (grade 2c evidence).
# Men and women older than 80 years of age
There is a paucity of data on screening patients older than 80 years. Many of the previous guidelines or recommenda tions were made before the widespread use of endovascular techniques. These minimally invasive therapies reduce pro cedural risks and should result in broader applicability of screening recommendations. As experience and advances in OSR and perioperative management improve, traditional open surgical therapies now carry less risk for older patients. Screening recommendations should also parallel realworld experience, and published aneurysm series include a sub stantial number of patients treated after age 80. 31,32,37 In the IMPROVE trial, the average patient age was 76.7 years, 31 and in a Canadian study of more than 1000 consecutive endovascular repairs, the average patient age was 79. 32 Makrygiannis and colleagues 37 studied a screening program in a cohort aged 75-85 and found an almost threefold increase in AAA prevalence in men and women compared to a younger cohort (65-74 yr).
Realworld experience with aneurysm repair in older adults has given acceptable results with high procedural success; women accounted for about 20% of patients. 38,39 It has been shown that women experience AAAassociated death at older ages, with 70% of deaths occurring after age 80. 24,40 Selecting an arbitrary age cohort suited for AAA screening in men may not be sufficient to answer the ques tion of benefit in women. With the increasing life expec tancy of the North American population and the larger cohort of older patients with higher AAA prevalence, coupled with the excellent results of both OSR and EVAR in older adults, screening in older patients should be indi vidualized based on life expectancy and patient choice.
We suggest consideration of AAA screening on an individual patient basis in men and women older than 80 years, depending on the patient's life expectancy and patient choice (grade 2c evidence).
# First-degree relatives
Although AAAs are thought of as a multifactorial disease, reports have consistently shown familial aggregation, with an incidence in firstdegree relatives of the proband (index patient with the AAA) about 5-10 times that in the general population. One Canadian study showed a prevalence of AAA of 19.2% among siblings of 166 probands, com pared to 2.3% in a control population. 46 In particular, female firstdegree relatives of probands have a high preva lence of AAA compared to all women in the general popu lation (5%-7% v. 0.5%), although the prevalence of AAA is always higher in men regardless of the presence or absence of a proband. 47,48 Aneurysms in firstdegree relatives occur at an earlier age and may have a more pernicious natural history, with higher rates of rupture. 44, As such, an improved bene fit from targeted screening for AAA in probandrelated populations has been suggested. 12,51,52 In a recent study, Hultgren and colleagues 53 performed modelbased analysis and found that asking probands about their sib lings and then inviting the siblings for screening could reduce mortality from AAA, with further improved cost effectiveness compared to AAA screening in the general population.
We suggest one-time screening ultrasonography after 55 years of age for all first-degree relatives of patients with AAA (grade 2c evidence).
# Repeat screening for ectatic nonaneurysmal abdominal aortas
Initial screening ultrasonography showing an ectatic aorta (2-3 cm) may not effectively identify all patients who may ultimately develop an AAA or, worse, a ruptured AAA. The ectatic aorta, although not aneurysmal, is abnormal, with the same degenerative events occurring within the aortic wall that may predispose to further degeneration. Typ ically, the aorta in patients with an aneurysm grows 1-3 mm per year, and most patients will die from other causes before the aorta reaches surgical maturity.
The MASS showed that, among the 25 500 patients who had normal aortic diameters at the time of screening, 60 experienced a ruptured aneurysm, the majority of which had a diameter of 2.5-2.9 cm. 9 In a Swedish study follow ing ectatic aortas measuring 2.5-2.9 cm in women, 46% had progressed to an AAA at 5 years. 54
# E465
Although not well studied in the literature, it seems that larger ectatic aortas (> 2.5 cm but < 3 cm) may require repeat assessment, especially in patients who have a long life expectancy and may decide on repair at an older age. Currently, no evidence exists as to the costeffectiveness or aorticspecific benefits of this strategy. However, it appears that some patients with an ectatic aorta on initial screening may be falsely reassured regarding future aortic events and may benefit from rescreening. 9,54 We suggest consideration of repeat ultrasonography 10 years after the initial screening in patients with an initial aortic diameter greater than 2.5 cm and less than 3 cm, depending on the patient's life expectancy and patient choice (grade 2c evidence).
# Use of previous other imaging studies in lieu of screening ultrasonography
In the modern era, in which the use of radiologic imaging continues to increase, the average person may have had imaging modalities other than ultrasonography for indica tions not related to AAA screening. If an imaging study has been performed in which the abdominal aorta can be seen in its entirety, with a report commenting on aortic meas urement or the absence of an AAA, this would obviate the need for screening ultrasonography.
# ConClusion
Abdominal aortic aneurysms are lifethreatening conditions that can be easily detected with ultrasonography, which has been shown to save lives and prevent aortic rupture. This simple tool can be applied to a specific cohort of patients at increased risk for AAAs. Screening should be done only in patients who would be considered possible operative candi dates, in whom intervention then could be considered.
We suggest consideration of screening for all men aged 65-80 years and for women aged 65-80 years with a history of smoking or cardiovascular disease. Screening can be con sidered in patients older than 80 years, depending on life expectancy and patient choice. In contrast to other recent guidelines, 16 we believe the evidence to exclude women from AAA screening programs does not exist. Given realworld data suggesting the devastating natural history of AAA in women compared with men, and the sizeable proportion of women among patients who are treated for AAA, it is imper ative that women not be excluded from screening programs.
Screening firstdegree family members of patients with an AAA should be considered after the age of 55. For those who have been found to have abdominal aortic ectasia with an initial aortic diameter of 2.5-3 cm, repeat ultrasonog raphy after 10 years should be considered depending on life expectancy and patient choice.
There exists a need for a national screening program in Canada, similar to those in other countries. With such a program identifying patients at high risk as per our recom mendations, many deaths from a ruptured AAA event could be prevented. Further study into the costeffectiveness of these recommendations will be required and is currently being considered by the CSVS. Contributors: All authors designed the study, and acquired and ana lyzed the data. V. Kapila, P. Jetty, D. Wooster and L. Dubois wrote the manuscript, which all authors critically revised. All authors gave final approval of the article to be published.
Content licence: This is an Open Access article distributed in accor dance with the terms of the Creative Commons Attribution (CC BY NCND 4.0) licence, which permits use, distribution and reproduction in any medium, provided that the original publication is properly cited, the use is noncommercial (i.e., research or educational use), and no modifications or adaptations are made. See: . org/licenses/byncnd/4.0/. | Screening for abdominal aortic aneurysms in Canada: 2020 review and position statement of the Canadian Society for Vascular Surgery A n abdominal aortic aneurysm (AAA) occurs when the abdominal aorta is more than 3 cm in maximal diameter, about 1.5 times larger than normal. The development of AAAs is associated with tradi tional cardiovascular risk factors, such as smoking, age, male sex, hypercho lesterolemia and family history. 1 The prevalence of AAAs in the general population aged 66 years or older ranges between 1% and 5%, 2 with a lower incidence in females, those with diabetes and those of African descent. 3 As the aorta expands beyond its normal size, the risk of aortic rupture increases. Rupture is often fatal, with more than 80% of all patients with ruptured AAAs dying, many before hospital admission or even after emergent surgery. These aneurysms are often asymptomatic and therefore underdiagnosed, with symptoms occurring only once the aneurysm has ruptured or immedi ately before rupture. Detecting AAAs before they pose a threat to life has proven to be an excellent way to decrease the devastating sequelae of untreated large aneur ysms. Screening with abdominal ultrasonography has proven highly effective and can be performed in a variety of settings, with high specificity and sensi tivity. 4 Detecting AAAs before they rupture has been shown to reduce aortic specific mortality, allcause mortality and rupture events, while proving to be costeffective. 4 In 2007, the Canadian Society for Vascular Surgery (CSVS) published a review and position statement for AAA screening in Canada. 5 Since that#
Abdominal aortic aneurysms (AAAs) remain a major risk to patients, despite level 1 evidence for screening to prevent rupture events and decrease mortality. In 2007, the Canadian Society for Vascular Surgery (CSVS) published a review and position statement for AAA screening in Canada. Since that publication, there have been a number of updates in the published literature affecting screen ing recommendations. In this paper, we present a review of some of the contro versies in the AAA screening literature to help elucidate differences in the vari ous published screening guidelines. This article represents a review of the data and updated recommendations for AAA screening in the Canadian population on behalf of the CSVS.
Les anévrismes de l'aorte abdominale (AAA) continuent de poser un risque majeur pour les patients, malgré des données probantes de niveau 1 à l'appui du dépistage pour prévenir les ruptures et réduire la mortalité. En 2007, la Société canadienne de chirurgie vasculaire (SCCV) a publié une revue et un énoncé de position sur le dépistage de l'AAA au Canada. Depuis lors, plu sieurs mises à jour ont paru dans la littérature et elles ont un impact sur les recommandations relatives au dépistage. Dans le présent article, nous présen tons une synthèse de quelques controverses soulevées dans la littérature sur le dépistage de l'AAA afin d'expliquer les différences entre les diverses lignes directrices publiées à ce sujet. Cet article propose au nom de la SCCV une revue des données probantes et des recommandations à jour sur le dépistage de l'AAA dans la population canadienne. publication, there have been updates to the published liter ature affecting screening recommendations. The CSVS enlisted a panel to review the literature and produce con sensus recommendations for AAA screening practices for CSVS members, primary care providers and patients.
# Current state of abdominal aortiC aneurysm sCreening
Despite the evidence supporting AAA screening, there are few structured national screening programs. The United Kingdom, Sweden and parts of Norway currently offer screening, with other countries currently evaluating the costeffectiveness of screening programs before imple menting them. 6 In the United States, the Screening Abdom inal Aortic Aneurysms Very Efficiently (SAAAVE) Act, effec tive as of Jan. 1, 2007, allows onetime free screening for patients at risk (men aged > 65 yr who have ever smoked, and men and women with a family history of AAA disease) as part of the "Welcome to Medicare" physical examina tion. In Canada, currently no national or provincial screen ing program exists.
The CSVS's position statement on AAA screening included screening for all men aged 65-75 and for women aged 66 or older with history of smoking, family history of AAA or cerebrovascular disease. 5 Since its publication, there have been updates from the 4 large populationbased AAA screening studies, 7-10 2 North American task force systematic reviews, 11 a recent US Society for Vascular Sur gery guidelines publication 12 and other studies reporting reallife experience of national screening studies. [13][14][15] In addition, in 2017, the Canadian Task Force on Pre ventive Health Care published recommendations for AAA screening in Canada that included onetime screening in men aged 65-80 but no screening in women. 16 The recom mendations were a major departure from previous Can adian and other North American recommendations, espe cially regarding screening of women.
# development of 2020 Canadian soCiety for vasCular surgery position statement
The position statement panel consisted of members from the CSVS with experience in the full spectrum of care and therapies of AAA management. These members were highly selected by the executive of the CSVS. Any poten tial members who had any conflict of interest or disclosure were excluded.
The panel members reviewed the data from the 4 major randomized controlled trials (RCTs) 2,7,8,13 and the more recent publications describing their longterm follow up. [7][8][9][10] In addition, the panel reviewed systematic reviews and observational studies including results from large national screening programs. A review of all the various published screening recommendations was also performed.
The strength of the panel's recommendations and the quality of evidence was determined with the Grading of Recommendations Assessment, Development and Evalua tion (GRADE) system. 17 The quality of evidence from ran domized trials has an initial rating of "high," which is fur ther modified based on consideration of risk of bias, inconsistency of the results across studies, indirectness of the evidence, imprecision of the estimates of effect and study limitations. Highquality evidence that an interven tion's desirable effects are clearly greater than its undesir able effects, or are clearly not, warrants a "strong" recom mendation, whereas uncertainty about the tradeoffs (because of lowquality evidence or because the desirable and undesirable effects are closely balanced) warrants a "weak" recommendation.
# Controversies in abdominal aortiC aneurysm sCreening
From the detailed review of the literature, the panel identified controversies that have likely contributed to some of the disparities in screening recommendations for AAAs. 5,12,16 By discussing these topics, the panel was ultimately able to provide more robust recommendations for screening.
# Decline in prevalence of abdominal aortic aneurysm at the population level
The Multicentre Aneurysm Screening Study (MASS), an RCT of screening for AAA in a large UK population, showed a prevalence of an aortic aneurysm of 4.9%. 2,9 This trial was considered the benchmark for screening recom mendations as it showed a significant reduction in aortic specific mortality and a modest reduction in overall mor tality associated with ultrasonography screening.
These benefits have been called into question with the publication of more recent populationlevel studies, which have shown a much lower prevalence of AAA. In a nationwide Swedish AAA screening program offered to all men older than 65 years, the prevalence of AAA was 1.5%. 13 Similarly, a study from Gloucestershire showed a decrease in AAA prevalence from 5% to 1.3% over 25 years in their screening program. 18 Among the first 700 000 men screened (2009-2013) in the Abdominal Aortic Aneurysm Screening Programme in the UK, the prevalence of AAA was 1.3%. 14 A reduction in smoking rates and better modification of cardiovascular risk factors have been cited as reasons for the decline in AAA preva lence. 19 This does result in having to screen a larger num ber of patients in order to prevent AAArelated events, which affects the potential costeffectiveness of the screening program and its expected gains in reduced overall mortality as AAArelated deaths become less common.
# E463
# Decline in mortality rates after abdominal aortic aneurysm repair
With the development of endovascular techniques for AAA repair (EVAR) and better perioperative care for patients undergoing open surgical AAA repair (OSR), the risks of operative intervention have decreased, which may further increase the benefits of screening. In the MASS, the mor tality rate after elective OSR was 6%. 2 More recent studies of aneurysm screening programs that include a mix of elec tive EVAR and OSR have shown substantially lower rates of postoperative mortality. In the Swedish nationwide screening program, the mortality rate after elective aneur ysm repair was 0.9%, 13 and in the UK Abdominal Aortic Aneurysm Screening Programme, the mortality rate was 0.8% in patients who had their aneurysm treated after it was detected by means of screening ultrasonography. 14 If modern surgical therapy can be provided in a safer and more minimally invasive fashion, the benefits of screening and, ultimately, intervention may be greater than traditionally reported. This has helped to balance the riskbenefit ratio of AAA screening in the face of lower AAA prevalence. In a simulation study, Svensjö and colleagues 20 estimated that AAA screening would still be costeffective even with an AAA prevalence rate of only 0.5%, given the improved postoperative outcomes seen with elective repair of aneurysms detected on screening.
# Uncertainties regarding risks and benefits of screening in women
In most AAA screening studies, women were either excluded or underrepresented. Only 1 of the 4 major RCTs included women, 10,15 and they accounted for only a small proportion (about 7%) of the patients in that trial. In the US, almost 40% of all AAArelated deaths and one third of hospital admissions for ruptured AAA occur in women. 21,22 The UK Small Aneurysm Trial showed a rup ture rate 3 times higher in women than in men, 23 and a more recent study indicates that this excess risk may be as high as fourfold. 24 The prevalence of AAA in women is relatively low, with one screening study indicating a prevalence of 1.3%, compared with 7.6% for men. 15 This lower prevalence is somewhat offset by the fact that AAAs in women tend to rupture more frequently and at lower aortic diameters. 23 In addition, women have higher mortality rates after both elective and emergent aneurysm repair. 25 Further more, the anatomy of AAAs in women is distinct, with a larger proportion not fulfilling the standard anatomic cri teria for EVAR compared to those in men. 26 The incon sistency between guidelines for AAA screening in women is understandable, as there is a paucity of evidence to guide recommendations. However, although AAA is less common in women, it is a much deadlier diagnosis than in men. Currently, national screening programs in Italy, New Zealand and the US include women. 6 reCommendations for abdominal aortiC aneurysm sCreening
# Men aged 65-80 years
The 4 major screening trials 2,7-10 showed a decrease in AAA related mortality in men who were screened. Screening is also associated with a decreased risk of AAA rupture and emergency procedures, including a decrease in mortality after any AAArelated procedure. 16 The number needed to screen to prevent an AAArelated death is estimated at 311, better than the benefit of breast cancer screening (number needed to screen = 1904 27 ) or fecal occult blood testing for colon cancer (number needed to screen = 1374 28 ).
Although the largest of the 4 major screening studies limited the upper age to 74 years, 2 the Chichester 10 and Western Australia 29 studies had higher upper age limits (80 yr and 83 yr, respectively) and showed benefit in these more inclusive cohorts. Given the aging population and excellent results of both OSR and EVAR in the modern era, we believe including patients aged 65-80 years will improve yield in AAA screening. Furthermore, a substantial propor tion of patients in populationbased aneurysm studies are within this inclusive age group at the time of aneurysm repair. [13][14][15]18,[30][31][32] It is also important to note that there may have been a selection bias in the trial data, as in the Western Australia study, 29 in which those older than 75 were less likely than younger people to participate in AAA screening.
We recommend one-time screening ultrasonography for all men aged 65-80 years (grade 1a [strong, high-quality] evidence).
# Women aged 65-80 years
The issue of AAA screening in women is important, given the discrepant recommendations between previous and current guidelines. In the Chichester study, women aged 65-80 were included. 15 The study did not identify a benefit to screening women but was significantly underpowered to determine differences in this subgroup.
A US screening study that included 10 012 women showed an overall prevalence of AAA of 0.7%, but the prev alence was higher in certain risk factor groups. 33 Women older than 65 with at least 1 risk factor for AAA were included. The prevalence of AAA among men was 3.9%. A history of smoking or cardiovascular disease (previous myo cardial infarction, coronary revascularization or other cardiac surgery), or increased age significantly increased the preva lence of AAA. The prevalence was 1.4% among women aged 75-85 and 2.7% among women older than age 85. Among patients with a history of tobacco use or heart dis ease, the prevalence rose to 3.4%, and the addition of family history increased the prevalence to 6.4%. Women with a history of tobacco use or cardiovascular disease had a three to fourfold increased prevalence with either risk factor. The Women's Health Initiative Cohort Study assessed a myriad of cardiovascular events, including AAA events, in more than 160 000 patients aged 50-79 over nearly 8 years. 30 Abdominal aortic aneurysm events were strongly associated with smoking and increased age. Current smokers were at higher risk than patients who had ever smoked (odds ratio 4.19 v. 1.94).
Many national screening studies have shown cost effectiveness in screening for AAA in men, despite a preva lence of 1%-2%. 2,34 It follows that women with a similar disease prevalence and known poorer longterm outcomes of AAA should be similarly screened and that screening should be beneficial and costeffective. In recent reports of AAA interventions, women accounted for about 20%-25% of AAAs treated. 35,36 We believe that the lack of screening data for women should not exclude this group from the possible benefits of ultrasonography screening.
We suggest one-time screening ultrasonography for all women aged 65-80 years with a history of smoking or cardiovascular disease (grade 2c [weak, low-quality] evidence).
# Men and women older than 80 years of age
There is a paucity of data on screening patients older than 80 years. Many of the previous guidelines or recommenda tions were made before the widespread use of endovascular techniques. These minimally invasive therapies reduce pro cedural risks and should result in broader applicability of screening recommendations. As experience and advances in OSR and perioperative management improve, traditional open surgical therapies now carry less risk for older patients. Screening recommendations should also parallel realworld experience, and published aneurysm series include a sub stantial number of patients treated after age 80. 31,32,37 In the IMPROVE trial, the average patient age was 76.7 years, 31 and in a Canadian study of more than 1000 consecutive endovascular repairs, the average patient age was 79. 32 Makrygiannis and colleagues 37 studied a screening program in a cohort aged 75-85 and found an almost threefold increase in AAA prevalence in men and women compared to a younger cohort (65-74 yr).
Realworld experience with aneurysm repair in older adults has given acceptable results with high procedural success; women accounted for about 20% of patients. 38,39 It has been shown that women experience AAAassociated death at older ages, with 70% of deaths occurring after age 80. 24,40 Selecting an arbitrary age cohort suited for AAA screening in men may not be sufficient to answer the ques tion of benefit in women. With the increasing life expec tancy of the North American population and the larger cohort of older patients with higher AAA prevalence, coupled with the excellent results of both OSR and EVAR in older adults, screening in older patients should be indi vidualized based on life expectancy and patient choice.
We suggest consideration of AAA screening on an individual patient basis in men and women older than 80 years, depending on the patient's life expectancy and patient choice (grade 2c [weak, low-quality] evidence).
# First-degree relatives
Although AAAs are thought of as a multifactorial disease, reports have consistently shown familial aggregation, with an incidence in firstdegree relatives of the proband (index patient with the AAA) about 5-10 times that in the general population. [41][42][43][44][45] One Canadian study showed a prevalence of AAA of 19.2% among siblings of 166 probands, com pared to 2.3% in a control population. 46 In particular, female firstdegree relatives of probands have a high preva lence of AAA compared to all women in the general popu lation (5%-7% v. 0.5%), although the prevalence of AAA is always higher in men regardless of the presence or absence of a proband. 47,48 Aneurysms in firstdegree relatives occur at an earlier age and may have a more pernicious natural history, with higher rates of rupture. 44,[47][48][49][50] As such, an improved bene fit from targeted screening for AAA in probandrelated populations has been suggested. 12,51,52 In a recent study, Hultgren and colleagues 53 performed modelbased analysis and found that asking probands about their sib lings and then inviting the siblings for screening could reduce mortality from AAA, with further improved cost effectiveness compared to AAA screening in the general population.
We suggest one-time screening ultrasonography after 55 years of age for all first-degree relatives of patients with AAA (grade 2c [weak, low-quality] evidence).
# Repeat screening for ectatic nonaneurysmal abdominal aortas
Initial screening ultrasonography showing an ectatic aorta (2-3 cm) may not effectively identify all patients who may ultimately develop an AAA or, worse, a ruptured AAA. The ectatic aorta, although not aneurysmal, is abnormal, with the same degenerative events occurring within the aortic wall that may predispose to further degeneration. Typ ically, the aorta in patients with an aneurysm grows 1-3 mm per year, and most patients will die from other causes before the aorta reaches surgical maturity.
The MASS showed that, among the 25 500 patients who had normal aortic diameters at the time of screening, 60 experienced a ruptured aneurysm, the majority of which had a diameter of 2.5-2.9 cm. 9 In a Swedish study follow ing ectatic aortas measuring 2.5-2.9 cm in women, 46% had progressed to an AAA at 5 years. 54
# E465
Although not well studied in the literature, it seems that larger ectatic aortas (> 2.5 cm but < 3 cm) may require repeat assessment, especially in patients who have a long life expectancy and may decide on repair at an older age. Currently, no evidence exists as to the costeffectiveness or aorticspecific benefits of this strategy. However, it appears that some patients with an ectatic aorta on initial screening may be falsely reassured regarding future aortic events and may benefit from rescreening. 9,54 We suggest consideration of repeat ultrasonography 10 years after the initial screening in patients with an initial aortic diameter greater than 2.5 cm and less than 3 cm, depending on the patient's life expectancy and patient choice (grade 2c [weak, low-quality] evidence).
# Use of previous other imaging studies in lieu of screening ultrasonography
In the modern era, in which the use of radiologic imaging continues to increase, the average person may have had imaging modalities other than ultrasonography for indica tions not related to AAA screening. If an imaging study has been performed in which the abdominal aorta can be seen in its entirety, with a report commenting on aortic meas urement or the absence of an AAA, this would obviate the need for screening ultrasonography.
# ConClusion
Abdominal aortic aneurysms are lifethreatening conditions that can be easily detected with ultrasonography, which has been shown to save lives and prevent aortic rupture. This simple tool can be applied to a specific cohort of patients at increased risk for AAAs. Screening should be done only in patients who would be considered possible operative candi dates, in whom intervention then could be considered.
We suggest consideration of screening for all men aged 65-80 years and for women aged 65-80 years with a history of smoking or cardiovascular disease. Screening can be con sidered in patients older than 80 years, depending on life expectancy and patient choice. In contrast to other recent guidelines, 16 we believe the evidence to exclude women from AAA screening programs does not exist. Given realworld data suggesting the devastating natural history of AAA in women compared with men, and the sizeable proportion of women among patients who are treated for AAA, it is imper ative that women not be excluded from screening programs.
Screening firstdegree family members of patients with an AAA should be considered after the age of 55. For those who have been found to have abdominal aortic ectasia with an initial aortic diameter of 2.5-3 cm, repeat ultrasonog raphy after 10 years should be considered depending on life expectancy and patient choice.
There exists a need for a national screening program in Canada, similar to those in other countries. With such a program identifying patients at high risk as per our recom mendations, many deaths from a ruptured AAA event could be prevented. Further study into the costeffectiveness of these recommendations will be required and is currently being considered by the CSVS. Contributors: All authors designed the study, and acquired and ana lyzed the data. V. Kapila, P. Jetty, D. Wooster and L. Dubois wrote the manuscript, which all authors critically revised. All authors gave final approval of the article to be published.
Content licence: This is an Open Access article distributed in accor dance with the terms of the Creative Commons Attribution (CC BY NCND 4.0) licence, which permits use, distribution and reproduction in any medium, provided that the original publication is properly cited, the use is noncommercial (i.e., research or educational use), and no modifications or adaptations are made. See: https://creativecommons. org/licenses/byncnd/4.0/. | None | None |
0308d201c161bfecb8186038d65c67a7aa02ecbf | cma | None | This guidance is intended for health-care providers responsible for newborn care. It is based on known evidence as of April 9, 2021.#
testing and is waiting to be tested or waiting for the results of a test. A pregnant mother/individual who presents during labour with a temperature above 38 degrees Celsius will be tested for SARS-CoV-2 even in the absence of exposure criteria and/or close contact with a person with a confirmed COVID-19 diagnosis or a person under clinical investigation for COVID-19.
- Newborn under clinical investigation: A newborn who is symptomatic and/or had close contact with a person with a confirmed COVID-19 diagnosis, or a person under clinical investigation for COVID-19. They can be either waiting to be tested for SARS-CoV-2 or waiting for the results of a test.
- Close contact: A person or newborn who had close physical contact with, or who lived with a person with, a confirmed COVID-19 diagnosis or a person under clinical investigation for COVID-19.
Newborn: Infant in the first 28 days after birth. Mother/individual: The term individual is used in this guideline to be inclusive of transgender individuals who gave birth to the newborn and in cases where the caregiver of the newborn is not the mother (e.g., foster parent). Vertical transmission: Transmission of infection directly from mother/individual to embryo, fetus or newborn during the perinatal period through the placenta or human milk. Horizontal transmission: Transmission of infection from one person to another through contact with bodily fluids (respiratory droplets, sputum, blood, etc.).
# General Information
SARS-CoV-2 is a novel coronavirus that causes COVID-19 illness in adults, children and newborns. The incubation period is two to 14 days, with a median of five days. 3 Studies continue to show that COVID-19 infection in newborns is uncommon and most newborns who may become infected are asymptomatic or present with mild to moderate disease.
Clinical outcomes following COVID-19 infection during pregnancy are mostly good with spontaneous and iatrogenic preterm birth the most commonly reported adverse outcomes. While there is currently no reported increased risk of congenital anomaly, available data is limited and, at this time, the risk of teratogenicity cannot be excluded. 4,5 While there is no strong evidence of vertical transmission of SARS-CoV-2, the newborn is at risk for postpartum horizontal transmission. 4 -6, 8 -10 The rate of infection in the newborn born to the mother/individual with a confirmed diagnosis of COVID-19, or is a person under clinical investigation, does not vary regardless of mode of delivery, breast/chest feeding or rooming-in practices. 10 Clinical Manifestation of COVID-19 in Newborns Neurological Temperature instability, lethargy, irritability
# Respiratory
Grunting, nasal flaring, tachypnea, chest retractions, central cyanosis/pallor, apnea, cough, nasal congestion
# Gastrointestinal
Abdominal distension, feeding intolerance, diarrhea/watery stools, emesis Laboratory Findings Normal or leukopenia, lymphopenia, mild thrombocytopenia, elevated CK, ALP, ALT, AST and LDH
# Radiology Findings
Chest X-ray infiltrates Consider and exclude alternative diagnoses in the newborn that presents with respiratory distress soon after birth as many COVID-19 symptoms are also common to other conditions such as neonatal respiratory distress syndrome. 4 Recommendations
# Personal Protective Equipment (PPE) and Infection Prevention and Control (IPC) Precautions
Refer to health authority specific guidance and the BCCDC's resources on PPE and aerosol generating medical procedures (AGMP) for the most up-to-date information.
Droplet and contact precautions are recommended for all team members involved in the direct care of an unwell newborn and/or a premature newborn who is symptomatic and/or who had close contact with a person with a confirmed COVID-19 diagnosis or a person under clinical investigation for COVID-19.
Use airborne precautions during AGMP. This includes any time a ventilator, continuous positive airway pressure (CPAP) or high flow circuits are intentionally or unintentionally opened or disconnected, as this is considered aerosol generating. Ensure that equipment used during resuscitation and management to support ventilation is equipped with HEPA filters to filter expired air. Consult a local respiratory therapist and IPC for further advice.
Proactive care such as planned intubations vs. emergent intubation is essential to ensure practitioners can don appropriate PPE. If available, consider using video laryngoscope with a clear, disposable blade cover.
# Bed Allocation to Minimize Viral Transmission
Manage newborns who are close contacts, under clinical investigation or have a confirmed diagnosis of COVID-19 in a cohort. 11 Admit the newborn with mild respiratory distress into a closed incubator or into a single patient room, if available. Admit the symptomatic newborn requiring positive pressure ventilation or continuous positive airway pressure for moderate to severe respiratory distress to a negative pressure isolation room. If a negative pressure room is not available, a single patient room with a door that closes can be used.
Consult with local IPC to ensure that bed allocation meets local guidelines.
# Isolation Precautions
If a newborn tests positive for SARS-CoV-2, the newborn needs to isolate until: At least 10 days have passed since the onset of symptoms; AND Symptoms (respiratory, gastrointestinal and systemic) have improved.
If a newborn tests negative for SARS-CoV-2, isolate as a close contact and monitor for symptoms suggestive of COVID-19 for 14 days to ensure the full incubation and infectious period has passed.
Investigations for SARS-CoV-2
If indicated, obtain a specimen for SARS-CoV-2 (and other respiratory viruses, if needed). Newborns should be tested within two hours after birth or upon admission if not newly born.
Procedure: Obtain informed consent from the mother/individual. Cleanse newborn's face prior to specimen collection: o Use warm water and soap for the newborn born at or after 32 weeks gestation. o Use warm water only for the newborn born at less than 32 weeks. Nasopharyngeal swab for non-intubated newborn and newborn greater than 750 grams. Nasopharyngeal washing for non-intubated newborn equal and less than 750 grams. Endotracheal aspirate for intubated newborn, include respiratory panel in test requisition.
Add HOSP to specimen label to prioritize testing requisition. If symptomatic, consider adding CBC, CRP, blood culture and ALP/ALT/AST to initial workup. Newborn stool samples are NOT to be collected for diagnostic purposes.
Management of an Unwell and/or Premature Newborn who is a Close Contact, Under Clinical Investigation or has a Confirmed Diagnosis of COVID-19 (See Figure 1) Admit to appropriate bed allocation as described above. Supportive care is currently the only known effective care approach for COVID-19. Advanced support may be indicated if severe respiratory deterioration is occurring. Consider transfer to higher level of care if indicated.
There is currently not enough evidence to support the use of routine anti-viral medications, steroids or interferon. Consultation with pediatric infectious diseases is recommended for ongoing management.
Refer to pediatric clinical guidance for COVID-19 for additional information.
# Intra-Hospital Transfer of the Neonate
Limit intra-hospital transfer. 3,13 Complete a risk assessment to determine the need for clinical intervention out of the newborn care space that would require a transfer, such as CT, MRI, eye exam. Postpone if possible.
If clinical intervention cannot be postponed, the newborn must be transported in a closed incubator and local IPC procedures to minimize spread of infection must be followed.
# Patient and Family Engagement
Where possible, families will be kept together. However, if separation is required, support should be provided.
- Engage support services early such as a lactation consultant and social worker. Provide newborn mementoes, photos. Engage with the family as often as possible. Consider using a virtual communication tool to provide audio-visual connections between mother/individual, family and newborn.
The decision to allow family to be present should be made in conjunction with local IPC teams and based on the infection risk of their presence compared to the harm of their absence. For persons under quarantine or in a unique circumstance where they are symptomatic or within their infectious window but must be present, contact the local IPC teams for guidance on the presence or exclusion, as the degree of risk is determined on a case-by-case basis.
Family presence is dependent on: Current site and health authority-specific visitor guidelines. Risk of transmission between newborn and family. Compassionate reasons. Known negative impacts of separation (delayed or diminished bonding) on the newborn and family.
# Skin-to-Skin
Skin-to-skin is still appropriate and encouraged. Mother/individual and/or the parent should put on a medical mask and practice hand hygiene before skin-to-skin to reduce infection spread through droplet and contact transmission. 3, 12 -18 Feeding of the Newborn Human milk is the best source of nutrition for most newborns. Currently, there is no evidence of horizontal transmission of COVID-19 to infants and children from human milk feeding. 3, 12 -18 Human milk feeding provides higher protection against infection as it provides antibodies targeted towards the microbes to which the newborn is exposed.
Breast/chest feeding or expressed human milk feeding is recommended and should be facilitated with appropriate IPC measures in place. The family should participate in the decision to use human milk to feed the newborn with the support of the health-care providers. If a mother/individual wishes to breast/chest feed, they should put on a medical mask and practice hand hygiene before each feeding to reduce disease spread through droplet and contact transmission. 3, 12 -16 When the newborn is separated from their mother/individual due to IPC restrictions or medical reasons, every effort should be made to provide education on hand expression and pumping. Ensure access to an electric breast pump for a mother/individual whose long-term plan is to breast/chest feed. If the mother/individual is planning to express milk, they should practice hand hygiene and don a medical mask if they are a contact, under clinical investigation or have a confirmed diagnosis of COVID-19.
After each pumping session, all parts that come into contact with human milk should be thoroughly washed and the entire pump should be appropriately disinfected as per the manufacturer's instructions. 3, 12 -16 It is not recommended to wash the breast or chest before every feed or prior to expressing milk. It is only recommended as an added precaution for a mother/individual under clinical investigation or has a confirmed diagnosis of COVID-19 to cleanse their breast or chest area with soap and water before a feeding if they have just coughed/sneezed over their exposed breast or chest. 17 For more information, review lactation guidelines for women/individuals who are confirmed or suspect cases of COVID-19.
# Discontinuation of Isolation Precautions
Discontinuation of precautions should occur ONLY in consultation with IPC and based on the underlying disease process, microbiology test results and disease history within the family.
# Discharge Considerations
Complete all routine screening, immunization and discharge teaching. For more information, see pages five and six of maternal and newborn acute care discharge planning and continued care in community settings during the COVID-19 pandemic.
Continue isolation at home if newborn is discharged prior to the end of the isolation period. If newborn tests positive for SARS-CoV-2, isolate until:
- At least 10 days have passed since the onset of symptoms; AND Symptoms (respiratory, gastrointestinal and systemic) have improved.
If a newborn tests negative for SARS-CoV-2, isolate as a close contact and monitor for symptoms suggestive of COVID-19. If a mother/individual is a confirmed COVID-19 case and the newborn tests negative for SARS-CoV-2, isolate as a close contact with the parent for 14 days to ensure the full incubation and infectious period has passed and monitor for cold or influenza-like symptoms.
The B.C. community liaison record -postpartum & newborn is an important tool to connect acute care, primary care and public health services for discharge planning. COVID-19 positive status should be indicated on this record.
# Additional Discharge Teaching for if Mother/Individual Under Clinical Investigation or Has a Confirmed Diagnosis of COVID-19
How to Limit Transmission of the SARS-CoV-2 Virus to a Newborn Practice hand hygiene using either soap and water or alcohol-based hand sanitizer before and after caring for and feeding the newborn.
Wear a mask to minimize respiratory secretions to the newborn during care and feeding. If a parent is unable to source medical face masks once they are at home, homemade face masks can be used. Do not place a mask on a newborn. For more information, see non-medical masks and face coverings.
Avoid coughing or sneezing on the newborn or newborn care equipment. Clean and disinfect high touch areas and surfaces in the newborn care environment with approved product(s). See more information on cleaning and disinfecting.
# Signs to Look for in The Newborn
While most newborns who become infected are asymptomatic or present with mild to moderate illness, the mother/individual needs to know what signs of COVID-19 to look for in the newborn. If the newborn develops any of these signs at home, the mother/individual must contact their primary care provider. If the primary care provider is not available, then the mother/individual must phone 8-1-1 to communicate the findings and determine a plan for their newborn. If it is determined that the newborn should be taken to the hospital for assessment, the health-care provider should call ahead to notify the emergency department. In cases where there is no primary health-care provider, the mother/individual should go directly to the emergency department with a mask on, perform hand hygiene and inform the triage nurse that they have COVID-19 and that there is a concern about the newborn.
# Neurological | This guidance is intended for health-care providers responsible for newborn care. It is based on known evidence as of April 9, 2021.#
testing and is waiting to be tested or waiting for the results of a test. A pregnant mother/individual who presents during labour with a temperature above 38 degrees Celsius will be tested for SARS-CoV-2 even in the absence of exposure criteria and/or close contact with a person with a confirmed COVID-19 diagnosis or a person under clinical investigation for COVID-19.
Newborn under clinical investigation: A newborn who is symptomatic and/or had close contact with a person with a confirmed COVID-19 diagnosis, or a person under clinical investigation for COVID-19. They can be either waiting to be tested for SARS-CoV-2 or waiting for the results of a test.
Close contact: A person or newborn who had close physical contact with, or who lived with a person with, a confirmed COVID-19 diagnosis or a person under clinical investigation for COVID-19.
Newborn: Infant in the first 28 days after birth. Mother/individual: The term individual is used in this guideline to be inclusive of transgender individuals who gave birth to the newborn and in cases where the caregiver of the newborn is not the mother (e.g., foster parent). Vertical transmission: Transmission of infection directly from mother/individual to embryo, fetus or newborn during the perinatal period through the placenta or human milk. Horizontal transmission: Transmission of infection from one person to another through contact with bodily fluids (respiratory droplets, sputum, blood, etc.).
# General Information
SARS-CoV-2 is a novel coronavirus that causes COVID-19 illness in adults, children and newborns. The incubation period is two to 14 days, with a median of five days. 3 Studies continue to show that COVID-19 infection in newborns is uncommon and most newborns who may become infected are asymptomatic or present with mild to moderate disease.
# 4, 6, 7
Clinical outcomes following COVID-19 infection during pregnancy are mostly good with spontaneous and iatrogenic preterm birth the most commonly reported adverse outcomes. [4][5][6] While there is currently no reported increased risk of congenital anomaly, available data is limited and, at this time, the risk of teratogenicity cannot be excluded. 4,5 While there is no strong evidence of vertical transmission of SARS-CoV-2, the newborn is at risk for postpartum horizontal transmission. 4 -6, 8 -10 The rate of infection in the newborn born to the mother/individual with a confirmed diagnosis of COVID-19, or is a person under clinical investigation, does not vary regardless of mode of delivery, breast/chest feeding or rooming-in practices. 10 Clinical Manifestation of COVID-19 in Newborns Neurological Temperature instability, lethargy, irritability
# Respiratory
Grunting, nasal flaring, tachypnea, chest retractions, central cyanosis/pallor, apnea, cough, nasal congestion
# Gastrointestinal
Abdominal distension, feeding intolerance, diarrhea/watery stools, emesis Laboratory Findings Normal or leukopenia, lymphopenia, mild thrombocytopenia, elevated CK, ALP, ALT, AST and LDH
# Radiology Findings
Chest X-ray infiltrates Consider and exclude alternative diagnoses in the newborn that presents with respiratory distress soon after birth as many COVID-19 symptoms are also common to other conditions such as neonatal respiratory distress syndrome. 4 Recommendations
# Personal Protective Equipment (PPE) and Infection Prevention and Control (IPC) Precautions
Refer to health authority specific guidance and the BCCDC's resources on PPE and aerosol generating medical procedures (AGMP) for the most up-to-date information.
Droplet and contact precautions are recommended for all team members involved in the direct care of an unwell newborn and/or a premature newborn who is symptomatic and/or who had close contact with a person with a confirmed COVID-19 diagnosis or a person under clinical investigation for COVID-19.
Use airborne precautions during AGMP. This includes any time a ventilator, continuous positive airway pressure (CPAP) or high flow circuits are intentionally or unintentionally opened or disconnected, as this is considered aerosol generating. Ensure that equipment used during resuscitation and management to support ventilation is equipped with HEPA filters to filter expired air. Consult a local respiratory therapist and IPC for further advice.
Proactive care such as planned intubations vs. emergent intubation is essential to ensure practitioners can don appropriate PPE. If available, consider using video laryngoscope with a clear, disposable blade cover.
# Bed Allocation to Minimize Viral Transmission
Manage newborns who are close contacts, under clinical investigation or have a confirmed diagnosis of COVID-19 in a cohort. 11 Admit the newborn with mild respiratory distress into a closed incubator or into a single patient room, if available. Admit the symptomatic newborn requiring positive pressure ventilation or continuous positive airway pressure for moderate to severe respiratory distress to a negative pressure isolation room. If a negative pressure room is not available, a single patient room with a door that closes can be used.
Consult with local IPC to ensure that bed allocation meets local guidelines.
# Isolation Precautions
If a newborn tests positive for SARS-CoV-2, the newborn needs to isolate until: At least 10 days have passed since the onset of symptoms; AND Symptoms (respiratory, gastrointestinal and systemic) have improved.
If a newborn tests negative for SARS-CoV-2, isolate as a close contact and monitor for symptoms suggestive of COVID-19 for 14 days to ensure the full incubation and infectious period has passed.
Investigations for SARS-CoV-2
If indicated, obtain a specimen for SARS-CoV-2 (and other respiratory viruses, if needed). Newborns should be tested within two hours after birth or upon admission if not newly born.
Procedure: Obtain informed consent from the mother/individual. Cleanse newborn's face prior to specimen collection: o Use warm water and soap for the newborn born at or after 32 weeks gestation. o Use warm water only for the newborn born at less than 32 weeks. Nasopharyngeal swab for non-intubated newborn and newborn greater than 750 grams. Nasopharyngeal washing for non-intubated newborn equal and less than 750 grams. Endotracheal aspirate for intubated newborn, include respiratory panel in test requisition.
Add HOSP to specimen label to prioritize testing requisition. If symptomatic, consider adding CBC, CRP, blood culture and ALP/ALT/AST to initial workup. Newborn stool samples are NOT to be collected for diagnostic purposes.
Management of an Unwell and/or Premature Newborn who is a Close Contact, Under Clinical Investigation or has a Confirmed Diagnosis of COVID-19 (See Figure 1) Admit to appropriate bed allocation as described above. Supportive care is currently the only known effective care approach for COVID-19. Advanced support may be indicated if severe respiratory deterioration is occurring. Consider transfer to higher level of care if indicated.
There is currently not enough evidence to support the use of routine anti-viral medications, steroids or interferon. Consultation with pediatric infectious diseases is recommended for ongoing management.
Refer to pediatric clinical guidance for COVID-19 for additional information.
# Intra-Hospital Transfer of the Neonate
Limit intra-hospital transfer. 3,13 Complete a risk assessment to determine the need for clinical intervention out of the newborn care space that would require a transfer, such as CT, MRI, eye exam. Postpone if possible.
If clinical intervention cannot be postponed, the newborn must be transported in a closed incubator and local IPC procedures to minimize spread of infection must be followed.
# Patient and Family Engagement
Where possible, families will be kept together. However, if separation is required, support should be provided.
Engage support services early such as a lactation consultant and social worker. Provide newborn mementoes, photos. Engage with the family as often as possible. Consider using a virtual communication tool to provide audio-visual connections between mother/individual, family and newborn.
The decision to allow family to be present should be made in conjunction with local IPC teams and based on the infection risk of their presence compared to the harm of their absence. For persons under quarantine or in a unique circumstance where they are symptomatic or within their infectious window but must be present, contact the local IPC teams for guidance on the presence or exclusion, as the degree of risk is determined on a case-by-case basis.
Family presence is dependent on: Current site and health authority-specific visitor guidelines. Risk of transmission between newborn and family. Compassionate reasons. Known negative impacts of separation (delayed or diminished bonding) on the newborn and family.
# Skin-to-Skin
Skin-to-skin is still appropriate and encouraged. Mother/individual and/or the parent should put on a medical mask and practice hand hygiene before skin-to-skin to reduce infection spread through droplet and contact transmission. 3, 12 -18 Feeding of the Newborn Human milk is the best source of nutrition for most newborns. Currently, there is no evidence of horizontal transmission of COVID-19 to infants and children from human milk feeding. 3, 12 -18 Human milk feeding provides higher protection against infection as it provides antibodies targeted towards the microbes to which the newborn is exposed.
Breast/chest feeding or expressed human milk feeding is recommended and should be facilitated with appropriate IPC measures in place. The family should participate in the decision to use human milk to feed the newborn with the support of the health-care providers. If a mother/individual wishes to breast/chest feed, they should put on a medical mask and practice hand hygiene before each feeding to reduce disease spread through droplet and contact transmission. 3, 12 -16 When the newborn is separated from their mother/individual due to IPC restrictions or medical reasons, every effort should be made to provide education on hand expression and pumping. Ensure access to an electric breast pump for a mother/individual whose long-term plan is to breast/chest feed. If the mother/individual is planning to express milk, they should practice hand hygiene and don a medical mask if they are a contact, under clinical investigation or have a confirmed diagnosis of COVID-19.
After each pumping session, all parts that come into contact with human milk should be thoroughly washed and the entire pump should be appropriately disinfected as per the manufacturer's instructions. 3, 12 -16 It is not recommended to wash the breast or chest before every feed or prior to expressing milk. It is only recommended as an added precaution for a mother/individual under clinical investigation or has a confirmed diagnosis of COVID-19 to cleanse their breast or chest area with soap and water before a feeding if they have just coughed/sneezed over their exposed breast or chest. 17 For more information, review lactation guidelines for women/individuals who are confirmed or suspect cases of COVID-19.
# Discontinuation of Isolation Precautions
Discontinuation of precautions should occur ONLY in consultation with IPC and based on the underlying disease process, microbiology test results and disease history within the family.
# Discharge Considerations
Complete all routine screening, immunization and discharge teaching. For more information, see pages five and six of maternal and newborn acute care discharge planning and continued care in community settings during the COVID-19 pandemic.
Continue isolation at home if newborn is discharged prior to the end of the isolation period. If newborn tests positive for SARS-CoV-2, isolate until:
At least 10 days have passed since the onset of symptoms; AND Symptoms (respiratory, gastrointestinal and systemic) have improved.
If a newborn tests negative for SARS-CoV-2, isolate as a close contact and monitor for symptoms suggestive of COVID-19. If a mother/individual is a confirmed COVID-19 case and the newborn tests negative for SARS-CoV-2, isolate as a close contact with the parent for 14 days to ensure the full incubation and infectious period has passed and monitor for cold or influenza-like symptoms.
The B.C. community liaison record -postpartum & newborn is an important tool to connect acute care, primary care and public health services for discharge planning. COVID-19 positive status should be indicated on this record.
# Additional Discharge Teaching for if Mother/Individual Under Clinical Investigation or Has a Confirmed Diagnosis of COVID-19
How to Limit Transmission of the SARS-CoV-2 Virus to a Newborn Practice hand hygiene using either soap and water or alcohol-based hand sanitizer before and after caring for and feeding the newborn.
Wear a mask to minimize respiratory secretions to the newborn during care and feeding. If a parent is unable to source medical face masks once they are at home, homemade face masks can be used. Do not place a mask on a newborn. For more information, see non-medical masks and face coverings.
Avoid coughing or sneezing on the newborn or newborn care equipment. Clean and disinfect high touch areas and surfaces in the newborn care environment with approved product(s). See more information on cleaning and disinfecting.
# Signs to Look for in The Newborn
While most newborns who become infected are asymptomatic or present with mild to moderate illness, the mother/individual needs to know what signs of COVID-19 to look for in the newborn. If the newborn develops any of these signs at home, the mother/individual must contact their primary care provider. If the primary care provider is not available, then the mother/individual must phone 8-1-1 to communicate the findings and determine a plan for their newborn. If it is determined that the newborn should be taken to the hospital for assessment, the health-care provider should call ahead to notify the emergency department. In cases where there is no primary health-care provider, the mother/individual should go directly to the emergency department with a mask on, perform hand hygiene and inform the triage nurse that they have COVID-19 and that there is a concern about the newborn.
# Neurological
| None | None |
b8e7e18bffbad84baef34f18b770eb098dffdfc8 | cma | None | Many Canadian health-care providers have limited knowledge about the specifics of fasting during Ramadan. - Providers find it difficult to counsel their patients with diabetes who intend to fast during Ramadan. - Providers must teach patients about healthful behaviours, glucose monitoring and adjustments of antihyperglycemic medications so patients can maintain their health and safety during fasting.#
- Adults with type 1 or 2 diabetes who intend to fast should receive individualized assessments before Ramadan to judge their suitability for fasting and to formulate individualized management plans.
Keywords: diabetes glucose monitoring insulin pharmacotherapy Ramadan fasting a b s t r a c t Objective: Fasting from dawn to dusk during Ramadan, including abstaining from water and food, is 1 of the pillars of Islam and is observed by the majority of Muslims. Most research concerning diabetes and fasting during Ramadan originates from Middle Eastern or South Asian countries; however, differences exist in hours of work and fasting, pharmacotherapy and blood glucose monitoring between these countries and Canada. Methods: An expert forum of 7 Canadian experts and 1 international expert collaborated to develop Canadian guidelines using the same evidence-based principles, with the exception of an independent methods review used for the Diabetes Canada clinical practice guidelines. Diabetes Canada scientific leadership and Canadian health-care providers performed independent external reviews. Religious leaders endorsed the position statement and provided letters of support. An informed patient participated in the positionstatement development. Each recommendation was approved with 100% consensus of the expert forum.
# Introduction
According to Canada's 2011 National Household Survey, there were 1,053,945 Muslims in Canada, constituting 3.2% of the population (1). The Public Health Agency of Canada estimates the prevalence of diabetes in Canada to be 3.5 million, according to 2011 data, or 9% of the total population (2). Based on these numbers, it is estimated that there are approximately 95,000 Muslims with diabetes living in Canada. However, this may be an underestimation due to the recognized higher risk for type 2 diabetes among immigrants from South Asian and Middle Eastern countries (3,4). A recent report from the Washington-based Pew Forum on Religion and Public Life suggested that the Muslim population will increase both in number and proportion to 2.7 million, or 6.6% of the Canadian population by 2030 (5). Based on this prediction, it is essential that prevention and management strategies be developed that are culturally appropriate and tailored to the Muslim population in Canada.
Fasting from dawn to dusk during Ramadan, including abstaining from water and food, is 1 of the pillars of Islam and is observed by the majority of Muslims (6). This necessitates changes in eating and sleeping habits. Traditionally, the predawn and sunset meals are different from regular meals and often include more carbohydratecontaining foods that have high glycemic indexes. In addition, individuals tend to consume larger-than-usual portions during these meals, especially at the sunset meal when they break the fast.
Each subsequent calendar year, Ramadan month starts 10 to 11 days earlier than the previous year because the Islamic calendar follows a lunar pattern and is, therefore, shorter than the Gregorian calendar. As a result, in Canada, the fasting time from dawn to dusk can vary significantly from a short day in winter to a very long day in summer. Additionally, because day length varies by latitude, the number of fasting hours can vary significantly by location in Canada; for instance, the fasting period in Toronto may be shorter than that in the same day in Edmonton. For the next 6 years, until about 2024, fasting times will be longer than 12 h for the majority of the Ramadan fasting days in most parts of Canada, with many of the fasting days being longer than 18 h. Long hours of absolute fasting during the daytime and eating during the night can increase the risk for complications, such as dehydration, hypoglycemia and hyperglycemia for individuals with diabetes. Muslims living in Muslim-majority countries have some flexibility in terms of working hours during Ramadan, but these accommodations are not typically available in Canada, adding to the challenge of observing the fast, especially for those with diabetes.
Islam offers exceptions for those who are unable to fast, including those who are traveling, sick or at risk for serious harm to health. However, fasting during Ramadan is such an integral part of the Muslim culture that many individuals ignore these allowances and choose to fast despite their medical conditions. When asked, Islamic scholars usually advise Muslims to ask their health-care providers about their ability to fast safely during Ramadan. Conversely, most health-care providers, especially those practicing in North America, have limited knowledge about the specifics of fasting during Ramadan, making it difficult for many Muslims to make informed decisions.
Most of the epidemiologic and observational research published on the topic of diabetes and fasting during Ramadan originates from Middle Eastern or South Asian countries. As mentioned, differences exist in work hours and hours of fasting during Ramadan between these countries and Canada. In addition, pharmacotherapy usage, in regard to both insulin and noninsulin antihyperglycemic agents, is known to differ according to geography (7). The availability of technology for diabetes management (e.g. continuous subcutaneous insulin infusion therapy and continuous and flash glucose monitoring) is also different in Canada than in Asia and North Africa. As a result, conclusions derived from studies in these countries may not be readily generalizable to Canada.
The International Diabetes Federation (IDF) and Diabetes and Ramadan (DAR) International Alliance guidelines categorize people living with diabetes into risk groups based on various patient characteristics and the antihyperglycemic agents used (Table 1) (8). The Diabetes Canada 2018 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada recommend, in the Nutrition Therapy chapter, that Canadians living with diabetes who fast during Ramadan should follow the IDF-DAR guidelines on dietary counselling (9).
The intent of this Canadian position statement on diabetes and Ramadan fasting is to complement the exhaustive IDF-DAR guidelines, as well as Diabetes Canada's clinical practice guidelines, by formulating evidence-based recommendations concerning glucose monitoring and pharmacotherapy for adults with diabetes in Canada who intend to fast during Ramadan. The position statement is meant to serve as a guide for Canadian health-care providers to help maintain the health and safety of their Muslim patients during Ramadan fasting. The recommendations in this position statement are based on a literature review of diabetes and Ramadan fasting, but the clinical principles could be adapted for other instances of fasting performed for religious or alternative reasons by people with diabetes.
# Methods
An expert forum of 7 Canadian experts and an international topic expert (MH) collaborated to formulate, edit and review the Canadian position statement on diabetes and Ramadan fasting. The same guiding principles used in the development of the Diabetes Canada clinical practice guidelines were used to develop the position statement (10), and the chair of the 2018 Diabetes Canada clinical practice guidelines participated in the statement's development. An informed patient (a 78-year-old man with a 34-year history of diabetes who fasts yearly for Ramadan) also participated in the position statement's development so as to ensure that patient values and preferences were represented.
Clinically relevant questions were developed by the expert committee and served as the focus of a PubMed literature search. Only antihyperglycemic medications or glucose-monitoring devices with Health Canada Notice of Compliance granted by February 15, 2018, were included in the recommendations. Each recommendation was reviewed and graded by the expert committee and was approved with 100% consensus. The grading of the recommendations was based on the best available evidence, as well as the applicability to the Canadian population and followed the methods used by the 2018 Diabetes Canada clinical practice guidelines (11). However, unlike the 2018 Diabetes Canada clinical practice guidelines, the position statement did not undergo an independent methods review process to assess the accuracy of the grading of the evidence. In addition, the assigned grading was lowered if any of the following conditions existed: 1) evidence was not applicable to the Canadian population; 2) findings from relevant (and equally rigorous) studies of the topic were conflicting; and/or 3) specific subgroups of interest were not well represented in a study.
The position statement underwent independent external review for endorsement by the chair of the 2013 Diabetes Canada clinical practice guidelines, the president of Diabetes Canada, the Diabetes Canada Professional Section co-chair, a diabetes specialist, a general practitioner, 2 certified diabetes educators, a pharmacy student and a person with diabetes. A religious scholar from the Islamic Society of North America Canada endorsed the position statement and provided his letter of support.
The position statement is broken down into sections based on key topics addressed during its development.
# Pre-Ramadan Diabetes Management Planning
Optimization of diabetes management pre-Ramadan is essential because glycemic control prior to Ramadan has been shown to correlate with glycemic control during the period of fasting (12). The pre-Ramadan period represents an opportunity for healthcare providers to encourage their patients to make positive changes in their healthful behaviors via dietary modifications during and beyond Ramadan.
The recommended time to evaluate a patient's suitability for Ramadan fasting, to counsel on dietary modifications and to implement therapeutic changes in diabetes management is during the 1 to 3 months prior to the beginning of the fasting month. In a retrospective study, individuals with type 2 diabetes who had not received structured education were observed to have an increased rate of hypoglycemia and weight gain during Ramadan. Those who received pre-Ramadan education exhibited an approximate 50% reduction in their rate of hypoglycemia, experienced 0.7 kg of weight loss during Ramadan and had stable glycemic control (13). (8). - The level of glycemic control is to be agreed upon between the health-care provider and the person living with diabetes.
d. Discussion of the importance of antihyperglycemia medication adjustment, meals, physical activity, frequency of self-monitoring of blood glucose (SMBG) and situations where it would be medically indicated to break the fast (Grade D, Consensus for all).
# Dietary counselling should be provided based on IDF-DAR and
Diabetes Canada clinical practice guidelines (Grade D, Consensus). 3. Risk stratification for people living with diabetes, including veryhigh-risk special populations (i.e. frail individuals, pregnant women, etc.), should be based on the published IDF-DAR guidelines (Table 1) (Grade D, Consensus). 4. For individuals who intend to fast despite being advised of their high-risk stratification, scheduled contact during Ramadan (either in clinic, virtually or over the phone) with their healthcare providers or diabetes health-care team is recommended to review glucose records and make further adjustments to therapy (Grade D, Consensus). 5. People in any risk strata of the IDF-DAR guidelines should be advised to break their fast and seek immediate medical attention if they experience any documented episode of hypoglycemia or symptomatic hyperglycemia during Ramadan (Grade D, Consensus). 6. A post-Ramadan follow-up health-care visit should be considered to review any concerns with diabetes management and to help formulate a strategy for future fasting (Grade D, Consensus).
# Noninsulin Pharmacotherapy for People with Type 2 Diabetes During Ramadan
Below is an alphabetical list of drug classes used to treat diabetes in Canada and a discussion of their use during Ramadan.
# Alpha-glucosidase inhibitors
Although commonly used in countries in Asia, this drug class is infrequently prescribed in Canada due to its modest glycated hemoglobin (A1C)-lowering efficacy and its adverse gastrointestinal effects. Because of its low risk for resulting in hypoglycemia, this drug class is safe to continue during Ramadan if it is tolerable from a gastrointestinal standpoint and should be taken with both meals.
# Biguanides
Similar to its first-line use in the treatment of type 2 diabetes, metformin maintains its primacy during Ramadan. Although it is generally considered safe for fasting, given its low risk for hypoglycemia, there are no safety studies of metformin during Ramadan. To minimize gastrointestinal intolerance, metformin should be taken ideally with the sunset and predawn meals while fasting during Ramadan. Alternatively, extended-release versions of this medication can be taken once daily with the main meal, usually the sunset meal, during Ramadan.
# Dipeptidyl-4 inhibitors
Over the past 10 years, the use of this drug class has grown due to its ability to lower blood glucose levels while including a low risk for hypoglycemia and good tolerability. Multiple studies comparing these agents to sulfonylureas have suggested a significant reduction in symptomatic hypoglycemia during Ramadan in favour of dipeptidyl-4 (DPP-4) inhibitors (14)(15)(16)(17)(18). For people who eat a light predawn meal during the fasting month and for those who prefer to take their medications only with their sunset meals, switching to a once-daily, extended-release, fixed-dose combination of metformin with a DPP-4 inhibitor taken at the sunset meal may be preferred during Ramadan.
# Glucagon-like peptide-1 receptor agonists
In addition to potent A1C reduction and low risk for hypoglycemia, an additional benefit of glucagon-like peptide (GLP)-1 receptor agonists relevant to the fasting period includes increased satiety along with a beneficial impact on weight. Studies conducted during Ramadan showed that liraglutide leads to significant improvement in glycemic control and reduction in symptomatic hypoglycemia and weight compared to sulfonylureas (19,20). Because of the potential adverse effect of nausea and abdominal discomfort, this drug class should not be started during the 4 weeks prior to Ramadan but can be continued during the fasting month if it had been started previously and is tolerated well. Shorter-acting GLP-1 receptor agonists (exenatide and lixisenatide) should be taken before meals (especially prior to the sunset meal during Ramadan), while longer-acting agents can be taken at any time.
# Insulin secretagogues
Insulin secretagogues have been associated with a 20% increased risk for hypoglycemia during Ramadan (21). However, this risk is not seen uniformly throughout the class; both gliclazide and repaglinide show relatively lower risk for hypoglycemia during Ramadan (14,15,21,22). Because of the hypoglycemia risk, secretagogues should be adjusted prior to Ramadan, preferably by switching to another class of antihyperglycemic agent that does not include increased risk for hypoglycemia. If insulin secretagogues are continued, counselling about hypoglycemia and risk-reduction strategies, including reduced dosages, discontinuing glyburide in favour of gliclazide or a shorter-acting secretagogue taken only with the postsunset meal, are strongly recommended. If glyburide must be continued during this month, the morning predawn meal dose should be held or reduced by at least 50% to reduce the risk for hypoglycemia.
# Sodium-glucose cotransporter-2 inhibitors
Because of the osmotic diuresis and natriuresis associated with this class of antihyperglycemics, a concern regarding the risk of volume depletion exists during Ramadan, especially during the longer summer fasting periods in Canada. Studies conducted during Ramadan have compared this drug class to sulfonylureas, and they showed significantly lower risks for hypoglycemia and no increase in diabetic ketoacidosis, albeit with a slightly increased risk for volume-depletion symptoms (23,24). Because of the risk for dehydration, these medications should not be started during the 4 weeks prior to Ramadan. Health-care providers should consider, on an individual basis, the pros and cons of either reducing or holding the dosage of sodium-glucose cotransporter-2 (SGLT2) inhibitors temporarily during the month of fasting. A temporary hold may be considered, especially for individuals at high risk for volume depletion, such as age older than 75 years, estimated glomerular filtration rate lower than 60 mL/min/1.73 m 2 and those taking loop diuretics. However, caution should be used when reducing or holding this drug class in individuals with histories of established clinical cardiovascular disease because it has the potential to result in heart-failure exacerbation or an interruption of the cardioprotective benefit of these agents. If such high-risk individuals become symptomatic with either orthostasis or heart-failure symptoms during Ramadan, they should automatically be restratified as being at very high risk and discouraged from future fasting.
# Thiazolidinediones
A study comparing pioglitazone to other oral antihyperglycemic agents during Ramadan did not show a significant risk for hypoglycemia (25). Individuals who are currently taking this medication can continue taking it during Ramadan. Because the maximum glucose-lowering effect of this class takes approximately 1 month, this timeline should be considered prior to switching or initiating thiazolidinediones during Ramadan.
# General Pharmacotherapy Advice Before Ramadan
People living with type 2 diabetes, who are taking metformin, GLP-1 receptor agonists, insulin secretagogues or SGLT2 inhibitors prior to initiating Ramadan fasting should be educated about the symptoms of vomiting, diarrhea and orthostasis, with instructions to break their fast and seek immediate medical attention should any of these symptoms develop.
# Recommendations
See
# Insulin Management of Type 2 Diabetes During Ramadan
There is limited literature about the use of commonly used insulin regimens during Ramadan. Most studies (either observational or randomized trials) have been small, but 2 observational studies found insulin glargine to be safe during Ramadan, showing no significant increases in hypoglycemia compared to nonfasting individuals or when compared to those taking oral antihyperglycemic agents (26,27). A multinational study reported an increased rate of hypoglycemic events in 349 patients treated with insulin glargine and repaglinide once daily with the sunset meal during Ramadan compared to before Ramadan (28). An open-label study randomized 49 fasting subjects to glimepiride, repaglinide or insulin glargine and compared them to 16 nonfasting subjects with type 2 diabetes. This study found no difference in the risk for hypoglycemia between the fasting and nonfasting groups (27).
A small, randomized, open-label crossover study compared insulin lispro to regular human insulin, both taken at predawn and sunset meals, in combination with twice-daily neutral protamine Hagedorn (NPH) insulin as basal insulin. The insulin lispro group showed lower 1-h and 2-h postsunset meal blood glucose values compared to the regular human insulin group. Although the number of subjects with hypoglycemic episodes was similar in both arms, the frequency of hypoglycemia was higher with regular insulin compared to insulin lispro (2.6±0.2 vs. 1.3±0.1 episodes per person every 14 days; p<0.002) (29).
Insulin lispro Mix 25 was compared to human insulin 30/70 in an open-label randomized crossover study of 151 subjects. The evening premeal fasting and the 2-h postprandial excursion after the sunset meal were significantly lower with insulin lispro Mix 25 compared to insulin 30/70. There was no difference in hypoglycemia between the 2 groups (30). Another observational study switching the evening dose of human insulin 30/70 twice daily to lispro Mix 50 in one half of the participants 2 weeks before Ramadan found no significant reduction in hypoglycemia (31).
A recent open-label treat-to-target trial randomized 263 subjects from 5 different countries to twice-daily insulin degludecaspart combination (not available in Canada) or biphasic insulin aspart 30. The degludec-aspart combination had significantly lower rates of overall and nocturnal hypoglycemia, with similar A1C efficacy (32). In this trial, the insulin dosage adjustment pre-Ramadan was in tandem with the IDF-DAR recommendations (8). Another open-label controlled multicentre cluster randomized trial comparing insulin detemir (40% total daily dosage) given at sunrise and biphasic insulin aspart (60% total daily dosage) given at the evening meal to standard care. The intervention group was noninferior to the control group in terms of the mean 4-point SMBG levels during fasting; however, the intervention group was associated with a lower rate of adverse events, including hypoglycemia and syncope (33).
In conclusion, despite the limited data available regarding the optimal insulin regimen or type for patients with type 2 diabetes during Ramadan, results from small studies suggest that it may be safe to fast on insulin therapy as long as the treatment is individualized and modified. Individuals treated with premixed or intermediate-acting NPH insulin may be at higher risk for hypoglycemia and insulin stacking when the duration of the fast exceeds 15 h and the time difference between the predawn and sunset meals is shorter than 8 h. - Consider switching to longer acting basal analogs or reduce dose by 25% to 50%
# Short-acting
Aspart/faster aspart, glulisine, lispro
- Preferred options. Take usual evening meal dose at sunset meal, reduce predawn meal dose by 25% to 50%, omit lunchtime dose Human regular insulin - Consider switching from human regular insulin to rapid-acting insulin analogs
# Premixed
Biphasic insulin aspart, human insulin mix 30, lispro mix 25, lispro mix 50
- Consider switching to an alternative regimen (basal insulinoral agents, basal insulin GLP-1 receptor agonist, basal insulin plus 1 mealtime bolus insulin, or basal-bolus insulin taken with each meal), depending on patient-and agent-level characteristics, when feasible
- If continuing, reduce predawn meal dose by 25% to 50% and take usual evening meal dose at sunset meal BID, twice daily; DPP-4, dipeptidyl peptidase; eGFR, estimated glomerular filtration rate; GLP-1, glucagon-like peptide-1; OD, once daily; SGLT2, sodium-glucose cotransporter-2; TID, three times daily.
# Recommendations
- For adults with type 2 diabetes needing insulin initiation just prior to or during Ramadan, a basal, long-acting analog insulin (detemir, glargine) or an ultralong analog insulin (degludec, glargine U300) may be preferred over intermediate-acting basal or premixed insulin options during the fasting month to reduce the risk for hypoglycemia (Grade D, Consensus). 2. For individuals already on a regimen containing intermediateacting insulins (NPH, premixed): a. Consider switching to a long-acting or ultralong insulin basal analog 1 to 3 months prior to Ramadan, when feasible, so as to lower the risk for hypoglycemia (Grade D, Consensus) b. U500 formulation of human regular insulin should be treated like intermediate-acting insulin, and consideration should be given to switching to an alternative insulin regimen pre-Ramadan (Grade D, Consensus) c. When switching from premixed or self-mixed insulin, the choice of regimen options (basal insulin-oral antihyperglycemic agents, basal insulin-GLP-1 receptor agonists, basal insulin-plus 1 mealtime bolus insulin or basalbolus insulin given with each meal) should be individualized (Grade D, Consensus) d. If a switch is not feasible, the dose of NPH or premixed insulin taken with the predawn meal should be reduced by 25% to 50%, depending on carbohydrate content, timing of last insulin dose and risk for hypoglycemia (Grade D, Consensus). 3. For individuals already taking a regimen containing longacting basal insulin analogs (degludec, detemir, glargine, glargine U300), a dosage reduction of 15% to 30% should be considered on fasting days to reduce the risk for hypoglycemia (Grade D, Consensus). 4. For individuals already taking a regimen containing bolus insulin: a. A rapid-acting insulin analog (aspart, faster-acting aspart, glulisine, lispro) is preferred over human regular insulin so as to lower the risk for hypoglycemia and postprandial hyperglycemia (Grade C, Level 2 for lispro; Grade D, Consensus for aspart, faster-acting aspart, glulisine) b. Patients should be advised to take their normal bolus dose with their sunset meal, omit their lunchtime bolus dose and lower their predawn meal dose by 5% to 50%, depending on carbohydrate intake and glucose readings (Grade D, Consensus). 5. For individuals managed by any insulin regimen, less intensive glycemic targets during Ramadan, aiming for fasting and premeal SMBGs of 5.5 to 7.5 mmol/L, are preferred so as to reduce the risk for hypoglycemia (Grade D, Consensus). Insulin dosage adjustment to achieve these conservative targets should be individualized, taking into consideration insulin sensitivity and total daily insulin dosage as well as the duration of fast (Grade D, Consensus). 6. Individuals taking a complex insulin regimen, especially those with increased risk for hypoglycemia, should be evaluated by a diabetes-management team pre-Ramadan (Grade D, Consensus).
# Management of Type 1 Diabetes During Ramadan
Fasting poses unique challenges for individuals with type 1 diabetes because of the severity of the risks involved. Extreme excursions in blood glucose levels can lead to life-threatening consequences, such as severe hypoglycemia, dehydration or diabetic ketoacidosis. Because of this, the IDF-DAR guidelines categorize any individual with type 1 diabetes as being at high risk or very high risk (8). Despite being considered at high risk, many individuals with type 1 diabetes do fast. The large populationbased Epidemiology of Diabetes and Ramadan study, conducted in 12,243 people with diabetes from 13 Muslim-majority countries, reported that 42.8% of individuals with type 1 diabetes fasted for at least 15 days during Ramadan (34). However, there was a 3-fold increase in severe hyperglycemia with and without ketoacidosis and a 4.7-fold increase in severe hypoglycemia in those with type 1 diabetes. Small observational studies, however, suggest that children, adolescents and adults with type 1 diabetes who are otherwise healthy and have stable glycemic control may fast safely with regular self-monitoring and under professional guidance with close supervision (35). Criteria for stability of glucose control include absence of serious complications and no episodes of severe hypoglycemia or ketoacidosis within 3 months prior to Ramadan. Individuals with type 1 diabetes who have poor control, do not comply with blood glucose monitoring or have hypoglycemia unawareness should be actively discouraged from fasting.
Limited studies have investigated the safety and efficacy of various insulin regimens for individuals with type 1 diabetes who fast during Ramadan. Insulin lispro was superior to regular human insulin for the prevention of hypoglycemia when used in combination with an intermediate-acting insulin taken twice daily (36). Insulin pump therapy has not been shown to be superior to basalbolus injection therapy in reducing rates of hypoglycemia during fasting, but it is associated with less glucose variability (37). Using the low-glucose suspend feature on certain insulin pumps reduced the rates of hypoglycemia without excessive severe hyperglycemia, but this technology, together with continuous glucose monitoring (CGM), may not be available routinely (38). It is important to note that none of the insulin-pump studies that took place during Ramadan were randomized.
Dosing of bolus insulin should be individualized according to unique eating patterns during Ramadan. Titration based on carbohydrate counting or estimation should be encouraged during fasting. Reducing the dosage of basal insulin is recommended in general, especially during daytime fasting hours when on an insulin pump. One study investigated self-reduction of basal insulin on pump therapy or basal-bolus insulin by individuals living with type 1 diabetes, but this strategy did not decrease the risk for hypoglycemia (39). Several studies investigated a basal insulin dosage reduction between 5% and 25%; however, hypoglycemia rates remained high (40)(41)(42). Especially considering the prolonged fasting duration in Canadian summers, a conservative, individualized initial reduction of 20% to 40% in basal insulin injections (or daytime insulin with pumps) is recommended, with weekly reassessments, ideally based on uploaded CGM or SMBG data.
# Recommendations
- For people with type 1 diabetes who intend to fast, a medical assessment should be performed 1 to 3 months prior to Ramadan to evaluate individual risks for fasting and to optimize insulin management (Grade D, Consensus). 2. People with poorly controlled type 1 diabetes (i.e. pre-Ramadan A1C levels >9.0%, infrequent blood glucose monitoring and those with hypoglycemia unawareness) should be advised to not fast (Grade D, Consensus). 3. For those using regular human insulin as their bolus insulin, switching to a rapid-acting insulin analog (aspart, fasteracting aspart, glulisine, lispro) should be considered so as to reduce the rates of hypoglycemia (Grade C, Level 2 for lispro; Grade D, Consensus for aspart, faster-acting aspart, glulisine) 1 to 3 months prior to Ramadan.
- For those using basal-bolus injection therapy, a basal analog insulin (detemir, glargine) is preferred over intermediateacting insulin during Ramadan (Grade D, Consensus). Alternatively, a once-daily ultra-long-acting basal insulin (degludec, glargine U300) may be used to further reduce the risk for hypoglycemia and minimize the chance of missed insulin doses or periods of inadequate background insulin on board during prolonged fasting periods (Grade D, Consensus). 5. Insulin-to-carbohydrate ratios and insulin-sensitivity factors should remain unchanged during fasting if stable and well controlled (Grade D, Consensus). 6. All basal insulin doses and daytime basal doses when on insulinpump therapy should be reduced by a minimum of 20% for fasting days to reduce the risk for hypoglycemia (Grade D, Consensus) and reassessed weekly for further adjustments (Grade D, Consensus). 7. People with type 1 diabetes should monitor blood ketones when SMBG readings are elevated (>14.0 mmol/L) to screen for diabetic ketoacidosis. Those with blood ketones >0.6 mmol/L should break their fasts, take a supplemental dose of rapid-acting insulin for correction of blood ketones and reevaluate their ability to fast safely during Ramadan (Grade D, Consensus).
# Monitoring Glycemic Control While Fasting During Ramadan
Self-monitoring of blood glucose SMBG forms the cornerstone of the management of diabetes, both during and outside of fasting. Although there is a misconception that pricking the skin for monitoring glycemic control invalidates the fast, religious authorities agree that this is not the case (43). Another commonly held myth that makes people minimize SMBG checks is that they may have to break their fast on finding out about their hypoglycemic episodes if they were to check frequently. In fact, frequent SMBG may reduce the frequency and severity of hypoglycemic episodes so that fasting can be performed safely during Ramadan.
Types 1 and 2 diabetes treated with insulin. For insulin-treated subjects, SMBG ≥3 times daily has been associated with improved glycemic control outside of fasting in both types of diabetes (44,45). Fasting during Ramadan is associated with an increased risk for severe hypoglycemic episodes in individuals with both types of diabetes, while hyperglycemic episodes are increased, particularly in those with type 1 diabetes (34). Evidence that employing SMBG improves glycemic control during Ramadan is derived principally from observational studies that examined it as a part of the effectiveness of diabetes education programs, making it difficult to determine whether the effects observed were the result of frequent SMBG or other aspects of the program. In a small cohort of 21 subjects with both type 1 and 2 diabetes using the basal-bolus insulin regimen, a diabetes-education program including SMBG ≥5 times per day was associated with a reduction in hypoglycemic episodes during Ramadan (46). Another prospective study, which assessed twice-daily SMBG among subjects with type 1 or type 2 diabetes (67% taking insulin) showed a reduction in hypoglycemic episodes during Ramadan (47). Although limited by study methodology, these reports provide the only available evidence associating frequent SMBG with a reduction in hypoglycemic episodes in individuals with diabetes who were fasting during Ramadan. However, as mentioned above, insulin dosage adjustment to optimize care and to prevent and detect hypoglycemia indicates the need for regular SMBG. This is of particular concern before the main meal (usually the sunset meal). Indeed, monitoring for postprandial SMBG excursions may help many individuals to adjust their food intake and/or their insulin dosages during Ramadan.
Type 2 diabetes treated with noninsulin regimens. Similar methodologic limitations exist in studies examining the effect of SMBG in diabetes treated with noninsulin medications during Ramadan. In a prospective study, participants in an education program that included SMBG twice daily experienced a decrease in body mass index, A1C levels and severe hypoglycemic episodes during Ramadan (13). Similarly, weight loss and a decrease in the number of hypoglycemic episodes was observed in a retrospective study in which participants in a diabetes education program were advised to test glucose when symptomatic while fasting (48). Neither study, however, listed the daily SMBG frequency in the control groups. Additionally, sulfonylurea use was common among participants in these studies, questioning the generalizability of these findings to current nonsulfonylurea, noninsulin regimens commonly used in Canada.
Continuous and flash glucose monitoring. CGM and flash glucose monitoring (FGM) by individuals with either type 1 or type 2 diabetes and FGM by those with type 1 diabetes have not identified a worsening of glycemic control during Ramadan (49-51). To our knowledge, no study to date has compared the utility of CGM or FGM vs. SMBG in improving glycemic control when fasting during Ramadan. Further studies are needed to assess the utility of CGM or FGM in individuals with diabetes who fast during Ramadan, particularly among those using complex insulin regimens.
# Recommendations
- For individuals fasting during Ramadan who use insulin:
a. Education on the frequency of SMBG testing during fasting should be provided to improve A1C levels and reduce rates of hypoglycemia (Grade C, Level 3 ). SMBG should be undertaken at least 5 times per day for people living with type 1 diabetes (Grade D, Consensus) and 2 to 5 times per day for those living with type 2 diabetes (Grade D, Consensus), in addition to periods of symptomatic hyper/ hypoglycemia (Grade D, Consensus) b. In the short term, real-time CGM or FGM during fasting to adjust insulin doses and prevent hypoglycemia risk may be considered for people living with type 1 or type 2 diabetes who are taking complex insulin regimens, defined as basal plus at least 1 additional administration of bolus insulin (Grade D, Consensus) c. For individuals with diabetes who do not require insulin, SMBG should be individualized according to the type of therapy, the risks for hypoglycemia or hyperglycemia, the levels of glycemic control and the durations of fast (Grade D, Consensus).
# Conclusions
This is the first Canadian position statement on the topic of Ramadan fasting and diabetes. It was developed by an expert faculty in collaboration with Diabetes Canada, and it provides guidance on pharmacotherapy and glucose monitoring for health-care providers so that they can assist Canadian Muslims living with diabetes to fast safely during Ramadan. The best available evidence was used to formulate recommendations using a standard grading system. The literature search revealed significant knowledge gaps, which highlights the need for further research in this field, including more studies performed in the Canadian population.
Overall, this Canadian position statement for Ramadan fasting and diabetes highlights the need for further education for healthcare providers and patients about the risks associated with fasting (hypoglycemia, hyperglycemia, dehydration, diabetic ketoacidosis), their prevention and management, as well as the importance of healthful eating during Ramadan. Sustained education and dissemination of the recommendations included in this position statement may assist people living with diabetes to manage their diabetes safely during Ramadan fasting.
# Supplementary Material
To access the supplementary material accompanying this article, visit the online version of the Canadian Journal of Diabetes at . | Many Canadian health-care providers have limited knowledge about the specifics of fasting during Ramadan. • Providers find it difficult to counsel their patients with diabetes who intend to fast during Ramadan. • Providers must teach patients about healthful behaviours, glucose monitoring and adjustments of antihyperglycemic medications so patients can maintain their health and safety during fasting.#
• Adults with type 1 or 2 diabetes who intend to fast should receive individualized assessments before Ramadan to judge their suitability for fasting and to formulate individualized management plans.
Keywords: diabetes glucose monitoring insulin pharmacotherapy Ramadan fasting a b s t r a c t Objective: Fasting from dawn to dusk during Ramadan, including abstaining from water and food, is 1 of the pillars of Islam and is observed by the majority of Muslims. Most research concerning diabetes and fasting during Ramadan originates from Middle Eastern or South Asian countries; however, differences exist in hours of work and fasting, pharmacotherapy and blood glucose monitoring between these countries and Canada. Methods: An expert forum of 7 Canadian experts and 1 international expert collaborated to develop Canadian guidelines using the same evidence-based principles, with the exception of an independent methods review used for the Diabetes Canada clinical practice guidelines. Diabetes Canada scientific leadership and Canadian health-care providers performed independent external reviews. Religious leaders endorsed the position statement and provided letters of support. An informed patient participated in the positionstatement development. Each recommendation was approved with 100% consensus of the expert forum.
# Introduction
According to Canada's 2011 National Household Survey, there were 1,053,945 Muslims in Canada, constituting 3.2% of the population (1). The Public Health Agency of Canada estimates the prevalence of diabetes in Canada to be 3.5 million, according to 2011 data, or 9% of the total population (2). Based on these numbers, it is estimated that there are approximately 95,000 Muslims with diabetes living in Canada. However, this may be an underestimation due to the recognized higher risk for type 2 diabetes among immigrants from South Asian and Middle Eastern countries (3,4). A recent report from the Washington-based Pew Forum on Religion and Public Life suggested that the Muslim population will increase both in number and proportion to 2.7 million, or 6.6% of the Canadian population by 2030 (5). Based on this prediction, it is essential that prevention and management strategies be developed that are culturally appropriate and tailored to the Muslim population in Canada.
Fasting from dawn to dusk during Ramadan, including abstaining from water and food, is 1 of the pillars of Islam and is observed by the majority of Muslims (6). This necessitates changes in eating and sleeping habits. Traditionally, the predawn and sunset meals are different from regular meals and often include more carbohydratecontaining foods that have high glycemic indexes. In addition, individuals tend to consume larger-than-usual portions during these meals, especially at the sunset meal when they break the fast.
Each subsequent calendar year, Ramadan month starts 10 to 11 days earlier than the previous year because the Islamic calendar follows a lunar pattern and is, therefore, shorter than the Gregorian calendar. As a result, in Canada, the fasting time from dawn to dusk can vary significantly from a short day in winter to a very long day in summer. Additionally, because day length varies by latitude, the number of fasting hours can vary significantly by location in Canada; for instance, the fasting period in Toronto may be shorter than that in the same day in Edmonton. For the next 6 years, until about 2024, fasting times will be longer than 12 h for the majority of the Ramadan fasting days in most parts of Canada, with many of the fasting days being longer than 18 h. Long hours of absolute fasting during the daytime and eating during the night can increase the risk for complications, such as dehydration, hypoglycemia and hyperglycemia for individuals with diabetes. Muslims living in Muslim-majority countries have some flexibility in terms of working hours during Ramadan, but these accommodations are not typically available in Canada, adding to the challenge of observing the fast, especially for those with diabetes.
Islam offers exceptions for those who are unable to fast, including those who are traveling, sick or at risk for serious harm to health. However, fasting during Ramadan is such an integral part of the Muslim culture that many individuals ignore these allowances and choose to fast despite their medical conditions. When asked, Islamic scholars usually advise Muslims to ask their health-care providers about their ability to fast safely during Ramadan. Conversely, most health-care providers, especially those practicing in North America, have limited knowledge about the specifics of fasting during Ramadan, making it difficult for many Muslims to make informed decisions.
Most of the epidemiologic and observational research published on the topic of diabetes and fasting during Ramadan originates from Middle Eastern or South Asian countries. As mentioned, differences exist in work hours and hours of fasting during Ramadan between these countries and Canada. In addition, pharmacotherapy usage, in regard to both insulin and noninsulin antihyperglycemic agents, is known to differ according to geography (7). The availability of technology for diabetes management (e.g. continuous subcutaneous insulin infusion [insulin pump] therapy and continuous and flash glucose monitoring) is also different in Canada than in Asia and North Africa. As a result, conclusions derived from studies in these countries may not be readily generalizable to Canada.
The International Diabetes Federation (IDF) and Diabetes and Ramadan (DAR) International Alliance guidelines categorize people living with diabetes into risk groups based on various patient characteristics and the antihyperglycemic agents used (Table 1) (8). The Diabetes Canada 2018 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada recommend, in the Nutrition Therapy chapter, that Canadians living with diabetes who fast during Ramadan should follow the IDF-DAR guidelines on dietary counselling (9).
The intent of this Canadian position statement on diabetes and Ramadan fasting is to complement the exhaustive IDF-DAR guidelines, as well as Diabetes Canada's clinical practice guidelines, by formulating evidence-based recommendations concerning glucose monitoring and pharmacotherapy for adults with diabetes in Canada who intend to fast during Ramadan. The position statement is meant to serve as a guide for Canadian health-care providers to help maintain the health and safety of their Muslim patients during Ramadan fasting. The recommendations in this position statement are based on a literature review of diabetes and Ramadan fasting, but the clinical principles could be adapted for other instances of fasting performed for religious or alternative reasons by people with diabetes.
# Methods
An expert forum of 7 Canadian experts and an international topic expert (MH) collaborated to formulate, edit and review the Canadian position statement on diabetes and Ramadan fasting. The same guiding principles used in the development of the Diabetes Canada clinical practice guidelines were used to develop the position statement (10), and the chair of the 2018 Diabetes Canada clinical practice guidelines participated in the statement's development. An informed patient (a 78-year-old man with a 34-year history of diabetes who fasts yearly for Ramadan) also participated in the position statement's development so as to ensure that patient values and preferences were represented.
Clinically relevant questions were developed by the expert committee and served as the focus of a PubMed literature search. Only antihyperglycemic medications or glucose-monitoring devices with Health Canada Notice of Compliance granted by February 15, 2018, were included in the recommendations. Each recommendation was reviewed and graded by the expert committee and was approved with 100% consensus. The grading of the recommendations was based on the best available evidence, as well as the applicability to the Canadian population and followed the methods used by the 2018 Diabetes Canada clinical practice guidelines (11). However, unlike the 2018 Diabetes Canada clinical practice guidelines, the position statement did not undergo an independent methods review process to assess the accuracy of the grading of the evidence. In addition, the assigned grading was lowered if any of the following conditions existed: 1) evidence was not applicable to the Canadian population; 2) findings from relevant (and equally rigorous) studies of the topic were conflicting; and/or 3) specific subgroups of interest were not well represented in a study.
The position statement underwent independent external review for endorsement by the chair of the 2013 Diabetes Canada clinical practice guidelines, the president of Diabetes Canada, the Diabetes Canada Professional Section co-chair, a diabetes specialist, a general practitioner, 2 certified diabetes educators, a pharmacy student and a person with diabetes. A religious scholar from the Islamic Society of North America Canada endorsed the position statement and provided his letter of support.
The position statement is broken down into sections based on key topics addressed during its development.
# Pre-Ramadan Diabetes Management Planning
Optimization of diabetes management pre-Ramadan is essential because glycemic control prior to Ramadan has been shown to correlate with glycemic control during the period of fasting (12). The pre-Ramadan period represents an opportunity for healthcare providers to encourage their patients to make positive changes in their healthful behaviors via dietary modifications during and beyond Ramadan.
The recommended time to evaluate a patient's suitability for Ramadan fasting, to counsel on dietary modifications and to implement therapeutic changes in diabetes management is during the 1 to 3 months prior to the beginning of the fasting month. In a retrospective study, individuals with type 2 diabetes who had not received structured education were observed to have an increased rate of hypoglycemia and weight gain during Ramadan. Those who received pre-Ramadan education exhibited an approximate 50% reduction in their rate of hypoglycemia, experienced 0.7 kg of weight loss during Ramadan and had stable glycemic control (13). (8). * The level of glycemic control is to be agreed upon between the health-care provider and the person living with diabetes.
d. Discussion of the importance of antihyperglycemia medication adjustment, meals, physical activity, frequency of self-monitoring of blood glucose (SMBG) and situations where it would be medically indicated to break the fast (Grade D, Consensus for all).
# Dietary counselling should be provided based on IDF-DAR and
Diabetes Canada clinical practice guidelines (Grade D, Consensus). 3. Risk stratification for people living with diabetes, including veryhigh-risk special populations (i.e. frail individuals, pregnant women, etc.), should be based on the published IDF-DAR guidelines (Table 1) (Grade D, Consensus). 4. For individuals who intend to fast despite being advised of their high-risk stratification, scheduled contact during Ramadan (either in clinic, virtually or over the phone) with their healthcare providers or diabetes health-care team is recommended to review glucose records and make further adjustments to therapy (Grade D, Consensus). 5. People in any risk strata of the IDF-DAR guidelines should be advised to break their fast and seek immediate medical attention if they experience any documented episode of hypoglycemia or symptomatic hyperglycemia during Ramadan (Grade D, Consensus). 6. A post-Ramadan follow-up health-care visit should be considered to review any concerns with diabetes management and to help formulate a strategy for future fasting (Grade D, Consensus).
# Noninsulin Pharmacotherapy for People with Type 2 Diabetes During Ramadan
Below is an alphabetical list of drug classes used to treat diabetes in Canada and a discussion of their use during Ramadan.
# Alpha-glucosidase inhibitors
Although commonly used in countries in Asia, this drug class is infrequently prescribed in Canada due to its modest glycated hemoglobin (A1C)-lowering efficacy and its adverse gastrointestinal effects. Because of its low risk for resulting in hypoglycemia, this drug class is safe to continue during Ramadan if it is tolerable from a gastrointestinal standpoint and should be taken with both meals.
# Biguanides
Similar to its first-line use in the treatment of type 2 diabetes, metformin maintains its primacy during Ramadan. Although it is generally considered safe for fasting, given its low risk for hypoglycemia, there are no safety studies of metformin during Ramadan. To minimize gastrointestinal intolerance, metformin should be taken ideally with the sunset and predawn meals while fasting during Ramadan. Alternatively, extended-release versions of this medication can be taken once daily with the main meal, usually the sunset meal, during Ramadan.
# Dipeptidyl-4 inhibitors
Over the past 10 years, the use of this drug class has grown due to its ability to lower blood glucose levels while including a low risk for hypoglycemia and good tolerability. Multiple studies comparing these agents to sulfonylureas have suggested a significant reduction in symptomatic hypoglycemia during Ramadan in favour of dipeptidyl-4 (DPP-4) inhibitors (14)(15)(16)(17)(18). For people who eat a light predawn meal during the fasting month and for those who prefer to take their medications only with their sunset meals, switching to a once-daily, extended-release, fixed-dose combination of metformin with a DPP-4 inhibitor taken at the sunset meal may be preferred during Ramadan.
# Glucagon-like peptide-1 receptor agonists
In addition to potent A1C reduction and low risk for hypoglycemia, an additional benefit of glucagon-like peptide (GLP)-1 receptor agonists relevant to the fasting period includes increased satiety along with a beneficial impact on weight. Studies conducted during Ramadan showed that liraglutide leads to significant improvement in glycemic control and reduction in symptomatic hypoglycemia and weight compared to sulfonylureas (19,20). Because of the potential adverse effect of nausea and abdominal discomfort, this drug class should not be started during the 4 weeks prior to Ramadan but can be continued during the fasting month if it had been started previously and is tolerated well. Shorter-acting GLP-1 receptor agonists (exenatide and lixisenatide) should be taken before meals (especially prior to the sunset meal during Ramadan), while longer-acting agents can be taken at any time.
# Insulin secretagogues
Insulin secretagogues have been associated with a 20% increased risk for hypoglycemia during Ramadan (21). However, this risk is not seen uniformly throughout the class; both gliclazide and repaglinide show relatively lower risk for hypoglycemia during Ramadan (14,15,21,22). Because of the hypoglycemia risk, secretagogues should be adjusted prior to Ramadan, preferably by switching to another class of antihyperglycemic agent that does not include increased risk for hypoglycemia. If insulin secretagogues are continued, counselling about hypoglycemia and risk-reduction strategies, including reduced dosages, discontinuing glyburide in favour of gliclazide or a shorter-acting secretagogue taken only with the postsunset meal, are strongly recommended. If glyburide must be continued during this month, the morning predawn meal dose should be held or reduced by at least 50% to reduce the risk for hypoglycemia.
# Sodium-glucose cotransporter-2 inhibitors
Because of the osmotic diuresis and natriuresis associated with this class of antihyperglycemics, a concern regarding the risk of volume depletion exists during Ramadan, especially during the longer summer fasting periods in Canada. Studies conducted during Ramadan have compared this drug class to sulfonylureas, and they showed significantly lower risks for hypoglycemia and no increase in diabetic ketoacidosis, albeit with a slightly increased risk for volume-depletion symptoms (23,24). Because of the risk for dehydration, these medications should not be started during the 4 weeks prior to Ramadan. Health-care providers should consider, on an individual basis, the pros and cons of either reducing or holding the dosage of sodium-glucose cotransporter-2 (SGLT2) inhibitors temporarily during the month of fasting. A temporary hold may be considered, especially for individuals at high risk for volume depletion, such as age older than 75 years, estimated glomerular filtration rate lower than 60 mL/min/1.73 m 2 and those taking loop diuretics. However, caution should be used when reducing or holding this drug class in individuals with histories of established clinical cardiovascular disease because it has the potential to result in heart-failure exacerbation or an interruption of the cardioprotective benefit of these agents. If such high-risk individuals become symptomatic with either orthostasis or heart-failure symptoms during Ramadan, they should automatically be restratified as being at very high risk and discouraged from future fasting.
# Thiazolidinediones
A study comparing pioglitazone to other oral antihyperglycemic agents during Ramadan did not show a significant risk for hypoglycemia (25). Individuals who are currently taking this medication can continue taking it during Ramadan. Because the maximum glucose-lowering effect of this class takes approximately 1 month, this timeline should be considered prior to switching or initiating thiazolidinediones during Ramadan.
# General Pharmacotherapy Advice Before Ramadan
People living with type 2 diabetes, who are taking metformin, GLP-1 receptor agonists, insulin secretagogues or SGLT2 inhibitors prior to initiating Ramadan fasting should be educated about the symptoms of vomiting, diarrhea and orthostasis, with instructions to break their fast and seek immediate medical attention should any of these symptoms develop.
# Recommendations
See
# Insulin Management of Type 2 Diabetes During Ramadan
There is limited literature about the use of commonly used insulin regimens during Ramadan. Most studies (either observational or randomized trials) have been small, but 2 observational studies found insulin glargine to be safe during Ramadan, showing no significant increases in hypoglycemia compared to nonfasting individuals or when compared to those taking oral antihyperglycemic agents (26,27). A multinational study reported an increased rate of hypoglycemic events in 349 patients treated with insulin glargine and repaglinide once daily with the sunset meal during Ramadan compared to before Ramadan (28). An open-label study randomized 49 fasting subjects to glimepiride, repaglinide or insulin glargine and compared them to 16 nonfasting subjects with type 2 diabetes. This study found no difference in the risk for hypoglycemia between the fasting and nonfasting groups (27).
A small, randomized, open-label crossover study compared insulin lispro to regular human insulin, both taken at predawn and sunset meals, in combination with twice-daily neutral protamine Hagedorn (NPH) insulin as basal insulin. The insulin lispro group showed lower 1-h and 2-h postsunset meal blood glucose values compared to the regular human insulin group. Although the number of subjects with hypoglycemic episodes was similar in both arms, the frequency of hypoglycemia was higher with regular insulin compared to insulin lispro (2.6±0.2 vs. 1.3±0.1 episodes per person every 14 days; p<0.002) (29).
Insulin lispro Mix 25 was compared to human insulin 30/70 in an open-label randomized crossover study of 151 subjects. The evening premeal fasting and the 2-h postprandial excursion after the sunset meal were significantly lower with insulin lispro Mix 25 compared to insulin 30/70. There was no difference in hypoglycemia between the 2 groups (30). Another observational study switching the evening dose of human insulin 30/70 twice daily to lispro Mix 50 in one half of the participants 2 weeks before Ramadan found no significant reduction in hypoglycemia (31).
A recent open-label treat-to-target trial randomized 263 subjects from 5 different countries to twice-daily insulin degludecaspart combination (not available in Canada) or biphasic insulin aspart 30. The degludec-aspart combination had significantly lower rates of overall and nocturnal hypoglycemia, with similar A1C efficacy (32). In this trial, the insulin dosage adjustment pre-Ramadan was in tandem with the IDF-DAR recommendations (8). Another open-label controlled multicentre cluster randomized trial comparing insulin detemir (40% total daily dosage) given at sunrise and biphasic insulin aspart (60% total daily dosage) given at the evening meal to standard care. The intervention group was noninferior to the control group in terms of the mean 4-point SMBG levels during fasting; however, the intervention group was associated with a lower rate of adverse events, including hypoglycemia and syncope (33).
In conclusion, despite the limited data available regarding the optimal insulin regimen or type for patients with type 2 diabetes during Ramadan, results from small studies suggest that it may be safe to fast on insulin therapy as long as the treatment is individualized and modified. Individuals treated with premixed or intermediate-acting NPH insulin may be at higher risk for hypoglycemia and insulin stacking when the duration of the fast exceeds 15 h and the time difference between the predawn and sunset meals is shorter than 8 h. • Consider switching to longer acting basal analogs or reduce dose by 25% to 50%
# Short-acting
Aspart/faster aspart, glulisine, lispro
• Preferred options. Take usual evening meal dose at sunset meal, reduce predawn meal dose by 25% to 50%, omit lunchtime dose Human regular insulin • Consider switching from human regular insulin to rapid-acting insulin analogs
# Premixed
Biphasic insulin aspart, human insulin mix 30, lispro mix 25, lispro mix 50
• Consider switching to an alternative regimen (basal insulinoral agents, basal insulin GLP-1 receptor agonist, basal insulin plus 1 mealtime bolus insulin, or basal-bolus insulin taken with each meal), depending on patient-and agent-level characteristics, when feasible
• If continuing, reduce predawn meal dose by 25% to 50% and take usual evening meal dose at sunset meal BID, twice daily; DPP-4, dipeptidyl peptidase; eGFR, estimated glomerular filtration rate; GLP-1, glucagon-like peptide-1; OD, once daily; SGLT2, sodium-glucose cotransporter-2; TID, three times daily.
# Recommendations
1. For adults with type 2 diabetes needing insulin initiation just prior to or during Ramadan, a basal, long-acting analog insulin (detemir, glargine) or an ultralong analog insulin (degludec, glargine U300) may be preferred over intermediate-acting basal or premixed insulin options during the fasting month to reduce the risk for hypoglycemia (Grade D, Consensus). 2. For individuals already on a regimen containing intermediateacting insulins (NPH, premixed): a. Consider switching to a long-acting or ultralong insulin basal analog 1 to 3 months prior to Ramadan, when feasible, so as to lower the risk for hypoglycemia (Grade D, Consensus) b. U500 formulation of human regular insulin should be treated like intermediate-acting insulin, and consideration should be given to switching to an alternative insulin regimen pre-Ramadan (Grade D, Consensus) c. When switching from premixed or self-mixed insulin, the choice of regimen options (basal insulin-oral antihyperglycemic agents, basal insulin-GLP-1 receptor agonists, basal insulin-plus 1 mealtime bolus insulin or basalbolus insulin given with each meal) should be individualized (Grade D, Consensus) d. If a switch is not feasible, the dose of NPH or premixed insulin taken with the predawn meal should be reduced by 25% to 50%, depending on carbohydrate content, timing of last insulin dose and risk for hypoglycemia (Grade D, Consensus). 3. For individuals already taking a regimen containing longacting basal insulin analogs (degludec, detemir, glargine, glargine U300), a dosage reduction of 15% to 30% should be considered on fasting days to reduce the risk for hypoglycemia (Grade D, Consensus). 4. For individuals already taking a regimen containing bolus insulin: a. A rapid-acting insulin analog (aspart, faster-acting aspart, glulisine, lispro) is preferred over human regular insulin so as to lower the risk for hypoglycemia and postprandial hyperglycemia (Grade C, Level 2 [29,30] for lispro; Grade D, Consensus for aspart, faster-acting aspart, glulisine) b. Patients should be advised to take their normal bolus dose with their sunset meal, omit their lunchtime bolus dose and lower their predawn meal dose by 5% to 50%, depending on carbohydrate intake and glucose readings (Grade D, Consensus). 5. For individuals managed by any insulin regimen, less intensive glycemic targets during Ramadan, aiming for fasting and premeal SMBGs of 5.5 to 7.5 mmol/L, are preferred so as to reduce the risk for hypoglycemia (Grade D, Consensus). Insulin dosage adjustment to achieve these conservative targets should be individualized, taking into consideration insulin sensitivity and total daily insulin dosage as well as the duration of fast (Grade D, Consensus). 6. Individuals taking a complex insulin regimen, especially those with increased risk for hypoglycemia, should be evaluated by a diabetes-management team pre-Ramadan (Grade D, Consensus).
# Management of Type 1 Diabetes During Ramadan
Fasting poses unique challenges for individuals with type 1 diabetes because of the severity of the risks involved. Extreme excursions in blood glucose levels can lead to life-threatening consequences, such as severe hypoglycemia, dehydration or diabetic ketoacidosis. Because of this, the IDF-DAR guidelines categorize any individual with type 1 diabetes as being at high risk or very high risk (8). Despite being considered at high risk, many individuals with type 1 diabetes do fast. The large populationbased Epidemiology of Diabetes and Ramadan study, conducted in 12,243 people with diabetes from 13 Muslim-majority countries, reported that 42.8% of individuals with type 1 diabetes fasted for at least 15 days during Ramadan (34). However, there was a 3-fold increase in severe hyperglycemia with and without ketoacidosis and a 4.7-fold increase in severe hypoglycemia in those with type 1 diabetes. Small observational studies, however, suggest that children, adolescents and adults with type 1 diabetes who are otherwise healthy and have stable glycemic control may fast safely with regular self-monitoring and under professional guidance with close supervision (35). Criteria for stability of glucose control include absence of serious complications and no episodes of severe hypoglycemia or ketoacidosis within 3 months prior to Ramadan. Individuals with type 1 diabetes who have poor control, do not comply with blood glucose monitoring or have hypoglycemia unawareness should be actively discouraged from fasting.
Limited studies have investigated the safety and efficacy of various insulin regimens for individuals with type 1 diabetes who fast during Ramadan. Insulin lispro was superior to regular human insulin for the prevention of hypoglycemia when used in combination with an intermediate-acting insulin taken twice daily (36). Insulin pump therapy has not been shown to be superior to basalbolus injection therapy in reducing rates of hypoglycemia during fasting, but it is associated with less glucose variability (37). Using the low-glucose suspend feature on certain insulin pumps reduced the rates of hypoglycemia without excessive severe hyperglycemia, but this technology, together with continuous glucose monitoring (CGM), may not be available routinely (38). It is important to note that none of the insulin-pump studies that took place during Ramadan were randomized.
Dosing of bolus insulin should be individualized according to unique eating patterns during Ramadan. Titration based on carbohydrate counting or estimation should be encouraged during fasting. Reducing the dosage of basal insulin is recommended in general, especially during daytime fasting hours when on an insulin pump. One study investigated self-reduction of basal insulin on pump therapy or basal-bolus insulin by individuals living with type 1 diabetes, but this strategy did not decrease the risk for hypoglycemia (39). Several studies investigated a basal insulin dosage reduction between 5% and 25%; however, hypoglycemia rates remained high (40)(41)(42). Especially considering the prolonged fasting duration in Canadian summers, a conservative, individualized initial reduction of 20% to 40% in basal insulin injections (or daytime insulin with pumps) is recommended, with weekly reassessments, ideally based on uploaded CGM or SMBG data.
# Recommendations
1. For people with type 1 diabetes who intend to fast, a medical assessment should be performed 1 to 3 months prior to Ramadan to evaluate individual risks for fasting and to optimize insulin management (Grade D, Consensus). 2. People with poorly controlled type 1 diabetes (i.e. pre-Ramadan A1C levels >9.0%, infrequent blood glucose monitoring and those with hypoglycemia unawareness) should be advised to not fast (Grade D, Consensus). 3. For those using regular human insulin as their bolus insulin, switching to a rapid-acting insulin analog (aspart, fasteracting aspart, glulisine, lispro) should be considered so as to reduce the rates of hypoglycemia (Grade C, Level 2 [36] for lispro; Grade D, Consensus for aspart, faster-acting aspart, glulisine) 1 to 3 months prior to Ramadan.
4. For those using basal-bolus injection therapy, a basal analog insulin (detemir, glargine) is preferred over intermediateacting insulin during Ramadan (Grade D, Consensus). Alternatively, a once-daily ultra-long-acting basal insulin (degludec, glargine U300) may be used to further reduce the risk for hypoglycemia and minimize the chance of missed insulin doses or periods of inadequate background insulin on board during prolonged fasting periods (Grade D, Consensus). 5. Insulin-to-carbohydrate ratios and insulin-sensitivity factors should remain unchanged during fasting if stable and well controlled (Grade D, Consensus). 6. All basal insulin doses and daytime basal doses when on insulinpump therapy should be reduced by a minimum of 20% for fasting days to reduce the risk for hypoglycemia (Grade D, Consensus) and reassessed weekly for further adjustments (Grade D, Consensus). 7. People with type 1 diabetes should monitor blood ketones when SMBG readings are elevated (>14.0 mmol/L) to screen for diabetic ketoacidosis. Those with blood ketones >0.6 mmol/L should break their fasts, take a supplemental dose of rapid-acting insulin for correction of blood ketones and reevaluate their ability to fast safely during Ramadan (Grade D, Consensus).
# Monitoring Glycemic Control While Fasting During Ramadan
Self-monitoring of blood glucose SMBG forms the cornerstone of the management of diabetes, both during and outside of fasting. Although there is a misconception that pricking the skin for monitoring glycemic control invalidates the fast, religious authorities agree that this is not the case (43). Another commonly held myth that makes people minimize SMBG checks is that they may have to break their fast on finding out about their hypoglycemic episodes if they were to check frequently. In fact, frequent SMBG may reduce the frequency and severity of hypoglycemic episodes so that fasting can be performed safely during Ramadan.
Types 1 and 2 diabetes treated with insulin. For insulin-treated subjects, SMBG ≥3 times daily has been associated with improved glycemic control outside of fasting in both types of diabetes (44,45). Fasting during Ramadan is associated with an increased risk for severe hypoglycemic episodes in individuals with both types of diabetes, while hyperglycemic episodes are increased, particularly in those with type 1 diabetes (34). Evidence that employing SMBG improves glycemic control during Ramadan is derived principally from observational studies that examined it as a part of the effectiveness of diabetes education programs, making it difficult to determine whether the effects observed were the result of frequent SMBG or other aspects of the program. In a small cohort of 21 subjects with both type 1 and 2 diabetes using the basal-bolus insulin regimen, a diabetes-education program including SMBG ≥5 times per day was associated with a reduction in hypoglycemic episodes during Ramadan (46). Another prospective study, which assessed twice-daily SMBG among subjects with type 1 or type 2 diabetes (67% taking insulin) showed a reduction in hypoglycemic episodes during Ramadan (47). Although limited by study methodology, these reports provide the only available evidence associating frequent SMBG with a reduction in hypoglycemic episodes in individuals with diabetes who were fasting during Ramadan. However, as mentioned above, insulin dosage adjustment to optimize care and to prevent and detect hypoglycemia indicates the need for regular SMBG. This is of particular concern before the main meal (usually the sunset meal). Indeed, monitoring for postprandial SMBG excursions may help many individuals to adjust their food intake and/or their insulin dosages during Ramadan.
Type 2 diabetes treated with noninsulin regimens. Similar methodologic limitations exist in studies examining the effect of SMBG in diabetes treated with noninsulin medications during Ramadan. In a prospective study, participants in an education program that included SMBG twice daily experienced a decrease in body mass index, A1C levels and severe hypoglycemic episodes during Ramadan (13). Similarly, weight loss and a decrease in the number of hypoglycemic episodes was observed in a retrospective study in which participants in a diabetes education program were advised to test glucose when symptomatic while fasting (48). Neither study, however, listed the daily SMBG frequency in the control groups. Additionally, sulfonylurea use was common among participants in these studies, questioning the generalizability of these findings to current nonsulfonylurea, noninsulin regimens commonly used in Canada.
Continuous and flash glucose monitoring. CGM and flash glucose monitoring (FGM) by individuals with either type 1 or type 2 diabetes and FGM by those with type 1 diabetes have not identified a worsening of glycemic control during Ramadan (49-51). To our knowledge, no study to date has compared the utility of CGM or FGM vs. SMBG in improving glycemic control when fasting during Ramadan. Further studies are needed to assess the utility of CGM or FGM in individuals with diabetes who fast during Ramadan, particularly among those using complex insulin regimens.
# Recommendations
1. For individuals fasting during Ramadan who use insulin:
a. Education on the frequency of SMBG testing during fasting should be provided to improve A1C levels and reduce rates of hypoglycemia (Grade C, Level 3 [13,48]). SMBG should be undertaken at least 5 times per day for people living with type 1 diabetes (Grade D, Consensus) and 2 to 5 times per day for those living with type 2 diabetes (Grade D, Consensus), in addition to periods of symptomatic hyper/ hypoglycemia (Grade D, Consensus) b. In the short term, real-time CGM or FGM during fasting to adjust insulin doses and prevent hypoglycemia risk may be considered for people living with type 1 or type 2 diabetes who are taking complex insulin regimens, defined as basal plus at least 1 additional administration of bolus insulin (Grade D, Consensus) c. For individuals with diabetes who do not require insulin, SMBG should be individualized according to the type of therapy, the risks for hypoglycemia or hyperglycemia, the levels of glycemic control and the durations of fast (Grade D, Consensus).
# Conclusions
This is the first Canadian position statement on the topic of Ramadan fasting and diabetes. It was developed by an expert faculty in collaboration with Diabetes Canada, and it provides guidance on pharmacotherapy and glucose monitoring for health-care providers so that they can assist Canadian Muslims living with diabetes to fast safely during Ramadan. The best available evidence was used to formulate recommendations using a standard grading system. The literature search revealed significant knowledge gaps, which highlights the need for further research in this field, including more studies performed in the Canadian population.
Overall, this Canadian position statement for Ramadan fasting and diabetes highlights the need for further education for healthcare providers and patients about the risks associated with fasting (hypoglycemia, hyperglycemia, dehydration, diabetic ketoacidosis), their prevention and management, as well as the importance of healthful eating during Ramadan. Sustained education and dissemination of the recommendations included in this position statement may assist people living with diabetes to manage their diabetes safely during Ramadan fasting.
# Supplementary Material
To access the supplementary material accompanying this article, visit the online version of the Canadian Journal of Diabetes at https://www.canadianjournalofdiabetes.com.
# Acknowledgments
Dr. Alice Cheng (Chair, 2013 Diabetes Canada Clinical Practice Guidelines); Dr. Peter Senior (Co-Chair, Diabetes Canada Professional Section); Dr. Jan Hux (President, Diabetes Canada); Jovita Sundaramoorthy (Vice President, Research and Education, Diabetes Canada); Tracy Barnes (Director, Guidelines & Research Knowledge Translation; Executive Editor, 2018 Clinical Practice Guidelines, Diabetes Canada); Alarica Fernandes (Professional Publications Coordinator, Research and Education, Diabetes Canada); Dr. Elizabeth Sellers (Chief Editor, Canadian Journal of Diabetes); Dr. Kamran Qureshi (endocrinologist); Dr. Sabina Parimoo (family physician); Shaista Zainul (certified diabetes educator); Gagan Gill-Mangat (certified diabetes educator); Amandeep Taank (PharmD candidate); Manzur Bhinder (person living with diabetes); Dr. Abdalla Idris Ali (National Director of Community Outreach and Religion, Islamic Society of North America, Canada). Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Mylan, Novo Nordisk, Sanofi-Aventis and Valeant; and research grants from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, Sanofi and Valeant. Dr. Abouhassan reports honoraria outside the submitted work from Abbott, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk and Sanofi. Dr. Ahsan reports no disclosures. Dr. Arnaout reports support outside the submitted work: research support from Allergan and Sanofi-Aventis; and serving on advisory panels for Boehringer Ingelheim, Medtronic, Novo Nordisk and Sanofi-Aventis. Dr. Hassanein reports honoraria outside the submitted work from Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk and Sanofi-Aventis. Dr. Houlden reports grants outside the submitted work from Boehringer Ingelheim, Eli Lilly and Novo Nordisk. Dr. Khan reports honorarium outside the submitted work from Novo Nordisk. Dr. Khandwala reports honoraria outside the submitted work from Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, Sanofi-Aventis and Valeant; and research support from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, Sanofi and Valeant. Dr. Verma reports support outside the submitted work: research support from AstraZeneca, Amgen, Boehringer Ingelheim and Eli Lilly; service on advisory panels for AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen and Merck; and speaker bureaus for Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck, Janssen, Novartis and Sanofi.
# Funding Statement
Logistic support for the expert forum was arranged by the Canadian Medical & Surgical Knowledge Translation Research Group through unrestricted grants from Abbott Diagnostics (Canada), AstraZeneca (Canada), Boehringer Ingelheim (Canada), Eli Lilly (Canada), Janssen (Canada), Merck (Canada), Novo Nordisk (Canada) and Sanofi (Canada). These companies were not involved in the literature search, preparation, review or approval of the position statement nor in the decision to submit the manuscript for publication.
# Author Disclosures
Dr. Bajaj reports honoraria outside the submitted work from
# Author Contributions
All authors actively discussed the content of the manuscript, drafted portions of the manuscript, critically revised the completed manuscript and approved the final version for submission. | None | None |
81c5a72e01ef1bbeb57aa2145361e500115ae461 | cma | None | To guide clinicians in the selection of antithrombotic therapy for the prevention of ischemic stroke and arterial thromboembolism in patients with atrial fibrillation.# BACKGROUND:
Atrial fibrillation (AF) is the most common pathologic arrhythmia and increases in prevalence with increasing age (prevalence of 10-15% in patients who are ≥80 years). The most devastating complication of AF is arterial embolism of a left atrial thrombus resulting in ischemic stroke, peripheral limb ischemia, or other end organ damage. AF is associated with a 3-to 6-fold increased risk of stroke or non-central nervous system (CNS) systemic embolism. Furthermore, ischemic strokes in patients with AF are larger and more frequently associated with death and disability than strokes that occur in the absence of AF. Therefore, stroke prevention is a critical part of AF treatment.
The risk of arterial thromboembolism can be significantly reduced with anticoagulant therapy (warfarin, apixaban, dabigatran, edoxaban or rivaroxaban) and, to a much lesser extent, with antiplatelet therapy. Selection of antithrombotic therapy should be guided by assessment of presumed thrombotic risk, assessment of presumed bleeding risk on antithrombotic therapy and patient preference.
Thrombotic Risk: Prognostic models incorporating patient age and co-morbidities provide validated estimates of the annual risk for thromboembolism without anticoagulant therapy. These models were developed for patients with non-valvular AF, which refers to AF occurring in the absence of a mechanical heart valve or rheumatic heart disease with severe mitral stenosis or regurgitation. The most frequently used score is the CHADS2 score (see Table 1).
# TOTAL score
The Canadian Cardiovascular Society and this guide use a modified "CHADS-65"scoring system as the basis for recommendations (see Recommendations and Figure 1).
Risk calculators for the CHADS2 score and, another modification, CHA2DS2-VASc score are available on the Thrombosis Canada website . In general, in patients with a CHADS2 score or a CHA2DS2-VASc score ≥1, the risk of arterial thromboembolism (and resulting morbidity/mortality) without anticoagulation outweighs the risk of bleeding from anticoagulants.
Bleeding Risk: Bleeding risk should also be assessed in all patients. However, in most cases, bleeding risk should not preclude the use of anticoagulant therapy. The risk-benefit ratio almost always favours anticoagulation unless the risks for bleeding are very high and the risk of thromboembolism is very low. Patients at increased risk for bleeding, typically, are also those who will benefit the most from anticoagulation to prevent stroke, and attempts should be made to modify bleeding risk factors (i.e. NSAID or alcohol use, frequent falls). There are prognostic models for the estimation of bleeding risk in patients with AF on warfarin therapy (e.g. HAS-BLED, available on Thrombosis Canada website ), which can help to identify potentially reversible risk factors for bleeding.
# AGENTS AND DOSING:
Anticoagulants: Warfarin (with target INR of 2-3) was the anticoagulant of choice for the prevention of stroke in patients with AF for many years. Antiplatelet agents: In patients with AF at low risk of stroke, who decline oral anticoagulation, or in whom oral anticoagulation is considered contraindicated due to bleeding risk, low dose aspirin (80-100 mg/day) may be considered. However, aspirin provides less protection than an anticoagulant and increases bleeding risk.
# RECOMMENDATIONS:
See Figure 1 Patients with AF and valvular heart disease (severe mitral stenosis, mechanical heart valves) are at significantly increased risk for ischemic stroke, and warfarin is recommended for this indication.
Treatment with a DOAC is not recommended in these patients with AF and these drugs are not approved for this use.
In patients with coronary artery disease, antithrombotic management should be individualized and based on an assessment of risk of atrial fibrillation-related stroke, ischemic coronary event, and clinically relevant bleeding associated with the use of antithrombotic agents.
OTHER RELEVANT THROMBOSIS CANADA CLINICAL GUIDES:
- Apixaban (Eliquis®)
# Date of Version: 14Jan2020
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein. | To guide clinicians in the selection of antithrombotic therapy for the prevention of ischemic stroke and arterial thromboembolism in patients with atrial fibrillation.# BACKGROUND:
Atrial fibrillation (AF) is the most common pathologic arrhythmia and increases in prevalence with increasing age (prevalence of 10-15% in patients who are ≥80 years). The most devastating complication of AF is arterial embolism of a left atrial thrombus resulting in ischemic stroke, peripheral limb ischemia, or other end organ damage. AF is associated with a 3-to 6-fold increased risk of stroke or non-central nervous system (CNS) systemic embolism. Furthermore, ischemic strokes in patients with AF are larger and more frequently associated with death and disability than strokes that occur in the absence of AF. Therefore, stroke prevention is a critical part of AF treatment.
The risk of arterial thromboembolism can be significantly reduced with anticoagulant therapy (warfarin, apixaban, dabigatran, edoxaban or rivaroxaban) and, to a much lesser extent, with antiplatelet therapy. Selection of antithrombotic therapy should be guided by assessment of presumed thrombotic risk, assessment of presumed bleeding risk on antithrombotic therapy and patient preference.
Thrombotic Risk: Prognostic models incorporating patient age and co-morbidities provide validated estimates of the annual risk for thromboembolism without anticoagulant therapy. These models were developed for patients with non-valvular AF, which refers to AF occurring in the absence of a mechanical heart valve or rheumatic heart disease with severe mitral stenosis or regurgitation. The most frequently used score is the CHADS2 score (see Table 1).
# TOTAL score
The Canadian Cardiovascular Society and this guide use a modified "CHADS-65"scoring system as the basis for recommendations (see Recommendations and Figure 1).
Risk calculators for the CHADS2 score and, another modification, CHA2DS2-VASc score are available on the Thrombosis Canada website [http://thrombosiscanada.ca/?page_id=502]. In general, in patients with a CHADS2 score or a CHA2DS2-VASc score ≥1, the risk of arterial thromboembolism (and resulting morbidity/mortality) without anticoagulation outweighs the risk of bleeding from anticoagulants.
Bleeding Risk: Bleeding risk should also be assessed in all patients. However, in most cases, bleeding risk should not preclude the use of anticoagulant therapy. The risk-benefit ratio almost always favours anticoagulation unless the risks for bleeding are very high and the risk of thromboembolism is very low. Patients at increased risk for bleeding, typically, are also those who will benefit the most from anticoagulation to prevent stroke, and attempts should be made to modify bleeding risk factors (i.e. NSAID or alcohol use, frequent falls). There are prognostic models for the estimation of bleeding risk in patients with AF on warfarin therapy (e.g. HAS-BLED, available on Thrombosis Canada website [https://thrombosiscanada.ca/tools/?calc=has-bled]), which can help to identify potentially reversible risk factors for bleeding.
# AGENTS AND DOSING:
Anticoagulants: Warfarin (with target INR of 2-3) was the anticoagulant of choice for the prevention of stroke in patients with AF for many years. Antiplatelet agents: In patients with AF at low risk of stroke, who decline oral anticoagulation, or in whom oral anticoagulation is considered contraindicated due to bleeding risk, low dose aspirin (80-100 mg/day) may be considered. However, aspirin provides less protection than an anticoagulant and increases bleeding risk.
# RECOMMENDATIONS:
See Figure 1 Patients with AF and valvular heart disease (severe mitral stenosis, mechanical heart valves) are at significantly increased risk for ischemic stroke, and warfarin is recommended for this indication.
Treatment with a DOAC is not recommended in these patients with AF and these drugs are not approved for this use.
In patients with coronary artery disease, antithrombotic management should be individualized and based on an assessment of risk of atrial fibrillation-related stroke, ischemic coronary event, and clinically relevant bleeding associated with the use of antithrombotic agents.
OTHER RELEVANT THROMBOSIS CANADA CLINICAL GUIDES:
• Apixaban (Eliquis®)
# Date of Version: 14Jan2020
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein. | None | None |
711cf3334941850647aee3d9f2f4ee23e842ea17 | cma | None | This guidance is intended for general pediatricians, family physicians and other primary care providers. It is based on known evidence as of September 27, 2021.# Introduction
Knowledge is changing rapidly and information below may be modified in response.
This document addresses issues relating to pediatric patients and COVID-19 and is intended for health-care professionals. This document does not specifically address babies born to mothers/individuals with suspected or confirmed COVID-19. That information is provided in a separate document.
# Microbiology and Transmission
The SARS-CoV-2 virus is a betacoronavirus that causes the clinical disease of COVID-19 and is related to the viruses that cause severe acute respiratory syndrome (SARS) and middle east respiratory syndrome (MERS). The incubation period is a median of three to five days but can range from two to 14 days.
The infection mainly spreads from respiratory droplets or prolonged close contact. Airborne spread is possible during aerosol-generating procedures.
The spread of COVID-19 through vertical transmission (mother/individual to child) is being closely studied. Intrauterine transmission may occur but is rare. Postnatal transmission from a caregiver is more likely to occur. Please refer to Perinatal Services BC's COVID-19 newborn guidance for more details on this topic.
Children do not appear to be a major source of SARS-CoV-2 transmission in households or schools, a finding which has been consistent globally. The majority of children with COVID-19 were in contact with a household member who was positive for COVID-19. Children with COVID-19 have been found to have high viral loads despite milder symptoms, with prolonged shedding in nasal secretions (up to 22 days) and in fecal samples (over 30 days). Asymptomatic children have tested positive on nasopharyngeal and fecal specimens. Children appear to shed the virus for longer than adults but the evidence for the infectivity of shed virus remains limited.
# Infection Prevention and Control (IPC)
Please refer to the B.C. Centre For Disease Control's (BCCDC) webpage for up-to-date IPC recommendations.
Each health authority has site-specific IPC guidelines and the B.C. Children's Hospital has specific recommendations, policies and procedures.
Droplet and contact precautions should be used for all suspected or confirmed cases of COVID-19 with the addition of airborne precautions for any aerosol generating medical procedures (AGMPs).
AGMPs include, but are not limited to:
- Endotracheal tube insertion or removal - Tracheotomy or tracheostomy care - Bronchoscopy - Nebulized therapy - High-flow nasal cannulae therapy or continuous positive airway pressure therapy Refer to the BCCDC website for a full list of current AGMPs.
IPC guidelines for donning and doffing personal protective equipment (PPE) should be followed. See BCCDC's personal protective equipment webpage for more information.
# Clinical Features and Diagnosis
# Clinical Presentation
Pediatric studies continue to report that most children with COVID-19 will have mild disease or asymptomatic infection. It is not known why children have been significantly less affected compared to adults. Symptomatic children typically present with fever and cough. Other common symptoms include sore throat, nasal congestion and rhinorrhea. Less common symptoms in children are myalgia, fatigue, diarrhea, nausea, vomiting, headache and dizziness. Rarely, severe cases may progress to respiratory distress or failure after one week. Co-infection of COVID-19 with other pathogens like influenza, respiratory syncytial virus (RSV) and mycoplasma has been reported.
Compared to adults, children report more gastrointestinal symptoms, including abdominal discomfort, nausea, vomiting and diarrhea. These symptoms may be the sole presentation, without any accompanying respiratory symptoms.
Children with COVID-19 can present with skin changes, including acrocyanosis, pernio-like changes and acral ischemia. Skin lesions may appear as red-purple papules or nodules on extremities such as limbs, fingers or toes and should be tested and referred to a pediatric dermatologist.
After a COVID-19 infection, children and adolescents very rarely present with multisystem inflammatory syndrome in children (MIS-C) -an acute multisystemic inflammatory disease with overlapping features of toxic shock syndrome and Kawasaki disease. This syndrome is thought to be a post-infectious entity that occurs two to six weeks following infection with COVID-19. Most of these cases have known exposures to a case of COVID-19 or have tested positive on COVID-19 polymerase chain reaction (PCR)/serology. A separate document discusses case definitions and the management of suspected MIS-C cases.
# Disease Severity
The latest Canadian data shows that up to 16% of the confirmed COVID-19 cases have been reported in those ≤19 years old. An umbrella review found 10-19% of children with COVID-19 had asymptomatic infection but there is evidence to suggest the percentage may be as high as 45%. In B.C., the true proportion of asymptomatic children is unknown because testing is not routinely performed in asymptomatic individuals unless advised by public health.
Severe and critical illness from COVID-19 infection in children is still rare. Approximately 1% of children with labconfirmed COVID-19 have required hospitalization and a similar percentage have required intensive care unit admission.
There is evidence that infants (under one year old) might be at increased risk for severe infection. Similarly, children with underlying medical conditions/comorbidities are at a higher risk for severe manifestations of COVID-19 and have more associated mortality compared to healthy children. There is also evidence that childhood obesity is likely associated with a worse prognosis. Otherwise, it is unclear what underlying conditions place a child with COVID-19 at increased risk. Like adults, infants and children with severe COVID-19 infection can progress to respiratory failure, shock and multisystem organ failure. These symptoms may develop days after symptom onset.
# Chest Imaging
Chest imaging should be done if clinically indicated but should not be used as a screening or diagnostic tool.
Chest imaging often shows consolidation, ground-glass opacities or bilateral infiltrates. Radiographic abnormalities have been reported in asymptomatic children.
# Testing
Microbiologic confirmation of COVID-19 is made by a positive PCR test for SARS-CoV-2 (the virus which causes COVID-19) from a nasopharyngeal swab (preferable) or a lower respiratory tract sample (e.g., sputum or endotracheal secretions). In the outpatient setting, a saline gargle and swish test is available.
Stool PCR and serological testing are not routinely performed to diagnose acute COVID-19. Consultation with microbiology must be done prior to ordering either test. As children may shed SARS-CoV-2 in their stools even after their illness has resolved, stool testing is restricted to those with no alternative diagnosis and a high suspicion of COVID-19 disease. In B.C., serologic testing is currently performed in children with suspected MIS-C or another post-viral inflammatory complication, to help diagnose patients who are SARS-CoV-2 ribonucleic acid negative but have a compatible syndrome, or who present later during their disease course.
For further details, refer to the BCCDC antibody testing webpage.
# Who to test:
Unlike adults, there are no specific signs or symptoms that are highly predictive of COVID-19 in children. Some present with mild upper respiratory tract infection symptoms while up to one-third may be asymptomatic. Importantly, the majority of children diagnosed with COVID-19 in B.C. have been a close contact with another known case. Health-care providers should refer to BCCDC's testing guidelines for information on provincial public health testing criteria and instructions. However, testing for clinical care needs to use a lower threshold, particularly for testing children with a known COVID-19 contact and any possible symptoms, even if the child does not meet provincial testing criteria.
For a child who will be hospitalized, testing should be done for any symptom that could be consistent with COVID-19 regardless of contacts (see clinical presentation, above). Testing asymptomatic children should only be done at the request of public health.
Children requiring urgent/elective surgery may require pre-operative testing. Testing guidance for this population can be found in the IPC protocol for surgical procedures during COVID-19: pediatrics.
Like any test, nucleic acid amplification tests may result in false negative results. If there is strong clinical suspicion for COVID-19 in the event of a negative test result, consider repeat testing at least 24 hours apart.
# Management and Treatment
Therapeutic options for COVID-19 are actively being studied worldwide and are rapidly evolving. The majority of data available is from literature on adults. Current literature suggests that most children will have mild disease and will recover at home one to two weeks after symptom onset with no medical intervention necessary.
Immunocompromised children with suspected or confirmed COVID-19 should self-isolate at home for 10 days from symptom onset and at least 24 hours of fever resolution. Caregivers of children with COVID-19 should provide similar support to children as other viral infections, including regular fluids and antipyretics (fever-reducing medicine) if needed for comfort. After 10 days, if the child's temperature is normal and they feel better, they can return to their regular activities. Coughing may persist for several weeks, so a cough alone does not mean they need to continue to self-isolate for more than 10 days. The duration of isolation of immunocompromised children with COVID-19 is at least 20 days as directed by public health.
Families of children and adolescents who have recovered from the acute phase of COVID-19 should be counselled about the possibility developing MIS-C. Providers should seek specialist advice from B.C. Children's Hospital if their patient develops features such as fever, mucocutaneous inflammation, gastrointestinal symptoms or other systemic symptoms, particularly if symptoms occur within two to six weeks from the initial COVID-19 illness.
# Hospitalization
Hospitalization of a child with suspected or confirmed COVID-19 disease is indicated for those with moderate to critical disease. Definitions of clinical severity of COVID-19 in pediatric patients are outlined in the Canadian Paediatric Society's practice point.
Children with medical complexity or co-morbidities should be considered at higher risk for severe COVID-19 disease. However, being at a higher risk does not necessitate automatic hospitalization in the absence of moderate to critical disease. The decision to hospitalize such children should factor in the family's ability to care for the child and accessibility to health-care in case their condition deteriorates.
Refer to the BCCDC website for more information on the management of MIS-C.
# Supportive Care
Recommendation: Supportive care is still an effective therapy for COVID-19. Use conservative fluid management when there is no evidence of shock.
Advanced organ support including hemodynamic support, mechanical ventilation and renal replacement may be necessary if severe respiratory deterioration occurs or if the child is showing signs of MIS-C possibly associated with COVID-19. In such instances, arrangements for transfer to a higher level of care and consultation with a pediatric intensive care unit (PICU) is required.
# Fever Management
Recommendation: Acetaminophen and ibuprofen at routine doses can be safely administered for fever and symptom relief in children with suspected or confirmed COVID-19.
Early in the pandemic, there were concerns that the use of nonsteroidal anti-inflammatory drugs (NSAIDs) may worsen the severity of COVID-19 infection. However, the evidence has not demonstrated a link.
There is no indication at this time to discontinue NSAIDs for those patients needing them for other diagnoses (e.g., juvenile idiopathic arthritis, etc.). Decisions should be made on a case-by-case basis in consultation with the child's doctor, nurse practitioner or sub-specialist in pediatric infectious diseases. Dexamethasone is strongly recommended in critically and severely ill COVID-19 adult patients. Patients with severe COVID-19 can develop a systemic inflammatory response that can lead to lung injury and multi-system organ dysfunction. It has been proposed that the potent anti-inflammatory effects of corticosteroids might prevent or mitigate these harmful effects. The use of corticosteroids for COVID-19 is mainly based on the RECOVERY trial conducted in the United Kingdom. Mortality at 28 days was lower among patients who were randomized to receive up to 10 days of dexamethasone than among those who received the standard of care. No benefit of dexamethasone was seen in patients who did not require supplemental oxygen at enrollment. The trial did not include a significant number of pediatric patients.
# Immunomodulatory Therapies
Corticosteroids are not indicated in mild illness outside of clinical trials. As mentioned previously, several epidemiologic studies suggest that acute disease manifestations are substantially less severe in children than in adults, although there are reports of children with COVID-19 requiring PICU-level care.
Patients who are regularly on corticosteroids for other indications (e.g., underlying adrenal insufficiency, rheumatologic disease, etc.) should be discussed on a case-by-case basis with pediatric infectious diseases and the physicians or nurse practitioners involved in their care.
Children with asthma exacerbations and suspected/confirmed COVID-19 should receive inhaled or systemic corticosteroids according to current asthma guidelines.
Similarly, children with moderate to severe croup should be given corticosteroids as per current guidelines. Consider avoiding corticosteroids in cases of milder croup with no respiratory distress.
# Tocilizumab
Recommendation: Tocilizumab is not recommended as a treatment of acute COVID-19 in children.
Tocilizumab is an interleukin-6 (IL-6) inhibitor. It is thought that modulating the levels of pro-inflammatory IL-6 or its effects may improve the course of COVID-19. Tocilizumab is currently recommended for adult patients requiring life support as a result of COVID-19. There are no trials that have evaluated the use of this drug for children with COVID-19.
For children who receive tocilizumab for another diagnosis (e.g., juvenile idiopathic arthritis), consultation with their subspecialist is recommended.
# Intravenous Immunoglobulin (IVIG)
Recommendation: IVIG is not recommended as a treatment of acute COVID-19.
IVIG has been used in some pediatric cases of COVID-19, but there is no clear evidence of benefit in COVID-19 disease in children.
However, IVIG is now considered standard treatment for MIS-C in children. It is important to note that the features of MIS-C overlap with those of Kawasaki disease and toxic shock syndrome. The decision to administer IVIG when the diagnosis is unclear should be made in consultation with pediatric rheumatology and pediatric infectious diseases. Please refer to MIS-C specific guidance document regarding evaluation, recommended consultations and management of this condition.
# Passive Immunotherapies
Recommendation: Passive immunotherapies are not recommended outside of approved clinical trials.
These therapies include convalescent plasma/monoclonal antibodies/antibody cocktail therapies/REGN-COV2/bamlanivimab or colchicine. These therapies are not recommended outside of approved clinical trials.
# Antibacterial Therapy
Recommendation: Empiric antibiotics should be given for sepsis or other suspected bacterial co-infection based on clinical assessment of the patient.
Antibiotics have no effect against the COVID-19 virus. Please collect relevant cultures (blood, urine, etc.) before initiating antibiotics. Empiric antibiotics should be de-escalated on the basis of microbiology results and clinical judgment.
For sepsis, children should be empirically treated with an intravenous (IV) third generation cephalosporin +/-IV vancomycin, depending on methicillin-resistant staphylococcus aureus risk factors. Empiric therapy for sepsis in children who are immunocompromised (e.g., febrile neutropenia) or have history of infections with drug resistant organisms should be discussed with the infectious disease service at B.C. Children's Hospital.
For pneumonia, children should be treated with intravenous ampicillin or oral amoxicillin based on their clinical severity, as per community acquired pneumonia guidelines.
# Antiviral Medications
Recommendation: There are currently no approved antiviral therapies to treat COVID-19. Please contact pediatric infectious diseases to discuss a specific case. As per the World Health Organization guidelines, investigational anti-COVID-19 medications will only be used in approved, randomized controlled trials.
The antivirals discussed below are not an exhaustive list of medications that have been studied against COVID-19. Please see the B.C. COVID-19 Therapeutics Committee's summary for more details on unproven therapies against COVID-19.
# Chloroquine/Hydroxychloroquine
Chloroquine/hydroxychloroquine is not a recognized treatment of adult outpatients and adult hospitalized patients with COVID-19.
# Lopinavir/Ritonavir
Lopinavir/ritonavir has been shown to inhibit the protease activity of coronavirus but has been shown to have no benefit for patients with COVID-19.
# Remdesivir
Remdesivir has not demonstrated benefit in survival, progression to ventilation, length of hospital stay or shortening recovery time. The use of remdesivir is not considered a standard of care. The safety and effectiveness against COVID-19 in children has not yet been evaluated.
# Oseltamivir
Oseltamivir is not recommended for COVID-19 as it is highly specific to the influenza virus. Empiric therapy for children with symptoms compatible with influenza is reasonable during influenza season.
# Contributors
Lead Author: Dr. Ashley Roberts Co-Authors: Dr. Alison Lopez, Dr. Sarah Silverberg, Ethan Zhang, Jessica Li, Dr. Laura Sauvé Versions 1 & 2 Reviewed By:
- Pediatric infectious diseases, B.C. Children's Hospital (BCCH): Dr. Laura Sauvé, Dr. Alison Lopez, Dr. Soren Gantt, Dr. Manish Sadarangani, Dr. David Goldfarb, Dr. Hana Mitchell Pediatric subcommittee members include: Dr. Hana Mitchell (co-chair), Dr. Laura Sauvé (co-chair), Dr. Catherine Briggs, Dr. Matthew Carwana, Dr. Tommy Gerschman, Dr. Esther Lee, Dr Alison Lopez, Dr. Srinivas Murthy, Dr. Ashley Roberts, Dr. Peter Skippen, Trisha Thomson and Dr. Tom Warshawski. | This guidance is intended for general pediatricians, family physicians and other primary care providers. It is based on known evidence as of September 27, 2021.# Introduction
Knowledge is changing rapidly and information below may be modified in response.
This document addresses issues relating to pediatric patients and COVID-19 and is intended for health-care professionals. This document does not specifically address babies born to mothers/individuals with suspected or confirmed COVID-19. That information is provided in a separate document.
# Microbiology and Transmission
The SARS-CoV-2 virus is a betacoronavirus that causes the clinical disease of COVID-19 and is related to the viruses that cause severe acute respiratory syndrome (SARS) and middle east respiratory syndrome (MERS). The incubation period is a median of three to five days but can range from two to 14 days.
The infection mainly spreads from respiratory droplets or prolonged close contact. Airborne spread is possible during aerosol-generating procedures.
The spread of COVID-19 through vertical transmission (mother/individual to child) is being closely studied. Intrauterine transmission may occur but is rare. Postnatal transmission from a caregiver is more likely to occur. Please refer to Perinatal Services BC's COVID-19 newborn guidance for more details on this topic.
Children do not appear to be a major source of SARS-CoV-2 transmission in households or schools, a finding which has been consistent globally. The majority of children with COVID-19 were in contact with a household member who was positive for COVID-19. Children with COVID-19 have been found to have high viral loads despite milder symptoms, with prolonged shedding in nasal secretions (up to 22 days) and in fecal samples (over 30 days). Asymptomatic children have tested positive on nasopharyngeal and fecal specimens. Children appear to shed the virus for longer than adults but the evidence for the infectivity of shed virus remains limited.
# Infection Prevention and Control (IPC)
Please refer to the B.C. Centre For Disease Control's (BCCDC) webpage for up-to-date IPC recommendations.
Each health authority has site-specific IPC guidelines and the B.C. Children's Hospital has specific recommendations, policies and procedures.
Droplet and contact precautions should be used for all suspected or confirmed cases of COVID-19 with the addition of airborne precautions for any aerosol generating medical procedures (AGMPs).
AGMPs include, but are not limited to:
• Endotracheal tube insertion or removal • Tracheotomy or tracheostomy care • Bronchoscopy • Nebulized therapy • High-flow nasal cannulae therapy or continuous positive airway pressure therapy Refer to the BCCDC website for a full list of current AGMPs.
IPC guidelines for donning and doffing personal protective equipment (PPE) should be followed. See BCCDC's personal protective equipment webpage for more information.
# Clinical Features and Diagnosis
# Clinical Presentation
Pediatric studies continue to report that most children with COVID-19 will have mild disease or asymptomatic infection. It is not known why children have been significantly less affected compared to adults. Symptomatic children typically present with fever and cough. Other common symptoms include sore throat, nasal congestion and rhinorrhea. Less common symptoms in children are myalgia, fatigue, diarrhea, nausea, vomiting, headache and dizziness. Rarely, severe cases may progress to respiratory distress or failure after one week. Co-infection of COVID-19 with other pathogens like influenza, respiratory syncytial virus (RSV) and mycoplasma has been reported.
Compared to adults, children report more gastrointestinal symptoms, including abdominal discomfort, nausea, vomiting and diarrhea. These symptoms may be the sole presentation, without any accompanying respiratory symptoms.
Children with COVID-19 can present with skin changes, including acrocyanosis, pernio-like changes and acral ischemia. Skin lesions may appear as red-purple papules or nodules on extremities such as limbs, fingers or toes and should be tested and referred to a pediatric dermatologist.
After a COVID-19 infection, children and adolescents very rarely present with multisystem inflammatory syndrome in children (MIS-C) -an acute multisystemic inflammatory disease with overlapping features of toxic shock syndrome and Kawasaki disease. This syndrome is thought to be a post-infectious entity that occurs two to six weeks following infection with COVID-19. Most of these cases have known exposures to a case of COVID-19 or have tested positive on COVID-19 polymerase chain reaction (PCR)/serology. A separate document discusses case definitions and the management of suspected MIS-C cases.
# Disease Severity
The latest Canadian data shows that up to 16% of the confirmed COVID-19 cases have been reported in those ≤19 years old. An umbrella review found 10-19% of children with COVID-19 had asymptomatic infection but there is evidence to suggest the percentage may be as high as 45%. In B.C., the true proportion of asymptomatic children is unknown because testing is not routinely performed in asymptomatic individuals unless advised by public health.
Severe and critical illness from COVID-19 infection in children is still rare. Approximately 1% of children with labconfirmed COVID-19 have required hospitalization and a similar percentage have required intensive care unit admission.
There is evidence that infants (under one year old) might be at increased risk for severe infection. Similarly, children with underlying medical conditions/comorbidities are at a higher risk for severe manifestations of COVID-19 and have more associated mortality compared to healthy children. There is also evidence that childhood obesity is likely associated with a worse prognosis. Otherwise, it is unclear what underlying conditions place a child with COVID-19 at increased risk. Like adults, infants and children with severe COVID-19 infection can progress to respiratory failure, shock and multisystem organ failure. These symptoms may develop days after symptom onset.
# Chest Imaging
Chest imaging should be done if clinically indicated but should not be used as a screening or diagnostic tool.
Chest imaging often shows consolidation, ground-glass opacities or bilateral infiltrates. Radiographic abnormalities have been reported in asymptomatic children.
# Testing
Microbiologic confirmation of COVID-19 is made by a positive PCR test for SARS-CoV-2 (the virus which causes COVID-19) from a nasopharyngeal swab (preferable) or a lower respiratory tract sample (e.g., sputum or endotracheal secretions). In the outpatient setting, a saline gargle and swish test is available.
Stool PCR and serological testing are not routinely performed to diagnose acute COVID-19. Consultation with microbiology must be done prior to ordering either test. As children may shed SARS-CoV-2 in their stools even after their illness has resolved, stool testing is restricted to those with no alternative diagnosis and a high suspicion of COVID-19 disease. In B.C., serologic testing is currently performed in children with suspected MIS-C or another post-viral inflammatory complication, to help diagnose patients who are SARS-CoV-2 ribonucleic acid negative but have a compatible syndrome, or who present later during their disease course.
For further details, refer to the BCCDC antibody testing webpage.
# Who to test:
Unlike adults, there are no specific signs or symptoms that are highly predictive of COVID-19 in children. Some present with mild upper respiratory tract infection symptoms while up to one-third may be asymptomatic. Importantly, the majority of children diagnosed with COVID-19 in B.C. have been a close contact with another known case. Health-care providers should refer to BCCDC's testing guidelines for information on provincial public health testing criteria and instructions. However, testing for clinical care needs to use a lower threshold, particularly for testing children with a known COVID-19 contact and any possible symptoms, even if the child does not meet provincial testing criteria.
For a child who will be hospitalized, testing should be done for any symptom that could be consistent with COVID-19 regardless of contacts (see clinical presentation, above). Testing asymptomatic children should only be done at the request of public health.
Children requiring urgent/elective surgery may require pre-operative testing. Testing guidance for this population can be found in the IPC protocol for surgical procedures during COVID-19: pediatrics.
Like any test, nucleic acid amplification tests may result in false negative results. If there is strong clinical suspicion for COVID-19 in the event of a negative test result, consider repeat testing at least 24 hours apart.
# Management and Treatment
Therapeutic options for COVID-19 are actively being studied worldwide and are rapidly evolving. The majority of data available is from literature on adults. Current literature suggests that most children will have mild disease and will recover at home one to two weeks after symptom onset with no medical intervention necessary.
Immunocompromised children with suspected or confirmed COVID-19 should self-isolate at home for 10 days from symptom onset and at least 24 hours of fever resolution. Caregivers of children with COVID-19 should provide similar support to children as other viral infections, including regular fluids and antipyretics (fever-reducing medicine) if needed for comfort. After 10 days, if the child's temperature is normal and they feel better, they can return to their regular activities. Coughing may persist for several weeks, so a cough alone does not mean they need to continue to self-isolate for more than 10 days. The duration of isolation of immunocompromised children with COVID-19 is at least 20 days as directed by public health.
Families of children and adolescents who have recovered from the acute phase of COVID-19 should be counselled about the possibility developing MIS-C. Providers should seek specialist advice from B.C. Children's Hospital if their patient develops features such as fever, mucocutaneous inflammation, gastrointestinal symptoms or other systemic symptoms, particularly if symptoms occur within two to six weeks from the initial COVID-19 illness.
# Hospitalization
Hospitalization of a child with suspected or confirmed COVID-19 disease is indicated for those with moderate to critical disease. Definitions of clinical severity of COVID-19 in pediatric patients are outlined in the Canadian Paediatric Society's practice point.
Children with medical complexity or co-morbidities should be considered at higher risk for severe COVID-19 disease. However, being at a higher risk does not necessitate automatic hospitalization in the absence of moderate to critical disease. The decision to hospitalize such children should factor in the family's ability to care for the child and accessibility to health-care in case their condition deteriorates.
Refer to the BCCDC website for more information on the management of MIS-C.
# Supportive Care
Recommendation: Supportive care is still an effective therapy for COVID-19. Use conservative fluid management when there is no evidence of shock.
Advanced organ support including hemodynamic support, mechanical ventilation and renal replacement may be necessary if severe respiratory deterioration occurs or if the child is showing signs of MIS-C possibly associated with COVID-19. In such instances, arrangements for transfer to a higher level of care and consultation with a pediatric intensive care unit (PICU) is required.
# Fever Management
Recommendation: Acetaminophen and ibuprofen at routine doses can be safely administered for fever and symptom relief in children with suspected or confirmed COVID-19.
Early in the pandemic, there were concerns that the use of nonsteroidal anti-inflammatory drugs (NSAIDs) may worsen the severity of COVID-19 infection. However, the evidence has not demonstrated a link.
There is no indication at this time to discontinue NSAIDs for those patients needing them for other diagnoses (e.g., juvenile idiopathic arthritis, etc.). Decisions should be made on a case-by-case basis in consultation with the child's doctor, nurse practitioner or sub-specialist in pediatric infectious diseases. Dexamethasone is strongly recommended in critically and severely ill COVID-19 adult patients. Patients with severe COVID-19 can develop a systemic inflammatory response that can lead to lung injury and multi-system organ dysfunction. It has been proposed that the potent anti-inflammatory effects of corticosteroids might prevent or mitigate these harmful effects. The use of corticosteroids for COVID-19 is mainly based on the RECOVERY trial conducted in the United Kingdom. Mortality at 28 days was lower among patients who were randomized to receive up to 10 days of dexamethasone than among those who received the standard of care. No benefit of dexamethasone was seen in patients who did not require supplemental oxygen at enrollment. The trial did not include a significant number of pediatric patients.
# Immunomodulatory Therapies
Corticosteroids are not indicated in mild illness outside of clinical trials. As mentioned previously, several epidemiologic studies suggest that acute disease manifestations are substantially less severe in children than in adults, although there are reports of children with COVID-19 requiring PICU-level care.
Patients who are regularly on corticosteroids for other indications (e.g., underlying adrenal insufficiency, rheumatologic disease, etc.) should be discussed on a case-by-case basis with pediatric infectious diseases and the physicians or nurse practitioners involved in their care.
Children with asthma exacerbations and suspected/confirmed COVID-19 should receive inhaled or systemic corticosteroids according to current asthma guidelines.
Similarly, children with moderate to severe croup should be given corticosteroids as per current guidelines. Consider avoiding corticosteroids in cases of milder croup with no respiratory distress.
# Tocilizumab
Recommendation: Tocilizumab is not recommended as a treatment of acute COVID-19 in children.
Tocilizumab is an interleukin-6 (IL-6) inhibitor. It is thought that modulating the levels of pro-inflammatory IL-6 or its effects may improve the course of COVID-19. Tocilizumab is currently recommended for adult patients requiring life support as a result of COVID-19. There are no trials that have evaluated the use of this drug for children with COVID-19.
For children who receive tocilizumab for another diagnosis (e.g., juvenile idiopathic arthritis), consultation with their subspecialist is recommended.
# Intravenous Immunoglobulin (IVIG)
Recommendation: IVIG is not recommended as a treatment of acute COVID-19.
IVIG has been used in some pediatric cases of COVID-19, but there is no clear evidence of benefit in COVID-19 disease in children.
However, IVIG is now considered standard treatment for MIS-C in children. It is important to note that the features of MIS-C overlap with those of Kawasaki disease and toxic shock syndrome. The decision to administer IVIG when the diagnosis is unclear should be made in consultation with pediatric rheumatology and pediatric infectious diseases. Please refer to MIS-C specific guidance document regarding evaluation, recommended consultations and management of this condition.
# Passive Immunotherapies
Recommendation: Passive immunotherapies are not recommended outside of approved clinical trials.
These therapies include convalescent plasma/monoclonal antibodies/antibody cocktail therapies/REGN-COV2/bamlanivimab or colchicine. These therapies are not recommended outside of approved clinical trials.
# Antibacterial Therapy
Recommendation: Empiric antibiotics should be given for sepsis or other suspected bacterial co-infection based on clinical assessment of the patient.
Antibiotics have no effect against the COVID-19 virus. Please collect relevant cultures (blood, urine, etc.) before initiating antibiotics. Empiric antibiotics should be de-escalated on the basis of microbiology results and clinical judgment.
For sepsis, children should be empirically treated with an intravenous (IV) third generation cephalosporin +/-IV vancomycin, depending on methicillin-resistant staphylococcus aureus risk factors. Empiric therapy for sepsis in children who are immunocompromised (e.g., febrile neutropenia) or have history of infections with drug resistant organisms should be discussed with the infectious disease service at B.C. Children's Hospital.
For pneumonia, children should be treated with intravenous ampicillin or oral amoxicillin based on their clinical severity, as per community acquired pneumonia guidelines.
# Antiviral Medications
Recommendation: There are currently no approved antiviral therapies to treat COVID-19. Please contact pediatric infectious diseases to discuss a specific case. As per the World Health Organization guidelines, investigational anti-COVID-19 medications will only be used in approved, randomized controlled trials.
The antivirals discussed below are not an exhaustive list of medications that have been studied against COVID-19. Please see the B.C. COVID-19 Therapeutics Committee's summary for more details on unproven therapies against COVID-19.
# Chloroquine/Hydroxychloroquine
Chloroquine/hydroxychloroquine is not a recognized treatment of adult outpatients and adult hospitalized patients with COVID-19.
# Lopinavir/Ritonavir
Lopinavir/ritonavir has been shown to inhibit the protease activity of coronavirus but has been shown to have no benefit for patients with COVID-19.
# Remdesivir
Remdesivir has not demonstrated benefit in survival, progression to ventilation, length of hospital stay or shortening recovery time. The use of remdesivir is not considered a standard of care. The safety and effectiveness against COVID-19 in children has not yet been evaluated.
# Oseltamivir
Oseltamivir is not recommended for COVID-19 as it is highly specific to the influenza virus. Empiric therapy for children with symptoms compatible with influenza is reasonable during influenza season.
# Contributors
Lead Author: Dr. Ashley Roberts Co-Authors: Dr. Alison Lopez, Dr. Sarah Silverberg, Ethan Zhang, Jessica Li, Dr. Laura Sauvé Versions 1 & 2 Reviewed By:
• Pediatric infectious diseases, B.C. Children's Hospital (BCCH): Dr. Laura Sauvé, Dr. Alison Lopez, Dr. Soren Gantt, Dr. Manish Sadarangani, Dr. David Goldfarb, Dr. Hana Mitchell Pediatric subcommittee members include: Dr. Hana Mitchell (co-chair), Dr. Laura Sauvé (co-chair), Dr. Catherine Briggs, Dr. Matthew Carwana, Dr. Tommy Gerschman, Dr. Esther Lee, Dr Alison Lopez, Dr. Srinivas Murthy, Dr. Ashley Roberts, Dr. Peter Skippen, Trisha Thomson and Dr. Tom Warshawski. | None | None |
969a235de4025e31e01c6b845f661970594ede1c | cma | None | To provide practical strategies supported by the best available evidence for managing out-ofrange international normalized ratios (INRs) for patients on long-term warfarin therapy.# BACKGROUND:
- Warfarin can be challenging to manage due to its narrow therapeutic range, variable doseresponse among patients and common interactions with drugs, diet, alcohol, and other factors. 2. In patients who are taking warfarin, thromboembolic events and bleeding are strongly related to the time in therapeutic range (TTR). This is the proportion of treatment time that the INR is within the target therapeutic range (typically 2.0 to 3.0 or 2.5-3.5 for patients with mechanical mitral valve replacements). 3. Clinicians may underdose warfarin due to a perceived greater risk of harm from bleeding associated with supratherapeutic INR values. However, subtherapeutic anticoagulation has been shown to increase the frequency and severity of thromboembolic events. 4. Good INR control, defined empirically as a TTR >60%, may be best achieved by appropriately addressing both high and low INR values using a consistent approach (paper-based dosing nomogram or computerized decision support program).
# APPROACH TO OUT-OF-RANGE INR VALUES:
- For each out-of-range INR value, attempt to identify the cause. See the section below, "Summary of Common Causes of Out-of-Range INRs". 2. Determine whether a one-time change in the dose is all that is required or if a change in the maintenance dose is required or both.
- A change in the maintenance dose should be considered if there are at least two consecutive out-of-range INR values (in the same direction) in a patient with previously stable, in-range INRs and for which there is no identified temporary cause. - A one-time change in the dose is appropriate for patients in which a transient cause is identified.
# MANAGING SINGLE OUT-OF-RANGE INR VALUES
- For patients with previously in-range INR values who present with a single slightly outof-range INR (e.g. INR 0.5 above or below the target range), there are two management options:
- Continue current maintenance dose and repeat INR in 1-2 weeks, OR 2. Make a one-time dose change (increase or hold by ½ to 1 single dose) and resume current maintenance dose. Repeat INR in 1-2 weeks - The specific approach is influenced by the magnitude of the out-of-range value, previous experience of similar values in the patient and whether the patient has strong risk factors for thrombosis/stroke or bleeding.
# MAINTENANCE DOSING ALGORITHMS:
There are many warfarin dosing algorithms available. Physicians should become familiar with one approach in order to develop experience and consistency in making dosing changes.
# SUMMARY OF COMMON CAUSES FOR OUT-OF-RANGE INRs:
Table 1 and Table 2 summarize common causes and management strategies for LOW and HIGH INRs, respectively.
# Table 1: Common Causes of LOW INRs and Management Strategies COMMON CAUSES OF LOW INRS MANAGEMENT STRATEGIES MISSED DOSES, NON-COMPLIANCE, or ERRORS IN DOSING
- Review the doses of warfarin actually taken over the past several weeks.
- If patient is receiving more than one strength of tablet, consider adjusting dose to enable use of a single strength to avoid confusion.
# ANTIPLATELET AGENTS:
Antiplatelet agents (acetylsalicylic acid , clopidogrel, prasugrel, ticagrelor) and Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) significantly increase the risk of bleeding when combined with warfarin but generally do not change the INR. The indication and clinical necessity of using these agents should be carefully weighed against the increased bleeding risk and should be avoided unless specifically indicated. Refer to the Clinical Guide: Warfarin for more information.
# OTHER RELEVANT THROMBOSIS CANADA CLINICAL GUIDES:
- Warfarin - Warfarin: Point-of-Care INR Monitoring
# Date of Version: 07August2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein. | To provide practical strategies supported by the best available evidence for managing out-ofrange international normalized ratios (INRs) for patients on long-term warfarin therapy.# BACKGROUND:
1. Warfarin can be challenging to manage due to its narrow therapeutic range, variable doseresponse among patients and common interactions with drugs, diet, alcohol, and other factors. 2. In patients who are taking warfarin, thromboembolic events and bleeding are strongly related to the time in therapeutic range (TTR). This is the proportion of treatment time that the INR is within the target therapeutic range (typically 2.0 to 3.0 or 2.5-3.5 for patients with mechanical mitral valve replacements). 3. Clinicians may underdose warfarin due to a perceived greater risk of harm from bleeding associated with supratherapeutic INR values. However, subtherapeutic anticoagulation has been shown to increase the frequency and severity of thromboembolic events. 4. Good INR control, defined empirically as a TTR >60%, may be best achieved by appropriately addressing both high and low INR values using a consistent approach (paper-based dosing nomogram or computerized decision support program).
# APPROACH TO OUT-OF-RANGE INR VALUES:
1. For each out-of-range INR value, attempt to identify the cause. See the section below, "Summary of Common Causes of Out-of-Range INRs". 2. Determine whether a one-time change in the dose is all that is required or if a change in the maintenance dose is required or both.
• A change in the maintenance dose should be considered if there are at least two consecutive out-of-range INR values (in the same direction) in a patient with previously stable, in-range INRs and for which there is no identified temporary cause. • A one-time change in the dose is appropriate for patients in which a transient cause is identified.
# MANAGING SINGLE OUT-OF-RANGE INR VALUES
• For patients with previously in-range INR values who present with a single slightly outof-range INR (e.g. INR 0.5 above or below the target range), there are two management options:
1. Continue current maintenance dose and repeat INR in 1-2 weeks, OR 2. Make a one-time dose change (increase or hold by ½ to 1 single dose) and resume current maintenance dose. Repeat INR in 1-2 weeks • The specific approach is influenced by the magnitude of the out-of-range value, previous experience of similar values in the patient and whether the patient has strong risk factors for thrombosis/stroke or bleeding.
# MAINTENANCE DOSING ALGORITHMS:
There are many warfarin dosing algorithms available. Physicians should become familiar with one approach in order to develop experience and consistency in making dosing changes.
# SUMMARY OF COMMON CAUSES FOR OUT-OF-RANGE INRs:
Table 1 and Table 2 summarize common causes and management strategies for LOW and HIGH INRs, respectively.
# Table 1: Common Causes of LOW INRs and Management Strategies COMMON CAUSES OF LOW INRS MANAGEMENT STRATEGIES MISSED DOSES, NON-COMPLIANCE, or ERRORS IN DOSING
• Review the doses of warfarin actually taken over the past several weeks.
• If patient is receiving more than one strength of tablet, consider adjusting dose to enable use of a single strength to avoid confusion.
# ANTIPLATELET AGENTS:
Antiplatelet agents (acetylsalicylic acid [ASA], clopidogrel, prasugrel, ticagrelor) and Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) significantly increase the risk of bleeding when combined with warfarin but generally do not change the INR. The indication and clinical necessity of using these agents should be carefully weighed against the increased bleeding risk and should be avoided unless specifically indicated. Refer to the Clinical Guide: Warfarin for more information.
# OTHER RELEVANT THROMBOSIS CANADA CLINICAL GUIDES:
• Warfarin • Warfarin: Point-of-Care INR Monitoring
# Date of Version: 07August2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein. | None | None |
bbc7d33ef1f3e8df5af8d58ea8d7f4c48fc1a6c2 | cma | None | While every attempt has been made to ensure that the information contained herein is clinically accurate and current, Perinatal Services BC acknowledges that many issues remain controversial, and therefore may be subject to practice interpretation#
In July 2018 the government of British Columbia repealed section 17 of the Health Act Communicable Disease Regulation that mandated universal newborn baby eye prophylaxis Perinatal Services BC (PSBC) recommends the following:
All women should be offered screening for Chlamydia trachomatis and Neisseria gonorrhoeae at the first prenatal visit 1,2 ⦁ ⦁ Additional screening is recommended in each trimester for women with ongoing risk factors 1,2 ⦁ ⦁ Universal eye prophylaxis of all newborns to prevent Ophthalmia Neonatorum, caused by Chlamydia trachomatis and Neisseria gonorrhoeae, until there is a safe alternative to erythromycin, such as rapid screening for women who have not been screened during pregnancy or with ongoing risk factors at the time of delivery for Chlamydia trachomatis and Neisseria gonorrhoeae The only agent approved in Canada for newborn eye prophylaxis is erythromycin 3 ⦁ ⦁ Monitor all newborns for signs and symptoms of Ophthalmia Neonatorum It is imperative for both health care providers and parents to recognize the signs and symptoms of Ophthalmia Neonatorum and to respond appropriately 2,4,5,6 ⦁ ⦁ If infection is suspected collect conjunctival specimen and test for Chlamydia trachomatis and Neisseria gonorrhoeae ⦁ ⦁ Cefotaxime is the recommended treatment for infants at risk for, or diagnosed with, Ophthalmia Neonatorum caused by Neisseria gonorrhoeae Due to adverse reactions associated with ceftriaxone in the neonatal population, cefotaxime is the preferred antimicrobial 7,8 ⦁ ⦁ Consider a single dose of intramuscular cefotaxime prior to discharge if the infant is at risk for exposure to Neisseria gonorrhoeae and there is any concern that the mother or caregiver may not recognize the signs of Ophthalmia Neonatorum, and/or respond appropriately 2,6 ⦁ ⦁ Asymptomatic infants born to mothers with untreated Neisseria gonorrhoeae infection at the time of birth should receive a single dose of cefotaxime 100 mg/kg IV/IM 2
Infants born to mothers with untreated Neisseria gonorrhoeae at the time of birth that are unwell require: Treat infants that test positive for Chlamydia trachomatis with oral or intravenous erythromycin 4,6,9,10
⦁ A full
# Highlights of this Guideline
Ophthalmia Neonatorum (ON) is defined as acute conjunctivitis of any cause during the neonatal period and presents with conjunctival erythema, edema of the eyelids and ocular discharge Causes of ON can be chemical, viral or bacterial This guideline focuses on Ophthalmia Neonatorum caused by Chlamydia trachomatis and Neisseria gonorrhoeae and discusses best evidence-based practice to prevent, diagnose, and manage ON caused by these two pathogens This document is intended for use by physicians, midwives, nurse practitioners, acute care and public health nurses who provide health care to newborns in British Columbia It incorporates recommendations and evidence-based information from a variety of trusted sources including provincial, national and international guidelines Experts and stakeholders across BC were consulted during the development of this document A parent information brochure (Appendix A) has been developed to provide parents and/or caregivers with information about the signs and symptoms of Ophthalmia Neonatorum and when to bring the newborn for consultation with a health care provider Primary care providers are responsible for providing this resource to patients, which can be downloaded and printed from Perinatal Services BC's website: www.perinatalservicesbc.ca/health-professionals/guidelines-standards/newborn
The Highlights of this Guideline (on page 2) is a quick reference guide and is intended to serve as a high-level overview of information and action items that are considered relevant in the prevention and management of Ophthalmia Neonatorum caused by Chlamydia trachomatis and Neisseria gonorrhoeae This document is provided for guidance and is not meant to replace clinical judgment
# Executive Summary
Chlamydia trachomatis is the most commonly reported sexually transmitted infection in Canada 11 , and the most common pathogen causing Ophthalmia Neonatorum Approximately 23 per cent 12 of infants born to women with active and untreated Chlamydia trachomatis infections typically present with mild to moderate conjunctivitis Fifty per cent of these infants will also develop a nasopharyngeal infection and 10 to 20 per cent of these infants may develop a concomitant pneumonia 13 Complications from Ophthalmia Neonatorum caused by Neisseria gonorrhoeae are more severe and can lead to corneal scarring, ocular perforation and blindness Skin wounds, such as scalp lesions due to fetal scalp electrodes, may become infected and disseminated infection can also occur 4,14 Two to 40 per cent of infants born to women with active and untreated Neisseria gonorrhoeae infection, and who did not receive eye prophylaxis, may develop Ophthalmia Neonatorum 14,15,16 Neonatal eye prophylaxis was introduced by Credé in 1881 at a time when the maternal infection rates were high and there was no effective treatment for gonococcal Ophthalmia Neonatorum Credé found that routine prophylaxis with topical 2% silver nitrate led to a dramatic reduction in the incidence of blindness caused by gonococcal Ophthalmia Neonatorum 11 The discovery of antibiotics, prenatal screening and treatment of maternal sexually transmitted infections has had a dramatic effect on the prevention of Ophthalmia Neonatorum caused by Chlamydia trachomatis and Neisseria gonorrhoeae 17 As of January 2000, gonococcal Ophthalmia Neonatorum was removed from national surveillance in Canada due to its low incidence Several western countries abandoned prophylaxis in the 1960s in favor of monitoring, swabbing suspicious discharges and treating with appropriate solutions as required 17 Eye prophylaxis is mandatory in the USA 18 ; however, the US Preventative Task Force is currently reviewing the effectiveness of different eye prophylaxis agents to prevent Ophthalmia Neonatorum and blindness, as well as the potential harms related to eye prophylaxis 19 The American Academy of Pediatrics is currently advocating for the revision of mandated eye prophylaxis, and improvement of antenatal screening to prevent Ophthalmia Neonatorum 4
In July 2018 the government of British Columbia repealed section 17 of the Health Act Communicable Disease Regulation that mandated universal newborn eye prophylaxis Currently there are no other legislatively mandated communicable disease prophylaxis or treatment measures, even for immunization programs that do protect and improve public health Mandating babies' eye prophylaxis infringes on the autonomy of the parent as surrogate decision maker and does not necessarily protect or improve public health 17 In Canada, newborn eye prophylaxis remains to be mandated in all provinces/territories except for New Brunswick, Newfoundland, Saskatchewan and now British Columbia Although New Brunswick, Newfoundland and Saskatchewan do not mandate newborn eye prophylaxis it is still recommended and part of their policy Prevalence of Chlamydia trachomatis and Neisseria gonorrhoeae in BC Since 2003 a steady increase in the prevalence of both Chlamydia trachomatis and Neisseria gonorrhoeae have been noted in the BC population, echoing the national trend This can be attributed to a true rise in disease, improved screening and uptake of testing, and an increase in the sensitivity of diagnostic testing 10,11,20,21 The increase in the reported prevalence of Neisseria gonorrhoeae can also be attributed to updated national guidelines promoting specimen collection from oropharyngeal and rectal sites 5,22 and antibiotic resistance 23,24 Between 2014 to 2016, a 70 per cent increase in the prevalence of Neisseria gonorrhoeae in BC has been noted, leading the BC CDC to collaborate with the National Microbiology Laboratory to determine the reason for this rapid rise 20 The highest prevalence among people of reproductive age is among those aged less than 25 years Rates for the Overview less than 1-year old group for Chlamydia trachomatis in BC between 2003 and 2016 are less than 3/100,000 During this time period, no cases of Neisseria gonorrhoeae in the same population group were reported except in 2014 (23/100,000), following the increase in prevalence observed in the adult population between 2014 and 2016 20
# Case For or Against Universal Eye Prophylaxis and Impact on Care
The Canadian Pediatric Society (CPS) 2015 Position Statement (reaffirmed 2018) on preventing Ophthalmia Neonatorum argues against universal mandated eye prophylaxis and recommends universal screening for Chlamydia trachomatis and Neisseria gonorrhoeae of all pregnant women at the first prenatal visit Women (and sexual partners) who tested positive for Chlamydia trachomatis and/or Neisseria gonorrhoeae need to be treated and retested after treatment to ensure that the treatment was effective The CPS recommends additional targeted testing during the third trimester of all pregnant women who tested positive for Chlamydia trachomatis and Neisseria gonorrhoeae during the first trimester, as well as all women at risk for contracting Chlamydia trachomatis and Neisseria gonorrhoeae Rapid screening for Chlamydia trachomatis and Neisseria gonorrhoeae should be available for all women at delivery who were not screened during their pregnancy 2 This position statement is not supported by the Canadian Association for Pediatric Ophthalmology and Strabismus (CAPOS) citing concerns with the quality of evidence against eye prophylaxis, and the increased risk to infants born to women of marginalized communities with limited access to prenatal care 25 While the CPS Position Statement advocates for comprehensive antenatal screening for Chlamydia trachomatis and Neisseria gonorrhoeae, data collected between 2011 and 2014 in Manitoba indicates that antenatal screening is suboptimal and implies that some infants may be at higher risk to develop gonococcal Ophthalmia Neonatorum without universal eye prophylaxis 26 Finding current evidence-based research relevant to the Canadian population, and specific to the British Columbia population, on Ophthalmia Neonatorum and eye prophylaxis is challenging Much of the primary research was conducted in countries other than Canada, some dating back to the 1980s The Canadian Agency for Drugs and Technologies in Health (CADTH) Rapid Response Report on neonatal eye prophylaxis (2016) concluded that the evidence for, or against, eye prophylaxis is of low quality due to different populations, settings and issues with heterogeneity 27 A Cochrane systemic review on the interventions for preventing Ophthalmia Neonatorum is currently underway The two main objectives of the Cochrane review are to determine if eye prophylaxis reduces the incidence of Ophthalmia Neonatorum, and if so, what eye prophylaxis is the most effective 28 The only agent approved in Canada for eye prophylaxis is erythromycin 3 The efficacy of topical erythromycin to prevent Chlamydia trachomatis Ophthalmia Neonatorum is questionable 29,30,31,32 and not recommended by the American Academy of Pediatrics 14 and the Canadian Pediatric Society 17 Antimicrobial resistance is a global barrier to the successful treatment of Neisseria gonorrhoeae and will have a significant impact on the health and economic burden to manage this disease The Canadian Antimicrobial Resistance Surveillance System (2017) reported a 325 per cent failure rate when treating Neisseria gonorrhoeae with erythromycin 33 , and according to the Canadian Pediatric Society, is the reason for discontinuation of using erythromycin as ocular prophylaxis 12 The incidence of suboptimal antenatal screening rates, the prevalence of Chlamydia trachomatis and/or Neisseria gonorrhoeae infections in pregnant women, and the potential for adverse obstetric outcomes and newborn morbidities due to Chlamydia trachomatis and/or Neisseria gonorrhoeae lend support to the recommendation to improve antenatal screening and the continuation of universal newborn eye prophylaxis Overview, cont'd.
# Screening
All women should be screened for Chlamydia trachomatis and Neisseria gonorrhoeae at the first prenatal visit. Targeted screening is recommended in each trimester for women with ongoing risk factors.
Currently, Perinatal Services BC (PSBC) recommends that all women should be offered screening for Chlamydia trachomatis and Neisseria gonorrhoeae at the first prenatal visit In addition to screening all women at the first prenatal visit, additional screening is recommended in each trimester for women with ongoing risk factors 1 Maternal Risk factors are as follows:
25 years or younger and sexually active 9,23,24,34,35,36,37,38 ⦁ ⦁ New and/or more than one sex partner 9,24,36,37,38 ⦁ ⦁ Previous documented diagnosis of Chlamydia trachomatis and/or Neisseria gonorrhoeae 5,9,35,36,37,38,39 ⦁ ⦁ Sexual contact with a person with suspected or confirmed Chlamydia trachomatis and/or Neisseria gonorrhoeae infection 5,35,36 ⦁ ⦁ Unprotected sex with a resident from area with high prevalence of Chlamydia trachomatis and/or Neisseria gonorrhoeae infection 5,36
Unprotected sexual contact with resident from area with high risk of antimicrobial resistance to Chlamydia trachomatis and/or Neisseria gonorrhoeae 5,36 Maternal health care providers must inform newborn's health care providers regarding maternal risk factors, screening results and treatment for Chlamydia trachomatis and Neisseria gonorrhoeae as this will direct the care of the newborn related to Ophthalmia Neonatorum 2
For the most current information on disease prevalence in an area consult the BC Centre for Disease Control Reportable Disease Dashboard: www.bccdc.ca/health-info/disease-system-statistics/reportable-disease-dashboard
# Recommendations Eye Prophylaxis
Universal eye prophylaxis of all newborns to prevent Ophthalmia Neonatorum caused by Chlamydia trachomatis and Neisseria gonorrhoeae is recommended.
While the law mandating universal eye prophylaxis has been repealed, PSBC and CAPOS continue to recommend universal eye prophylaxis of the newborn until there is a safe alternative to erythromycin such as rapid maternal screening at the time of delivery for Chlamydia trachomatis and Neisseria gonorrhoeae Currently erythromycin 05% ointment is the only ocular prophylactic agent approved in Canada and needs to be administered within one hour after birth 3
Procedure to Administer 0.5% Erythromycin Ointment 1 Use gloves when administering erythromycin 2 To prevent cross contamination, use a single-use tube of 05% erythromycin and discard remainder of tube after administering to both eyes 3 Before administration, wipe each eyelid gently with sterile cotton to remove foreign matter and to permit adequate eversion of the lower lid 4 Apply a line of 05% erythromycin ointment, about 1 cm long, in the inferior conjunctival fornix, by pulling the lower eyelid gently down Care is needed to prevent injury to the eye or the eyelid from the tip of the tube 5 Gently massage the closed eyelids to help spread the solution to all areas of the conjunctiva 6 In the very premature newborns whose eye lids are fused at the time of birth, apply the erythromycin ointment without separating the eyelids Ointment absorption through the immature skin is expected
Recommendations, cont'd.
# Monitor for Signs and Symptoms of Ophthalmia Neonatorum
It is imperative for both health care providers and parents to recognize the signs and symptoms of Ophthalmia Neonatorum and to respond appropriately 2,4,5,6 Advise mother or caregiver of all newborns how to recognize Ophthalmia Neonatorum prior to discharge and when to contact a health care provider (see Appendix A: Information for Families) Currently, erythromycin 05% ointment is the only prophylactic agent approved in Canada and needs to be administered within one hour after birth 3 It is recommended that erythromycin eye prophylaxis continues to be administered to all newborns until there is a safe alternative, including newborns at risk of exposure to Neisseria gonorrhoeae Advise mother or caregiver how to recognize Ophthalmia Neonatorum prior to discharge and when to contact a health care provider (see Appendix A: Information for Families) If there is any concern that the mother or caregiver may not recognize the signs of Ophthalmia Neonatorum and/or respond appropriately, consider administering a single dose of cefotaxime IM prior to discharge if the newborn is discharged before five days of age 3 Prophylactic antibiotic treatment is not indicated unless follow up with physician cannot be guaranteed 14,17 4 Newborns should be monitored for signs of Chlamydia trachomatis infection (conjunctivitis and/or pneumonitis) 2,4,5,6 5 Advise mother how to recognize Ophthalmia Neonatorum prior to discharge and when to contact a health care provider (see Appendix A: Information for Families)
Management of Ophthalmia Neonatorum Caused by Chlamydia trachomatis 1 Collect conjunctival swabs obtained from the everted eyelid Specimens must contain conjunctival cells, not just exudate 30 Test for Neisseria gonorrhoeae at the same time 2 Treat infant if test is positive for Chlamydia trachomatis with oral or intravenous erythromycin 4,6,9,10 Dosing and frequency of administration are determined by weight and postnatal age 41 Consult local guidelines for neonatal dosing information 3 Consider referral to higher level of care if indicated 4 There is a documented association between orally administered erythromycin and infantile hypertrophic pyloric stenosis- especially in newborns less than two weeks of age 4,10,42 5 Inform parents about the signs and potential risks of developing infantile hypertrophic pyloric stenosis- (nonbilious and forceful vomiting immediately after feed) 6 Follow up visit with newborn three to four weeks after completion of the treatment is recommended since the efficacy of erythromycin therapy is approximately 80% A second course of treatment may be required 4 - Functional gastric outlet obstruction leading to forceful vomiting
Management of the Newborn at Risk of Exposure to Chlamydia trachomatis
Appendix A: Information for Families: Eye Infection and Your Newborn Baby www.perinatalservicesbc.ca Most of the time, puffy or red eyes in your baby are caused by a blocked tear duct or infection by viruses or bacteria. Some eye infections may be serious and need special medication.
Contact your doctor or go to the emergency department or health clinic at once if your baby is under two weeks and:
- Your baby's eyes are red - Your baby's eyes have thick pus
- Your baby's eyelids are swollen or puffy Your baby's eye needs to be examined to find out if it is an infection that needs to be treated. | While every attempt has been made to ensure that the information contained herein is clinically accurate and current, Perinatal Services BC acknowledges that many issues remain controversial, and therefore may be subject to practice interpretation�#
In July 2018 the government of British Columbia repealed section 17 of the Health Act Communicable Disease Regulation that mandated universal newborn baby eye prophylaxis� Perinatal Services BC (PSBC) recommends the following:
⦁ ⦁
All women should be offered screening for Chlamydia trachomatis and Neisseria gonorrhoeae at the first prenatal visit� 1,2 ⦁ ⦁ Additional screening is recommended in each trimester for women with ongoing risk factors� 1,2 ⦁ ⦁ Universal eye prophylaxis of all newborns to prevent Ophthalmia Neonatorum, caused by Chlamydia trachomatis and Neisseria gonorrhoeae, until there is a safe alternative to erythromycin, such as rapid screening for women who have not been screened during pregnancy or with ongoing risk factors at the time of delivery for Chlamydia trachomatis and Neisseria gonorrhoeae� The only agent approved in Canada for newborn eye prophylaxis is erythromycin� 3 ⦁ ⦁ Monitor all newborns for signs and symptoms of Ophthalmia Neonatorum� It is imperative for both health care providers and parents to recognize the signs and symptoms of Ophthalmia Neonatorum and to respond appropriately� 2,4,5,6 ⦁ ⦁ If infection is suspected collect conjunctival specimen and test for Chlamydia trachomatis and Neisseria gonorrhoeae� ⦁ ⦁ Cefotaxime is the recommended treatment for infants at risk for, or diagnosed with, Ophthalmia Neonatorum caused by Neisseria gonorrhoeae� Due to adverse reactions associated with ceftriaxone in the neonatal population, cefotaxime is the preferred antimicrobial� 7,8 ⦁ ⦁ Consider a single dose of intramuscular cefotaxime prior to discharge if the infant is at risk for exposure to Neisseria gonorrhoeae and there is any concern that the mother or caregiver may not recognize the signs of Ophthalmia Neonatorum, and/or respond appropriately� 2,6 ⦁ ⦁ Asymptomatic infants born to mothers with untreated Neisseria gonorrhoeae infection at the time of birth should receive a single dose of cefotaxime 100 mg/kg IV/IM� 2
# ⦁ ⦁
Infants born to mothers with untreated Neisseria gonorrhoeae at the time of birth that are unwell require: Treat infants that test positive for Chlamydia trachomatis with oral or intravenous erythromycin� 4,6,9,10
⦁ A full
# Highlights of this Guideline
Ophthalmia Neonatorum (ON) is defined as acute conjunctivitis of any cause during the neonatal period and presents with conjunctival erythema, edema of the eyelids and ocular discharge� Causes of ON can be chemical, viral or bacterial� This guideline focuses on Ophthalmia Neonatorum caused by Chlamydia trachomatis and Neisseria gonorrhoeae and discusses best evidence-based practice to prevent, diagnose, and manage ON caused by these two pathogens� This document is intended for use by physicians, midwives, nurse practitioners, acute care and public health nurses who provide health care to newborns in British Columbia� It incorporates recommendations and evidence-based information from a variety of trusted sources including provincial, national and international guidelines� Experts and stakeholders across BC were consulted during the development of this document� A parent information brochure (Appendix A) has been developed to provide parents and/or caregivers with information about the signs and symptoms of Ophthalmia Neonatorum and when to bring the newborn for consultation with a health care provider� Primary care providers are responsible for providing this resource to patients, which can be downloaded and printed from Perinatal Services BC's website: www.perinatalservicesbc.ca/health-professionals/guidelines-standards/newborn�
The Highlights of this Guideline (on page 2) is a quick reference guide and is intended to serve as a high-level overview of information and action items that are considered relevant in the prevention and management of Ophthalmia Neonatorum caused by Chlamydia trachomatis and Neisseria gonorrhoeae� This document is provided for guidance and is not meant to replace clinical judgment�
# Executive Summary
Chlamydia trachomatis is the most commonly reported sexually transmitted infection in Canada 11 , and the most common pathogen causing Ophthalmia Neonatorum� Approximately 23 per cent 12 of infants born to women with active and untreated Chlamydia trachomatis infections typically present with mild to moderate conjunctivitis� Fifty per cent of these infants will also develop a nasopharyngeal infection and 10 to 20 per cent of these infants may develop a concomitant pneumonia� 13 Complications from Ophthalmia Neonatorum caused by Neisseria gonorrhoeae are more severe and can lead to corneal scarring, ocular perforation and blindness� Skin wounds, such as scalp lesions due to fetal scalp electrodes, may become infected and disseminated infection can also occur� 4,14 Two to 40 per cent of infants born to women with active and untreated Neisseria gonorrhoeae infection, and who did not receive eye prophylaxis, may develop Ophthalmia Neonatorum� 14,15,16 Neonatal eye prophylaxis was introduced by Credé in 1881 at a time when the maternal infection rates were high and there was no effective treatment for gonococcal Ophthalmia Neonatorum� Credé found that routine prophylaxis with topical 2% silver nitrate led to a dramatic reduction in the incidence of blindness caused by gonococcal Ophthalmia Neonatorum� 11 The discovery of antibiotics, prenatal screening and treatment of maternal sexually transmitted infections has had a dramatic effect on the prevention of Ophthalmia Neonatorum caused by Chlamydia trachomatis and Neisseria gonorrhoeae� 17 As of January 2000, gonococcal Ophthalmia Neonatorum was removed from national surveillance in Canada due to its low incidence� Several western countries abandoned prophylaxis in the 1960s in favor of monitoring, swabbing suspicious discharges and treating with appropriate solutions as required� 17 Eye prophylaxis is mandatory in the USA 18 ; however, the US Preventative Task Force is currently reviewing the effectiveness of different eye prophylaxis agents to prevent Ophthalmia Neonatorum and blindness, as well as the potential harms related to eye prophylaxis� 19 The American Academy of Pediatrics is currently advocating for the revision of mandated eye prophylaxis, and improvement of antenatal screening to prevent Ophthalmia Neonatorum� 4
In July 2018 the government of British Columbia repealed section 17 of the Health Act Communicable Disease Regulation that mandated universal newborn eye prophylaxis� Currently there are no other legislatively mandated communicable disease prophylaxis or treatment measures, even for immunization programs that do protect and improve public health� Mandating babies' eye prophylaxis infringes on the autonomy of the parent as surrogate decision maker and does not necessarily protect or improve public health� 17 In Canada, newborn eye prophylaxis remains to be mandated in all provinces/territories except for New Brunswick, Newfoundland, Saskatchewan and now British Columbia� Although New Brunswick, Newfoundland and Saskatchewan do not mandate newborn eye prophylaxis it is still recommended and part of their policy� Prevalence of Chlamydia trachomatis and Neisseria gonorrhoeae in BC Since 2003 a steady increase in the prevalence of both Chlamydia trachomatis and Neisseria gonorrhoeae have been noted in the BC population, echoing the national trend� This can be attributed to a true rise in disease, improved screening and uptake of testing, and an increase in the sensitivity of diagnostic testing� 10,11,20,21 The increase in the reported prevalence of Neisseria gonorrhoeae can also be attributed to updated national guidelines promoting specimen collection from oropharyngeal and rectal sites 5,22 and antibiotic resistance� 23,24 Between 2014 to 2016, a 70 per cent increase in the prevalence of Neisseria gonorrhoeae in BC has been noted, leading the BC CDC to collaborate with the National Microbiology Laboratory to determine the reason for this rapid rise� 20 The highest prevalence among people of reproductive age is among those aged less than 25 years� Rates for the Overview less than 1-year old group for Chlamydia trachomatis in BC between 2003 and 2016 are less than 3/100,000� During this time period, no cases of Neisseria gonorrhoeae in the same population group were reported except in 2014 (2�3/100,000), following the increase in prevalence observed in the adult population between 2014 and 2016� 20
# Case For or Against Universal Eye Prophylaxis and Impact on Care
The Canadian Pediatric Society (CPS) 2015 Position Statement (reaffirmed 2018) on preventing Ophthalmia Neonatorum argues against universal mandated eye prophylaxis and recommends universal screening for Chlamydia trachomatis and Neisseria gonorrhoeae of all pregnant women at the first prenatal visit� Women (and sexual partners) who tested positive for Chlamydia trachomatis and/or Neisseria gonorrhoeae need to be treated and retested after treatment to ensure that the treatment was effective� The CPS recommends additional targeted testing during the third trimester of all pregnant women who tested positive for Chlamydia trachomatis and Neisseria gonorrhoeae during the first trimester, as well as all women at risk for contracting Chlamydia trachomatis and Neisseria gonorrhoeae� Rapid screening for Chlamydia trachomatis and Neisseria gonorrhoeae should be available for all women at delivery who were not screened during their pregnancy� 2 This position statement is not supported by the Canadian Association for Pediatric Ophthalmology and Strabismus (CAPOS) citing concerns with the quality of evidence against eye prophylaxis, and the increased risk to infants born to women of marginalized communities with limited access to prenatal care� 25 While the CPS Position Statement advocates for comprehensive antenatal screening for Chlamydia trachomatis and Neisseria gonorrhoeae, data collected between 2011 and 2014 in Manitoba indicates that antenatal screening is suboptimal and implies that some infants may be at higher risk to develop gonococcal Ophthalmia Neonatorum without universal eye prophylaxis� 26 Finding current evidence-based research relevant to the Canadian population, and specific to the British Columbia population, on Ophthalmia Neonatorum and eye prophylaxis is challenging� Much of the primary research was conducted in countries other than Canada, some dating back to the 1980s� The Canadian Agency for Drugs and Technologies in Health (CADTH) Rapid Response Report on neonatal eye prophylaxis (2016) concluded that the evidence for, or against, eye prophylaxis is of low quality due to different populations, settings and issues with heterogeneity� 27 A Cochrane systemic review on the interventions for preventing Ophthalmia Neonatorum is currently underway� The two main objectives of the Cochrane review are to determine if eye prophylaxis reduces the incidence of Ophthalmia Neonatorum, and if so, what eye prophylaxis is the most effective� 28 The only agent approved in Canada for eye prophylaxis is erythromycin� 3 The efficacy of topical erythromycin to prevent Chlamydia trachomatis Ophthalmia Neonatorum is questionable 29,30,31,32 and not recommended by the American Academy of Pediatrics 14 and the Canadian Pediatric Society� 17 Antimicrobial resistance is a global barrier to the successful treatment of Neisseria gonorrhoeae and will have a significant impact on the health and economic burden to manage this disease� The Canadian Antimicrobial Resistance Surveillance System (2017) reported a 32�5 per cent failure rate when treating Neisseria gonorrhoeae with erythromycin 33 , and according to the Canadian Pediatric Society, is the reason for discontinuation of using erythromycin as ocular prophylaxis� 12 The incidence of suboptimal antenatal screening rates, the prevalence of Chlamydia trachomatis and/or Neisseria gonorrhoeae infections in pregnant women, and the potential for adverse obstetric outcomes and newborn morbidities due to Chlamydia trachomatis and/or Neisseria gonorrhoeae lend support to the recommendation to improve antenatal screening and the continuation of universal newborn eye prophylaxis� Overview, cont'd.
# Screening
All women should be screened for Chlamydia trachomatis and Neisseria gonorrhoeae at the first prenatal visit. Targeted screening is recommended in each trimester for women with ongoing risk factors.
Currently, Perinatal Services BC (PSBC) recommends that all women should be offered screening for Chlamydia trachomatis and Neisseria gonorrhoeae at the first prenatal visit� In addition to screening all women at the first prenatal visit, additional screening is recommended in each trimester for women with ongoing risk factors� 1 Maternal Risk factors are as follows:
⦁ ⦁
25 years or younger and sexually active 9,23,24,34,35,36,37,38 ⦁ ⦁ New and/or more than one sex partner 9,24,36,37,38 ⦁ ⦁ Previous documented diagnosis of Chlamydia trachomatis and/or Neisseria gonorrhoeae 5,9,35,36,37,38,39 ⦁ ⦁ Sexual contact with a person with suspected or confirmed Chlamydia trachomatis and/or Neisseria gonorrhoeae infection 5,35,36 ⦁ ⦁ Unprotected sex with a resident from area with high prevalence of Chlamydia trachomatis and/or Neisseria gonorrhoeae infection 5,36
# ⦁ ⦁
Unprotected sexual contact with resident from area with high risk of antimicrobial resistance to Chlamydia trachomatis and/or Neisseria gonorrhoeae 5,36 Maternal health care providers must inform newborn's health care providers regarding maternal risk factors, screening results and treatment for Chlamydia trachomatis and Neisseria gonorrhoeae as this will direct the care of the newborn related to Ophthalmia Neonatorum� 2
For the most current information on disease prevalence in an area consult the BC Centre for Disease Control Reportable Disease Dashboard: www.bccdc.ca/health-info/disease-system-statistics/reportable-disease-dashboard
# Recommendations Eye Prophylaxis
Universal eye prophylaxis of all newborns to prevent Ophthalmia Neonatorum caused by Chlamydia trachomatis and Neisseria gonorrhoeae is recommended.
While the law mandating universal eye prophylaxis has been repealed, PSBC and CAPOS continue to recommend universal eye prophylaxis of the newborn until there is a safe alternative to erythromycin such as rapid maternal screening at the time of delivery for Chlamydia trachomatis and Neisseria gonorrhoeae� Currently erythromycin 0�5% ointment is the only ocular prophylactic agent approved in Canada and needs to be administered within one hour after birth� 3
Procedure to Administer 0.5% Erythromycin Ointment 1� Use gloves when administering erythromycin� 2� To prevent cross contamination, use a single-use tube of 0�5% erythromycin and discard remainder of tube after administering to both eyes� 3� Before administration, wipe each eyelid gently with sterile cotton to remove foreign matter and to permit adequate eversion of the lower lid� 4� Apply a line of 0�5% erythromycin ointment, about 1 cm long, in the inferior conjunctival fornix, by pulling the lower eyelid gently down� Care is needed to prevent injury to the eye or the eyelid from the tip of the tube� 5� Gently massage the closed eyelids to help spread the solution to all areas of the conjunctiva� 6� In the very premature newborns whose eye lids are fused at the time of birth, apply the erythromycin ointment without separating the eyelids� Ointment absorption through the immature skin is expected�
Recommendations, cont'd.
# Monitor for Signs and Symptoms of Ophthalmia Neonatorum
It is imperative for both health care providers and parents to recognize the signs and symptoms of Ophthalmia Neonatorum and to respond appropriately� 2,4,5,6 Advise mother or caregiver of all newborns how to recognize Ophthalmia Neonatorum prior to discharge and when to contact a health care provider (see Appendix A: Information for Families)� Currently, erythromycin 0�5% ointment is the only prophylactic agent approved in Canada and needs to be administered within one hour after birth� 3 It is recommended that erythromycin eye prophylaxis continues to be administered to all newborns until there is a safe alternative, including newborns at risk of exposure to Neisseria gonorrhoeae� Advise mother or caregiver how to recognize Ophthalmia Neonatorum prior to discharge and when to contact a health care provider (see Appendix A: Information for Families)� If there is any concern that the mother or caregiver may not recognize the signs of Ophthalmia Neonatorum and/or respond appropriately, consider administering a single dose of cefotaxime IM prior to discharge if the newborn is discharged before five days of age� 3� Prophylactic antibiotic treatment is not indicated unless follow up with physician cannot be guaranteed� 14,17 4� Newborns should be monitored for signs of Chlamydia trachomatis infection (conjunctivitis and/or pneumonitis)� 2,4,5,6 5� Advise mother how to recognize Ophthalmia Neonatorum prior to discharge and when to contact a health care provider (see Appendix A: Information for Families)�
Management of Ophthalmia Neonatorum Caused by Chlamydia trachomatis 1� Collect conjunctival swabs obtained from the everted eyelid� Specimens must contain conjunctival cells, not just exudate� 30 Test for Neisseria gonorrhoeae at the same time� 2� Treat infant if test is positive for Chlamydia trachomatis with oral or intravenous erythromycin� 4,6,9,10 Dosing and frequency of administration are determined by weight and postnatal age� 41 Consult local guidelines for neonatal dosing information� 3� Consider referral to higher level of care if indicated� 4� There is a documented association between orally administered erythromycin and infantile hypertrophic pyloric stenosis* especially in newborns less than two weeks of age� 4,10,42 5� Inform parents about the signs and potential risks of developing infantile hypertrophic pyloric stenosis* (nonbilious and forceful vomiting immediately after feed)� 6� Follow up visit with newborn three to four weeks after completion of the treatment is recommended since the efficacy of erythromycin therapy is approximately 80%� A second course of treatment may be required� 4 * Functional gastric outlet obstruction leading to forceful vomiting
Management of the Newborn at Risk of Exposure to Chlamydia trachomatis
#
Appendix A: Information for Families: Eye Infection and Your Newborn Baby www.perinatalservicesbc.ca Most of the time, puffy or red eyes in your baby are caused by a blocked tear duct or infection by viruses or bacteria. Some eye infections may be serious and need special medication.
Contact your doctor or go to the emergency department or health clinic at once if your baby is under two weeks and:
• Your baby's eyes are red • Your baby's eyes have thick pus
• Your baby's eyelids are swollen or puffy Your baby's eye needs to be examined to find out if it is an infection that needs to be treated. | None | None |
43dfc29d09db7437419f6ad0674f549e08a3abde | cma | None | The performance of tracheotomy is a common procedural request by Critical Care to the surgical services of General Surgery and Otolaryngology -Head & Neck Surgery. COVID-19 pandemic planning anticipates a large volume of ventilated patients with a possibly prolonged period of endotracheal intubation. The evidence for dealing with many aspects of this evolving situation is still somewhat anecdotal at the time and subject to future modification. This document provides guidance on the use of tracheotomy in such patients.# Guiding Principles:
The tracheotomy procedure is highly aerosol generating and directly exposes the surgical team to the viral aerosol plume and secretions, thereby increasing the risk of transmission to healthcare providers. In general, extended endotracheal intubation with a balloon inflated prior to the first breath should be the standard of care for the entire duration of ventilation in patients.
# Recommendations:
In the COVID-19 positive patient, tracheotomy should not be routinely considered in any endotracheally intubated patient until the patient has been determined to be cleared of the COVID virus and isolation precautions have been discontinued.
- We strongly recommend against performing a tracheotomy in COVID-19 patients who are still infectious. This should only be considered in this group if the endotracheal tube is proving insufficient to provide an adequate airway. - In the COVID-19 positive patient, requests for tracheotomy should generally not be considered regardless of duration of endotracheal intubation. Requests for tracheotomy should be considered only in exceptional circumstances on a case by case basis with thorough discussion of the risks and benefits between the ICU Attending and the Attending Surgeon. In this exceptional circumstance, the use of PPE with PAPRs is required.
The following recommendations are made regarding performance of the tracheotomy procedure in the COVID-19 negative patient:
- We recommend the tracheotomy should be performed in an open fashion in the operating room or in the ICU, ideally in a negative pressure room. The tracheotomy should be performed using complete neuromuscular paralysis to help reduce the potential for aerosol generation. o Percutaneous tracheotomy requires the use of flexible fiber-optic bronchoscopy, with bronchoscopy being an AGMP itself. The risk/benefits of transferring from an ICU setting to the OR needs to be weighed against the risk of aerosolization with bronchoscopy. o The tracheotomy should be performed primarily by the most experienced surgeon, preferably the attending surgeon and most experienced anesthesiologist. o The surgical staff, anesthesia and nursing staff should be kept to the lowest number possible to safely carry out the procedure and any transportation required. o Additionally, any upper airway surgery that must proceed should have the requirement of urgent COVID-19 testing/clearance of the patient before initiating surgery. o Due to the possibility of false negative COVID-19 testing at this time and the high risk level of viral contamination with airway surgery, we are recommending N95 masks and face shield be worn by the surgical team for patients that have thus far tested negative for COVID-19 during this pandemic. This may be modified as test certainty improves.
# Emergency Tracheotomy (Imminent airway obstruction with unknown COVID-19 status)
- Manage the patient as presumed COVID-19 positive. o Full aerosol PPE including PAPR equipment or equivalent should be used. N95 masks alone may not be sufficient according to colleagues from China. o Intubation rather than tracheotomy would be highly preferable. o Avoid use of high flow oxygen/high flow nasal cannula. o Intubation should be performed by the most skilled person present to maximize initial attempt success. o Most skilled and available airway manager (Otolaryngology, General Surgeon, Thoracic Surgeon, TTL) for tracheotomy if required. o Reduce unnecessary team members to limit potential spread of disease. o See Procedure for elective tracheotomy above. o Awake tracheotomy and cricothyroidotomy are to be considered very high risk for viral plume spread and should be avoided. Only in very extenuating circumstances should this be considered.
A discussion between team members (e.g. anesthesia, otolaryngology-hns, general/thoracic surgeon, TTL, emergency physician, critical care physician) should be undertaken to determine the risk/benefit profile for each situation.
# Elective/Emergent Tracheotomy Procedural Considerations
- Paralyze the patient to avoid coughing. o Non-fenestrated, cuffed tracheotomy tube of appropriate size, with balloon inflated sufficiently to avoid cuff leak/avoid aerosolizing the virus. o Careful attention to avoid damaging the endotracheal tube cuff during insertion. o Initial advancement of the endotracheal tube could be performed to make the cuff distal to the tracheotomy incision (to prevent airflow through the surgical tracheotomy). o If possible, cease ventilation during tracheal incision and ensure the cuff is still inflated before reinitiating ventilation. o Ventilation to cease prior to tracheotomy tube insertion and ensure swift and accurate placement of tracheotomy tube with prompt inflation of the cuff (generous inflation of cuff to ensure seal against tracheal wall). o Attach anesthetic circuit to the tracheostomy tube and manually ventilate gently with the aim of minimizing an airway leak. o Ideally, confirm placement with end tidal CO2 measurement. o Ensure there is no leak from the cuff and the tube is secured. o HME should be placed on the tracheotomy to reduce shedding of the virus should the anesthetic tubing be disconnected. o Avoid disconnecting HME, but if necessary, disconnect distal to HME. o Avoid/minimize use of open suction in the airway prior to insertion of tracheotomy as this is aerosol generating. Safer suction through the closed airway circuit is recommended if possible. o We caution the use of bronchoscopy as detailed above. If required, utilize a video bronchoscope and appropriate connectors to minimize aerosol generation. Limit the presence of staff in the room to the bare minimum.
# Abbreviations
AGMP -Aerosol Generating Medical Procedure PAPRs -Powered Air Purifying Respirators- PPE -Personal Protective Equipment HME -Heat and moisture exchanger TTL -Trauma Team Leader *PAPRs are reusable respirators that are typically loose-fitting hooded or helmeted. They are equipped with a battery-powered blower to force air through a particle filter for the wearer to breath. They are capable of reducing airborne exposures at efficiencies that typically exceed the N95 and EHFR, using a high-efficiency particulate air filter (information from the Department of Health and Human Services, Centre for Disease Control and Prevention, United States).
# Post-operative Care
The post-operative care of tracheotomized patients in the COVID-19 era is a complex issue. As such, we are developing a second document which will deal with this topic.
# Canadian Society of Otolaryngology -Head and Neck Surgery / Société canadienne d'oto-rhino-laryngologie et de chirurgie cervico-faciale | The performance of tracheotomy is a common procedural request by Critical Care to the surgical services of General Surgery and Otolaryngology -Head & Neck Surgery. COVID-19 pandemic planning anticipates a large volume of ventilated patients with a possibly prolonged period of endotracheal intubation. The evidence for dealing with many aspects of this evolving situation is still somewhat anecdotal at the time and subject to future modification. This document provides guidance on the use of tracheotomy in such patients.# Guiding Principles:
The tracheotomy procedure is highly aerosol generating and directly exposes the surgical team to the viral aerosol plume and secretions, thereby increasing the risk of transmission to healthcare providers. In general, extended endotracheal intubation with a balloon inflated prior to the first breath should be the standard of care for the entire duration of ventilation in patients.
# Recommendations:
In the COVID-19 positive patient, tracheotomy should not be routinely considered in any endotracheally intubated patient until the patient has been determined to be cleared of the COVID virus and isolation precautions have been discontinued.
• We strongly recommend against performing a tracheotomy in COVID-19 patients who are still infectious. This should only be considered in this group if the endotracheal tube is proving insufficient to provide an adequate airway. • In the COVID-19 positive patient, requests for tracheotomy should generally not be considered regardless of duration of endotracheal intubation. Requests for tracheotomy should be considered only in exceptional circumstances on a case by case basis with thorough discussion of the risks and benefits between the ICU Attending and the Attending Surgeon. In this exceptional circumstance, the use of PPE with PAPRs is required.
The following recommendations are made regarding performance of the tracheotomy procedure in the COVID-19 negative patient:
o We recommend the tracheotomy should be performed in an open fashion in the operating room or in the ICU, ideally in a negative pressure room. The tracheotomy should be performed using complete neuromuscular paralysis to help reduce the potential for aerosol generation. o Percutaneous tracheotomy requires the use of flexible fiber-optic bronchoscopy, with bronchoscopy being an AGMP itself. The risk/benefits of transferring from an ICU setting to the OR needs to be weighed against the risk of aerosolization with bronchoscopy. o The tracheotomy should be performed primarily by the most experienced surgeon, preferably the attending surgeon and most experienced anesthesiologist. o The surgical staff, anesthesia and nursing staff should be kept to the lowest number possible to safely carry out the procedure and any transportation required. o Additionally, any upper airway surgery that must proceed should have the requirement of urgent COVID-19 testing/clearance of the patient before initiating surgery. o Due to the possibility of false negative COVID-19 testing at this time and the high risk level of viral contamination with airway surgery, we are recommending N95 masks and face shield be worn by the surgical team for patients that have thus far tested negative for COVID-19 during this pandemic. This may be modified as test certainty improves.
# Emergency Tracheotomy (Imminent airway obstruction with unknown COVID-19 status)
o Manage the patient as presumed COVID-19 positive. o Full aerosol PPE including PAPR equipment or equivalent should be used. N95 masks alone may not be sufficient according to colleagues from China. o Intubation rather than tracheotomy would be highly preferable. o Avoid use of high flow oxygen/high flow nasal cannula. o Intubation should be performed by the most skilled person present to maximize initial attempt success. o Most skilled and available airway manager (Otolaryngology, General Surgeon, Thoracic Surgeon, TTL) for tracheotomy if required. o Reduce unnecessary team members to limit potential spread of disease. o See Procedure for elective tracheotomy above. o Awake tracheotomy and cricothyroidotomy are to be considered very high risk for viral plume spread and should be avoided. Only in very extenuating circumstances should this be considered.
A discussion between team members (e.g. anesthesia, otolaryngology-hns, general/thoracic surgeon, TTL, emergency physician, critical care physician) should be undertaken to determine the risk/benefit profile for each situation.
# Elective/Emergent Tracheotomy Procedural Considerations
o Paralyze the patient to avoid coughing. o Non-fenestrated, cuffed tracheotomy tube of appropriate size, with balloon inflated sufficiently to avoid cuff leak/avoid aerosolizing the virus. o Careful attention to avoid damaging the endotracheal tube cuff during insertion. o Initial advancement of the endotracheal tube could be performed to make the cuff distal to the tracheotomy incision (to prevent airflow through the surgical tracheotomy). o If possible, cease ventilation during tracheal incision and ensure the cuff is still inflated before reinitiating ventilation. o Ventilation to cease prior to tracheotomy tube insertion and ensure swift and accurate placement of tracheotomy tube with prompt inflation of the cuff (generous inflation of cuff to ensure seal against tracheal wall). o Attach anesthetic circuit to the tracheostomy tube and manually ventilate gently with the aim of minimizing an airway leak. o Ideally, confirm placement with end tidal CO2 measurement. o Ensure there is no leak from the cuff and the tube is secured. o HME should be placed on the tracheotomy to reduce shedding of the virus should the anesthetic tubing be disconnected. o Avoid disconnecting HME, but if necessary, disconnect distal to HME. o Avoid/minimize use of open suction in the airway prior to insertion of tracheotomy as this is aerosol generating. Safer suction through the closed airway circuit is recommended if possible. o We caution the use of bronchoscopy as detailed above. If required, utilize a video bronchoscope and appropriate connectors to minimize aerosol generation. Limit the presence of staff in the room to the bare minimum.
# Abbreviations
AGMP -Aerosol Generating Medical Procedure PAPRs -Powered Air Purifying Respirators* PPE -Personal Protective Equipment HME -Heat and moisture exchanger TTL -Trauma Team Leader *PAPRs are reusable respirators that are typically loose-fitting hooded or helmeted. They are equipped with a battery-powered blower to force air through a particle filter for the wearer to breath. They are capable of reducing airborne exposures at efficiencies that typically exceed the N95 and EHFR, using a high-efficiency particulate air filter (information from the Department of Health and Human Services, Centre for Disease Control and Prevention, United States).
# Post-operative Care
The post-operative care of tracheotomized patients in the COVID-19 era is a complex issue. As such, we are developing a second document which will deal with this topic.
# Canadian Society of Otolaryngology -Head and Neck Surgery / Société canadienne d'oto-rhino-laryngologie et de chirurgie cervico-faciale
# Disclaimer
The Canadian Society of Otolaryngology -Head & Neck Surgery (CSO-HNS) has developed this information as guidance for its members. This is based on information available at the time of writing (March 22, 2020) and the Society recognizes that the situation is evolving rapidly, so recommendations may change. The guidance included in this document does not replace regular standards of care, nor do they replace the application of clinical judgement to each individual presentation, nor variations due to jurisdiction or facility type.
The CSO-HNS is not liable for the accuracy or completeness of the information in this document. The information in this document cannot replace professional advice. | None | None |
ffa4c8d149d0c507ba839aaa32b0a40f8e749715 | cma | None | Both randomized controlled and observational studies demonstrate a reduction in the risk of food allergy with early introduction of common allergens, in particular peanut and egg. While these studies vary in design, population, dose and allergen used, there is a strong and consistent trend that early introduction has a role in the prevention of food allergy. As a result, guidelines clearly and consistently recommend early allergen ingestion (commonly operationalised as between ages 4-6 months), often in particular for higher risk populations, as a means of food allergy prevention. 3,5 The current Canadian Society of Allergy and Clinical Immunology/Canadian Pediatric Society position statement recommends introduction of common allergens in high risk infants (with eczema or an immediate family history) at around 6, but not before 4 months of age; and in lower risk infants at around 6 months of age. 5 However, despite changes in guidance, recent epidemiologic evidence suggests that early introduction alone is not sufficient to reduce peanut allergy prevalence. In Australia, where uptake of peanut introduction in the first year of life increased more than 3-fold with adoption of early introduction guidelines, Soriano et al reported observational data that peanut allergy prevalence had not significantly changed between 2007 and 2018 (3.1% to 2.6%, respectively; difference −0.5% ; p = 0.26). This suggests that additional factors continue to play a role in the development of peanut and other food allergy (although with the guidelines only changing in 2016 studies may need longer to completely address this). 6 .
While most Australian families were introducing peanut in infancy, Soriano reported that only ~30% of infants were eating peanut 2 or more times a week. A substantial proportion were eating peanut less than once a week and some had even eaten peanut only once (a bite or taste). This suggests that a lack of regular ingestion may be a key reason for the lack of change in prevalence despite early introduction. 7 Although most allergy prevention guidelines, including the current CSACI/CPS guideline, recommend ongoing regular ingestion as a means of food allergy prevention, this guidance is often not translated into practice, or individual recommendations to parents. Therefore, the goal of this statement is to emphasize that current best evidence supports the importance of regularity of infant allergen ingestion, operationalised as at least once weekly, as a means of food allergy prevention.
Immunologically, the premise of the "dual-allergen exposure hypothesis" is based on the need for oral tolerance to supersede cutaneous (or possibly respiratory) sensitization, and mechanistically this implies that consistent, regular oral ingestion is necessary to induce and maintain tolerance. 8,9 Recent animal data suggests that regular peanut ingestion induces a regulatory T-cell population that express high levels of CTLA-4, which in turn suppresses T follicular helper cells and germinal center B-cells induced by environmental peanut exposure. 10,11 All clinical studies on food allergy prevention have suggested both early introduction and ongoing regular ingestion to achieve optimal food allergy prevention. For example, in the Learning Early About Peanut (LEAP) study, infants in the early introduction group were introduced to peanut at age 4-11 months but also ate peanut at least 3 times a week (total of 6 grams, or the equivalent of about 24 peanuts, per week) until age 5 years compared to strict avoidance. 1 Similarly, in the PETIT randomized controlled trial that compared early (age 6 months) vs delayed (age 12 months) egg introduction in infants with atopic dermatitis, the early introduction arm included ongoing feeding of egg at least daily. 4 Observational studies on early food introduction also support ongoing regular ingestion. For example, Katz et al reported a large observational study in which delayed (after 14 days) and/or irregular (<1/day) cow's milk ingestion significantly increased the risk of cow's milk allergy (OR 19.3) compared to introduction in first 14 days of life. 12 In another case-control study of children with confirmed cow's milk allergy (compared to nonatopic controls and children with egg allergy), irregularity of ingestion (<1/day) increased the risk of cow's milk allergy. 13 A recent large prospective interventional study in which 1992 newborns were recruited shortly before birth to either exclusive breastfeeding or at least one meal of cow's milk formula (with or without breastfeeding) daily for the first 2 months of life found a significant reduction in cow's milk allergy at 12 months (1.58% in the breastfed group compared to 0% in the other groups; relative risk 29.98, p<.001) with regular cow's milk formula ingestion. The vast majority of those who developed cow's milk allergy while being breastfed were exposed to small amounts of cow's milk formula during the first 2 months of life (prevalence of 0.7% in the per-protocol exclusively breastfed group versus 3.27% among infants exposed to small amounts of cow's milk formula), resulting in the authors' conclusion that early continuous exposure should be encouraged, while occasional exposure increases risk of IgE-mediated cow's milk allergy and should be avoided. 14 The randomized controlled trials and observational studies regarding early ingestion of allergens have focused on the infant population, but there are now emerging data in older children (in particular those at risk of allergy such as siblings of peanut allergic children) that irregularity of ingestion may also increase the risk of food allergy. 15 A dose-dependent relationship between frequency of peanut ingestion and reduced risk of peanut allergy was reported among siblings of peanut allergic children. These siblings had tolerated oral peanut challenges at baseline, and during a median 2.9 years of follow up, none (0%) of the siblings who ate peanut at least once a month had peanut allergy vs 3% who ate it less than once a month and 18% who completely avoided peanut. 15 The exact frequency of allergen ingestion required to maintain tolerance is not yet clearly established. For example, in a recently published cluster-randomized trial, general population infants introduced to peanut, cow's milk, wheat and egg from 3 months of age (but only eaten once a week; and less so after 6 months of age) had a significantly lower risk of food allergy than those introduced at standard age (no intervention). 16 However, given the above updated evidence, a pragmatic recommendation is for the relevant allergen/s to be consumed multiple times per month (with a goal of at least once each week), integrated into a family's diet. The amount of allergen required for ingestion also remains undetermined, although a secondary analysis of the Enquiring About Tolerance (EAT) randomized controlled trial suggested a dose of about 2 grams each of egg white and peanut protein per week (the equivalent of approximately one small boiled egg and 1.5 tsp peanut butter, respectively) is likely an amount that would be tolerated in infancy although further research is required and it is possible that smaller amounts may be effective as well. 4,17 The long term duration of ingestion is unclear, but the LEAP-On study showed that when peanut was introduced in the first year of life and continued until 5 years of age, a subsequent 12 months of avoidance did not increase the prevalence of peanut allergy. 18 Based on this study roughly 5 years of regular ingestion starting in infancy is likely long enough duration to induce long term tolerance.
In conclusion, our recommendations and considerations on frequency of ingestion are as follows:
Recommendation:
- Both early introduction and regular ingestion of age-appropriate amounts of allergens multiple times per month (with a goal of at least once each week) are very likely to be useful to establish and maintain tolerance.
Considerations: 2. Once introduced, current evidence suggests that a single exposure or occasional exposures could be detrimental and result in increased risk of sensitization and development of food allergy. 3. If an allergen is not a common component of the family's diet, and regular ingestion is not feasible for that family, avoidance may be preferable to intermittent ingestion although further research is required. 4. The ideal amount and frequency of regular ingestion remains unknown, but the above recommendation is based on a balance of evidence and practicality. A duration of 5 years appears to be enough to maintain tolerance to peanut, and other foods may require similar exposures. | #
Both randomized controlled and observational studies demonstrate a reduction in the risk of food allergy with early introduction of common allergens, in particular peanut and egg. [1][2][3][4] While these studies vary in design, population, dose and allergen used, there is a strong and consistent trend that early introduction has a role in the prevention of food allergy. As a result, guidelines clearly and consistently recommend early allergen ingestion (commonly operationalised as between ages 4-6 months), often in particular for higher risk populations, as a means of food allergy prevention. 3,5 The current Canadian Society of Allergy and Clinical Immunology/Canadian Pediatric Society position statement recommends introduction of common allergens in high risk infants (with eczema or an immediate family history) at around 6, but not before 4 months of age; and in lower risk infants at around 6 months of age. 5 However, despite changes in guidance, recent epidemiologic evidence suggests that early introduction alone is not sufficient to reduce peanut allergy prevalence. In Australia, where uptake of peanut introduction in the first year of life increased more than 3-fold with adoption of early introduction guidelines, Soriano et al reported observational data that peanut allergy prevalence had not significantly changed between 2007 and 2018 (3.1% to 2.6%, respectively; difference −0.5% [95%CI, −1.4%to 0.4%]; p = 0.26). This suggests that additional factors continue to play a role in the development of peanut and other food allergy (although with the guidelines only changing in 2016 studies may need longer to completely address this). 6 .
While most Australian families were introducing peanut in infancy, Soriano reported that only ~30% of infants were eating peanut 2 or more times a week. A substantial proportion were eating peanut less than once a week and some had even eaten peanut only once (a bite or taste). This suggests that a lack of regular ingestion may be a key reason for the lack of change in prevalence despite early introduction. 7 Although most allergy prevention guidelines, including the current CSACI/CPS guideline, recommend ongoing regular ingestion as a means of food allergy prevention, this guidance is often not translated into practice, or individual recommendations to parents. Therefore, the goal of this statement is to emphasize that current best evidence supports the importance of regularity of infant allergen ingestion, operationalised as at least once weekly, as a means of food allergy prevention.
Immunologically, the premise of the "dual-allergen exposure hypothesis" is based on the need for oral tolerance to supersede cutaneous (or possibly respiratory) sensitization, and mechanistically this implies that consistent, regular oral ingestion is necessary to induce and maintain tolerance. 8,9 Recent animal data suggests that regular peanut ingestion induces a regulatory T-cell population that express high levels of CTLA-4, which in turn suppresses T follicular helper cells and germinal center B-cells induced by environmental peanut exposure. 10,11 All clinical studies on food allergy prevention have suggested both early introduction and ongoing regular ingestion to achieve optimal food allergy prevention. For example, in the Learning Early About Peanut (LEAP) study, infants in the early introduction group were introduced to peanut at age 4-11 months but also ate peanut at least 3 times a week (total of 6 grams, or the equivalent of about 24 peanuts, per week) until age 5 years compared to strict avoidance. 1 Similarly, in the PETIT randomized controlled trial that compared early (age 6 months) vs delayed (age 12 months) egg introduction in infants with atopic dermatitis, the early introduction arm included ongoing feeding of egg at least daily. 4 Observational studies on early food introduction also support ongoing regular ingestion. For example, Katz et al reported a large observational study in which delayed (after 14 days) and/or irregular (<1/day) cow's milk ingestion significantly increased the risk of cow's milk allergy (OR 19.3) compared to introduction in first 14 days of life. 12 In another case-control study of children with confirmed cow's milk allergy (compared to nonatopic controls and children with egg allergy), irregularity of ingestion (<1/day) increased the risk of cow's milk allergy. 13 A recent large prospective interventional study in which 1992 newborns were recruited shortly before birth to either exclusive breastfeeding or at least one meal of cow's milk formula (with or without breastfeeding) daily for the first 2 months of life found a significant reduction in cow's milk allergy at 12 months (1.58% in the breastfed group compared to 0% in the other groups; relative risk 29.98, p<.001) with regular cow's milk formula ingestion. The vast majority of those who developed cow's milk allergy while being breastfed were exposed to small amounts of cow's milk formula during the first 2 months of life (prevalence of 0.7% in the per-protocol exclusively breastfed group versus 3.27% among infants exposed to small amounts of cow's milk formula), resulting in the authors' conclusion that early continuous exposure should be encouraged, while occasional exposure increases risk of IgE-mediated cow's milk allergy and should be avoided. 14 The randomized controlled trials and observational studies regarding early ingestion of allergens have focused on the infant population, but there are now emerging data in older children (in particular those at risk of allergy such as siblings of peanut allergic children) that irregularity of ingestion may also increase the risk of food allergy. 15 A dose-dependent relationship between frequency of peanut ingestion and reduced risk of peanut allergy was reported among siblings of peanut allergic children. These siblings had tolerated oral peanut challenges at baseline, and during a median 2.9 years of follow up, none (0%) of the siblings who ate peanut at least once a month had peanut allergy vs 3% who ate it less than once a month and 18% who completely avoided peanut. 15 The exact frequency of allergen ingestion required to maintain tolerance is not yet clearly established. For example, in a recently published cluster-randomized trial, general population infants introduced to peanut, cow's milk, wheat and egg from 3 months of age (but only eaten once a week; and less so after 6 months of age) had a significantly lower risk of food allergy than those introduced at standard age (no intervention). 16 However, given the above updated evidence, a pragmatic recommendation is for the relevant allergen/s to be consumed multiple times per month (with a goal of at least once each week), integrated into a family's diet. The amount of allergen required for ingestion also remains undetermined, although a secondary analysis of the Enquiring About Tolerance (EAT) randomized controlled trial suggested a dose of about 2 grams each of egg white and peanut protein per week (the equivalent of approximately one small boiled egg and 1.5 tsp peanut butter, respectively) is likely an amount that would be tolerated in infancy although further research is required and it is possible that smaller amounts may be effective as well. 4,17 The long term duration of ingestion is unclear, but the LEAP-On study showed that when peanut was introduced in the first year of life and continued until 5 years of age, a subsequent 12 months of avoidance did not increase the prevalence of peanut allergy. 18 Based on this study roughly 5 years of regular ingestion starting in infancy is likely long enough duration to induce long term tolerance.
In conclusion, our recommendations and considerations on frequency of ingestion are as follows:
Recommendation:
1. Both early introduction and regular ingestion of age-appropriate amounts of allergens multiple times per month (with a goal of at least once each week) are very likely to be useful to establish and maintain tolerance.
Considerations: 2. Once introduced, current evidence suggests that a single exposure or occasional exposures could be detrimental and result in increased risk of sensitization and development of food allergy. 3. If an allergen is not a common component of the family's diet, and regular ingestion is not feasible for that family, avoidance may be preferable to intermittent ingestion although further research is required. 4. The ideal amount and frequency of regular ingestion remains unknown, but the above recommendation is based on a balance of evidence and practicality. A duration of 5 years appears to be enough to maintain tolerance to peanut, and other foods may require similar exposures.
#
Acknowledgements: The authors would like to acknowledge the CSACI Board Members P Begin, L Connors, A Ellis, K Hildebrand, H Kim, V Kim, M Latrous, D Mack, A O'Keefe, J Quirt, J Upton, T Vander Leek, H Vliagoftis for their assistance. | None | None |
31b4822d603675d4d949ed431ac13400f4fc69bb | cma | None | Note: It is the policy of the Canadian Psychiatric Association to review each position paper, policy statement and clinical practice guideline every five years after publication or last review. Any such document that has been published more than five years ago and does not explicitly state it has been reviewed and retained as an official document of the CPA, either with revisions or as originally published, should be considered as a historical reference document only.#
Intimate partner violence (IPV; also known as domestic violence) refers to behaviour by an intimate partner or expartner that can cause or causes physical, sexual or psychological harm. These behaviours include physical aggression, sexual coercion, psychological abuse and controlling behaviours. 2 Stalking and financial abuse have now been included in the list of IPV behaviours by some authorities. 3 The Centers for Disease Control and Prevention has provided definitions and examples of four major types of IPV. 4 Physical IPV includes hitting, choking, shaking, biting, shoving, grabbing, slapping, burning, scratching, hair pulling and the threat of or the use of a weapon or restraints, as well as other aggressive physical acts. Sexual IPV includes forced sexual acts or attempts including acts committed when a partner is unable to give informed consent due to alcohol, drugs or mental incapacity. Sexual IPV may involve exploitation of economic or immigration vulnerability, intimidation or false promise (to marry), as well as sexually based degradation or threats. Psychological IPV includes the use of verbal and non-verbal communication to harm another person mentally or emotionally and/or exert control over their behaviours or decisions. Examples include expressive aggression (degradation, belittling, humiliation), mind games, exploitation of vulnerability, control of reproductive or sexual health, threats of violence to people or pets, as well as coercive control; the latter includes limiting access to money, friends or family, excessive monitoring, or threats of harm to self or others. 4,5 Stalking IPV consists of repeated unwanted attention that causes the person to fear for their personal safety or the safety of someone they know. 6 Examples include watching or following, repeated phone or electronic messages, spying, leaving gifts or threatening objects for the partner/ex-partner, or damaging a current or former partner's property. 5 IPV can occur across genders and the term "intimate partner" does not require that individuals exposed to this form of violence have a history of sexual intimacy or a marital relationship. 2,7 Although IPV can occur in any intimate relationship, including dating relationships, it disproportionately affects women and gender/sexual minorities but can also be directed toward men. IPV has also been called family violence, domestic violence or spouse abuse, but these terms are less specific, and some include violence against children in the categories of family or domestic violence, which can be confusing. When IPV is directed toward women, the terms wife abuse, wife battering or wife assault are often used. All of these terms have in common an understanding of violence as an expression of power, control and domination enacted through a range of behaviours that often escalate, especially after the relationship has ended. 5 IPV is a violation of human rights that can result in serious mental and physical health impairment including death. IPV is an underrecognized problem that can have an enormous impact on the health and well-being of women, men and children. It is a major public health and social problem globally that results in significant personal, health, economic and social costs. 3,5,8 One study estimated that the costs arising as a result of IPV experienced by women aged 19 to 65 years who have left their partners are $7.2 billion annually for Canada. 9 This paper discusses the epidemiology of IPV (including special populations and situations), risk indicators, health impacts, as well as approaches to identification, assessment, documentation, intervention, prognosis, prevention, education and research. We also provide recommendations for best practice in psychiatry. In general, this paper highlights key findings and common themes from the highest quality evidence available internationally, with a special focus on Canadian data. The Canadian Psychiatric Association (CPA) previously incorporated IPV in its 1992 Guidelines for the Evaluation and Management of Family Violence, 10 and they published a position paper on IPV in 2013, 1 but new information and resources require an update on this topic. 2, As IPV is associated with a broad range of health problems experienced by patients seen by psychiatrists, including depression, anxiety disorders, posttraumatic stress disorder (PTSD), chronic pain, eating disorders, sleep disorders, psychosomatic disorders, alcohol and other substance use disorders, suicidal and self-harm behaviours, personality disorders (such as borderline and antisocial), nonaffective psychosis and health risk behaviours, the rationale for this position paper is clear. 14 IPV should be of vital interest to mental health professionals and, more specifically, psychiatrists.
# Epidemiology
# Self-report Data
IPV occurs in all countries, cultures, religions and socioeconomic groups in the world. Generally speaking, IPV is a gendered phenomenon as women are disproportionately affected by IPV. However, evidence indicates that IPV may be perpetrated by men toward women, women toward men, and in same-sex relationships. It may occur in marriage, common-law relationships, cohabitation or any intimate relationship including dating. In general, most data have focused on IPV perpetrated by men against women in heterosexual relationships as discussed in the following sections. The literature shows that the extent of IPV varies greatly across countries. Attempts to make comparison between Canada and other nations are difficult due to differences in IPV definitions, survey methods and measurement, including the reference period of IPV exposure (e.g., lifetime vs. previous 12 months, lifetime vs. current relationship). The best available cross-country comparison of IPV rates comes from the 2000-2003 World Health Organization's Multi-country Study on Women's Health and Domestic Violence against Women, though data from Canada were not collected. Prevalence data for 10 countries show significant variation in women's lifetime of exposure to physical and/or sexual violence by a current or former male intimate partner; estimates of prevalence ranged from 15 per cent to 71 per cent among ever-partnered women. In all sites but one, women were more at risk of violence from a partner or ex-partner than from violence by other people. There were also significant differences in IPV exposure across rural versus urban areas, with higher IPV rates usually reported by women residing in rural regions. 15 In Canada, national data on IPV reported by men and women were first collected by Statistics Canada in its population-based 1999 General Social Survey (GSS), which is a quinquennial survey of the violence and victimization experiences of Canadians aged 15 and over. 16 In 1999, almost equal proportions of men (seven per cent) and women (eight per cent) reported being a victim of physical abuse in intimate relationships in the previous five years. 16 In 2009, 11.9 per cent of the GSS sample reported exposure to either physical/sexual IPV, emotional IPV or financial control/abuse. Data for 2014 showed reduced rates of exposure to physical or sexual IPV, with four per cent of Canadians aged 15 and over reporting one or both of these forms of IPV in the previous five years, with no difference between men and women. 17 Fourteen per cent of Canadians aged 15 or over said they had experienced emotional or financial abuse from a spouse or common-law partner sometime in the past. 18 Importantly, the most serious types of IPV, including sexual assault and being beaten, choked, threatened with a knife or gun, were reported by 25 per cent of abused Canadians, with women twice as likely as men. 18 Women victims were also more likely than men to have a physical injury (40 per cent vs. 24 per cent), to have experienced attempted murder or death (0.2 per cent of victims but 78 per cent were women) and are more likely to experience PTSD following IPV. 18
# Canadian Crime Data
Annual administrative data from the Canadian Homicide Survey and the Canadian Uniform Crime Reporting Survey (UCRS) provide compelling insights about the extent of IPV reported to Canadian police services. Generally speaking, police-reported IPV is much lower than self-reported IPV. In 2016, 79 per cent of IPV cases reported to police; women are the identified victims, and the majority of individuals charged in these cases are men (80 per cent). 19 Although majority of police-reported IPV (82 per cent) involves opposite-sex partnerships where females are victims and males are the perpetrators, approximately 55 per cent of police-reported same-sex IPV involves male partnerships. 20 In addition, violence within current or former spousal or dating relationships was the most common form of violence reported to police by females in 2017, with women and girls accounting for nearly 8 in 10 reports of IPV that year. With respect to youth, in 2010, approximately one per cent of policedreported cases of dating victimization involved youth aged 12 to 14 years; approximately 93 per cent of these victimization reports were made by females, and 52 per cent of the reports involved sexual assault. 21 In 2017, 15,535 females aged 15 to 24 years reported dating victimization to Canadian police services: 19 per cent and 11 per cent of these reports were in reference to a current versus a former dating partner, respectively. 22 Notably, these gender-specific findings have remained consistent across iterations of the UCRS. 19 Threats, name calling, limiting contact with family or friends were reported by eight per cent of women and six per cent of men. 6 It is important to note that many incidents of IPV are not reported to police out of shame, embarrassment, denial, fear of not being believed, fear of rejection or retaliation, or believing the abuse to be their fault. Risk factors for dating violence include past abuse, beliefs and attitudes, lower relationship skills, drinking and drug use, peer influences and pornography. 23 Bilateral (i.e., Common Couple) Violence
Historically, there has been the stereotype of the abusive male who uses severe and unilateral violence against a nonviolent female victim. It is now recognized that bilateral violence is more common than previously recognized, although women experience the overwhelming burden of morbidity and mortality associated with violence in intimate relationships. 24 Bilateral violence, otherwise referred to as common couple violence, is considered less serious than the pattern of violence known as battering or intimate terrorismwhich is a severe and often escalating form of IPV characterized by threats and multiple forms of violence and controlling behaviour by the abusive partner. Research suggests that women are most often subjected to battering by male perpetrators. 24 Canadian women are more likely than men IPV victims to experience sexual offences (88 per cent), criminal harassment (76 per cent) and indecent and harassing communications (72 per cent). 6 In the 2014 GSS, stalking (one form of criminal harassment) was self-reported by six per cent of Canadians; 21 per cent of these reports involved a current or former intimate partner. Among those who reported stalking, women were the disproportionate victims. Compared to men, women's exposure to stalking is more likely to occur in parallel with exposure to violence after a spousal relationship had ended. Threats or intimidation, repeated obscene or silent phone calls were common, but the greatest increase in reported IPV behaviour between 2004 and 2014 was in unwanted emails, texts or social media messages. 6,11 These ongoing forms of IPV continue to have significant health and economic impacts on women. The 2018 report on Gender-Based Violence and Unwanted Sexual Behaviour in Canada, although not focused on intimate partner relationships, reported that 32 per cent of women and 13 per cent of men experienced unwanted sexual behaviour in public including unwanted sexual attention, physical contact or comments about their sex or gender. 31 Despite more severe exposure and impacts for women, physical abuse, as well as psychological abuse, is also experienced by men. However, the context in which these acts occur has not been assessed, and evidence indicates that within heterosexual relationships, both sexes are sometimes perpetrators. Men have reported bruises, abrasions, genital injuries, minor head trauma, lacerations and internal injuries, as well as that their exposure to IPV leaves them feeling emasculated, marginalized, shamed and embarrassed. According to male victims, their reports of abuse are often met with skepticism or disbelief by medical and legal professionals, as well as friends and neighbours. 32 This disbelief was most marked for sexual IPV, as many people were unaware that erection and ejaculation could sometimes be caused by fear, anger or pain and not only by consensual sexual arousal. 33
# Special Populations and Situations
Cultural factors. Deep-seated values about the relative priority of one's own goals and autonomy (individualism) and those of the society (collectivism) to which one belongs are thought to be related to IPV rates. Collectivist cultures that are also patriarchal have rigid gender roles, subscribe to men's control of women's behaviour, link masculinity to dominance, control, honour and aggression and are suggested to condone the use of violence as a way of resolving conflict in intimate relationships. Similarly, qualitative research with women residing in communities with collectivist cultures report being urged to endure rather than reject IPV, as a way of preserving cultural values, the family and honour. A recent meta-analysis examining cultural or structural factors in the risk for IPV reports emerging longitudinal, quantitative evidence supporting these claims. 5,38 New immigrants. Migrant populations in Canadawhich include immigrants and refugees-face the same types of IPV as their non-migrant peers, but additional challenges related to their migration status-including a fear of deportation, loss of refugee status, social isolation, threats of forced marriage, inability to speak either of the official languages, economic exclusion or collectivist or religious values that support and privilege men's power and keeping the family together or not disclosing "private matters"-may prevent these individuals from reporting their abuse exposure in surveys or to the police. While community-based studies of IPV involving immigrants from certain countries indicate high rates of abuse, the extent to which these rates differ from non-migrants is inconclusive. 39 Methods, measurement issues, access and acceptance of some types of IPV among immigrant/ refugee groups make prevalence comparison difficult. 40,41 Indigenous peoples. First Nations, Metis and Inuit (collectively referred to as "Indigenous") people account for 4.9 per cent of the total Canadian population. 42 Evidence from the 2014 GSS as well as national crime data indicate that Indigenous individuals are more than twice as likely as their non-Indigenous counterparts to report exposure to physical IPV in the last five years (nine per cent vs. four per cent). In addition, Indigenous women were three times more likely to report IPV compared to non-Indigenous women (10 per cent vs. three per cent), but no difference was found between Indigenous and non-Indigenous men. Indigenous people who experience IPV are also more likely than non-Indigenous people to suffer the most serious forms of IPV, such as being beaten, choked, threatened with a weapon or sexually assaulted (52 per cent vs. 23 per cent). Indigenous people are also more likely to report childhood exposure to abuse or neglect by an adult caregiver (40 per cent), a factor known to be associated with later spousal abuse. Indigenous individuals were also more likely as a child to have been exposed to IPV committed by a parent, step-parent or guardian. 11,42 A seminal eight-wave longitudinal study including data from youth aged 15 to 19 years who were living on one of the seven reservations/reserves located in the United States and Canada reported that 31 per cent of youth had already experienced physical IPV in their lifetime. 43 The dynamics of IPV and dating violence in Indigenous communities has been linked to colonization, structural violence, poverty, racism, discrimination, residential schools, foster care, alcohol and substance use disorders, and loss of traditional ways and culture. 44 Psychiatric patients. Higher rates of IPV have been found among women in out-and in-patient psychiatric services in several countries. 14, A systematic review and meta-analysis of 41 studies found increased odds ratios of lifetime IPV in women with depressive disorders (2.77), anxiety disorders (4.08) and PTSD (7.34), compared with women without mental disorders. Individual studies reported increased odds ratios for both women and men for all psychiatric diagnostic categories, including psychoses, with a higher prevalence reported for women. Few longitudinal studies were found; thus, the direction of causality could not be determined. 14 Gender and sexual minorities. There has been a longstanding lack of data on Canadian IPV prevalence among lesbian, gay, bisexual, transgender, queer, questioning, intersex and two-spirited (LGBTQQI2S) individuals. While some of these gaps are beginning to be addressed, many remain. In 2016, Statistics Canada reported that about one per cent of all legally married and common-law couples in Canada had same-sex spouses, similar to data in the United Kingdom and Australia. 11 Individuals who selfreported as lesbian, gay or bisexual were twice as likely to report spousal violence as heterosexual couples (eight per cent vs. four per cent). In dating relationships, the double prevalence of IPV in same-sex partners compared to heterosexual partners has remained stable for the last five years (18 per cent vs. nine per cent), with an even higher prevalence among lesbian/bisexual women compared to male counterparts (23 per cent vs. 11 per cent).
Police-reported violence among same-sex intimate partners in Canada between 2009 and 2017 revealed that these incidents represented three per cent of all reported incidents of IPV. 20 Over 55 per cent of police-reported same-sex IPV involved male partners. Major assault and use of a weapon were also more common among men (18 per cent compared to 12 per cent in women). Homicides involving same-sex partners represented five per cent of all IPV homicides over this time period. Rural victims of same-sex IPV (35 per cent of all same-sex IPV cases) were more likely to request that no further action be taken against the accused. Gender stereotypes about violence and mutual violence as well as social stigma may be factors in these decisions. 20 Some unique risk factors, such as the threat of outing, disclosure of human immunodeficiency virus (HIV) status, social stigma and the lack of emergency shelters for sexual minority victims, have been identified. 48 A Canadian survey on IPV of 7,918 respondents in the workplace found that 8.5 per cent reported gender/sexual minority status. 49 Gender/sexual minority participants were significantly more likely to report IPV and that it continued at or near their workplace, negatively impacted their work performance and their co-workers. They also reported poorer mental health and quality of life. Some labour unions and provincial governments have supported paid domestic violence leave policies. A U.S. study found 51.8 per cent of transgender individuals reported lifetime IPV compared to 34.2 per cent of cisgender individuals.
LGBTQQI2S people generally experience higher rates of all forms of IPV. 50,51 People living with disabilities. People living with disabilities are not a homogeneous group; Statistics Canada recognizes four categories of disability (sensory, physical, cognitive and mental health), all of which may vary in severity and interact with numerous other sociodemographic characteristics to impact an individual's risk for exposure to IPV. 52 Compared to men, women have a higher reported prevalence of disability that limits their daily activities (14.9 per cent vs. 12.5 per cent) and approximately 23 per cent of women and 22 per cent of men who live with a disability report IPV exposure in the last five years (a rate much higher than those living without a disability). Of those who experienced spousal abuse, 39 per cent of women living with a disability report the most severe forms of abuse compared to men (16 per cent). Unique experiences of people living with a disability related to IPV include the abusive partner restricting the individual's access to mobility aids, medication or medical technologies. Data from Statistics Canada indicate that emotional or financial abuse by a partner is reported by 22 per cent of women and 21 per cent of men living with disabilities. Women living with a cognitive disability reported some form of IPV exposure more often than their male counterparts (43 per cent vs. 27 per cent), and this was most evident for physical or sexual assault (16 per cent vs. 9 per cent), respectively. 52 Perinatal period. IPV may begin, escalate or decrease during pregnancy or the postpartum year. Canadian studies report IPV rates between six per cent and 10.5 per cent during pregnancy. Risk factors for perinatal IPV exposure include prior abuse, age under 20 years, low income, single status, stressful life events, depression, substance and alcohol use. 53,54 IPV exposure was four times more likely to be reported by women if the pregnancy was unplanned or unwanted. 55 IPV exposure during pregnancy is associated with adverse neonatal and maternal health, including maternal depression. 56 Of particular note, evidence indicates that IPV exposure among women tends to increase after the baby is born. 57 Alcohol use by IPV perpetrators and victims. Alcohol use increases the occurrence and the severity of IPV. It directly affects cognitive and physical function, reduces self-control and leaves people less capable of negotiating a nonviolent resolution to conflicts within relationships. 61 Excessive drinking by one partner can exacerbate stress related to financial difficulties, childcare problems, infidelity 62 or other family stressors, creating relationship tensions and conflicts and increasing the risk of IPV. 63 Alcohol use may also reduce the abused partner's ability to perceive, resist or escape from IPV. Experiencing IPV can lead to alcohol consumption as a method of coping or self-medicating. 64 However, individual and societal beliefs that alcohol causes aggression can encourage violent behaviour after drinking, and alcohol may be used as an excuse for violent behaviour. 65 It is likely that other types of substance use also lead to higher prevalence rates of IPV, but reliable data are lacking.
Poverty. Although IPV can and does occur across all socioeconomic groups, it occurs most often among people living in poverty. 66,67 This may partly reflect the greater power, higher education and more options available to escape violent relationships among higherincome people, as well as the general life stress caused by insufficient financial resources.
Senior age. Better data are now available for Canadians who are 65 years of age or over and who experience IPV, including neglect, physical, sexual, emotional and financial abuse. 68 It is estimated that only 20 per cent of incidents among this age group are reported to police due to language, culture, health, transportation and technology barriers. Police reports of violence against seniors reveal that victimization by a spouse was the most common type of abuse (33 per cent) for women, while victimization by a child was the most common abuse reported by men (34 per cent). 68 Family-related homicides against seniors have risen, with a spouse being the perpetrator for 50 per cent of women victims and eight per cent of men victims. 68 Abusers may be socially isolated, stressed or suffer from a mental illness or substance use disorder. Dementias or other brain dysfunction may be major factors, as cognitive dysfunction along with sensory impairment may lead to deterioration in reality testing and paranoid ideation. Frontal lobe disturbances may result in a lack of normal inhibition, with little apparent remorse or insight after IPV. It is important to remember that older people can be aggressive, violent or dangerous. However, IPV perpetrated in old age is often regarded less seriously. In addition, more sympathy tends to be extended to the perpetrators because of their perceived physical frailty or infirmity, which complicates the ability to estimate the true prevalence and consequences of IPV in older individuals. 69
# Risk Indicators
Many Canadian studies, including national, populationbased surveys, have shown a fairly consistent pattern in demographic, relationship-and partner-specific indicators for exposure to IPV, including a young partner, being in a common-law (rather than legally married) relationship or separated; being in a relationship with an un-or underemployed partner, low economic status, high stress and abuse of alcohol or other substances. 5 International studies have identified personality disorders, psychosis, depression, marital conflict and poor family functioning as factors associated with a man's risk for abusing his partner. 5 Marked jealousy, hostiledependency, low self-esteem, low assertiveness, emotional inexpressiveness, and social and sexual inadequacy have also all been described in perpetrators of IPV. 69 For male victims, younger men were four to five times at greater risk of IPV than men over 45 years in age. Ecologic risk factors for IPV include individual, partner, family and community/social factors. 5 Although IPV can occur in any intimate relationship, individual factors for victimization include (among others) past exposure to IPV (intergenerational cycle of abuse), exposure to child maltreatment, poverty, disability, Indigenous identity, gender/sexual minority status, substance use and unemployment. Perpetration factors at the individual level include substance use, need for over control, exposure to child maltreatment, exposure to IPV, negative attitudes toward women, unemployment, lower education and other partners. Family factors include male dominance, marital conflict, violence as a way of resolving disputes and poverty. There are numerous community and social factors; examples include gender inequality, cultural acceptance of IPV, lack of community cohesion, restricted access to divorce, property ownership, or inheritance, media portrayal of IPV, patriarchal laws or religious values and lack of policies or legal safeguards against IPV. Protective factors identified in some studies include gender equality, monitoring and enforcement of effective policies against IPV, services for victims, safe environments, formal marriage and higher social economic status and education. 5,38 Health Impacts
# Mental Health Impact
IPV is consistently associated with high rates of depression, anxiety disorders (especially phobias and panic disorder), PTSD, alcohol and other substance abuse, sleep disorders, psychosomatic disorders, and suicidal behaviour and self-harm after exposure to IPV. 5,12,70,71 Depression and PTSD are the most prevalent mental health disorders associated with IPV, with considerable comorbidity of the two disorders. 72 In a meta-analysis of studies of women exposed to IPV, the mean prevalence of depression was estimated at 47.6 per cent, and PTSD at 63.8 per cent (3.5 and 5.0 times the general female population rates, respectively). 73 Loss, feelings of shame and guilt, humiliation, entrapment and lack of control contribute to the development of poor self-esteem and depression. 74,75 Other studies have also identified increased rates of eating disorders, antisocial and borderline personality disorders and non-affective psychosis in women exposed to IPV. 12,15,73, IPV is also associated with health risk behaviours including alcohol and drug abuse, sexual risk behaviours and smoking. 5 Because evidence is mounting that depression and PTSD are pathways by which abuse affects physical health, 27,80,81 addressing mental health effects may also be important for preventing physical health problems such as chronic pain or cardiac disease. It has also been found that when violence decreases or is eliminated, physical and mental health both improve. 82
# Physical Health Impact
According to the Statistics Canada 2017 Homicide Survey, women account for approximately eight in 10 victims of intimate partner homicide, with the rate of intimate partner homicide five times greater for females compared to males. 22 This maps onto previous estimates. Specifically, between 2003 and 2013, police services reported 960 domestic homicides in Canada; 78 per cent of victims were women. In homicides between spouses six in 10 (60 per cent) between 2008 and 2018 were preceded by a known history of family violence. 83 Homicide rates for men and women are substantially lower than the early 1990s, which can be partly attributed to rising divorce rates and more equitable male-female employment rates, thereby offering women more options. Laws, law enforcement, shelters and advocacy may also contribute to declining spousal homicides. In the 1990s, men were more likely than women to commit suicide following domestic homicide. In addition, women were more likely to kill their partner if violence was prolonged or they feared for themselves or their children. Men were more likely to kill their partner from rage or despair over actual or impeding estrangement. 84 A range of acute injuries including bruises, factures, lacerations, bites, dental injuries, burns and other injuries may follow IPV. A recent systematic review found that certain injury patterns can differentiate people exposed to IPV, compared with other kinds of injurious events. Specifically, head, neck, dental or facial injuries that were not witnessed (i.e., as would likely occur with a motor vehicle injury) are indicators. In addition, multiple injuries are associated with IPV exposure, whereas thoracic or abdominal extremity injuries alone, tend to not differentiate between abused and non-abused women. 76,85 IPV has been linked to many other physical health outcomes including those related to chronic conditions and infectious diseases. An international systematic review and meta-analysis by the World Health Organization and other studies have found IPV to be associated with, in addition to the injuries above, chronic pain syndromes, fibromyalgia, gastrointestinal disorders, including irritable bowel syndrome, sleep disorders, physical inactivity, disability and general reductions in physical functioning and (or) health-related quality of life. 5,12,76,86 IPV is also associated with gynecological disorders, infertility, pelvic inflammatory disease, pregnancy complications and (or) miscarriage, sexual/ reproductive dysfunction, unsafe sexual behaviour, sexually transmitted diseases (including HIV/AIDS), as well as unsafe or forced abortion and unwanted pregnancy. 5,12,76 In addition to maternal health, IPV during pregnancy can threaten the health of the fetus. Abuse directed to the abdomen can result in poor pregnancy outcomes, preterm birth and perinatal death. 12,76, Children's Exposure to IPV Exposure of a child to any psychological, physical, sexual, financial or emotional abuse between adults who are, or have been, intimate partners or family members is considered a form of child maltreatment in many jurisdictions within Canada 2,91 and may have short-or long-term mental and physical health impacts. Adverse outcomes include an increased risk of physical, psychological, social, emotional and behavioural problems, including mood and anxiety disorders, and substance use disorders and school-related problems in children and adolescents. 2, These negative effects may continue into adulthood and become part of an intergenerational cycle of violence. 91,95,96 Children who are exposed to IPV in the home are more likely to maltreat their own children 96,97 and are more likely to have violent dating and intimate relationships as adults (either as victims or perpetrators). Children exposed to IPV are at increased risk of experiencing other forms of abuse by caregivers (e.g., physical and sexual abuse). 102,103 Identification, Assessment and Documentation
# Victims of IPV
There is no evidence for universal screening for IPV, based on three randomized controlled trials (RCTs), conducted in Canada, 104 New Zealand 105 and the United States. 106,107 Across these trials, IPV screening did not reduce IPV or improve health outcomes, 106 a fact highlighted in most major evidence-based systematic reviews though not necessarily reflected in some specific practice guidelines. 111,112 The discrepancy can contribute to confusion among policy makers and health professionals. While screening is not recommended, it is especially important for mental health clinicians to be alert to the signs and symptoms of IPV exposure and to practice case finding for IPV in the assessment of patients who present with a wide range of psychological signs or symptoms as discussed above. Consequently, inquiring about current and past IPV victimization or perpetration should be part of the clinical assessment of all patients, both men and women, in mental health, addiction and perinatal care settings. Such inquiry is referred to as case finding because it involves including questions about exposure to and perpetration of violence within the diagnostic assessment; it does not involve screening-the use of standardized questions administered in the same way to all patients. 2 Being aware of a history of IPV is necessary to inform diagnostic formulation and treatment approaches; without this information, a key contributing factor to the onset and persistence of mental illness, as well as any opportunity for interventions, may be missed. 69 Many IPV victims seeking health care present with vague signs and symptoms or chronic somatic complaints, including chronic pain, rather than signs of obvious physical, sexual or emotional trauma. Other behaviours that may suggest IPV exposure or perpetration are delays in seeking care or multiple missed appointments. 113 Lack of knowledge about or interest in IPV, time constraints, fear of retribution or of legal involvement are not acceptable reasons for mental health professionals to avoid inquiring about IPV. It should be noted that some individuals and organizations prefer the term "survivor" of IPV and the preferred term should be used if it is known. A private, safe, supportive, confidential environment is essential to conduct a full diagnostic assessment that includes inquiry about IPV. There are many barriers to patients disclosing IPV, including the fear of potential retaliation from the abusive partner, family or community censure, embarrassment, shame, economic dependency, or apprehension about child custody, immigration status or the legal system. It is important to ask about exposure to IPV privately (with no one else present including the partner or a child beyond infancy); if the inquiry and (or) response is overheard, it could put the patient at risk for further IPV. 2 Special arrangements may be needed for immigrants or refugees whose primary language is not English or for whom a request to speak privately from other family members or partners may be perceived as an unusual or culturally insensitive request. The patient should be seen alone or by a same-sex interviewer if culturally indicated, and family and friends should not be involved as translators. Cultural competence should allow a person to not only reject violence but also maintain their cultural identity. Patients may also lack knowledge that IPV is a crime in Canada or that support services exist. Some patients may not see IPV or what happens within their intimate relationship or partner-conflict as a health issue that is appropriate to disclose to a healthcare provider.
It may be helpful to preface direct questions about IPV by asking about the patient's relationships more generally. An introduction such as "How are things at home?" or "How do you and your partner get along?" could be used. Possible follow-up questions to ask include the following, when appropriate: How does your partner respond when there is disagreement in the family? With these arguments, do you ever feel frightened by them? Sometimes partners or ex-partners use physical force. Is this happening to you?
Have you felt humiliated or emotionally harmed by your partner or ex-partner? Do you feel safe in your current or previous relationships?
Have you ever been physically threatened or hurt by your partner or ex-partner?
Have you been forced to have any kind of sexual activity by your partner or ex-partner?
When IPV is first disclosed by an abused partner, the initial clinical response should include validation of the experience (e.g., "Violence is, unfortunately, a common problem in our society" ); affirmation that violence is unacceptable (e.g., "Everyone deserves to feel safe at home"); and expression of support (e.g., "There are things we can discuss that can help"). It is crucial that insensitive (e.g., "Why don't you just leave?") or critical remarks ("Well, did you do something to make them angry? Just don't do that.") are not made by mental health professionals as these may reinforce existing feelings of helplessness, inadequacy or selfblame in victims. 69 The clinician needs to acknowledge the complexity of IPV and respect the patient's individual concerns and decisions. All discussions in which IPV is disclosed must include an inquiry about current safety. If the patient denies IPV, but injuries, signs or symptoms suggest that it may be occurring, inquiries should be repeated at later visits when an atmosphere of greater trust may facilitate further discussion. 2 IPV among adults is not reportable to the police unless a practitioner is concerned about a serious imminent risk to the patient or someone else. Although the decision to involve legal authorities usually belongs to the abused patient alone, a disclosure that indicates that a child is also being abused, or at risk of harm related to IPV exposure among caregivers, requires mandatory reporting to provincial or territorial child protection services (CPS). The legislation varies somewhat across provinces and territories; thus, it is important to understand the specific legislation in one's region of practice. Given the limits of confidentiality, owing to mandatory reporting to CPS, it is important that patients be advised about these limits to confidentiality before any inquiry about IPV exposure. 2 A practitioner's workplace (including hospitals) may have specific guidance about inquiring about or acting on disclosures of IPV as part of workplace safety, and psychiatrists should be familiar with their workplace requirements.
Decisions to leave an abusive relationship may require time and may follow six stages of change outlined by Prochaska (i.e., precontemplation, contemplation, preparation, action, maintenance and termination). 114,115 Women planning to leave a relationship involving IPV should be cautioned that the risk of more serious violence (at times, even homicide) is increased during and following leaving the partner. 11 Safety should be a consideration whenever a person discloses IPV, and simple questions can be useful, such as "Do you feel safe to return home today?" "Do you have a safety plan?" and "Does your partner have a weapon?" Assessment. Following disclosure of IPV, the abused patient should receive a full psychiatric assessment to ascertain any mood, anxiety, personality, psychotic, substance use disorder or organic brain syndrome that may predate or follow IPV. Psychological sequelae of IPV should be noted and the patient reassured that these are common and may spontaneously resolve or can be treated.
In general, studies exploring women's preferred responses after disclosing IPV suggest that women want physicians to ask questions about the abuse, to listen and believe them, express concern, be nonjudgmental and supportive, and to make appropriate referrals to a shelter, and to social and legal services. 116 Women do not want to be pressured to disclose IPV (or to leave their partner); they prefer to be asked about it in a way that is confident and comfortable, with assurance of confidentiality (with the potential exceptions regarding child welfare, outlined above). It is important to state to the patient that all people have a right to live without abuse.
# Perpetrators of IPV
Perpetrators of IPV may present with personality disorders, substance use disorders, depression, fear of losing control, obsessional jealousy, paranoid ideas, psychosis or brain dysfunction. Questions that may uncover IPV, such as "What happens when you lose your temper?" or "Have you ever become violent or threatened someone?" or "Has this person ever been your partner?" can initiate the inquiry about IPV perpetration. More specific questions about the types of abuse being perpetrated should follow. A Canadian study found that male and female psychiatric patient perpetrators of IPV fell into one of the following groupings: generally violent and antisocial; borderline and dysphoric; or low psychopathology. 117 Personality disorders were most common. Disclosures by perpetrators should not be dismissed, minimized, met with indifference or dealt with in a way that seems to collude with the perpetrator's justification of the use of violence. 69 The assessment of the abusive partner should ideally be conducted by a professional who is not treating the victim to avoid a conflict of interest and/or an accidental or inadvertent disclosure of confidential information that may place the victim at greater risk. Collateral information about the abuser from other individuals in their life (e.g., other providers, family members independent from the abuser) should be sought to increase accuracy. A structured clinical evaluation should include any acute or chronic psychiatric disorders or personality disorders, the pattern, frequency, severity of abuse, any criminal convictions, as well as their insight and judgment about their behaviour. Various tools can serve as memory aids in the assessment of risk of IPV recurrence including the Spousal Assault Risk Assessment Guide, 118 based on the 20-item Historical, Clinical and Risk management tool. 119
# Documentation
Careful, accurate documentation in the medical chart for victims or perpetrators is vital for monitoring, diagnosis, formulation and treatment planning. It may also be needed for legal proceedings. 120 The reported history and chronology of IPV and its relation to perpetrator or victim psychiatric symptoms, and its effects on a victim, should be recorded. It is important to differentiate facts from opinions. 69 Factual information, such as documenting visible injuries in a victim (a body diagram or photograph may be useful), a personal description of the IPV and its context by the patient in quotation marks, and noting the patient's mental status, is useful. Patient records (as always) should only be released by written patient consent or by subpoena (unless reporting to child welfare authorities is mandated).
# Management, Treatment and Prognosis
# Victims of IPV
Following a full psychiatric assessment of an adult exposed to IPV, treatment for any specific symptoms or conditions should be in accordance with national practice guidelines delivered by professionals with a good understanding of IPV and its consequences. 2 Treatment approaches will depend on the psychiatric diagnosis and be informed by issues specific to the patient, the relationship, the trajectory of abuse, the patient's readiness for change, culture and the IPV characteristics.
Advocacy interventions for people exposed to IPV aim to empower victims and link them to community resources such as shelters, housing, safety planning advice, informal counselling and legal services. A systematic review of all controlled studies of IPV advocacy interventions, including some in healthcare settings, found a reduction in abuse, increased social support, improved quality of life, increased safety behaviours and use of community resources. 108,121 Shelters provide safety for women at moderate risk of IPV and their children. 2 In a systematic review of controlled studies of psychological interventions for IPV, victims reported improvements in psychological outcomes, including depression, PTSD and self-esteem, with a wide range of psychological interventions, including individual or group cognitive trauma therapy. 122,123 For victims of IPV and living with related PTSD, there appear to be a number of possible interventions. Specifically, a systematic review update by the Agency for Healthcare Research and Quality on psychological and pharmacological treatments found high strength of efficacy (SOE) for cognitive behaviour therapy, exposure and CBT-mixed treatments and moderate SOE for cognitive processing therapy, cognitive therapy, eye movement desensitization and reprocessing therapy and narrative exposure therapy to improve symptoms related to PTSD. Among pharmacotherapies, moderate SOE was found for fluoxetine, paroxetine and venlafaxine and low SOE for sertraline, olanzapine, risperidone, topiramate and prazosin. 123 Although no studies were found that identified resilience as the primary outcome, components of resilience, such as self-esteem, self-efficacy and improved quality of life, were assessed among some of the intervention studies included in the review. 124 Importantly, most studies included in the systematic review were conducted with women who were no longer in abusive relationships; their relevance for male victims of IPV and with PTSD or in people with PTSD symptoms and who are still experiencing abuse is unknown. 113 Couples' interventions may take various forms including multi-couple or individual couple sessions which may offer separate sessions for the victim and abuser. In general, couple-based interventions are thought to pose safety risks to the victim and effectiveness is uncertain. Thus, couples' therapy is not recommended, especially for those experiencing intimate partner terrorism (VEGA Systematic Review). The evidence for working with the whole family is inconclusive. 2 Studies of children exposed to IPV have shown positive outcomes for specific interventions, such as child-parent psychotherapy, 125,126 teaching child management skills combined with providing support to mothers, 127 advocacy for mothers and their children, combined with a support and education group for children, 128 and trauma-focused cognitive-behavioural therapy, involving individual sessions for mothers and children as well as joint sessions. 129 These interventions, focused on the motherchild dyad, have been shown to improve behaviour problems and (or) PTSD symptoms in children, 125,126,129 as well as children's competence and self-worth. 128 They are promising in their level of evidence but require replication.
The prognosis for victims of IPV is uncertain, as intervention studies usually have small samples, short follow-up and high attrition. Cohort studies of the natural history of IPV are rare. There are numerous descriptive reports of women successfully leaving abusive partners and establishing healthy relationships with subsequent partners. However, one follow-up study of women who received an advocacy-based intervention after leaving a shelter found that 44 per cent had been assaulted by their original or a new partner 3.5 years after leaving the shelter. In addition, despite significantly lower recurrence rates in the intervention group at two-year follow-up, this difference was not sustained at the three-year follow-up period. However, importantly, there was a significant improvement in quality of life and social support among women who participated in the advocacy-based intervention, compared with those who did not. 130 We were unable to find prognostic data about men or members of special population groups who were abused.
# Perpetrators of IPV
Various programs have been developed for abusive partners, some of which are voluntary and others courtmandated. Nearly all of these are for men abusers, and adherence is often low. The evidence of effectiveness is mixed, 131 although motivational interviewing may be promising and requires further research. No studies were found for women perpetrators or perpetrators identifying as gender/sexual minorities. Thus, the focus of intervention, in addition to treating any mental illness that may be present, is to encourage the abuser to take responsibility for IPV perpetration, to recognize internal and external triggers for IPV and to understand and take responsibility for the consequences of their perpetration. Specific behavioural strategies that can reduce the risk of violence perpetration, offering advice on reducing alcohol or drug intake, as well as referral to appropriate perpetrator services may be helpful for specific people. 69 There is some evidence to suggest that permanent (not temporary) civil protection orders for men abusers may reduce future IPV. 132
# Prevention
Primary prevention of IPV consists of educational programs that focus on respectful relationships, conflict resolution strategies, changes in attitudes, and knowledge. However, a Cochrane systematic review of interventions to prevent relationship and dating violence in adolescents and young people found no convincing evidence that these programs decrease relationship/dating violence, attitudes, behaviours or skills. The only positive effect noted in the review related to improving knowledge about relationship violence. 133 Although scientific evidence is lacking, many authorities recommend intersectoral collaboration between health, social, education and legal services, as well as between health specialties and disciplines to advocate for IPV prevention and policy. 134,135 The media can also be helpful in raising public awareness of IPV as a critical mental health determinant and in censuring public statements that sensationalize or normalize IPV as an acceptable or cultural norm. 135 However, it is important to evaluate the effectiveness of such approaches in reducing IPV.
Secondary prevention interventions for IPV have been described for pregnant women, consisting of advocacy and empowerment programs that reduced psychological and minor physical violence and improved pregnancy outcomes. 136,137 One trial of intensive advocacy (12 hours or more) reduced physical abuse after 12 to 24 months in women leaving shelters, but this was not the case for shorter or longer follow-up periods. 130 Other treatment interventions are discussed earlier in this paper.
# Education and Research
Some psychiatric associations (e.g., the World Psychiatric Association 138 and the Royal College of Psychiatrists 69 ) and a few Canadian medical specialty associations in addition to the CPA (e.g., the Society of Obstetricians and Gynaecologists of Canada 87 and the Canadian Orthopaedic Association 139 ) have issued policy statements and educational objectives on the topic of IPV.
Trainees in psychiatry at the undergraduate and postgraduate level, including international medical graduates, and all mental health professionals should receive education about IPV from faculty who are familiar with this issue. Currently, rates of inclusion of IPV content in the Canadian curriculum of medical and allied health professionals, including mental health professionals, are very low. 140 This training should be included in the curriculum and be composed of both a didactic and a clinical component. The didactic component should include the prevalence (including special populations), etiology, health effects (especially mental health), how to inquire about IPV and safety using a case-finding approach, the range of interventions for IPV-related impairment, as well as risk assessment and management of victims and perpetrators of IPV. Continuing professional education programs should also include sessions on IPV. All psychiatrists should become familiar with, and implement, the guidance outlined in this CPA position paper, Recognizing and Responding to Intimate Partner Violence: An Update (informed by the CPA's position paper on cultural competence 141 ).
In terms of research, there is now considerable descriptive information about IPV, especially in women, but it is also important to examine IPV against men perpetrated by women and IPV in special populations. Studies of effective interventions for the prevention and treatment of victims and perpetrators are still in their infancy and there are important knowledge gaps. Specifically, there is a need for rigorously designed studies comparing different psychological interventions, and which focus on people at different stages of the abuse trajectory, as well as studies testing the impact of interventions of differing durations and follow-up periods. Both patient-and system-centred interventions should use standardized or comparable outcome measures.
# Summary
IPV is an under-recognized problem that impacts all genders and which occurs in all countries, cultures and socioeconomic groups.
IPV has an enormous impact on personal health, and economic and social well-being.
IPV may occur in heterosexual and gender/sexual minority relationships and may be perpetrated by individuals identifying with either sex, gender and by non-binary individuals.
Canadian data from 2014 show equal proportions of men and women (four per cent) have been victims of physical IPV in the previous five years.
Women are more likely than men to report severe IPV, to report chronic violence or to be killed. They are also more likely to be criminally harassed or killed after the relationship ends.
Exposure to IPV has deleterious effects on children and other family members. Some populations are at greater risk for IPV. These include Indigenous women, gender/sexual minorities, people with disabilities, those in dating relationships, those with alcohol and other substance use disorders, those with low-income and those who have a previous partner that was abusive.
Mental health problems associated with IPV include depression, anxiety disorders, PTSD, chronic pain syndromes, eating disorders, sleep disorders, psychosomatic disorders, alcohol and other substance use problems, suicidal and self-harm behaviours, psychosis, some personality disorders and harmful health behaviours, such as risk taking and smoking. As IPV is a major determinant of mental health, it is of vital importance to mental health professionals.
Physical health problems associated with IPV include death, a broad range of injuries, reproductive disorders, gastrointestinal disorders, chronic pain syndromes, fibromyalgia, poor physical functioning and lower health-related quality of life. Sexually transmitted diseases, unwanted pregnancies and physical inactivity are also increased.
Children's exposure to IPV may have short-and long-term health impacts on the child, especially mental health effects.
Perpetrators of IPV most frequently have personality disorders, but substance use disorders and other types of mental illness or brain dysfunction may also occur.
# Recommendations for Best Practice
Psychiatrists and other mental health professionals should inquire about IPV victimization and perpetration using a case-finding approach as part of the clinical assessment of all patients. A person does not need to be in a current relationship to be experiencing IPV.
Case-finding in patients with symptoms associated with IPV should be a priority and inquiries made about possible IPV in a private, safe, confidential, empathic setting. These questions may need to be repeated at subsequent sessions when the therapeutic relationship is better established.
Particular attention to case-finding should be given to special populations and situations known to be at higher risk of IPV.
If a patient discloses IPV, inquiries should be made about current safety (risk assessment) and referrals offered to appropriate services for people experiencing violence (e.g., shelters, local resource centres, social and/or legal resources and/or police if indicated).
Safety should be an ongoing concern, especially if the abused partner plans to leave the abusive situation.
Careful documentation of IPV in the patient's chart is essential. It should be released only with patient consent or by subpoena.
CPS must be notified in accordance with provincial or territorial legislation if a child is exposed to IPV or is in danger. Victims of abuse should be informed of this duty to report, and that not all types of disclosures will be strictly confidential.
Mental health professionals should ask about children in the family and determine the need for any children to be referred for assessment of emotional and behavioural problems.
Treatment approaches will depend on the psychiatric diagnosis and national treatment guidelines and be informed by special issues particular to the person, the relationship, the trajectory of abuse, the patient's readiness for change, culture and the IPV characteristics. Mental health professionals should consider referral of patients to advocacy services and the need for specific psychological interventions as outlined above. They should be aware of the moderate strength of evidence for only a few psychotropic medications for treating PTSD following IPV as outlined above.
Psychiatrists should be familiar with the principles of risk assessment and management for perpetrators of IPV. In addition to treating any mental illness or substance use disorder that may be present, the main focus of treatment should be on assisting the perpetrator to take responsibility for IPV and its consequences, to recognize its triggers and to develop behavioural strategies to stop IPV. Avis : L'Association des psychiatres du Canada a comme politique de réviser chaque énoncé de principe, déclaration de politique et guide de pratique clinique tous les cinq ans après la publication ou la dernière révision. Tout document qui a été publié plus de cinq ans auparavant et dans lequel il n'est pas mentionné explicitement qu'il a été révisé ou conservé à titre de document officiel de l'APC, soit révisé ou tel que publié à l'origine, doit être considéré comme un document de référence historique uniquement.
les gens ou les animaux, ainsi que le contrôle contraignant, qui comprend limiter l'accès à l'argent, aux amis ou à la famille, une surveillance excessive ou des menaces de faire du tort à soi ou aux autres. 4,5 Le harcèlement dans la VPI consiste dans une attention répétée non voulue, qui fait que la personne craint pour sa sécurité personnelle ou celle d'une connaissance. 6 Il comporte par exemple surveiller ou suivre des messages électroniques ou téléphoniques répétés, espionner, laisser des cadeaux ou des objets menaçants pour le partenaire ou ex-partenaire, ou endommager la propriété d'un partenaire actuel ou passé. 5 La VPI peut se produire chez tous les genres et le terme « partenaire intime » n'implique pas que les personnes qui sont exposées à cette forme de violence aient des antécédents d'intimité sexuelle ou de relation maritale. 19 Bien que la majorité des VPI rapportées par la police (82%) impliquent des partenaires de sexe opposé où les femmes sont les victimes et les hommes les auteurs, environ 55% des VPI de même sexe rapportées à la police impliquent des partenaires masculins. 20 En outre, la violence avec un conjoint ou un ex-conjoint ou dans le cadre de fréquentations était la forme de violence la plus commune déclarée à la police par les femmes en 2017, les femmes et les filles représentant près de 8 à 10 rapports de VPI cette année-là. En ce qui a trait aux jeunes, en 2010, environ un pour cent des cas de victimisation dans le cadre de fréquentations rapportés par la police impliquaient des adolescents de 12 à 14 ans; quelque 93% de ces rapports de victimisation étaient faits par des femmes et 52% d'entre eux impliquaient une agression sexuelle. 21 En 2017, 15 535 femmes âgées de 15 à 24 ans ont déclaré une victimisation dans le cadre de fréquentations aux services de police canadiens: 19% et 11% de ces rapports référaient à un partenaire actuel plutôt qu'ancien, respectivement. 22 Notablement, ces résultats propres au genre sont demeurés constants dans les cycles de la DUC. 19 Les menaces, les injures, le fait de limiter les contacts avec la famille ou les amis ont été rapportés par 8% des femmes et 6% des hommes. 6 Il est important de noter que de nombreux incidents de VPI ne sont pas déclarés à la police en raison de la honte, de l'embarras, du déni, de la peur de ne pas être cru, de la peur du rejet ou des représailles, ou de se croire responsable de la violence. Les facteurs de risque de la violence dans les fréquentations sont notamment l'abus passé, les croyances et les attitudes, de faibles aptitudes aux relations, la consommation d'alcool et de drogues, les influences des pairs et la pornographie. 23 Violence bilate´rale (c.-a`-d., re´ciproque dans le couple)
Le stéréotype qui a longtemps prévalu voulait que l'homme violent utilise une violence grave et unilatérale à l'endroit d'une victime féminine non violente. Nous savons désormais que la violence bilatérale est plus répandue que ce que nous estimions, mais les femmes subissent le fardeau écrasant de morbidité et de mortalité associé à la violence entre partenaires intimes. 24 32 Cette incrédulité est plus évidente dans le contexte de la violence sexuelle, car peu savent que la peur, la colère ou la douleur peuvent provoquer une érection et l'éjaculation au même titre que l'excitation sexuelle consensuelle. 33 Populations et situations spe´ciales Facteurs culturels. Les valeurs profondément ancrées à propos de la priorité relative des buts et de l'autonomie de la personne (l'individualisme) et de ceux de la société (le collectivisme) à laquelle la personsne appartient sont présumées être liées aux taux de VPI. La culture collectiviste patriarcale a une conception rigide des rôles sexuels, souscrit au principe de l'emprise de l'homme sur la femme, associe masculinité et domination, maîtrise, honneur et agressivité et admet la violence comme moyen de résoudre les conflits dans les relations intimes. De même la recherche qualitative sur les femmes de communautés soumises à la culture collectiviste affirme que celles-ci ne peuvent qu'endurer plutôt que de rejeter la VPI afin de préserver les valeurs culturelles, la famille et l'honneur. Une récente méta-analyse qui examine les facteurs culturels ou structurels du risque de la VPI rapporte des données probantes longitudinales, quantitatives émergentes à l'appui de ces affirmations. 5,38 Nouveaux arrivants. Les populations migrantes au Canada, dont les immigrants et les réfugiés, font face au même type de VPI que leurs pairs non migrants, mais des difficultés additionnelles liées à leur statut de migration, notamment la peur de la déportation, la perte du statut de réfugié, l'isolement social, les menaces de mariage forcé, l'incapacité de parler l'une des langues officielles, l'exclusion économique ou les valeurs collectivistes ou religieuses qui soutiennent et privilégient le pouvoir des hommes et gardent la famille entière et l'empêchent de divulguer « des affaires privées », tout cela peut empêcher ces personnes de déclarer leur exposition à la violence dans des enquêtes ou à la police. Même si des études communautaires sur la VPI comportant des immigrants indiquent des taux élevés de violence, la mesure dans laquelle ces taux diffèrent de ceux des non-migrants n'est pas concluante. 39 Les méthodes, les questions de mesure, l'accès et l'acceptation de certains types de VPI chez les groupes d'immigrants/réfugiés rendent difficile de comparer la prévalence. 40,41 Peuples autochtones. 64 Cependant, la mentalité individuelle ou sociétale voulant que l'alcool soit la cause de l'agression peut encourager le comportement violent après avoir bu et l'alcool peut devenir un prétexte au comportement violent. 65 Il est fort probable que la consommation d'autres substances se traduise par une prévalence accrue de VPI, mais l'absence de données fiables ne permet pas de confirmer cette supposition.
Pauvreté . Bien que la VPI puisse être perpétrée, et se produise de fait, dans tous les groupes socioéconomiques, elle s'installe le plus souvent chez des gens pauvres. 66,67 Cette constatation tient en partie du moins à ce que les personnes jouissant d'une certaine aisance financière ont un certain pouvoir, un niveau d'instruction et un plus grand nombre d'options à leur disposition pour échapper aux relations violentes et à ce que l'insuffisance des ressources financières occasionne un stress accru au quotidien.
Personnes â gé es. De meilleures données sont désormais disponibles pour les Canadiens de 65 ans et plus qui subissent la VPI, notamment la négligence, et l'abus physique, sexuel, émotionnel et financier. 68 On estime que seulement 20% des incidents dans ce groupe d'âge sont rapportés à la police en raison des obstacles de langue, de culture, de santé, de transport et de technologie. Les rapports de police sur la violence contre les personnes âgées révèlent que la victimisation par un conjoint était le type d'abus le plus commun (33%) pour les femmes, alors que la victimisation par un enfant était l'abus le plus commun rapporté par les hommes (34%). 68 Les homicides liés à la famille contre des personnes âgées sont en hausse, le conjoint étant le contrevenant pour 50% des femmes victimes et 8% des hommes victimes. 68 Le partenaire violent peut souffrir d'isolement social, être rongé par le stress, souffrir d'une maladie mentale ou être aux prises avec une toxicomanie. Sans compter que la démence et d'autres troubles neurologiques peuvent être des facteurs majeurs dans cette propension à la violence, alors que l'altération cognitive doublée d'une déficience sensorielle peut conduire à une perte de contact avec la réalité et une pensée paranoïaque. L'atteinte du lobe frontal peut chasser l'inhibition normale et être à l'origine de l'absence apparente de remords et de lucidité de l'auteur des actes de violence. Il importe de se rappeler que la personne âgée peut être agressive, violente, voire dangereuse. Néanmoins, la violence entre partenaires intimes âgés est souvent perçue comme étant moins sérieuse et l'agresseur s'attire plus de sympathie en raison de son apparence de fragilité ou d'incapacité physique, ce qui complique la tâche d'estimer la véritable prévalence et les conséquences de la VPI chez les personnes âgées. 69
# Indicateurs de risque
De nombreuses études canadiennes, dont des enquêtes nationales menées auprès d'un échantillon représentatif de la population générale, et des études de grande envergure dans d'autres milieux font ressortir sensiblement les mêmes caractéristiques démographiques, relationnelles et spécifiques des partenaires à titre d'indicateurs du risque de VPI, dont le jeune âge, l'union de fait par opposition au mariage, la séparation, la relation avec un chômeur ou un partenaire sous-employé, la situation économique précaire, l'alcoolisme ou la toxicomanie. 5 Des études internationales considèrent les troubles de la personnalité, la psychose, la dépression, les difficultés conjugales et le dysfonctionnement familial comme étant des facteurs de risque de violence exercée par le partenaire masculin. 5 On a noté certains traits chez des auteurs de VPI, dont la jalousie maladive, la passivité agressive, la faible estime de soi, l'incapacité à s'affirmer, l'inémotivité, les carences sociales et l'inaptitude sexuelle. 69 Quant aux victimes masculines, l'homme plus jeune est de quatre à cinq fois plus à risque de VPI que l'homme d'âge mûr (plus de 45 ans). Les facteurs de risque écologique de la VPI sont des facteurs individuels, du partenaire, familiaux et communautaires/sociaux. 5 Bien que la VPI puisse se produire dans toute relation intime, les facteurs individuels de la victimisation sont entre autres l'exposition antérieure à la VPI (cycle d'abus intergénérationnel), l'exposition à la maltraitance dans l'enfance, la pauvreté, l'incapacité, l'identité autochtone, le statut de minorité de genre/ sexuelle, l'utilisation de substances et le chômage. Les facteurs de perpétration au niveau individuel comprennent l'utilisation de substances, le besoin de sur-contrôle, l'exposition à la maltraitance dans l'enfance, l'exposition à la VPI, les attitudes négatives à l'endroit des femmes, le chômage, une faible instruction et d'autres partenaires. Les facteurs familiaux sont notamment la domination masculine, le conflit conjugal, la violence comme moyen de résoudre des différends et la pauvreté. Il y a de nombreux facteurs communautaires et sociaux; par exemple, l'inégalité entre les sexes, l'acceptation culturelle de la VPI, le manque de cohésion communautaire, l'accès restreint au divorce, la propriété ou l'héritage des biens, la présentation de la VPI dans les médias, les lois patriarcales ou les valeurs religieuses, et l'absence de politiques ou de protections juridiques contre la VPI. Les facteurs de protection identifiés dans certaines études sont entre autres l'égalité des sexes, la surveillance et l'application de politiques efficaces contre la VPI, les services pour les victimes, des environnements sécuritaires, un mariage officiel, un statut socio-économique plus élevé et une meilleure instruction. 5,38 Répercussions sur la santé
# Re´percussions sur la sante´mentale
La VPI est continuellement associée à des taux élevés de dépression, de troubles anxieux (particulièrement les phobies et les troubles de panique), le TSPT, l'abus d'alcool et d'autres substances, les troubles du sommeil, les troubles psychosomatiques, les comportements suicidaires et actes autodestructeurs subséquents aux épisodes de violence. 5,12,70,71 La dépression et le TSPT ont la prévalence la plus élevée des troubles de santé mentale associés à la VPI, et une comorbidité considérable accompagne ces deux troubles. 72 Une métaanalyse d'études menées auprès de femmes ayant subi la VPI révèle que la prévalence moyenne de dépression est de 47,6% et que celle du trouble de stress posttraumatique est de 63,8%, des taux plus élevés que dans la population féminine en général, d'un facteur de 3,5 pour la première et de 5,0 pour le second. 73 Des sentiments de perte, de honte, de culpabilité, l'humiliation, le sentiment d'être prise au piège et l'impossibilité de maîtriser la situation contribuent à la baisse de l'estime de soi et à l'apparition de la dépression. 74,75 D'autres études ont aussi fait ressortir des taux accrus de troubles alimentaires, de troubles de la personnalité antisociale et limite, et de psychose non affective chez les femmes exposées à la VPI. 12,15,73, La VPI est aussi associée à des comportements risqués pour la santé, dont l'abus de drogues et d'alcool, les comportements à risque sexuel et le tabagisme. 5 Comme les données probantes suggèrent que la dépression et le trouble de stress posttraumatique sont des médiateurs par lesquels la violence affecte la santé physique, 27,80,81 il devient évident que la prise en charge des effets sur la santé mentale permettrait de prévenir des problèmes de santé physique, telles la douleur chronique ou la maladie cardiaque. La recherche établit en outre que lorsque la violence diminue ou cesse, la santé physique et la santé mentale s'améliorent. 82 Re´percussions sur la sante´physique Selon l'Enquête sur les homicides de 2017 de Statistique Canada, les femmes représentent environ 8 victimes sur 10 des homicides de partenaires intimes, le taux de ces derniers étant 5 fois plus grand pour les femmes que pour les hommes. 22 Cela s'accorde aux estimations précédentes. Précisément, entre 2003 et 2013, les services de police ont rapporté 960 homicides domestique au Canada; et 78% des victimes étaient des femmes. Dans 6 homicides aux mains d'un conjoint sur 10 (60 %) qui se sont produits de 2008 à 2018, il y avait des antécédents de violence familiale connus. 83 Les taux d'homicide pour les hommes et les femmes étaient substantiellement plus faibles qu'au début des années 1990, ce qui peut être attribué en partie aux taux de divorce croissants et à des taux d'emploi plus équitables pour hommes et femmes, qui offraient ainsi plus d'options aux femmes. Les lois, le respect des lois, les refuges et la défense des droits peuvent aussi contribuer à la baisse des homicides entre conjoints. À la fin des années 1990, les hommes étaient plus enclins que les femmes à se suicider par suite d'un homicide conjugal. En outre, les femmes étaient plus susceptibles de tuer leur partenaire si la violence se prolongeait ou qu'elles craignaient pour leur vie ou celle de leurs enfants. Les hommes étaient plus susceptibles de tuer leur partenaire par rage ou désespoir à cause d'une séparation réelle ou imminente 84 Une série de blessures graves, dont des ecchymoses, des fractures, des lacérations, des morsures, des dents abîmées, des brûlures et d'autres peuvent être la conséquence de la VPI. Une revue systématique récente a observé que la nature de certaines blessures permet de différencier les personnes exposées à la VPI, comparé à d'autres types de blessures. Plus précisément, les blessures à la tête, au cou, à la mâchoire ou au visage survenues en l'absence de témoins (qui se produiraient par un accident de la route), sont des indicateurs. En outre, les blessures multiples sont associées à l'exposition à la VPI, alors que les blessures thoraciques ou abdominales qui se présentent seules ne permettent pas de différencier entre les femmes victimes de violence ou pas. 76,85 La VPI a bien d'autres répercussions sur la santé physique, notamment sur la santé reproductive, et l'apparition de maladies chroniques et de maladies infectieuses. Selon une revue systématique et une métaanalyse de l'OMS et d'autres études, la VPI peut entraîner, en plus des blessures précédentes, des syndromes de douleur chronique, de la fibromyalgie, des troubles gastro-intestinaux, dont le syndrome du côlon irritable, des troubles du sommeil, l'inactivité physique, l'incapacité et la détérioration générale de l'état fonctionnel ou de la qualité de vie liée à la santé. 5,12,76,86 La VPI est également associée à des troubles gynécologiques, l'infertilité, la maladie inflammatoire pelvienne, des complications durant la grossesse, la fausse couche, la dysfonction sexuelle ou reproductive, les comportements sexuels à risque, les infections transmissibles sexuellement, dont le VIH et le sida, l'avortement non salubre ou forcé et la grossesse non désirée. 5,12,76 Cette forme de violence infligée à la femme durant la grossesse met en péril non seulement la santé maternelle, mais également la santé foetale. Les coups et blessures à l'abdomen peuvent compromettre l'évolution de la grossesse et provoquer une naissance prématurée ou la mort périnatale. 12,76, Exposition des enfants a`la VPI Ê tre témoin d'épisodes de violence psychologique, physique, sexuelle, financière ou affective entre des adultes qui sont des partenaires intimes ou l'ont été ou qui sont des membres de la famille est, pour un enfant, une forme de maltraitance dans bien des endroits au Canada 2,91 qui peut avoir des répercussions à brève ou à longue échéance sur sa santé physique et mentale. L'exposition à la VPI durant l'enfance entraîne un risque accru de problèmes d'ordre physique, psychologique, social, affectif et comportemental, notamment de troubles de l'humeur et de troubles anxieux, de problèmes scolaires et de troubles d'utilisation de substances dans l'enfance et à l'adolescence. 2, Les effets négatifs peuvent perdurer à l'âge adulte et donner lieu à un cycle de violence intergénérationnelle. 91,95,96 Les enfants exposés à la VPI à la maison sont plus enclins à maltraiter leurs propres enfants 96,97 et à entretenir des relations amoureuses marquées par la violence à l'âge adulte (qu'ils en soient l'auteur ou la victime). Les enfants exposés à la VPI sont plus vulnérables que les autres enfants à d'autres types de violence exercée par les personnes qui en prennent soin (p. ex., la violence physique ou sexuelle). 102,103 Dépistage, évaluation, documentation 106 un fait souligné dans la plupart des revues systématiques majeures fondées sur des données probantes mais pas nécessairement reflété dans certaines lignes de conduite spécifiques de la pratique. 111,112 Le clinicien est tenu de prévenir les instances de protection de l'enfance, conformément à la législation de la province ou du territoire où il exerce sa profession, quand il sait qu'un enfant est témoin de VPI ou qu'il est en danger. Il devrait informer les victimes de cette obligation de signaler de tels cas et des limites de la confidentialité dans la divulgation de certains faits.
Le professionnel de la santé mentale devrait s'informer de l'état des enfants de la famille et déterminer s'il y a lieu de les référer à une évaluation de difficultés émotionnelles ou comportementales. Les auteurs remercient Dr Pierre Gagné pour ses suggestions et son aide dans la préparation de la version française de cet énoncé de principe. | Note: It is the policy of the Canadian Psychiatric Association to review each position paper, policy statement and clinical practice guideline every five years after publication or last review. Any such document that has been published more than five years ago and does not explicitly state it has been reviewed and retained as an official document of the CPA, either with revisions or as originally published, should be considered as a historical reference document only.#
Intimate partner violence (IPV; also known as domestic violence) refers to behaviour by an intimate partner or expartner that can cause or causes physical, sexual or psychological harm. These behaviours include physical aggression, sexual coercion, psychological abuse and controlling behaviours. 2 Stalking and financial abuse have now been included in the list of IPV behaviours by some authorities. 3 The Centers for Disease Control and Prevention has provided definitions and examples of four major types of IPV. 4 Physical IPV includes hitting, choking, shaking, biting, shoving, grabbing, slapping, burning, scratching, hair pulling and the threat of or the use of a weapon or restraints, as well as other aggressive physical acts. Sexual IPV includes forced sexual acts or attempts including acts committed when a partner is unable to give informed consent due to alcohol, drugs or mental incapacity. Sexual IPV may involve exploitation of economic or immigration vulnerability, intimidation or false promise (to marry), as well as sexually based degradation or threats. Psychological IPV includes the use of verbal and non-verbal communication to harm another person mentally or emotionally and/or exert control over their behaviours or decisions. Examples include expressive aggression (degradation, belittling, humiliation), mind games, exploitation of vulnerability, control of reproductive or sexual health, threats of violence to people or pets, as well as coercive control; the latter includes limiting access to money, friends or family, excessive monitoring, or threats of harm to self or others. 4,5 Stalking IPV consists of repeated unwanted attention that causes the person to fear for their personal safety or the safety of someone they know. 6 Examples include watching or following, repeated phone or electronic messages, spying, leaving gifts or threatening objects for the partner/ex-partner, or damaging a current or former partner's property. 5 IPV can occur across genders and the term "intimate partner" does not require that individuals exposed to this form of violence have a history of sexual intimacy or a marital relationship. 2,7 Although IPV can occur in any intimate relationship, including dating relationships, it disproportionately affects women and gender/sexual minorities but can also be directed toward men. IPV has also been called family violence, domestic violence or spouse abuse, but these terms are less specific, and some include violence against children in the categories of family or domestic violence, which can be confusing. When IPV is directed toward women, the terms wife abuse, wife battering or wife assault are often used. All of these terms have in common an understanding of violence as an expression of power, control and domination enacted through a range of behaviours that often escalate, especially after the relationship has ended. 5 IPV is a violation of human rights that can result in serious mental and physical health impairment including death. IPV is an underrecognized problem that can have an enormous impact on the health and well-being of women, men and children. It is a major public health and social problem globally that results in significant personal, health, economic and social costs. 3,5,8 One study estimated that the costs arising as a result of IPV experienced by women aged 19 to 65 years who have left their partners are $7.2 billion annually for Canada. 9 This paper discusses the epidemiology of IPV (including special populations and situations), risk indicators, health impacts, as well as approaches to identification, assessment, documentation, intervention, prognosis, prevention, education and research. We also provide recommendations for best practice in psychiatry. In general, this paper highlights key findings and common themes from the highest quality evidence available internationally, with a special focus on Canadian data. The Canadian Psychiatric Association (CPA) previously incorporated IPV in its 1992 Guidelines for the Evaluation and Management of Family Violence, 10 and they published a position paper on IPV in 2013, 1 but new information and resources require an update on this topic. 2, [11][12][13] As IPV is associated with a broad range of health problems experienced by patients seen by psychiatrists, including depression, anxiety disorders, posttraumatic stress disorder (PTSD), chronic pain, eating disorders, sleep disorders, psychosomatic disorders, alcohol and other substance use disorders, suicidal and self-harm behaviours, personality disorders (such as borderline and antisocial), nonaffective psychosis and health risk behaviours, the rationale for this position paper is clear. 14 IPV should be of vital interest to mental health professionals and, more specifically, psychiatrists.
# Epidemiology
# Self-report Data
IPV occurs in all countries, cultures, religions and socioeconomic groups in the world. Generally speaking, IPV is a gendered phenomenon as women are disproportionately affected by IPV. However, evidence indicates that IPV may be perpetrated by men toward women, women toward men, and in same-sex relationships. It may occur in marriage, common-law relationships, cohabitation or any intimate relationship including dating. In general, most data have focused on IPV perpetrated by men against women in heterosexual relationships as discussed in the following sections. The literature shows that the extent of IPV varies greatly across countries. Attempts to make comparison between Canada and other nations are difficult due to differences in IPV definitions, survey methods and measurement, including the reference period of IPV exposure (e.g., lifetime vs. previous 12 months, lifetime vs. current relationship). The best available cross-country comparison of IPV rates comes from the 2000-2003 World Health Organization's Multi-country Study on Women's Health and Domestic Violence against Women, though data from Canada were not collected. Prevalence data for 10 countries show significant variation in women's lifetime of exposure to physical and/or sexual violence by a current or former male intimate partner; estimates of prevalence ranged from 15 per cent to 71 per cent among ever-partnered women. In all sites but one, women were more at risk of violence from a partner or ex-partner than from violence by other people. There were also significant differences in IPV exposure across rural versus urban areas, with higher IPV rates usually reported by women residing in rural regions. 15 In Canada, national data on IPV reported by men and women were first collected by Statistics Canada in its population-based 1999 General Social Survey (GSS), which is a quinquennial survey of the violence and victimization experiences of Canadians aged 15 and over. 16 In 1999, almost equal proportions of men (seven per cent) and women (eight per cent) reported being a victim of physical abuse in intimate relationships in the previous five years. 16 In 2009, 11.9 per cent of the GSS sample reported exposure to either physical/sexual IPV, emotional IPV or financial control/abuse. Data for 2014 showed reduced rates of exposure to physical or sexual IPV, with four per cent of Canadians aged 15 and over reporting one or both of these forms of IPV in the previous five years, with no difference between men and women. 17 Fourteen per cent of Canadians aged 15 or over said they had experienced emotional or financial abuse from a spouse or common-law partner sometime in the past. 18 Importantly, the most serious types of IPV, including sexual assault and being beaten, choked, threatened with a knife or gun, were reported by 25 per cent of abused Canadians, with women twice as likely as men. 18 Women victims were also more likely than men to have a physical injury (40 per cent vs. 24 per cent), to have experienced attempted murder or death (0.2 per cent of victims but 78 per cent were women) and are more likely to experience PTSD following IPV. 18
# Canadian Crime Data
Annual administrative data from the Canadian Homicide Survey and the Canadian Uniform Crime Reporting Survey (UCRS) provide compelling insights about the extent of IPV reported to Canadian police services. Generally speaking, police-reported IPV is much lower than self-reported IPV. In 2016, 79 per cent of IPV cases reported to police; women are the identified victims, and the majority of individuals charged in these cases are men (80 per cent). 19 Although majority of police-reported IPV (82 per cent) involves opposite-sex partnerships where females are victims and males are the perpetrators, approximately 55 per cent of police-reported same-sex IPV involves male partnerships. 20 In addition, violence within current or former spousal or dating relationships was the most common form of violence reported to police by females in 2017, with women and girls accounting for nearly 8 in 10 reports of IPV that year. With respect to youth, in 2010, approximately one per cent of policedreported cases of dating victimization involved youth aged 12 to 14 years; approximately 93 per cent of these victimization reports were made by females, and 52 per cent of the reports involved sexual assault. 21 In 2017, 15,535 females aged 15 to 24 years reported dating victimization to Canadian police services: 19 per cent and 11 per cent of these reports were in reference to a current versus a former dating partner, respectively. 22 Notably, these gender-specific findings have remained consistent across iterations of the UCRS. 19 Threats, name calling, limiting contact with family or friends were reported by eight per cent of women and six per cent of men. 6 It is important to note that many incidents of IPV are not reported to police out of shame, embarrassment, denial, fear of not being believed, fear of rejection or retaliation, or believing the abuse to be their fault. Risk factors for dating violence include past abuse, beliefs and attitudes, lower relationship skills, drinking and drug use, peer influences and pornography. 23 Bilateral (i.e., Common Couple) Violence
Historically, there has been the stereotype of the abusive male who uses severe and unilateral violence against a nonviolent female victim. It is now recognized that bilateral violence is more common than previously recognized, although women experience the overwhelming burden of morbidity and mortality associated with violence in intimate relationships. 24 Bilateral violence, otherwise referred to as common couple violence, is considered less serious than the pattern of violence known as battering or intimate terrorismwhich is a severe and often escalating form of IPV characterized by threats and multiple forms of violence and controlling behaviour by the abusive partner. Research suggests that women are most often subjected to battering by male perpetrators. 24 Canadian women are more likely than men IPV victims to experience sexual offences (88 per cent), criminal harassment (76 per cent) and indecent and harassing communications (72 per cent). 6 In the 2014 GSS, stalking (one form of criminal harassment) was self-reported by six per cent of Canadians; 21 per cent of these reports involved a current or former intimate partner. Among those who reported stalking, women were the disproportionate victims. Compared to men, women's exposure to stalking is more likely to occur in parallel with exposure to violence after a spousal relationship had ended. Threats or intimidation, repeated obscene or silent phone calls were common, but the greatest increase in reported IPV behaviour between 2004 and 2014 was in unwanted emails, texts or social media messages. 6,11 These ongoing forms of IPV continue to have significant health and economic impacts on women. [25][26][27][28][29][30] The 2018 report on Gender-Based Violence and Unwanted Sexual Behaviour in Canada, although not focused on intimate partner relationships, reported that 32 per cent of women and 13 per cent of men experienced unwanted sexual behaviour in public including unwanted sexual attention, physical contact or comments about their sex or gender. 31 Despite more severe exposure and impacts for women, physical abuse, as well as psychological abuse, is also experienced by men. However, the context in which these acts occur has not been assessed, and evidence indicates that within heterosexual relationships, both sexes are sometimes perpetrators. Men have reported bruises, abrasions, genital injuries, minor head trauma, lacerations and internal injuries, as well as that their exposure to IPV leaves them feeling emasculated, marginalized, shamed and embarrassed. According to male victims, their reports of abuse are often met with skepticism or disbelief by medical and legal professionals, as well as friends and neighbours. 32 This disbelief was most marked for sexual IPV, as many people were unaware that erection and ejaculation could sometimes be caused by fear, anger or pain and not only by consensual sexual arousal. 33
# Special Populations and Situations
Cultural factors. Deep-seated values about the relative priority of one's own goals and autonomy (individualism) and those of the society (collectivism) to which one belongs are thought to be related to IPV rates. Collectivist cultures that are also patriarchal have rigid gender roles, subscribe to men's control of women's behaviour, link masculinity to dominance, control, honour and aggression and are suggested to condone the use of violence as a way of resolving conflict in intimate relationships. [34][35][36][37] Similarly, qualitative research with women residing in communities with collectivist cultures report being urged to endure rather than reject IPV, as a way of preserving cultural values, the family and honour. A recent meta-analysis examining cultural or structural factors in the risk for IPV reports emerging longitudinal, quantitative evidence supporting these claims. 5,38 New immigrants. Migrant populations in Canadawhich include immigrants and refugees-face the same types of IPV as their non-migrant peers, but additional challenges related to their migration status-including a fear of deportation, loss of refugee status, social isolation, threats of forced marriage, inability to speak either of the official languages, economic exclusion or collectivist or religious values that support and privilege men's power and keeping the family together or not disclosing "private matters"-may prevent these individuals from reporting their abuse exposure in surveys or to the police. While community-based studies of IPV involving immigrants from certain countries indicate high rates of abuse, the extent to which these rates differ from non-migrants is inconclusive. 39 Methods, measurement issues, access and acceptance of some types of IPV among immigrant/ refugee groups make prevalence comparison difficult. 40,41 Indigenous peoples. First Nations, Metis and Inuit (collectively referred to as "Indigenous") people account for 4.9 per cent of the total Canadian population. 42 Evidence from the 2014 GSS as well as national crime data indicate that Indigenous individuals are more than twice as likely as their non-Indigenous counterparts to report exposure to physical IPV in the last five years (nine per cent vs. four per cent). In addition, Indigenous women were three times more likely to report IPV compared to non-Indigenous women (10 per cent vs. three per cent), but no difference was found between Indigenous and non-Indigenous men. Indigenous people who experience IPV are also more likely than non-Indigenous people to suffer the most serious forms of IPV, such as being beaten, choked, threatened with a weapon or sexually assaulted (52 per cent vs. 23 per cent). Indigenous people are also more likely to report childhood exposure to abuse or neglect by an adult caregiver (40 per cent), a factor known to be associated with later spousal abuse. Indigenous individuals were also more likely as a child to have been exposed to IPV committed by a parent, step-parent or guardian. 11,42 A seminal eight-wave longitudinal study including data from youth aged 15 to 19 years who were living on one of the seven reservations/reserves located in the United States and Canada reported that 31 per cent of youth had already experienced physical IPV in their lifetime. 43 The dynamics of IPV and dating violence in Indigenous communities has been linked to colonization, structural violence, poverty, racism, discrimination, residential schools, foster care, alcohol and substance use disorders, and loss of traditional ways and culture. 44 Psychiatric patients. Higher rates of IPV have been found among women in out-and in-patient psychiatric services in several countries. 14,[45][46][47] A systematic review and meta-analysis of 41 studies found increased odds ratios of lifetime IPV in women with depressive disorders (2.77), anxiety disorders (4.08) and PTSD (7.34), compared with women without mental disorders. Individual studies reported increased odds ratios for both women and men for all psychiatric diagnostic categories, including psychoses, with a higher prevalence reported for women. Few longitudinal studies were found; thus, the direction of causality could not be determined. 14 Gender and sexual minorities. There has been a longstanding lack of data on Canadian IPV prevalence among lesbian, gay, bisexual, transgender, queer, questioning, intersex and two-spirited (LGBTQQI2S) individuals. While some of these gaps are beginning to be addressed, many remain. In 2016, Statistics Canada reported that about one per cent of all legally married and common-law couples in Canada had same-sex spouses, similar to data in the United Kingdom and Australia. 11 Individuals who selfreported as lesbian, gay or bisexual were twice as likely to report spousal violence as heterosexual couples (eight per cent vs. four per cent). In dating relationships, the double prevalence of IPV in same-sex partners compared to heterosexual partners has remained stable for the last five years (18 per cent vs. nine per cent), with an even higher prevalence among lesbian/bisexual women compared to male counterparts (23 per cent vs. 11 per cent).
Police-reported violence among same-sex intimate partners in Canada between 2009 and 2017 revealed that these incidents represented three per cent of all reported incidents of IPV. 20 Over 55 per cent of police-reported same-sex IPV involved male partners. Major assault and use of a weapon were also more common among men (18 per cent compared to 12 per cent in women). Homicides involving same-sex partners represented five per cent of all IPV homicides over this time period. Rural victims of same-sex IPV (35 per cent of all same-sex IPV cases) were more likely to request that no further action be taken against the accused. Gender stereotypes about violence and mutual violence as well as social stigma may be factors in these decisions. 20 Some unique risk factors, such as the threat of outing, disclosure of human immunodeficiency virus (HIV) status, social stigma and the lack of emergency shelters for sexual minority victims, have been identified. 48 A Canadian survey on IPV of 7,918 respondents in the workplace found that 8.5 per cent reported gender/sexual minority status. 49 Gender/sexual minority participants were significantly more likely to report IPV and that it continued at or near their workplace, negatively impacted their work performance and their co-workers. They also reported poorer mental health and quality of life. Some labour unions and provincial governments have supported paid domestic violence leave policies. A U.S. study found 51.8 per cent of transgender individuals reported lifetime IPV compared to 34.2 per cent of cisgender individuals.
LGBTQQI2S people generally experience higher rates of all forms of IPV. 50,51 People living with disabilities. People living with disabilities are not a homogeneous group; Statistics Canada recognizes four categories of disability (sensory, physical, cognitive and mental health), all of which may vary in severity and interact with numerous other sociodemographic characteristics to impact an individual's risk for exposure to IPV. 52 Compared to men, women have a higher reported prevalence of disability that limits their daily activities (14.9 per cent vs. 12.5 per cent) and approximately 23 per cent of women and 22 per cent of men who live with a disability report IPV exposure in the last five years (a rate much higher than those living without a disability). Of those who experienced spousal abuse, 39 per cent of women living with a disability report the most severe forms of abuse compared to men (16 per cent). Unique experiences of people living with a disability related to IPV include the abusive partner restricting the individual's access to mobility aids, medication or medical technologies. Data from Statistics Canada indicate that emotional or financial abuse by a partner is reported by 22 per cent of women and 21 per cent of men living with disabilities. Women living with a cognitive disability reported some form of IPV exposure more often than their male counterparts (43 per cent vs. 27 per cent), and this was most evident for physical or sexual assault (16 per cent vs. 9 per cent), respectively. 52 Perinatal period. IPV may begin, escalate or decrease during pregnancy or the postpartum year. Canadian studies report IPV rates between six per cent and 10.5 per cent during pregnancy. Risk factors for perinatal IPV exposure include prior abuse, age under 20 years, low income, single status, stressful life events, depression, substance and alcohol use. 53,54 IPV exposure was four times more likely to be reported by women if the pregnancy was unplanned or unwanted. 55 IPV exposure during pregnancy is associated with adverse neonatal and maternal health, including maternal depression. 56 Of particular note, evidence indicates that IPV exposure among women tends to increase after the baby is born. 57 Alcohol use by IPV perpetrators and victims. Alcohol use increases the occurrence and the severity of IPV. [58][59][60] It directly affects cognitive and physical function, reduces self-control and leaves people less capable of negotiating a nonviolent resolution to conflicts within relationships. 61 Excessive drinking by one partner can exacerbate stress related to financial difficulties, childcare problems, infidelity 62 or other family stressors, creating relationship tensions and conflicts and increasing the risk of IPV. 63 Alcohol use may also reduce the abused partner's ability to perceive, resist or escape from IPV. Experiencing IPV can lead to alcohol consumption as a method of coping or self-medicating. 64 However, individual and societal beliefs that alcohol causes aggression can encourage violent behaviour after drinking, and alcohol may be used as an excuse for violent behaviour. 65 It is likely that other types of substance use also lead to higher prevalence rates of IPV, but reliable data are lacking.
Poverty. Although IPV can and does occur across all socioeconomic groups, it occurs most often among people living in poverty. 66,67 This may partly reflect the greater power, higher education and more options available to escape violent relationships among higherincome people, as well as the general life stress caused by insufficient financial resources.
Senior age. Better data are now available for Canadians who are 65 years of age or over and who experience IPV, including neglect, physical, sexual, emotional and financial abuse. 68 It is estimated that only 20 per cent of incidents among this age group are reported to police due to language, culture, health, transportation and technology barriers. Police reports of violence against seniors reveal that victimization by a spouse was the most common type of abuse (33 per cent) for women, while victimization by a child was the most common abuse reported by men (34 per cent). 68 Family-related homicides against seniors have risen, with a spouse being the perpetrator for 50 per cent of women victims and eight per cent of men victims. 68 Abusers may be socially isolated, stressed or suffer from a mental illness or substance use disorder. Dementias or other brain dysfunction may be major factors, as cognitive dysfunction along with sensory impairment may lead to deterioration in reality testing and paranoid ideation. Frontal lobe disturbances may result in a lack of normal inhibition, with little apparent remorse or insight after IPV. It is important to remember that older people can be aggressive, violent or dangerous. However, IPV perpetrated in old age is often regarded less seriously. In addition, more sympathy tends to be extended to the perpetrators because of their perceived physical frailty or infirmity, which complicates the ability to estimate the true prevalence and consequences of IPV in older individuals. 69
# Risk Indicators
Many Canadian studies, including national, populationbased surveys, have shown a fairly consistent pattern in demographic, relationship-and partner-specific indicators for exposure to IPV, including a young partner, being in a common-law (rather than legally married) relationship or separated; being in a relationship with an un-or underemployed partner, low economic status, high stress and abuse of alcohol or other substances. 5 International studies have identified personality disorders, psychosis, depression, marital conflict and poor family functioning as factors associated with a man's risk for abusing his partner. 5 Marked jealousy, hostiledependency, low self-esteem, low assertiveness, emotional inexpressiveness, and social and sexual inadequacy have also all been described in perpetrators of IPV. 69 For male victims, younger men were four to five times at greater risk of IPV than men over 45 years in age. Ecologic risk factors for IPV include individual, partner, family and community/social factors. 5 Although IPV can occur in any intimate relationship, individual factors for victimization include (among others) past exposure to IPV (intergenerational cycle of abuse), exposure to child maltreatment, poverty, disability, Indigenous identity, gender/sexual minority status, substance use and unemployment. Perpetration factors at the individual level include substance use, need for over control, exposure to child maltreatment, exposure to IPV, negative attitudes toward women, unemployment, lower education and other partners. Family factors include male dominance, marital conflict, violence as a way of resolving disputes and poverty. There are numerous community and social factors; examples include gender inequality, cultural acceptance of IPV, lack of community cohesion, restricted access to divorce, property ownership, or inheritance, media portrayal of IPV, patriarchal laws or religious values and lack of policies or legal safeguards against IPV. Protective factors identified in some studies include gender equality, monitoring and enforcement of effective policies against IPV, services for victims, safe environments, formal marriage and higher social economic status and education. 5,38 Health Impacts
# Mental Health Impact
IPV is consistently associated with high rates of depression, anxiety disorders (especially phobias and panic disorder), PTSD, alcohol and other substance abuse, sleep disorders, psychosomatic disorders, and suicidal behaviour and self-harm after exposure to IPV. 5,12,70,71 Depression and PTSD are the most prevalent mental health disorders associated with IPV, with considerable comorbidity of the two disorders. 72 In a meta-analysis of studies of women exposed to IPV, the mean prevalence of depression was estimated at 47.6 per cent, and PTSD at 63.8 per cent (3.5 and 5.0 times the general female population rates, respectively). 73 Loss, feelings of shame and guilt, humiliation, entrapment and lack of control contribute to the development of poor self-esteem and depression. 74,75 Other studies have also identified increased rates of eating disorders, antisocial and borderline personality disorders and non-affective psychosis in women exposed to IPV. 12,15,73,[76][77][78][79] IPV is also associated with health risk behaviours including alcohol and drug abuse, sexual risk behaviours and smoking. 5 Because evidence is mounting that depression and PTSD are pathways by which abuse affects physical health, 27,80,81 addressing mental health effects may also be important for preventing physical health problems such as chronic pain or cardiac disease. It has also been found that when violence decreases or is eliminated, physical and mental health both improve. 82
# Physical Health Impact
According to the Statistics Canada 2017 Homicide Survey, women account for approximately eight in 10 victims of intimate partner homicide, with the rate of intimate partner homicide five times greater for females compared to males. 22 This maps onto previous estimates. Specifically, between 2003 and 2013, police services reported 960 domestic homicides in Canada; 78 per cent of victims were women. In homicides between spouses six in 10 (60 per cent) between 2008 and 2018 were preceded by a known history of family violence. 83 Homicide rates for men and women are substantially lower than the early 1990s, which can be partly attributed to rising divorce rates and more equitable male-female employment rates, thereby offering women more options. Laws, law enforcement, shelters and advocacy may also contribute to declining spousal homicides. In the 1990s, men were more likely than women to commit suicide following domestic homicide. In addition, women were more likely to kill their partner if violence was prolonged or they feared for themselves or their children. Men were more likely to kill their partner from rage or despair over actual or impeding estrangement. 84 A range of acute injuries including bruises, factures, lacerations, bites, dental injuries, burns and other injuries may follow IPV. A recent systematic review found that certain injury patterns can differentiate people exposed to IPV, compared with other kinds of injurious events. Specifically, head, neck, dental or facial injuries that were not witnessed (i.e., as would likely occur with a motor vehicle injury) are indicators. In addition, multiple injuries are associated with IPV exposure, whereas thoracic or abdominal extremity injuries alone, tend to not differentiate between abused and non-abused women. 76,85 IPV has been linked to many other physical health outcomes including those related to chronic conditions and infectious diseases. An international systematic review and meta-analysis by the World Health Organization and other studies have found IPV to be associated with, in addition to the injuries above, chronic pain syndromes, fibromyalgia, gastrointestinal disorders, including irritable bowel syndrome, sleep disorders, physical inactivity, disability and general reductions in physical functioning and (or) health-related quality of life. 5,12,76,86 IPV is also associated with gynecological disorders, infertility, pelvic inflammatory disease, pregnancy complications and (or) miscarriage, sexual/ reproductive dysfunction, unsafe sexual behaviour, sexually transmitted diseases (including HIV/AIDS), as well as unsafe or forced abortion and unwanted pregnancy. 5,12,76 In addition to maternal health, IPV during pregnancy can threaten the health of the fetus. Abuse directed to the abdomen can result in poor pregnancy outcomes, preterm birth and perinatal death. 12,76,[87][88][89][90] Children's Exposure to IPV Exposure of a child to any psychological, physical, sexual, financial or emotional abuse between adults who are, or have been, intimate partners or family members is considered a form of child maltreatment in many jurisdictions within Canada 2,91 and may have short-or long-term mental and physical health impacts. Adverse outcomes include an increased risk of physical, psychological, social, emotional and behavioural problems, including mood and anxiety disorders, and substance use disorders and school-related problems in children and adolescents. 2, [91][92][93][94][95] These negative effects may continue into adulthood and become part of an intergenerational cycle of violence. 91,95,96 Children who are exposed to IPV in the home are more likely to maltreat their own children 96,97 and are more likely to have violent dating and intimate relationships as adults (either as victims or perpetrators). [98][99][100][101] Children exposed to IPV are at increased risk of experiencing other forms of abuse by caregivers (e.g., physical and sexual abuse). 102,103 Identification, Assessment and Documentation
# Victims of IPV
There is no evidence for universal screening for IPV, based on three randomized controlled trials (RCTs), conducted in Canada, 104 New Zealand 105 and the United States. 106,107 Across these trials, IPV screening did not reduce IPV or improve health outcomes, 106 a fact highlighted in most major evidence-based systematic reviews [108][109][110] though not necessarily reflected in some specific practice guidelines. 111,112 The discrepancy can contribute to confusion among policy makers and health professionals. While screening is not recommended, it is especially important for mental health clinicians to be alert to the signs and symptoms of IPV exposure and to practice case finding for IPV in the assessment of patients who present with a wide range of psychological signs or symptoms as discussed above. Consequently, inquiring about current and past IPV victimization or perpetration should be part of the clinical assessment of all patients, both men and women, in mental health, addiction and perinatal care settings. Such inquiry is referred to as case finding because it involves including questions about exposure to and perpetration of violence within the diagnostic assessment; it does not involve screening-the use of standardized questions administered in the same way to all patients. 2 Being aware of a history of IPV is necessary to inform diagnostic formulation and treatment approaches; without this information, a key contributing factor to the onset and persistence of mental illness, as well as any opportunity for interventions, may be missed. 69 Many IPV victims seeking health care present with vague signs and symptoms or chronic somatic complaints, including chronic pain, rather than signs of obvious physical, sexual or emotional trauma. Other behaviours that may suggest IPV exposure or perpetration are delays in seeking care or multiple missed appointments. 113 Lack of knowledge about or interest in IPV, time constraints, fear of retribution or of legal involvement are not acceptable reasons for mental health professionals to avoid inquiring about IPV. It should be noted that some individuals and organizations prefer the term "survivor" of IPV and the preferred term should be used if it is known. A private, safe, supportive, confidential environment is essential to conduct a full diagnostic assessment that includes inquiry about IPV. There are many barriers to patients disclosing IPV, including the fear of potential retaliation from the abusive partner, family or community censure, embarrassment, shame, economic dependency, or apprehension about child custody, immigration status or the legal system. It is important to ask about exposure to IPV privately (with no one else present including the partner or a child beyond infancy); if the inquiry and (or) response is overheard, it could put the patient at risk for further IPV. 2 Special arrangements may be needed for immigrants or refugees whose primary language is not English or for whom a request to speak privately from other family members or partners may be perceived as an unusual or culturally insensitive request. The patient should be seen alone or by a same-sex interviewer if culturally indicated, and family and friends should not be involved as translators. Cultural competence should allow a person to not only reject violence but also maintain their cultural identity. Patients may also lack knowledge that IPV is a crime in Canada or that support services exist. Some patients may not see IPV or what happens within their intimate relationship or partner-conflict as a health issue that is appropriate to disclose to a healthcare provider.
It may be helpful to preface direct questions about IPV by asking about the patient's relationships more generally. An introduction such as "How are things at home?" or "How do you and your partner get along?" could be used. Possible follow-up questions to ask include the following, when appropriate: How does your partner respond when there is disagreement in the family? With these arguments, do you ever feel frightened by them? Sometimes partners or ex-partners use physical force. Is this happening to you?
Have you felt humiliated or emotionally harmed by your partner or ex-partner? Do you feel safe in your current or previous relationships?
Have you ever been physically threatened or hurt by your partner or ex-partner?
Have you been forced to have any kind of sexual activity by your partner or ex-partner?
When IPV is first disclosed by an abused partner, the initial clinical response should include validation of the experience (e.g., "Violence is, unfortunately, a common problem in our society" [or, "in many families"]); affirmation that violence is unacceptable (e.g., "Everyone deserves to feel safe at home"); and expression of support (e.g., "There are things we can discuss that can help"). It is crucial that insensitive (e.g., "Why don't you just leave?") or critical remarks ("Well, did you do something to make them angry? Just don't do that.") are not made by mental health professionals as these may reinforce existing feelings of helplessness, inadequacy or selfblame in victims. 69 The clinician needs to acknowledge the complexity of IPV and respect the patient's individual concerns and decisions. All discussions in which IPV is disclosed must include an inquiry about current safety. If the patient denies IPV, but injuries, signs or symptoms suggest that it may be occurring, inquiries should be repeated at later visits when an atmosphere of greater trust may facilitate further discussion. 2 IPV among adults is not reportable to the police unless a practitioner is concerned about a serious imminent risk to the patient or someone else. Although the decision to involve legal authorities usually belongs to the abused patient alone, a disclosure that indicates that a child is also being abused, or at risk of harm related to IPV exposure among caregivers, requires mandatory reporting to provincial or territorial child protection services (CPS). The legislation varies somewhat across provinces and territories; thus, it is important to understand the specific legislation in one's region of practice. Given the limits of confidentiality, owing to mandatory reporting to CPS, it is important that patients be advised about these limits to confidentiality before any inquiry about IPV exposure. 2 A practitioner's workplace (including hospitals) may have specific guidance about inquiring about or acting on disclosures of IPV as part of workplace safety, and psychiatrists should be familiar with their workplace requirements.
Decisions to leave an abusive relationship may require time and may follow six stages of change outlined by Prochaska (i.e., precontemplation, contemplation, preparation, action, maintenance and termination). 114,115 Women planning to leave a relationship involving IPV should be cautioned that the risk of more serious violence (at times, even homicide) is increased during and following leaving the partner. 11 Safety should be a consideration whenever a person discloses IPV, and simple questions can be useful, such as "Do you feel safe to return home today?" "Do you have a safety plan?" and "Does your partner have a weapon?" Assessment. Following disclosure of IPV, the abused patient should receive a full psychiatric assessment to ascertain any mood, anxiety, personality, psychotic, substance use disorder or organic brain syndrome that may predate or follow IPV. Psychological sequelae of IPV should be noted and the patient reassured that these are common and may spontaneously resolve or can be treated.
In general, studies exploring women's preferred responses after disclosing IPV suggest that women want physicians to ask questions about the abuse, to listen and believe them, express concern, be nonjudgmental and supportive, and to make appropriate referrals to a shelter, and to social and legal services. 116 Women do not want to be pressured to disclose IPV (or to leave their partner); they prefer to be asked about it in a way that is confident and comfortable, with assurance of confidentiality (with the potential exceptions regarding child welfare, outlined above). It is important to state to the patient that all people have a right to live without abuse.
# Perpetrators of IPV
Perpetrators of IPV may present with personality disorders, substance use disorders, depression, fear of losing control, obsessional jealousy, paranoid ideas, psychosis or brain dysfunction. Questions that may uncover IPV, such as "What happens when you lose your temper?" or "Have you ever become violent or threatened someone?" or "Has this person ever been your partner?" can initiate the inquiry about IPV perpetration. More specific questions about the types of abuse being perpetrated should follow. A Canadian study found that male and female psychiatric patient perpetrators of IPV fell into one of the following groupings: generally violent and antisocial; borderline and dysphoric; or low psychopathology. 117 Personality disorders were most common. Disclosures by perpetrators should not be dismissed, minimized, met with indifference or dealt with in a way that seems to collude with the perpetrator's justification of the use of violence. 69 The assessment of the abusive partner should ideally be conducted by a professional who is not treating the victim to avoid a conflict of interest and/or an accidental or inadvertent disclosure of confidential information that may place the victim at greater risk. Collateral information about the abuser from other individuals in their life (e.g., other providers, family members independent from the abuser) should be sought to increase accuracy. A structured clinical evaluation should include any acute or chronic psychiatric disorders or personality disorders, the pattern, frequency, severity of abuse, any criminal convictions, as well as their insight and judgment about their behaviour. Various tools can serve as memory aids in the assessment of risk of IPV recurrence including the Spousal Assault Risk Assessment Guide, 118 based on the 20-item Historical, Clinical and Risk management tool. 119
# Documentation
Careful, accurate documentation in the medical chart for victims or perpetrators is vital for monitoring, diagnosis, formulation and treatment planning. It may also be needed for legal proceedings. 120 The reported history and chronology of IPV and its relation to perpetrator or victim psychiatric symptoms, and its effects on a victim, should be recorded. It is important to differentiate facts from opinions. 69 Factual information, such as documenting visible injuries in a victim (a body diagram or photograph may be useful), a personal description of the IPV and its context by the patient in quotation marks, and noting the patient's mental status, is useful. Patient records (as always) should only be released by written patient consent or by subpoena (unless reporting to child welfare authorities is mandated).
# Management, Treatment and Prognosis
# Victims of IPV
Following a full psychiatric assessment of an adult exposed to IPV, treatment for any specific symptoms or conditions should be in accordance with national practice guidelines delivered by professionals with a good understanding of IPV and its consequences. 2 Treatment approaches will depend on the psychiatric diagnosis and be informed by issues specific to the patient, the relationship, the trajectory of abuse, the patient's readiness for change, culture and the IPV characteristics.
Advocacy interventions for people exposed to IPV aim to empower victims and link them to community resources such as shelters, housing, safety planning advice, informal counselling and legal services. A systematic review of all controlled studies of IPV advocacy interventions, including some in healthcare settings, found a reduction in abuse, increased social support, improved quality of life, increased safety behaviours and use of community resources. 108,121 Shelters provide safety for women at moderate risk of IPV and their children. 2 In a systematic review of controlled studies of psychological interventions for IPV, victims reported improvements in psychological outcomes, including depression, PTSD and self-esteem, with a wide range of psychological interventions, including individual or group cognitive trauma therapy. 122,123 For victims of IPV and living with related PTSD, there appear to be a number of possible interventions. Specifically, a systematic review update by the Agency for Healthcare Research and Quality on psychological and pharmacological treatments found high strength of efficacy (SOE) for cognitive behaviour therapy, exposure and CBT-mixed treatments and moderate SOE for cognitive processing therapy, cognitive therapy, eye movement desensitization and reprocessing therapy and narrative exposure therapy to improve symptoms related to PTSD. Among pharmacotherapies, moderate SOE was found for fluoxetine, paroxetine and venlafaxine and low SOE for sertraline, olanzapine, risperidone, topiramate and prazosin. 123 Although no studies were found that identified resilience as the primary outcome, components of resilience, such as self-esteem, self-efficacy and improved quality of life, were assessed among some of the intervention studies included in the review. 124 Importantly, most studies included in the systematic review were conducted with women who were no longer in abusive relationships; their relevance for male victims of IPV and with PTSD or in people with PTSD symptoms and who are still experiencing abuse is unknown. 113 Couples' interventions may take various forms including multi-couple or individual couple sessions which may offer separate sessions for the victim and abuser. In general, couple-based interventions are thought to pose safety risks to the victim and effectiveness is uncertain. Thus, couples' therapy is not recommended, especially for those experiencing intimate partner terrorism (VEGA Systematic Review). The evidence for working with the whole family is inconclusive. 2 Studies of children exposed to IPV have shown positive outcomes for specific interventions, such as child-parent psychotherapy, 125,126 teaching child management skills combined with providing support to mothers, 127 advocacy for mothers and their children, combined with a support and education group for children, 128 and trauma-focused cognitive-behavioural therapy, involving individual sessions for mothers and children as well as joint sessions. 129 These interventions, focused on the motherchild dyad, have been shown to improve behaviour problems [125][126][127] and (or) PTSD symptoms in children, 125,126,129 as well as children's competence and self-worth. 128 They are promising in their level of evidence but require replication.
The prognosis for victims of IPV is uncertain, as intervention studies usually have small samples, short follow-up and high attrition. Cohort studies of the natural history of IPV are rare. There are numerous descriptive reports of women successfully leaving abusive partners and establishing healthy relationships with subsequent partners. However, one follow-up study of women who received an advocacy-based intervention after leaving a shelter found that 44 per cent had been assaulted by their original or a new partner 3.5 years after leaving the shelter. In addition, despite significantly lower recurrence rates in the intervention group at two-year follow-up, this difference was not sustained at the three-year follow-up period. However, importantly, there was a significant improvement in quality of life and social support among women who participated in the advocacy-based intervention, compared with those who did not. 130 We were unable to find prognostic data about men or members of special population groups who were abused.
# Perpetrators of IPV
Various programs have been developed for abusive partners, some of which are voluntary and others courtmandated. Nearly all of these are for men abusers, and adherence is often low. The evidence of effectiveness is mixed, 131 although motivational interviewing may be promising and requires further research. No studies were found for women perpetrators or perpetrators identifying as gender/sexual minorities. Thus, the focus of intervention, in addition to treating any mental illness that may be present, is to encourage the abuser to take responsibility for IPV perpetration, to recognize internal and external triggers for IPV and to understand and take responsibility for the consequences of their perpetration. Specific behavioural strategies that can reduce the risk of violence perpetration, offering advice on reducing alcohol or drug intake, as well as referral to appropriate perpetrator services may be helpful for specific people. 69 There is some evidence to suggest that permanent (not temporary) civil protection orders for men abusers may reduce future IPV. 132
# Prevention
Primary prevention of IPV consists of educational programs that focus on respectful relationships, conflict resolution strategies, changes in attitudes, and knowledge. However, a Cochrane systematic review of interventions to prevent relationship and dating violence in adolescents and young people found no convincing evidence that these programs decrease relationship/dating violence, attitudes, behaviours or skills. The only positive effect noted in the review related to improving knowledge about relationship violence. 133 Although scientific evidence is lacking, many authorities recommend intersectoral collaboration between health, social, education and legal services, as well as between health specialties and disciplines to advocate for IPV prevention and policy. 134,135 The media can also be helpful in raising public awareness of IPV as a critical mental health determinant and in censuring public statements that sensationalize or normalize IPV as an acceptable or cultural norm. 135 However, it is important to evaluate the effectiveness of such approaches in reducing IPV.
Secondary prevention interventions for IPV have been described for pregnant women, consisting of advocacy and empowerment programs that reduced psychological and minor physical violence and improved pregnancy outcomes. 136,137 One trial of intensive advocacy (12 hours or more) reduced physical abuse after 12 to 24 months in women leaving shelters, but this was not the case for shorter or longer follow-up periods. 130 Other treatment interventions are discussed earlier in this paper.
# Education and Research
Some psychiatric associations (e.g., the World Psychiatric Association 138 and the Royal College of Psychiatrists 69 ) and a few Canadian medical specialty associations in addition to the CPA (e.g., the Society of Obstetricians and Gynaecologists of Canada 87 and the Canadian Orthopaedic Association 139 ) have issued policy statements and educational objectives on the topic of IPV.
Trainees in psychiatry at the undergraduate and postgraduate level, including international medical graduates, and all mental health professionals should receive education about IPV from faculty who are familiar with this issue. Currently, rates of inclusion of IPV content in the Canadian curriculum of medical and allied health professionals, including mental health professionals, are very low. 140 This training should be included in the curriculum and be composed of both a didactic and a clinical component. The didactic component should include the prevalence (including special populations), etiology, health effects (especially mental health), how to inquire about IPV and safety using a case-finding approach, the range of interventions for IPV-related impairment, as well as risk assessment and management of victims and perpetrators of IPV. Continuing professional education programs should also include sessions on IPV. All psychiatrists should become familiar with, and implement, the guidance outlined in this CPA position paper, Recognizing and Responding to Intimate Partner Violence: An Update (informed by the CPA's position paper on cultural competence 141 ).
In terms of research, there is now considerable descriptive information about IPV, especially in women, but it is also important to examine IPV against men perpetrated by women and IPV in special populations. Studies of effective interventions for the prevention and treatment of victims and perpetrators are still in their infancy and there are important knowledge gaps. Specifically, there is a need for rigorously designed studies comparing different psychological interventions, and which focus on people at different stages of the abuse trajectory, as well as studies testing the impact of interventions of differing durations and follow-up periods. Both patient-and system-centred interventions should use standardized or comparable outcome measures.
# Summary
IPV is an under-recognized problem that impacts all genders and which occurs in all countries, cultures and socioeconomic groups.
IPV has an enormous impact on personal health, and economic and social well-being.
IPV may occur in heterosexual and gender/sexual minority relationships and may be perpetrated by individuals identifying with either sex, gender and by non-binary individuals.
Canadian data from 2014 show equal proportions of men and women (four per cent) have been victims of physical IPV in the previous five years.
Women are more likely than men to report severe IPV, to report chronic violence or to be killed. They are also more likely to be criminally harassed or killed after the relationship ends.
Exposure to IPV has deleterious effects on children and other family members. Some populations are at greater risk for IPV. These include Indigenous women, gender/sexual minorities, people with disabilities, those in dating relationships, those with alcohol and other substance use disorders, those with low-income and those who have a previous partner that was abusive.
Mental health problems associated with IPV include depression, anxiety disorders, PTSD, chronic pain syndromes, eating disorders, sleep disorders, psychosomatic disorders, alcohol and other substance use problems, suicidal and self-harm behaviours, psychosis, some personality disorders and harmful health behaviours, such as risk taking and smoking. As IPV is a major determinant of mental health, it is of vital importance to mental health professionals.
Physical health problems associated with IPV include death, a broad range of injuries, reproductive disorders, gastrointestinal disorders, chronic pain syndromes, fibromyalgia, poor physical functioning and lower health-related quality of life. Sexually transmitted diseases, unwanted pregnancies and physical inactivity are also increased.
Children's exposure to IPV may have short-and long-term health impacts on the child, especially mental health effects.
Perpetrators of IPV most frequently have personality disorders, but substance use disorders and other types of mental illness or brain dysfunction may also occur.
# Recommendations for Best Practice
Psychiatrists and other mental health professionals should inquire about IPV victimization and perpetration using a case-finding approach as part of the clinical assessment of all patients. A person does not need to be in a current relationship to be experiencing IPV.
Case-finding in patients with symptoms associated with IPV should be a priority and inquiries made about possible IPV in a private, safe, confidential, empathic setting. These questions may need to be repeated at subsequent sessions when the therapeutic relationship is better established.
Particular attention to case-finding should be given to special populations and situations known to be at higher risk of IPV.
If a patient discloses IPV, inquiries should be made about current safety (risk assessment) and referrals offered to appropriate services for people experiencing violence (e.g., shelters, local resource centres, social and/or legal resources and/or police if indicated).
Safety should be an ongoing concern, especially if the abused partner plans to leave the abusive situation.
Careful documentation of IPV in the patient's chart is essential. It should be released only with patient consent or by subpoena.
CPS must be notified in accordance with provincial or territorial legislation if a child is exposed to IPV or is in danger. Victims of abuse should be informed of this duty to report, and that not all types of disclosures will be strictly confidential.
Mental health professionals should ask about children in the family and determine the need for any children to be referred for assessment of emotional and behavioural problems.
Treatment approaches will depend on the psychiatric diagnosis and national treatment guidelines and be informed by special issues particular to the person, the relationship, the trajectory of abuse, the patient's readiness for change, culture and the IPV characteristics. Mental health professionals should consider referral of patients to advocacy services and the need for specific psychological interventions as outlined above. They should be aware of the moderate strength of evidence for only a few psychotropic medications for treating PTSD following IPV as outlined above.
Psychiatrists should be familiar with the principles of risk assessment and management for perpetrators of IPV. In addition to treating any mental illness or substance use disorder that may be present, the main focus of treatment should be on assisting the perpetrator to take responsibility for IPV and its consequences, to recognize its triggers and to develop behavioural strategies to stop IPV. Avis : L'Association des psychiatres du Canada a comme politique de réviser chaque énoncé de principe, déclaration de politique et guide de pratique clinique tous les cinq ans après la publication ou la dernière révision. Tout document qui a été publié plus de cinq ans auparavant et dans lequel il n'est pas mentionné explicitement qu'il a été révisé ou conservé à titre de document officiel de l'APC, soit révisé ou tel que publié à l'origine, doit être considéré comme un document de référence historique uniquement.
les gens ou les animaux, ainsi que le contrôle contraignant, qui comprend limiter l'accès à l'argent, aux amis ou à la famille, une surveillance excessive ou des menaces de faire du tort à soi ou aux autres. 4,5 Le harcèlement dans la VPI consiste dans une attention répétée non voulue, qui fait que la personne craint pour sa sécurité personnelle ou celle d'une connaissance. 6 Il comporte par exemple surveiller ou suivre des messages électroniques ou téléphoniques répétés, espionner, laisser des cadeaux ou des objets menaçants pour le partenaire ou ex-partenaire, ou endommager la propriété d'un partenaire actuel ou passé. 5 La VPI peut se produire chez tous les genres et le terme « partenaire intime » n'implique pas que les personnes qui sont exposées à cette forme de violence aient des antécédents d'intimité sexuelle ou de relation maritale. 19 Bien que la majorité des VPI rapportées par la police (82%) impliquent des partenaires de sexe opposé où les femmes sont les victimes et les hommes les auteurs, environ 55% des VPI de même sexe rapportées à la police impliquent des partenaires masculins. 20 En outre, la violence avec un conjoint ou un ex-conjoint ou dans le cadre de fréquentations était la forme de violence la plus commune déclarée à la police par les femmes en 2017, les femmes et les filles représentant près de 8 à 10 rapports de VPI cette année-là. En ce qui a trait aux jeunes, en 2010, environ un pour cent des cas de victimisation dans le cadre de fréquentations rapportés par la police impliquaient des adolescents de 12 à 14 ans; quelque 93% de ces rapports de victimisation étaient faits par des femmes et 52% d'entre eux impliquaient une agression sexuelle. 21 En 2017, 15 535 femmes âgées de 15 à 24 ans ont déclaré une victimisation dans le cadre de fréquentations aux services de police canadiens: 19% et 11% de ces rapports référaient à un partenaire actuel plutôt qu'ancien, respectivement. 22 Notablement, ces résultats propres au genre sont demeurés constants dans les cycles de la DUC. 19 Les menaces, les injures, le fait de limiter les contacts avec la famille ou les amis ont été rapportés par 8% des femmes et 6% des hommes. 6 Il est important de noter que de nombreux incidents de VPI ne sont pas déclarés à la police en raison de la honte, de l'embarras, du déni, de la peur de ne pas être cru, de la peur du rejet ou des représailles, ou de se croire responsable de la violence. Les facteurs de risque de la violence dans les fréquentations sont notamment l'abus passé, les croyances et les attitudes, de faibles aptitudes aux relations, la consommation d'alcool et de drogues, les influences des pairs et la pornographie. 23 Violence bilate´rale (c.-a`-d., re´ciproque dans le couple)
Le stéréotype qui a longtemps prévalu voulait que l'homme violent utilise une violence grave et unilatérale à l'endroit d'une victime féminine non violente. Nous savons désormais que la violence bilatérale est plus répandue que ce que nous estimions, mais les femmes subissent le fardeau écrasant de morbidité et de mortalité associé à la violence entre partenaires intimes. 24 32 Cette incrédulité est plus évidente dans le contexte de la violence sexuelle, car peu savent que la peur, la colère ou la douleur peuvent provoquer une érection et l'éjaculation au même titre que l'excitation sexuelle consensuelle. 33 Populations et situations spe´ciales Facteurs culturels. Les valeurs profondément ancrées à propos de la priorité relative des buts et de l'autonomie de la personne (l'individualisme) et de ceux de la société (le collectivisme) à laquelle la personsne appartient sont présumées être liées aux taux de VPI. La culture collectiviste patriarcale a une conception rigide des rôles sexuels, souscrit au principe de l'emprise de l'homme sur la femme, associe masculinité et domination, maîtrise, honneur et agressivité et admet la violence comme moyen de résoudre les conflits dans les relations intimes. [34][35][36][37] De même la recherche qualitative sur les femmes de communautés soumises à la culture collectiviste affirme que celles-ci ne peuvent qu'endurer plutôt que de rejeter la VPI afin de préserver les valeurs culturelles, la famille et l'honneur. Une récente méta-analyse qui examine les facteurs culturels ou structurels du risque de la VPI rapporte des données probantes longitudinales, quantitatives émergentes à l'appui de ces affirmations. 5,38 Nouveaux arrivants. Les populations migrantes au Canada, dont les immigrants et les réfugiés, font face au même type de VPI que leurs pairs non migrants, mais des difficultés additionnelles liées à leur statut de migration, notamment la peur de la déportation, la perte du statut de réfugié, l'isolement social, les menaces de mariage forcé, l'incapacité de parler l'une des langues officielles, l'exclusion économique ou les valeurs collectivistes ou religieuses qui soutiennent et privilégient le pouvoir des hommes et gardent la famille entière et l'empêchent de divulguer « des affaires privées », tout cela peut empêcher ces personnes de déclarer leur exposition à la violence dans des enquêtes ou à la police. Même si des études communautaires sur la VPI comportant des immigrants indiquent des taux élevés de violence, la mesure dans laquelle ces taux diffèrent de ceux des non-migrants n'est pas concluante. 39 Les méthodes, les questions de mesure, l'accès et l'acceptation de certains types de VPI chez les groupes d'immigrants/réfugiés rendent difficile de comparer la prévalence. 40,41 Peuples autochtones. 64 Cependant, la mentalité individuelle ou sociétale voulant que l'alcool soit la cause de l'agression peut encourager le comportement violent après avoir bu et l'alcool peut devenir un prétexte au comportement violent. 65 Il est fort probable que la consommation d'autres substances se traduise par une prévalence accrue de VPI, mais l'absence de données fiables ne permet pas de confirmer cette supposition.
Pauvreté . Bien que la VPI puisse être perpétrée, et se produise de fait, dans tous les groupes socioéconomiques, elle s'installe le plus souvent chez des gens pauvres. 66,67 Cette constatation tient en partie du moins à ce que les personnes jouissant d'une certaine aisance financière ont un certain pouvoir, un niveau d'instruction et un plus grand nombre d'options à leur disposition pour échapper aux relations violentes et à ce que l'insuffisance des ressources financières occasionne un stress accru au quotidien.
Personnes â gé es. De meilleures données sont désormais disponibles pour les Canadiens de 65 ans et plus qui subissent la VPI, notamment la négligence, et l'abus physique, sexuel, émotionnel et financier. 68 On estime que seulement 20% des incidents dans ce groupe d'âge sont rapportés à la police en raison des obstacles de langue, de culture, de santé, de transport et de technologie. Les rapports de police sur la violence contre les personnes âgées révèlent que la victimisation par un conjoint était le type d'abus le plus commun (33%) pour les femmes, alors que la victimisation par un enfant était l'abus le plus commun rapporté par les hommes (34%). 68 Les homicides liés à la famille contre des personnes âgées sont en hausse, le conjoint étant le contrevenant pour 50% des femmes victimes et 8% des hommes victimes. 68 Le partenaire violent peut souffrir d'isolement social, être rongé par le stress, souffrir d'une maladie mentale ou être aux prises avec une toxicomanie. Sans compter que la démence et d'autres troubles neurologiques peuvent être des facteurs majeurs dans cette propension à la violence, alors que l'altération cognitive doublée d'une déficience sensorielle peut conduire à une perte de contact avec la réalité et une pensée paranoïaque. L'atteinte du lobe frontal peut chasser l'inhibition normale et être à l'origine de l'absence apparente de remords et de lucidité de l'auteur des actes de violence. Il importe de se rappeler que la personne âgée peut être agressive, violente, voire dangereuse. Néanmoins, la violence entre partenaires intimes âgés est souvent perçue comme étant moins sérieuse et l'agresseur s'attire plus de sympathie en raison de son apparence de fragilité ou d'incapacité physique, ce qui complique la tâche d'estimer la véritable prévalence et les conséquences de la VPI chez les personnes âgées. 69
# Indicateurs de risque
De nombreuses études canadiennes, dont des enquêtes nationales menées auprès d'un échantillon représentatif de la population générale, et des études de grande envergure dans d'autres milieux font ressortir sensiblement les mêmes caractéristiques démographiques, relationnelles et spécifiques des partenaires à titre d'indicateurs du risque de VPI, dont le jeune âge, l'union de fait par opposition au mariage, la séparation, la relation avec un chômeur ou un partenaire sous-employé, la situation économique précaire, l'alcoolisme ou la toxicomanie. 5 Des études internationales considèrent les troubles de la personnalité, la psychose, la dépression, les difficultés conjugales et le dysfonctionnement familial comme étant des facteurs de risque de violence exercée par le partenaire masculin. 5 On a noté certains traits chez des auteurs de VPI, dont la jalousie maladive, la passivité agressive, la faible estime de soi, l'incapacité à s'affirmer, l'inémotivité, les carences sociales et l'inaptitude sexuelle. 69 Quant aux victimes masculines, l'homme plus jeune est de quatre à cinq fois plus à risque de VPI que l'homme d'âge mûr (plus de 45 ans). Les facteurs de risque écologique de la VPI sont des facteurs individuels, du partenaire, familiaux et communautaires/sociaux. 5 Bien que la VPI puisse se produire dans toute relation intime, les facteurs individuels de la victimisation sont entre autres l'exposition antérieure à la VPI (cycle d'abus intergénérationnel), l'exposition à la maltraitance dans l'enfance, la pauvreté, l'incapacité, l'identité autochtone, le statut de minorité de genre/ sexuelle, l'utilisation de substances et le chômage. Les facteurs de perpétration au niveau individuel comprennent l'utilisation de substances, le besoin de sur-contrôle, l'exposition à la maltraitance dans l'enfance, l'exposition à la VPI, les attitudes négatives à l'endroit des femmes, le chômage, une faible instruction et d'autres partenaires. Les facteurs familiaux sont notamment la domination masculine, le conflit conjugal, la violence comme moyen de résoudre des différends et la pauvreté. Il y a de nombreux facteurs communautaires et sociaux; par exemple, l'inégalité entre les sexes, l'acceptation culturelle de la VPI, le manque de cohésion communautaire, l'accès restreint au divorce, la propriété ou l'héritage des biens, la présentation de la VPI dans les médias, les lois patriarcales ou les valeurs religieuses, et l'absence de politiques ou de protections juridiques contre la VPI. Les facteurs de protection identifiés dans certaines études sont entre autres l'égalité des sexes, la surveillance et l'application de politiques efficaces contre la VPI, les services pour les victimes, des environnements sécuritaires, un mariage officiel, un statut socio-économique plus élevé et une meilleure instruction. 5,38 Répercussions sur la santé
# Re´percussions sur la sante´mentale
La VPI est continuellement associée à des taux élevés de dépression, de troubles anxieux (particulièrement les phobies et les troubles de panique), le TSPT, l'abus d'alcool et d'autres substances, les troubles du sommeil, les troubles psychosomatiques, les comportements suicidaires et actes autodestructeurs subséquents aux épisodes de violence. 5,12,70,71 La dépression et le TSPT ont la prévalence la plus élevée des troubles de santé mentale associés à la VPI, et une comorbidité considérable accompagne ces deux troubles. 72 Une métaanalyse d'études menées auprès de femmes ayant subi la VPI révèle que la prévalence moyenne de dépression est de 47,6% et que celle du trouble de stress posttraumatique est de 63,8%, des taux plus élevés que dans la population féminine en général, d'un facteur de 3,5 pour la première et de 5,0 pour le second. 73 Des sentiments de perte, de honte, de culpabilité, l'humiliation, le sentiment d'être prise au piège et l'impossibilité de maîtriser la situation contribuent à la baisse de l'estime de soi et à l'apparition de la dépression. 74,75 D'autres études ont aussi fait ressortir des taux accrus de troubles alimentaires, de troubles de la personnalité antisociale et limite, et de psychose non affective chez les femmes exposées à la VPI. 12,15,73,[76][77][78][79] La VPI est aussi associée à des comportements risqués pour la santé, dont l'abus de drogues et d'alcool, les comportements à risque sexuel et le tabagisme. 5 Comme les données probantes suggèrent que la dépression et le trouble de stress posttraumatique sont des médiateurs par lesquels la violence affecte la santé physique, 27,80,81 il devient évident que la prise en charge des effets sur la santé mentale permettrait de prévenir des problèmes de santé physique, telles la douleur chronique ou la maladie cardiaque. La recherche établit en outre que lorsque la violence diminue ou cesse, la santé physique et la santé mentale s'améliorent. 82 Re´percussions sur la sante´physique Selon l'Enquête sur les homicides de 2017 de Statistique Canada, les femmes représentent environ 8 victimes sur 10 des homicides de partenaires intimes, le taux de ces derniers étant 5 fois plus grand pour les femmes que pour les hommes. 22 Cela s'accorde aux estimations précédentes. Précisément, entre 2003 et 2013, les services de police ont rapporté 960 homicides domestique au Canada; et 78% des victimes étaient des femmes. Dans 6 homicides aux mains d'un conjoint sur 10 (60 %) qui se sont produits de 2008 à 2018, il y avait des antécédents de violence familiale connus. 83 Les taux d'homicide pour les hommes et les femmes étaient substantiellement plus faibles qu'au début des années 1990, ce qui peut être attribué en partie aux taux de divorce croissants et à des taux d'emploi plus équitables pour hommes et femmes, qui offraient ainsi plus d'options aux femmes. Les lois, le respect des lois, les refuges et la défense des droits peuvent aussi contribuer à la baisse des homicides entre conjoints. À la fin des années 1990, les hommes étaient plus enclins que les femmes à se suicider par suite d'un homicide conjugal. En outre, les femmes étaient plus susceptibles de tuer leur partenaire si la violence se prolongeait ou qu'elles craignaient pour leur vie ou celle de leurs enfants. Les hommes étaient plus susceptibles de tuer leur partenaire par rage ou désespoir à cause d'une séparation réelle ou imminente 84 Une série de blessures graves, dont des ecchymoses, des fractures, des lacérations, des morsures, des dents abîmées, des brûlures et d'autres peuvent être la conséquence de la VPI. Une revue systématique récente a observé que la nature de certaines blessures permet de différencier les personnes exposées à la VPI, comparé à d'autres types de blessures. Plus précisément, les blessures à la tête, au cou, à la mâchoire ou au visage survenues en l'absence de témoins (qui se produiraient par un accident de la route), sont des indicateurs. En outre, les blessures multiples sont associées à l'exposition à la VPI, alors que les blessures thoraciques ou abdominales qui se présentent seules ne permettent pas de différencier entre les femmes victimes de violence ou pas. 76,85 La VPI a bien d'autres répercussions sur la santé physique, notamment sur la santé reproductive, et l'apparition de maladies chroniques et de maladies infectieuses. Selon une revue systématique et une métaanalyse de l'OMS et d'autres études, la VPI peut entraîner, en plus des blessures précédentes, des syndromes de douleur chronique, de la fibromyalgie, des troubles gastro-intestinaux, dont le syndrome du côlon irritable, des troubles du sommeil, l'inactivité physique, l'incapacité et la détérioration générale de l'état fonctionnel ou de la qualité de vie liée à la santé. 5,12,76,86 La VPI est également associée à des troubles gynécologiques, l'infertilité, la maladie inflammatoire pelvienne, des complications durant la grossesse, la fausse couche, la dysfonction sexuelle ou reproductive, les comportements sexuels à risque, les infections transmissibles sexuellement, dont le VIH et le sida, l'avortement non salubre ou forcé et la grossesse non désirée. 5,12,76 Cette forme de violence infligée à la femme durant la grossesse met en péril non seulement la santé maternelle, mais également la santé foetale. Les coups et blessures à l'abdomen peuvent compromettre l'évolution de la grossesse et provoquer une naissance prématurée ou la mort périnatale. 12,76,[87][88][89][90] Exposition des enfants a`la VPI Ê tre témoin d'épisodes de violence psychologique, physique, sexuelle, financière ou affective entre des adultes qui sont des partenaires intimes ou l'ont été ou qui sont des membres de la famille est, pour un enfant, une forme de maltraitance dans bien des endroits au Canada 2,91 qui peut avoir des répercussions à brève ou à longue échéance sur sa santé physique et mentale. L'exposition à la VPI durant l'enfance entraîne un risque accru de problèmes d'ordre physique, psychologique, social, affectif et comportemental, notamment de troubles de l'humeur et de troubles anxieux, de problèmes scolaires et de troubles d'utilisation de substances dans l'enfance et à l'adolescence. 2, [91][92][93][94][95] Les effets négatifs peuvent perdurer à l'âge adulte et donner lieu à un cycle de violence intergénérationnelle. 91,95,96 Les enfants exposés à la VPI à la maison sont plus enclins à maltraiter leurs propres enfants 96,97 et à entretenir des relations amoureuses marquées par la violence à l'âge adulte (qu'ils en soient l'auteur ou la victime). [98][99][100][101] Les enfants exposés à la VPI sont plus vulnérables que les autres enfants à d'autres types de violence exercée par les personnes qui en prennent soin (p. ex., la violence physique ou sexuelle). 102,103 Dépistage, évaluation, documentation 106 un fait souligné dans la plupart des revues systématiques majeures fondées sur des données probantes [108][109][110] mais pas nécessairement reflété dans certaines lignes de conduite spécifiques de la pratique. 111,112 Le clinicien est tenu de prévenir les instances de protection de l'enfance, conformément à la législation de la province ou du territoire où il exerce sa profession, quand il sait qu'un enfant est témoin de VPI ou qu'il est en danger. Il devrait informer les victimes de cette obligation de signaler de tels cas et des limites de la confidentialité dans la divulgation de certains faits.
Le professionnel de la santé mentale devrait s'informer de l'état des enfants de la famille et déterminer s'il y a lieu de les référer à une évaluation de difficultés émotionnelles ou comportementales. Les auteurs remercient Dr Pierre Gagné pour ses suggestions et son aide dans la préparation de la version française de cet énoncé de principe.
# Acknowledgements
| None | None |
bd9bdcbe5b1bda27767024b88c9938885871953c | cma | None | Can patients receive the Covid-19 vaccine if they are taking warfarin?#
- We encourage patients who are receiving warfarin treatment to receive vaccinations, including the Covid-19 vaccine. - There is a small risk of bruising at the vaccination injection site, but we do not expect any serious effects related to being on blood thinning treatment. - We suggest that after the vaccine injection prolonged pressure for 3 to 5 minutes is applied to the injection site to reduce bruising. - There is no need to measure the blood thinning level (INR test) just before receiving a vaccination; you should continue INR testing according to the schedule recommended by your doctor.
Can patients receive the Covid-19 vaccine if they are taking a newer blood thinner, one of apixaban (Eliquis), dabigatran (Pradaxa), edoxaban (Lixiana), or rivaroxaban (Xarelto)?
- We encourage patients who are receiving blood thinning (anticoagulant) treatment to receive vaccinations, including the Covid-19 vaccine. - There is a small risk of bruising at the vaccination injection site, but we do not expect any serious effects related to being on blood thinning treatment. - We suggest that after the vaccine injection prolonged pressure for 3 to 5 minutes is applied to the injection site to reduce bruising.
Can patients receive the Covid-19 vaccine if they are receiving aspirin or a similar drug because of a previous heart attack or stroke?
- We encourage patients who are receiving aspirin or similar drugs like clopidogrel (Plavix) or ticagrelor (Brillinta) to receive vaccinations, including the Covid-19 vaccine. - There is a small risk of bruising at the vaccination injection site, but we do not expect any serious effects related to being on blood thinning treatment. - We suggest that after the vaccine injection prolonged pressure for 3 to 5 minutes is applied to the injection site to reduce bruising.
For additional questions e-mail us at [email protected] | Can patients receive the Covid-19 vaccine if they are taking warfarin?#
• We encourage patients who are receiving warfarin treatment to receive vaccinations, including the Covid-19 vaccine. • There is a small risk of bruising at the vaccination injection site, but we do not expect any serious effects related to being on blood thinning treatment. • We suggest that after the vaccine injection prolonged pressure for 3 to 5 minutes is applied to the injection site to reduce bruising. • There is no need to measure the blood thinning level (INR test) just before receiving a vaccination; you should continue INR testing according to the schedule recommended by your doctor.
Can patients receive the Covid-19 vaccine if they are taking a newer blood thinner, one of apixaban (Eliquis), dabigatran (Pradaxa), edoxaban (Lixiana), or rivaroxaban (Xarelto)?
• We encourage patients who are receiving blood thinning (anticoagulant) treatment to receive vaccinations, including the Covid-19 vaccine. • There is a small risk of bruising at the vaccination injection site, but we do not expect any serious effects related to being on blood thinning treatment. • We suggest that after the vaccine injection prolonged pressure for 3 to 5 minutes is applied to the injection site to reduce bruising.
Can patients receive the Covid-19 vaccine if they are receiving aspirin or a similar drug because of a previous heart attack or stroke?
• We encourage patients who are receiving aspirin or similar drugs like clopidogrel (Plavix) or ticagrelor (Brillinta) to receive vaccinations, including the Covid-19 vaccine. • There is a small risk of bruising at the vaccination injection site, but we do not expect any serious effects related to being on blood thinning treatment. • We suggest that after the vaccine injection prolonged pressure for 3 to 5 minutes is applied to the injection site to reduce bruising.
For additional questions e-mail us at [email protected] | None | None |
e82c89372970c1d3ddde766312351d30ad6b9e1a | cma | None | This document relates to patients with solid tumours. For information on patients with hematological malignancies and those who have undergone hematopoietic stem cell transplant or CAR-T-cell therapy, please refer to the other guidance document for that patient population. For general information, please refer to BCCDC Guidance and information COVID-19 vaccines for providers. Is COVID-19 immunization recommended for people with solid cancers? COVID-19 vaccines should be encouraged for people with solid cancers and are not contraindicated, including those who have had COVID-19 infection. This recommendation is based on the following review: - The National Advisory Committee on Immunization (NACI) recommends that immunosuppressed individuals be offered the vaccine if the benefits of vaccines outweigh the potential risks. 1 - Patients with cancer have an increased risk of death related to COVID-19 infection. - The United Kingdom, the United States, France, and Australia have prioritized patients with cancer for COVID-19 immunizations, highlighting that this population is considered as having an increased COVID-19 risk. Is the COVID-19 vaccine efficacious and safe in patients with solid cancers? There are data to suggest that the currently available COVID-19 vaccines have efficacy in patients with cancer or undergoing therapy for their cancer (cytotoxic chemotherapy, endocrine therapy, targeted therapy, immunotherapy) and/or radiation therapy (external-beam, brachytherapy, or systemic), while there may still be uncertainty as to the timing of immunization in relation to their cancer treatments. As with most vaccines, there may be a blunted immune response in individuals who are immunocompromised due to their disease or treatment. Patients with active cancer or undergoing active cancer treatment seemed to be generally excluded from the COVID-19 vaccine trials. However, in the COMIRNATY (Pfizer-BioNTech) vaccine trial, 3.9% of enrolled participants had a malignancy. 22 There is one study that suggests that a third dose of COVID-19 vaccine in immunocompromised patients can increase COVID-19 Vaccines for People with Solid Cancers#
antibody levels. 23 Small studies on third doses of the mRNA COVID-19 vaccines have shown that immunogenicity (immunity measured in the blood) may increase with a third dose. However, it is unclear how much antibody is needed for protection and/or the role of other immunological responses. 22 The frequency and severity of adverse events following vaccination with an mRNA COVID-19 vaccine in these populations were comparable to that of non-immunosuppressed individuals in these studies and what was reported in clinical trials. Safety data in these populations following vaccination with a viral vector vaccine is not available. 24 Informed consent should include discussion about the possibility that individuals who are immunosuppressed may have a diminished immune response to any of the authorized COVID-19 vaccines. 25 Are there any specific contraindications or exceptions for people with solid cancers?
Individuals who have had a severe allergic reaction to an ingredient of one type of COVID-19 vaccine are still able to receive future doses of the other type of vaccine. 26 BCCDC has a list of the individual components and their purpose in the vaccines. For a complete list of components in the vaccine, consult the vaccine monographs found at: www.bccdc.ca/health-info/diseases-conditions/covid-19/covid-19-vaccine/vaccines-for-covid-19.
People with a history of anaphylaxis without known or obvious cause, and those with suspected hypersensitivity or nonanaphylactic allergy to COVID-19 vaccine components, are advised to consult with an allergist prior to immunization. Healthcare providers with patients with a history of severe allergic reactions should refer to the vaccine monographs to review the complete list of components. If there is a specific concern about a possible allergy to a component of the COVID-19 vaccine being administered, an extended period of observation for 30 minutes post-vaccination may be warranted. Alternatively, the vaccine can be administered in an emergency room setting with an extended observation period. 27 Potential allergens known to cause type I hypersensitivities include polyethylene glycol (PEG) in the mRNA vaccines and polysorbate 80 in the viral vector vaccines:
# Polyethylene glycol (PEG)
Polysorbate 80
- COMIRNATY, COMIRNATY Bivalent 28,29 (Pfizer-BioNTech) 19 - SPIKEVAX, SPIKEVAX Bivalent 30 (Moderna) 20 - VAXZEVRIA (AstraZeneca) 21 - JCOVDEN (Janssen) 31 - NUVAXOVID (Novovax) 32 Health Canada continues to monitor any adverse events following immunization through their post-authorization surveillance process.
Currently, it is recommended that COVID-19 vaccines can be given concomitantly with, or any time before or after any other indicated vaccine including the seasonal influenza vaccine. COVID-19 Vaccines for People with Solid Cancers Updated: April 18, 2023 Are there specific recommendations or considerations for safe and/or most effective administration?
There are no known studies regarding the timing of COVID-19 vaccine in relation to systemic therapy for cancer. The current vaccines reviewed in this clinical guidance are given as two doses (COMIRNATY, COMIRNATY Bivalent , SPIKEVAX, SPIKEVAX Bivalent , VAXZEVRIA ). For the two-dose vaccines, optimal protection assumed after the second dose for the general population. The efficacy and duration of immunity after the first dose of a two-dose vaccine are continuously being evaluated and recommendations are evolving rapidly. The optimal protection and degree of protection, if any, in immunosuppressed individuals are currently unknown. Therefore, patients should be vaccinated following the current advice from the BC Centre for Disease Control.
The general recommendation for patients on cancer therapy is to proceed with COVID-19 immunization, with considerations outlined below in Table 2 and under Special Considerations for Immunotherapy. Patients with cancer who are undergoing chemotherapy or other cancer treatments that affect the immune system will be offered vaccination according to B.C.'s COVID-19 Immunization Plan. In general, it is preferred that patients complete immunization before starting immunosuppressive therapy if possible, ideally with at least 14 days after the second dose of the vaccines. However, there is emerging evidence that significant protection against severe illness and death is obtained even after the first dose of the two-dose vaccines. BCCDC recommends a third dose of vaccine at least 28 days after the second dose for immunocompromised. 37 *However, life-saving or -prolonging therapy should not be delayed solely to complete immunization Any other timing would require case-by-case assessment based on: a. Risk of morbidity related to COVID-19 infection (including local incidence of the pandemic, cancer type, comorbidities that confer higher risk in the general population, etc.) b. Cancer-related morbidity due to delay of active treatment, and c. Suboptimal immunity protection due to insufficient time window between immunization and immunosuppressive therapy.
Recommendations for timing of COVID-19 immunization for patients aged 12 and above with solid malignancies starting or already receiving treatment (outside the setting of bone marrow, hematopoietic stem cell transplant, or CAR-T) are listed in Table 2 below.
# Special considerations for immunotherapy:
The general recommendation for patients on immunotherapy is to proceed with COVID-19 immunization.- a. Rituximab and other anti-CD20 monoclonal antibodies Of note, patients receiving these agents may have a reduced immune response to vaccines in general that can extend up to 6 months following treatment completion. These patients may benefit from a 3rd dose of vaccine as per BCCDC guidance, to be given at least 28 days after the second dose. 37 COVID-19 Vaccines for People with Solid Cancers Updated: April 18, 2023 b. Checkpoint inhibitors Previous studies have not signalled an increased risk of complications of COVID-19 disease for patients on checkpoint inhibitors such as CTLA-4 inhibitors (e.g., ipilimumab), PD-1 inhibitors (e.g., nivolumab, pembrolizumab, cemiplimab) and PD-L1 inhibitors (e.g., atezolizumab, avelumab, durvalumab). There have been theoretical concerns of an enhanced immune reaction to COVID-19 vaccines, particularly with CTLA-4 inhibitors.
- Given the seriousness of COVID-19 infection, COVID-19 immunization is recommended with consideration of both the patient's risk profile and immunotherapy regimen. This follows the general vaccination guidelines for immunocompromised patients :
- First dose of two-dose vaccines (single dose if singledose vaccine) at least 2 weeks before treatment
- For two-dose vaccines, second dose at least two weeks before treatment- *In general, it is preferred that patients complete immunization before starting immunosuppressive therapy if possible, based on the timing of the treatments and the availability of vaccines at the time. However, life-saving or -prolonging therapy should not be delayed solely to complete immunization. Some immunity may be achieved following the first dose of the two-dose vaccines.
For patients who received 2 doses while on or shortly after active treatment, a third dose is advised.
-During cyclical treatment First dose of two-dose vaccines (or single dose if singledose vaccine) in the week before next treatment as this is when counts are likely to be the highest.
For patients who received 2 doses while on or shortly after active treatment, a third dose is advised. This should also be given in the week before the next treatment. At any time during treatment Systemic corticosteroids † Ideally, systemic corticosteroids (at daily doses 20 mg or higher of prednisone or equivalent for 1 month or longer) 36 should be avoided or completed at least 28 days before commencing the first vaccine dose when possible. If it is not possible, immunization should proceed.
For patients who received 2 doses while on or shortly after this treatment, a third dose is advised.
Patients due to start radiation therapy If immunization is pending, and it is possible to delay radiation therapy without compromising outcomes, radiation therapy should be postponed until anticipated immunity is achieved before commencing radiation therapy. Life-saving or prolonging therapy should not be delayed solely to complete immunization.
For patients who received 2 doses while on or shortly after active treatment, a third dose is advised.
Patients on radiation therapy ‡ At any time during treatment while blood counts are near normal range, ideally as early in the course of radiation therapy as possible.
Patients who have completed a course of radiation therapy or during a regimen of cyclical radio-isotope therapy ‡
Radiation therapy can suppress lymphocyte counts for months to years after treatment in a dose-and volumedependent fashion. As it is not known what level of WBC counts would alter vaccine efficacy, there is no specific blood count level to target for vaccine delivery; however, if the radiation therapy regimen § is expected to cause transient myelosuppression for up to eight weeks, immunization should start at least one week after the nadir of myelosuppression.
- Immunosuppressive therapy -including but not limited to cytotoxic chemotherapy, rituximab, obinutuzumab, alemtuzumab † This recommendation does not relate to inhaled, nebulized, intra-articular, intrabursal or topical corticosteroids, which have no bearing on immunization timing. ‡Injection should be given on the opposite side if unilateral radiation treatment is, or was, given to area of injection site § Myelosuppression on radiation therapy regimens varies with dose, fractionation, and patient factors but typically examples of suppressive regimens include hemi-body, total body, total marrow, whole abdominal, craniospinal, or total skin radiation. | This document relates to patients with solid tumours. For information on patients with hematological malignancies and those who have undergone hematopoietic stem cell transplant or CAR-T-cell therapy, please refer to the other guidance document for that patient population. For general information, please refer to BCCDC Guidance and information COVID-19 vaccines for providers. Is COVID-19 immunization recommended for people with solid cancers? COVID-19 vaccines should be encouraged for people with solid cancers and are not contraindicated, including those who have had COVID-19 infection. This recommendation is based on the following review: • The National Advisory Committee on Immunization (NACI) recommends that immunosuppressed individuals be offered the vaccine if the benefits of vaccines outweigh the potential risks. 1 • Patients with cancer have an increased risk of death related to COVID-19 infection. [2][3][4] • The United Kingdom, the United States, France, and Australia have prioritized patients with cancer for COVID-19 immunizations, highlighting that this population is considered as having an increased COVID-19 risk. [4][5][6] Is the COVID-19 vaccine efficacious and safe in patients with solid cancers? There are data to suggest that the currently available COVID-19 vaccines have efficacy in patients with cancer or undergoing therapy for their cancer (cytotoxic chemotherapy, endocrine therapy, targeted therapy, immunotherapy) and/or radiation therapy (external-beam, brachytherapy, or systemic), while there may still be uncertainty as to the timing of immunization in relation to their cancer treatments. [7][8][9][10][11][12][13][14][15][16][17][18] As with most vaccines, there may be a blunted immune response in individuals who are immunocompromised due to their disease or treatment. Patients with active cancer or undergoing active cancer treatment seemed to be generally excluded from the COVID-19 vaccine trials. [19][20][21] However, in the COMIRNATY (Pfizer-BioNTech) vaccine trial, 3.9% of enrolled participants had a malignancy. 22 There is one study that suggests that a third dose of COVID-19 vaccine in immunocompromised patients can increase COVID-19 Vaccines for People with Solid Cancers#
antibody levels. 23 Small studies on third doses of the mRNA COVID-19 vaccines have shown that immunogenicity (immunity measured in the blood) may increase with a third dose. However, it is unclear how much antibody is needed for protection and/or the role of other immunological responses. 22 The frequency and severity of adverse events following vaccination with an mRNA COVID-19 vaccine in these populations were comparable to that of non-immunosuppressed individuals in these studies and what was reported in clinical trials. Safety data in these populations following vaccination with a viral vector vaccine is not available. 24 Informed consent should include discussion about the possibility that individuals who are immunosuppressed may have a diminished immune response to any of the authorized COVID-19 vaccines. 25 Are there any specific contraindications or exceptions for people with solid cancers?
Individuals who have had a severe allergic reaction to an ingredient of one type of COVID-19 vaccine are still able to receive future doses of the other type of vaccine. 26 BCCDC has a list of the individual components and their purpose in the vaccines. For a complete list of components in the vaccine, consult the vaccine monographs found at: www.bccdc.ca/health-info/diseases-conditions/covid-19/covid-19-vaccine/vaccines-for-covid-19.
People with a history of anaphylaxis without known or obvious cause, and those with suspected hypersensitivity or nonanaphylactic allergy to COVID-19 vaccine components, are advised to consult with an allergist prior to immunization. Healthcare providers with patients with a history of severe allergic reactions should refer to the vaccine monographs to review the complete list of components. If there is a specific concern about a possible allergy to a component of the COVID-19 vaccine being administered, an extended period of observation for 30 minutes post-vaccination may be warranted. Alternatively, the vaccine can be administered in an emergency room setting with an extended observation period. 27 Potential allergens known to cause type I hypersensitivities include polyethylene glycol (PEG) in the mRNA vaccines and polysorbate 80 in the viral vector vaccines:
# Polyethylene glycol (PEG)
Polysorbate 80
• COMIRNATY, COMIRNATY Bivalent 28,29 (Pfizer-BioNTech) 19 • SPIKEVAX, SPIKEVAX Bivalent 30 (Moderna) 20 • VAXZEVRIA (AstraZeneca) 21 • JCOVDEN (Janssen) 31 • NUVAXOVID (Novovax) 32 Health Canada continues to monitor any adverse events following immunization through their post-authorization surveillance process.
Currently, it is recommended that COVID-19 vaccines can be given concomitantly with, or any time before or after any other indicated vaccine including the seasonal influenza vaccine. [33][34][35][36] COVID-19 Vaccines for People with Solid Cancers Updated: April 18, 2023 Are there specific recommendations or considerations for safe and/or most effective administration?
There are no known studies regarding the timing of COVID-19 vaccine in relation to systemic therapy for cancer. The current vaccines reviewed in this clinical guidance are given as two doses (COMIRNATY, COMIRNATY Bivalent [Pfizer-BioNTech], SPIKEVAX, SPIKEVAX Bivalent [Moderna], VAXZEVRIA [AstraZeneca]). For the two-dose vaccines, optimal protection assumed after the second dose for the general population. The efficacy and duration of immunity after the first dose of a two-dose vaccine are continuously being evaluated and recommendations are evolving rapidly. The optimal protection and degree of protection, if any, in immunosuppressed individuals are currently unknown. Therefore, patients should be vaccinated following the current advice from the BC Centre for Disease Control.
The general recommendation for patients on cancer therapy is to proceed with COVID-19 immunization, with considerations outlined below in Table 2 and under Special Considerations for Immunotherapy. Patients with cancer who are undergoing chemotherapy or other cancer treatments that affect the immune system will be offered vaccination according to B.C.'s COVID-19 Immunization Plan. In general, it is preferred that patients complete immunization before starting immunosuppressive therapy if possible, ideally with at least 14 days after the second dose of the vaccines. However, there is emerging evidence that significant protection against severe illness and death is obtained even after the first dose of the two-dose vaccines. BCCDC recommends a third dose of vaccine at least 28 days after the second dose for immunocompromised. 37 *However, life-saving or -prolonging therapy should not be delayed solely to complete immunization Any other timing would require case-by-case assessment based on: a. Risk of morbidity related to COVID-19 infection (including local incidence of the pandemic, cancer type, comorbidities that confer higher risk in the general population, etc.) b. Cancer-related morbidity due to delay of active treatment, and c. Suboptimal immunity protection due to insufficient time window between immunization and immunosuppressive therapy.
Recommendations for timing of COVID-19 immunization for patients aged 12 and above with solid malignancies starting or already receiving treatment (outside the setting of bone marrow, hematopoietic stem cell transplant, or CAR-T) are listed in Table 2 below.
# Special considerations for immunotherapy:
The general recommendation for patients on immunotherapy is to proceed with COVID-19 immunization.* a. Rituximab and other anti-CD20 monoclonal antibodies Of note, patients receiving these agents may have a reduced immune response to vaccines in general that can extend up to 6 months following treatment completion. These patients may benefit from a 3rd dose of vaccine as per BCCDC guidance, to be given at least 28 days after the second dose. 37 COVID-19 Vaccines for People with Solid Cancers Updated: April 18, 2023 b. Checkpoint inhibitors Previous studies have not signalled an increased risk of complications of COVID-19 disease for patients on checkpoint inhibitors such as CTLA-4 inhibitors (e.g., ipilimumab), PD-1 inhibitors (e.g., nivolumab, pembrolizumab, cemiplimab) and PD-L1 inhibitors (e.g., atezolizumab, avelumab, durvalumab). There have been theoretical concerns of an enhanced immune reaction to COVID-19 vaccines, particularly with CTLA-4 inhibitors.
* Given the seriousness of COVID-19 infection, COVID-19 immunization is recommended with consideration of both the patient's risk profile and immunotherapy regimen. This follows the general vaccination guidelines for immunocompromised patients [38][39][40] :
• First dose of two-dose vaccines (single dose if singledose vaccine) at least 2 weeks before treatment
• For two-dose vaccines, second dose at least two weeks before treatment* *In general, it is preferred that patients complete immunization before starting immunosuppressive therapy if possible, based on the timing of the treatments and the availability of vaccines at the time. However, life-saving or -prolonging therapy should not be delayed solely to complete immunization. Some immunity may be achieved following the first dose of the two-dose vaccines.
For patients who received 2 doses while on or shortly after active treatment, a third dose is advised.
-During cyclical treatment First dose of two-dose vaccines (or single dose if singledose vaccine) in the week before next treatment as this is when counts are likely to be the highest.
For patients who received 2 doses while on or shortly after active treatment, a third dose is advised. This should also be given in the week before the next treatment. At any time during treatment Systemic corticosteroids † Ideally, systemic corticosteroids (at daily doses 20 mg or higher of prednisone or equivalent for 1 month or longer) 36 should be avoided or completed at least 28 days before commencing the first vaccine dose when possible. If it is not possible, immunization should proceed.
For patients who received 2 doses while on or shortly after this treatment, a third dose is advised.
Patients due to start radiation therapy If immunization is pending, and it is possible to delay radiation therapy without compromising outcomes, radiation therapy should be postponed until anticipated immunity is achieved before commencing radiation therapy. Life-saving or prolonging therapy should not be delayed solely to complete immunization.
For patients who received 2 doses while on or shortly after active treatment, a third dose is advised.
Patients on radiation therapy ‡ At any time during treatment while blood counts are near normal range, ideally as early in the course of radiation therapy as possible.
Patients who have completed a course of radiation therapy or during a regimen of cyclical radio-isotope therapy ‡
Radiation therapy can suppress lymphocyte counts for months to years after treatment in a dose-and volumedependent fashion. As it is not known what level of WBC counts would alter vaccine efficacy, there is no specific blood count level to target for vaccine delivery; however, if the radiation therapy regimen § is expected to cause transient myelosuppression for up to eight weeks, immunization should start at least one week after the nadir of myelosuppression.
* Immunosuppressive therapy -including but not limited to cytotoxic chemotherapy, rituximab, obinutuzumab, alemtuzumab † This recommendation does not relate to inhaled, nebulized, intra-articular, intrabursal or topical corticosteroids, which have no bearing on immunization timing. ‡Injection should be given on the opposite side if unilateral radiation treatment is, or was, given to area of injection site § Myelosuppression on radiation therapy regimens varies with dose, fractionation, and patient factors but typically examples of suppressive regimens include hemi-body, total body, total marrow, whole abdominal, craniospinal, or total skin radiation. | None | None |
e7cbc2f08eec5805ee6fffc506e4e5c18fa972bb | cma | None | This position statement aims to provide rapid guidance for Canadian health care professionals in treating patients with COPD during the COVID-19 pandemic. A very limited body of published data, inference from indirect data, and recommendations from other international guideline bodies inform these recommendations. As such, these recommendations are primarily based on expert opinion and we recommend that treatment decisions be individualized. As well, these recommendations are subject to change as information regarding COVID-19 and its effects are further understood. We plan to update this guidance as new information becomes available, and recommend periodically checking the Canadian Thoracic Society website for updates.Rationale: Longitudinal experience with seasonal influenza and preliminary data in SARS-CoV-2 infection (see below) suggests that patients with chronic lung disease are at risk for severe complications of SARS-CoV-2 infection (COVID-19). Physical distancing is an important public health measure to 'flatten the curve' of community spread of the virus. The workplace is a social environment which may expose patients to others in their community, particularly if physical distancing in the workplace setting is difficult to implement. Until we fully understand the risks associated with SARS-CoV-2 infection in patients with chronic lung disease we have placed a high value on limiting exposure based on prior experience with influenza.In the absence of direct or indirect data that use of current inhaled COPD therapies impacts the severity of SARS-CoV-2 infection, we recommend that maintenance and exacerbation management for COPD be continued according to current CTS treatment guidelines. 1,2 Based on what we know about viral# respiratory infections in patients with COPD, optimal pharmacological treatment is the best way to prevent exacerbations and/or reduce the severity of exacerbations secondary to SARS-CoV-2. Maintenance inhaled therapies have been shown to improve lung function, symptoms, quality of life and decrease the risk of future exacerbations, including those precipitated by viral exacerbations.
This includes patients using their long-acting bronchodilators (LAMA and/or LABA) and if indicated ICS/LABA combination inhalers. There is no current evidence that inhaled corticosteroids increase the risk of acquiring SARS-CoV-2 infection (COVID-19) or cause complications/worsening of this infection, such as increasing the need for hospitalization, intubation for mechanical ventilation, or death.
# Risk of acquiring SARS-CoV-2 infection (COVID 19) in patients with COPD
# There DOES NOT appear to be an increased risk for COPD patients to acquire SARS-CoV-2 infection (COVID-19) compared to the general population.
Rationale: Two studies from China and one from Korea did not find that hospitalized patients with COPD were over-represented in the COVID-19 populations studied. 3,4,5 However, this finding may be subject to change as more reports regarding patient demographics in different countries are published. We will update this document as information becomes available.
# Severity of Acute Exacerbation of COPD caused by SARS-CoV-2 (COVID 19)
# We recommend that COPD patients who are diagnosed with a COVID 19 infection continue their inhaled maintenance therapies. It is probable that COPD patients will also experience more severe symptoms of a COVID-19 infection due to their underlying lung disease and that this should be factored into your management plan for the patient.
Rationale: It is probable that COVID-19 can trigger a COPD exacerbation. Viral respiratory tract infections are a common cause of COPD exacerbations. 6 In addition to following public health recommendations, optimizing the outpatient management of COPD (both non-pharmacological and pharmacological) is recommended to reduce the risk of future exacerbations. It should be anticipated that patients with COPD who become infected with COVID-19 are at an increased risk of developing more severe symptoms given their underlying lung disease. A report by Guan et al indicates that hospitalized patients with COPD were more likely to require ICU support and had higher mortality when compared to other groups. 7 This is further supported by a small meta-analysis by Lippi suggesting that COPD patients with COVID-19 had over a 5-fold risk of having a severe infection. 8 We suggest careful clinical monitoring of these patients based on their symptoms and response to therapy.
# Safety of using systemic corticosteroids (prednisone) to treat Acute Exacerbations of COPD during the SARS-CoV-2 (COVID 19) pandemic
# We suggest using oral prednisone (or other forms of systemic steroids if clinically warranted) to treat Acute Exacerbations of COPD, whether or not the exacerbation is triggered by SARS-CoV-2.
Rationale: There is no direct clinical research to inform an efficacy and safety recommendation. A) Use of prednisone to treat Acute Exacerbations of COPD NOT suspected to be caused by SARS-CoV-2. Prednisone is recommended for the treatment of COPD exacerbations. 1,2 If exacerbations requiring treatment with prednisone are not treated accordingly, patients may require an avoidable emergency department visit or hospitalization (which could also expose them to SARS-CoV-2). There is no available evidence of harm caused by using prednisone to treat COPD exacerbations during the pandemic. B) Use of prednisone to treat Acute Exacerbations of COPD suspected to be caused by SARS-CoV-2. This analysis is relevant to a harm discussion since patients with COPD may receive prednisone for a SARS-CoV-2 triggered exacerbation. There is a concern that prednisone may prolong viral replication. 6 It remains unclear as to whether prednisone is helpful or harmful in the treatment of COVID-19. Most of what we know is coming from studies on SARS-CoV-2 lung injury. Russel and colleagues reviewed observational data and concluded there was no benefit to using prednisone to treat SARS-CoV-2 lung injury. 9 Front-line physicians from the Chinese Thoracic Society challenge this assertion and take the position that since the evidence is inconclusive, and since SARS-CoV-2 lung injury is profoundly inflammatory, that corticosteroids may play an important role. They recommend that physicians should follow basic principles when using corticosteroids: "(1) the benefits and harms should be carefully weighed before using corticosteroids; (2) corticosteroids should be used prudently in critically ill patients with 2019-nCoV pneumonia; (3) for patients with hypoxemia due to underlying diseases or who regularly use corticosteroids for chronic diseases, further use of corticosteroids should be cautious; and (4) the dosage should be low to-moderate (≤05-1 mg/kg per day methylprednisolone or equivalent) and the duration should be short (≤7 days)." 10 Arabi and colleagues found that after adjusting for confounders, there was no mortality signal associated with prednisone use in the Middle East Respiratory Syndrome. 11 In the absence of evidence of harm and an expectation of a low risk of harm, we prioritized the high value of current evidence-based care recommendations to treat COPD exacerbations with prednisone to reduce the need for urgent health service utilization.
# Safety of nebulizer use in COPD
# We advise against the use of nebulized therapy during this pandemic. We recommend that metered dose inhalers with spacing devices, soft mist inhalers or dry powder inhalers be used to administer all COPD medications in all clinical circumstances. This includes at home, and inside healthcare facilities including nursing homes. This is to reduce the risk of aerosol spread of the virus particles that could occur with the use of nebulized therapy. Patients who are already using nebulizers to administer therapy at home should continue until such time as their provider can discuss switching to alternative delivery methods and advise on technique. However, they must be made aware of the potential of spread of the virus to others in the household and that they should consider nebulizing their medicines in a separate room from others and implement other infection control recommendations.
Rationale: Metered dose inhalers with spacing devices are as effective as nebulization and the preferred method of delivery even for acute exacerbations in the emergency department and hospital, even under non-pandemic circumstances. 12 A dry powder inhaler (terbutaline) or soft mist inhaler (salbutamol/ipratropium bromide) is another alternative. Although the risk associated with nebulization in the context of SARS-CoV-2 is unknown, it is possible that nebulization can increase aerosolization of SARS-CoV-2, as was suggested in a recent simulation study. 13 This may increase the risk of infection for healthcare workers and caregivers.
We placed a high value on selecting an effective method of delivery of inhaled medications while reducing any potential risk of disease transmission. If switching from nebulized to MDI for short acting reliever agents, a conversion table is provided below.
# Reminder: Approx. Equivalent Nebule vs puffers (MDI) Salbutamol
1 Nebule (2.5 mg / neb) 4 puffs (100 mcg/puff) Ipratropium 1 Nebule (500 mcg/neb) 4-8 puffs (20 mcg/puff)
# Self-management Education, Pulmonary Rehabilitation and Exercise for patients with COPD
During this pandemic, self-management education and pulmonary rehabilitation in-person programs will be closed until further notice. Self-management and pulmonary rehabilitation counseling can still be done remotely by telephone or via tele-health technologies in some institutions. This is also an opportune time to review existing COPD Action Plans or discuss the development of an action plan for your patient to limit the need for the patient to leave the home.
Although rehabilitation programs may be closed, this does not mean that the patient should remain inactive during this period of the COVID-19 pandemic, nor that they should not continue to implement their self-management strategies at home. Recommendations for patients are to continue to:
i) adhere to their treatment plan (regular medication and action plan with additional treatment in the event of an exacerbation); and ii) practice a healthy lifestyle including remaining physically active. An example of this includes going for daily walks while practicing physical distancing of at least 2 meters from others, and using functional resistance exercises for strength training at home.
A free online learning self-management education course including resources from the Canadian Pulmonary Rehabilitation Program are available at www.livingwellwithcopd.com. Patients will need to create an account to access the information. "Learning Activities" and "Rehabilitation" sections as well as a series of videos that cover all aspects of the "Living Well with COPD" program are available in English and French.
The CTS COVID-19 webpage provides links to various online resources that can help facilitate the teaching and implementation of self-management and rehabilitation strategies.
# Home Oxygen use for patients with COPD
Patients who currently are on oxygen should continue to use their oxygen as prescribed. They should clean their equipment, including their hosing, routinely and follow the manufacturer's instructions for cleaning and maintenance. If the patient has had to increase their flow rates of their home oxygen, the patient should inform the physician, and/or case-manager, and/or if in extreme distress, call 911.
# We will review our recommendations at least every two weeks and as more information becomes available
The pandemic is a rapidly evolving situation. Health care professionals are advised to look to the Canadian Thoracic Society website for additional COPD resources (action plans and tutorial videos for adults for the proper use of inhalers, etc.) as well as further updates on COVID-19 and lung diseases. | This position statement aims to provide rapid guidance for Canadian health care professionals in treating patients with COPD during the COVID-19 pandemic. A very limited body of published data, inference from indirect data, and recommendations from other international guideline bodies inform these recommendations. As such, these recommendations are primarily based on expert opinion and we recommend that treatment decisions be individualized. As well, these recommendations are subject to change as information regarding COVID-19 and its effects are further understood. We plan to update this guidance as new information becomes available, and recommend periodically checking the Canadian Thoracic Society website for updates.Rationale: Longitudinal experience with seasonal influenza and preliminary data in SARS-CoV-2 infection (see below) suggests that patients with chronic lung disease are at risk for severe complications of SARS-CoV-2 infection (COVID-19). Physical distancing is an important public health measure to 'flatten the curve' of community spread of the virus. The workplace is a social environment which may expose patients to others in their community, particularly if physical distancing in the workplace setting is difficult to implement. Until we fully understand the risks associated with SARS-CoV-2 infection in patients with chronic lung disease we have placed a high value on limiting exposure based on prior experience with influenza.In the absence of direct or indirect data that use of current inhaled COPD therapies impacts the severity of SARS-CoV-2 infection, we recommend that maintenance and exacerbation management for COPD be continued according to current CTS treatment guidelines. 1,2 Based on what we know about viral# respiratory infections in patients with COPD, optimal pharmacological treatment is the best way to prevent exacerbations and/or reduce the severity of exacerbations secondary to SARS-CoV-2. Maintenance inhaled therapies have been shown to improve lung function, symptoms, quality of life and decrease the risk of future exacerbations, including those precipitated by viral exacerbations.
This includes patients using their long-acting bronchodilators (LAMA and/or LABA) and if indicated ICS/LABA combination inhalers. There is no current evidence that inhaled corticosteroids increase the risk of acquiring SARS-CoV-2 infection (COVID-19) or cause complications/worsening of this infection, such as increasing the need for hospitalization, intubation for mechanical ventilation, or death.
# Risk of acquiring SARS-CoV-2 infection (COVID 19) in patients with COPD
# There DOES NOT appear to be an increased risk for COPD patients to acquire SARS-CoV-2 infection (COVID-19) compared to the general population.
Rationale: Two studies from China and one from Korea did not find that hospitalized patients with COPD were over-represented in the COVID-19 populations studied. 3,4,5 However, this finding may be subject to change as more reports regarding patient demographics in different countries are published. We will update this document as information becomes available.
# Severity of Acute Exacerbation of COPD caused by SARS-CoV-2 (COVID 19)
# We recommend that COPD patients who are diagnosed with a COVID 19 infection continue their inhaled maintenance therapies. It is probable that COPD patients will also experience more severe symptoms of a COVID-19 infection due to their underlying lung disease and that this should be factored into your management plan for the patient.
Rationale: It is probable that COVID-19 can trigger a COPD exacerbation. Viral respiratory tract infections are a common cause of COPD exacerbations. 6 In addition to following public health recommendations, optimizing the outpatient management of COPD (both non-pharmacological and pharmacological) is recommended to reduce the risk of future exacerbations. It should be anticipated that patients with COPD who become infected with COVID-19 are at an increased risk of developing more severe symptoms given their underlying lung disease. A report by Guan et al indicates that hospitalized patients with COPD were more likely to require ICU support and had higher mortality when compared to other groups. 7 This is further supported by a small meta-analysis by Lippi suggesting that COPD patients with COVID-19 had over a 5-fold risk of having a severe infection. 8 We suggest careful clinical monitoring of these patients based on their symptoms and response to therapy.
# Safety of using systemic corticosteroids (prednisone) to treat Acute Exacerbations of COPD during the SARS-CoV-2 (COVID 19) pandemic
# We suggest using oral prednisone (or other forms of systemic steroids if clinically warranted) to treat Acute Exacerbations of COPD, whether or not the exacerbation is triggered by SARS-CoV-2.
Rationale: There is no direct clinical research to inform an efficacy and safety recommendation. A) Use of prednisone to treat Acute Exacerbations of COPD NOT suspected to be caused by SARS-CoV-2. Prednisone is recommended for the treatment of COPD exacerbations. 1,2 If exacerbations requiring treatment with prednisone are not treated accordingly, patients may require an avoidable emergency department visit or hospitalization (which could also expose them to SARS-CoV-2). There is no available evidence of harm caused by using prednisone to treat COPD exacerbations during the pandemic. B) Use of prednisone to treat Acute Exacerbations of COPD suspected to be caused by SARS-CoV-2. This analysis is relevant to a harm discussion since patients with COPD may receive prednisone for a SARS-CoV-2 triggered exacerbation. There is a concern that prednisone may prolong viral replication. 6 It remains unclear as to whether prednisone is helpful or harmful in the treatment of COVID-19. Most of what we know is coming from studies on SARS-CoV-2 lung injury. Russel and colleagues reviewed observational data and concluded there was no benefit to using prednisone to treat SARS-CoV-2 lung injury. 9 Front-line physicians from the Chinese Thoracic Society challenge this assertion and take the position that since the evidence is inconclusive, and since SARS-CoV-2 lung injury is profoundly inflammatory, that corticosteroids may play an important role. They recommend that physicians should follow basic principles when using corticosteroids: "(1) the benefits and harms should be carefully weighed before using corticosteroids; (2) corticosteroids should be used prudently in critically ill patients with 2019-nCoV pneumonia; (3) for patients with hypoxemia due to underlying diseases or who regularly use corticosteroids for chronic diseases, further use of corticosteroids should be cautious; and (4) the dosage should be low to-moderate (≤0•5-1 mg/kg per day methylprednisolone or equivalent) and the duration should be short (≤7 days)." 10 Arabi and colleagues found that after adjusting for confounders, there was no mortality signal associated with prednisone use in the Middle East Respiratory Syndrome. 11 In the absence of evidence of harm and an expectation of a low risk of harm, we prioritized the high value of current evidence-based care recommendations to treat COPD exacerbations with prednisone to reduce the need for urgent health service utilization.
# Safety of nebulizer use in COPD
# We advise against the use of nebulized therapy during this pandemic. We recommend that metered dose inhalers with spacing devices, soft mist inhalers or dry powder inhalers be used to administer all COPD medications in all clinical circumstances. This includes at home, and inside healthcare facilities including nursing homes. This is to reduce the risk of aerosol spread of the virus particles that could occur with the use of nebulized therapy. Patients who are already using nebulizers to administer therapy at home should continue until such time as their provider can discuss switching to alternative delivery methods and advise on technique. However, they must be made aware of the potential of spread of the virus to others in the household and that they should consider nebulizing their medicines in a separate room from others and implement other infection control recommendations.
Rationale: Metered dose inhalers with spacing devices are as effective as nebulization and the preferred method of delivery even for acute exacerbations in the emergency department and hospital, even under non-pandemic circumstances. 12 A dry powder inhaler (terbutaline) or soft mist inhaler (salbutamol/ipratropium bromide) is another alternative. Although the risk associated with nebulization in the context of SARS-CoV-2 is unknown, it is possible that nebulization can increase aerosolization of SARS-CoV-2, as was suggested in a recent simulation study. 13 This may increase the risk of infection for healthcare workers and caregivers.
We placed a high value on selecting an effective method of delivery of inhaled medications while reducing any potential risk of disease transmission. If switching from nebulized to MDI for short acting reliever agents, a conversion table is provided below.
# Reminder: Approx. Equivalent Nebule vs puffers (MDI) Salbutamol
1 Nebule (2.5 mg / neb) 4 puffs (100 mcg/puff) Ipratropium 1 Nebule (500 mcg/neb) 4-8 puffs (20 mcg/puff)
# Self-management Education, Pulmonary Rehabilitation and Exercise for patients with COPD
During this pandemic, self-management education and pulmonary rehabilitation in-person programs will be closed until further notice. Self-management and pulmonary rehabilitation counseling can still be done remotely by telephone or via tele-health technologies in some institutions. This is also an opportune time to review existing COPD Action Plans or discuss the development of an action plan for your patient to limit the need for the patient to leave the home.
Although rehabilitation programs may be closed, this does not mean that the patient should remain inactive during this period of the COVID-19 pandemic, nor that they should not continue to implement their self-management strategies at home. Recommendations for patients are to continue to:
i) adhere to their treatment plan (regular medication and action plan with additional treatment in the event of an exacerbation); and ii) practice a healthy lifestyle including remaining physically active. An example of this includes going for daily walks while practicing physical distancing of at least 2 meters from others, and using functional resistance exercises for strength training at home.
A free online learning self-management education course including resources from the Canadian Pulmonary Rehabilitation Program are available at www.livingwellwithcopd.com. Patients will need to create an account to access the information. "Learning Activities" and "Rehabilitation" sections as well as a series of videos that cover all aspects of the "Living Well with COPD" program are available in English and French.
The CTS COVID-19 webpage provides links to various online resources that can help facilitate the teaching and implementation of self-management and rehabilitation strategies.
# Home Oxygen use for patients with COPD
Patients who currently are on oxygen should continue to use their oxygen as prescribed. They should clean their equipment, including their hosing, routinely and follow the manufacturer's instructions for cleaning and maintenance. If the patient has had to increase their flow rates of their home oxygen, the patient should inform the physician, and/or case-manager, and/or if in extreme distress, call 911.
# We will review our recommendations at least every two weeks and as more information becomes available
The pandemic is a rapidly evolving situation. Health care professionals are advised to look to the Canadian Thoracic Society website for additional COPD resources (action plans and tutorial videos for adults for the proper use of inhalers, etc.) as well as further updates on COVID-19 and lung diseases. | None | None |
af7cc5cb84e98de748daef68775b211b4c0a719f | cma | None | The antimalarial drugs, chloroquine and hydroxychloroquine (HCQ), are essential drugs in the treatment of rheumatic diseases. HCQ is currently the only anti-malarial drug available in Canada for the treatment of rheumatic diseases. HCQ is important in the management of systemic lupus erythematosus (SLE) (1,2). It has been shown to improve patient survival (3,4,5) and prevent disease flares (6,7). Other important benefits include lowering cholesterol (8,9,10), improving glucose metabolism (11,12), decreasing thrombovascular (13) and cardiovascular events (14), and decreasing organ damage (15). In addition, it is safe to use during pregnancy (16). HCQ is also important in the treatment of rheumatoid arthritis and is one of the more commonly prescribed disease-modifying antirheumatic drugs (17,18).
As with all medications, the safety of HCQ needs to be monitored. Retinal toxicity is an important potential side effect encountered and monitoring for this is important (19,20). Skin hyperpigmentation (21), myopathy (22,23), including cardiomyopathy (24,25), are other uncommon side effects. Nonetheless, HCQ is considered to be one of the safest drugs used by the rheumatologist. Data from a rheumatic disease registry found that in evaluating the relative toxicity of several drugs used in rheumatology, HCQ was the least toxic of the drugs studied (26).
With the COVID-19 pandemic, significant cardiac toxicity has been reported with the use of antimalarial drugs (27,28). Concerns have been raised about the increased occurrence of QT prolongation leading to serious arrhythmias such as Torsade de Pointes and cardiac arrest (27,28). However, this pandemic resulted in the unconventional use of HCQ (29), frequently at much higher doses than used to treat rheumatic diseases, and often in combination with azithromycin which may further prolong the QT interval (28). In addition, COVID-19 infection itself can cause arrhythmias and cardiomyopathy (28,30). These patients also commonly have hypokalemia, hypomagnesemia, as well as fever, which can potentiate QT prolongation (30). Cardiac toxicity is known to increase with the concomitant use of drugs that may prolong the QT interval and azithromycin is one of the drugs known to do this (28).
With conventional dosing and use, cardiac toxicity has been rarely encountered in rheumatology practice (29). Recently, concerns have been raised about the occurrence of the prolonged QT interval and resultant cardiac arrhythmias with antimalarials. However, in a study in SLE patients on antimalarials, the prevalence of prolonged QT interval was very low, only 0.7% (31). This study also demonstrated that higher cumulative anti-malarial dose decreases the odds of ECG conduction abnormalities in SLE patients, suggesting a protective effect (31). Others showed that the prevalence of conduction abnormalities in SLE patients on HCQ is similar to a comparable healthy population (32). There was a non-statistically significant increase in the odds of ECG structural abnormalities in those having cumulative antimalarial dose above the median (31). Possible risk factors for cardiotoxicity in patients receiving antimalarials include older age, pre-existing cardiac disease and renal insufficiency (31).
The use of HCQ to treat rheumatic diseases is overall felt to be safe when prescribed appropriately and when the patient is monitored and followed by a rheumatologist (29). The significant benefits of HCQ, particularly in SLE, certainly outweigh its risks. | #
The antimalarial drugs, chloroquine and hydroxychloroquine (HCQ), are essential drugs in the treatment of rheumatic diseases. HCQ is currently the only anti-malarial drug available in Canada for the treatment of rheumatic diseases. HCQ is important in the management of systemic lupus erythematosus (SLE) (1,2). It has been shown to improve patient survival (3,4,5) and prevent disease flares (6,7). Other important benefits include lowering cholesterol (8,9,10), improving glucose metabolism (11,12), decreasing thrombovascular (13) and cardiovascular events (14), and decreasing organ damage (15). In addition, it is safe to use during pregnancy (16). HCQ is also important in the treatment of rheumatoid arthritis and is one of the more commonly prescribed disease-modifying antirheumatic drugs (17,18).
As with all medications, the safety of HCQ needs to be monitored. Retinal toxicity is an important potential side effect encountered and monitoring for this is important (19,20). Skin hyperpigmentation (21), myopathy (22,23), including cardiomyopathy (24,25), are other uncommon side effects. Nonetheless, HCQ is considered to be one of the safest drugs used by the rheumatologist. Data from a rheumatic disease registry found that in evaluating the relative toxicity of several drugs used in rheumatology, HCQ was the least toxic of the drugs studied (26).
With the COVID-19 pandemic, significant cardiac toxicity has been reported with the use of antimalarial drugs (27,28). Concerns have been raised about the increased occurrence of QT prolongation leading to serious arrhythmias such as Torsade de Pointes and cardiac arrest (27,28). However, this pandemic resulted in the unconventional use of HCQ (29), frequently at much higher doses than used to treat rheumatic diseases, and often in combination with azithromycin which may further prolong the QT interval (28). In addition, COVID-19 infection itself can cause arrhythmias and cardiomyopathy (28,30). These patients also commonly have hypokalemia, hypomagnesemia, as well as fever, which can potentiate QT prolongation (30). Cardiac toxicity is known to increase with the concomitant use of drugs that may prolong the QT interval and azithromycin is one of the drugs known to do this (28).
With conventional dosing and use, cardiac toxicity has been rarely encountered in rheumatology practice (29). Recently, concerns have been raised about the occurrence of the prolonged QT interval and resultant cardiac arrhythmias with antimalarials. However, in a study in SLE patients on antimalarials, the prevalence of prolonged QT interval was very low, only 0.7% (31). This study also demonstrated that higher cumulative anti-malarial dose decreases the odds of ECG conduction abnormalities in SLE patients, suggesting a protective effect (31). Others showed that the prevalence of conduction abnormalities in SLE patients on HCQ is similar to a comparable healthy population (32). There was a non-statistically significant increase in the odds of ECG structural abnormalities in those having cumulative antimalarial dose above the median (31). Possible risk factors for cardiotoxicity in patients receiving antimalarials include older age, pre-existing cardiac disease and renal insufficiency (31).
The use of HCQ to treat rheumatic diseases is overall felt to be safe when prescribed appropriately and when the patient is monitored and followed by a rheumatologist (29). The significant benefits of HCQ, particularly in SLE, certainly outweigh its risks. | None | None |
05ed1907207d8e6e239497ebdf00a6533b8bc0cc | cma | None | To provide an overview of the mechanism of action, licensed indications, dosing regimens, and side effects of dabigatran.# INDICATIONS:
Dabigatran is currently licensed in Canada for the following indications:
- Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation.
- Treatment of venous thromboembolism events (deep vein thrombosis , pulmonary embolism ) and prevention of recurrent DVT and PE. - Prevention of DVT and PE after elective hip or knee replacement surgery.
# DOSING:
- Prevention of stroke and systemic embolism in atrial fibrillation: 110 mg twice daily (BID) or 150 mg BID. Patients aged 80 years and older or at higher risk of bleeding, including those 75 years of age or older with 1 risk factor for bleeding (e.g. clinical risk factor such as coagulation disorder, thrombocytopenia, functional platelet defect or recent bleed or invasive procedure; bacterial endocarditis, moderate renal impairment with creatinine clearance There is no recommended dose adjustment in patients with moderate renal impairment (CrCl 30 to 50 mL/min). Dabigatran is contraindicated in patients with CrCl <30 mL/min.
- Thromboprophylaxis after hip or knee arthroplasty: Start with 110 mg 1-4 hours after surgery (and establishment of hemostasis) and increase to 220 mg once daily starting the day after surgery; the 220 mg daily dose is continued for at least 10 days and up to 35 days. Patients with moderate renal impairment (CrCl 30-50 ml/min) may take a one-time dose of 75 mg followed by 150 mg daily.
# MONITORING:
Laboratory monitoring of the anticoagulant effect of dabigatran is not recommended during routine clinical use. Periodic clinical assessment is important to determine and reinforce adherence, review comorbidity and medication changes, drug-drug interactions, and provide education. Furthermore, for most patients, at least yearly assessment of creatinine clearance is recommended. The creatinine should be measured more frequently in patients with an abnormal value at baseline or at risk of worsening renal function. The prothrombin time/international normalized ratio (PT/INR) does not provide a reliable measure of the anticoagulant activity of dabigatran. The activated partial thromboplastin time (aPTT) is prolonged by dabigatran but the prolongation of the aPTT is reagent-dependent and the values plateau with higher dabigatran concentrations. Nonetheless, a prolonged aPTT with a sensitive reagent indicates the presence of dabigatran and a normal test renders high dabigatran levels unlikely. The thrombin clotting time (TCT) is the most sensitive assay for the presence of dabigatran. It is always prolonged in the presence of dabigatran, but it should not be used to monitor the anticoagulant activity. The major adverse effect of dabigatran is bleeding; concomitant use of antiplatelet drugs or strong Pglycoprotein inhibitors (see below under Special Considerations: Drug Interactions) increases this risk. Dabigatran should be avoided in patients with indwelling epidural catheters or recent spinal punctures in order to reduce the risk of epidural or spinal hematomas. Dabigatran may be associated with dyspepsia in up to 10% of users; the frequency of this complication can be reduced by having patients take the drug with meals. Dyspepsia usually resolves with time and may improve with the use of an anti-ulcer medication such as a proton pump inhibitor, but caution is advised as the absorption of dabigatran is decreased when co-administered with antacids containing aluminum, magnesium, or calcium.
# PERI-PROCEDURAL MANAGEMENT:
See Clinical Guide: NOACs/DOACs: Peri-Operative Management and the Tool: Perioperative Anticoagulant Management.
# SPECIAL CONSIDERATIONS:
Administration and storage: Dabigatran may be taken with or without food. Capsules should be swallowed whole. The capsule should not be crushed, chewed or opened before swallowing. Capsules should be stored in their blister package to protect them from moisture.
Bleeding: Idarucizumab, a humanized antibody fragment against dabigatran, is now available as an antidote for dabigatran in situations of life-threatening or uncontrolled bleeding due to dabigatran. Idarucizumab, which is given as an intravenous bolus dose of 5 grams, rapidly reverses the anticoagulant effect of dabigatran. Approaches to the management of bleeding can be found in the Clinical Guide: NOACs/DOACs: Management of Bleeding and the Tool: Bleed Management.
Drug Interactions: Dabigatran absorption is decreased by agents that increase gastric pH (i.e. antacids containing magnesium or aluminum); however, there is no contraindication to concurrent use of proton pump inhibitors, though diminished clinical effect may occur.
Selective serotonin re-uptake inhibitors (SSRIs) increased the relative risk of bleeding by 50-100% and selective serotonin norepinephrine re-uptake inhibitors (SNRIs) increased bleeding by 100% in atrial fibrillation on dabigatran. Concomitant use of these drugs should be undertaken with caution.
Because dabigatran etexilate is a substrate of the P-glycoprotein transport system, potent inhibitors or inducers are expected to alter plasma levels of dabigatran.
a) Inhibitors of P-glycoprotein: Drugs that inhibit this transport system can increase systemic exposure to dabigatran. Concomitant use of the strong P-glycoprotein inhibitors (e.g. ketoconazole, dronedarone) is contraindicated. Caution is advised if taken with moderate inhibitors (e.g. cyclosporine, itraconazole, ritonavir, nelfinavir, saquinavir, tipranavir, posaconazole, and tacrolimus). Patients who are taking the P-glycoprotein inhibitors verapamil and quinidine should take the dabigatran dose 2 hours prior to a dose of verapamil or quinidine. No dosage adjustment to dabigatran is recommended for patients concurrently taking these interacting medications for atrial fibrillation or VTE treatment, but dose reduction to 150 mg once daily is recommended by the manufacturer for thromboprophylaxis in hip or knee replacement.
b) Inducers of P-glycoprotein: Drugs that induce P-glycoprotein can decrease the systemic exposure to dabigatran. Co-administration with potent inducers such as carbamazepine, phenytoin, rifampin, and Saint John's wort should be avoided.
Renal and hepatic dysfunction: Dabigatran is contraindicated in patients with CrCl <30 mL/min. Dose modification is not needed in patients with hepatic impairment, but dabigatran should be used with caution in those with cirrhosis or baseline coagulopathy who are at high risk of bleeding.
# Mechanical heart valves:
Dabigatran is contraindicated in patients with mechanical heart valves due to increased rates of thrombotic and bleeding complications when compared to warfarin.
Pregnancy and breast feeding: Dabigatran crosses the placenta and should not be used in pregnancy. Small amounts of dabigatran were found in the breast milk of two women treated with a single oral dose of dabigatran 220 mg. The impact of repeated dosing and potential effects on nursing infants of women taking dabigatran is unknown.
Pediatrics: Dabigatran is not recommended for use in anyone under the age of 18 until ongoing studies establish the pharmacokinetics, pharmacodynamics, safety, and efficacy of dabigatran.
# Date of Version: 06July2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein. | To provide an overview of the mechanism of action, licensed indications, dosing regimens, and side effects of dabigatran.# INDICATIONS:
Dabigatran is currently licensed in Canada for the following indications:
• Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation.
• Treatment of venous thromboembolism events (deep vein thrombosis [DVT], pulmonary embolism [PE]) and prevention of recurrent DVT and PE. • Prevention of DVT and PE after elective hip or knee replacement surgery.
# DOSING:
1. Prevention of stroke and systemic embolism in atrial fibrillation: 110 mg twice daily (BID) or 150 mg BID. Patients aged 80 years and older or at higher risk of bleeding, including those 75 years of age or older with 1 risk factor for bleeding (e.g. clinical risk factor such as coagulation disorder, thrombocytopenia, functional platelet defect or recent bleed or invasive procedure; bacterial endocarditis, moderate renal impairment with creatinine clearance [CrCl] There is no recommended dose adjustment in patients with moderate renal impairment (CrCl 30 to 50 mL/min). Dabigatran is contraindicated in patients with CrCl <30 mL/min.
3. Thromboprophylaxis after hip or knee arthroplasty: Start with 110 mg 1-4 hours after surgery (and establishment of hemostasis) and increase to 220 mg once daily starting the day after surgery; the 220 mg daily dose is continued for at least 10 days and up to 35 days. Patients with moderate renal impairment (CrCl 30-50 ml/min) may take a one-time dose of 75 mg followed by 150 mg daily.
# MONITORING:
Laboratory monitoring of the anticoagulant effect of dabigatran is not recommended during routine clinical use. Periodic clinical assessment is important to determine and reinforce adherence, review comorbidity and medication changes, drug-drug interactions, and provide education. Furthermore, for most patients, at least yearly assessment of creatinine clearance is recommended. The creatinine should be measured more frequently in patients with an abnormal value at baseline or at risk of worsening renal function. The prothrombin time/international normalized ratio (PT/INR) does not provide a reliable measure of the anticoagulant activity of dabigatran. The activated partial thromboplastin time (aPTT) is prolonged by dabigatran but the prolongation of the aPTT is reagent-dependent and the values plateau with higher dabigatran concentrations. Nonetheless, a prolonged aPTT with a sensitive reagent indicates the presence of dabigatran and a normal test renders high dabigatran levels unlikely. The thrombin clotting time (TCT) is the most sensitive assay for the presence of dabigatran. It is always prolonged in the presence of dabigatran, but it should not be used to monitor the anticoagulant activity. The major adverse effect of dabigatran is bleeding; concomitant use of antiplatelet drugs or strong Pglycoprotein inhibitors (see below under Special Considerations: Drug Interactions) increases this risk. Dabigatran should be avoided in patients with indwelling epidural catheters or recent spinal punctures in order to reduce the risk of epidural or spinal hematomas. Dabigatran may be associated with dyspepsia in up to 10% of users; the frequency of this complication can be reduced by having patients take the drug with meals. Dyspepsia usually resolves with time and may improve with the use of an anti-ulcer medication such as a proton pump inhibitor, but caution is advised as the absorption of dabigatran is decreased when co-administered with antacids containing aluminum, magnesium, or calcium.
# PERI-PROCEDURAL MANAGEMENT:
See Clinical Guide: NOACs/DOACs: Peri-Operative Management and the Tool: Perioperative Anticoagulant Management.
# SPECIAL CONSIDERATIONS:
Administration and storage: Dabigatran may be taken with or without food. Capsules should be swallowed whole. The capsule should not be crushed, chewed or opened before swallowing. Capsules should be stored in their blister package to protect them from moisture.
Bleeding: Idarucizumab, a humanized antibody fragment against dabigatran, is now available as an antidote for dabigatran in situations of life-threatening or uncontrolled bleeding due to dabigatran. Idarucizumab, which is given as an intravenous bolus dose of 5 grams, rapidly reverses the anticoagulant effect of dabigatran. Approaches to the management of bleeding can be found in the Clinical Guide: NOACs/DOACs: Management of Bleeding and the Tool: Bleed Management.
Drug Interactions: Dabigatran absorption is decreased by agents that increase gastric pH (i.e. antacids containing magnesium or aluminum); however, there is no contraindication to concurrent use of proton pump inhibitors, though diminished clinical effect may occur.
Selective serotonin re-uptake inhibitors (SSRIs) increased the relative risk of bleeding by 50-100% and selective serotonin norepinephrine re-uptake inhibitors (SNRIs) increased bleeding by 100% in atrial fibrillation on dabigatran. Concomitant use of these drugs should be undertaken with caution.
Because dabigatran etexilate is a substrate of the P-glycoprotein transport system, potent inhibitors or inducers are expected to alter plasma levels of dabigatran.
a) Inhibitors of P-glycoprotein: Drugs that inhibit this transport system can increase systemic exposure to dabigatran. Concomitant use of the strong P-glycoprotein inhibitors (e.g. ketoconazole, dronedarone) is contraindicated. Caution is advised if taken with moderate inhibitors (e.g. cyclosporine, itraconazole, ritonavir, nelfinavir, saquinavir, tipranavir, posaconazole, and tacrolimus). Patients who are taking the P-glycoprotein inhibitors verapamil and quinidine should take the dabigatran dose 2 hours prior to a dose of verapamil or quinidine. No dosage adjustment to dabigatran is recommended for patients concurrently taking these interacting medications for atrial fibrillation or VTE treatment, but dose reduction to 150 mg once daily is recommended by the manufacturer for thromboprophylaxis in hip or knee replacement.
b) Inducers of P-glycoprotein: Drugs that induce P-glycoprotein can decrease the systemic exposure to dabigatran. Co-administration with potent inducers such as carbamazepine, phenytoin, rifampin, and Saint John's wort should be avoided.
Renal and hepatic dysfunction: Dabigatran is contraindicated in patients with CrCl <30 mL/min. Dose modification is not needed in patients with hepatic impairment, but dabigatran should be used with caution in those with cirrhosis or baseline coagulopathy who are at high risk of bleeding.
# Mechanical heart valves:
Dabigatran is contraindicated in patients with mechanical heart valves due to increased rates of thrombotic and bleeding complications when compared to warfarin.
Pregnancy and breast feeding: Dabigatran crosses the placenta and should not be used in pregnancy. Small amounts of dabigatran were found in the breast milk of two women treated with a single oral dose of dabigatran 220 mg. The impact of repeated dosing and potential effects on nursing infants of women taking dabigatran is unknown.
Pediatrics: Dabigatran is not recommended for use in anyone under the age of 18 until ongoing studies establish the pharmacokinetics, pharmacodynamics, safety, and efficacy of dabigatran.
# Date of Version: 06July2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein. | None | None |
211ca6a05b4cf7eb8a967d6ce05f66d6489527a5 | cma | None | These guidelines are not binding on nurses, other health providers or the organizations that employ them. The use of these guidelines should be flexible and based on individual needs and local circumstances. They constitute neither a liability nor discharge from liability. While every effort has been made to ensure the accuracy of the contents at the time of publication, neither the authors nor the Registered Nurses' Association of Ontario (RNAO) gives any guarantee as to the accuracy of the information contained in them or accepts any liability with respect to loss, damage, injury or expense arising from any such errors or omission in the contents of this work.With the exception of those portions of this document for which a specific prohibition or limitation against copying appears, the balance of this document may be produced, reproduced and published in its entirety, without modification, in any form, including in electronic form, for educational or non-commercial purposes. Should any adaptation of the material be required for any reason, written permission must be obtained from RNAO. Appropriate credit or citation must appear on all copied materials as follows: Registered Nurses' Association of Ontario. A palliative approach to care in the last 12 months of life. Toronto (ON): Registered Nurses' Association of Ontario; 2020.# Table of Contents
# Table of Contents
# How to Use this Document
This best practice guideline (BPG) G - is a comprehensive document that provides guidance and resources for evidence-based nursing practice G . It is not intended to be a manual or "how-to" guide; rather, it supports best practices and decision making for nurses G , the interprofessional health team G and health-service organizations. This BPG should be reviewed and applied in accordance with the needs and preferences G of adults (18 years and older) who are experiencing the last 12 months of a progressive life-limiting illness and their families G . This document provides evidence-based recommendation G statements and descriptions of (a) practice, education G and organizational considerations, (b) benefits and harms, (c) values G and preferences and (d) health equity considerations.
Nurses, members of the interprofessional health team and administrators who lead and facilitate practice changes will find this document invaluable for developing policies, procedures, protocols and educational programs to support service delivery. Nurses and members of the interprofessional health team delivering direct care will benefit from reviewing the recommendations and supporting evidence. We encourage practice settings to adapt this BPG into formats that are feasible for daily use.
If your organization is adopting this BPG, we recommend the following steps:
- Assess your existing policies, procedures, protocols and educational programs in relation to the recommendations and supporting evidence in this BPG.
- Identify existing needs or gaps in your policies, procedures, protocols and educational programs.
- Note the recommendations that are applicable to your setting and that can be used to address your organization's existing needs or gaps.
- Develop a plan for implementing recommendations, sustaining best practices and evaluating outcomes G .
Implementation resources, including the RNAO Toolkit: Implementation of Best Practice Guidelines, Second Edition (1), are available at RNAO.ca. For more information, see Implementation Strategies on p. 84.
All of the RNAO BPGs are available for download, free of charge, on the RNAO website at RNAO.ca/bpg. To locate a particular BPG, search by keyword or browse by topic.
We are interested in hearing your feedback on this BPG and how you implemented it. Please share your story with us at RNAO.ca/contact. - Throughout this document, terms that are marked with a superscript G ( G ) can be found in the Glossary of Terms (Appendix A).
# BAC K G R O U N D
A Palliative Approach to Care in the Last 12 Months of Life
# Purpose and Scope
Purpose RNAO BPGs are systematically developed, evidence-based documents that include recommendations on specific clinical, healthy work environment and health system topics. They are intended for nurses and members of the interprofessional health team in direct care positions, and for educators, administrators and executives, policymakers, researchers, and persons G and families with lived experience. BPGs promote consistency and excellence in clinical care, administrative practices, policies, and education, with the aim of achieving optimal health outcomes for people, communities and the health system as a whole.
The purpose of this BPG is to provide evidence-based recommendations to nurses and the interprofessional health team who support adults (18 years and older) experiencing the last 12 months of a progressive life-limiting illness, their families and their caregivers. The goals of the recommendations are to: (a) improve delivery of psychosocial, spiritual and culturally safe care; (b) enhance coordination of care; and (c) facilitate supportive work environments.
The recommendations within this BPG are meant to be implemented as part of a holistic approach to care, as outlined in Figure 2: Domains of Issues Associated with Illness and Bereavement (10). It is also in alignment with the aims of palliative care G (see "Key Concepts Used in this Guideline, " p. 7).
Nurses and the interprofessional health team are required to have basic skills, training and competencies in palliative care in order to implement the recommendations of this BPG. For further information, please refer to Appendix C (Education Statements G ), the Ontario Palliative Care Network (OPCN) The Ontario Palliative Care Competency Framework-Nursing Competencies (summarized in Appendix K) and the Framework on Palliative Care in Canada (available at / reports-publications/palliative-care/framework-palliative-care-canada.html#p2.3.1).
In March 2017, RNAO convened an expert panel to determine the scope of this BPG. The RNAO expert panel was interprofessional in composition, including family caregivers G and individuals with knowledge and experience in clinical practice, education, research and policy from a range of health-service and academic organizations, practice areas and sectors. Expert panel members shared their insights on supporting and caring for adults with progressive life-limiting illness across the continuum of care (e.g., community, long-term care and acute care). A systematic and comprehensive analysis was completed by the RNAO Best Practice Guideline Development and Research Team and the RNAO expert panel to determine the scope and priority recommendation questions for this BPG (see Appendix D).
# BAC K G R O U N D
A Palliative Approach to Care in the Last 12 Months of Life
# Scope
To determine the scope of this BPG, the RNAO Best Practice Guideline Development and Research Team conducted the following steps:
reviewed the RNAO BPG End-of-life Care During the Last Days and Hours (2011) (2);
conducted a search for published guidelines in this topic area and identified gaps in guidance;
conducted a scoping review G to determine the breadth and depth of peer-reviewed studies in the area of Medical Assistance in Dying (MAiD) G , with a specific focus on nursing practice;
interviewed 24 key informants with experience and expertise in the field, including health providers G in direct care, administrators, researchers and family caregivers; and
consulted with the expert panel co-chairs and the expert panel in March 2017.
This BPG is applicable to all practice settings where persons and families require palliative care and end-of-life care G services (e.g., acute care, community care, and long-term care). Specifically, this BPG will focus on persons experiencing the last 12 months of progressive life-limiting illness and their families. It will address the following areas:
# BAC K G R O U N D
A Palliative Approach to Care in the Last 12 Months of Life Family caregiver: "Any relative, partner, friend or neighbor who has a significant personal relationship with, and provides a broad range of assistance for, an older person or an adult with a chronic or disabling condition. These individuals may be primary or secondary caregivers and live with, or separately from, the person receiving care" (5).
Health provider: Refers to both regulated workers (e.g., nurses, physicians, dieticians and social workers) and unregulated workers (e.g., personal support workers) who are part of the interprofessional health team.
Regulated health provider: In Ontario, the Regulated Health Professional Act (RHPA), 1991, provides a framework for regulating 23 health professions, outlining the scope of practice and the profession-specific controlled or authorized acts that each regulated professional is authorized to perform when providing health care and services (6).
Unregulated health provider: Unregulated health providers fulfill a variety of roles in areas that are not subject to the RHPA. They are accountable to their employers but not to an external regulating professional body (e.g., the College of Nurses of Ontario). Unregulated health providers fulfill a variety of roles and perform tasks that are determined by their employer and employment setting. Unregulated health providers only have the authority to perform a controlled act as set out in the RHPA if the procedure falls under one of the exemptions set out in the Act (7).
# BAC K G R O U N D
A Palliative Approach to Care in the Last 12 Months of Life Topics Outside the Scope of this Best Practice Guideline Advance care planning G , grief and bereavement support, palliative care competency requirements, pharmacological interventions and symptom management were considered outside of scope. These subjects have been addressed in recent, evidence-based and credible resources currently in publication and/or in legislation.
See Appendix I for supporting resources related to pain and symptom management.
See Appendix J and K for supporting resources related to palliative care and end-of-life care education and competency resources.
See Appendix M for supporting resources related to advance care planning, and grief and bereavement support.
The scoping review indicated that robust, Canadian-based, peer-reviewed studies that address the role of nurses with MAiD were limited. The role of nurses and MAiD represents an opportunity for future guideline development. In addition, the legislation for MAiD varies between jurisdictions, and this BPG is to be implemented provincially, nationally and internationally.
See Appendix L for supporting resources related to MAiD.
Palliative care and end-of-life care for the pediatric population (i.e., infants and children younger than 18 years) is outside the scope of this BPG. The expert panel recognizes that the pediatric population is a unique population with specific considerations for palliative care and end-of-life care. This therefore represents an opportunity for future guideline development.
This BPG does not address the funding of palliative care and end-of-life care services, although this is an important aspect of every health system and one that governments and government agencies should investigate.
# Differences between this BPG and RNAO's End-of-life Care During the Last Days and Hours (2011) BPG
This BPG does not replace RNAO's 2011 BPG, End-of-life Care During the Last Days and Hours. Rather, the two guidelines differ in the following ways:
The time frame of this BPG extends beyond the last days and hours of life to include the last 12 months of a progressive life-limiting illness in order to provide recommendations that may be implemented earlier in the palliative care trajectory.
Based upon the priority recommendation questions and outcomes identified by the expert panel, practice recommendations within this BPG focus on the psychosocial aspect of care; they do not include activities that address physical symptom management. Attention is given to the spiritual, emotional, existential and cultural domains of care, but the recommendations are meant to be implemented as part of a holistic approach to care, as outlined in Figure 2: Domains of Issues Associated with Illness and Bereavement (10).
# BAC K G R O U N D
A Palliative Approach to Care in the Last 12 Months of Life
# Recommendation Questions
Within the determined scope defined above, the following priority recommendation questions and outcomes were developed by the expert panel. They informed the development of this BPG.
# BAC K G R O U N D
A Palliative Approach to Care in the Last 12 Months of Life Registered Nurses' Association of Ontario Best Practice Guidelines and Resources that Align with this Best Practice Guideline
Other RNAO BPGs and evidence-based resources may support implementation of this BPG. See Appendix B for RNAO BPGs and other resources on the following related topics:
care transitions;
crisis intervention;
constipation;
delirium, dementia and depression;
end-of-life care in the last days and hours;
implementation science, implementation frameworks and resources;
interprofessional collaboration;
pain;
person-and family-centred care;
pressure injuries; and
social determinants of health G .
For more information on the guideline development process, systematic review and search strategy for this BPG, see Appendix D.
# BAC K G R O U N D
A Palliative Approach to Care in the Last 12 Months of Life
# Interpretation of Evidence and Strength of Recommendations
This BPG was developed using an adaptation of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) G and Confidence in the Evidence from Reviews of Qualitative Research (CERQual) G methods. For more information about the guideline development process, including the use of GRADE and GRADE-CERQual methods, see Appendix D.
# Certainty of Evidence
The certainty of evidence (i.e., the level of confidence we have that an estimate of effect G is true) for quantitative research is determined using an adaptation of GRADE methods (11). After synthesizing the evidence for each prioritized outcome, the certainty of evidence is assessed. The overall certainty of evidence is determined by considering the certainty of evidence across all prioritized outcomes of included studies per recommendation. GRADE categorizes the overall certainty of evidence as high, moderate, low or very low. See Table 1 for the definition of these categories.
# Table 1: Certainty of Evidence
# CERTAINTY OF EVIDENCE DEFINITION High
We are very confident that the true effect G lies close to that of the estimate of the effect.
# Moderate
We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
# Low
Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
# Very low
We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
Source: Reprinted from The GRADE Working Group. Quality of evidence. In Schunemann H, Brozek J, Guyatt G, Oxman A, editors. Handbook for grading the quality of evidence and the strength of recommendations using the GRADE approach . : The GRADE Working Group; 2013. Table 5.1, Quality of evidence grades. Available from: #h.wsfivfhuxv4r. Reprinted with permission.
# BAC K G R O U N D
A Palliative Approach to Care in the Last 12 Months of Life
# Confidence in Evidence
The confidence in evidence for qualitative research G (i.e., the extent to which the review finding is a reasonable representation of the phenomenon of interest) is determined using GRADE-CERQual methods (hereafter referred to as CERQual) (12). For qualitative evidence, an overall judgment of the confidence is made per finding in relation to each recommendation statement, as relevant. CERQual categorizes the confidence in evidence as high, moderate, low or very low. See Table 2 for the definitions of these categories.
# CONFIDENCE IN EVIDENCE DEFINITION High
It is highly likely that the finding is a reasonable representation of the phenomenon of interest.
# Moderate
It is likely that the finding is a reasonable representation of the phenomenon of interest.
# Low
It is possible that the review finding is a reasonable representation of the phenomenon of interest
# Very low
It is not clear whether the review finding is a reasonable representation of the phenomenon of interest.
Source: Reprinted from Lewin S, Booth A, Glenton C, Munthe-Kass H, Rashidian A, Wainright M et al. Applying GRADE-CERQual to qualitative evidence synthesis findings: introduction to the series. Implement Sci. 2018;13(Suppl 1):1-10. Table 3, Description of level of confidence in a review finding in the CERQual approach; p. 6. Reprinted with permission.
The assigned certainty and/or confidence of evidence can be found directly below each recommendation statement. For more information on the process of determining the certainty and/or confidence of the evidence and the documented decisions made by RNAO guideline development methodologists, see Appendix D. NOTE: Due to the complex and multi-faceted nature of palliative care and end-of-life care, the use of control G groups and the adjustment of confounding variables G are difficult to achieve. Therefore, the majority of research in this area was from observational or non-randomized studies as opposed to randomized controlled trials G (which eliminate contextual factors). For this reason, all of the recommendations have a certainty of evidence that is either low or very low. Despite the generally low certainty of evidence, however, the expert panel determined that the benefits, values and preferences for many of the interventions outweighed the potential harms noted in the research evidence or from personal practice experience. As such, the strength of many of the recommendations is strong (see Strength of Recommendations). This also highlights the need for more rigorous research in the areas of palliative care and end-of-life care.
# BAC K G R O U N D
A Palliative Approach to Care in the Last 12 Months of Life
# Strength of Recommendations
Recommendations are formulated as strong or conditional by considering the certainty and/or confidence in evidence, and the following key criteria (see the relevant Discussion of Evidence, below, for definitions):
balance of benefits and harms values and preferences health equity.
# Strong Recommendation
A strong recommendation reflects the expert panel's confidence "that the desirable effects of an intervention outweigh its undesirable effects (strong recommendation for an intervention) or that the undesirable effects of an intervention outweigh its desirable effects (strong recommendation against an intervention)" (11). A strong recommendation implies that the majority of persons will be best served by the recommended action (11).
# Conditional Recommendation
A conditional recommendation reflects the expert panel's confidence that while some uncertainty exists, the desirable effects probably outweigh the undesirable effects (i.e., a conditional recommendation for an intervention) or that the undesirable effects probably outweigh the desirable effects (i.e., conditional recommendation against an intervention) (11). A conditional recommendation implies that not all persons will be best served by the recommended action: "there is a need for more careful consideration of personal circumstances, preferences and values" (11).
Note: The strength of the recommendation statement is detailed directly below each recommendation statement and in the Summary of Recommendations. For more information on the process the expert panel used for determining the strength of each recommendation, please see Appendix D.
# Discussion of Evidence
The Discussion of Evidence that follows each recommendation includes the following main sections.
- Benefits and Harms: Identifies the potential desirable and undesirable outcomes reported in the literature when the recommended practice is used. Content in this section solely includes research from the systematic review.
- Values and Preferences: Denotes the relative importance or worth placed on health outcomes from following a particular clinical action from a person-centered perspective. Content for this section may include research from the systematic reviews and, when applicable, observations and/or considerations from the expert panel.
# Health Equity:
Identifies the potential impact that the recommended practice could have on health across different populations and/or barriers to implementing the recommended practice in particular settings. This section may include research from the systematic reviews and, when applicable, observations and/or considerations from the expert panel.
# Expert Panel Justification of Recommendation:
Provides a rationale for why the expert panel made the decision to rate a recommendation as strong or conditional.
- Practice Notes: Highlights pragmatic information for nurses and members of the interprofessional health team. This section may include supporting evidence from the systematic review and/or from other literature and sources (e.g., the expert panel).
# BAC K G R O U N D
A Palliative Approach to Care in the Last 12 Months of Life 6. Supporting Resources: Includes a list of relevant resources (e.g., websites, books and organizations) that support the recommendations. As there are numerous accessible palliative care and end-of-life care resources this section includes a sample published within the last five to six years and that aligns with the recommendations (with the exception of unique or seminal publications). Content listed in this section was not part of the systematic review and was not quality appraised. As such, the list is not exhaustive, and the inclusion of a resource in one of these lists does not imply an endorsement from RNAO.
Note: Palliative care and end-of-life care legislation can vary between jurisdictions. The supporting resources have been organized to identify resources found within Ontario and those that exist outside of the province.
# BAC K G R O U N D
A Palliative Approach to Care in the Last 12 Months of Life
# Summary of Recommendations
# RECOMMENDATIONS STRENGTH OF THE RECOMMENDATION
Recommendation Question #1:
Should an interprofessional approach be recommended for the provision of care to adults in the last 12 months of life?
Outcomes: Outcomes: Person and family experience with care; effectiveness of provided care from the person and family perspective; access to care; coordination of care; transitions in care; effectiveness of provided care from the health provider perspective Recommendation 1 .1:
The expert panel recommends that health-service organizations implement an interprofessional model of care for the provision of palliative care and end-of-life care to persons and families .
# Strong Recommendation 1 .2:
The expert panel recommends that the interprofessional health team, in collaboration with the person and family, develop an individualized, person-centred plan of care and re-evaluate the plan of care based on the changing status, needs and preferences of the person .
# Strong
Recommendation Question #2:
What nurse-led interventions should be recommended for a palliative approach to the delivery of care in the last 12 months of life?
Outcomes: Outcomes: Support for spiritual care; support for emotional care; support for existential care; care in alignment with the person's wishes; culturally safe care; place of death
The following recommendations are applicable within the context of an interprofessional health team (see Recommendations 1 .1 and 1 .2) .
Recommendation 2 .1:
The expert panel recommends that nurses assess the cultural needs and values of persons and families .
# Strong Recommendation 2 .2:
The expert panel recommends that nurses perform ongoing assessments of persons and families for the following:
values, beliefs, expectations and preferences about progressive life-limiting illness and death; and preferred place of death .
# Strong BAC K G R O U N D
A Palliative Approach to Care in the Last 12 Months of Life Recommendation 2 .3:
The expert panel suggests that as part of a holistic assessment, nurses assess the spiritual, emotional and existential needs of persons and families, including:
concerns about end of life; and presence of spiritual, emotional and existential distress .
# Conditional Recommendation 2 .4:
The expert panel recommends that nurses address the person's and family's palliative care and end-of-life care expectations .
# Strong
Recommendation 2 .5:
The expert panel suggests that nurses provide opportunities for life reflection to persons and families .
# Conditional Recommendation 2 .6:
The expert panel recommends that nurses facilitate access to resources, space and services needed by persons and families for cultural, spiritual and/or religious practices .
# Strong Recommendation 2 .7:
The expert panel recommends that for persons who prefer to die at home, health-service organizations implement high-quality home and community care, which includes:
access to after-hours services; care coordination; and support provided by an interprofessional health team .
# Strong
Recommendation Question #3: Should continuing education, targeted skills training and debriefing be recommended for supporting nurses and the interprofessional health team who provide care to persons in the last 12 months of life and their families?
Outcomes: Outcomes: Compassion fatigue; stress/distress; resilience
The following recommendations are applicable to nurses and the interprofessional health team who provide palliative care and end-of-life care to persons, their families and their caregivers . The expert panel recommends that health-service organizations provide education and skills training for nurses and the interprofessional health team related to self-care, including stress management and mitigation of compassion fatigue .
# Strong Recommendation 3 .2:
The expert panel recommends that health-service organizations provide time and resources for nurses and the interprofessional health team to engage in debriefing .
# Strong BAC K G R O U N D
A Palliative Approach to Care in the Last 12 Months of Life
# Best Practice Guideline Evaluation
As you implement the recommendations in this BPG, we ask you to consider how you will monitor and evaluate its implementation and impact.
The Donabedian model informs the development of indicators for evaluating quality health care. It includes three categories: structure, process and outcome (13).
Structure describes the required attributes of the health system, health-service organization or academic institution to ensure quality care. It includes physical resources, human resources, and information and financial resources.
Process examines the health activities being provided to, for and with persons or populations as part of the provision of quality care.
Outcome analyzes the effect of quality care on the health status of persons and populations, health workforce, health-service organizations, academic institutions or health systems (13).
For additional information, please refer to the RNAO Toolkit: Implementation of Best Practice Guidelines, Second Edition (2012).
It is important to evaluate evidence-based practice changes when implementing a BPG. Tables 3 and 4 provide potential process and outcome measures to assess BPG success. Select the measures most relevant to the practice setting. The data repositories and indicator libraries available for palliative care and end-of-life care are outlined to support quality improvement and evaluation.
Table 3 supports evaluation of practice changes during implementation. The measures are directly associated with specific recommendation statements and support process improvement.
# Stakeholder Acknowledgment
As a component of the BPG development process, feedback was obtained from participants across a wide range of health-service organizations, academic institutions, practice areas and sectors. Participants include nurses and other members of the interprofessional team, educators, students, and knowledgeable administrators. Stakeholders G representing diverse perspectives were also solicited for their feedback (see Appendix D). RNAO wishes to acknowledge the following individuals for their contribution in reviewing this BPG. Stakeholder reviewers have given consent to the publication of their names and relevant information in this BPG.
# BAC K G R O U N D
A Palliative Approach to Care in the Last 12 Months of Life
# Background Context
What Are Palliative Care and End-of-life Care?
Palliative care refers to a philosophy and an approach to care. Palliative care aims to improve the quality of life for persons facing life-limiting illness and their families through the prevention and relief of suffering. It does this through the early identification, assessment and treatment of symptoms (4). Palliative care extends across the trajectory of life-limiting illness, including care at the point of diagnosis, during treatment and at the end of life, as well as grief and bereavement support (see Figure 1 for a visual depicting the palliative care trajectory). Note: Other models exist that provide visual depictions of palliative care. One example is The Bow Tie Model by Dr. Pippa Halwey. For more information, please visit +Site+Navigation/Home/ For+Professionals/For+Professionals/The+Exchange/Current/The+Bow+Tie+Model+of+21st+Century+Palliative+C are.aspx
According to the CHPCA, palliative care (also referred to as "hospice palliative care") is an approach to care that aims to do the following:
Relieve suffering and improve the quality of living and dying.
Address the physical, psychological, social, spiritual (existential) and practical issues of persons and their families, and their associated expectations, needs, hopes and fears.
Prepare persons and their families for self-determined life closure and the dying process and help them manage it.
Help families cope with loss and grief during the illness and bereavement experience.
Treat all active issues, prevent new issues from occurring and promote opportunities for meaningful and valuable experiences, personal and spiritual growth, and self-actualization (10).
# BAC K G R O U N D
A Palliative Approach to Care in the Last 12 Months of Life
Based on these key aims, the recommendations within this BPG focus on quality of life, emphasizing a holistic approach to care that incorporates the person's individuality and preferences, and that recognizes the person and family as the unit of care. Figure 2 identifies complex issues persons and their families may face when receiving palliative care, which are categorized into eight equally important domains (10). End-of-life care is a component of the palliative care trajectory, and it specifically refers to care for persons who are expected to die in the foreseeable future and their families (refer to Figure 1). It includes helping persons and families prepare for death, ensuring their comfort and supporting decision making that is consistent with the person's prognosis and goals of care (3).
# BAC K G R O U N D
A Palliative Approach to Care in the Last 12 Months of Life
# Delivery of Palliative Care and End-of-life Care
The delivery of palliative care and end-of-life care is based on comprehensive and ongoing assessment of the needs of persons and families, along with their wishes and preferences (15). Depending on where the person is along the illness trajectory, considerable variability exists with respect to the type and level of care and the services that are required from health providers. See Figure 3 for a model depicting the illness trajectory, complexity of needs and level of service. For more information regarding the trajectories of illnesses, please refer to the Gold Standards Framework Proactive Identification Guidance, available at / uploads/files/PIG/NEW%20PIG%20-%20%20%2020.1.17%20KT%20vs17.pdf. The majority of persons and families will receive palliative care from primary care clinicians and non-specialist palliative care providers (Patient C in Figure 3). Complex issues facing persons and families may require the involvement of specialist palliative care teams, such that a consultation and shared care approach is used to assist non-specialist palliative care providers in delivering care (Patient B in Figure 3). In a smaller number of cases, complex palliative care needs may necessitate the transfer of care to specialist palliative care teams (Patient A in Figure 3).
As the needs of persons and families are multi-faceted, palliative and end-of-life care are most effective when delivered by an interprofessional health team that is knowledgeable and skilled in palliative care and end-of-life care (10). The interprofessional health team consists of regulated and unregulated care providers, as well as volunteers, family caregivers, and persons and their families.
# BAC K G R O U N D
A Palliative Approach to Care in the Last 12 Months of Life
# Access to Palliative Care and End-of-life Care
Palliative care and end-of-life care are appropriate for any person and their family living with (or at risk of) developing a progressive life-limiting illness. In other words, persons facing any diagnosis-regardless of prognosis and age-who have unmet needs and/or expectations can have palliative care and end-of-life care when they are ready to accept it. It is important for persons to receive palliative care as early as possible along their illness trajectory. Compared to late palliative care initiation, early access to palliative care has been found to be associated with improved end-of-life outcomes and lower odds of using acute care services (22). Despite this, access to palliative care services is not equitable across Canada (16). For example, of the persons who died in Ontario in the 2014/15 calendar year, only 57 per cent received at least one palliative care service, while 40.5 per cent did not receive any palliative care services (17). Of those who did receive palliative care, the majority (60.6 per cent) only received care within the last one to two months of life (17). Across disease groups, a report from the Canadian Institute for Health Information (CIHI) found that persons with cancer are three times more likely to receive palliative care than others, and adults aged 45 to 74 years are more likely than younger adults and older adults to receive palliative care across most care settings (16).
A major barrier to access of palliative care and end-of-life care services is cost. For example, the average cost of endof-life care per person in the last year of life is greater than $50,000 in Ontario, with inpatient care and long-term care representing a substantial portion of total end-of-life care costs (23). For Ontarians receiving palliative care services within the home G , the total cost has been estimated to be approximately $25,000 per month, with $17,500 per month due to lost wages and leisure time for caregivers (17). Not surprisingly, these home-based palliative care services are less likely to be used by persons living in the poorest neighbourhoods compared to those living in the wealthiest neighbourhoods (17). Therefore, funding models to support equitable access to palliative care and end-of-life services are an important aspect of every health system and one that government and government agencies need to address.
Inequitable access to palliative care and end-of-life care services is perhaps most prominent for persons who are structurally vulnerable G (e.g., persons who are experiencing homelessness) who tend to have inequitable access due to social, economic and environmental factors (18). A systematic review found that barriers to providing care to persons experiencing homelessness and who were seriously ill included: a small social network and lack of support from family and friends, limited insight into their health, living on a "day-to-day" basis with end of life not being a priority, and the belief G that health providers do not have the knowledge and skill to meet their palliative and endof-life care needs (187). Although the recommendations in this BPG are clinically applicable to all populations, a fundamental barrier to their implementation is the inequitable access to palliative care and end-of-life care services across all populations. For that reason, awareness and capacity to provide care to diverse populations, inclusive of principles of culturally safe and trauma-informed approaches, remains a priority in palliative care and end-of-life care.
For more information regarding social determinants of health, please refer to the RNAO Social Determinants of Health Brochure: RNAO.ca/sites/rnao-ca/files/rnao_sdh_brochure_2013.pdf. For more information regarding Ontario's action plan for access to equitable palliative care, please refer to the Ontario Palliative Care Network Action Plan 1: 2017-2020: www.ontariopalliativecarenetwork.ca/sites/opcn/files/OPCNActionPlan1.pdf.
# BAC K G R O U N D
A Palliative Approach to Care in the Last 12 Months of Life
# Psychosocial Needs of Health Providers
Health providers who work in palliative care and end-of-life care are often faced with highly emotional situations. When health providers regularly encounter pain, suffering, death and grief, this can manifest in compassion fatigue and stress (24,25). Compassion fatigue is a state of "physical and mental exhaustion and emotional withdrawal experienced by those that care for sick or traumatized people over an extended period of time" (26). Recent literature indicates that 52.55 per cent of nurses experience compassion fatigue (27).
Long-lasting compassion fatigue has been linked to negative outcomes at the individual and organizational levels. For the individual health provider, ongoing compassion fatigue may result in: increased fatigue; feelings of hopelessness, frustration and despair; negative impacts on personal relationships; and thoughts of leaving the profession (28,29). At the organizational level, compassion fatigue may result in high staff turnover rates and increased staff shortages (25,30). High turnover is linked to significant financial costs for the organization, and most importantly, to adverse patient outcomes (31,32).
In order to mitigate the negative consequences related to compassion fatigue and stress, strategies to develop resilience and self-care for health providers are required. Resilience refers to a person's ability to thrive in the face of stress and traumatic experiences (33). Increased resilience is associated with improved health, well-being and job satisfaction for health providers; by developing resilience and self-care strategies, they can proactively recognize and mitigate signs of compassion fatigue and stress (24). Health-service organizations also have a responsibility to create environments that promote resilience through interventions that focus on education and skill-building for self-care (24,34,35).
# Conclusion
This BPG provides evidence-based best practice recommendations for health-service organizations, nurses and members of the interprofessional health team to support adults (18 years and older) who are experiencing the last 12 months of progressive life-limiting illness, their families and their caregivers.
# RECOMMENDATIONS
A Palliative Approach to Care in the Last 12 Months of Life
# Recommendations
# RECOMMENDATION QUESTION #1:
Should an interprofessional approach be recommended for the provision of care to adults in the last 12 months of life?
Outcomes: Person and family experience with care; effectiveness of provided care from the person and family perspective; access to care; coordination of care; transitions in care; effectiveness of provided care from the health provider perspective RECOMMENDATION 1.1:
The expert panel recommends that health-service organizations implement an interprofessional model of care for the provision of palliative care and end-of-life care to persons and families.
# Strength of the recommendation: Strong
# Certainty of the evidence of effects: Low
Confidence in the evidence: Low
# Discussion of Evidence: Benefits and Harms
Within the literature, interprofessional models of care consisting of varying team compositions were explored within diverse health settings. An interprofessional model of care refers to a team of different health providers (regulated and unregulated) working together towards a common goal to meet the needs of a patient population. Within this model, team members divide the work based on their scope of practice, sharing information to support their respective work and coordinating processes and interventions to provide a number of services and programs (8). In palliative care and end-of-life care, the person and family are included as key members of the interprofessional health team.
Evidence suggests that interprofessional models of care may improve: (a) the effectiveness of care from the perspective of persons, families and health providers; (b) the experience that a person and their family have with care; and (c) the coordination of care.
# Effectiveness of Care from the Perspective of Persons, Families and Health Providers
The effectiveness of interprofessional models of care from the perspective of the person and/or their family has been reported in the literature. An interprofessional model of care has the potential to improve the experiences of care for persons and families through increased satisfaction and improved care (36). For example, patients at an interdisciplinary palliative care out-patient clinic felt that interprofessional care: (a) increased the frequency and timeliness of symptom assessments; (b) improved the person's understanding of medications, side effects and pain management; and (c) ultimately supported enhanced symptom management and care coordination G (37).
# RECOMMENDATIONS
A Palliative Approach to Care in the Last 12 Months of Life Evidence suggests that health providers also may find interprofessional models of care to be effective. For example, interprofessional health teams may support stronger relationships with the person and family, and they may aid in reducing power imbalances between the interprofessional health team, the person and their family (38). Health providers also report that interprofessional collaboration can promote greater productivity, flexibility and shared responsibility, enabling them to achieve the person's care goals (39). In one study, four health provider groups (physicians, nurses, social workers and spiritual care providers) felt positively about interprofessional collaboration and rated their hospice work environments as supportive. However, social workers reported feeling less valued and connected to other members of the interprofessional health team (38).
# Person and Family Experience with Care and Coordination of Care
Interprofessional models of care also may affect the experience that persons and families have with the care they receive. Interprofessional care may increase psychological support and support for daily living activities for the person while decreasing caregiver burden and anxiety (40). Persons and families also report increased satisfaction with care and improved quality of life when receiving care from a specialized out-patient palliative care team (40,41).
With respect to experiences with care and coordination of care, qualitative evidence suggests that persons with a progressive life-limiting illness and their families who are cared for by an interprofessional health team report: (a) improved continuity of care and holistic care; and (b) increased feelings of security, timely care and responsiveness of health providers when accommodating changing conditions (42).
Although there are findings to support the improved experiences of persons and families with care and the increased coordination of care that are linked to interprofessional models of care, one study demonstrated that communication with health providers may not be enhanced by an interprofessional model of care (40).
# Values and Preferences
An interprofessional model of care was positively received, both from the perspective of persons and from health providers (39)(40)(41). Health providers who engaged in interprofessional rounds for palliative care reported that the approach facilitated communication and added value to patient care without increasing burden (44).
# Health Equity
The expert panel acknowledged that across health-service organizations, there may be inequitable access to the health human resources required to implement interprofessional models of care in an effective way. In rural and remote areas, access to certain health provider groups is limited due to the lower number of health providers employed in these areas (45). As an alternative, the expert panel suggests that telemedicine can be used to support increased access to an interprofessional health team, including in rural and remote geographical areas. The authors of one study outlined the benefits of including a telephone service to increase accessibility to interprofessional models of care, particularly for individuals living in remote areas (37).
# Expert Panel Justification of Recommendation
The expert panel attributed value to the interprofessional model of care, wherein interprofessional health teams practice with a shared purpose to provide holistic person-and family-centered care. The expert panel determined that the benefits of interprofessional care outweighed the harms, and that persons experiencing the last 12 months of progressive life-limiting illness would value improvements in the effectiveness, coordination and experiences of
# RECOMMENDATIONS
A Palliative Approach to Care in the Last 12 Months of Life the care they received. Despite the fact that there was a low certainty of evidence and low confidence in the evidence, there were several benefits identified to having an interprofessional approach to care, and few harms were reported.
For that reason, the expert panel determined the strength of the recommendation to be strong.
# Practice Notes
Interprofessional health teams vary in composition, depending on the health setting (e.g., hospice, acute care, home care or long-term care), so the exact composition of team members required for interprofessional palliative care and end-of-life care is context-dependent and based on the needs of the person receiving care and their family. Regardless, each team member's role should be clearly communicated within the interprofessional health team, as clarity of roles facilitates the provision of coordinated care (47).
Within the research literature, interprofessional health teams who provide palliative care and end-of-life care services generally include a combination of regulated and unregulated health providers, such as: (54).
The expert panel further notes that nurse practitioners, volunteers, Indigenous spiritual/traditional healers, elders and medicine persons are key members of the interprofessional health team.
The expert panel highlighted the importance of clear and ongoing communication between interprofessional health team members, the person and the family. Clear and ongoing communication promotes a mutual understanding of the person's goals of care and avoids potential distress resulting from persons and families having to repeat information to multiple interprofessional health team members.
It is important for health-service organizations to provide access to and support the use of documentation systems that enable equal access to and timely sharing of information between interprofessional health team members.
# RECOMMENDATIONS
A The expert panel recommends that the interprofessional health team, in collaboration with the person and family, develop an individualized, person-centred plan of care and re-evaluate the plan of care based on the changing status, needs and preferences of the person.
# Strength of the recommendation: Strong
# Certainty of the evidence of effects: Low
Confidence in the evidence: Low
# Discussion of Evidence: Benefits and Harms
The evidence on the development of a plan of care G by the interprofessional health team varied with respect to team composition and health context. However, the literature generally demonstrated that the development of an individualized person-centred plan of care by the interprofessional health team-in collaboration with the person receiving care and their family-may improve transitions in care, coordination of care, access to care, and the experiences of care for persons and families.
# Transitions in Care and Coordination of Care
Care planning with an interprofessional health team can promote the provision of holistic care, because the perspectives gained from interprofessional health team discussions may be more comprehensive than independent provider assessments (50). Developing a plan of care with the interprofessional health team, the person receiving care and their family involves shared decision-making G and ongoing communication. This communication and collaboration improves transitions in care, including both the quality of a person's transition to end-of-life care and the transition from home care to an in-patient hospice setting (51,55). In one qualitative research G study, individualized plans of care were discussed with persons and their families during home visits prior to being reviewed at interprofessional health team meetings. Plans of care were subsequently modified based on the changing physical and psychological needs of the person and family. If care could not be provided in the home, and if hospice eligibility was met, the transition to a hospice setting was facilitated (51). In rural environments, care coordination was supported by members of the interprofessional health team, with health providers discussing their unique roles on the team to help ensure that persons with progressive life-limiting illness and their families received appropriate and comprehensive care (45).
# Experiences of Care for Persons and their Families, and Access to Care
Active involvement of the person and family in care planning with the interprofessional health team may facilitate positive person and family experiences, and it may increase satisfaction with care (48). For persons with early-stage cancer, for instance, evidence indicates that care planning with the interprofessional health team may improve the person's quality of life and spiritual well-being and reduce psychological distress (53). Furthermore, with regards to access to care, interprofessional care planning may increase the number of referrals to specialized services, including referrals to palliative care, supportive care, chaplaincy, nutrition and social work (53). Care planning with the person, family and interprofessional health team also may allow for discussion and acknowledgement of the person's preference for place of death and improve the person's emotional responses to dying (49,51). A reduction of pain experienced by the person also may occur (49).
# RECOMMENDATIONS
A Palliative Approach to Care in the Last 12 Months of Life Care planning with the interprofessional health team also may improve the family's experience with care received. For example, caregivers who are part of end-of-life discussions report increased satisfaction with care, and they are more receptive to bereavement visits and experience less distress during those visits (49). When families are included in the care planning process, family caregivers report improvements in their quality of life, a reduction in psychological distress and a reduction in caregiver burden (52).
Interestingly, one study found that caregivers who are not part of interprofessional care planning may have greater spiritual well-being than those who are part of the care planning. The authors of the study report that this may be due to the intervention being provided with insufficient frequency, and that minimal content related to spiritual wellbeing was discussed during the intervention (52).
# Values and Preferences
Persons value being involved in care planning, and because their family may represent a source of social support, both groups value the opportunity to be involved in decision-making (56).
# Health Equity
The expert panel recognizes that some persons receiving palliative care and end-of-life care may have reduced social and financial resources; this may influence individualized care planning and transitions in care (51). The expert panel also acknowledged that access to the resources required for an interprofessional approach to care planning may be limited in certain health-service organizations or geographical locations, which can negatively impact health equity. For example, one study found that when access to specific health providers was limited, functioning of the interprofessional health team and overall care delivery were affected (50).
In another study, providers in rural environments recognized their role in collaborating with one another to advocate for the needs of populations underserved by the health system. While meeting face-to-face with persons with progressive life-limiting illness and their families was valued, providers reported that opportunities and resources were not readily available to them to engage in interprofessional care planning in an effective manner (45).
# Expert Panel Justification of Recommendation
There were several benefits identified when the person and their family collaborated with the interprofessional health team in their care planning, and no harms were found. Despite the low certainty of evidence and low confidence in the evidence, the expert panel determined that persons and their families would value improvements in: (a) coordination of care, (b) transitions in care, (c) access to care, and (d) experiences with care. For that reason, the expert panel determined the strength of the recommendation to be strong.
# RECOMMENDATIONS
A Palliative Approach to Care in the Last 12 Months of Life
# Practice Notes
Implementation considerations from the expert panel:
Early referrals to interprofessional palliative care teams, along with early conversations between persons with progressive life-limiting illness, families and the interprofessional health team are important in order to discuss preferences, values and plans of care. The importance of early conversations and care planning with the interprofessional health team, person and family is also echoed in the literature (53). If conversations with the person are initiated in the later stages of a person's illness, they may be too unwell to participate in discussions regarding their transitions in care (55).
Plans of care should be modified in a timely manner based on the changing health status and the needs of the person and family. This will help to support coordination of care, transitions in care and positive person and family experiences.
Documenting and sharing the plan of care between interprofessional health team members is important. Ongoing and frequent communication (in-person or through written or electronic documentation) between the interprofessional health team and the person and family is a facilitator to achieving the benefits of coordinated and collaborative care planning (47).
In order to support coordination and continuity in care, interprofessional collaboration should exist both within and between health-service organizations when persons and families transition between settings.
# RECOMMENDATION 2.1:
The expert panel recommends that nurses assess the cultural needs and values of persons and families.
# Strength of the recommendation: Strong
Confidence in the evidence: Low
# Discussion of Evidence: Benefits and Harms
Qualitative evidence indicates that assessing the cultural needs G and values of persons and families enables nurses to provide culturally safe palliative care and end-of-life care, bridge gaps in communication and gain an inclusive understanding of the person and family (19,57). In some cases, language barriers can make it difficult to understand a person's cultural beliefs, needs and values; this can potentially lead to gaps in communication, as persons and families are unable to express their needs and wishes and/or health providers have difficulty understanding them (57). Table 5 provides information from the literature on the components of cultural assessments and on strategies for conducting them.
# Values and Preferences
No literature was identified that reported on the values and preferences of persons, their families or their health providers with respect to assessing the cultural needs and values of persons and families.
# Health Equity
Incorporating a cultural assessment as part of a comprehensive assessment promotes inclusive care for all populations (19). When language barriers exist, access to high-quality translation services represents an important factor in effectively communicating with persons and families; however, not all health-service organizations have the funding and resources to implement translation services. It is important to note that translation is not interpretation: translation services that can interpret information, promote understanding and meet the individual needs of persons and families are required.
# RECOMMENDATIONS
A Palliative Approach to Care in the Last 12 Months of Life
# Expert Panel Justification of Recommendation
The expert panel attributed value to conducting cultural assessments so that care plans can be tailored to the person's needs and preferences. Moreover, the expert panel determined that persons would value even small improvements in their care if they received culturally safe care that was in alignment with their wishes. Therefore, despite the fact that there was low confidence in the evidence, the expert panel determined the strength of the recommendation to be strong.
# Practice Notes
Organizational policies for health providers are required in order to facilitate culturally safe care in palliative care and end-of-life care (46).
Nurses should regularly assess their knowledge level and ability to conduct an appropriate cultural assessment prior to doing so in clinical practice, and the expert panel highlights that trust must be established before conversations with persons and families occur. Furthermore, communication is central to culturally safe care, and nurses must avoid making assumptions about persons and families, regardless of their cultural, ethnic or spiritual background (46,61).
The expert panel emphasized that culture is unique to each individual, and there are individual differences within the same cultural umbrella.
While culture is defined broadly, evidence within the systematic review was not found specific to certain population groups. Research is required in these areas. Refer to Table 10 for research gaps and future implications.
# Components of cultural assessments
Components within the research included:
Exploring the person's family context, coping strategies, holistic needs, expression of emotions, meaning of behaviours and all dimensions of pain (57).
Within the literature, nurses reported that because a person's experience of suffering is multidimensional, it was valuable to explore their experience from various domains in order for the person to feel truly understood (19).
Components identified by the expert panel:
Asking persons and families if they have any religious or cultural concerns related to progressive life-limiting illness and death may assist in assessing the cultural needs and values of persons and families.
For a subset of the population, culture and spirituality are intertwined; thus, acknowledging both domains during a cultural assessment may be warranted (see Recommendations 2.2 and 2.6).
# RECOMMENDATIONS
A Palliative Approach to Care in the Last 12 Months of Life
# Strategies for conducting cultural assessments
Strategies within the research included:
Nurses observed persons and families to learn about care practices and inquired about practices that would typically be conducted at home (57).
A cultural assessment may also involve the active involvement of family, including determining the family contact person, exploring factors of personal importance to the family and examining family communication (57).
Strategies identified by the expert panel:
Cultural assessments should be implemented and completed as part of a holistic approach to care, as outlined in Figure 2
# Discussion of Evidence: Benefits and Harms
The research evidence demonstrates the importance of nurses discussing with persons and their families their values, beliefs, expectations and preferences about their life-limiting illness, death and preferred place of death. Doing so will support future care planning and the person's ability to experience a death in alignment with their wishes.
# Values, Beliefs, Expectations and Preferences about Progressive Life-limiting Illness and Death
Qualitative evidence demonstrates that when nurses and other health providers discuss care preferences with persons and their families, it may promote the establishment of a trusting rapport between the nurse and patient, encourage open communication and allow them to identify areas in which coordination of care is required (62). Engaging and supporting the person to be involved actively in the decision-making process also can have psychological benefits for the person, including providing them with a sense of control and self-determination (62). In a study that evaluated a nurse practitioner-directed intervention that focused on the effect of exploring the values, beliefs, preferences and expectations of persons, the emotional well-being of persons at the end of life was found to improve; however, the intervention was not found to have an impact on their spiritual well-being (63).
# Preferred Place of Death
Examining a person's preferred place of death can promote a holistic approach to care (e.g., emotional and psychological) that extends beyond physical symptom management. Nurses within a qualitative study acknowledged that a person's preferred place of death may change over time or may not be feasible; however, initiating the conversation with the person is viewed as an important first step in assessing whether the person's request is attainable (62). Potential issues may arise if a person's care preferences are not feasible; this can result in negative emotional outcomes for persons, families and health providers (62).
# Values and Preferences
Changes in care preferences are occasionally associated with alterations in a person's health condition, but the experience and direction of these changes are unique to the person receiving the care (67). Potential shifts in a person's care preferences indicate a need for ongoing assessment of their care preferences as end of life approaches (68).
# RECOMMENDATIONS
A Palliative Approach to Care in the Last 12 Months of Life
One study noted that discussing the topic of a person's preferred place of death too early, particularly if the person is not yet aware of their proximity to death, may be perceived as unsupportive and uncaring (62). When persons do not wish to engage in discussion on topics such as preferred place of death, the topic can be revisited at a more appropriate time, depending on the person's needs and wishes (62). The expert panel acknowledged that the interprofessional health team should explore the person's understanding of their illness early in the palliative care trajectory, before conversations are initiated regarding a person's preferred place of death.
# Health Equity
A person's decision with regards to preferred place of death is multi-faceted. The expert panel highlights that a person's choice for preferred place of death may be influenced by access to supportive care providers, living in rural or remote areas, complications of illness, access to supplies and medication, and caregiver burnout G . These factors can ultimately impact health equity.
Unfortunately, although the evidence shows that most people prefer to die at home, over 60 per cent of Canadians continue to die in hospitals, and only 15 per cent receive palliative home care services in the last month of life (16,64,65).
# Expert Panel Justification of Recommendation
Despite the very low certainty of the evidence of effects and the low confidence in the evidence, the expert panel determined that the benefits outweigh the harms when it comes to assessing the preferred place of death and the values, beliefs, expectations and preferences of a person and their family. The expert panel also believes that persons would value improvements in spiritual, emotional, existential and culturally safe care, and that they would appreciate receiving care in alignment with their wishes. For that reason, the panel determined the strength of the recommendation to be strong.
# Practice Notes
Persons with progressive life-limiting illness experience changes regarding expectations for their life and future as they come to terms with the nature of their illness (66). The expert panel emphasized that the conversation about preferred place of death is dynamic, and that assessment must continuously occur as the person's condition and needs change (i.e., it is not a static situation). Ongoing assessments reflect that status and needs of the person, and thus may include re-assessments as well as new assessments.
The expert panel also highlights the importance of considering the family and substitute decision-makers G in discussions regarding preferred place of death.
The expert panel emphasized that communicating assessments to the interprofessional health team is important. It is also important to document the person's preferences in their plan of care and to re-assess as changes occur; this will allow attention to be paid to the person's care expectations throughout the trajectory of their illness (62).
Refer to Appendix M for resources related to advance care planning and goals of care.
# RECOMMENDATIONS
A
# RECOMMENDATIONS
A Palliative Approach to Care in the Last 12 Months of Life
# RECOMMENDATION 2.3:
The expert panel suggests that as part of a holistic assessment, nurses assess the spiritual, emotional and existential needs of persons and families, including:
concerns about end of life; and presence of spiritual, emotional and existential distress.
# Strength of the recommendation: Conditional
# Certainty of the evidence of effects: Very low
Confidence in the evidence: Low
# Discussion of Evidence: Benefits and Harms
Assessing the spiritual, emotional and existential needs of persons and families represents one important aspect of person-and family-centered holistic care. Refer to Table 6 (below) for strategies identified within the literature to assess the spiritual, emotional and existential needs of the person and their family.
# Assessment of Spiritual, Emotional and Existential Needs
When assessing for spiritual, emotional and existential needs, health providers asked questions pertaining to a range of topics, including the following:
concerns, hopes, dreams and wishes;
feelings of peace;
impact of illness on family;
whether the person is part of a spiritual or religious community; and meaning behind feelings of sadness, guilt or defeat (69).
Evidence suggests that persons and families may respond positively to nurse-led spiritual assessments. In a study by Taylor & Brander (2013), persons were given a 21-item spiritual assessment questionnaire to ascertain their comfort level when being asked questions pertaining to spirituality. Approximately 25 per cent of the respondents "liked to be asked", approximately 50 per cent were "okay" with being asked, and approximately 25 per cent "did not want to be asked" questions pertaining to spirituality (70). Persons were also receptive to questions about support systems, because it allowed them to reflect on what was helpful to them during difficult times in the past, and it prompted them to recall positive aspects of their lives (70). Moreover, when nurses supported persons to share their feelings, persons were able to gain trust in the nursing care they received (71). However, nurses also reported instances in which the family was not psychologically prepared to discuss loss; this in turn caused distress for the person, their family and the nurse (69).
# RECOMMENDATIONS
A Palliative Approach to Care in the Last 12 Months of Life
# Presence of Spiritual, Emotional and Existential Distress
In a qualitative study, hospice nurses emphasized the importance of identifying spiritual distress in persons with life-limiting progressive illness, and they recognized this as an experience unique to each individual (72). Moreover, these domains can be heavily intertwined with a person's physical health, such that nurses in one study assessed for existential and spiritual distress during their assessment of the person's total pain experience (73). When hospice nurses recognize and provide the appropriate care to persons in spiritual distress, nurse-person relationships may be positively impacted. For example, when persons were actively in distress, hospice nurses used open-ended questions to explore the person's feelings and provide them with the opportunity to express their emotions, if they desired. Thus, hospice nurses who engaged in conversation with the person in a professional manner allowed persons to express their emotions, obtain needed support and alleviate emotional suffering (74).
# Values and Preferences
Variability in preferences regarding spiritual, emotional and existential assessments was found in the literature. In one study, some persons did not wish to be asked about their involvement in a religious community, and they felt that it was inappropriate for nurses to ask questions about their spiritual beliefs (70). Some persons and families stated that they preferred their spiritual assessment to be conducted first by spiritual care experts, followed by counselors and then nurses (70).
# Health Equity
The expert panel acknowledged that health equity may vary due to issues related to resources and staffing, in addition to provider education and training in how to conduct spiritual, emotional and existential assessments for persons with a life-limiting progressive illness.
# Expert Panel Justification of Recommendation
There were both benefits and harms identified for completing spiritual, emotional and existential assessments. The expert panel noted that although conducting these assessments is valuable, not all individuals may wish to answer questions or partake in assessments of this nature. Responding to cues (verbal and non-verbal) and recognizing the appropriateness of such assessments for the person and their family is integral to quality holistic care. Given the very low certainty of the evidence of effects, the low confidence in the evidence, and the variability in how persons value these assessments, the expert panel determined the strength of the recommendation to be conditional.
# Practice Notes
The expert panel emphasized that nurses should reflect on their knowledge level, comfort and ability to conduct appropriate spiritual, emotional and existential assessments prior to doing so, because when such assessments are done incorrectly-or if the nurse is not prepared to deal with the outcomes of the assessment-they can be harmful to persons and their families.
Organizations can support health providers to engage in these assessments by providing appropriate training so that they can gain an understanding of the person and more appropriately assess and explore their needs (75).
Assessments should be communicated to the interprofessional health team and documented. Moreover, the expert panel highlighted the importance of nurses recognizing when the complexity of the needs of the person and their family exceeds their knowledge, training and scope of practice. In these instances, interprofessional approaches may be necessary to meet the needs of persons and families, and nurses should seek the involvement of appropriate interprofessional health team members in a timely manner (76). Interprofessional health team support has been demonstrated to assist in addressing spiritual needs, particularly when health providers are not comfortable addressing spiritual care needs when it is beyond their knowledge or skill (76).
# RECOMMENDATIONS
A Palliative Approach to Care in the Last 12 Months of Life The expert panel identified that home care nurses must know the supports available within the community in order to connect persons and families to appropriate resources.
The expert panel emphasizes that the physical and psychosocial domains of health are interrelated. Thus, when physical incapacity is an issue, the person may experience emotional distress related to their loss of independence and functional ability. Similarly, while pain control represents a central aspect of palliative care and end-of-life care, pain is a multidimensional concept: the "total pain" a person experiences is influenced by physical, psychological, social and spiritual factors (77). All of these factors are interrelated and must be considered in unison to gain an accurate understanding of the person (77).
Refer to Appendix G for a list of assessment tools that explore different domains of health and illness as part of a holistic approach to care. Once trust and rapport are established, utilizing non-intrusive ways to explore the spiritual or existential beliefs of persons in their care (73).
Recognizing the importance of reading body language and non-verbal cues as part of the assessment, and the importance of being mindful of their own non-verbal behaviour during the process (69).
Assessments also involve the needs of the family, including coping, communication and family dynamics (73).
An assessment of a person's spiritual, emotional and existential preferences needs to be initiated early in a person's illness trajectory. This provides the interprofessional health team with the means to ensure that the person's preferences are honoured at the time of death (78).
# Areas explored through assessment questions
Feelings of peace.
The impact of illness on family.
Whether the person is part of a spiritual or religious community.
The meaning behind feelings of sadness, guilt or defeat.
Problems, concerns, hopes, dreams and wishes (69).
# Signs of spiritual distress
Some signs of spiritual distress for a person at the end of life, as identified within the research, include the following:
questioning the meaning of life;
changes in behaviour, such as withdrawing or distancing oneself from others; and physical symptoms, such as pain (72).
# RECOMMENDATIONS
A Palliative Approach to Care in the Last 12 Months of Life Report addressing the current landscape of research regarding spirituality and palliative care.
Identifies next steps to advance the field.
# RECOMMENDATIONS
A Palliative Approach to Care in the Last 12 Months of Life
# RECOMMENDATION 2.4:
The expert panel recommends that nurses address the person's and family's palliative care and end-of-life care expectations.
# Strength of the recommendation: Strong
Confidence in the evidence: Low
# Discussion of Evidence: Benefits and Harms
Generally, evidence from qualitative literature identifies that addressing palliative care and end-of-life care expectations with persons and their families may promote supportive care and care that is delivered in harmony with the person's wishes (62,69,79). To address expectations in a supportive way, nurses-in collaboration with the interprofessional health team-need to ensure that persons have realistic expectations about the care that can be provided, the type of assistance that can be given and the amount of time that can be dedicated in order to prevent feelings of disappointment (62,69). Addressing expectations also involved preparing the person for anticipated care and exploring the person's and family's current understanding of palliative care (79).
Harmony between persons and their families on palliative care and end-of-life care issues may improve quality care and facilitate a comfortable death for the person (79). Moreover, nurses provided continuous support to family members by engaging them throughout the care process and offering appropriate support in the face of escalating family stress, particularly if they were having difficulties with coping (79). When nurses were not able to manage expectations, the nursing relationship was compromised, nurses were not able to provide quality care and the person may not have experienced a comfortable death (79).
# Values and Preferences
Persons value supportive discussions, opportunities to discuss questions they may have and receiving information from health providers in order to obtain information on their condition and treatment possibilities (66).
# Health Equity
The expert panel acknowledged that health equity may vary due to issues related to resources and staffing, and differences in provider education and training in how to assess expectations of palliative care and end-of-life care.
Recognition of how social determinants of health impact access to and provision of palliative care and end-of-life care must be considered in order to support access to care for those who are structurally vulnerable.
# Expert Panel Justification of Recommendation
Several benefits were identified as a result of addressing the end-of-life care expectations of the person and their family. Despite low confidence in the evidence, the expert panel attributed value to addressing the expectations of the person and their family. For that reason, the expert panel determined the strength of the recommendation to be strong.
# RECOMMENDATIONS
A Palliative Approach to Care in the Last 12 Months of Life
# Practice Notes
Nurses should assess the readiness of persons to discuss their expectations for palliative care and end-of-life care and their understanding of their illness. The expert panel emphasized that conversations should occur at an appropriate time (i.e., when persons are ready), and that it should be early in the care process. When nurses and the interprofessional health team facilitate early conversations, it promotes empowerment and provides an opportunity for the person to make decisions while mentally capable of doing so (i.e., as opposed to decisions being made by a substitute decision-maker if conversations are initiated when the person is no longer mentally capable).
The expert panel emphasized that past experiences with death and past coping strategies may impact palliative care and end-of-life care expectations. When nurses and the interprofessional health team engage in dialogue with the person and family on their care expectations, the person's values and preferences can be thoughtfully reflected in the care plan.
Communication with persons needs to be flexible to meet their individual needs.
It is important to note that consent for treatment(s) within the plan of care is given by the person receiving the care or, if the person is incapable, by their substitute decision-maker in accordance with the person's goals and wishes.
Strategies identified in the literature that nurses can use to achieve agreement between persons and their families include the following:
providing ongoing support to ensure that families remain engaged throughout the care process;
accommodating individuality and each family's unique ways of caring;
preparing families for forthcoming care; and
being responsive to individual perspectives and remaining flexible regarding family practices in order to facilitate positive engagement with persons and families (79).
# Supporting Resources
# RESOURCE DESCRIPTION ONTARIO-BASED RESOURCES
Caregiver tips for coping with advancing illnesses.
In Guidance regarding end-of-life conversations.
# RECOMMENDATIONS
A Palliative Approach to Care in the Last 12 Months of Life
# RECOMMENDATION 2.5:
The expert panel suggests that nurses provide opportunities for life reflection to persons and families.
# Strength of the recommendation: Conditional
# Certainty of the evidence of effects: Low
Confidence in the evidence: Low
# Discussion of Evidence: Benefits and Harms
Various strategies to enable persons to engage in reflection were explored in the research, including both structured and unstructured approaches. For the purposes of this BPG, "structured approaches" are organized or formal interventions with a specific set of components, while "unstructured approaches" may involve more flexible, natural and spontaneous conversations to explore life reflection. Due to the limited research on structured life reflection interventions, a specific intervention program cannot be recommended at this time (80).
In general, life reflection may support a person-centred approach to care by acknowledging individuality, spirituality, fear and distress in order for persons to find meaning and acceptance and to alleviate their spiritual distress (69,72,78,80). Regardless of the type of strategy used for life reflection, nurses can provide opportunities for reflection to persons living with progressive life-limiting illness and their families.
# Unstructured Reflection
In qualitative studies, nurses reported that life reflection-if desired by persons with progressive life-limiting illnessallowed persons to experience a more peaceful death in comparison to those who did not wish to reflect and share (73). Providing opportunities for reflection allowed persons to (a) work through fear and regret, (b) reduce their suffering and (c) find meaning in their lives. In one study, when persons demonstrated fear about death, nurses acknowledged their feelings which eased the person's distress and allowed them to accept what was happening (72). Refer to the Practice Notes section for this recommendation (found below) for strategies identified within the literature that health providers used to engage in reflection conversations.
# Structured Reflection
A structured approach to life reflection was generally found to improve spiritual well-being in persons at the end of life, and to demonstrate improvement with regards to existential distress scores and quality of life (81,82). One study had a high attrition rate due to death, deterioration of condition or refusal to participate in the intervention (82). In another study, some persons found the questions asked as part of the intervention to be upsetting because it emphasized the limited time they had left to live (81). See Table 7 for more information about the two structured interventions evaluated: Outlook and The Meaning of Life Intervention.
# Values and Preferences
Persons reported that the structured intervention brought meaning to their lives; however, some found the questions asked as part of the intervention to be difficult to answer or not relevant to their stage of life (81).
# RECOMMENDATIONS
A Palliative Approach to Care in the Last 12 Months of Life
In a 2014 study by Keall et al., nurses reported that persons often wanted to share their story because it humanized them and allowed them to share their wisdom and legacy. Nurses viewed structured intervention positively because it provided a framework for care and supported therapeutic relationships. Nurses also reported that a structured intervention contributed to the holistic care of persons, and that it helped persons identify value in their lives (83).
# Health Equity
The expert panel acknowledged that not all health-service organizations have adequate resources (e.g., staff, volunteers, time and training) to support health providers to engage in conversations about life experiences.
# Expert Panel Justification of Recommendation
There were both benefits and harms identified for providing opportunities for life reflection. The expert panel felt that the benefits outweighed the harms with regards to the identified outcomes for most people; however, they emphasized that life reflection may not be appropriate for everyone. For some persons, life reflection may be detrimental (e.g., distressing or traumatizing) for their psychological and emotional well-being, especially if they do not wish to engage in the life reflection process or do not find meaning in it. Given the low certainty of evidence of effects, the low confidence in the evidence, and the variability in how persons value opportunities to reflect on their lives, the expert panel determined the strength of the recommendation to be conditional.
# Practice Notes
The expert panel emphasized that in order to provide effective support to persons with progressive life-limiting illness and their families-and to provide opportunities for reflection-nurses and other health providers must first be provided with training to enhance their practice with the knowledge and skills needed to approach life reflection conversations. This includes trauma-informed approaches and recognizing when such conversations may not be appropriate. See Appendix B for a resource related to trauma-informed approaches.
A person-and family-centred approach to life reflection includes providing flexibility, both in the timing of the dialogue and in the number of sessions offered (81). For instance, life reflection should not be introduced immediately after the diagnosis of a progressive life-limiting illness because time is required for a person to process the information and adapt. The authors of one review study also suggest that life reflection programs remain brief in duration due to the shortened life expectancy of persons at the end of life (80).
Strategies identified within the literature that were used by health providers to engage in life reflection conversations with persons with progressive life-limiting illness included the following:
spending time with persons in a non-judgemental manner;
establishing rapport and trust with the person (72, 78); | These guidelines are not binding on nurses, other health providers or the organizations that employ them. The use of these guidelines should be flexible and based on individual needs and local circumstances. They constitute neither a liability nor discharge from liability. While every effort has been made to ensure the accuracy of the contents at the time of publication, neither the authors nor the Registered Nurses' Association of Ontario (RNAO) gives any guarantee as to the accuracy of the information contained in them or accepts any liability with respect to loss, damage, injury or expense arising from any such errors or omission in the contents of this work.With the exception of those portions of this document for which a specific prohibition or limitation against copying appears, the balance of this document may be produced, reproduced and published in its entirety, without modification, in any form, including in electronic form, for educational or non-commercial purposes. Should any adaptation of the material be required for any reason, written permission must be obtained from RNAO. Appropriate credit or citation must appear on all copied materials as follows: Registered Nurses' Association of Ontario. A palliative approach to care in the last 12 months of life. Toronto (ON): Registered Nurses' Association of Ontario; 2020.# Table of Contents
# Table of Contents
# How to Use this Document
This best practice guideline (BPG) G * is a comprehensive document that provides guidance and resources for evidence-based nursing practice G . It is not intended to be a manual or "how-to" guide; rather, it supports best practices and decision making for nurses G , the interprofessional health team G and health-service organizations. This BPG should be reviewed and applied in accordance with the needs and preferences G of adults (18 years and older) who are experiencing the last 12 months of a progressive life-limiting illness and their families G . This document provides evidence-based recommendation G statements and descriptions of (a) practice, education G and organizational considerations, (b) benefits and harms, (c) values G and preferences and (d) health equity considerations.
Nurses, members of the interprofessional health team and administrators who lead and facilitate practice changes will find this document invaluable for developing policies, procedures, protocols and educational programs to support service delivery. Nurses and members of the interprofessional health team delivering direct care will benefit from reviewing the recommendations and supporting evidence. We encourage practice settings to adapt this BPG into formats that are feasible for daily use.
If your organization is adopting this BPG, we recommend the following steps:
1. Assess your existing policies, procedures, protocols and educational programs in relation to the recommendations and supporting evidence in this BPG.
2. Identify existing needs or gaps in your policies, procedures, protocols and educational programs.
3. Note the recommendations that are applicable to your setting and that can be used to address your organization's existing needs or gaps.
4. Develop a plan for implementing recommendations, sustaining best practices and evaluating outcomes G .
Implementation resources, including the RNAO Toolkit: Implementation of Best Practice Guidelines, Second Edition (1), are available at RNAO.ca. For more information, see Implementation Strategies on p. 84.
All of the RNAO BPGs are available for download, free of charge, on the RNAO website at RNAO.ca/bpg. To locate a particular BPG, search by keyword or browse by topic.
We are interested in hearing your feedback on this BPG and how you implemented it. Please share your story with us at RNAO.ca/contact. * Throughout this document, terms that are marked with a superscript G ( G ) can be found in the Glossary of Terms (Appendix A).
# BAC K G R O U N D
A Palliative Approach to Care in the Last 12 Months of Life
# Purpose and Scope
Purpose RNAO BPGs are systematically developed, evidence-based documents that include recommendations on specific clinical, healthy work environment and health system topics. They are intended for nurses and members of the interprofessional health team in direct care positions, and for educators, administrators and executives, policymakers, researchers, and persons G and families with lived experience. BPGs promote consistency and excellence in clinical care, administrative practices, policies, and education, with the aim of achieving optimal health outcomes for people, communities and the health system as a whole.
The purpose of this BPG is to provide evidence-based recommendations to nurses and the interprofessional health team who support adults (18 years and older) experiencing the last 12 months of a progressive life-limiting illness, their families and their caregivers. The goals of the recommendations are to: (a) improve delivery of psychosocial, spiritual and culturally safe care; (b) enhance coordination of care; and (c) facilitate supportive work environments.
The recommendations within this BPG are meant to be implemented as part of a holistic approach to care, as outlined in Figure 2: Domains of Issues Associated with Illness and Bereavement (10). It is also in alignment with the aims of palliative care G (see "Key Concepts Used in this Guideline, " p. 7).
Nurses and the interprofessional health team are required to have basic skills, training and competencies in palliative care in order to implement the recommendations of this BPG. For further information, please refer to Appendix C (Education Statements G ), the Ontario Palliative Care Network (OPCN) The Ontario Palliative Care Competency Framework-Nursing Competencies (summarized in Appendix K) and the Framework on Palliative Care in Canada (available at https://www.canada.ca/en/health-canada/services/health-care-system/ reports-publications/palliative-care/framework-palliative-care-canada.html#p2.3.1).
In March 2017, RNAO convened an expert panel to determine the scope of this BPG. The RNAO expert panel was interprofessional in composition, including family caregivers G and individuals with knowledge and experience in clinical practice, education, research and policy from a range of health-service and academic organizations, practice areas and sectors. Expert panel members shared their insights on supporting and caring for adults with progressive life-limiting illness across the continuum of care (e.g., community, long-term care and acute care). A systematic and comprehensive analysis was completed by the RNAO Best Practice Guideline Development and Research Team and the RNAO expert panel to determine the scope and priority recommendation questions for this BPG (see Appendix D).
# BAC K G R O U N D
A Palliative Approach to Care in the Last 12 Months of Life
# Scope
To determine the scope of this BPG, the RNAO Best Practice Guideline Development and Research Team conducted the following steps:
reviewed the RNAO BPG End-of-life Care During the Last Days and Hours (2011) (2);
conducted a search for published guidelines in this topic area and identified gaps in guidance;
conducted a scoping review G to determine the breadth and depth of peer-reviewed studies in the area of Medical Assistance in Dying (MAiD) G , with a specific focus on nursing practice;
interviewed 24 key informants with experience and expertise in the field, including health providers G in direct care, administrators, researchers and family caregivers; and
consulted with the expert panel co-chairs and the expert panel in March 2017.
This BPG is applicable to all practice settings where persons and families require palliative care and end-of-life care G services (e.g., acute care, community care, and long-term care). Specifically, this BPG will focus on persons experiencing the last 12 months of progressive life-limiting illness and their families. It will address the following areas:
# BAC K G R O U N D
A Palliative Approach to Care in the Last 12 Months of Life Family caregiver: "Any relative, partner, friend or neighbor who has a significant personal relationship with, and provides a broad range of assistance for, an older person or an adult with a chronic or disabling condition. These individuals may be primary or secondary caregivers and live with, or separately from, the person receiving care" (5).
Health provider: Refers to both regulated workers (e.g., nurses, physicians, dieticians and social workers) and unregulated workers (e.g., personal support workers) who are part of the interprofessional health team.
Regulated health provider: In Ontario, the Regulated Health Professional Act (RHPA), 1991, provides a framework for regulating 23 health professions, outlining the scope of practice and the profession-specific controlled or authorized acts that each regulated professional is authorized to perform when providing health care and services (6).
Unregulated health provider: Unregulated health providers fulfill a variety of roles in areas that are not subject to the RHPA. They are accountable to their employers but not to an external regulating professional body (e.g., the College of Nurses of Ontario). Unregulated health providers fulfill a variety of roles and perform tasks that are determined by their employer and employment setting. Unregulated health providers only have the authority to perform a controlled act as set out in the RHPA if the procedure falls under one of the exemptions set out in the Act (7).
# BAC K G R O U N D
A Palliative Approach to Care in the Last 12 Months of Life Topics Outside the Scope of this Best Practice Guideline Advance care planning G , grief and bereavement support, palliative care competency requirements, pharmacological interventions and symptom management were considered outside of scope. These subjects have been addressed in recent, evidence-based and credible resources currently in publication and/or in legislation.
See Appendix I for supporting resources related to pain and symptom management.
See Appendix J and K for supporting resources related to palliative care and end-of-life care education and competency resources.
See Appendix M for supporting resources related to advance care planning, and grief and bereavement support.
The scoping review indicated that robust, Canadian-based, peer-reviewed studies that address the role of nurses with MAiD were limited. The role of nurses and MAiD represents an opportunity for future guideline development. In addition, the legislation for MAiD varies between jurisdictions, and this BPG is to be implemented provincially, nationally and internationally.
See Appendix L for supporting resources related to MAiD.
Palliative care and end-of-life care for the pediatric population (i.e., infants and children younger than 18 years) is outside the scope of this BPG. The expert panel recognizes that the pediatric population is a unique population with specific considerations for palliative care and end-of-life care. This therefore represents an opportunity for future guideline development.
This BPG does not address the funding of palliative care and end-of-life care services, although this is an important aspect of every health system and one that governments and government agencies should investigate.
# Differences between this BPG and RNAO's End-of-life Care During the Last Days and Hours (2011) BPG
This BPG does not replace RNAO's 2011 BPG, End-of-life Care During the Last Days and Hours. Rather, the two guidelines differ in the following ways:
The time frame of this BPG extends beyond the last days and hours of life to include the last 12 months of a progressive life-limiting illness in order to provide recommendations that may be implemented earlier in the palliative care trajectory.
Based upon the priority recommendation questions and outcomes identified by the expert panel, practice recommendations within this BPG focus on the psychosocial aspect of care; they do not include activities that address physical symptom management. Attention is given to the spiritual, emotional, existential and cultural domains of care, but the recommendations are meant to be implemented as part of a holistic approach to care, as outlined in Figure 2: Domains of Issues Associated with Illness and Bereavement (10).
# BAC K G R O U N D
A Palliative Approach to Care in the Last 12 Months of Life
# Recommendation Questions
Within the determined scope defined above, the following priority recommendation questions and outcomes were developed by the expert panel. They informed the development of this BPG.
# BAC K G R O U N D
A Palliative Approach to Care in the Last 12 Months of Life Registered Nurses' Association of Ontario Best Practice Guidelines and Resources that Align with this Best Practice Guideline
Other RNAO BPGs and evidence-based resources may support implementation of this BPG. See Appendix B for RNAO BPGs and other resources on the following related topics:
care transitions;
crisis intervention;
constipation;
delirium, dementia and depression;
end-of-life care in the last days and hours;
implementation science, implementation frameworks and resources;
interprofessional collaboration;
pain;
person-and family-centred care;
pressure injuries; and
social determinants of health G .
For more information on the guideline development process, systematic review and search strategy for this BPG, see Appendix D.
# BAC K G R O U N D
A Palliative Approach to Care in the Last 12 Months of Life
# Interpretation of Evidence and Strength of Recommendations
This BPG was developed using an adaptation of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) G and Confidence in the Evidence from Reviews of Qualitative Research (CERQual) G methods. For more information about the guideline development process, including the use of GRADE and GRADE-CERQual methods, see Appendix D.
# Certainty of Evidence
The certainty of evidence (i.e., the level of confidence we have that an estimate of effect G is true) for quantitative research is determined using an adaptation of GRADE methods (11). After synthesizing the evidence for each prioritized outcome, the certainty of evidence is assessed. The overall certainty of evidence is determined by considering the certainty of evidence across all prioritized outcomes of included studies per recommendation. GRADE categorizes the overall certainty of evidence as high, moderate, low or very low. See Table 1 for the definition of these categories.
# Table 1: Certainty of Evidence
# CERTAINTY OF EVIDENCE DEFINITION High
We are very confident that the true effect G lies close to that of the estimate of the effect.
# Moderate
We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
# Low
Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
# Very low
We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
Source: Reprinted from The GRADE Working Group. Quality of evidence. In Schunemann H, Brozek J, Guyatt G, Oxman A, editors. Handbook for grading the quality of evidence and the strength of recommendations using the GRADE approach [Internet]. [place unknown]: The GRADE Working Group; 2013. Table 5.1, Quality of evidence grades. Available from: https://gdt.gradepro.org/app/handbook/handbook.html#h.wsfivfhuxv4r. Reprinted with permission.
# BAC K G R O U N D
A Palliative Approach to Care in the Last 12 Months of Life
# Confidence in Evidence
The confidence in evidence for qualitative research G (i.e., the extent to which the review finding is a reasonable representation of the phenomenon of interest) is determined using GRADE-CERQual methods (hereafter referred to as CERQual) (12). For qualitative evidence, an overall judgment of the confidence is made per finding in relation to each recommendation statement, as relevant. CERQual categorizes the confidence in evidence as high, moderate, low or very low. See Table 2 for the definitions of these categories.
# CONFIDENCE IN EVIDENCE DEFINITION High
It is highly likely that the finding is a reasonable representation of the phenomenon of interest.
# Moderate
It is likely that the finding is a reasonable representation of the phenomenon of interest.
# Low
It is possible that the review finding is a reasonable representation of the phenomenon of interest
# Very low
It is not clear whether the review finding is a reasonable representation of the phenomenon of interest.
Source: Reprinted from Lewin S, Booth A, Glenton C, Munthe-Kass H, Rashidian A, Wainright M et al. Applying GRADE-CERQual to qualitative evidence synthesis findings: introduction to the series. Implement Sci. 2018;13(Suppl 1):1-10. Table 3, Description of level of confidence in a review finding in the CERQual approach; p. 6. Reprinted with permission.
The assigned certainty and/or confidence of evidence can be found directly below each recommendation statement. For more information on the process of determining the certainty and/or confidence of the evidence and the documented decisions made by RNAO guideline development methodologists, see Appendix D. NOTE: Due to the complex and multi-faceted nature of palliative care and end-of-life care, the use of control G groups and the adjustment of confounding variables G are difficult to achieve. Therefore, the majority of research in this area was from observational or non-randomized studies as opposed to randomized controlled trials G (which eliminate contextual factors). For this reason, all of the recommendations have a certainty of evidence that is either low or very low. Despite the generally low certainty of evidence, however, the expert panel determined that the benefits, values and preferences for many of the interventions outweighed the potential harms noted in the research evidence or from personal practice experience. As such, the strength of many of the recommendations is strong (see Strength of Recommendations). This also highlights the need for more rigorous research in the areas of palliative care and end-of-life care.
# BAC K G R O U N D
A Palliative Approach to Care in the Last 12 Months of Life
# Strength of Recommendations
Recommendations are formulated as strong or conditional by considering the certainty and/or confidence in evidence, and the following key criteria (see the relevant Discussion of Evidence, below, for definitions):
balance of benefits and harms values and preferences health equity.
# Strong Recommendation
A strong recommendation reflects the expert panel's confidence "that the desirable effects of an intervention outweigh its undesirable effects (strong recommendation for an intervention) or that the undesirable effects of an intervention outweigh its desirable effects (strong recommendation against an intervention)" (11). A strong recommendation implies that the majority of persons will be best served by the recommended action (11).
# Conditional Recommendation
A conditional recommendation reflects the expert panel's confidence that while some uncertainty exists, the desirable effects probably outweigh the undesirable effects (i.e., a conditional recommendation for an intervention) or that the undesirable effects probably outweigh the desirable effects (i.e., conditional recommendation against an intervention) (11). A conditional recommendation implies that not all persons will be best served by the recommended action: "there is a need for more careful consideration of personal circumstances, preferences and values" (11).
Note: The strength of the recommendation statement is detailed directly below each recommendation statement and in the Summary of Recommendations. For more information on the process the expert panel used for determining the strength of each recommendation, please see Appendix D.
# Discussion of Evidence
The Discussion of Evidence that follows each recommendation includes the following main sections.
1. Benefits and Harms: Identifies the potential desirable and undesirable outcomes reported in the literature when the recommended practice is used. Content in this section solely includes research from the systematic review.
2. Values and Preferences: Denotes the relative importance or worth placed on health outcomes from following a particular clinical action from a person-centered perspective. Content for this section may include research from the systematic reviews and, when applicable, observations and/or considerations from the expert panel.
# Health Equity:
Identifies the potential impact that the recommended practice could have on health across different populations and/or barriers to implementing the recommended practice in particular settings. This section may include research from the systematic reviews and, when applicable, observations and/or considerations from the expert panel.
# Expert Panel Justification of Recommendation:
Provides a rationale for why the expert panel made the decision to rate a recommendation as strong or conditional.
5. Practice Notes: Highlights pragmatic information for nurses and members of the interprofessional health team. This section may include supporting evidence from the systematic review and/or from other literature and sources (e.g., the expert panel).
# BAC K G R O U N D
A Palliative Approach to Care in the Last 12 Months of Life 6. Supporting Resources: Includes a list of relevant resources (e.g., websites, books and organizations) that support the recommendations. As there are numerous accessible palliative care and end-of-life care resources this section includes a sample published within the last five to six years and that aligns with the recommendations (with the exception of unique or seminal publications). Content listed in this section was not part of the systematic review and was not quality appraised. As such, the list is not exhaustive, and the inclusion of a resource in one of these lists does not imply an endorsement from RNAO.
Note: Palliative care and end-of-life care legislation can vary between jurisdictions. The supporting resources have been organized to identify resources found within Ontario and those that exist outside of the province.
# BAC K G R O U N D
A Palliative Approach to Care in the Last 12 Months of Life
# Summary of Recommendations
# RECOMMENDATIONS STRENGTH OF THE RECOMMENDATION
Recommendation Question #1:
Should an interprofessional approach be recommended for the provision of care to adults in the last 12 months of life?
Outcomes: Outcomes: Person and family experience with care; effectiveness of provided care from the person and family perspective; access to care; coordination of care; transitions in care; effectiveness of provided care from the health provider perspective Recommendation 1 .1:
The expert panel recommends that health-service organizations implement an interprofessional model of care for the provision of palliative care and end-of-life care to persons and families .
# Strong Recommendation 1 .2:
The expert panel recommends that the interprofessional health team, in collaboration with the person and family, develop an individualized, person-centred plan of care and re-evaluate the plan of care based on the changing status, needs and preferences of the person .
# Strong
Recommendation Question #2:
What nurse-led interventions should be recommended for a palliative approach to the delivery of care in the last 12 months of life?
Outcomes: Outcomes: Support for spiritual care; support for emotional care; support for existential care; care in alignment with the person's wishes; culturally safe care; place of death
The following recommendations are applicable within the context of an interprofessional health team (see Recommendations 1 .1 and 1 .2) .
Recommendation 2 .1:
The expert panel recommends that nurses assess the cultural needs and values of persons and families .
# Strong Recommendation 2 .2:
The expert panel recommends that nurses perform ongoing assessments of persons and families for the following:
values, beliefs, expectations and preferences about progressive life-limiting illness and death; and preferred place of death .
# Strong BAC K G R O U N D
A Palliative Approach to Care in the Last 12 Months of Life Recommendation 2 .3:
The expert panel suggests that as part of a holistic assessment, nurses assess the spiritual, emotional and existential needs of persons and families, including:
concerns about end of life; and presence of spiritual, emotional and existential distress .
# Conditional Recommendation 2 .4:
The expert panel recommends that nurses address the person's and family's palliative care and end-of-life care expectations .
# Strong
Recommendation 2 .5:
The expert panel suggests that nurses provide opportunities for life reflection to persons and families .
# Conditional Recommendation 2 .6:
The expert panel recommends that nurses facilitate access to resources, space and services needed by persons and families for cultural, spiritual and/or religious practices .
# Strong Recommendation 2 .7:
The expert panel recommends that for persons who prefer to die at home, health-service organizations implement high-quality home and community care, which includes:
access to after-hours services; care coordination; and support provided by an interprofessional health team .
# Strong
Recommendation Question #3: Should continuing education, targeted skills training and debriefing be recommended for supporting nurses and the interprofessional health team who provide care to persons in the last 12 months of life and their families?
Outcomes: Outcomes: Compassion fatigue; stress/distress; resilience
The following recommendations are applicable to nurses and the interprofessional health team who provide palliative care and end-of-life care to persons, their families and their caregivers . The expert panel recommends that health-service organizations provide education and skills training for nurses and the interprofessional health team related to self-care, including stress management and mitigation of compassion fatigue .
# Strong Recommendation 3 .2:
The expert panel recommends that health-service organizations provide time and resources for nurses and the interprofessional health team to engage in debriefing .
# Strong BAC K G R O U N D
A Palliative Approach to Care in the Last 12 Months of Life
# Best Practice Guideline Evaluation
As you implement the recommendations in this BPG, we ask you to consider how you will monitor and evaluate its implementation and impact.
The Donabedian model informs the development of indicators for evaluating quality health care. It includes three categories: structure, process and outcome (13).
Structure describes the required attributes of the health system, health-service organization or academic institution to ensure quality care. It includes physical resources, human resources, and information and financial resources.
Process examines the health activities being provided to, for and with persons or populations as part of the provision of quality care.
Outcome analyzes the effect of quality care on the health status of persons and populations, health workforce, health-service organizations, academic institutions or health systems (13).
For additional information, please refer to the RNAO Toolkit: Implementation of Best Practice Guidelines, Second Edition (2012).
It is important to evaluate evidence-based practice changes when implementing a BPG. Tables 3 and 4 provide potential process and outcome measures to assess BPG success. Select the measures most relevant to the practice setting. The data repositories and indicator libraries available for palliative care and end-of-life care are outlined to support quality improvement and evaluation.
Table 3 supports evaluation of practice changes during implementation. The measures are directly associated with specific recommendation statements and support process improvement.
# Stakeholder Acknowledgment
As a component of the BPG development process, feedback was obtained from participants across a wide range of health-service organizations, academic institutions, practice areas and sectors. Participants include nurses and other members of the interprofessional team, educators, students, and knowledgeable administrators. Stakeholders G representing diverse perspectives were also solicited for their feedback (see Appendix D). RNAO wishes to acknowledge the following individuals for their contribution in reviewing this BPG. Stakeholder reviewers have given consent to the publication of their names and relevant information in this BPG.
# BAC K G R O U N D
A Palliative Approach to Care in the Last 12 Months of Life
# Background Context
What Are Palliative Care and End-of-life Care?
Palliative care refers to a philosophy and an approach to care. Palliative care aims to improve the quality of life for persons facing life-limiting illness and their families through the prevention and relief of suffering. It does this through the early identification, assessment and treatment of symptoms (4). Palliative care extends across the trajectory of life-limiting illness, including care at the point of diagnosis, during treatment and at the end of life, as well as grief and bereavement support (see Figure 1 for a visual depicting the palliative care trajectory). Note: Other models exist that provide visual depictions of palliative care. One example is The Bow Tie Model by Dr. Pippa Halwey. For more information, please visit http://www.virtualhospice.ca/en_US/Main+Site+Navigation/Home/ For+Professionals/For+Professionals/The+Exchange/Current/The+Bow+Tie+Model+of+21st+Century+Palliative+C are.aspx
According to the CHPCA, palliative care (also referred to as "hospice palliative care") is an approach to care that aims to do the following:
Relieve suffering and improve the quality of living and dying.
Address the physical, psychological, social, spiritual (existential) and practical issues of persons and their families, and their associated expectations, needs, hopes and fears.
Prepare persons and their families for self-determined life closure and the dying process and help them manage it.
Help families cope with loss and grief during the illness and bereavement experience.
Treat all active issues, prevent new issues from occurring and promote opportunities for meaningful and valuable experiences, personal and spiritual growth, and self-actualization (10).
# BAC K G R O U N D
A Palliative Approach to Care in the Last 12 Months of Life
Based on these key aims, the recommendations within this BPG focus on quality of life, emphasizing a holistic approach to care that incorporates the person's individuality and preferences, and that recognizes the person and family as the unit of care. Figure 2 identifies complex issues persons and their families may face when receiving palliative care, which are categorized into eight equally important domains (10). End-of-life care is a component of the palliative care trajectory, and it specifically refers to care for persons who are expected to die in the foreseeable future and their families (refer to Figure 1). It includes helping persons and families prepare for death, ensuring their comfort and supporting decision making that is consistent with the person's prognosis and goals of care (3).
# BAC K G R O U N D
A Palliative Approach to Care in the Last 12 Months of Life
# Delivery of Palliative Care and End-of-life Care
The delivery of palliative care and end-of-life care is based on comprehensive and ongoing assessment of the needs of persons and families, along with their wishes and preferences (15). Depending on where the person is along the illness trajectory, considerable variability exists with respect to the type and level of care and the services that are required from health providers. See Figure 3 for a model depicting the illness trajectory, complexity of needs and level of service. For more information regarding the trajectories of illnesses, please refer to the Gold Standards Framework Proactive Identification Guidance, available at https://www.goldstandardsframework.org.uk/cd-content/ uploads/files/PIG/NEW%20PIG%20-%20%20%2020.1.17%20KT%20vs17.pdf. The majority of persons and families will receive palliative care from primary care clinicians and non-specialist palliative care providers (Patient C in Figure 3). Complex issues facing persons and families may require the involvement of specialist palliative care teams, such that a consultation and shared care approach is used to assist non-specialist palliative care providers in delivering care (Patient B in Figure 3). In a smaller number of cases, complex palliative care needs may necessitate the transfer of care to specialist palliative care teams (Patient A in Figure 3).
As the needs of persons and families are multi-faceted, palliative and end-of-life care are most effective when delivered by an interprofessional health team that is knowledgeable and skilled in palliative care and end-of-life care (10). The interprofessional health team consists of regulated and unregulated care providers, as well as volunteers, family caregivers, and persons and their families.
# BAC K G R O U N D
A Palliative Approach to Care in the Last 12 Months of Life
# Access to Palliative Care and End-of-life Care
Palliative care and end-of-life care are appropriate for any person and their family living with (or at risk of) developing a progressive life-limiting illness. In other words, persons facing any diagnosis-regardless of prognosis and age-who have unmet needs and/or expectations can have palliative care and end-of-life care when they are ready to accept it. It is important for persons to receive palliative care as early as possible along their illness trajectory. Compared to late palliative care initiation, early access to palliative care has been found to be associated with improved end-of-life outcomes and lower odds of using acute care services (22). Despite this, access to palliative care services is not equitable across Canada (16). For example, of the persons who died in Ontario in the 2014/15 calendar year, only 57 per cent received at least one palliative care service, while 40.5 per cent did not receive any palliative care services (17). Of those who did receive palliative care, the majority (60.6 per cent) only received care within the last one to two months of life (17). Across disease groups, a report from the Canadian Institute for Health Information (CIHI) found that persons with cancer are three times more likely to receive palliative care than others, and adults aged 45 to 74 years are more likely than younger adults and older adults to receive palliative care across most care settings (16).
A major barrier to access of palliative care and end-of-life care services is cost. For example, the average cost of endof-life care per person in the last year of life is greater than $50,000 in Ontario, with inpatient care and long-term care representing a substantial portion of total end-of-life care costs (23). For Ontarians receiving palliative care services within the home G , the total cost has been estimated to be approximately $25,000 per month, with $17,500 per month due to lost wages and leisure time for caregivers (17). Not surprisingly, these home-based palliative care services are less likely to be used by persons living in the poorest neighbourhoods compared to those living in the wealthiest neighbourhoods (17). Therefore, funding models to support equitable access to palliative care and end-of-life services are an important aspect of every health system and one that government and government agencies need to address.
Inequitable access to palliative care and end-of-life care services is perhaps most prominent for persons who are structurally vulnerable G (e.g., persons who are experiencing homelessness) who tend to have inequitable access due to social, economic and environmental factors (18). A systematic review found that barriers to providing care to persons experiencing homelessness and who were seriously ill included: a small social network and lack of support from family and friends, limited insight into their health, living on a "day-to-day" basis with end of life not being a priority, and the belief G that health providers do not have the knowledge and skill to meet their palliative and endof-life care needs (187). Although the recommendations in this BPG are clinically applicable to all populations, a fundamental barrier to their implementation is the inequitable access to palliative care and end-of-life care services across all populations. For that reason, awareness and capacity to provide care to diverse populations, inclusive of principles of culturally safe and trauma-informed approaches, remains a priority in palliative care and end-of-life care.
For more information regarding social determinants of health, please refer to the RNAO Social Determinants of Health Brochure: RNAO.ca/sites/rnao-ca/files/rnao_sdh_brochure_2013.pdf. For more information regarding Ontario's action plan for access to equitable palliative care, please refer to the Ontario Palliative Care Network Action Plan 1: 2017-2020: www.ontariopalliativecarenetwork.ca/sites/opcn/files/OPCNActionPlan1.pdf.
# BAC K G R O U N D
A Palliative Approach to Care in the Last 12 Months of Life
# Psychosocial Needs of Health Providers
Health providers who work in palliative care and end-of-life care are often faced with highly emotional situations. When health providers regularly encounter pain, suffering, death and grief, this can manifest in compassion fatigue and stress (24,25). Compassion fatigue is a state of "physical and mental exhaustion and emotional withdrawal experienced by those that care for sick or traumatized people over an extended period of time" (26). Recent literature indicates that 52.55 per cent of nurses experience compassion fatigue (27).
Long-lasting compassion fatigue has been linked to negative outcomes at the individual and organizational levels. For the individual health provider, ongoing compassion fatigue may result in: increased fatigue; feelings of hopelessness, frustration and despair; negative impacts on personal relationships; and thoughts of leaving the profession (28,29). At the organizational level, compassion fatigue may result in high staff turnover rates and increased staff shortages (25,30). High turnover is linked to significant financial costs for the organization, and most importantly, to adverse patient outcomes (31,32).
In order to mitigate the negative consequences related to compassion fatigue and stress, strategies to develop resilience and self-care for health providers are required. Resilience refers to a person's ability to thrive in the face of stress and traumatic experiences (33). Increased resilience is associated with improved health, well-being and job satisfaction for health providers; by developing resilience and self-care strategies, they can proactively recognize and mitigate signs of compassion fatigue and stress (24). Health-service organizations also have a responsibility to create environments that promote resilience through interventions that focus on education and skill-building for self-care (24,34,35).
# Conclusion
This BPG provides evidence-based best practice recommendations for health-service organizations, nurses and members of the interprofessional health team to support adults (18 years and older) who are experiencing the last 12 months of progressive life-limiting illness, their families and their caregivers.
# RECOMMENDATIONS
A Palliative Approach to Care in the Last 12 Months of Life
# Recommendations
# RECOMMENDATION QUESTION #1:
Should an interprofessional approach be recommended for the provision of care to adults in the last 12 months of life?
Outcomes: Person and family experience with care; effectiveness of provided care from the person and family perspective; access to care; coordination of care; transitions in care; effectiveness of provided care from the health provider perspective RECOMMENDATION 1.1:
The expert panel recommends that health-service organizations implement an interprofessional model of care for the provision of palliative care and end-of-life care to persons and families.
# Strength of the recommendation: Strong
# Certainty of the evidence of effects: Low
Confidence in the evidence: Low
# Discussion of Evidence: Benefits and Harms
Within the literature, interprofessional models of care consisting of varying team compositions were explored within diverse health settings. An interprofessional model of care refers to a team of different health providers (regulated and unregulated) working together towards a common goal to meet the needs of a patient population. Within this model, team members divide the work based on their scope of practice, sharing information to support their respective work and coordinating processes and interventions to provide a number of services and programs (8). In palliative care and end-of-life care, the person and family are included as key members of the interprofessional health team.
Evidence suggests that interprofessional models of care may improve: (a) the effectiveness of care from the perspective of persons, families and health providers; (b) the experience that a person and their family have with care; and (c) the coordination of care.
# Effectiveness of Care from the Perspective of Persons, Families and Health Providers
The effectiveness of interprofessional models of care from the perspective of the person and/or their family has been reported in the literature. An interprofessional model of care has the potential to improve the experiences of care for persons and families through increased satisfaction and improved care (36). For example, patients at an interdisciplinary palliative care out-patient clinic felt that interprofessional care: (a) increased the frequency and timeliness of symptom assessments; (b) improved the person's understanding of medications, side effects and pain management; and (c) ultimately supported enhanced symptom management and care coordination G (37).
# RECOMMENDATIONS
A Palliative Approach to Care in the Last 12 Months of Life Evidence suggests that health providers also may find interprofessional models of care to be effective. For example, interprofessional health teams may support stronger relationships with the person and family, and they may aid in reducing power imbalances between the interprofessional health team, the person and their family (38). Health providers also report that interprofessional collaboration can promote greater productivity, flexibility and shared responsibility, enabling them to achieve the person's care goals (39). In one study, four health provider groups (physicians, nurses, social workers and spiritual care providers) felt positively about interprofessional collaboration and rated their hospice work environments as supportive. However, social workers reported feeling less valued and connected to other members of the interprofessional health team (38).
# Person and Family Experience with Care and Coordination of Care
Interprofessional models of care also may affect the experience that persons and families have with the care they receive. Interprofessional care may increase psychological support and support for daily living activities for the person while decreasing caregiver burden and anxiety (40). Persons and families also report increased satisfaction with care and improved quality of life when receiving care from a specialized out-patient palliative care team (40,41).
With respect to experiences with care and coordination of care, qualitative evidence suggests that persons with a progressive life-limiting illness and their families who are cared for by an interprofessional health team report: (a) improved continuity of care and holistic care; and (b) increased feelings of security, timely care and responsiveness of health providers when accommodating changing conditions (42).
Although there are findings to support the improved experiences of persons and families with care and the increased coordination of care that are linked to interprofessional models of care, one study demonstrated that communication with health providers may not be enhanced by an interprofessional model of care (40).
# Values and Preferences
An interprofessional model of care was positively received, both from the perspective of persons and from health providers (39)(40)(41). Health providers who engaged in interprofessional rounds for palliative care reported that the approach facilitated communication and added value to patient care without increasing burden (44).
# Health Equity
The expert panel acknowledged that across health-service organizations, there may be inequitable access to the health human resources required to implement interprofessional models of care in an effective way. In rural and remote areas, access to certain health provider groups is limited due to the lower number of health providers employed in these areas (45). As an alternative, the expert panel suggests that telemedicine can be used to support increased access to an interprofessional health team, including in rural and remote geographical areas. The authors of one study outlined the benefits of including a telephone service to increase accessibility to interprofessional models of care, particularly for individuals living in remote areas (37).
# Expert Panel Justification of Recommendation
The expert panel attributed value to the interprofessional model of care, wherein interprofessional health teams practice with a shared purpose to provide holistic person-and family-centered care. The expert panel determined that the benefits of interprofessional care outweighed the harms, and that persons experiencing the last 12 months of progressive life-limiting illness would value improvements in the effectiveness, coordination and experiences of
# RECOMMENDATIONS
A Palliative Approach to Care in the Last 12 Months of Life the care they received. Despite the fact that there was a low certainty of evidence and low confidence in the evidence, there were several benefits identified to having an interprofessional approach to care, and few harms were reported.
For that reason, the expert panel determined the strength of the recommendation to be strong.
# Practice Notes
Interprofessional health teams vary in composition, depending on the health setting (e.g., hospice, acute care, home care or long-term care), so the exact composition of team members required for interprofessional palliative care and end-of-life care is context-dependent and based on the needs of the person receiving care and their family. Regardless, each team member's role should be clearly communicated within the interprofessional health team, as clarity of roles facilitates the provision of coordinated care (47).
Within the research literature, interprofessional health teams who provide palliative care and end-of-life care services generally include a combination of regulated and unregulated health providers, such as: (54).
The expert panel further notes that nurse practitioners, volunteers, Indigenous spiritual/traditional healers, elders and medicine persons are key members of the interprofessional health team.
The expert panel highlighted the importance of clear and ongoing communication between interprofessional health team members, the person and the family. Clear and ongoing communication promotes a mutual understanding of the person's goals of care and avoids potential distress resulting from persons and families having to repeat information to multiple interprofessional health team members.
It is important for health-service organizations to provide access to and support the use of documentation systems that enable equal access to and timely sharing of information between interprofessional health team members.
# RECOMMENDATIONS
A The expert panel recommends that the interprofessional health team, in collaboration with the person and family, develop an individualized, person-centred plan of care and re-evaluate the plan of care based on the changing status, needs and preferences of the person.
# Strength of the recommendation: Strong
# Certainty of the evidence of effects: Low
Confidence in the evidence: Low
# Discussion of Evidence: Benefits and Harms
The evidence on the development of a plan of care G by the interprofessional health team varied with respect to team composition and health context. However, the literature generally demonstrated that the development of an individualized person-centred plan of care by the interprofessional health team-in collaboration with the person receiving care and their family-may improve transitions in care, coordination of care, access to care, and the experiences of care for persons and families.
# Transitions in Care and Coordination of Care
Care planning with an interprofessional health team can promote the provision of holistic care, because the perspectives gained from interprofessional health team discussions may be more comprehensive than independent provider assessments (50). Developing a plan of care with the interprofessional health team, the person receiving care and their family involves shared decision-making G and ongoing communication. This communication and collaboration improves transitions in care, including both the quality of a person's transition to end-of-life care and the transition from home care to an in-patient hospice setting (51,55). In one qualitative research G study, individualized plans of care were discussed with persons and their families during home visits prior to being reviewed at interprofessional health team meetings. Plans of care were subsequently modified based on the changing physical and psychological needs of the person and family. If care could not be provided in the home, and if hospice eligibility was met, the transition to a hospice setting was facilitated (51). In rural environments, care coordination was supported by members of the interprofessional health team, with health providers discussing their unique roles on the team to help ensure that persons with progressive life-limiting illness and their families received appropriate and comprehensive care (45).
# Experiences of Care for Persons and their Families, and Access to Care
Active involvement of the person and family in care planning with the interprofessional health team may facilitate positive person and family experiences, and it may increase satisfaction with care (48). For persons with early-stage cancer, for instance, evidence indicates that care planning with the interprofessional health team may improve the person's quality of life and spiritual well-being and reduce psychological distress (53). Furthermore, with regards to access to care, interprofessional care planning may increase the number of referrals to specialized services, including referrals to palliative care, supportive care, chaplaincy, nutrition and social work (53). Care planning with the person, family and interprofessional health team also may allow for discussion and acknowledgement of the person's preference for place of death and improve the person's emotional responses to dying (49,51). A reduction of pain experienced by the person also may occur (49).
# RECOMMENDATIONS
A Palliative Approach to Care in the Last 12 Months of Life Care planning with the interprofessional health team also may improve the family's experience with care received. For example, caregivers who are part of end-of-life discussions report increased satisfaction with care, and they are more receptive to bereavement visits and experience less distress during those visits (49). When families are included in the care planning process, family caregivers report improvements in their quality of life, a reduction in psychological distress and a reduction in caregiver burden (52).
Interestingly, one study found that caregivers who are not part of interprofessional care planning may have greater spiritual well-being than those who are part of the care planning. The authors of the study report that this may be due to the intervention being provided with insufficient frequency, and that minimal content related to spiritual wellbeing was discussed during the intervention (52).
# Values and Preferences
Persons value being involved in care planning, and because their family may represent a source of social support, both groups value the opportunity to be involved in decision-making (56).
# Health Equity
The expert panel recognizes that some persons receiving palliative care and end-of-life care may have reduced social and financial resources; this may influence individualized care planning and transitions in care (51). The expert panel also acknowledged that access to the resources required for an interprofessional approach to care planning may be limited in certain health-service organizations or geographical locations, which can negatively impact health equity. For example, one study found that when access to specific health providers was limited, functioning of the interprofessional health team and overall care delivery were affected (50).
In another study, providers in rural environments recognized their role in collaborating with one another to advocate for the needs of populations underserved by the health system. While meeting face-to-face with persons with progressive life-limiting illness and their families was valued, providers reported that opportunities and resources were not readily available to them to engage in interprofessional care planning in an effective manner (45).
# Expert Panel Justification of Recommendation
There were several benefits identified when the person and their family collaborated with the interprofessional health team in their care planning, and no harms were found. Despite the low certainty of evidence and low confidence in the evidence, the expert panel determined that persons and their families would value improvements in: (a) coordination of care, (b) transitions in care, (c) access to care, and (d) experiences with care. For that reason, the expert panel determined the strength of the recommendation to be strong.
# RECOMMENDATIONS
A Palliative Approach to Care in the Last 12 Months of Life
# Practice Notes
Implementation considerations from the expert panel:
Early referrals to interprofessional palliative care teams, along with early conversations between persons with progressive life-limiting illness, families and the interprofessional health team are important in order to discuss preferences, values and plans of care. The importance of early conversations and care planning with the interprofessional health team, person and family is also echoed in the literature (53). If conversations with the person are initiated in the later stages of a person's illness, they may be too unwell to participate in discussions regarding their transitions in care (55).
Plans of care should be modified in a timely manner based on the changing health status and the needs of the person and family. This will help to support coordination of care, transitions in care and positive person and family experiences.
Documenting and sharing the plan of care between interprofessional health team members is important. Ongoing and frequent communication (in-person or through written or electronic documentation) between the interprofessional health team and the person and family is a facilitator to achieving the benefits of coordinated and collaborative care planning (47).
In order to support coordination and continuity in care, interprofessional collaboration should exist both within and between health-service organizations when persons and families transition between settings.
# RECOMMENDATION 2.1:
The expert panel recommends that nurses assess the cultural needs and values of persons and families.
# Strength of the recommendation: Strong
Confidence in the evidence: Low
# Discussion of Evidence: Benefits and Harms
Qualitative evidence indicates that assessing the cultural needs G and values of persons and families enables nurses to provide culturally safe palliative care and end-of-life care, bridge gaps in communication and gain an inclusive understanding of the person and family (19,57). In some cases, language barriers can make it difficult to understand a person's cultural beliefs, needs and values; this can potentially lead to gaps in communication, as persons and families are unable to express their needs and wishes and/or health providers have difficulty understanding them (57). Table 5 provides information from the literature on the components of cultural assessments and on strategies for conducting them.
# Values and Preferences
No literature was identified that reported on the values and preferences of persons, their families or their health providers with respect to assessing the cultural needs and values of persons and families.
# Health Equity
Incorporating a cultural assessment as part of a comprehensive assessment promotes inclusive care for all populations (19). When language barriers exist, access to high-quality translation services represents an important factor in effectively communicating with persons and families; however, not all health-service organizations have the funding and resources to implement translation services. It is important to note that translation is not interpretation: translation services that can interpret information, promote understanding and meet the individual needs of persons and families are required.
# RECOMMENDATIONS
A Palliative Approach to Care in the Last 12 Months of Life
# Expert Panel Justification of Recommendation
The expert panel attributed value to conducting cultural assessments so that care plans can be tailored to the person's needs and preferences. Moreover, the expert panel determined that persons would value even small improvements in their care if they received culturally safe care that was in alignment with their wishes. Therefore, despite the fact that there was low confidence in the evidence, the expert panel determined the strength of the recommendation to be strong.
# Practice Notes
Organizational policies for health providers are required in order to facilitate culturally safe care in palliative care and end-of-life care (46).
Nurses should regularly assess their knowledge level and ability to conduct an appropriate cultural assessment prior to doing so in clinical practice, and the expert panel highlights that trust must be established before conversations with persons and families occur. Furthermore, communication is central to culturally safe care, and nurses must avoid making assumptions about persons and families, regardless of their cultural, ethnic or spiritual background (46,61).
The expert panel emphasized that culture is unique to each individual, and there are individual differences within the same cultural umbrella.
While culture is defined broadly, evidence within the systematic review was not found specific to certain population groups. Research is required in these areas. Refer to Table 10 for research gaps and future implications.
# Components of cultural assessments
Components within the research included:
Exploring the person's family context, coping strategies, holistic needs, expression of emotions, meaning of behaviours and all dimensions of pain (57).
Within the literature, nurses reported that because a person's experience of suffering is multidimensional, it was valuable to explore their experience from various domains in order for the person to feel truly understood (19).
Components identified by the expert panel:
Asking persons and families if they have any religious or cultural concerns related to progressive life-limiting illness and death may assist in assessing the cultural needs and values of persons and families.
For a subset of the population, culture and spirituality are intertwined; thus, acknowledging both domains during a cultural assessment may be warranted (see Recommendations 2.2 and 2.6).
# RECOMMENDATIONS
A Palliative Approach to Care in the Last 12 Months of Life
# Strategies for conducting cultural assessments
Strategies within the research included:
Nurses observed persons and families to learn about care practices and inquired about practices that would typically be conducted at home (57).
A cultural assessment may also involve the active involvement of family, including determining the family contact person, exploring factors of personal importance to the family and examining family communication (57).
Strategies identified by the expert panel:
Cultural assessments should be implemented and completed as part of a holistic approach to care, as outlined in Figure 2
# Discussion of Evidence: Benefits and Harms
The research evidence demonstrates the importance of nurses discussing with persons and their families their values, beliefs, expectations and preferences about their life-limiting illness, death and preferred place of death. Doing so will support future care planning and the person's ability to experience a death in alignment with their wishes.
# Values, Beliefs, Expectations and Preferences about Progressive Life-limiting Illness and Death
Qualitative evidence demonstrates that when nurses and other health providers discuss care preferences with persons and their families, it may promote the establishment of a trusting rapport between the nurse and patient, encourage open communication and allow them to identify areas in which coordination of care is required (62). Engaging and supporting the person to be involved actively in the decision-making process also can have psychological benefits for the person, including providing them with a sense of control and self-determination (62). In a study that evaluated a nurse practitioner-directed intervention that focused on the effect of exploring the values, beliefs, preferences and expectations of persons, the emotional well-being of persons at the end of life was found to improve; however, the intervention was not found to have an impact on their spiritual well-being (63).
# Preferred Place of Death
Examining a person's preferred place of death can promote a holistic approach to care (e.g., emotional and psychological) that extends beyond physical symptom management. Nurses within a qualitative study acknowledged that a person's preferred place of death may change over time or may not be feasible; however, initiating the conversation with the person is viewed as an important first step in assessing whether the person's request is attainable (62). Potential issues may arise if a person's care preferences are not feasible; this can result in negative emotional outcomes for persons, families and health providers (62).
# Values and Preferences
Changes in care preferences are occasionally associated with alterations in a person's health condition, but the experience and direction of these changes are unique to the person receiving the care (67). Potential shifts in a person's care preferences indicate a need for ongoing assessment of their care preferences as end of life approaches (68).
# RECOMMENDATIONS
A Palliative Approach to Care in the Last 12 Months of Life
One study noted that discussing the topic of a person's preferred place of death too early, particularly if the person is not yet aware of their proximity to death, may be perceived as unsupportive and uncaring (62). When persons do not wish to engage in discussion on topics such as preferred place of death, the topic can be revisited at a more appropriate time, depending on the person's needs and wishes (62). The expert panel acknowledged that the interprofessional health team should explore the person's understanding of their illness early in the palliative care trajectory, before conversations are initiated regarding a person's preferred place of death.
# Health Equity
A person's decision with regards to preferred place of death is multi-faceted. The expert panel highlights that a person's choice for preferred place of death may be influenced by access to supportive care providers, living in rural or remote areas, complications of illness, access to supplies and medication, and caregiver burnout G . These factors can ultimately impact health equity.
Unfortunately, although the evidence shows that most people prefer to die at home, over 60 per cent of Canadians continue to die in hospitals, and only 15 per cent receive palliative home care services in the last month of life (16,64,65).
# Expert Panel Justification of Recommendation
Despite the very low certainty of the evidence of effects and the low confidence in the evidence, the expert panel determined that the benefits outweigh the harms when it comes to assessing the preferred place of death and the values, beliefs, expectations and preferences of a person and their family. The expert panel also believes that persons would value improvements in spiritual, emotional, existential and culturally safe care, and that they would appreciate receiving care in alignment with their wishes. For that reason, the panel determined the strength of the recommendation to be strong.
# Practice Notes
Persons with progressive life-limiting illness experience changes regarding expectations for their life and future as they come to terms with the nature of their illness (66). The expert panel emphasized that the conversation about preferred place of death is dynamic, and that assessment must continuously occur as the person's condition and needs change (i.e., it is not a static situation). Ongoing assessments reflect that status and needs of the person, and thus may include re-assessments as well as new assessments.
The expert panel also highlights the importance of considering the family and substitute decision-makers G in discussions regarding preferred place of death.
The expert panel emphasized that communicating assessments to the interprofessional health team is important. It is also important to document the person's preferences in their plan of care and to re-assess as changes occur; this will allow attention to be paid to the person's care expectations throughout the trajectory of their illness (62).
Refer to Appendix M for resources related to advance care planning and goals of care.
# RECOMMENDATIONS
A
# RECOMMENDATIONS
A Palliative Approach to Care in the Last 12 Months of Life
# RECOMMENDATION 2.3:
The expert panel suggests that as part of a holistic assessment, nurses assess the spiritual, emotional and existential needs of persons and families, including:
concerns about end of life; and presence of spiritual, emotional and existential distress.
# Strength of the recommendation: Conditional
# Certainty of the evidence of effects: Very low
Confidence in the evidence: Low
# Discussion of Evidence: Benefits and Harms
Assessing the spiritual, emotional and existential needs of persons and families represents one important aspect of person-and family-centered holistic care. Refer to Table 6 (below) for strategies identified within the literature to assess the spiritual, emotional and existential needs of the person and their family.
# Assessment of Spiritual, Emotional and Existential Needs
When assessing for spiritual, emotional and existential needs, health providers asked questions pertaining to a range of topics, including the following:
concerns, hopes, dreams and wishes;
feelings of peace;
impact of illness on family;
whether the person is part of a spiritual or religious community; and meaning behind feelings of sadness, guilt or defeat (69).
Evidence suggests that persons and families may respond positively to nurse-led spiritual assessments. In a study by Taylor & Brander (2013), persons were given a 21-item spiritual assessment questionnaire to ascertain their comfort level when being asked questions pertaining to spirituality. Approximately 25 per cent of the respondents "liked to be asked", approximately 50 per cent were "okay" with being asked, and approximately 25 per cent "did not want to be asked" questions pertaining to spirituality (70). Persons were also receptive to questions about support systems, because it allowed them to reflect on what was helpful to them during difficult times in the past, and it prompted them to recall positive aspects of their lives (70). Moreover, when nurses supported persons to share their feelings, persons were able to gain trust in the nursing care they received (71). However, nurses also reported instances in which the family was not psychologically prepared to discuss loss; this in turn caused distress for the person, their family and the nurse (69).
# RECOMMENDATIONS
A Palliative Approach to Care in the Last 12 Months of Life
# Presence of Spiritual, Emotional and Existential Distress
In a qualitative study, hospice nurses emphasized the importance of identifying spiritual distress in persons with life-limiting progressive illness, and they recognized this as an experience unique to each individual (72). Moreover, these domains can be heavily intertwined with a person's physical health, such that nurses in one study assessed for existential and spiritual distress during their assessment of the person's total pain experience (73). When hospice nurses recognize and provide the appropriate care to persons in spiritual distress, nurse-person relationships may be positively impacted. For example, when persons were actively in distress, hospice nurses used open-ended questions to explore the person's feelings and provide them with the opportunity to express their emotions, if they desired. Thus, hospice nurses who engaged in conversation with the person in a professional manner allowed persons to express their emotions, obtain needed support and alleviate emotional suffering (74).
# Values and Preferences
Variability in preferences regarding spiritual, emotional and existential assessments was found in the literature. In one study, some persons did not wish to be asked about their involvement in a religious community, and they felt that it was inappropriate for nurses to ask questions about their spiritual beliefs (70). Some persons and families stated that they preferred their spiritual assessment to be conducted first by spiritual care experts, followed by counselors and then nurses (70).
# Health Equity
The expert panel acknowledged that health equity may vary due to issues related to resources and staffing, in addition to provider education and training in how to conduct spiritual, emotional and existential assessments for persons with a life-limiting progressive illness.
# Expert Panel Justification of Recommendation
There were both benefits and harms identified for completing spiritual, emotional and existential assessments. The expert panel noted that although conducting these assessments is valuable, not all individuals may wish to answer questions or partake in assessments of this nature. Responding to cues (verbal and non-verbal) and recognizing the appropriateness of such assessments for the person and their family is integral to quality holistic care. Given the very low certainty of the evidence of effects, the low confidence in the evidence, and the variability in how persons value these assessments, the expert panel determined the strength of the recommendation to be conditional.
# Practice Notes
The expert panel emphasized that nurses should reflect on their knowledge level, comfort and ability to conduct appropriate spiritual, emotional and existential assessments prior to doing so, because when such assessments are done incorrectly-or if the nurse is not prepared to deal with the outcomes of the assessment-they can be harmful to persons and their families.
Organizations can support health providers to engage in these assessments by providing appropriate training so that they can gain an understanding of the person and more appropriately assess and explore their needs (75).
Assessments should be communicated to the interprofessional health team and documented. Moreover, the expert panel highlighted the importance of nurses recognizing when the complexity of the needs of the person and their family exceeds their knowledge, training and scope of practice. In these instances, interprofessional approaches may be necessary to meet the needs of persons and families, and nurses should seek the involvement of appropriate interprofessional health team members in a timely manner (76). Interprofessional health team support has been demonstrated to assist in addressing spiritual needs, particularly when health providers are not comfortable addressing spiritual care needs when it is beyond their knowledge or skill (76).
# RECOMMENDATIONS
A Palliative Approach to Care in the Last 12 Months of Life The expert panel identified that home care nurses must know the supports available within the community in order to connect persons and families to appropriate resources.
The expert panel emphasizes that the physical and psychosocial domains of health are interrelated. Thus, when physical incapacity is an issue, the person may experience emotional distress related to their loss of independence and functional ability. Similarly, while pain control represents a central aspect of palliative care and end-of-life care, pain is a multidimensional concept: the "total pain" a person experiences is influenced by physical, psychological, social and spiritual factors (77). All of these factors are interrelated and must be considered in unison to gain an accurate understanding of the person (77).
Refer to Appendix G for a list of assessment tools that explore different domains of health and illness as part of a holistic approach to care. Once trust and rapport are established, utilizing non-intrusive ways to explore the spiritual or existential beliefs of persons in their care (73).
Recognizing the importance of reading body language and non-verbal cues as part of the assessment, and the importance of being mindful of their own non-verbal behaviour during the process (69).
Assessments also involve the needs of the family, including coping, communication and family dynamics (73).
An assessment of a person's spiritual, emotional and existential preferences needs to be initiated early in a person's illness trajectory. This provides the interprofessional health team with the means to ensure that the person's preferences are honoured at the time of death (78).
# Areas explored through assessment questions
Feelings of peace.
The impact of illness on family.
Whether the person is part of a spiritual or religious community.
The meaning behind feelings of sadness, guilt or defeat.
Problems, concerns, hopes, dreams and wishes (69).
# Signs of spiritual distress
Some signs of spiritual distress for a person at the end of life, as identified within the research, include the following:
questioning the meaning of life;
changes in behaviour, such as withdrawing or distancing oneself from others; and physical symptoms, such as pain (72).
# RECOMMENDATIONS
A Palliative Approach to Care in the Last 12 Months of Life Report addressing the current landscape of research regarding spirituality and palliative care.
Identifies next steps to advance the field.
# RECOMMENDATIONS
A Palliative Approach to Care in the Last 12 Months of Life
# RECOMMENDATION 2.4:
The expert panel recommends that nurses address the person's and family's palliative care and end-of-life care expectations.
# Strength of the recommendation: Strong
Confidence in the evidence: Low
# Discussion of Evidence: Benefits and Harms
Generally, evidence from qualitative literature identifies that addressing palliative care and end-of-life care expectations with persons and their families may promote supportive care and care that is delivered in harmony with the person's wishes (62,69,79). To address expectations in a supportive way, nurses-in collaboration with the interprofessional health team-need to ensure that persons have realistic expectations about the care that can be provided, the type of assistance that can be given and the amount of time that can be dedicated in order to prevent feelings of disappointment (62,69). Addressing expectations also involved preparing the person for anticipated care and exploring the person's and family's current understanding of palliative care (79).
Harmony between persons and their families on palliative care and end-of-life care issues may improve quality care and facilitate a comfortable death for the person (79). Moreover, nurses provided continuous support to family members by engaging them throughout the care process and offering appropriate support in the face of escalating family stress, particularly if they were having difficulties with coping (79). When nurses were not able to manage expectations, the nursing relationship was compromised, nurses were not able to provide quality care and the person may not have experienced a comfortable death (79).
# Values and Preferences
Persons value supportive discussions, opportunities to discuss questions they may have and receiving information from health providers in order to obtain information on their condition and treatment possibilities (66).
# Health Equity
The expert panel acknowledged that health equity may vary due to issues related to resources and staffing, and differences in provider education and training in how to assess expectations of palliative care and end-of-life care.
Recognition of how social determinants of health impact access to and provision of palliative care and end-of-life care must be considered in order to support access to care for those who are structurally vulnerable.
# Expert Panel Justification of Recommendation
Several benefits were identified as a result of addressing the end-of-life care expectations of the person and their family. Despite low confidence in the evidence, the expert panel attributed value to addressing the expectations of the person and their family. For that reason, the expert panel determined the strength of the recommendation to be strong.
# RECOMMENDATIONS
A Palliative Approach to Care in the Last 12 Months of Life
# Practice Notes
Nurses should assess the readiness of persons to discuss their expectations for palliative care and end-of-life care and their understanding of their illness. The expert panel emphasized that conversations should occur at an appropriate time (i.e., when persons are ready), and that it should be early in the care process. When nurses and the interprofessional health team facilitate early conversations, it promotes empowerment and provides an opportunity for the person to make decisions while mentally capable of doing so (i.e., as opposed to decisions being made by a substitute decision-maker if conversations are initiated when the person is no longer mentally capable).
The expert panel emphasized that past experiences with death and past coping strategies may impact palliative care and end-of-life care expectations. When nurses and the interprofessional health team engage in dialogue with the person and family on their care expectations, the person's values and preferences can be thoughtfully reflected in the care plan.
Communication with persons needs to be flexible to meet their individual needs.
It is important to note that consent for treatment(s) within the plan of care is given by the person receiving the care or, if the person is incapable, by their substitute decision-maker in accordance with the person's goals and wishes.
Strategies identified in the literature that nurses can use to achieve agreement between persons and their families include the following:
providing ongoing support to ensure that families remain engaged throughout the care process;
accommodating individuality and each family's unique ways of caring;
preparing families for forthcoming care; and
being responsive to individual perspectives and remaining flexible regarding family practices in order to facilitate positive engagement with persons and families (79).
# Supporting Resources
# RESOURCE DESCRIPTION ONTARIO-BASED RESOURCES
Caregiver tips for coping with advancing illnesses.
In Guidance regarding end-of-life conversations.
# RECOMMENDATIONS
A Palliative Approach to Care in the Last 12 Months of Life
# RECOMMENDATION 2.5:
The expert panel suggests that nurses provide opportunities for life reflection to persons and families.
# Strength of the recommendation: Conditional
# Certainty of the evidence of effects: Low
Confidence in the evidence: Low
# Discussion of Evidence: Benefits and Harms
Various strategies to enable persons to engage in reflection were explored in the research, including both structured and unstructured approaches. For the purposes of this BPG, "structured approaches" are organized or formal interventions with a specific set of components, while "unstructured approaches" may involve more flexible, natural and spontaneous conversations to explore life reflection. Due to the limited research on structured life reflection interventions, a specific intervention program cannot be recommended at this time (80).
In general, life reflection may support a person-centred approach to care by acknowledging individuality, spirituality, fear and distress in order for persons to find meaning and acceptance and to alleviate their spiritual distress (69,72,78,80). Regardless of the type of strategy used for life reflection, nurses can provide opportunities for reflection to persons living with progressive life-limiting illness and their families.
# Unstructured Reflection
In qualitative studies, nurses reported that life reflection-if desired by persons with progressive life-limiting illnessallowed persons to experience a more peaceful death in comparison to those who did not wish to reflect and share (73). Providing opportunities for reflection allowed persons to (a) work through fear and regret, (b) reduce their suffering and (c) find meaning in their lives. In one study, when persons demonstrated fear about death, nurses acknowledged their feelings which eased the person's distress and allowed them to accept what was happening (72). Refer to the Practice Notes section for this recommendation (found below) for strategies identified within the literature that health providers used to engage in reflection conversations.
# Structured Reflection
A structured approach to life reflection was generally found to improve spiritual well-being in persons at the end of life, and to demonstrate improvement with regards to existential distress scores and quality of life (81,82). One study had a high attrition rate due to death, deterioration of condition or refusal to participate in the intervention (82). In another study, some persons found the questions asked as part of the intervention to be upsetting because it emphasized the limited time they had left to live (81). See Table 7 for more information about the two structured interventions evaluated: Outlook and The Meaning of Life Intervention.
# Values and Preferences
Persons reported that the structured intervention brought meaning to their lives; however, some found the questions asked as part of the intervention to be difficult to answer or not relevant to their stage of life (81).
# RECOMMENDATIONS
A Palliative Approach to Care in the Last 12 Months of Life
In a 2014 study by Keall et al., nurses reported that persons often wanted to share their story because it humanized them and allowed them to share their wisdom and legacy. Nurses viewed structured intervention positively because it provided a framework for care and supported therapeutic relationships. Nurses also reported that a structured intervention contributed to the holistic care of persons, and that it helped persons identify value in their lives (83).
# Health Equity
The expert panel acknowledged that not all health-service organizations have adequate resources (e.g., staff, volunteers, time and training) to support health providers to engage in conversations about life experiences.
# Expert Panel Justification of Recommendation
There were both benefits and harms identified for providing opportunities for life reflection. The expert panel felt that the benefits outweighed the harms with regards to the identified outcomes for most people; however, they emphasized that life reflection may not be appropriate for everyone. For some persons, life reflection may be detrimental (e.g., distressing or traumatizing) for their psychological and emotional well-being, especially if they do not wish to engage in the life reflection process or do not find meaning in it. Given the low certainty of evidence of effects, the low confidence in the evidence, and the variability in how persons value opportunities to reflect on their lives, the expert panel determined the strength of the recommendation to be conditional.
# Practice Notes
The expert panel emphasized that in order to provide effective support to persons with progressive life-limiting illness and their families-and to provide opportunities for reflection-nurses and other health providers must first be provided with training to enhance their practice with the knowledge and skills needed to approach life reflection conversations. This includes trauma-informed approaches and recognizing when such conversations may not be appropriate. See Appendix B for a resource related to trauma-informed approaches.
A person-and family-centred approach to life reflection includes providing flexibility, both in the timing of the dialogue and in the number of sessions offered (81). For instance, life reflection should not be introduced immediately after the diagnosis of a progressive life-limiting illness because time is required for a person to process the information and adapt. The authors of one review study also suggest that life reflection programs remain brief in duration due to the shortened life expectancy of persons at the end of life (80).
Strategies identified within the literature that were used by health providers to engage in life reflection conversations with persons with progressive life-limiting illness included the following:
spending time with persons in a non-judgemental manner;
establishing rapport and trust with the person (72, 78);
acknowledging the individuality of the person;
demonstrating compassion;
communicating with persons with full attention;
facilitating a safe environment (72);
sharing in silence with the person in order to demonstrate openness and availability for support (73);
providing persons with opportunities to discuss fears, explore hopes and dreams, remember past experiences and reflect on meaning in life (78);
# RECOMMENDATIONS
A Palliative Approach to Care in the Last 12 Months of Life listening actively in an uninterrupted, open and respectful manner when the person is ready to reflect and speak about their experiences (69); and supporting the person without trying to change their circumstances (69).
Challenges for health providers, such as finding sufficient time to engage in meaningful dialogue with persons and their families, may ultimately lead to the inability to meet a person's needs, creating moral distress and ethical dilemmas for the health provider (73,84).
Refer to Table 7 for details on the structured interventions within the research. Provides information on dignity therapy, which addresses many of the psychological, existential and spiritual challenges faced by patients with progressive life-limiting illness and their families.
# RECOMMENDATIONS
A Palliative Approach to Care in the Last 12 Months of Life
# RECOMMENDATION 2.6:
The expert panel recommends that nurses facilitate access to resources, space and services needed by persons and families for cultural, spiritual and/or religious practices.
# Strength of the recommendation: Strong
Confidence in the evidence: Low
# Discussion of Evidence: Benefits and Harms
Qualitative evidence demonstrates that in order to promote culturally safe care, it is important that nurses facilitate access to the resources, physical space and services needed by persons with progressive life-limiting illness and their families for cultural, spiritual and/or religious practices. By advocating for access to resources, space and services, nurses may be able to recognize potential unmet needs of persons and support persons and families to engage in practices and/or events of personal significance (19).
Facilitating access to space (e.g., by providing opportunities for family to visit outside of visiting hours) allowed persons to spend quality time with loved ones and engage in end-of-life rituals (85). Based on the needs and preferences of the person, nurses also provided referrals to other health providers-such as spiritual care specialists, chaplains, counselors or spiritual leaders-in order to support access to resources and services required for spiritual and/or religious practices (72). One study outlined potential benefits of interpretation services for persons and families experiencing language barriers, including supporting clear communication, gaining a true understanding of the person and family, and promoting continuity of care (57).
# Values and Preferences
The evidence highlights the varying preferences and needs of persons with progressive life-limiting illness. Some persons and family caregivers receiving end-of-life care strongly value spiritual care, believing that addressing spiritual and existential concerns are significant aspects of care (86). Engaging in personal practices-such as meditation, prayer, private rituals, discussion of spiritual topics, readings and other spiritual activities-can be significant aspects of their end-of-life care experience (86). Additionally, some persons and families value spiritual care resources, such as books, journals or multimedia (87).
# Health Equity
Including families in care and providing persons and their families with translation services, connecting them with traditional healers and making organizational accommodations for cultural or spiritual practices all have the potential to reduce health inequities among populations (20).
With respect to access to spiritual services, hospice nurses in one study reported that after-hours access to specialist health providers-such as spiritual care providers, chaplains and counselors-was a challenge within their organization. Specialist health providers were not readily available on weekends or at night, which was when persons often were experiencing the most distress (72). It was recognized that spiritual care services should have the same after-hours availability as other health services, emphasizing the importance of spiritual care as part of a holistic approach to end-of-life care (72).
# RECOMMENDATIONS
A Palliative Approach to Care in the Last 12 Months of Life
# Expert Panel Justification of Recommendation
Facilitating access to the resources, spaces and services based on the needs of persons and families was found to be beneficial. Despite the low confidence in evidence, the expert panel determined that persons would value having the opportunity to engage in their cultural, spiritual and/or religious practices. For that reason, the expert panel determined the strength of the recommendation to be strong.
# Practice Notes
The expert panel emphasized the necessity for nurses to have the appropriate education, knowledge and skills to engage in cultural, spiritual and/or religious conversations with persons with progressive life-limiting illness and their families.
Nurses must acknowledge their comfort level prior to engaging in discussions of this nature. Within the literature, some nurses recognized their own limitations and reported mixed feelings with regards to discussing spiritual or religious issues with persons because of their own personal life experiences, beliefs and feelings of insecurity (73,78). In these situations, however, nurses did facilitate spiritual support for persons by making the appropriate referrals to a chaplain or other spiritual leader (73).
Other services that may benefit the person and family include: psychological services, counselling, and grief and bereavement support. See Appendix M for resources related to grief and bereavement.
Within the literature, celebrating events of personal significance for persons and their families was recognized as the last opportunity to commemorate certain milestones; in these cases, however, nurses completed preparations for the celebrations outside of working hours and during their personal time (19). Health-service organizations need to allocate resources and time for nurses to accomplish holistic person-and family-centered care, such as preparing for events of personal significance, within working hours.
Health-service organizations need to provide the adequate resources and space for persons and families to engage in meaningful personal practices.
Strategies outlined in the literature that were used by nurses to support persons to engage in practices of personal importance include the following:
Negotiating with management to allow family members to visit outside of visiting hours in organizations where visiting hours are restricted (85).
Ensuring that persons and families had adequate time and space to engage in end-of-life rituals and prayers (85).
Providing referrals to other health providers such as spiritual care specialists, chaplains, counselors or spiritual leaders (72). These referrals are based on the needs and preferences of the person and whether they wish to speak to someone about their concerns or issues (69,78). The referral process requires nurses to be aware of when a referral is indicated and to whom the referral should be directed; this will help to ensure that persons have appropriate access to services (69).
Facilitating access to interpretation services for persons and families experiencing language barriers (57).
Working collaboratively with families and supporting them in their role as caregivers. Additionally, identifying networks in the community to provide support to the person and their family (88).
# RECOMMENDATIONS
A Explains the need for culturally competent and safe care, identifies the stakeholders in this process and outlines ways to evaluate health programs and policies.
# RECOMMENDATIONS
A Palliative Approach to Care in the Last 12 Months of Life
# RECOMMENDATION 2.7:
The expert panel recommends that for persons who prefer to die at home, health-service organizations implement high-quality home and community care, which includes:
access to after-hours services;
care coordination; and
support provided by an interprofessional health team.
# Strength of the recommendation: Strong
Certainty of the evidence of effects: Low
# Discussion of Evidence: Benefits and Harms
The majority of research on preferred place of death was conducted at the community and organizational level, focusing on service availability, team composition and environment of care. Overall, the research suggests that highquality home and community care-which includes access to after-hours services, care coordination and support provided by an interprofessional health team-may enable persons to die at home when that is their preferred place of death. Within this BPG, home is defined by the person receiving care, and it may refer to a physical house or other dwelling, such as long-term care, hospice or other community setting.
# Access to After-hours Services
Access to in-person and telephone-based after-hours services may support home deaths for persons with progressive life-limiting illness. The evidence suggests that persons who died at home were more likely to use an after-hours telephone service compared to persons admitted to a care facility (89). As part of a multi-component intervention, an after-hours telephone line was provided to persons and their families. Although it is difficult to confirm if it was the after-hours telephone line or another component of the multi-component intervention that led to the results, the authors found that persons who received the intervention were less likely to die in hospital or have an emergency department admission or visit (90).
In another study, it was found that 77 per cent of persons who received in-person home care and emotional support (available after hours for both day and night shifts) died at home, whereas only 35 per cent died at home when they did not use the service. Persons who received the service and who were cared for at home at the end of life also had lower hospital use, although there may have been increased demands placed on the community services used, such as nursing care, primary care and social care (91).
# Care Coordination
Care coordination also may help persons with progressive life-limiting illness to die at home. In one study, a multicomponent program that included two end-of-life coordination centres for community referrals as part of the intervention found that persons who used the program were less likely to die in hospital. The authors of the study report that coordination centres for community referrals appear to have the greatest impact on place of death (90).
# RECOMMENDATIONS
A Palliative Approach to Care in the Last 12 Months of Life Relational coordination G may also increase the likelihood for persons with progressive life-limiting illness to die at home. When nurse managers engage in high-quality and timely communication with other health providers about a person's preferred place of death, it may result in well-coordinated and individualized care that meets the person's needs (92).
# Support Provided by an Interprofessional Health Team
The evidence suggests that home visits by nurses in collaboration with primary physicians and increased duration of nursing services per home visit may be associated with greater frequency of deaths at home and may promote the development of caring relationships between providers, persons and their families (93). When care was provided by a specialist palliative home care team comprised of nurses and physicians, the overall rate of home deaths was 56.6 per cent. Of those who died at home, 62.6 per cent were cared for by palliative care nurses and physicians from the same home care agency (94). In another study, a multi-component intervention prior to the delivery of care that involved implementation of facility-based palliative care teams, palliative and end-of-life staff education, rounds with a geropalliative care nurse practitioner and coaching from the nurse practitioner was associated with a decline in hospital deaths for working palliative care teams, but it had no influence on place of death. These working palliative care teams had a "clear and shared mission, a sense that the team influenced residents' care, and a perception of continued team sustainability" (95).
In rural areas, home care nurses acted as advocates for persons who wished to die at home. Thus, strong relationships with persons in their care and communication, support and the environment of care can influence the ability of nurses to support the preferences of persons, including the preference to die at home (96).
# Values and Preferences
Families valued the multi-component program, which included two end-of-life coordination centres for the community, because it was found to improve access to care and equipment, and it provided flexibility in responding to the needs of persons and their families (90).
# Health Equity
Despite the aforementioned evidence, the majority of Canadians do not receive formal palliative care outside of the hospital setting in their last 12 months of life (16). In a 2013 Canadian survey, 75 per cent of people reported a preference to die at home (98); however, when measured in 2015, only 15 per cent actually died at home, while 61 per cent died in hospital, 15 per cent died in another health care facility and 8 per cent died in another specified locality (16).
Barriers to access of palliative care and end-of-life care services can are more pronounced for populations that are structurally vulnerable. For example, persons who are experiencing homelessness may not have the opportunity to die in a safe and secure place with access to family that will care for them (186). Persons living in rural and remote locations may also face barriers to access of palliative care and end-of-life services.
# Expert Panel Justification of Recommendation
Several benefits were identified as a result of high-quality home and community palliative care and end-of-life care, and the expert panel attributed value to supporting persons to die at home if that is in alignment with their wishes. Despite the low certainty of the effects, the expert panel determined the strength of the recommendation to be strong.
# RECOMMENDATIONS
A Palliative Approach to Care in the Last 12 Months of Life
# Practice Notes
It is important to assess each person's preference with regard to place of death, and reassess this preference based on their changing health and psychological status, needs and circumstances. Preferred place of death may change over time and can be influenced by the quality of care available, the access to home support and other services (e.g., volunteers) and impact on family caregivers (100). For more information regarding assessing the preferred place of death, see Recommendation 2.2.
The expert panel highlighted that persons who have access to social support systems (e.g., family and friends) may choose home as a preferred place of death, so support also must be available to family caregivers (101).
While surveys indicate that the majority of persons wish to die at home, other settings should be considered, such as an in-patient care unit, hospice or long-term care facility (17, 98). Access to alternative settings of care may be needed for persons whose preferred place of death changes later in their palliative care trajectory.
For remote locations where geographical challenges exist, telemedicine represents one option to support an interprofessional approach to care at home. The expert panel also recognized that community agencies need to develop collaborative approaches to support comprehensive palliative home care.
Refer to Table 8 for details of interventions included within the research. The following recommendations are applicable to nurses and the interprofessional health team who provide care to persons, their families and their caregivers.
# RECOMMENDATION 3.1:
The expert panel recommends that health-service organizations provide education and skills training for nurses and the interprofessional health team related to self-care, including stress management and mitigation of compassion fatigue.
# Strength of the recommendation: Strong
Certainty of the evidence of effects: Very low
# Discussion of Evidence: Benefits and Harms
Generally, evidence supports that education and training regarding self-care may improve outcomes for health providers, such as reducing stress and mitigating compassion fatigue and burnout (24,(102)(103)(104). Formal approaches to education and training (i.e., those offered by the organization) may promote positive coping in nurses, enable recognition of the importance of self-care and allow nurses to practice skills related to self-care (24). Informal approaches (i.e., those obtained from team relationships, friends and family) also may be beneficial because they facilitate social interaction and foster mutually supportive relationships (24). See Recommendation 3.2 for information about debriefing among health providers.
Within the literature, education and training programs varied with regards to structure, delivery and content. Refer to the Practice Notes for this recommendation (found below) for details regarding the specific interventions identified in the systematic review.
# Education
Continuing education may allow health providers to improve their theoretical and applied knowledge and practice regarding self-care behaviours (105). Health provider improvement in knowledge and skills regarding self-care was associated with increased resilience and reduced stress (105), and it also may be associated with long-term decreases in both work-related stress and work disappointment (103). Education sessions have the potential to allow health providers to reflect on their previous caring experiences and engage in discussions with colleagues, which can increase their understanding of the emotional and existential reactions of persons with progressive life-limiting illnesses. After the education sessions, they also may be more confident in supporting persons who are in existential distress, which may subsequently increase work satisfaction (103). In addition, health providers may be more readily able to provide the care they desire to give, and trust and understanding may increase between colleagues (103).
# RECOMMENDATIONS
A Palliative Approach to Care in the Last 12 Months of Life Conversely, some health providers reported that education increased exhaustion and there was inadequate time to attend the educational sessions (e.g., they did not want to leave colleagues with an unmanageable workload) (103).
# Skills Training
Skills-training interventions generally focused on self-regulation G , coping and self-care for health providers, although they varied in approach and mode of delivery. Skills-training interventions led to health providers feeling more relaxed, practicing self-compassion and experiencing an increased ability to cope with workplace problems, manage stress and provide emotional support to persons at the end of life and their families (104,106). A technologyenabled yoga therapy intervention that included components of meditation was found to be associated with a reduction in compassion fatigue (102), while an intervention combining education and meditation was found to be associated with increased compassion satisfaction (106). However, some health providers reported emotional difficulty at the start of meditation when they had a chance to reflect on how much they thought about others instead of thinking about themselves (106).
Alternatively, a mobile application that involved psycho-education and tools for self-assessment and symptom tracking was not found to impact levels of stress, compassion satisfaction and burnout (107). In fact, certain topics addressed in the application elicited feelings of anxiety or uneasiness among participants (e.g., such as topics that assessed compassion fatigue) (107).
# Group-based Interventions
Group-based interventions for managing compassion fatigue and/or stress may be effective in supporting health providers. In one group-based education intervention, there was a decrease in secondary traumatic stress G as evidenced by a decline in secondary traumatisation scores and burnout scores measured on the ProQOL IV selfassessment. Compassion satisfaction scores, however, remained unchanged (108).
A mindfulness-based group intervention was found to decrease compassion fatigue (109). Similarly, a brief group intervention that aimed to build the skills of nurses in managing challenging situations via training manuals, learning modules and group support was associated with decreases in stress (110).
# Values and Preferences
Within the literature, health providers were generally satisfied with skills-training interventions to mitigate and manage compassion fatigue, and they viewed them positively. Specifically, health providers gained knowledge regarding self-care strategies and recognized the value and relevance of the interventions used to address compassion fatigue (104,(108)(109)(110). As a result of interventions focused on mitigating compassion fatigue, some health providers reported that they were more likely to incorporate meditation into their lives, or they identified strategies that could be used at work or at home to make positive lifestyle changes (106,(108)(109)(110).
# Health Equity
Not all health-service organizations will have access to the appropriate personnel, space and resources to implement continuing education and workplace skills-training interventions to mitigate compassion fatigue and workplace stress, particularly in remote areas where staff and resources are scarce (111). For instance, nurses reported various challenges to attending education and training courses, including high patient-to-nurse ratios and long-term lack of control and power, both of which impact their ability to engage in continuing education and contribute to feelings of disappointment at work (103). For programs delivered outside of work hours or in rural areas, there may be further accessibility challenges related to program availability, funding and travel (112,113).
# RECOMMENDATIONS
A Palliative Approach to Care in the Last 12 Months of Life
# Expert Panel Justification of Recommendation
The expert panel attributed value to health-service organizations providing ongoing education and training related to self-care for health providers. The expert panel emphasized that compassion fatigue can affect all health providers in palliative care and end-of-life care, and that managing it should be a priority. There were both benefits and harms identified in the literature with respect to education and training for health provider self-care; however, the expert panel determined that health providers would value even small improvements in stress management and mitigations of compassion fatigue. Despite the very low certainty of evidence of effects, the expert panel determined the strength of the recommendation to be strong.
# Practice Notes
Education and skills training should also be extended to caregivers who may require additional support related to their self-care, including stress management and mitigation of compassion fatigue. See Supporting Resources for more information.
Health service organizations are responsible for promoting access to education and training regarding self-care while also ensuring that adequate time is allotted for staff to engage in these offerings. Placing the responsibility on health providers themselves to access education and training may not be equitable due to program costs, time requirements, travel constraints and personal responsibilities. Support from the organization is required to ensure that all health providers have access to education and training programs (104).
Management support is important: it allows health providers to take time off work to attend education sessions while ensuring that units are staffed in their absence and that funding is accessible (114).
Strategies that nurses identify to support coping with the deaths of persons in their care include: education and programs; daily routines and activity, including personal coping strategies; and debriefing (see Recommendation 3.2) (115).
See Table 9 for the key components of the education and skills-training interventions found in the evidence.
The expert panel acknowledges individuals may not be aware that they are experiencing compassion fatigue or stress. See Appendix H for a list of assessment tools that may assist health providers to recognize compassion fatigue and/or stress.
# RECOMMENDATIONS
A Palliative Approach to Care in the Last 12 Months of Life Teaching/learning strategies included formal education, small group activities, role-playing, experiential learning, educational materials and discussion (105).
# Skills training
Interventions generally focused on self-regulation, coping and self-care.
# Interventions included:
A technology-enabled yoga therapy intervention that included components of meditation. It was administered via smartphone to health providers in hospice and palliative care. The meditation sessions focused on breathing, attention and mental focus, with an aim to promote positive thoughts, reduce stress and increase self-awareness (102).
One-on-one educational session for oncology nurses, followed by individual meditation five days per week (106).
The Provider Resilience mobile app involved psycho-education on burnout, compassion satisfaction and stress, along with tools for self-assessment and symptom tracking. This intervention was not found to impact levels of stress, compassion satisfaction and burnout (107).
# Group-based interventions
Interventions included:
Educational components and small group activities, with an aim to promote resilience through self-regulation, self-validation and self-care (108). The expert panel recommends that health-service organizations provide time and resources for nurses and the interprofessional health team to engage in debriefing.
# Strength of the recommendation: Strong
Certainty of the evidence of effects: Very low Confidence in the evidence: Low
# Discussion of Evidence: Benefits and Harms
Within the literature, debriefing included workplace meetings, support obtained through group clinical supervision and informal sessions between colleagues. Overall, evidence suggests that debriefing may be effective in allowing health providers to share feelings, process emotions, develop skills and provide support to one another (24,116).
Qualitative literature indicates that monthly workplace support group meetings may present health providers with opportunities to develop communication strategies, discuss challenging situations, share resources and provide positive reinforcement to colleagues in a structured and safe environment (116). Support groups also may allow health providers to improve coping practices, express emotions, gain perspective, validate feelings (e.g., about grief and loss), improve work-life balance and manage stress (116).
Debriefing conducted through group clinical supervision was also identified within the literature. This process involved clinical supervision by trained registered nurses provided in a group setting, with the intention of helping health providers cope with demanding clinical situations, share experiences and connect with colleagues. Group clinical supervision was shown to be helpful in allowing health providers release emotions, reflect critically on events, learn from experiences, obtain support through conversations with colleagues, and improve coping and resilience (24).
Informal support from social networks and peers can also help health providers cope with work challenges and release stress by means of sharing experiences and emotions (24). Trusted team members can support each other through crisis, loss and frustration, while simultaneously providing understanding and acceptance (24). Team meetings can represent a way for health providers to share emotions and obtain support in a safe environment, but some health providers feel they do not have the appropriate skills to provide support to colleagues. This can be associated with lower levels of personal accomplishment (24).
# Values and Preferences
Health providers value discussions with colleagues and opportunities to converse about their emotions (117). Within the literature, health providers had a preference for workplace support group meetings that were conducted outside of the direct workplace (e.g., on a different floor) (116). Some health providers desired monthly meetings, others felt the frequency of monthly meetings was not sufficient and some preferred the meetings to be held as needed (116,117). While health providers valued support from friends and family with regards to care experiences, colleagues
# RECOMMENDATIONS
A Palliative Approach to Care in the Last 12 Months of Life were the preferred choice for debriefing due to a shared understanding of the environment, language and experiences encountered (24). Close relationships within teams and relationships that were built on trust, respect and openness were seen as facilitators for a supportive environment (24).
# Health Equity
The expert panel acknowledged that support for workplace debriefing interventions will vary between health-service organizations depending on available resources, funding and staff. For programs held outside of working hours, individual factors-such as transportation issues, funding or competing personal responsibilities-may represent barriers to accessing debriefing support in the workplace (113). Alternatively, for debriefing interventions that are held during working hours, health providers report that workload relief for staff is required from organizations (113).
# Expert Panel Justification of Recommendation
Several benefits were identified when health-service organizations provided time and resources for nurses and the interprofessional health team to engage in debriefing. Despite very low certainty of evidence of effects and low confidence in the evidence, the expert panel determined the strength of the recommendation to be strong.
# Practice Notes
The expert panel highlighted that debriefing could occur both formally and informally, and that both should be supported by health-service organizations and integrated into work-life culture. Please see the Supporting Resources and Appendix M for example debriefing tools.
Debriefing should be conducted in a safe space and occur regularly, which can allow debriefing skills to develop over time.
The expert panel proposed that health-service organizations should provide opportunities for health providers to engage in debriefing after the death of each person.
Specific suggestions from the expert panel regarding debriefing include the following:
Time within the working day to do these activities, with costs and coverage away from patient care supported by the employer.
Training for some staff to take a lead on these activities.
Support from professionals who are knowledgeable (e.g., psychologists and social workers).
An awareness in the organization of the factors that contribute to the health and safety of its employees and the measures that can be taken to mitigate issues (e.g., staffing ratios).
# RECOMMENDATIONS
A
# Research Gaps and Future Implications
The RNAO Best Practice Guideline Development and Research Team and expert panel identified priority areas for future research (outlined in Table 10). Studies conducted in these areas would provide further evidence to support high-quality and equitable support for persons at the end of life and their families. The list is not exhaustive; other areas of research may be required. Impact of continuing education, skills training and debriefing for the organization, including the economic impact.
An examination of various approaches to address compassion fatigue, stress and moral distress.
Translating continuing education into competency.
Evaluation (see Tables 3 and 4) Development of public data repositories and indicators for provincial, national and international data collection of outcomes relevant to palliative care and end-of-life care.
Development of reliable and valid instruments that capture the quality of life and the needs of persons at the end of life across the care continuum.
Standardized palliative care and end-of-life care education and training for program monitoring and evaluation.
Measures of quality palliative care and end-of-life care in rural versus urban centres.
# RECOMMENDATIONS
A Palliative Approach to Care in the Last 12 Months of Life
# Implementation Strategies
Implementing BPGs at the point-of-care is multi-faceted and challenging. It takes more than awareness and distribution of BPGs for practice to change: BPGs must be adapted for each practice setting in a systematic and participatory way to ensure that recommendations fit the local context (118). The 2012 RNAO Toolkit: Implementation of Best Practice Guidelines, Second Edition provides an evidence-based process for doing this. It can be downloaded at RNAO.ca/bpg/resources/toolkit-implementation-best-practice-guidelines-second-edition.
The Toolkit is based on emerging evidence that successful uptake of best practices in health care is more likely when the following occur:
leaders at all levels are committed to supporting BPG implementation;
BPGs are selected for implementation through a systematic, participatory process;
stakeholders for whom the BPGs are relevant are identified and engaged in the implementation;
environmental readiness for implementing BPGs is assessed;
the BPG is tailored to the local context;
barriers and facilitators to using the BPG are assessed and addressed;
interventions to promote use of the BPG are selected;
use of the BPG is systematically monitored and sustained;
evaluation of the BPG's impact is embedded in the process; and
there are adequate resources to complete all aspects of the implementation.
The Toolkit uses the "Knowledge-to-Action" framework (119) to demonstrate the process steps required for knowledge inquiry and synthesis (see Figure 4). It also guides the adaptation of the new knowledge to the local context and its implementation. This framework suggests identifying and using knowledge tools (such as BPGs) to identify gaps and begin the process of tailoring new knowledge to local settings.
RNAO is committed to widespread deployment and implementation of our BPGs. We use a coordinated approach to dissemination, incorporating a variety of strategies, including the following:
1. The Best Practice Champion Network®, which develops the capacity of individual nurses to foster awareness, engagement and adoption of BPGs. 2. The BPG Order Sets TM provide clear, concise and actionable intervention statements derived from practice recommendations. BPG Order Sets can be readily embedded within electronic records, but they also may be used in paper-based or hybrid environments. 3. The BPSO® designation, which supports implementation at the organization and system levels. BPSOs focus on developing evidence-based cultures with the specific mandate to implement, evaluate and sustain multiple RNAO BPGs.
# RECOMMENDATIONS
A Palliative Approach to Care in the Last 12 Months of Life
In addition, we offer annual capacity-building learning institutes on specific BPGs and their implementation.
Information about our implementation strategies can be found at:
RNAO
# A P P E N D I C E S
A Palliative Approach to Care in the Last 12 Months of Life SHARING their wishes, values, and beliefs through conversations with the SDM and others that clarify their wishes, values and beliefs, and more generally how they would like to be cared for in the event of incapacity to give or refuse consent.
Rather than being a single event, advance care planning is ongoing and dynamic, with the potential for personal preferences to change over time as health status changes. It may be initiated at any point in the health care process, and may involve individuals who are currently healthy" (6, emphasis original).
Belief: "Acceptance of the truth, reality, or validity of something (e.g., a phenomenon, a person's veracity), particularly in the absence of substantiation" (120).
Bereavement: "The state of having suffered the loss of a loved one. It is the time after a loss during which grief is experienced and mourning occurs" (121).
Best practice guideline (BPG): BPGs are systematically developed, evidence-based documents that include recommendations for nurses and the interprofessional health team, educators, leaders, policy-makers, and persons and their families on specific clinical and healthy work environment topics. BPGs promote consistency and excellence in clinical care, health policies and health education, ultimately leading to optimal health outcomes for people, communities and the health system (122).
BPG Order Set TM : Provides clear, concise and actionable intervention statements derived from a practice recommendation. BPG Order Sets TM can be readily embedded within electronic records, but they also may be used in paper-based or hybrid environments.
Burnout: "Exhaustion of physical or emotional strength or motivation, usually as a result of prolonged stress or frustration" (123).
Care coordination: "Deliberate organization of patient care activities between two or more participants (including the patient) involved in a patient's care to facilitate the appropriate delivery of health care services.
Organizing care involves the marshalling of personnel and other resources needed to carry out all required patient care activities, and is often managed by the exchange of information among participants responsible for different aspects of care" (124).
# A P P E N D I C E S
A Palliative Approach to Care in the Last 12 Months of Life CERQual criteria: When using CERQual, four components contribute to the assessment of confidence in the evidence for each individual finding: 1. Methodological limitations, which look at issues in the design of the primary study or problems in the way it was conducted. 2. Relevance, whereby all primary studies that support a finding are assessed together and a decision is made regarding the applicability of the findings to the population, phenomenon and setting outlined in the research question. 3. Coherence, whereby an assessment is made of whether the primary studies provide sufficient data and a convincing explanation for the review findings. 4. Adequacy of data, whereby an overall assessment is made about the richness and quantity of data that supports the review finding and phenomenon of interest (125).
Compassion fatigue: "Physical and mental exhaustion and emotional withdrawal experienced by those that care for sick or traumatized people over an extended period of time" (26).
# Confidence in the Evidence from Reviews of Qualitative Research (CERQual):
The Confidence in the Evidence from Reviews of Qualitative Research (CERQual) is a methodological approach for assessing the amount of confidence that can be placed in findings from a body of qualitative evidence about an outcome of interest. The assessment provides a transparent means to decide if the review finding reasonably represents the phenomenon under study, which can help expert panels make health recommendations (125).
Confounding variable: "Variables that have the potential to affect the outcome of a study, which are recognized before the study is initiated but that cannot be controlled, or variables not recognized until the study is in process" (126).
Consensus: A process used to reach agreement among a group or expert panel during a Delphi or modified Delphi technique (127). A consensus of 70 per cent agreement from all voting expert panel members was required to determine the direction and strength of the recommendations within this BPG.
Control: Rules implemented by a researcher to decrease the likelihood of error in a research study and to increase the probability that findings are a true representation of reality. A control group within a research study refers to a group of elements or subjects that are not exposed to an experimental treatment or intervention (126).
Cultural need: Anything required by and important to persons and families who are receiving palliative care that is related to their culture, values, beliefs, norms and ways of life (128). To provide culturally appropriate palliative and end-of-life care, the meaning of death and dying from the person's cultural perspective must be explored, including asking persons and families what that means to them, what is important to them, and what services, space and supports they require. Cultural needs can be related to information about diagnosis and prognosis, food and refreshments, pain management, medical practices, end-of-life rituals, and post-death rituals and procedures (129).
See cultural safety and culture.
# A P P E N D I C E S
A Palliative Approach to Care in the Last 12 Months of Life Cultural safety: An environment that is physically, spiritually, socially and emotionally safe for people, where there is no assault, challenge or denial of their identity or what they need. It is about shared respect (130).
Culturally safe practices recognize and respect the cultural identities of others, and they safely meet their needs, expectations and rights (131).
See cultural need and culture.
Culture: Within this BPG, culture is broadly defined as the shared and learned values, beliefs, norms and ways of life of an individual or a group. Culture influences thinking, decisions and actions (128).
See cultural need and cultural safety.
Debriefing: Following an event or incident, debriefing involves obtaining emotional support from colleagues, followed by learning from the experience. The goal is to promote recovery, mitigate stress-related responses and prevent negative long-term effects. Debriefing should be a peer-driven approach (132). Debriefing can be both formal and informal.
Formal debriefing: Formal debriefing includes guidance from an individual trained in providing psychological support (132).
Informal debriefing: Informal debriefing includes emotional support from colleagues or any guidance offered by those who are not professionally trained or experienced in mental health (132).
Downgrade: When limitations in individual studies potentially bias the results in GRADE and GRADE-CERQual, the quality of evidence will decrease or be downgraded (133). For example, a body of quantitative evidence for one priority outcome may begin with high certainty, but due to serious limitations in one or more of the five GRADE criteria, it will be rated down one or two levels (134).
Education: Refers to obtaining theoretical knowledge and cultivating the ability to use critical thinking and decision-making skills. Education includes three continuous and fluid levels: awareness, training for specific needs and competency-based skills, and specialization (135). Education should be tailored to the scope of practice of the health provider and their role within the organization.
Education statement: Organizational approaches to the delivery of education in health-service organizations and academic institutions to support evidence-based practice. Education statements are based on an analysis of educational recommendations across several BPGs on diverse clinical topics and populations. Education statements can be applicable to all clinical BPGs and can be contextually adapted within health-service organizations and academic institutions to support implementation of clinical recommendations.
# Effect (treatment effect):
Best estimate of the outcomes related to the use of a treatment or intervention (136).
Emotion: "Complex reaction pattern, involving experiential, behavioral, and physiological elements, by which an individual attempts to deal with a personally significant matter or event" (137).
# A P P E N D I C E S
A Palliative Approach to Care in the Last 12 Months of Life End of life: Persons are "approaching the end of life when they are likely to die within the next 12 months. This includes people whose death is imminent (expected within a few hours or days) and those with:
Advanced, progressive, incurable conditions.
General frailty and co-existing conditions that mean they are expected to die within 12 months.
Existing conditions if they are at risk of dying from a sudden acute crisis in their condition.
Life threatening acute conditions caused by sudden catastrophic events" (138).
End-of-life care: are for persons who are expected to die in the foreseeable future and their families. It includes helping persons and families prepare for death, ensuring comfort and supporting decision making in a manner consistent with the person's prognosis and goals of care (6).
Estimate of effect: "A statistical measure indicating the magnitude of a treatment effect" (139).
# Evidence-based nursing practice:
The integration of the methodologically strongest research evidence with clinical expertise and patient values; unifies research evidence with clinical expertise and encourages the inclusion of patient preferences (140).
# Evidence-to-Decision (EtD) Framework:
A table that facilitates expert panels to make decisions when moving from evidence to recommendations. The purpose of the framework is to summarize the research evidence, outline important factors that can determine the recommendation, inform expert panel members about the benefits and harms of each intervention considered, and increase transparency about the decision-making process in the development of recommendations (11).
Existential: "The existential domain includes concerns regarding death (existential obliteration), freedom (the absence of external structure), isolation (the final unbridgeable gap separating self from all else), and the question of meaning (the dilemma of meaning-seeking creatures who recognize the possibility of a cosmos without meaning)" (141).
Expectations: Expectations as they relate to the plan of care are issues, hopes and fears identified by the person and/or family that require attention (3).
Family: "Those closest to the patient in knowledge, care and affection. The person defines his or her 'family' and who will be involved in his/her care and/or present at the bedside. May include:
the biological family the family of acquisition (related by marriage/contract)
the family of choice and friends (including pets)" (3).
# A P P E N D I C E S
A Palliative Approach to Care in the Last 12 Months of Life Family caregiver: "Any relative, partner, friend or neighbor who has a significant personal relationship with, and provides a broad range of assistance for, an older person or an adult with a chronic or disabling condition. These individuals may be primary or secondary caregivers and live with, or separately from, the person receiving care" (8). The term may be used interchangeably with caregiver, carer, informal caregiver and primary caregiver.
Goals of care: "A goals of care discussion between a patient (or his/her Substitute Decision Maker if the patient lacks capacity) and [health provider(s)] addresses the patient's goals for his or her care in the context of health-care consent and decision-making in advanced illness. The purpose of these discussions is to outline the patient's values, beliefs, wishes, perception of quality of life and what he or she characterizes as meaningful and important. Other elements include the patient's understanding of current health conditions, prognosis, and likely course of events if his or her goals of care are applied to potential treatment decisions. The goals of care discussion provides the foundation for decision-making and will often include the development of (and obtaining informed consent to) a plan of treatment" (6).
# Gold Standards Framework (GSF):
"The National Gold Standards Framework (GSF) Centre in End of Life Care is the national [UK] training and coordinating centre for all GSF programmes, enabling generalist frontline staff to provide a gold standard of care for people nearing the end of life. GSF improves the quality, coordination and organisation of care leading to better patient outcomes in line with their needs and preferences and greater cost efficiency through reducing hospitalisation" (142).
GRADE Criteria for observational studies: When using GRADE to assess the body of evidence for observational studies, in addition to the five criteria in "GRADE Criteria for Randomized Controlled Trials" three criteria assessed are:
1. Magnitude of effect, where magnitude of effect of an intervention on the outcome is assessed.
2. Dose-response gradient, where consideration is made regarding the effect of the intervention on the outcome.
3. Effect of plausible confounding, where consideration is made regarding residual confounders that cause an underestimation of treatment effect (11).
# A P P E N D I C E S
A Palliative Approach to Care in the Last 12 Months of Life GRADE Criteria for randomized controlled trials: When using GRADE to assess the body of evidence for randomized controlled trials, five components contribute to the assessment of confidence in the evidence for each outcome:
1. Risk of bias, which focuses on the flaws in the design of a study or problems in its execution.
2. Inconsistency, which looks at a body of evidence and assesses whether the results point in the same direction, or if they are different.
3. Imprecision, which refers to the accuracy of results based on the number of participants and/or events included and the width of the confidence intervals across a body of evidence.
4. Indirectness, whereby each primary study that supports an outcome is assessed and a decision is made regarding the applicability of the findings to the population, intervention and outcome outlined in the research question.
5. Publication bias, where a decision is made about whether the body of published literature for an outcome potentially includes only positive or statistically significant results (11).
# Grading of Recommendations Assessment, Development and Evaluation (GRADE):
The Grading of Recommendations Assessment, Development and Evaluation (GRADE) is a methodological approach to assess the quality of a body of evidence in a consistent and transparent way, and to develop recommendations in a systematic manner. The body of evidence for an important and/or critical outcome is evaluated based on risk of bias, consistency of results, relevance of the studies, precision of the estimates and publication bias (125).
Grief: "A normal reaction to the loss of a loved one. It can also be a reaction to the loss of relationships, physical ability, opportunities or future hopes and dreams" (121).
Health provider: "A formal caregiver who is a member of an organization and accountable to norms of conduct and standards of practice. They may be professionals, support workers or volunteers" (3). Health provider refers to both regulated workers (e.g., nurses, physicians, dieticians or social workers) and unregulated workers (e.g., personal support workers) who are part of the interprofessional health team.
# Regulated health provider:
In Ontario, the Regulated Health Professional Act (RHPA), 1991, provides a framework for regulating 23 health professions, outlining the scope of practice and profession-specific controlled or authorized acts that each regulated professional is authorized to perform when providing health care and services (9).
Unregulated care provider: Unregulated health providers fulfill a variety of roles in areas that are not subject to the RHPA. They are accountable to their employers but not to an external regulating professional body (e.g., the College of Nurses of Ontario). Unregulated health providers fulfill a variety of roles and perform tasks that are determined by their employer and employment setting. Unregulated health providers only have the authority to perform a controlled act as set out in the RHPA if the procedure falls under one of the exemptions set out in the Act (10).
# A P P E N D I C E S
A Palliative Approach to Care in the Last 12 Months of Life Home: Home refers to a physical house or other dwelling, such as long-term care, a hospice or other community setting. In palliative care, home impacts the person and their family's ways of experiencing, feeling or acting. It is something people have feelings for-a part of their personal identity, a location with complex and relational spatial connections, a site for care, a passive background and an absolute space-and it is constantly changing over time (143). For Indigenous persons, home may also refer to the final destination in their spiritual journey.
Interprofessional health team: "A team comprised of multiple health providers (regulated and unregulated) who work collaboratively to deliver comprehensive and quality health care and services to people within, between, and across health-care settings" (144). In palliative care and end-of-life care, interprofessional health teams include patients, family members, volunteers and caregivers, along with regulated and unregulated health providers.
See interprofessional model of care.
Interprofessional model of care: Refers to "teams with different health-care disciplines working together towards common goals to meet the needs of a patient population. Team members divide the work based on their scope of practice; they share information to support one another's work and coordinate processes and interventions to provide a number of services and programs" (7).
See interprofessional health team.
# Medical Assistance in Dying (MAiD):
While there is an intersection between MAiD and palliative care, and each may be part of the person's care path, "in accordance with federal legislation, MAiD [specifically] includes circumstances where a medical practitioner or nurse practitioner, at an individual's request: (a) administers a substance that causes an individual's death; or (b) prescribes a substance for an individual to self-administer to cause their own death" (145).
# Meta-analysis:
A systematic review of randomized controlled trials that uses statistical methods to analyze and summarize the results of the included studies (146).
See systematic review.
Nurse: "Refers to registered nurses, licensed practical nurses (referred to as registered practical nurses in Ontario), registered psychiatric nurses and nurses in advanced practice roles such as nurse practitioners and clinical nurse specialists" (144).
Nurse-led care: Nurse-led care refers to "a continuum with, at one end, nurses undertaking highly protocol driven, focused tasks and, at the other end, responding to far more diverse challenges in terms of clinical decision making" (147).
# A P P E N D I C E S
A Palliative Approach to Care in the Last 12 Months of Life Outcomes: A dependent variable or the clinical and/or functional status of a patient, provider or population that is used to assess if an intervention is successful. In GRADE, outcomes are prioritized based on if they are critical for decision making, important but not critical for decision making or not important. This helps the literature search and systematic reviews to be more focused (11).
Palliative care: A philosophy of-and approach to-care. Palliative care aims to improve the quality of life of persons and their families facing life-limiting illness by preventing and relieving suffering through early identification, assessment and treatment of symptoms (9). Also referred to as hospice palliative care.
Principles of palliative care include the following:
Relieve suffering and improve the quality of living and dying.
Address the physical, psychological, social, spiritual (existential) and practical issues of persons and their families, and their associated expectations, needs, hopes and fears.
Prepare persons and their families for self-determined life closure and the dying process and help them manage it.
Helps families cope with loss and grief during the illness and bereavement experience.
Treat all active issues, prevent new issues from occurring and promote opportunities for meaningful and valuable experiences, personal and spiritual growth, and self-actualization (10).
Person: In the context of this Guideline, "person" refers to those experiencing the last 12 months of progressive life-limiting illness. The term is used interchangeably with patient, resident and other terms found in the literature.
# PICO research question:
A framework to outline a focused question. It specifies four components:
1. The patient or population being studied.
2. The intervention to be investigated.
# The alternative or comparison intervention.
4. The outcome that is of interest (11).
# Plan of care:
The plan of care is individualized and person-centred. It reflects the wishes, goals and values of the person in the last 12 months of life and their family.
# Preference:
The power or opportunity of choosing (148).
# Qualitative research:
An approach to research that seeks to convey how human behaviour and experiences can be explained within the context of social structures using an interactive and subjective approach to investigate and describe phenomena (149).
# A P P E N D I C E S
A Palliative Approach to Care in the Last 12 Months of Life
# Quasi-experimental study:
A study that estimates causal effects by observing the exposure of interest, but in which the experiments are not directly controlled by the researcher and lack randomization (e.g., before-andafter designs) (150).
# Randomized controlled trial (RCT):
An experiment in which the investigator assigns one or more interventions to participants who are randomly allocated to either the experimental group (receives intervention) and the comparison (conventional treatment) or control group (no intervention or placebo) (146).
Recommendation: A course of suggested action(s) that directly answer a recommendation question. A recommendation is based on a systematic review of the literature and is made in consideration of its potential benefits and harms, values and preferences from a person-centered perspective, and its impact on health equity. All recommendations are given a strength-either strong or conditional-through expert panel consensus. It is important to note that recommendations should not be viewed as prescriptive, as recommendations cannot take into account all of the unique features of individual, organizational and clinical circumstances (11).
A strong recommendation "…reflects the expert panel's confidence that the desirable effects of an intervention outweigh its undesirable effects (strong recommendation for an intervention) or that the undesirable effects of an intervention outweigh its desirable effects (strong recommendation against an intervention)" (11). A strong recommendation implies that the majority of persons will be best serviced by the recommended action (11).
A conditional recommendation reflects the expert panel's confidence that while some uncertainty exists, the desirable effects probably outweigh the undesirable effects (i.e., conditional recommendation for an intervention) or that the undesirable effects probably outweigh the desirable effects (i.e., a conditional recommendation against an intervention) (11). A conditional recommendation implies that not all persons will be best served by the recommended action, and that there is a need for more careful consideration of personal circumstances, preferences and values (11).
Relational coordination: Includes shared goals, shared knowledge and mutual respect, supported by clear, timely and effective communication within an organization (151).
Resilience: A person's ability to thrive in the face of stress and traumatic experiences (33).
Scoping review: "Scoping reviews have been described as a process of mapping the existing literature or evidence base. Scoping reviews can be used in a number of ways, for example identifying research gaps and summarizing findings of research. They can also be used to inform systematic reviews" (152).
Secondary traumatic stress: "The natural, consequent behaviors and emotions resulting from knowledge about a traumatizing event experienced by a significant other. It is the stress resulting from helping or wanting to help a traumatized or suffering person" (153).
See compassion fatigue.
# A P P E N D I C E S
A Palliative Approach to Care in the Last 12 Months of Life Self-regulation: "The control of one's behavior through the use of self-monitoring (keeping a record of behavior), self-evaluation (assessing the information obtained during self-monitoring), and self-reinforcement (rewarding oneself for appropriate behavior or for attaining a goal)" (154).
# Setting of care:
The location where care is provided. Settings of care may include: the person's home; primary care settings (e.g., a doctor's office or community clinic); acute, chronic or long-term care facilities; hospice or palliative care units; jails or prisons; or (for persons with no home) the street or homeless shelters (3).
# Shared decision-making:
This approach to making decisions is based on an acknowledgement of each person's individual autonomy and right to self-determination (i.e., the freedom to make one's own decisions and control one's life). It relies on information from two experts: the health provider (the expert on evidence-based practices) and the person making the decisions for their health. The person is the expert on themselves (e.g., their beliefs, culture, spirituality and values), their experience of health and their life circumstances (i.e., their social world and lived experiences with health). Together, these experts share and discuss the best options for health and services so the person can make a decision and choose the best option for them (155)(156)(157).
# Social determinants of health: "
The conditions in which people are born, grow, live, work and age, and the systems put in place to deal with illness" (158).
Spirituality: "Dynamic dimension of human life that relates to the way persons (individual and community) experience, express and/or seek meaning, purpose and transcendence, and the way they connect to the moment, to self, to others, to nature, to the significant and/or the sacred. " Spirituality is multidimensional and considers existential challenges, value-based considerations and attitudes, and religious considerations and foundations (159).
Stakeholder: An individual, group or organization that has a vested interest in the decisions and actions of organizations, and that may attempt to influence decisions and actions (160). Stakeholders include all of the individuals and groups directly or indirectly affected by the change or solution to the problem.
Structurally vulnerable populations: "...people living in poverty and who are experiencing some level of homelessness, while at the same time are also experiencing various forms of racism, a history of or ongoing trauma and violence, social isolation, stigma associated with mental health issues, cognitive impairments, behavioural issues, substance use (previous or ongoing), interactions with the criminal justice system, and mobility issues and/or disability (186).
# A P P E N D I C E S
A Palliative Approach to Care in the Last 12 Months of Life Substitute decision-maker: "Person(s) who provides or refuses consent for treatment or to withdraw treatment on behalf of another person when that person is mentally incapable of making his or her decisions about treatment. The substitute decision-maker is required to make decisions on a person's behalf following any wishes expressed about care when mentally capable. If the substitute decision-maker does not know any wishes applicable to the treatment decision to be made, he or she is required to act in the person's best interests" (161).
"A substitute decision-maker can be chosen in several different ways.
By the person: The person can appoint someone to be their substitute decision-maker in a "Power of Attorney for Personal Care. " More than one substitute decision-maker may be appointed.
Automatically under the Ontario's Health Care Consent Act: If a substitute decision-maker is not appointed, the person who will make decisions on the person's behalf will be chosen based on the ranked list set out in Ontario's Health Care Consent Act.
By the court: If a person has a court-appointed guardian, then that person automatically becomes their substitute decision-maker.
By the Ontario Consent and Capacity Board: If the person is not mentally capable of making decisions, one of their family or friends can apply to the Consent and Capacity Board to be named as their "representative, " which is a type of substitute decision-maker. However, if the person prepared a valid Power of Attorney for Personal Care, the Consent and Capacity Board will not appoint anyone else.
By the government: If there is no other person capable, available or willing to give or refuse consent for treatment or to withdraw treatment on the person's behalf, the government will appoint the Public Trustee and Guardian to be the decision-maker of last resort for the person" (161).
# Surrogate outcome:
A surrogate outcome is a substitute measure to the one originally selected. Surrogate outcomes are considered when evidence about the desired outcomes is lacking or unexplored (11).
# Systematic reviews:
A comprehensive review of the literature that uses clearly formulated questions and systematic and explicit methods to identify, select and critically appraise relevant research. A systematic review collects and analyzes data from the included studies and presents them, sometimes using statistical methods (146).
See meta-analysis.
Value: "A moral, social, or aesthetic principle accepted by an individual or society as a guide to what is good, desirable, or important" (162).
Wish: A person's will or desire (163).
# A P P E N D I C E S
A Palliative Approach to Care in the Last 12 Months of Life
# Appendix B: RNAO Guidelines and Resources that Align with this Guideline
The following are topics that align with this guideline, with suggested BPGs and resources from other organizations.
# TOPIC RESOURCE(S)
Care
# A P P E N D I C E S
A Palliative Approach to Care in the Last 12 Months of Life Academic institutions should consider integrating guideline content into theoretical and practice-based courses for nurses and other regulated health providers, including social workers, physiotherapists, occupational therapists, dieticians and pharmacists in pre-licensure and post-licensure programs. Pre-licensure education establishes foundational knowledge that can be strengthened and augmented, as necessary, within healthservice organizations. Post-licensure education at the graduate level may include preparing nurses and other regulated health providers for advanced practice roles and functions within clinical practice, education, administration, research and policy (164). As such, the integration of guideline content into curricula will differ in terms of educational content and complexity, based on the overall educational objectives of the program.
In both cases, integrating guideline content into curricula supports student learning that is consistent with evidence-based practices, with the ultimate goal of enhancing the health outcomes of persons and families.
To support the integration of evidence-based guidelines into curricula, the following approaches may be utilized: (1) developing multi-level guideline-related learning objectives; and (2) designing guideline-related teaching and learning strategies (165). Both approaches are outlined below.
# Developing multi-level guideline-related learning objectives:
Guideline-related learning objectives at multiple levels of a program (pre-licensure and post-licensure) facilitate integration of guideline content into curricula.
At the program level, such integration broadens student knowledge, attitude, judgment and skills. For instance, a program-level outcome at the graduate level may include student awareness of elements of implementation science to support uptake and sustained use of guidelines in clinical settings (165). At the course level, integration of guideline content supports student learning that is consistent with evidence-based practices within academic and practice settings. For example, course-level outcomes at the undergraduate level may include students being able to gain increased knowledge about guidelines, select guidelines relevant to practice (and provide rationale for their selection) and integrate guideline recommendations into plans of care for persons and families (165).
# Designing guideline-related teaching and learning strategies:
Teaching strategies should be tailored to address the program-level educational objectives and needs of learners, and to equip the learner to improve practice and promote positive outcomes (166). The various guideline-related teaching and learning strategies are outlined below.
Access to BPG-related resources: Educators can promote and facilitate access to BPG-related links and resources. For example, providing access to the RNAO Nursing Best Practice Guidelines App (see RNAO. ca/bpg/pda/app) enables students to access content from guidelines within classroom and practice settings (165).
Assignments and tests: Students may be asked to incorporate guidelines into their learning plans or to write a reflective journal related to a guideline important to their area of practice. Tests or exam questions that demonstrate critical thinking related to guidelines can also be used. Overall, guideline-related assignments and tests can assist students to reflect upon guidelines, understand their application and critique them (165).
# A P P E N D I C E S
A Palliative Approach to Care in the Last 12 Months of Life Interactive classroom activities: Interactive learning activities within the classroom setting can support students to obtain additionwal information, participate in problem-solving and articulate knowledge gained. Examples include: (i) assigning group work to help students learn how to navigate a guideline and become familiar with its recommendations; (ii) using case studies to provide students with opportunities to identify and apply guideline recommendations in care plans; and (iii) using videos and role playing to promote skills in articulating the rationale for selecting specific guidelines and recommendations in care plans (165).
Lectures: Educators can use lectures as a means to provide a broad understanding of guidelines, specifically the rigorous process of guideline development and their various recommendations. Lectures can provide students with an understanding of the scope and strength of evidence that informs recommendations (165). Preceptorship or mentorship in clinical placements: Preceptors within clinical settings play an integral role in teaching practical skills that complement the theoretical learning of students. Preceptors are responsible for providing clinical teaching and supervision, and they perform formal student evaluation (168). Preceptors can support students to integrate guideline content into their learning objectives and clinical activities to promote evidence-based knowledge and practice.
Simulation: High-quality digital simulation within skills lab settings can ease the uncertainty of students related to clinical practice; it can also increase skill acquisition, self-confidence and satisfaction. Faculty trained in pedagogy can use simulation to teach students content related to safe and effective person and family care within a standardized clinical environment (167). Educators can support students to incorporate guideline content into simulated practice sessions when teaching evidence-based practice (165). Education and training programs should be based on the principles of adult learning, including the following:
# A P P E N D I C E S
A
Adults have an awareness of learning needs and goals.
Adults are self-directed and autonomous.
Adults value and utilize prior life experiences.
Adults have a readiness to learn.
Adults are motivated to learn.
Adults are presented knowledge and skills in the context of practical, real-life situations (170).
Furthermore, education and training should be appropriate to the health provider's scope of practice and their defined role. Education and training strategies may include the following:
# A P P E N D I C E S
A Palliative Approach to Care in the Last 12 Months of Life In-service education sessions: In-service education sessions can be planned by clinical experts within practice settings to support the utilization of a specific guideline or recommendations stimulating evidencebased practice among staff. The education may include one-on-one or group sessions, and it should address the needs of learners. It is recommended that the education sessions are followed with refresher or booster sessions to provide feedback and enhance staff learning (171,172).
Post-licensure mentorship: Post-licensure mentorship involves providing new graduates or less experienced staff with guidance for skill development and support for growth of professional roles. Research suggests that working with mentors reduces stress and improves satisfaction for new staff during the transition process (176). Mentors can support integration of guideline content while teaching evidence-based practice.
Quality improvement: Participating in quality improvement within workplace settings can support nurses and health workers to recognize sentinel events and examine ways to improve care. Meeting accreditation standards is an important quality improvement activity that bridges gaps between current and best practices and supports continued competence. Examples of strategies that nurses and other health providers can use to meet accreditation standards include the following:
Participating in a unit-based guideline implementation process to promote patient safety, reduce risks and improve care outcomes.
Choosing guideline-specific recommendations to facilitate practice change.
Sharing knowledge and lessons learned from reviewing guidelines with the accreditation committee (174,175).
Other quality improvement opportunities include participating in incident reporting, patient safety initiatives and other health initiatives within areas of practice.
Workshops/seminars: Highly interactive workshops and seminars help nurses and health providers maintain evidence-based best practice when they incorporate a variety of teaching-learning strategies, including pre-circulated materials, small group discussions using case studies, and multimedia such as Power Point and videos that integrate relevant guidelines and recommendations. RNAO's Best Practice Champions Workshop and BPG Learning Institutes are examples of programs that provide education on how to implement BPGs within practice settings (173).
# A P P E N D I C E S
A Palliative Approach to Care in the Last 12 Months of Life
# EVALUATION
All educational strategies require evaluation to monitor the adoption of knowledge and measure the impact on clinical outcomes. RNAO has developed the Educator's Resource: Integration of Best Practice Guidelines (2005) to provide strategies for educators within academia and practice settings to introduce BPGs to student nurses, faculty, nurses and other health providers. The resource provides guidance on student evaluation strategies that include self-evaluation, peer-evaluation and end-of-course evaluations by the educator.
Furthermore, RNAO has developed the Practice Education in Nursing (2016) BPG to provide evidence-based recommendations that support the application of knowledge by student nurses to various practice settings. The guideline also assists nurses, nurse educators, preceptors and other members of the interprofessional health team to understand the effective use of teaching-learning strategies in clinical settings.
The RNAO Toolkit: Implementation of Best Practice Guidelines (2012)* identifies the following strategies for evaluation of provider practice change and health outcomes for persons within health-service organizations:
Pre-and post-tests for staff educational sessions.
Staff focus groups/interviews.
Observation of patient-provider encounters.
Chart audits to determine the impact on person and family outcomes. * The RNAO Toolkit: Implementation of Best Practice Guidelines (2012) is under review. The next edition is expected to be issued in 2020.
# A P P E N D I C E S
A Palliative Approach to Care in the Last 12 Months of Life
# Appendix D: Guideline Development Methods
This appendix presents an overview of the RNAO guideline development process and methods. RNAO is unwavering in its commitment that every BPG be based on the best available evidence. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) and Confidence in the Evidence from Reviews of Qualitative Research (CERQual) methods have been implemented to provide a rigorous framework and meet international standards for guideline development.
# Scoping the Guideline
The scope sets out what an RNAO BPG will and will not cover (see Purpose and Scope). To determine the scope of this BPG, the RNAO Best Practice Guideline Development and Research Team conducted the following steps.
1. Reviewed the RNAO BPG End-of-life Care During the Last Days and Hours (2011) to understand its purpose, scope and recommendations.
# Conducted a guideline search and gap analysis. The RNAO Best Practice Guideline Development and Research
Team searched an established list of websites for guidelines and other relevant content published between January 2011 and April 2017. The purpose of the guideline search and gap analysis was to gain an understanding of existing guidelines regarding end-of-life care in order to identify opportunities for addressing the purpose and scope of this BPG. The resulting list was compiled based on knowledge of evidence-based practice websites and recommendations from the literature. The RNAO expert panel members were asked to suggest additional guidelines (see Figure 5 in Appendix E). Detailed information about the search strategy for existing guidelines, including the list of websites searched and the inclusion criteria used, is available at RNAO.ca/bpg/guidelines/palliative-approachcare-last-12-months-life.
The guidelines were reviewed for content, applicability to nursing scope of practice, accessibility and quality. Two guideline development methodologists appraised six international guidelines using the Appraisal of Guidelines for Research Evaluation Instrument II (AGREE II) tool and came to consensus on an overall score for each guideline (177). Guidelines with a score of 6 or 7 (on a 7-point Likert scale) were considered to be of high quality. The systematic reviews that answered research questions in high-quality guidelines were considered to be beyond the scope of this BPG.
The following guidelines were appraised as follows: The expert panel engaged in the following activities:
BC
approved the scope of this BPG;
determined the recommendation questions and outcomes to be addressed in this BPG;
participated in a consensus development process to finalize recommendation statements;
# A P P E N D I C E S
A Palliative Approach to Care in the Last 12 Months of Life provided feedback on the draft of this BPG;
participated in the development of evaluation indicators; and identified appropriate stakeholders to review the draft BPG prior to publication.
The expert panel co-chairs led the following activities:
monthly co-chair meetings with the guideline development methodologist and guideline development project coordinator;
facilitated expert panel meetings;
provided in-depth guidance on clinical and/or research issues; and
moderated and acted as tiebreakers in voting processes.
# Conflict of Interest
In the context of RNAO best practice guideline development, the term "conflict of interest" (or COI) refers to situations in which an expert panel member's or RNAO staff member's financial, professional, intellectual, personal, organizational or other relationships may compromise their ability to independently conduct panel work. Declarations of COI that might be construed as constituting a perceived and/or actual conflict were made by all members of the RNAO expert panel prior to their participation in guideline development work using a standard form. Expert panel members also updated their COI at the beginning of each in-person guideline meeting.
Any COI declared by an expert panel member was reviewed by the RNAO Best Practice Guidelines Development and Research Team and expert panel co-chairs. No limiting conflicts were identified. See "Declarations of Conflicts of Interest Summary" at https://rnao.ca/bpg/guidelines/palliative-approach-care-last-12-months-life.
# Identifying Priority Recommendation Questions and Outcomes
In March 2017, the RNAO Best Practice Guideline Development and Research Team and expert panel convened inperson to determine the purpose, scope and priority recommendation questions for this BPG. In the spring of 2017 the RNAO Best Practice Guideline Development and Research Team began to implement the GRADE and CERQual methodologies. As such, this BPG is considered a transitional GRADE BPG, in that the GRADE approach was adapted within the process of guideline development. In July 2017, the RNAO Best Practice Guideline Development and Research Team and the expert panel co-chairs modified the recommendation questions and outcomes in alignment with GRADE standards for assessing and presenting the evidence. The recommendation questions and priority outcomes were informed by the guideline gap analysis, the scoping review of the literature and discussion with the co-chairs.
Each recommendation question informed a PICO research question which guided the systematic reviews. The four recommendation questions and their respective PICO research questions are presented below: * The original intervention in Recommendation Question 1a and 1b explored a transdisciplinary approach; however, after completing literature searches, title and abstract screening, and a full-text relevance review, no literature was identified that answered the recommendation question. In consultation with the co-chairs, a proxy intervention-interprofessional care-was chosen as an alternative intervention.
A P P E N D I C E S A Palliative Approach
** The outcomes-person's expectations and moral distress-were not found in the literature. As a result, care in alignment with the person's wishes and stress/distress were respectively chosen as surrogate outcomes after consultation with expert panel co-chairs.
# A P P E N D I C E S
A Palliative Approach to Care in the Last 12 Months of Life were asked to review their personal libraries for key studies not found through the above search strategies. Detailed information on the search strategy for the systematic reviews, including the inclusion and exclusion criteria and search terms, is available at RNAO.ca/bpg/guidelines/palliative-approach-care-last-12-months-life.
Studies were independently assessed for relevance and eligibility by the inclusion and exclusion criteria. Any disagreements were resolved through consensus.
All included articles were independently assessed for risk of bias by study design using validated and reliable tools. Randomized controlled trials were assessed using the Risk of Bias 2.0 tool (178), quasi-experimental studies G and observational studies were assessed using the ROBINS-I tool ( 179), systematic reviews were assessed using the AMSTAR 2 tool (180), and qualitative studies were assessed using an adapted version of the Critical Appraisal Skills Program (CASP) qualitative checklist (181). One masters-prepared guideline development methodologist assessed risk of bias and a PhD-prepared research director reviewed and validated the assessments. Disagreements between reviewers were resolved through consensus discussion.
Data extraction was performed simultaneously. One masters-prepared guideline development methodologist performed data extraction, and a PhD-prepared research director reviewed and cross-checked for accuracy. In total, 53 studies were included across all three systematic reviews (see
# Determining Certainty and Confidence of Evidence
# Certainty of Evidence
The certainty of quantitative evidence (i.e., the extent to which one can be confident that an estimate of the effect is correct) is determined using GRADE methods (11). First, the certainty of the evidence is rated for each prioritized outcome across studies (i.e., for a body of evidence) per recommendation question (11). This process begins with the study design and then requires an examination of five criteria-risk of bias, inconsistency, imprecision, indirectness and publication bias-for the potential downgrade G of the certainty of evidence for each outcome. See Table 11 for a definition of each of these certainty criteria.
# A P P E N D I C E S
A Palliative Approach to Care in the Last 12 Months of Life
# Risk of bias
Limitations in the study design and execution that may bias study results. Valid and reliable quality appraisal tools are used to assess the risk of bias. First, risk of bias is examined for each individual study and then examined across all studies per defined outcome.
# Inconsistency
Unexplained differences (heterogeneity) of results across studies. Inconsistency is assessed by exploring the magnitude of difference and possible explanations in the direction and size of effects reported across studies for a defined outcome.
# Indirectness
Variability between the research and review question and the context within which the recommendations would be applied (applicability). There are four sources of indirectness which are assessed:
Differences in population.
Differences in interventions.
Differences in outcomes measured.
Differences in comparators.
# Imprecision
The degree of uncertainty around the estimate of effect. This is usually related to sample size and number of events. Studies are examined for sample size, number of events and confidence intervals.
# Publication bias
Selective publication of studies based on study results. If publication bias is strongly suspected, downgrading is considered. After considering the five criteria outlined in Table 11, three factors are assessed that can potentially enable rating up the certainty of evidence for observational studies:
1. Large magnitude of effect: If the body of evidence has not been rated down for any of the five criteria and a large estimate of the magnitude of intervention effect is present, there is consideration for rating up.
# Dose-response gradient:
If the body of evidence has not been rated down for any of the five criteria and a doseresponse gradient is present, there is consideration for rating up.
# Effect of plausible confounding:
If the body of evidence has not been rated down for any of the five criteria and all residual confounders would result in an underestimation of treatment effect G , there is consideration for rating up (11).
# A P P E N D I C E S
A Palliative Approach to Care in the Last 12 Months of Life GRADE categorizes the overall certainty of evidence as high, moderate, low or very low. See Table 12 for the definitions of these categories.
For this BPG, the five GRADE certainty criteria for potentially downgrading quantitative evidence and the three GRADE certainty criteria for potentially rating up quantitative evidence were independently assessed by two reviewers. Any discrepancies were resolved through consensus. The certainty of evidence assigned to each recommendation was based on the certainty of evidence of prioritized outcomes in the studies that informed the recommendation.
# High
We are very confident that the true effect lies close to that of the estimate of the effect.
# Moderate
We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
# Low
Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect.
# Very Low
We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.
# Confidence in Evidence
Similar to GRADE, CERQual has four criteria to assess the confidence in qualitative findings related to a phenomenon of interest:
1. methodological limitations 2. relevance 3. coherence
# adequacy
See Table 13 for a definition of each of these criteria.
# A P P E N D I C E S
A Palliative Approach to Care in the Last 12 Months of Life
# Methodological limitations
The extent to which there are concerns about the design or conduct of the primary studies that contributed evidence to an individual review finding.
# Coherence
An assessment of how clear and cogent the fit is between the data from the primary studies and a review finding that synthesises that data. Cogent refers to being well supported or compelling.
# Adequacy of data
An overall determination of the degree of richness and quantity of data supporting a review finding.
# Relevance
The extent to which the body of evidence from the primary studies supporting a review finding is applicable to the context (perspective or population, phenomenon of interest, setting) specified in the review question. Qualitative findings related to each of the prioritized outcomes were independently assessed by the two reviewers using the four criteria. Discrepancies were resolved through consensus. Recommendations that included qualitative evidence were assigned an overall confidence in evidence based on the corresponding review finding. See Table 14 for the definitions of these categories.
# High
It is highly likely that the finding is a reasonable representation of the phenomenon of interest.
# Moderate
It is likely that the finding is a reasonable representation of the phenomenon of interest.
# Low
It is possible that the review finding is a reasonable representation of the phenomenon of interest
# Very Low
It is not clear whether the review finding is a reasonable representation of the phenomenon of interest. 3, Description of level of confidence in a review finding in the CERQual approach; p. 6. Reprinted with permission.
# A P P E N D I C E S
A Palliative Approach to Care in the Last 12 Months of Life
# Summarizing the Evidence
GRADE and CERQual evidence profiles are used to present decisions on the certainty and confidence of evidence, as well as general general information about the body of research evidence, including key statistical or narrative results (182). Evidence profiles summarize the body of evidence for each systematic review per outcome and are developed by the guideline development methodologists.
Evidence profiles for the body of quantitative studies present the decisions made by the two reviewers on the five key GRADE certainty criteria for downgrading and the three GRADE certainty criteria for rating up. The evidence profiles also present general information about the body of evidence, including the population, the countries where the studies were conducted, a description of the intervention, the key results and the transparent judgments about the certainty underlying the evidence for each outcome (11). For this BPG, meta-analyses G were not performed; results were synthesized using narrative format.
CERQual evidence profiles were created for the body of qualitative evidence for each systematic review per outcome. Similar to the GRADE evidence profiles used for quantitative research, the CERQual evidence profiles presented the body of evidence supporting each theme as related to each outcome per recommendation question. These evidence profiles presented the decisions made by the two reviewers on the four key CERQual criteria G and transparent judgements about the confidence underlying the evidence for each theme.
For the GRADE and CERQual evidence profiles for each systematic review per outcome, please contact us at RNAO. ca/contact.
# Formulating Recommendations
# Evidence-to-Decision Frameworks
Evidence-to-Decision (EtD) frameworks G outline proposed recommendations and summarize all necessary factors and considerations based on available evidence and expert panel judgement for formulating the recommendation statements. EtD frameworks are used to help ensure that all of the important factors required to develop recommendation statements are considered by an expert panel (11). The guideline development methodologist drafted the frameworks with both quantitative and qualitative evidence from the systematic reviews.
For this BPG, the EtD frameworks included the following areas of consideration for each drafted recommendation statement (see Table 15):
background information on the magnitude of the problem;
includes the PICO research question and general context related to the research question;
the balance of benefits and harms of an intervention;
certainty and/or confidence of the evidence;
values and preferences; and health equity.
# A P P E N D I C E S
A Palliative Approach to Care in the Last 12 Months of Life
# Decision Making: Determining the Direction and Strength of Recommendations
Expert panel members were provided with the EtD frameworks to review prior to a scheduled two-day in-person meeting to determine the direction (i.e., a recommendation for or against an intervention) and strength (i.e., strong or conditional) of the BPG's recommendations. Expert panel members were also given access to the complete evidence profiles and full-text articles.
Using the EtD frameworks as a guiding document, the expert panel members participated in an online vote from May 14 to May 28, 2018. The following questions were posed to all expert panel members for each draft recommendation:
Is there important uncertainty about or variability in how much people value the main outcomes?
Does the balance between desirable and undesirable effects favor the intervention or the comparison?
What would be the impact on health equity?
Likert scales modeled after the GRADEpro software were used for voting on each factor (183). There was also the opportunity for expert panel members to provide free-text comments related to each of the judgement criteria.
The results of the online vote were calculated and presented to the expert panel at a two-day in-person meeting held on June 6 and 7, 2018. The online vote results were used to help guide discussion to determine the required direction and strength of each recommendation. The expert panel co-chairs and guideline development co-leads facilitated the meeting to allow for adequate discussion for each proposed recommendation.
The decision on direction and strength of each recommendation statement was determined by discussion and a consensus vote of 70 per cent. The voting process was moderated by the expert panel co-chairs and guideline development co-leads. In determining the strength of a recommendation statement, the expert panel was asked to consider the following:
the balance of benefits and harms;
certainty and confidence of the evidence;
values and preferences; and potential impact on health equity.
See Table 15 for more on these considerations.
Following the in-person meeting, the final decisions made on all recommendations were summarized and sent electronically to the full expert panel.
# A P P E N D I C E S
A Palliative Approach to Care in the Last 12 Months of Life
# Benefits and harms
Potential desirable and undesirable outcomes reported in the literature when the recommended practice or intervention is used.
"The larger the difference between the desirable and undesirable effects, the higher the likelihood that a strong recommendation is warranted. The narrower the gradient, the higher the likelihood that a conditional recommendation is warranted" (184).
Includes research exclusively from the systematic review.
# Certainty and confidence of evidence
The extent of confidence that the estimates of an effect are adequate to support a recommendation. The extent of confidence that a review finding is a reasonable representation of the phenomenon of interest (185).
Recommendations are made with different levels of certainty or confidence; the higher the certainty or confidence, the higher the likelihood that a strong recommendation is warranted (184).
Includes research exclusively from the systematic review.
# Values and preferences
The relative importance or worth of the health outcomes of following a particular clinical action from a person-centred perspective (184).
"The more values and preferences vary or the greater the uncertainty in values and preferences the higher the likelihood that a conditional recommendation is warranted" (184).
Includes evidence from the systematic review (when available) and other sources (e.g., insights from the expert panel).
# Health equity
Represents the potential impact of the recommended practice or intervention on health outcomes or health quality across different populations and/or barriers to implementing the recommended practice in particular settings.
The greater the potential for increasing health inequity, the higher the likelihood that a conditional recommendation is warranted.
Includes evidence from the systematic review (when available) and other sources (e.g., insights from the expert panel).
Source: Adapted by the RNAO expert panel from Schunemann H, Brozek J, Guyatt G, Oxman A, editors. Handbook for grading the quality of evidence and the strength of recommendations using the GRADE approach [Internet]. [place unknown]: The GRADE Working Group; 2013. Available from: https://gdt. gradepro.org/app/handbook/handbook.html#h.svwngs6pm0f2
# A P P E N D I C E S
A Palliative Approach to Care in the Last 12 Months of Life
# Drafting the Best Practice Guideline
The Guideline Development Methodologist wrote the draft of this BPG. The expert panel reviewed the draft and provided written feedback. A teleconference was held on October 12, 2018, to review the expert panel's feedback and incorporate changes, as necessary. The BPG then proceeded to external stakeholder review.
# Stakeholder Review
As part of the guideline development process, RNAO is committed to obtaining feedback from (a) nurses and other health providers from a wide range of practice settings and roles, (b) knowledgeable administrators and funders of health services, and (c) stakeholder associations.
Stakeholder reviewers for RNAO BPGs are identified in two ways. First, stakeholders are recruited through a public call issued on the RNAO website (RNAO.ca/bpg/get-involved/stakeholder). Second, individuals and organizations with expertise in the BPG topic area are identified by the RNAO Best Practice Guideline Development and Research Team and the expert panel; they are then directly invited to participate in the review.
Stakeholder reviewers are individuals with subject matter expertise in the BPG topic or those who may be affected by its implementation. Reviewers may be nurses, members of the interprofessional health team, nurse executives, administrators, research experts, educators, nursing students, or persons with lived experience and their family members.
Reviewers are asked to read a full draft of the BPG and participate in its review prior to publication. Stakeholder feedback is submitted online by completing a survey questionnaire. Stakeholders are asked the following questions about each recommendation:
Is the guideline title appropriate?
Is the guideline development process clear?
In addition, stakeholders are asked the following questions about each recommendation:
Is this recommendation clear?
Do you agree with this recommendation?
Is the discussion of evidence thorough, and does the evidence support the recommendation?
The survey also provides an opportunity to include comments and feedback for each section of the BPG, including the evaluation indicators. Survey submissions are compiled and feedback is summarized by the RNAO Best Practice Guideline Development and Research Team. A teleconference with the expert panel was held to review stakeholder feedback on January 30, 2019, BPG content and recommendations were modified prior to publication to reflect the feedback received.
For this BPG, the stakeholder review process was completed from December 14, 2018, to January 11, 2019. Diverse perspectives provided feedback (see Stakeholder Acknowledgement).
# A P P E N D I C E S
A Palliative Approach to Care in the Last 12 Months of Life
# Procedure for Updating This Guideline
The RNAO commits to updating all BPGs as follows:
1. Each BPG will be reviewed by a team of specialists in the topic area every five years following publication of the previous edition.
2. RNAO International Affairs and Best Practice Guideline Centre staff regularly monitor for new systematic reviews, randomized controlled trials and other relevant literature in the field.
3. Based on that monitoring, staff may recommend an earlier revision period for a particular BPG. Appropriate consultation with members of the original expert panel, other specialists and experts in the field will help inform the decision to review and revise the BPG earlier than planned.
4. Three months prior to the review milestone, the staff commences planning of the review as follows:
Compiling feedback received and questions encountered during the implementation, including comments and experiences of BPSOs® and other implementation sites regarding their experiences.
Compiling a list of new clinical practice guidelines in the field and refining the purpose and scope.
Developing a detailed work plan with target dates and deliverables for developing a new edition of the BPG.
Identifying the potential BPG expert panel co-chairs with RNAO's CEO.
Compile a list of specialists and experts in the field for potential participation on the expert panel. The expert panel will be comprised of members from the original expert panel and new ones.
5. New editions of BPGs will be disseminated based on established structures and processes.
# A P P E N D I C E S
A Palliative Approach to Care in the Last 12 Months of Life Appendix E: Process for Best Practice Guideline and Systematic Review The systematic reviews that answered recommendation questions in existing high-quality guidelines (scoring 6 or 7 on AGREE II) were considered to be beyond the scope of this Guideline. Recommendation Question #1: Should an interprofessional approach be recommended for the provision of care to adults in the last 12 months of life?
Outcomes: Person and family experience with care provided, effectiveness of provided care from the person and family perspective, access to care, coordination of care, transitions in care, effectiveness of provided care from health provider perspective Outcomes: Support for spiritual care, support for emotional care, support for existential care, care in alignment with the person's wishes, culturally safe care, place of death Steps 1 and 2
Step 3
Step 6
Step 4
Step 5
# A P P E N D I C E S
A Palliative Approach to Care in the Last 12 Months of Life
# Appendix G: Tools Used to Assess Domains of Health and Illness
Table 16 provides recommendations from panel members and stakeholders regarding tools used to assess domains of health and illness. It is important to note that this is not a comprehensive list of all possible tools available: healthservice organizations may review the table to support decision-making about the selection of approaches or tools for the setting and population(s) served.
Tools and approaches are ordered alphabetically in categories related to pain and physical symptoms, psychosocial and spiritual assessments/screening tools, and other assessment/screening tools. There is no specific ranking of tools or approaches. Inclusion of a tool in this list does not constitute an endorsement by RNAO.
# Appendix H: Assessment Tools for Health Providers
Table 17 provides assessment tools to assess compassion fatigue and/or stress. It is important to note that this is not a comprehensive list of all possible tools available: health-service organizations may review the findings below to support decision making about the selection of a tool.
Tools are ordered alphabetically; there is no specific ranking of tools or approaches. Inclusion of a tool in this list does not constitute an endorsement by RNAO. https://psychink.com/ti2012/ wp-content/uploads/2012/06/2 07TICAssign.20111.pdf
# A P P E N D I C E S
A Palliative Approach to Care in the Last 12 Months of Life
# Appendix I: Pain and Symptom Management Resources
Table 18 includes resources related to pain and symptom management in palliative care and end-of-life care. It is important to note that this is not an exhaustive list of all possible resources available.
# A P P E N D I C E S
A Palliative Approach to Care in the Last 12 Months of Life
# Appendix J: Education and Competency Resources
Table 19 contains a list of resources that provide information about education and competencies related to palliative care and end-of-life care. It is important to note that this is not an exhaustive list of all possible resources available. A textbook for registered nursing students that looks at death and dying, and how nurses can assist patients and families during their journey towards end of life.
Includes: overview of death and dying; historical examination of some of the conceptual models associated with how patients cope with impending loss; illness trajectories and models of care; and evidence-based approaches for pain and symptom management, ethical concerns, cultural considerations, care at the time of death, and grief/bereavement.
# A P P E N D I C E S
A Palliative Approach to Care in the Last 12 Months of Life Demonstrates understanding of palliative care standards, guidelines and policies.
Demonstrates understanding of the Ontario Drug Benefits Formulary, and the Palliative Care Facilitated Access mechanism.
# Cultural Safety and Humility
Demonstrates understanding of the influence of culture on key issues in palliative and end-of-life care.
Understands health, wellness, and serious illness from diverse perspectives particularly when caring for First Nations, Inuit, Métis and urban Indigenous peoples.
Examines attitudes towards death particularly for First Nations, Inuit, Métis and urban Indigenous peoples/ communities and how it compares to Western Views/Society.
Demonstrates understanding of the Indigenous Wellness Framework.
Demonstrates openness and sensitivity to social, spiritual and cultural values and practices that may influence individual and family preference and accommodates these.
Recognizes personal biases and values that may influence care and identifies mechanisms to overcome these to ensure they do not impact care and treatment.
Assesses the unique needs and preferences of the individual and their family, considering the social determinants of health, as well as their ethnicity, culture, gender, sexual orientation, language, religion, spirituality, age and ability.
Validates and preserves cultural preferences and values by identifying ways to incorporate them into goal setting, decision making and care planning.
Recognizes and respects who the person identifies as family, and responds to family members' unique needs and experiences.
Considers the community as an essential component of the unit of care for First Nations, Inuit, Métis and urban Indigenous peoples.
Explores the person and their family's cultural and religious needs, beliefs and preferences as they relate to end-oflife.
Creates an environment and provides opportunities for the person and their family to exercise religious, cultural and spiritual rituals, customs, rites and beliefs throughout the person's illness and through bereavement.
# Communication
Introduces individuals and their families to the concept and benefits of palliative care, along with other disease ameliorating treatments, or as the main focus of care.
Demonstrates understanding of the essential role communication plays in palliative care.
Demonstrates understanding that communication regarding palliative and end-of-life care is an on-going collaborative process.
Understands and recognizes that for First Nations, Inuit, Métis and urban Indigenous communities, the individual and family are the most important members of the care team and acknowledges the importance of on-going communication between the health care providers and the family.
Recognizes the multidimensional communication challenges may that arise when caring for people with lifelimiting conditions.
# A P P E N D I C E S
A Palliative Approach to Care in the Last 12 Months of Life Assesses the person's and family's understanding of the life-limiting condition.
Recognizes the potential for conflict in palliative care decision-making and contributes to its management.
Supports individuals to make informed decisions on the depth of information about diagnosis, prognosis and disease progression they wish to receive and share with their families.
Provides culturally relevant information and resources to support individuals and families, particularly when caring for those from First Nations, Inuit, Métis and urban Indigenous communities.
Invites, facilitates and respects the involvement of the person, their family and their care team in discussions regarding the plan of care.
Recognizes that communication and decision-making may involve the larger community, particularly when caring for First Nations, Inuit, Métis and urban Indigenous peoples, and supports facilitation of this.
Recognizes that family conversations may involve children and different communication approaches may be required.
Evaluates communication with the person and their family/caregiver to ensure their care plan meets the person's identified needs.
Identifies the importance of community care plans when caring for First Nations, Inuit, Métis and urban Indigenous peoples.
Applies requisite relational skills (e.g., negotiating, listening, clarifying) to support decision making and suggesting modes of palliative care on an ongoing basis.
Maintains open communication channels with First Nations, Inuit, Métis and urban Indigenous care teams when caring for First Nations, Inuit, Métis and urban Indigenous peoples.
Influences the discharge planning process to facilitate smooth transitions particularly when caring for First Nations and Inuit people and dual providers may be involved.
Recognizes and mitigates potential barriers and limitations to supporting transitions between specialty care and primary care, particularly in First Nations, Inuit, Métis and urban Indigenous communities.
Creates opportunities for the person to conduct a life review, either through use of individual skills or referral to other professionals.
Adapts communication and information sharing to the unique needs of the person and their family, and engages specialist support as needed to bridge communication barriers (e.g., interpreters, sign language interpreters and assistive technology).
Understands the role and importance of experienced translators for individuals with language barriers, particularly First Nations, Inuit, Métis and urban Indigenous peoples, and how to access their services to ensure strong communication and understanding between health care providers and the individual/family.
Recognizes translation is not interpretation and understanding.
Reviews and clarifies the person's and family's (and/or caregiver's) understanding of palliative care information presented by other providers.
Offers the individual and/or family an opportunity to connect with the Trillium Gift of Life Network to discuss eligibility for body, organ or tissue donation.
# A P P E N D I C E S
A Palliative Approach to Care in the Last 12 Months of Life
# Optimizing Comfort and Quality of Life
Demonstrates understanding of how the palliative approach can enhance the assessment and management of symptoms.
Recognizes common trajectories of life-limiting conditions, including common symptoms.
Anticipates and predicts the needs of the person who has been diagnosed with a life-limiting condition based on known disease trajectories.
Applies intra-and inter-professional approaches to optimize comfort and enhance quality of life of the person and family.
Understands the concept of "total pain" and associated impact to the person and family.
Understands common symptoms, other than pain, including but not limited to fatigue, cachexia, anorexia, muscle weakness and lymphedema.
Demonstrates knowledge of the pathophysiology of pain.
Distinguishes pain classifications and their importance in effective management.
Applies the principles of pain and symptom management.
Demonstrates understanding of the potential barriers to providing pain management, particularly when caring for First Nations, Inuit, Métis and urban Indigenous peoples.
Regularly screens for symptoms and needs.
Uses standardized instruments regularly and appropriately to screen and assess symptoms and needs.
Recognizes that symptoms and symptom meaning is highly subjective and should be assessed and understood from a person-centered perspective particularly when caring for First Nations, Inuit, Métis and urban Indigenous peoples.
Uses investigations appropriately, according to the trajectory of life-limiting conditions.
Evaluates the outcomes of pain and symptom management against baseline assessment.
Conducts assessments of the person's and their families' emotional, psychological, social, spiritual and practical strengths and needs.
Identifies priorities and concerns in collaboration with the person and family, taking into account their coping strategies and perception of diagnosis.
Attends to psychosocial and practical issues.
Consults with and/or refers to other providers when identified needs are beyond individual competencies or legislative scope of practice.
Assesses and shares the benefits, burdens and risks of clinical interventions.
Proposes options, based on the persons preferences and expressed wishes, and discusses these with the person, or if not capable to make decisions, with their Substitute Decision Maker.
Implements treatment plans that are consistent with the individuals expressed wishes, identified goals of care and the trajectory of their life-limiting condition.
Uses non-pharmacological symptom management to promote comfort and quality of life.
Recognizes the importance of Traditional Medicine, particularly when caring for First Nations, Inuit, Métis and urban Indigenous peoples.
# A P P E N D I C E S
A Palliative Approach to Care in the Last 12 Months of Life Discusses, teaches and assists the person and their family with the management of pain and symptoms, including the recognition of areas needing further assessment.
Recognizes the ways in which individuals can be engaged in self-management of their condition.
Recognizes the need for a change in the focus of care and treatment goals at critical decision points in the course of a life-limiting condition.
Interprets the impact of family role change when formulating relevant and realistic care plans.
Recognizes and anticipates the physical, psychological, social and spiritual issues that affect the person and their family.
Evaluates interventions within the care plan, discusses with the interprofessional team and proposes alternatives if necessary and as appropriate.
Demonstrates understanding of the pathophysiology of palliative care emergencies.
Identifies, assesses and manages palliative care emergencies including, but not limited to: biliary, bowel and urinary obstruction, catastrophic bleed, delirium, hypercalcemia, pain crisis, seizures, Spinal Cord Compression and Superior Vena Cava Obstruction.
Supports the person, family, Substitute Decision Maker (SDM) and care teams with end-of-life decision making, including withdrawing or withholding interventions.
Demonstrates awareness of one's own responses in the presence of a person who is nearing the end of life.
Provides care in a compassionate manner.
# Care Planning and Collaborative Practice
Identifies how interprofessional practice enhances individual outcomes.
Understands the collaborative relationship between the person, health professionals, family and caregivers.
Recognizes that care planning and decision-making may need to involve the family and larger community, particularly when caring for First Nations, Inuit, Métis and urban Indigenous peoples, and supports facilitation of this.
Collaborates with the care team to manage pain and symptoms effectively based on the persons identified goals of care.
Understands the Health Care Consent Act, 1996, and understands that a health provider must obtain informed consent from the person (or, if they are incapable, their Substitute Decision Maker) for any treatment or intervention proposed.
Understands how a Substitute Decision Maker (SDM) is determined (based on the hierarchy within the Health Care Consent Act, 1996) and the role the SDM plays in making health care decisions if the person is not capable.
Engages in conversations with individuals and their families about the role of the Substitute Decision Maker to help them understand the legislation.
Supports the person to express their wishes and/or identify goals of care.
Facilitates the active involvement of the person in goal setting, decision making and informed consent to support the best possible outcomes and quality of life.
Understands the importance of determining capacity prior to conversations with individuals regarding Advance Care Planning, Goals of Care and Health Care Consent.
# A P P E N D I C E S
A Palliative Approach to Care in the Last 12 Months of Life Anticipates factors/conditions that may affect the individuals cognition and functional capacity to make decisions including health status changes, and towards end-of-life.
Demonstrates ability to incorporate the person's expressed wishes, values and goals into their plan of treatment, and reviews and revises the plan, as needed, to reflect the person's current condition.
Facilitates informed decision-making and consent by the person (or, if incapable, their Substitute Decision Maker) regarding place of care, while identifying risks in a supportive manner.
Demonstrates responsiveness to the person's needs and preferences, acknowledging that their priorities can shift as their condition and health status changes.
When able, provides care in the person's preferred place, while recognizing the complexities and challenges involved for the person, the family and their caregiver(s).
Provides verbal and written information regarding the dying process, settings of death and after death care.
Recognizes clinical and personal limitations and professional boundaries and refers to other colleagues appropriately and in a timely manner. Assists the person and their family to prepare for the time of death.
# Last Days and Hours
Supports planning for expected deaths, particularly when caring for First Nations, Inuit, Métis and urban Indigenous peoples in the community.
Anticipates, recognizes and responds to the signs of imminent death.
Provides information and assurance to the person and family regarding expected changes, and comfort measures during the last days and hours of life.
Understands pronouncement of death (in accordance with regulations) in expected and unexpected deaths.
Facilitates discussion with appropriate professional if an autopsy is required or requested.
Assesses and respects the family's need for privacy at the time of death, offering presence as appropriate.
Supports the family's wishes and death rituals.
Provides opportunities for family and the extended community to gather and be together, particularly when caring First Nations, Inuit, Métis and urban Indigenous peoples.
Identifies situations when the Coroner must be contacted, and discusses with families in advance, if appropriate.
# Loss, Grief and Bereavement
Identifies types of grief and recognizes associated signs and symptoms.
Demonstrates knowledge of diverse perspectives on grief, loss, bereavement and mourning to support others from a cross-cultural perspective.
Recognizes the impact of colonization, historical loss and trauma when caring for First Nations, Inuit, Métis and urban Indigenous peoples.
Recognizes the range of individual physical, psychological, spiritual, emotional and social responses to loss and grief in self and others.
# A P P E N D I C E S
A Palliative Approach to Care in the Last 12 Months of Life Understands dimensions of grief and recognizes the factors that may increase the risk of complicated grief.
Understands cumulative grief, which can be particularly significant in First Nations and Inuit communities.
Uses therapeutic conversations when supporting individuals and families experiencing loss and grief.
Accurately assesses and manages individual's and families' loss, grief and bereavement needs, through interventions or referring to members of the interdisciplinary team.
Provides appropriate guidance, support and information to families, caregivers, and others, based on awareness of culture and needs, and makes referrals to bereavement services, as required.
# Professional and Ethical Practice
Anticipates and addresses ethical and legal issues that may be encountered when caring for individuals with lifelimiting conditions. Establishes and respects people's wishes regarding their care options and preferences. Respects the person's decisions regarding initiating, not initiating, withholding and withdrawing dialysis, hydration, nutrition support, resuscitation and other life-prolonging/life-sustaining interventions. Recognizes when personal beliefs, attitudes and values limit one's ability to be present and provide person-centred care; collaborates with others to ensure optimal care is provided. Demonstrates knowledge of and proficiency with relevant legislation and policies, e.g., Medical Assistance in Dying (MAiD), Child, Youth and Family Services Act, Adult Protection Act, the Health Care Consent Act, 1996, and the Substitute Decision Act. Understands distinctions among ethical and legal concepts, such as: the principle of double effect, Palliative Sedation Therapy and MAiD. Responds to inquiries regarding MAiD in accordance with regulatory body's relevant guidelines and standards and employer policies. 1 Accesses resources to ethically guide complex situations and implements possible resolutions.
# Self-care
Explores own attitudes regarding death, dying and caring for individuals with palliative care needs. Demonstrates awareness of the impact of past experiences of suffering, death and dying when providing palliative care. Demonstrates awareness of ways to manage and cope with the impact of dying and death. Demonstrates awareness of the emotional and spiritual supports available. Understands and attends to own emotional responses that result from caring for individuals with palliative care needs, including signs of loss, grief and bereavement. Recognizes compassion fatigue in self and colleagues; intervenes and refers appropriately. Engages in healthy activities that help prevent compassion fatigue. Demonstrates understanding of the concept of good "helping relationships" when working with First Nations, Inuit, Métis and urban Indigenous peoples. Demonstrates understanding of the concept of companioning, particularly when working with First Nations, Inuit, Métis and urban Indigenous peoples.
# Additional Competencies for Nurses Specializing in Palliative Care
Nurses specializing in palliative care may be members of a Specialist Palliative Care Consult Team, practice in a Palliative Care Unit or Hospice or practice in settings where the vast majority of individuals require palliative care. These competencies are meant to build on the foundational palliative care competencies for nurses in all practice settings [outlined above].
# Principles of Palliative Care
Facilitates empathic and responsive relationships between those experiencing life-limiting conditions and their care teams.
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Demonstrates leadership that encourages colleagues to foster a caring environment that supports all staff working in sensitive situations.
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Applies a dignity conserving approach to care when providing support.
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Practices person-centred palliative care that incorporates the unique contributions of the family and caregivers.
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Identifies and addresses beliefs and attitudes of society and health professionals towards palliative care that undermine access to high quality palliative care.
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Addresses misperceptions that the person, their family, their caregiver(s) and colleagues have about palliative care.
# Communication
Uses a variety of strategies to engage in compassionate, individualized and timely communication with the person, their family, their caregiver(s) and members of their care team.
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Assesses the person's/family's understanding of the life-limiting condition, and its trajectory and uses this to inform their communication approach.
Maintains ongoing communication with the person, family and their care teams regarding end-of-life plan of care.
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Identifies the person's and family's information needs and preferences prior to providing information and discussing diagnosis and prognosis.
Assesses health literacy.
During essential conversations, regularly inquires whether information is meeting the person's and family's needs.
Responds to family requests not to share information with the person regarding diagnosis, prognosis and other information.
Explores the person's/family's understanding of the expectations and wishes, prognosis and goals of care.
# A P P E N D I C E S
A Palliative Approach to Care in the Last 12 Months of Life Assesses and discusses prognosis and trajectory of a life-limiting condition on an ongoing basis.
Supports patients and families through uncertainty, using knowledge of the impact of disease and associated treatments to discuss care options and coping strategies.
#
Facilitates ongoing discussions regarding goals of care.
Reviews goals of care, particularly when changes occur in disease status and functional level.
Addresses conflicts between personal and family expectations regarding prognosis and treatment options.
Nurtures hope, relative to individual meaning and quality of life, in a way that is congruent with the trajectory of the life-limiting condition.
Promotes realistic goal setting in a way that is congruent with the trajectory of the life-limiting condition.
Discusses resuscitation preferences.
Discusses preferred settings of care and death.
Shares difficult news in a compassionate and supportive manner.
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Identifies situations that may benefit from a family meeting, and facilitates, when appropriate.
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Responds to concerns regarding starvation and dehydration at end-of-life.
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Responds appropriately to the person's and family's questions regarding expected death.
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Has knowledge of family dynamics and theories, including models for supporting families in crisis.
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Has in-depth knowledge of dying, death, grief, loss and bereavement and can recognize and respond to grief reactions.
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Explores questions and concerns expressed by the person and their family regarding the dying process and provides information about what to expect.
Documents discussions and informs other care providers of key points of discussions.
# [Nurse Practitioner-specific] Competencies
Facilitates conversations to support end-of-life decision making and informed consent.
Presents the person with care and treatment options and their anticipated benefits, burdens and risks, considering the person's identified Goals of Care.
Discusses withholding and withdrawing treatments to ensure that treatment decisions are informed and align with identified goals of care.
Establishes resuscitation preferences (if resuscitation as part of the treatment plan or not) and obtains consent when appropriate. Informs the person and family of anticipated progression of disease and other complications.
# Optimizing Comfort and Quality of Life
Applies comprehensive knowledge and understanding of the clinical presentation and disease trajectories of lifelimiting conditions when responding to complex and multidimensional care needs, in order to comprehensively identify current and prospective clinical issues in palliative care. Uses evidence-based tools to facilitate earlier identification of individuals who may benefit from palliative care. Draws from advanced education, knowledge and skill in palliative care to deliver holistic person-centred care.
Integrates physical, social, psychological and spiritual domains.
Explores the impact of a life-limiting condition on the different facets of a person's life and the lives of family and caregivers.
# A P P E N D I C E S
A Palliative Approach to Care in the Last 12 Months of Life Incorporates "quality of life, " as defined by the person, as a key outcome of care.
Uses research and audit to determine evidence of best practice as a rational for care interventions.
Acknowledges the cumulative losses inherent in the experience of a life-limiting condition and its impact on the person and family. Uses evidence informed tools to regularly screen for symptoms and needs.
Performs comprehensive, systems-based, physical assessments and postulates causes of symptoms and conditions.
Conducts histories and physical exams specifically focusing on the impacts of a life-limiting condition.
Uses investigations appropriately, according to the trajectory of the life-limiting condition and in a manner that is consistent with goals of care and within the scope of practice.
Formulates assessment priorities to inform management plan.
Supports and guides junior or generalist staff with implementation of the care plan.
# Screens, Assess and Manages Pain
Knows underlying mechanisms of pain, pathophysiology and impact of total pain.
Applies appropriate medication administration techniques relative to the types and severity of the person's pain and condition, recognizing oral route is best practice if applicable.
Identifies and addresses barriers to pain assessment and management, including the misconceptions of the person, family and health professional.
Identifies and addresses health system barriers to pain assessment and management.
Demonstrates a comprehensive in-depth understanding of the pharmacological and physiological use of adjuvant medications in managing pain and symptoms.
Demonstrates a comprehensive knowledge of common pain and symptom management medications and consults with other providers to guide management of potential side effects, interactions or complications.
Evaluates and revises the individual's pain management goals and plan of care in collaboration with the individual and the interdisciplinary care team.
Understands mechanisms of action of opiate drugs.
Addresses fears and concerns that the person may have about opioid medications.
Uses equianalgesic dose conversion tables for verifying opioid rotation or switching.
Describes the indications for opioid rotation.
# A P P E N D I C E S
A Palliative Approach to Care in the Last 12 Months of Life Assesses for risk of substance use disorder and manages treatment plan accordingly.
Identifies and differentiates opioid-induced neurotoxicity (OIN) from other conditions e.g., delirium.
Identifies individuals with difficult-to-control pain that requires further support, and refers to the Specialist Palliative Care Team or Pain Service as needed.
[Nurse Practitioner-specific] Competencies Uses accepted pain management guiding principles to select an appropriate analgesic regimen.
Prescribes an appropriate first-line opioid and dose when initiating opioid treatment.
Identifies individuals who may benefit from the addition of first-line adjuvant analgesics.
Prescribes an appropriate first-line adjuvant analgesic and dose in the management of neuropathic pain, visceral pain and malignant bone pain.
Prescribes second and third line analgesics, as required.
Identifies individuals who may benefit from palliative radiation therapy, and makes appropriate referrals.
Prevents and treats common opioid-induced side effects.
Titrates opioid doses appropriately.
Prescribes appropriate medications for breakthrough pain.
Switches between short-acting and long-acting formulations.
Implements appropriate strategies to manage Opioid Induced Neurotoxicity (OIN) as required.
Initiates and maintains a person on methadone for pain management in collaboration with a palliative care physician, or other specialist for methadone management, if required.
# Screens, Assesses and Manages Delirium
Differentiates between delirium, dementia, depression and pain.
Identifies, where possible and appropriate, underlying etiology, contributing factors and reversible measures.
Implements interventions within individual competencies and legislative scope of practice, as appropriate, including hydration, antibiotics, medication changes and/or prescribes antipsychotics at appropriate doses, based on the severity of delirium, to control symptoms.
Uses non-pharmacological approaches where possible.
Consults with and/or refers to appropriate interdisciplinary team member(s) when beyond individual competencies, or legislative scope of practice.
# [Nurse Practitioner-specific] Competencies
Diagnoses and differentiates between subtypes of delirium.
# A P P E N D I C E S
A Palliative Approach to Care in the Last 12 Months of Life
# Screens, Assesses and Respiratory Symptoms
Identifies underlying causes and contributing factors to dyspnea.
Manages dyspnea by addressing, when possible, underlying causes.
Uses non-pharmacological interventions to reduce dyspnea.
Manages upper and lower airway secretions and coughing.
Consults with and/or refers to appropriate interdisciplinary team member(s) when beyond individual competencies or legislative scope of practice.
# [Nurse Practitioner-specific] Competencies
Diagnoses dyspnea on the basis of a person's self-reporting, rather than clinical signs, lung function tests or oxygen saturation.
Prescribes non-pharmacological interventions to reduce dyspnea.
Prescribes opioids, oxygen and other appropriate pharmacological approaches to control dyspnea.
Prescribes second and third line approaches, as required.
Prescribes non-pharmacological and pharmacological interventions to help manage upper and lower airway secretions and coughing.
Identifies individuals who may benefit from a thoracentesis, and refers if appropriate.
# Assesses and Manages Gastrointestinal Symptoms
Knows gastrointestinal biophysiology and associated nausea and vomiting pathways.
Identifies and addresses underlying causes and contributing factors of nausea and vomiting.
Assess and manages constipation.
Identifies individuals with partial or complete malignant bowel obstruction.
Initiates basic management of malignant bowel obstruction when surgery is not an option.
Initiates constipation prevention with first-line laxative treatments.
Assesses and manages anorexia and cachexia.
Explores individuals' and families' concerns regarding appetite and weight loss.
Explains cachexia syndrome and its treatment implications.
Identifies reversible versus non-reversible causes of appetite loss.
Identifies individuals who could benefit from pharmacological appetite stimulation.
Identifies individuals who could benefit from artificial nutrition and those who are unlikely to benefit.
Consults with and/or refers to appropriate interdisciplinary team member(s) when beyond individual competencies or legislative scope of practice.
# A P P E N D I C E S
A Palliative Approach to Care in the Last 12 Months of Life
# [Nurse practitioner-specific] competencies
Prescribes a first-line antiemetic drug, based on the inferred underlying mechanism and the associated neurotransmitters.
Diagnoses constipation.
Prescribes a laxative regimen to prevent and treat constipation.
Identifies individuals who may benefit from a paracentesis.
Prescribes pharmacological appetite stimulation for individuals who may benefit from this type of treatment in balance with the potential adverse effects of these therapies.
# Assesses and Manages Fatigue
Identifies reversible versus non-reversible causes of fatigue.
Recommends evidence-based interventions for individuals with advanced disease experiencing fatigue.
Consults with and/or refers to appropriate interdisciplinary team member(s) when beyond individual competencies or legislative scope of practice.
# [Nurse practitioner-specific] competency
Prescribes pharmacological agents to stimulate energy when appropriate.
# Manages Hydration and Nutrition Concerns
Describes the benefits and limitations of artificial hydration and nutrition.
Identifies individuals who could benefit from artificial hydration and those who would not.
Initiates hypodermoclysis when appropriate.
Consults with and/or refers to appropriate interdisciplinary team member(s) when beyond individual competencies or legislative scope of practice.
[Nurse practitioner-specific] competency Prescribes hypodermoclysis when appropriate.
# Assesses and Manages Bleeding and Thrombo-embolic Events
Identifies individuals at risk for a hemorrhage.
Ensures care plan includes interventions to manage a major hemorrhage, if the person is at risk based on diagnosis.
Refers to appropriate interdisciplinary team member when beyond scope of practice.
# [Nurse practitioner-specific] competencies
Identifies individuals who could benefit from anticoagulants and prescribes if appropriate.
Develops an approach to manage anemia and thrombocytopenia in those with advanced disease, based on goals of care and trajectory of a life-limiting condition.
# A P P E N D I C E S
A Palliative Approach to Care in the Last 12 Months of Life
# Palliative Sedation Therapy
Assesses for and recognizes intractable symptoms that may benefit from using sedation to support the person's quality of life and identified goals of care.
Uses evidence informed interprofessional approaches to discuss sedation in palliative care, benefits and burdens, goals of care and education and teaching needs of person and family.
Describes the ethical issues regarding Palliative Sedation Therapy.
Collaborates with the Specialist Palliative Care Consult Team or Pain Service as needed to provide Palliative Sedation Therapy.
Evaluates expected affects and side effects of treatment.
[Nurse practitioner-specific] competency Prescribes appropriate pharmacological medications and doses to initiate Palliative Sedation Therapy and assesses the individual's response.
# Assesses and Manages Conditions that Constitute Emergencies in Individuals with Palliative Care Needs
Demonstrates in-depth biophysical and disease knowledge to anticipate which conditions are more at risk of palliative emergencies.
Anticipates, recognizes and responds to signs and symptoms of common emergencies in palliative care, and transfers to appropriate health care providers or emergency room as required.
# Identifies and Addresses Psychosocial, Spiritual and Existential Needs
Uses strategies that promote personal and spiritual growth through living with a life limiting condition.
Assesses and manages depression and anxiety.
Uses validated distress screening tools to identify depression and anxiety.
Differentiates between normal and abnormal levels of anxiety and depression in individuals with advanced disease.
Identifies individuals who could benefit from pharmacological management of depression and anxiety.
Initiates appropriate treatment for individuals with depression and anxiety disorders given clinical context.
Nurtures hope and meaning in a supportive way that is congruent with the individual's identified goals of care.
Assesses, identifies and addresses spiritual and existential needs of the person.
Engages appropriate spiritual and religious care providers.
Assesses, identifies and addresses the social needs of the person and their family.
Assesses, validates and acknowledges the person's and family's loss and grief throughout a life-limiting condition and into bereavement.
Provides supportive counseling to the person and their family.
Identifies individuals at risk for complicated grief reactions.
Refers the person and their family to appropriate resources as needed.
# A P P E N D I C E S
A Palliative Approach to Care in the Last 12 Months of Life
# Safe and Appropriate Medication Practices
Demonstrates knowledge of pharmacology, pharmacokinetics and side-effects of classes of medications commonly used in palliative care.
Assesses the efficacy of pharmacological treatments in alignment with the College of Nurses Medication Standard.
Demonstrates understanding of the principles of dose adjustment with regard to: the frail, elderly, children, those with altered metabolism or organ failure and individuals approaching imminent death.
Ensures the family, caregivers and care teams understand how to safely store medications and discard waste while the person is receiving care and how to safely remove medications from the home after the person has died.
# [Nurse practitioner-specific] competency
Demonstrates the ability to prescribe medications appropriate to treat a range of symptoms commonly seen in palliative care.
# Care Planning and Collaborative Practice
Collaborates with interdisciplinary care teams, primary care providers, community agencies and volunteers to meet the physical, psychological, social and spiritual needs for each person.
Develops therapeutic relationships with the person, family, caregivers, and their care teams to define goals of care and to develop, implement and evaluate a plan of care.
Facilitates participation of the person in their care planning.
Identifies and integrates strengths of the person in their plan of care.
Safely and appropriately delegates aspects of care to the family.
Assists the family in care giving and acquiring respite care.
Engages in family and team conferences.
Develops a plan of care for the family.
Periodically reviews treatments, including medications, to ensure congruence with goals of care and illness trajectory.
Assists with coordinating care and making referrals to other care team members and/or organizations e.g., visiting volunteers.
Collaborates within and between teams across the continuum of care to facilitate continuity in palliative care.
Identifies and supports navigation of the full range and continuum of palliative care services, resources and the settings in which they are available.
Collaborates with the person and family to identify resources that will provide support throughout their illness and during end-of-life care.
Demonstrates expertise and sensitivity in facilitating safe, smooth and seamless transitions of care for the person.
Recognizes transition points.
Coordinates smooth transition between institutions, settings and services.
Communicates with colleagues in other settings during transitions.
# A P P E N D I C E S
A Palliative Approach to Care in the Last 12 Months of Life Provides palliative care in all settings where individuals reside including the home, Long-Term Care facilities and acute care settings, such as community hospitals and [emergency departments] in rural and remote settings, group/supportive housing, shelters, jail/prison etc.
Effectively communicates the strengths and needs of the person and family with their care teams.
# Last Days and Hours
Demonstrates a comprehensive knowledge of pain and symptom assessment and management unique to last days and hours of life.
Assesses and manages families' and caregivers' needs through end-of-life.
Anticipates and plans for end-of-life needs.
Identifies individuals who are in the end of life phase.
Assists the family to cope with emotional responses, maintain a desired level of control, share preferences and needs, determine place of death, contact significant others, access resources and communicate meaningfully in the person's last days.
Demonstrates in-depth knowledge of caregiver exhaustion and strategies to support family resiliency including referrals to appropriate providers including respite.
Encourages the person and their family to make timely preparations following death.
Discusses with the family and other caregivers who to call in case of an emergency, and clarifies when 911 calls may be appropriate.
Discusses with the family and other caregivers who to call when death occurs.
Educates the family about the changes to expect in a person's condition at end-of-life including signs of imminent death and associated comfort measures.
Anticipates the person's needs at end-or-life, ensuring medications and supplies are available.
# Nursing specific competency
Pronounces and arranges for certification of death.
# [Nurse practitioner-specific] competency
Timely completion of death certificates.
# Loss, Grief and Bereavement
Demonstrates a comprehensive knowledge of the grieving process and reactions in order to support patients and families throughout the disease trajectory.
Demonstrates understanding of the needs of children of various developmental stages in dealing with grief and loss of a parent or sibling.
Demonstrates the ability to proactively respond to complex grief reactions and processes using own skills or appropriate referral.
# A P P E N D I C E S
A Palliative Approach to Care in the Last 12 Months of Life Assists the family in understanding the concepts of loss, process of grief and bereavement, considering developmental stages, referring as needed.
Identifies types of grief.
Recognizes the manifestations of grief.
Identifies those experiencing or at risk for complicated or disenfranchised grief, and discusses, documents and refers.
Recognizes the differences between depression and grief.
Assists the family to anticipate and cope with their unique grief reactions to loss and death.
Assists the family to recognize the person's legacy.
Facilitates the family's transition into ongoing bereavement services, where indicated.
Mentors and educates colleagues regarding the personal impact of loss, grief and bereavement, supporting them to recognize their own loss responses and encouraging engagement in activities to maintain their resilience on an on-going basis.
# Professional and Ethical Practice
Applies a comprehensive understanding of contemporary legal, ethical and professional standards to the provision of quality palliative care.
Facilitates discussion and management of ethical and legal issues in conjunction with the person, their family, and their care team.
Debriefs about ethical and legal issues individually and as a team, with appropriate professional(s).
Actively influences and promotes palliative care strategic initiatives and policy development.
# Education
Educates the person, their family, and their caregiver(s) about palliative care and the palliative approach.
Provides information appropriate to the uniqueness of the person and family regarding:
Disease process and illness progression.
Pain/symptom assessment and management.
Team roles.
Opportunities and challenges of care in specific settings.
Physical, psychosocial and spiritual support.
Treatments.
Dying process and death.
Medication administration routes.
Family dynamics and effective communication.
Age-appropriate resources regarding death, dying, loss, grief and bereavement.
# A P P E N D I C E S
A Palliative Approach to Care in the Last 12 Months of Life Develops, facilitates and provides palliative care related education, leadership and mentorship to members of the discipline and students.
# Research and Evaluation
Understands principles of dissemination of research and best practices to build capacity in other team members.
Advocates for research related to the field of palliative care.
Applies and disseminates knowledge gained from palliative care research.
Where possible, provides the family with opportunities to participate in palliative and end-of-life care giving research.
Where possible, leads, facilitates and engages in research in palliative care.
Acts as an expert resource contributing to palliative care development and delivery.
Where possible, identifies the opportunities for and barriers to discipline-specific research unique to palliative care.
# Advocacy
Advocates for the needs, decisions and rights of the person by recognizing potential vulnerabilities.
Supports principles of autonomy and self-management.
Promotes equitable and timely access to palliative care resources.
Demonstrates expertise as a mediator and advocate for the person to access appropriate and timely palliative care.
Advocates for the development, maintenance and improvement of health care and social policies related to palliative care.
Identifies the determinants of health for the populations served and contributes to efforts to ensure equity, including, but not limited to: barriers to access to palliative care and resources, availability of Primary Care, Interdisciplinary Care Teams and Specialized Services, delayed or lack of identification of individuals who would benefit from palliative care, lack of availability of community-based resources, geographic inequities and inequities for vulnerable and marginalized populations, poverty, cost of dying at home.
Identifies vulnerable and marginalized populations and responds appropriately.
Identifies barriers to palliative care for vulnerable or marginalized populations, including, but not limited to: the homeless, First Nations, Inuit, Métis and urban Indigenous peoples, those who are incarcerated and those living in rural communities.
Promotes Advance Care Planning, Goals of Care, and Health Care Consent in alignment with Ontario legislation.
Identifies organizational issues that affect the delivery of palliative care.
Participates as a member of organizations which advocate for equitable, accessible, safe and quality palliative care.
Describes the role of the Canadian Hospice Palliative Care Association, the Ontario Palliative Care Network, and Hospice Palliative Care Ontario in relation to advocating for high quality palliative care for individuals with palliative care needs.
# A P P E N D I C E S
A Palliative Approach to Care in the Last 12 Months of Life Describes how changes in legislation could affect individuals with palliative care needs.
Describes how changes in funding and structure of the health system could affect delivery of palliative care.
Identifies points of influence in the health system that could advance palliative care issues.
Describes the moral, ethical and professional issues inherent in health advocacy related to palliative care.
Advocates for health professionals to participate in palliative care continuing education opportunities.
Advocates for health professionals to have access to adequate resources to provide palliative care.
# A P P E N D I C E S
A Palliative Approach to Care in the Last 12 Months of Life
# Appendix L: Resources Related to Medical Assistance in Dying
Table 20 provides a list of resources related to Medical Assistance in Dying (MAiD). It is important to note that this is not an exhaustive list of all possible resources available.
Note: Palliative and end-of-life care legislation varies between jurisdictions. Please refer to the resources specific to your jurisdiction for relevant information regarding MAiD. This book explores how the dying and their families can bring deep meaning and great comfort to the care given at the end of a life.
# A P P E N D I C E S
A Palliative Approach to Care in the Last 12 Months of Life A companion of books which examines and redefines the role of the grief counselor and offers guides for caregivers.
# A P P E N D I C E S
A Palliative Approach to Care in the Last 12 Months of Life A resource book on palliative and end-oflife care for children and young adults with cancer and other life limiting illnesses. The purpose of this review is to identify the needs of the adolescent and young adult population with cancer and to discuss potential barriers and solutions to improvement of care in the context of palliation and symptom management.
# A P P E N D I C E S
A
Rosenberg AR, Wolfe J. Palliative care for adolescents and young adults with cancer. Clin Oncol Adolesc Young Adults. 2013;3:41-8.
This review describes the scope, benefits, and challenges of palliative care for adolescents and young adult oncology patients.
Tutelman PR, Drake EK, Urquhart R. "It could have been me": an interpretive phenomenological analysis of health care providers' experiences caring for adolescents and young adults with terminal cancer. J Adolesc Young Adult Oncol. 2019 Jun; https://doi. org/10.1089/jayao.2019.0015.
The purpose of the study was to understand health-care providers' experiences caring for adolescents and young adults with terminal cancer.
# E N D O R S E M E N T S
A Palliative Approach to Care in the Last 12 Months of Life Endorsements
# Funding
This work is funded by the Government of Ontario. All work produced by RNAO is editorially independent from its funding source.
# Conflict of Interest
In the context of RNAO best practice guideline (BPG) development, the term "conflict of interest" (COI) refers
# Appendix C: Education Statements Education Statements for This Guideline
RNAO has been at the forefront of creating BPGs since 1999; its first BPG was issued in 2002. From the outset, RNAO recognized the importance that individual and organizational approaches to the delivery of education had on clinical BPG content that had been developed to support evidence-based practice change. As such, RNAO clinical BPGs have included education recommendations directed to those responsible for the academic and in-service education of nursing students, nurses and the interprofessional health team. These recommendations have outlined core content and training strategies required for entry-level health programs, continued education and professional development.
An in-depth analysis of RNAO's educational recommendations was conducted in 2018. It included clinical BPGs published within a five-year time frame, as all clinical BPGs published within this period are based on a systematic review of the literature. It examined 26 education recommendations from nine different BPGs with diverse clinical topics and populations.
A rigorous thematic analysis showed similarities across BPGs. Thus, it was deemed appropriate to create standard education statements that would be applicable to all clinical BPGs to support evidence-based practice changes. The resulting education statements and associated discussion of the literature are described below. These statements can be contextually adapted within health-service organizations and academic institutions to support the implementation of clinical recommendations for various BPG topic areas.
# EDUCATION STATEMENT 1: ACADEMIC INSTITUTIONS INTEGRATE EVIDENCE-BASED GUIDELINES INTO CURRICULA FOR PRE-AND POST-LICENSURE NURSES AND OTHER REGULATED HEALTH PROVIDERS.
# Discussion of Literature:
The thematic analysis of the education recommendations described above, found the theme of: "academic institutions integrate evidence-based guidelines into curricula for pre-and post-licensure nurses and other regulated health providers, " as foundational to evidence-based practice capacity building.
# Appendix F: Indicator Development Process
The RNAO indicator development process steps are summarized below (Figure 9).
# Principles of Palliative Care
Demonstrates understanding of the philosophy of palliative care.
Provides culturally relevant explanations about palliative care particularly when caring for First Nations, Inuit, Métis and urban Indigenous peoples.
Demonstrates understanding that a palliative approach to care starts early in the trajectory of a progressive lifelimiting condition, and may be appropriate at the time of diagnosis.
Demonstrates ability to describe the meaning of the term "life-limiting condition. "
Identifies individuals who would benefit from a palliative approach early in a life-limiting condition.
Applies the principles of palliative care that affirm life, offers a support system to help individuals live as actively as possible until death, with optimal quality of life and helps families cope during illness and bereavement.
Conserves and promotes dignity of the person by facilitating expression of needs, hopes, feelings and concerns when planning palliative care.
Recognizes the role of primary and acute care in the provision of palliative care across a variety of settings.
Demonstrates understanding of the role and function of the Interdisciplinary Care Team in palliative care.
Demonstrates understanding of the role and function of the Specialist Palliative Care Team, including volunteers.
Demonstrates understanding of the guiding principles of First Nations, Inuit, Métis and urban Indigenous care teams.
Recognizes the contribution of community strengths, gaps and barriers in building palliative care teams within First Nations, Inuit, Métis and urban Indigenous communities and that care teams will be specific to each community.
# A P P E N D I C E S
A Palliative Approach to Care in the Last 12 Months of Life Scoping review which synthesizes the evidence on nurses' roles and responsibilities in relation to medical assistance in dying and identifies gaps in the literature.
# A P P E N D I C E S
A Palliative Approach to Care in the Last 12 Months of Life
# Appendix M: Supporting Resources
Note: Palliative care and end-of-life care laws vary between jurisdictions. Please refer to the resources specific to your jurisdiction for relevant information regarding palliative care and end-of-life care.
In addition to the resources listed for each recommendation, please see below for supporting resources related to the following:
advance care planning;
culture;
compassion fatigue, stress and resilience;
death doulas;
debriefing; grief and bereavement;
palliative and end-of-life care for Indigenous populations;
recognizing when a person may be in the last days of life or when a person may benefit from palliative care;
sexual orientation, gender identity and gender expression;
standards, policy documents, models, guides and frameworks;
toolkits and information for providing support in palliative care; and
young adult population.
It is important to note that the following table is not an exhaustive list of all possible resources available.
# A P P E N D I C E S
A Palliative Approach to Care in the Last 12 Months of Life
# Appendix N: Description of the Toolkit
BPGs can only be successfully implemented if planning, resources, and organizational and administrative supports are adequate, and if there is appropriate facilitation. To encourage successful implementation, an RNAO expert panel of nurses, researchers and administrators has developed the Toolkit: Implementation of Best Practice Guidelines (2012).
The Toolkit is based on available evidence, theoretical perspectives and consensus. We recommend the Toolkit for guiding the implementation of any clinical or healthy work environment BPG in a health organization.
The Toolkit provides step-by-step directions for the individuals and groups involved in planning, coordinating and facilitating BPG implementation. These steps reflect a process that is dynamic and iterative rather than linear. Therefore, at each phase, preparation for the next phases and reflection on the previous phase is essential. Specifically, the Toolkit addresses the following key steps, as illustrated in the Knowledge-to-Action Framework ( 119): | None | None |
b43a22138d802f002bb27b6935782d47006592a3 | cma | None | 1) All patients being considered for therapy should undergo a bone marrow aspiration and biopsy as well as peripheral blood films to establish a diagnosis and prognosis. a. Immunophenotyping by flow cytometry should be performed for diagnosis and to determine a leukemiaassociated immunophenotype (LAIP) if possible. b. Samples should also be sent for cytogenetics, including fluorescence in-situ hybridization (FISH) where appropriate. c. Molecular analysis should be sent. 2) Ancillary Tests: a. Organ function should be assessed including liver, kidneys, coagulation and cardiac function. b. Blood group and human leukocyte antigen (HLA) typing of patient and family should be done as soon as possible in transplant eligible patients. 3) A lumbar puncture, with the installation of intrathecal chemotherapy, should be performed if worrisome unexplained neurological symptoms are present without a mass lesion by imaging. a. Consider a screening lumbar puncture in cases of myelomonocytic or monocytic acute myeloid leukemia (AML) or in those with a presenting white cell count of >40 x 10 9 /L. 4) AML classification and risk stratification and transplant eligibility should be ascertained for all patients using age, performance status, World Health Organization (WHO) classification, cytogenetic and molecular risk group, as well response to therapy including minimal residual disease when possible. In the appropriate situations, establishing whether a genetic change is germline should be pursued. 5) Supportive care: a. In patients undergoing intensive chemotherapy a central venous catheter ideally should be placed. b. Red blood cell transfusions for symptomatic anemia. c. Platelets should be transfused at a threshold of 10 x 10 9 /L if there is no evidence of bleeding or to keep a platelet level of around 50 x 10 9 /L if there is active bleeding. d. Tumor lysis prophylaxis should be initiated in all patients. e. Antifungal prophylaxis should be considered during all phases of chemotherapy. f. Therapy of febrile neutropenia should include empiric broad spectrum antibiotics according to IDSA guideline. g. The use of growth factor support should be individualized. h. Steroid eye drops are recommended during the administration of intermediate to high dose cytarabine. These patients should also be screened for cerebellar toxicities before each dose of cytarabine. i. Sperm preservation should be discussed with male patients and a serum pregnancy test should be performed in female patients. 6) In transplant eligible patients treatment consists of induction and consolidation chemotherapy along with a FLT3 inhibitor in FLT3 positive cases a. Induction chemotherapy should consist of standard-dose cytarabine with an anthracycline b. Consolidation can consist of further cycles of chemotherapy alone or in association with a hematopoietic stem cell transplant depending on risk of relapse. i. Good riskchemotherapy alone. ii. Intermediate riskconsider transplantation. iii. High risktransplantation. 7) In transplant ineligible patients treatment options consist of palliation, low dose cytarabine, azacitidine or induction chemotherapy, depending on performance status and risk stratification. Strong consideration should be given to enrollment into a clinical trial. 8) In the instance of relapse re-induction chemotherapy can be considered depending on performance status, otherwise palliation should be instituted.#
Participation of members of the Alberta Provincial Hematology Tumour Team in the development of this guideline has been voluntary and the authors have not been remunerated for their contributions. There was no direct industry involvement in the development or dissemination of this guideline. CancerControl Alberta recognizes that although industry support of research, education and other areas is necessary in order to advance patient care, such support may lead to potential conflicts of interest. Some members of the Alberta Provincial Hematology Tumour Team are involved in research funded by industry or have other such potential conflicts of interest. However the developers of this guideline are satisfied it was developed in an unbiased manner.
# BACKGROUND
Acute myeloid leukemia (AML) is a group of infrequent neoplasms responsible for a significant number of cancer-related deaths. Its incidence has been relatively stable over the last years at about 3.7 per 100 000 persons per year in the western world. It is primarily a disease of later adulthood with an increasing incidence with age. The median age at diagnosis is 65 years with a slight male preponderance. Outcome varies greatly according to age at diagnosis due to disease and patient features. Untreated AML is a uniformly fatal disease with a median survival of 11-20 weeks 1 .
The etiology of AML in most cases is unclear. Known risk factors include exposure to chemotherapeutic agents particularly alkylating agents, topoisomerase-II inhibitors and anthracyclines as well as both therapeutic and nontherapeutic radiation. A higher than average incidence is seen in individuals with Down's syndrome, Klinfelter's syndrome, Ataxia telangectasia, Kostmann syndrome, neurofibromatosis or Fanconi anemia. Exposure to benzenes, pesticides, herbicides and cigarette smoking may also play a role in its development. There is also a greater incidence of AML in individuals with pre-existing hematologic disorders such as the myelodysplastic syndromes or myeloproliferative disorders.
# GUIDELINE GOALS AND OBJECTIVES
- To delineate the diagnostic criteria for acute myeloid leukemias To delineate the prognostic markers in acute myeloid leukemias To identify the management options for acute myeloid leukemias in adults including chemotherapy, hematopoietic stem cell transplantation, and palliation
# GUIDELINE QUESTIONS
- What is the optimal management of the acute myeloid leukemias in Alberta at the present time?
# DEVELOPMENT AND REVISION HISTORY
This guideline was reviewed and endorsed by the Alberta Provincial Hematology Tumour Team. Members of the Alberta Provincial Hematology Tumour Team include hematologists, medical oncologists, radiation oncologists, nurses, hematopathologists, and pharmacists. Evidence was selected and reviewed by a working group comprised of members from the Alberta Provincial Hematology Tumour Team and a Knowledge Management Specialist from the Guideline Resource Unit. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook.
This guideline was originally developed in 2008. This guideline was revised in 2015, 2017, 2018 and 2019.
# SEARCH STRATEGY
The original guideline (2008) was generated using systematic literature searches of the Pubmed and Medlinedatabases, ASCO abstracts and proceedings, and ASH abstracts and proceedings databases. The search included practice guidelines, systematic reviews, meta-analyses, randomized controlled trials and clinical trials. The 2015, 2017, 2018 and 2019 updates involved review of the Pubmed and Medline databases for relevant information on a topic-by-topic basis. The ASH, ASCO and EHA abstracts and proceedings databases were also screened.
# TARGET POPULATION
The following guidelines apply to adults over the age of 18 years. Different principles may apply to pediatric patients.
# DISCUSSION
# Diagnosis
AML describes a heterogeneous group of clonal hematopoietic progenitor cell disorders with a spectrum of morphologic, immunophenotypic, cytogenetic and molecular characteristics. For a diagnosis of AML, a marrow blast count of ≥ 20% is required, except for AML with the recurrent genetic abnormalities t(15;17), t(8;21), inv (16) or t (16;16) and some cases of erythroleukemia.
# Diagnostic Tests:
The diagnosis is often suspected and can at times be confirmed from the peripheral blood. However, all patients being considered for therapy should undergo a bone marrow aspiration and biopsy. Samples should be sent for morphology, flow cytometry, cytogenetics and molecular analysis.
Immunophenotyping by flow cytometry confirms myeloid lineage and stage of differentiation of the malignant cell. It may have a prognostic role by establishing a unique phenotype for minimal residual disease monitoring, the leukemia associated immunophenotyped (LAIP). A full karyotype will be determined at diagnosis in all cases. Fluorescence in-situ hybridization (FISH) will also be carried out in cases morphologically suspicious for specific subsets. Molecular analysis will be carried out in cases suspicious for promyelocytic leukemia looking for the PML/RAR, in the core binding factor leukemias looking for c-KIT mutations, as well as in cases with normal karyotypes looking for FLT3, NPM1 and CEBPA mutations. Information regarding FLT3-ITD allelic burden should also be provided. Next generation sequencing (NGS) should be performed at diagnosis, particularly in patients being treated with curative intent, with a panel that includes these genes as well as RUNX1, TP53, KIT and ASXL1 (see below). If there is no aspirate sample obtained the ancillary studies should be attempted on a peripheral blood sample. NGS is also available on a case by case basis in relapsed or elderly patients.
Results of FLT3 testing must be available by day 8 of initiation of induction chemotherapy (allelic burden can be provided later).
# Diagnostic Criteria:
The threshold number of immature clonal cells, typically blasts, required to make the diagnosis of AML is 20% of total nucleated cells in the bone marrow by morphology. Exceptions include AML with t(8;21), inv(16), t(16;16) or t (15;17), in which the diagnosis of AML is made regardless of the percentage of bone marrow blasts 2 . De novo AML and acute erythroid leukemia should refer to patients with no clinical history of prior myelodysplastic syndrome, myeloproliferative disorder or exposure to potentially leukemogenic therapies or agents. Secondary AML should refer to patients with prior hematologic disease. Therapy related (t-AML) is a well-recognized clinical syndrome occurring as a late complication following cytotoxic therapy or radiotherapy for a primary neoplasm or a non-neoplastic disorder.
# Epidemiological Distribution at Presentation:
There are four main groups of AML recognized by the WHO classification system: AML with recurrent genetic abnormalities (11% of cases), AML with myelodysplasia-related features (6% of cases), Therapyrelated AML (2% of cases) and AML, not otherwise specified (81% of cases) 3,4 . AML can occur in people of all ages; however, it is most common in elderly patients. In rare circumstances AML can be caused by exposure to ionizing radiation and/or drugs that damage DNA. Anthracyclines and epipodophylloxtoxins which target topoisomerase II can lead to rapidly proliferative disease with monocytic histology and cytogenetic abnormalities at the MLL gene (11q23) months to 2 years after treatment 5 . Exposure to alkylating agents may lead to alkylator agent-induced disease, usually 5 to 6 years after exposure and characterized deletions in chromosomes 5 and 7 and by a myelodysplastic prodrome with complex karyotypes 6 .
# Classification
The blast count, lineage commitment, and level of differentiation of the neoplastic cells have long been the basis of AML classification. The WHO classification includes features such as genetic abnormalities at the chromosomal and/or molecular level and history of previous therapy or antecedent hematologic disease. The AML portion of the WHO classification of myeloid neoplasms was updated in 2016 3,7 .
Table 1. Acute myeloid leukemia and related precursor neoplasms according to the WHO 2016 classification 3,7 .
A lumbar puncture, with the installation of intrathecal chemotherapy, should be performed if worrisome unexplained neurological symptoms are present without a mass lesion by imaging. Consider a screening lumbar puncture in cases of myelomonocytic or monocytic AML or in those with a presenting white cell count of greater than 40 x 10 9 /L. The lumbar puncture should be done after clearing of peripheral blood blasts with platelet transfusion support as necessary. If done prior to blast clearance and there are blasts in the cerebrospinal fluid (CSF) the Steiherz/Bleyer algorithm should be applied to determine the CNS (central nervous system) status as per in acute lymphoblastic leukemia (ALL) 8 . Minimal residual disease (MRD) is defined as the persistence of leukemic cells after chemotherapy at numbers below the sensitivity detection level of routine morphology 10 . Typically detected by polymerase chain reaction or flow cytometry. Morphological leukemia-free stateless than 5% blasts in an aspirate sample with marrow spicules and with a count of at least 500 nucleated cells Morphological complete remission (CR) has been defined using the following criteria developed by an International Working Group 9,11,12 .
# Definition of CNS Status
- Normal values for absolute neutrophil count (>1000/µl) and platelet count (>100,000/µl), and independence from red cell transfusion o A bone marrow biopsy which is free from clusters or collections of blast cells. Extramedullary leukemia (i.e., central nervous system or soft tissue involvement) must be absent o A bone marrow aspiration reveals normal maturation of all cellular components (i.e., erythrocytic, granulocytic, and megakaryocytic series). There is no requirement for bone marrow cellularity o Less than 5% blast cells are present in the bone marrow, and none can have a leukemic phenotype (i.e., Auer rods). The persistence of dysplasia is worrisome as an indicator of residual AML but has not been validated as a criterion for remission status o The absence of a previously detected clonal cytogenetic abnormality (i.e., complete cytogenetic remission, CRc) confirms the morphologic diagnosis of CR but is not currently a required criterion. However, conversion from an abnormal to a normal karyotype at the time of first CR is an important prognostic indicator, supporting the use of CRc as a criterion for CR in AML 10,13,14 Complete remission with incomplete recovery (CRi) -All CR criteria are met, however, residual neutropenia (<1.0 x 10 9 /L or <1000/µl) or thrombocytopenia (<100 x 10 9 /L or <100,000/µl) Cytogenetic complete remission (CRc)this category is recommended primarily for use in clinical research studies but likely to be informative Molecular complete remissionrecognized as a therapeutic objective in acute promyelocytic leukemia but still controversial in other subsets Treatment Failure Resistant disease (RD) -Failure to achieve CR or CRi (general practice; phase II/III trials), or failure to achieve CR, CRi or PR (phase I trials); only includes patients surviving ≥7 days following completion of initial treatment, with evidence of persistent leukemia by blood and/or bone marrow examination Death in aplasia -Deaths occurring ≥7 days following completion of initial treatment while cytopenic;
with an aplastic or hydroplastic bone marrow obtained within 7 days of death, without evidence of persistent leukemia Death from indeterminate cause -Deaths occurring before completion of therapy, or <7 days following its completion; or deaths occurring ≥7 days following completion of initial therapy with no blasts in the blood, but no bone marrow examination available Relapsea reappearance of leukemic blasts in the peripheral blood or greater than 5% blasts in the bone marrow not attributable to any other cause
# Prognosis/Risk Stratification
Several factors influence the ability to achieve and maintain a complete remission in acute myeloid leukemia. The most important of these are age and cytogenetic abnormalities (see Table 4 and 5).
Molecular findings (Table 6) are also emerging as having important significance. There is some evidence from a small prospective study which indicates that the presence of minimal residual disease is associated with a significantly elevated risk of recurrence in patients with core binding factor AML 15 . MRD may also have a role in determining whether or not stem cell transplant is appropriate after achieving first remission 16 , however, further evidence is required. AML evolving from a myelodysplastic disorder or myeloproliferative disorder is often more resistant to cytotoxic chemotherapy than de novo AML. However, it may also have a more indolent course. The need for greater than one cycle of induction chemotherapy to achieve a complete remission is also considered a poor prognostic factor.
# Age:
Older patients have a higher prevalence of unfavorable cytogenetics and antecedent myelodysplastic/myeloproliferative disorders, higher incidence of multidrug resistance and an increased frequency of comorbid medical conditions that affect the ability to tolerate intensive treatment 17 . Even when standard chemotherapy is given outcomes are generally inferior to those achieved in younger patients 18 .Treatment related mortality often exceeds any expected transient response in this group.
# Cytogenetics:
Karyotype represents the single most important prognostic factor for predicting remission rate, relapse, and overall survival. Three groups of cytogenetic abnormalities have been defined with respects to these outcomes classified as favorable, intermediate and unfavorable risk. For example, in a retrospective review of 1213 (median age 52 years; 36% over age 60 years) AML patients treated on CALGB (Cancer and Leukemia Group B) protocols up to the year 2000, the 5-year survival rate was 55% for patients with favorable cytogenetics, 24% for patients with intermediate cytogenetics and 5% for those with poor risk cytogenetics 19 . This categorization holds whether the therapy includes stem cell transplantation or consolidation with chemotherapy alone . See table 4 for the cytogenetic classification. Cytogenetics at diagnosis retain their independent predictive value in the older AML patient population 25,26 .
# Molecular Abnormalities:
In addition to basic cytogenetic analysis, molecular markers are helping refine prognostic groups. These include FMS-like tyrosine kinase 3 (FLT3), c-KIT, nucleophosmin 1 (NPM1) and CEPBA. The most recent National Comprehensive Cancer Network (NCCN) guidelines recommend testing for these in all patients 29 . Recent European Leukemia Net (ELN) guidelines suggest testing as well for TP53, ASXL1 and RUNX1 30 .
# FLT3 mutations
The FLT3 gene encodes an enzyme (fms-related tyrosine kinase 3) which belongs to the type III receptor tyrosine kinase family, and is mutated in about 30% of AML patients 31,32 . FLT3 is expressed on the cellular surface and plays a role in proliferation, survival, and differentiation of hematopoietic progenitor cells 33 . FLT3 internal tandem duplication (FLT3-ITD) mutations, which are seen in approx. 25% of AML cases, are a strong poor prognostic factor, with higher relapse rates and inferior long-term survival in AML patients, even with high-dose chemotherapy and allogeneic hematopoietic stem cell transplant 31,32, .
The FLT3-ITD allelic burden also has an impact on prognosis; patients with a high allelic burden, as defined by a mutant:wild type ratio of > 0.5, have a very high relapse rate and therefore constitute an adverse prognosis group. In contrast, those with a low allelic burden (mutant:wild type ratio < 0.5) have a relatively more favourable prognosis, particularly in the presence of a co-existing NPM1 mutation, and fall into an intermediate risk category . FLT3-tyrosine kinase domain (TKD) point mutations are seen in approx. 5% of cases; the prognostic value of this mutation is less clear, but it does not clearly appear to have a poor prognostic value 45 .
The development of FLT3 inhibitors has been an area of much interest and promise . The multikinase inhibitor midostaurin has been shown to increase complete remission rates and overall survival in FLT3 mutated patients when used in combination with 7 + 3 chemotherapy and HiDAC (high dose cytarabine) consolidation starting on day 8 of induction chemotherapy 49 . It has now been approved and is considered standard of care for AML patients with FLT3 mutations undergoing induction chemotherapy. FLT3 mutation analysis must therefore be available to act upon by day 8 after the initiation of induction chemotherapy.
# NPM1 mutations
Nucleophosmin 1 also nucleolar phosphoprotein B23 or numatrin is encoded by the NPM1 gene which is mutated in approximately 45-64% of cytogenetically normal AML patients. NPM1 mutations lead to abnormal cytoplasmic localization of the protein, which typically functions as a chaperone in the nucleoli and acts in the control and regulation of the ARF-p53 tumor suppressor pathway. The NPM1 mutation in AML patients is a favourable prognostic factor, associated with overall survival and relapse-free survival of approximately 60% . However, this effect is mitigated by the presence of co-existing FLT3-ITD, and possibly by DNMT3A mutations, although there are conflicting data regarding the latter 60,61 . The presence of a co-existing low allelic burden FLT3-ITD lowers the survival to approx. 40%, while a high allelic burden FLT3-ITD lowers survival to 20-30% .
c-KIT mutations c-KIT is a receptor tyrosine kinase which is expressed in 60-80% of myeloblasts 62 . It activates an important signaling pathway mediating cell proliferation and survival. c-KIT mutations are rare in most AML subtypes but are present in approx. 30% of core binding factor (CBF) AML, which includes t(8;21) and inv( 16); these cases are associated with a higher relapse rate compared with non-c-KIT mutated CBF . Because of this, these patients are frequently referred for allogeneic HSCT in first CR. However, a recent French GRAALL study found that, incorporating MRD testing post-cycle 2 of chemotherapy by qRT-PCR (see below) into a multivariate analysis, c-KIT mutation status was not an independent prognostic factor for relapse 66 . Therefore, if MRD monitoring is available, patients who achieve a >3 log reduction in RUNX1-RUNX1T1 or CBFB-MYH11 transcripts by qRT-PCR at the end of the second chemotherapy cycle could be serially monitored by qRT-PCR, without transplant.
# CEBPA mutations
The CCAAT/Enhancer Binding Protein α (CEBPA) gene encodes a transcription factor which is mutated in 10-15% of AML patients, mostly with normal cytogenetics or 9q deletion 67,68 . Three different mutation patterns are typically reported in AML patients: (i) A single mutated allele (single mutation CEBPA, therefore heterozygous with wild type) (CEBPAsm) representing approximately 50% of CEPBA mutated AML cases. (ii) AML with two CEPBA mutations (double-mutated, typically biallelic, no wild type CEBPA expression (CEBPAdm). (iii) AML carrying a homozygous CEBPA mutation due to loss of heterozygosity (no wild type CEPBA expression) 69,70 . Favourable prognosis in CEBPA-mutated AML patients is typically restricted to those cases with biallelic CEBPA in the absence of other cytogenetic aberrations or FLT3-ITD 57,71 . The favourable prognosis associated with biallelic CEBPA mutations is mitigated by FLT3-ITD mutations 71,72, , although it is unclear whether this applies to all such mutations or only those with higher FLT3 allelic burden.
Other mutations RUNX1 and AXSL1 mutations, each occurring in 10-15% of AML patients, have each been associated with adverse prognosis, particularly when occurring in intermediate risk disease, and these patients appear to benefit from transplant in CR1 . Similarly, TP53 and splicing factor mutations (e.g. SRSF2) have also been associated with independently adverse prognosis 77 . RUNX1, ASXL1 and TP53 mutated disease have been assigned to the adverse risk group in the 2017 ELN classification, except when they occur in otherwise ELN favourable risk disease 30 . Therefore, this mutational information can be helpful in risk stratification. With respect to other mutations (e.g. DNMT3A, IDH, TET2) the data regarding prognosis are less clear.
# Germline mutations
It is now recognized that patients with certain inherited mutations carry a higher risk of developing AML and other myeloid neoplasms; some of these can be detected in standard myeloid panels. These include RUNX1, GATA2 and CEBPA 78 . Detection of one of these mutations in a younger patient should prompt germline mutation testing, using non-hematopoietic tissues such as buccal swabs or cultured fibroblasts.
If a germline mutation is detected, any potential sibling donor should be tested, as this would present a theoretical risk of the donor marrow developing leukemia. TP53 mutations (as seen in Li-Fraumeni syndrome) predispose patients to the early development of a number of solid tumour malignancies; these patients are also at higher risk of developing AML or MDS with exposure to chemotherapy or radiation 78 . Therefore, detection of a TP53 mutation in patients with such a history should also prompt consideration of germline mutation testing. 80 The true prevalence of myeloid neoplasms with germline predisposition is uncertain, based largely on a lack of available population data; the WHO nevertheless describes these as relatively rare 80 . Despite the likely low prevalence of predisposing mutations in the general population, recent next-generation sequencing data suggest that germline mutations may be found in as many as 8.4-11.6% of AMLs and 12.9% of MPNs 81 , which would equate to one in every 5-10 patients with a new diagnosis. There is vast variation in germline mutation prevalence by subgroup, however; Down syndrome associated AML, for example, accounts for up to 14% of pediatric cases of AML 82 , whereas DDX41 germline mutations are observed in an estimated 1.4% 83 . There are also notable differences in malignancy penetrance by germline event: the relative risk of development of a myeloid malignancy in patients with germline CEBPA mutations is estimated to be near complete, for example, whereas the risk of AML in patients with Dyskeratosis Congenita is far lower 80,84 . Finally, variable age of onset of disease may be seen across the entities: patients with bone marrow failure syndromes may develop malignancies in early adulthood, whereas the mean age of onset of disease in patients with germline DDX41 mutations is the seventh decade 80 .
Population-based screening for germline mutations associated with increased risk of myeloid malignancies is not currently feasible, however advanced molecular testing might be considered in certain settings. Clinical suspicion for a myeloid neoplasm with germline predisposition may arise by way of specific clinical features: Personal history of multiple cancers Thrombocytopenia, bleeding propensity or macrocytosis preceding the diagnosis of a myeloid neoplasm by several years A first or second degree relative with a hematological neoplasm A first or second degree relative with a solid tumor suggestive of germline predisposition (e.g. early-onset breast cancer) Physical exam features compatible with an inherited condition Failure of a potential stem cell donor to mobilize using standard protocols Modified from 80,85 The possibility of germline predisposition might also arise in cases of myeloid neoplasia with specific mutational profiles, and some genetic changes cannot be discerned reliably as somatic or germline without confirmatory germline testing 86 . Variants in some genes established as germline predisposing factors may be acquired in the somatic context 86 . In the absence of tumor-normal paired testing (which is typical in hematologic neoplasms), germline variants tend to demonstrate heterozygous range variant burdens that remain fixed over time (and despite changes in tumor burden), tend not to be of high frequency in somatic mutation databases (with the potential for emphasis in germline variant databases), and tend to have specific functional implications 86 . Guidelines published by the American College of Medical Geneticists may be employed to assist in the assessment of a putative germline variant 87 .
Patients considered high risk, either by clinical assessment or tumor-only variant profiling, should have confirmatory testing. In Alberta, comprehensive testing for myeloid neoplasms with germline predisposition is largely unavailable, and therefore the approach to confirmatory testing is mainly dictated by the putative gene or condition under consideration. If a patient is presenting with a possible bone marrow failure syndrome or aplastic anemia, recommended testing approaches are elaborated in a separate CKCM document ( ). These conditions require chromosomal breakage or telomere length studies (the latter performed in British Columbia). Confirmatory testing by next-generation sequencing for possible Fanconi Anemia is available through AHS Genetics & Genomics, however the common genetic variants associated with Dyskeratosis Congenita are not available as part of the AHS Genetics & Genomics comprehensive germline testing panel. Similarly, this panel can provide testing for CEBPA, GATA2 and RUNX1, however the panel does not include test features for DDX41, ANKRD26, or ETV6. Testing using the AHS Genetics & Genomics comprehensive germline testing panel requires a specific requisition ( ). Send out testing to address the above genes not interrogable in Alberta must be organized through AHS Genetics & Genomics ( ); the University of Chicago offers a comprehensive familial myelodysplastic syndrome/acute leukemia panel ( )
Patients with an established familial germline predisposition syndrome should not be worked-up using comprehensive panels. Instead, testing tailored to the specific variant of interest should be organized through AHS Genetics & Genomics.
Determining if a genetic abnormality is germline or if a predisposing condition exits is important for genetic counselling with respects to other family members. It becomes particularly important if a hematopoietic stem cell transplant is being considered and donors are being sought within the family. In some rare instances such as Faconi anemia and Li Fraumeni syndrome (germline TP53 mutation) conditioning for the transplant would need to be altered to avoid excessive toxicity.
# Minimal (measurable) residual disease
Early response to therapy is one of the most important prognostic factors in acute leukemia. Evaluation of minimal or measurable residual disease (MRD) is critical to identify patients at elevated risk of relapse which influences clinical decision-making. The leukemia associated immunophenotype (LAIP) of each patient should be established at diagnosis by multiparameter flow cytometry (MPFC), particularly if there is not a molecular abnormality to follow. Analysis of MRD by a properly validated technique performed locally is then recommended to be followed regularly by bone marrow aspirate until negative or the patient proceeds to transplantation.
A study in de novo (n=126) AML evaluated the utility of MRD in predicting relapse. Patients were segregated by their detectable levels of cells with LAIP at the remission determination bone marrow. The patients were split into very low risk (n=8), defined as having fewer than 10 -4 LAP cells per sample, low risk (n=37), defined as having 10 -4 to 10 -3 LAP cells per sample, intermediate risk (n=64), defined as having fewer than 10 -3 to 10 -2 LAP cells per sample, and high risk (n=17), defined as having greater than 10 -2 LAP cells per sample. No patients from the very low risk category relapsed during the time observed, whereas 14%, 50% and 84% of patients in the low, intermediate and high-risk group relapsed after 3 years, respectively (p=0.0001). Additionally, there were significant differences in overall survival (OS) between groups, with 100%, 90%, 62% and 29% rates after 3 years of follow-up (p= 0.003) 88 .
Another study, by Perea and colleagues, evaluated the prognostic value of MRD amongst AML patients with favorable cytogenetics (t(8;21) and inv( 16)) (n=55). MRD was evaluated by tandem RT-PCR (reverse transcription polymerase chain reaction) and flow cytometry. The group found that the mean amount of MRD detected by flow cytometry at the end of treatment in relapsed vs non-relapsed patients was significantly different (0.3% vs 0.08%, respectively; p=0.002) 89 .
In a prospective, blinded study of pediatric patients (n=252) with de novo AML employing a multivariate analysis controlling for allogeneic marrow transplantation, age, sex, white blood count at diagnosis, presence of splenomegaly or hepatomegaly, and presence of more than 15% blasts in the marrow after the first course of induction (by flow cytometry), showed that patients with MRD, defined as ≥0.5% blasts, after one induction and one consolidation were 4.8-fold more likely to relapse (p<0.001) and 3.1-fold more likely to die (p< 0.001) when compared to MRD-negative patients 90 .
A large multi-center prospective study (n=471) was designed to determine cut-off points for MRD in determining relapse rates. MRD was tested after induction cycle 1, cycle 2, and consolidation treatment in age 0.1% after induction cycle 1 and after two cycles of chemotherapy, there was a significant increases in relapse rates compared to those with lower or undetectable MRD levels. On multivariate analysis, MRD positivity after cycle 2 remained an independent prognostic factor for relapse 91 .
Another prospective study (n=892) reporting findings from the United Kingdom National Cancer Research Institute AML 16 Trial evaluated the prognostic utility of MRD in elderly patients. MRD negativity amongst patients who achieved CR, was reported in 51% (n=286) of patients after first treatment, and 64% (n= 279) of patients after the second treatment, which was associated with a significantly better 3-year survival (p < 0.001 for both) and a significantly lower relapse rate (p< 0.001 for both) when compared to MRD-positive patients. Higher risk of early relapse was also reported amongst MRD-positive patients (median time to relapse 17.1 vs 8.5 months in MRD-negative patients) 92 .
A retrospective study sought to investigate the prognostic utility of MRD in pre-hematopoietic cell transplant (HCT) patients. The study consecutively enrolled patients (n=99) receiving myeloablative HCT for AML in first morphologic remission. MRD was defined as any detectable level of residual disease. Two-year overall survival was 30.2% amongst MRD-positive patients versus 76.6% in MRD-negative patients and two-year relapse rates were 64.9% amongst MRD-positive patients versus 17.6% in MRDnegative patients. After adjustment for all or a subset of cytogenetic risk, secondary disease, incomplete blood count recovery, and abnormal karyotype pre-HCT, MRD-positive HCT was associated with increased overall mortality (HR 4.05, 95% CI: 1.90 to 8.62; p <0.001) and relapse (HR 8.49, 95% CI 3.67 to 19.65; p <0.001) when compared to MRD-negative HCT 93 . A subsequent report confirmed the poor prognosis and high relapse rate of patients with MRD detectable disease by MPFC just prior to transplant 160 .
Molecular studies by quantitative RT-PCR can also be used for detection of MRD, with a sensitivity of 1 in 10 -4 cells. The value of RT-PCR in core binding factor AML has already been discussed. NPM1 mutations can also be monitored by this technique 94,95 . A study by the UK NRCI found that persistence of detectable NPM1 transcripts after the second cycle of chemotherapy was associated with a higher risk of relapse (82% vs. 30%; hazard ratio, 4.80, P 0.1% detectable disease by MPFC, following the second cycle of intensive chemotherapy (e.g. one induction and one consolidation) have high relapse rates. In these cases, consideration should be made to altering therapy. It was also recommended that serial monitoring by qRT-PCR be considered for those patients with RUNX1-RUNX1T1, CBFB-MYH11 or NPM1 who are not proceeding to transplant. Not all of these tests are currently routinely available or uniformly reported in Alberta; our goal is to work toward implementing standardized MRD testing, based on these guidelines.
A recent study found that mutational profiling by NGS can also be used for MRD detection postchemotherapy, and can be predictive of relapse 97 , however, this is not currently recommended for MRD assessment outside of clinical trials. Defined by the presence of one single monosomy (excluding loss of X or Y) in association with at least one additional monosomy or structural chromosome abnormality (excluding core-binding factor AML). g. These markers should not be used as an adverse prognostic marker if they co-occur with favorable-risk AML subtypes. h. TP53 mutations are significantly associated with AML with complex and monosomal karyotype.
# Risk Groups as per Cytogenetic and Molecular Status
Treatment 29,98,99 The initial goal of therapy for AML is to achieve a complete remission, given that a complete remission with currently available therapy is requisite, although not sufficient for a cure. It is the sole outcome currently associated with improved survival. Chemotherapy is the mainstay of treatment. Poor performance status and comorbid medical conditions, in addition to age, are factors which influence the ability of an individual to tolerate induction therapy.
In patients undergoing intensive chemotherapy a central venous catheter ideally should be placed.
Supportive care in all patients includes red blood cell transfusions for symptomatic anemia. Platelets should be transfused at a threshold of 10 x 10 9 /L if there is no evidence of bleeding or to keep a platelet level of around 50 x 10 9 /L if there is active bleeding.
Tumor lysis prophylaxis with allopurinol should be initiated in all patients. Monitoring for electrolyte abnormalities and renal function should be ongoing during the first few days of induction chemotherapy particularly in patients with significantly elevated white blood cell count. Rasburicase should be considered in those at high risk of significant tumor lysis.
Antifungal prophylaxis should be considered during all phases of chemotherapy depending on local incidence of invasive fungal infections 29,98 . In a large randomized trial in AML patients receiving induction and post-remission chemotherapy, posaconazole prophylaxis was associated with a lower incidence of invasive Aspergillosis and lower mortality compared with fluconazole or itraconazole 100 . Therapy of febrile neutropenia should include empiric broad spectrum antibiotics according to IDSA guidelines 101 .
The use of growth factor support should be individualized and should be considered in those with documented life-threatening infections. Recent use of G-CSF can increase the blast count in a bone marrow specimen obtained to determine remission status, however immunophentoyping may be useful in this situation if the leukemic cells are known to have an abnormal phenotype. Pegylated growth factors have not been studied in this setting.
Steroid eye drops are recommended during the administration of intermediate to high dose cytarabine to prevent conjunctivitis. These patients should also be screened for cerebellar toxicities before each dose of cytarabine.
Sperm preservation should be discussed with male patients and a serum pregnancy test should be performed in female patients. Women should be given their options regarding fertility preservation.
Rare patients who present with extramedullary disease should be treated with systemic therapy. Local therapy (surgery/radiotherapy may be useful for residual disease).
# Transplant Eligible Patients:
# Induction
Chemotherapy should consist of standard-dose cytarabine with an anthracycline, so called 7&3 chemotherapy (see appendix A for regimens). Studies looking at higher doses of cytarabine in induction have not shown an increased CR rate but have demonstrated an increased treatment related mortality . At count recovery or about day 28-35 from the start of chemotherapy a bone marrow aspirate should be done to determine remission status. The likelihood of establishing a CR with one cycle of induction chemotherapy varies amongst prognostic groups but overall is in the order of 60-70%. Consider repeating cytogenetic analysis if initially abnormal as part of the remission documentation 29 .Other regimens such as FLAG (fludarabine + high-dose cytarabine + G-CSF) or NOVE (mitoxantrone + etoposide) may need to be considered in the case of significant left ventricular dysfunction.
# Re-induction
If CR is not achieved after one cycle of induction chemotherapy another attempt is appropriate. This may consistent of a repeat of 7&3 chemotherapy or alternatively a different regimen such as NOVE, NOVE-HiDAC 80 , FLAG-Ida (FLAG + idarubicin), or high dose cytarabine (HiDAC) (see appendix A for regimens) may be tried. A bone marrow aspirate and biopsy should be done at count recovery or day 30-35 to document remission status. The likelihood of a second regimen being successful is in the order of 50%. If no remission is achieved after 2 cycles of induction chemotherapy palliation may become the goal of care.
# Consolidation
If CR has been achieved further therapy is necessary for potential cure. The nature of consolidation therapy must be individualized for each patient based on a risk analysis of the risk of relapse of the AML versus the risk of the proposed consolidation therapy. This will depend on prognostic features of the leukemia, response to therapy, performance status and type of hematopoietic stem cell donor available. HiDAC is the mainstay of consolidation chemotherapy as there has been shown to be a dose intensity effect to cytarabine suggesting that HiDAC is beneficial in induction or consolidation 103,104 . Generally at least one cycle is administered in all patients if only to allow for planning of an allogeneic stem cell transplant although the absolute need for this is controversial.
- Good risk patients: In patients with AML with t(8;21) or inv 16, data suggests that provided there are no additional risk factors multiple cycles of HiDAC provide higher overall survival than lower doses of cytarabine or stem cell transplant .Our recommendation is 3-4 cycles of HiDAC post induction chemotherapy. A recent retrospective study from Edmonton and Vancouver found similar outcomes with 2 cycles of consolidation compared with 3 110 , but this requires confirmation in a prospective study.
There is also evidence that the addition of gemtuzumab ozogamicin (GO) may produce better outcomes when combined with chemotherapy 111 ; however, this agent is not yet approved in Canada.
- Intermediate risk patients: HiDAC has been shown to be preferable over lower dose cytarabine in this cytogenetic group as well 26,107 but its superiority over stem cell transplantation has not been established. It is generally recognized that an allogeneic stem cell transplant provides a decreased relapse rate at a cost of increased treatment related mortality when compared to consolidation chemotherapy or autologous transplantation 109, . The transplant related mortality gap between matched related and unrelated donors has been shown to be significantly reduced in recent years 115,116 . A suitable hematopoietic stem cell donor should be sought. If a matched sibling donor is found a related myeloablative stem cell transplant should proceed as soon as possible, ideally after one dose of HiDAC. If there are no suitable family donors, the patient should proceed through 3-4 cycles of HiDAC consolidation while a match unrelated donor is sought. If one is found before the third cycle of consolidation chemotherapy, consider matched unrelated donor stem cell transplantation.
- High risk patients: All efforts should be undertaken to find a matched donor, related or unrelated for eligible patients. During that time the patient should receive ongoing cycles of HiDAC chemotherapy up to a total of 4 cycles. The patient should proceed to allogeneic stem cell transplantation as soon as a donor is identified. If no fully matched donor is available consideration should be given to a haploidentical related transplant if a suitable donor is available. Finally, unrelated cord blood transplantation is also an option in selected situations.
# FLT3 Mutation Positive Patients:
If not enrolled on a clinical trial with a FLT3 inhibitor, midostaurin should be added for these patients on day 8 of each induction and consolidation treatment cycle, as per the RATIFY clinical trial protocol (midostaurin and standard induction/consolidation chemotherapy). The Phase III RATIFY (CALGB 10603) trial randomized 717 AML patients with FLT3 mutation to receive standard induction and consolidation chemotherapy +/-midostaurin. After a median follow-up of 57 months, patients in the midostaurin arm had a significant improvement in median overall survival vs. placebo (74.7 months vs. 26 months, respectively; p=0.007), representing a 23% reduction in the risk for death 49 . It has now been approved by Health Canada for this indication.
# Relapse:
- Re-induction: An attempt at achieving a second CR should be attempted. If the remission was greater than one year 7&3 chemotherapy can be used again. Otherwise other regimens such as FLAG-Ida, NOVE, NOVE-HiDAC, or HiDAC are appropriate. Participation in a clinical trial is encouraged.
- Hematopoietic stem cell transplantation: If a stem cell transplant was not done in first CR it should be undertaken once a second CR has been achieved. The ideal donor would be an allogeneic matched related or unrelated donor, or if necessary a related haploidentical donor or cord blood unit.
# Palliation
If comorbid conditions affect the ability to proceed with optimal aggressive therapy, treatment with either low-dose cytarabine (LDAC) or azacitidine (VIDAZA®) is recommended as these have been shown to increase overall survival compared to supportive care alone 117,118 . Azacitidine is recommended for patients with 20-30% marrow blasts with dysplasia and for patients with adverse risk cytogenetics, based on two Phase III randomized trials 119,120 . For patients with >30% blasts and intermediate risk cytogenetics, LDAC and azacitidine have similar survivals 121 ; LDAC has the advantage of lower cost and the potential for athome administration.
The recommended dose of azacitidine is 75 mg/m 2 /day subcutaneously for 7 days, every 28 days, for at least six cycles 122 . This is also an appropriate approach in the setting of primary induction failure not eligible for further intensive therapy, or relapse, particularly after allogeneic stem cell transplantation. It may also be considered in patients in CR after induction where aggressive chemotherapy for consolidation is no longer indicated. The most commonly used dosing for LDAC is 20 mg subcutaneously twice daily for 10 days 117 , repeated every 4-5 weeks; 40 mg once daily may be used for home care administration. At least 4 cycles should be used, unless there is clear evidence of progression earlier. In patients not responding to LDAC, azacitidine may be utilized; however, LDAC does not appear to be effective in azacitidine failures.
For patients not able or willing to receive these treatments, or not responding to these, supportive care alone is appropriate, with hydroxyurea to control circulating blast counts.
Transplant Ineligible Patients: In patients with a normal karyotype, the remission rate on older patients is 50-60% with cytarabine combined with idarubicin, daunorubicin or mitoxantrone. In those with adverse risk cytogenetics the chance of achieving a remission is approximately 25%, with median OS of approximately 6 months 25,26,123 . Attempts to modify this by adjusting the chemotherapy regimens, adding growth factors or multidrug resistance protein regulators have not been successful 17, . Due to the poor outcomes in this group, clinical trials are particularly important. However, if none are available, azacitidine would be appropriate therapy in older patients with high-risk cytogenetics who are not considered candidates for allogeneic HSCT. In other elderly non-fit patients, low-dose cytarabine would also be appropriate
# Induction
In patients with an ECOG performance status of 2 or less and no prohibitive comorbid conditions, standard 7&3 induction chemotherapy is appropriate 127 , particularly in patients with core-binding factor leukemias. If consideration is being given to consolidation therapy or re-induction in the case of primary induction failure, a bone marrow aspirate should be performed to document remission. If no further therapy is planned this can be omitted.
# Consolidation
Consolidation chemotherapy in this group of patients is controversial. There is evidence to suggest that low-dose, prolonged ambulatory treatment should be preferred to intensive chemotherapy 123 ; however intermediate dose cytarabine can be considered if the patient maintains a good performance status, normal renal function, and has a good or normal karyotype. Consolidation has not been shown to prolong survival in patients with high risk karyotypes. There is limited retrospective data which suggests azacitidine may be appropriate in this setting, although prior cytotoxic therapy was associated with a decreased marrow response rate, azacitidine treatment still prolonged overall survival 128 . LDAC may also be considered in patients in CR who are not suitable candidates for further intensive chemotherapy.
# Relapse
In this age group, if acute leukemia recurs palliation with best supportive care or azacitidine is indicated if there are no available clinical trials.
# Mixed-Phenotype Acute Leukemia:
Mixed-phenotype acute leukemia (MPAL) is rare, accounting for less than 5% of acute leukemia cases 7 . Treatment approaches to MPAL vary, as there is no standard therapy for patients. Typical, treatment may include AML-type induction therapy, ALL-type induction therapy, or a hybrid combination of AML/ALL-type induction regimen 129 . An early allogeneic hematopoietic cell transplant should be considered for these patients. It should be noted that data regarding the treatment of MPAL is largely retrospective in nature, with limited studies available for review.
One international retrospective study of 100 children and adults with MPAL defined by the 2008 WHO classification reported a 5-year survival rate of 37% (median survival 1.5 years) 130 . Treatment was selected by the managing physician and information regarding the treatment choice by age group was not presented. Age >15, Philadelphia chromosome positive leukemia, and AML-type induction treatment approaches were associated with significantly reduced median survival. Data from this study is summarized below. , however, it remains unclear whether all of these risk factors still apply to patients treated with modern induction regimens.
Symptoms of increased intracranial pressure, cranial nerve palsies, symptoms of CNS hemorrhage, symptoms of spinal cord compression and/or visual changes indicate potential CNS involvement. Mass lesions are uncommon, although reported at a higher frequency in inv( 16) patients 132 . Diagnosis of CNS leukemia is typically confirmed by the identification of leukemic blasts on cytocentrifuge preparations of cerebrospinal fluid after lumber puncture.
No prospective studies comparing intrathecal chemotherapy, systemic chemotherapy and/or cranial radiation have been reported to guide treatment in patients with CNS leukemia. Intrathecal chemotherapy with methotrexate (12 to 15 mg/dose) or cytarabine (50-70 mg/dose) is a common approach. Systemic high dose methotrexate or cytarabine in combination with diaziquone has been shown to achieve clearance of the CNS tumour load 135 , however, even after successful therapy, treatment in this setting is associated with high relapse rates 136 . Patients with cranial nerve involvement or a tumour mass that impinges on important structures may require initial radiation therapy (18 to 25 Gy for the brain) followed by intrathecal chemotherapy 136,137 .
In patients with neurological symptoms imaging should be done to rule out a mass or bleed. If neither of these is present a lumbar puncture should be done and sent for morphology as well as flow cytometry. If this is negative for leukemic cells initially it should be repeated if the symptoms persist. If it is positive, as per the diagnostic criteria in section 3, intrathecal chemotherapy should be administered twice a week concurrently with induction chemotherapy until the cerebrospinal fluid is no longer positive by morphology and flow cytometry. An additional 2 intrathecal treatments should then be administered. Intrathecal chemotherapy should consist of alternating single agent cytarabine and methotrexate or "triple therapy" with cytarabine, methotrexate and hydrocortisone.
In patients with myelomonocytic or monocytic leukemia as well as those with a presenting blast count of greater than 40 x10 9 /L consider a screening lumbar puncture at diagnosis with intrathecal chemotherapy administered at the same time. If the cerebrospinal fluid is positive for leukemic cells the patient should be treated as above.
# Follow Up
Once all therapy is completed no further bone marrow aspirates are indicated unless there is concern of relapse or loss of graft in transplanted patients. Regular complete blood counts should be performed every month for the first few years then every 3 months until 5 years. The risk of recurrence after 5 years is very low and hematological follow up can be stopped at that point. Patients should be reminded of the signs and symptoms of leukemia including those of anemia, thrombocytopenia and infection and instructed to seek medical attention at any point if these develop. If there is concern of a relapse at any point, a bone marrow aspirate and biopsy should be performed and the patient should be sent for all the appropriate diagnostic tests.
# New Therapies
Gemtuzumab ozogamicin (GO) the anti-CD33 antibody carrying a toxic calicheamicin-γ1 derivative, which after intracellular hydrolytic release, induces DNA strand breaks, apoptosis, and cell death was the first anti-cancer immunoconjugate to obtain regulatory approval in the United States. It was subsequently withdrawn from the US by Pfizer after results from the S0106 trial demonstrated no overall survival benefit, while reporting an increased rate of early mortality in the GO arm of patients 18-60 years old with de novo AML receiving 2 cycles of induction chemotherapy with daunorubicin/cytarabine with or without GO (6 mg/m 2 ) 105 . However, emerging data from other well controlled studies did report benefits from the addition of GO to chemotherapy, particularly when used in smaller fractionated doses . A recent metanalysis of 5 randomized trials found an overall survival benefit for GO when added to intensive chemotherapy, most strikingly seen in patients with favourable risk cytogenetics, while those with adverse risk karyotypes did not benefit 111 . In September 2017 GO was approved by the FDA for this indication. It is currently under review by Health Canada (February 2019) and available via compassionate access.
CPX-351 (Vyxeos R ) is a nanoparticle formulation containing a fixed molar ratio of daunorubicin and cytarabine. A phase III randomized trial in previously untreated AML patients with secondary AML age 60-75 found that this agent was superior to standard 3+7 induction therapy 142 , while no benefit was seen in another study in de novo 143 . It has now been FDA approved for the treatment of secondary AML as of August 2017; approval in Canada is pending however it is available on a compassionate basis.
The development of more potent second generation FLT3 inhibitors remains an area of active investigation. The second-generation inhibitors (quizartinib, gilteritinib, crenolanib) have produced CR rates in the 40% range as single agents in relapsed AML 144,145 , but remain investigational. These agents are being actively investigated in combination with chemotherapy, both in the frontline and relapsed setting. Gilteritinib is now available by compassionate access.
Approximately 15-20% of AML patients have IDH1 or IDH2 mutations, which result in aberrant production of an oncoprotein, 5HG, which induces a block in cell differentiation. Enasidenib (AG221) is a selective oral IDH2 inhibitor that inhibits 5HG production and restores normal cell differentiation. Treatment with this agent in relapsed/refractory AML patients with IDH2 mutations has produced CR in approximately 30% of cases; responses may take up to 6 months to be seen 146 . This agent has now been approved by the FDA and Health Canada for this indication but not yet publically funded. It is available on a compassionate basis. Ivosidenib is a selective IDH1 inhibitor which has shown activity in IDH1 mutated disease in early clinical trials 147 .
Another promising agent is venetoclax, a selective oral small molecule BCL-2 inhibitor. Although it has limited activity as a single agent, it has been found to synergize with chemotherapy agents in preclinical models. In a study by Wei et al, venetoclax 600 mg daily was given in combination with low dose cytarabine to patients with newly diagnosed AML not eligible to receive intensive induction chemotherapy 148 . Of the 82 patients evaluable, 44 (54%) achieved CR or CR with incomplete count recovery (CRi), demonstrating that this is an active combination in patients with newly diagnosed AML. Venetoclax in combination with azacitdiine or decitabine was evaluated in older patients with AML unfit to receive intensive chemotherapy. Of the 145 patients enrolled, 67%of patients achieved CR/CRi. The median duration of response was 11.3 months 149 .
These regimens are now under evaluation in Phase III randomized clinical trials. Phase I studies are also ongoing adding it to intensive remission inducing chemotherapy. It has been approved by the FDA in patients over the age of 75 with de novo AML in combination with low dose cytarabine or hypomethylating agents as of November 2018.
Many other novel agents are currently in clinical trials in AML, including agents that target MDM2 (inhibition of which results in upregulation of p53, inducing apoptosis) 150 , DOT1L (associated with MLL overexpression/rearrangements) 151 , Polo-like kinase-1 152,153 , and CXCR4 152,153 . A number of novel immunocongugates are also in clinical trials, targeting antigens expressed on AML stem cells such as CD123 and CLL1. CAR-T (chimeric antigen receptor) cell therapy is a novel form of immunotherapy which has produced remissions in many patients with chemotherapy-refractory ALL and lymphoma; early trials in AML are in progress.
# MAINTENANCE
A formal review will be conducted in 2019, however if new evidence is brought forward before that time, the guideline will be changed accordingly.
# GLOSSARY OF ABBREVIATIONS
Acronym | 1) All patients being considered for therapy should undergo a bone marrow aspiration and biopsy as well as peripheral blood films to establish a diagnosis and prognosis. a. Immunophenotyping by flow cytometry should be performed for diagnosis and to determine a leukemiaassociated immunophenotype (LAIP) if possible. b. Samples should also be sent for cytogenetics, including fluorescence in-situ hybridization (FISH) where appropriate. c. Molecular analysis should be sent. 2) Ancillary Tests: a. Organ function should be assessed including liver, kidneys, coagulation and cardiac function. b. Blood group and human leukocyte antigen (HLA) typing of patient and family should be done as soon as possible in transplant eligible patients. 3) A lumbar puncture, with the installation of intrathecal chemotherapy, should be performed if worrisome unexplained neurological symptoms are present without a mass lesion by imaging. a. Consider a screening lumbar puncture in cases of myelomonocytic or monocytic acute myeloid leukemia (AML) or in those with a presenting white cell count of >40 x 10 9 /L. 4) AML classification and risk stratification and transplant eligibility should be ascertained for all patients using age, performance status, World Health Organization (WHO) classification, cytogenetic and molecular risk group, as well response to therapy including minimal residual disease when possible. In the appropriate situations, establishing whether a genetic change is germline should be pursued. 5) Supportive care: a. In patients undergoing intensive chemotherapy a central venous catheter ideally should be placed. b. Red blood cell transfusions for symptomatic anemia. c. Platelets should be transfused at a threshold of 10 x 10 9 /L if there is no evidence of bleeding or to keep a platelet level of around 50 x 10 9 /L if there is active bleeding. d. Tumor lysis prophylaxis should be initiated in all patients. e. Antifungal prophylaxis should be considered during all phases of chemotherapy. f. Therapy of febrile neutropenia should include empiric broad spectrum antibiotics according to IDSA guideline. g. The use of growth factor support should be individualized. h. Steroid eye drops are recommended during the administration of intermediate to high dose cytarabine. These patients should also be screened for cerebellar toxicities before each dose of cytarabine. i. Sperm preservation should be discussed with male patients and a serum pregnancy test should be performed in female patients. 6) In transplant eligible patients treatment consists of induction and consolidation chemotherapy along with a FLT3 inhibitor in FLT3 positive cases a. Induction chemotherapy should consist of standard-dose cytarabine with an anthracycline b. Consolidation can consist of further cycles of chemotherapy alone or in association with a hematopoietic stem cell transplant depending on risk of relapse. i. Good riskchemotherapy alone. ii. Intermediate riskconsider transplantation. iii. High risktransplantation. 7) In transplant ineligible patients treatment options consist of palliation, low dose cytarabine, azacitidine or induction chemotherapy, depending on performance status and risk stratification. Strong consideration should be given to enrollment into a clinical trial. 8) In the instance of relapse re-induction chemotherapy can be considered depending on performance status, otherwise palliation should be instituted.#
Participation of members of the Alberta Provincial Hematology Tumour Team in the development of this guideline has been voluntary and the authors have not been remunerated for their contributions. There was no direct industry involvement in the development or dissemination of this guideline. CancerControl Alberta recognizes that although industry support of research, education and other areas is necessary in order to advance patient care, such support may lead to potential conflicts of interest. Some members of the Alberta Provincial Hematology Tumour Team are involved in research funded by industry or have other such potential conflicts of interest. However the developers of this guideline are satisfied it was developed in an unbiased manner.
# BACKGROUND
Acute myeloid leukemia (AML) is a group of infrequent neoplasms responsible for a significant number of cancer-related deaths. Its incidence has been relatively stable over the last years at about 3.7 per 100 000 persons per year in the western world. It is primarily a disease of later adulthood with an increasing incidence with age. The median age at diagnosis is 65 years with a slight male preponderance. Outcome varies greatly according to age at diagnosis due to disease and patient features. Untreated AML is a uniformly fatal disease with a median survival of 11-20 weeks 1 .
The etiology of AML in most cases is unclear. Known risk factors include exposure to chemotherapeutic agents particularly alkylating agents, topoisomerase-II inhibitors and anthracyclines as well as both therapeutic and nontherapeutic radiation. A higher than average incidence is seen in individuals with Down's syndrome, Klinfelter's syndrome, Ataxia telangectasia, Kostmann syndrome, neurofibromatosis or Fanconi anemia. Exposure to benzenes, pesticides, herbicides and cigarette smoking may also play a role in its development. There is also a greater incidence of AML in individuals with pre-existing hematologic disorders such as the myelodysplastic syndromes or myeloproliferative disorders.
# GUIDELINE GOALS AND OBJECTIVES
To delineate the diagnostic criteria for acute myeloid leukemias To delineate the prognostic markers in acute myeloid leukemias To identify the management options for acute myeloid leukemias in adults including chemotherapy, hematopoietic stem cell transplantation, and palliation
# GUIDELINE QUESTIONS
What is the optimal management of the acute myeloid leukemias in Alberta at the present time?
# DEVELOPMENT AND REVISION HISTORY
This guideline was reviewed and endorsed by the Alberta Provincial Hematology Tumour Team. Members of the Alberta Provincial Hematology Tumour Team include hematologists, medical oncologists, radiation oncologists, nurses, hematopathologists, and pharmacists. Evidence was selected and reviewed by a working group comprised of members from the Alberta Provincial Hematology Tumour Team and a Knowledge Management Specialist from the Guideline Resource Unit. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook.
This guideline was originally developed in 2008. This guideline was revised in 2015, 2017, 2018 and 2019.
# SEARCH STRATEGY
The original guideline (2008) was generated using systematic literature searches of the Pubmed and Medlinedatabases, ASCO abstracts and proceedings, and ASH abstracts and proceedings databases. The search included practice guidelines, systematic reviews, meta-analyses, randomized controlled trials and clinical trials. The 2015, 2017, 2018 and 2019 updates involved review of the Pubmed and Medline databases for relevant information on a topic-by-topic basis. The ASH, ASCO and EHA abstracts and proceedings databases were also screened.
# TARGET POPULATION
The following guidelines apply to adults over the age of 18 years. Different principles may apply to pediatric patients.
# DISCUSSION
# Diagnosis
AML describes a heterogeneous group of clonal hematopoietic progenitor cell disorders with a spectrum of morphologic, immunophenotypic, cytogenetic and molecular characteristics. For a diagnosis of AML, a marrow blast count of ≥ 20% is required, except for AML with the recurrent genetic abnormalities t(15;17), t(8;21), inv (16) or t (16;16) and some cases of erythroleukemia.
# Diagnostic Tests:
The diagnosis is often suspected and can at times be confirmed from the peripheral blood. However, all patients being considered for therapy should undergo a bone marrow aspiration and biopsy. Samples should be sent for morphology, flow cytometry, cytogenetics and molecular analysis.
Immunophenotyping by flow cytometry confirms myeloid lineage and stage of differentiation of the malignant cell. It may have a prognostic role by establishing a unique phenotype for minimal residual disease monitoring, the leukemia associated immunophenotyped (LAIP). A full karyotype will be determined at diagnosis in all cases. Fluorescence in-situ hybridization (FISH) will also be carried out in cases morphologically suspicious for specific subsets. Molecular analysis will be carried out in cases suspicious for promyelocytic leukemia looking for the PML/RAR, in the core binding factor leukemias looking for c-KIT mutations, as well as in cases with normal karyotypes looking for FLT3, NPM1 and CEBPA mutations. Information regarding FLT3-ITD allelic burden should also be provided. Next generation sequencing (NGS) should be performed at diagnosis, particularly in patients being treated with curative intent, with a panel that includes these genes as well as RUNX1, TP53, KIT and ASXL1 (see below). If there is no aspirate sample obtained the ancillary studies should be attempted on a peripheral blood sample. NGS is also available on a case by case basis in relapsed or elderly patients.
Results of FLT3 testing must be available by day 8 of initiation of induction chemotherapy (allelic burden can be provided later).
# Diagnostic Criteria:
The threshold number of immature clonal cells, typically blasts, required to make the diagnosis of AML is 20% of total nucleated cells in the bone marrow by morphology. Exceptions include AML with t(8;21), inv(16), t(16;16) or t (15;17), in which the diagnosis of AML is made regardless of the percentage of bone marrow blasts 2 . De novo AML and acute erythroid leukemia should refer to patients with no clinical history of prior myelodysplastic syndrome, myeloproliferative disorder or exposure to potentially leukemogenic therapies or agents. Secondary AML should refer to patients with prior hematologic disease. Therapy related (t-AML) is a well-recognized clinical syndrome occurring as a late complication following cytotoxic therapy or radiotherapy for a primary neoplasm or a non-neoplastic disorder.
# Epidemiological Distribution at Presentation:
There are four main groups of AML recognized by the WHO classification system: AML with recurrent genetic abnormalities (11% of cases), AML with myelodysplasia-related features (6% of cases), Therapyrelated AML (2% of cases) and AML, not otherwise specified (81% of cases) 3,4 . AML can occur in people of all ages; however, it is most common in elderly patients. In rare circumstances AML can be caused by exposure to ionizing radiation and/or drugs that damage DNA. Anthracyclines and epipodophylloxtoxins which target topoisomerase II can lead to rapidly proliferative disease with monocytic histology and cytogenetic abnormalities at the MLL gene (11q23) months to 2 years after treatment 5 . Exposure to alkylating agents may lead to alkylator agent-induced disease, usually 5 to 6 years after exposure and characterized deletions in chromosomes 5 and 7 and by a myelodysplastic prodrome with complex karyotypes 6 .
# Classification
The blast count, lineage commitment, and level of differentiation of the neoplastic cells have long been the basis of AML classification. The WHO classification includes features such as genetic abnormalities at the chromosomal and/or molecular level and history of previous therapy or antecedent hematologic disease. The AML portion of the WHO classification of myeloid neoplasms was updated in 2016 3,7 .
Table 1. Acute myeloid leukemia and related precursor neoplasms according to the WHO 2016 classification 3,7 .
A lumbar puncture, with the installation of intrathecal chemotherapy, should be performed if worrisome unexplained neurological symptoms are present without a mass lesion by imaging. Consider a screening lumbar puncture in cases of myelomonocytic or monocytic AML or in those with a presenting white cell count of greater than 40 x 10 9 /L. The lumbar puncture should be done after clearing of peripheral blood blasts with platelet transfusion support as necessary. If done prior to blast clearance and there are blasts in the cerebrospinal fluid (CSF) the Steiherz/Bleyer algorithm should be applied to determine the CNS (central nervous system) status as per in acute lymphoblastic leukemia (ALL) 8 . Minimal residual disease (MRD) is defined as the persistence of leukemic cells after chemotherapy at numbers below the sensitivity detection level of routine morphology 10 . Typically detected by polymerase chain reaction or flow cytometry. Morphological leukemia-free stateless than 5% blasts in an aspirate sample with marrow spicules and with a count of at least 500 nucleated cells Morphological complete remission (CR) has been defined using the following criteria developed by an International Working Group 9,11,12 .
# Definition of CNS Status
o Normal values for absolute neutrophil count (>1000/µl) and platelet count (>100,000/µl), and independence from red cell transfusion o A bone marrow biopsy which is free from clusters or collections of blast cells. Extramedullary leukemia (i.e., central nervous system or soft tissue involvement) must be absent o A bone marrow aspiration reveals normal maturation of all cellular components (i.e., erythrocytic, granulocytic, and megakaryocytic series). There is no requirement for bone marrow cellularity o Less than 5% blast cells are present in the bone marrow, and none can have a leukemic phenotype (i.e., Auer rods). The persistence of dysplasia is worrisome as an indicator of residual AML but has not been validated as a criterion for remission status o The absence of a previously detected clonal cytogenetic abnormality (i.e., complete cytogenetic remission, CRc) confirms the morphologic diagnosis of CR but is not currently a required criterion. However, conversion from an abnormal to a normal karyotype at the time of first CR is an important prognostic indicator, supporting the use of CRc as a criterion for CR in AML 10,13,14 Complete remission with incomplete recovery (CRi) -All CR criteria are met, however, residual neutropenia (<1.0 x 10 9 /L or <1000/µl) or thrombocytopenia (<100 x 10 9 /L or <100,000/µl) Cytogenetic complete remission (CRc)this category is recommended primarily for use in clinical research studies but likely to be informative Molecular complete remissionrecognized as a therapeutic objective in acute promyelocytic leukemia but still controversial in other subsets Treatment Failure Resistant disease (RD) -Failure to achieve CR or CRi (general practice; phase II/III trials), or failure to achieve CR, CRi or PR (phase I trials); only includes patients surviving ≥7 days following completion of initial treatment, with evidence of persistent leukemia by blood and/or bone marrow examination Death in aplasia -Deaths occurring ≥7 days following completion of initial treatment while cytopenic;
with an aplastic or hydroplastic bone marrow obtained within 7 days of death, without evidence of persistent leukemia Death from indeterminate cause -Deaths occurring before completion of therapy, or <7 days following its completion; or deaths occurring ≥7 days following completion of initial therapy with no blasts in the blood, but no bone marrow examination available Relapsea reappearance of leukemic blasts in the peripheral blood or greater than 5% blasts in the bone marrow not attributable to any other cause
# Prognosis/Risk Stratification
Several factors influence the ability to achieve and maintain a complete remission in acute myeloid leukemia. The most important of these are age and cytogenetic abnormalities (see Table 4 and 5).
Molecular findings (Table 6) are also emerging as having important significance. There is some evidence from a small prospective study which indicates that the presence of minimal residual disease is associated with a significantly elevated risk of recurrence in patients with core binding factor AML 15 . MRD may also have a role in determining whether or not stem cell transplant is appropriate after achieving first remission 16 , however, further evidence is required. AML evolving from a myelodysplastic disorder or myeloproliferative disorder is often more resistant to cytotoxic chemotherapy than de novo AML. However, it may also have a more indolent course. The need for greater than one cycle of induction chemotherapy to achieve a complete remission is also considered a poor prognostic factor.
# Age:
Older patients have a higher prevalence of unfavorable cytogenetics and antecedent myelodysplastic/myeloproliferative disorders, higher incidence of multidrug resistance and an increased frequency of comorbid medical conditions that affect the ability to tolerate intensive treatment 17 . Even when standard chemotherapy is given outcomes are generally inferior to those achieved in younger patients 18 .Treatment related mortality often exceeds any expected transient response in this group.
# Cytogenetics:
Karyotype represents the single most important prognostic factor for predicting remission rate, relapse, and overall survival. Three groups of cytogenetic abnormalities have been defined with respects to these outcomes classified as favorable, intermediate and unfavorable risk. For example, in a retrospective review of 1213 (median age 52 years; 36% over age 60 years) AML patients treated on CALGB (Cancer and Leukemia Group B) protocols up to the year 2000, the 5-year survival rate was 55% for patients with favorable cytogenetics, 24% for patients with intermediate cytogenetics and 5% for those with poor risk cytogenetics 19 . This categorization holds whether the therapy includes stem cell transplantation or consolidation with chemotherapy alone [19][20][21][22][23][24] . See table 4 for the cytogenetic classification. Cytogenetics at diagnosis retain their independent predictive value in the older AML patient population 25,26 .
# Molecular Abnormalities:
In addition to basic cytogenetic analysis, molecular markers are helping refine prognostic groups. These include FMS-like tyrosine kinase 3 (FLT3), c-KIT, nucleophosmin 1 (NPM1) and CEPBA. The most recent National Comprehensive Cancer Network (NCCN) guidelines recommend testing for these in all patients 29 . Recent European Leukemia Net (ELN) guidelines suggest testing as well for TP53, ASXL1 and RUNX1 30 .
# FLT3 mutations
The FLT3 gene encodes an enzyme (fms-related tyrosine kinase 3) which belongs to the type III receptor tyrosine kinase family, and is mutated in about 30% of AML patients 31,32 . FLT3 is expressed on the cellular surface and plays a role in proliferation, survival, and differentiation of hematopoietic progenitor cells 33 . FLT3 internal tandem duplication (FLT3-ITD) mutations, which are seen in approx. 25% of AML cases, are a strong poor prognostic factor, with higher relapse rates and inferior long-term survival in AML patients, even with high-dose chemotherapy and allogeneic hematopoietic stem cell transplant 31,32,[34][35][36][37][38][39] .
The FLT3-ITD allelic burden also has an impact on prognosis; patients with a high allelic burden, as defined by a mutant:wild type ratio of > 0.5, have a very high relapse rate and therefore constitute an adverse prognosis group. In contrast, those with a low allelic burden (mutant:wild type ratio < 0.5) have a relatively more favourable prognosis, particularly in the presence of a co-existing NPM1 mutation, and fall into an intermediate risk category [40][41][42][43][44] . FLT3-tyrosine kinase domain (TKD) point mutations are seen in approx. 5% of cases; the prognostic value of this mutation is less clear, but it does not clearly appear to have a poor prognostic value 45 .
The development of FLT3 inhibitors has been an area of much interest and promise [46][47][48] . The multikinase inhibitor midostaurin has been shown to increase complete remission rates and overall survival in FLT3 mutated patients when used in combination with 7 + 3 chemotherapy and HiDAC (high dose cytarabine) consolidation starting on day 8 of induction chemotherapy 49 . It has now been approved and is considered standard of care for AML patients with FLT3 mutations undergoing induction chemotherapy. FLT3 mutation analysis must therefore be available to act upon by day 8 after the initiation of induction chemotherapy.
# NPM1 mutations
Nucleophosmin 1 also nucleolar phosphoprotein B23 or numatrin is encoded by the NPM1 gene which is mutated in approximately 45-64% of cytogenetically normal AML patients. NPM1 mutations lead to abnormal cytoplasmic localization of the protein, which typically functions as a chaperone in the nucleoli and acts in the control and regulation of the ARF-p53 tumor suppressor pathway. The NPM1 mutation in AML patients is a favourable prognostic factor, associated with overall survival and relapse-free survival of approximately 60% [50][51][52][53][54][55][56][57][58][59] . However, this effect is mitigated by the presence of co-existing FLT3-ITD, and possibly by DNMT3A mutations, although there are conflicting data regarding the latter 60,61 . The presence of a co-existing low allelic burden FLT3-ITD lowers the survival to approx. 40%, while a high allelic burden FLT3-ITD lowers survival to 20-30% [40][41][42][43][44][53][54][55] .
c-KIT mutations c-KIT is a receptor tyrosine kinase which is expressed in 60-80% of myeloblasts 62 . It activates an important signaling pathway mediating cell proliferation and survival. c-KIT mutations are rare in most AML subtypes but are present in approx. 30% of core binding factor (CBF) AML, which includes t(8;21) and inv( 16); these cases are associated with a higher relapse rate compared with non-c-KIT mutated CBF [63][64][65] . Because of this, these patients are frequently referred for allogeneic HSCT in first CR. However, a recent French GRAALL study found that, incorporating MRD testing post-cycle 2 of chemotherapy by qRT-PCR (see below) into a multivariate analysis, c-KIT mutation status was not an independent prognostic factor for relapse 66 . Therefore, if MRD monitoring is available, patients who achieve a >3 log reduction in RUNX1-RUNX1T1 or CBFB-MYH11 transcripts by qRT-PCR at the end of the second chemotherapy cycle could be serially monitored by qRT-PCR, without transplant.
# CEBPA mutations
The CCAAT/Enhancer Binding Protein α (CEBPA) gene encodes a transcription factor which is mutated in 10-15% of AML patients, mostly with normal cytogenetics or 9q deletion 67,68 . Three different mutation patterns are typically reported in AML patients: (i) A single mutated allele (single mutation CEBPA, therefore heterozygous with wild type) (CEBPAsm) representing approximately 50% of CEPBA mutated AML cases. (ii) AML with two CEPBA mutations (double-mutated, typically biallelic, no wild type CEBPA expression (CEBPAdm). (iii) AML carrying a homozygous CEBPA mutation due to loss of heterozygosity (no wild type CEPBA expression) 69,70 . Favourable prognosis in CEBPA-mutated AML patients is typically restricted to those cases with biallelic CEBPA in the absence of other cytogenetic aberrations or FLT3-ITD 57,71 . The favourable prognosis associated with biallelic CEBPA mutations is mitigated by FLT3-ITD mutations 71,72, , although it is unclear whether this applies to all such mutations or only those with higher FLT3 allelic burden.
Other mutations RUNX1 and AXSL1 mutations, each occurring in 10-15% of AML patients, have each been associated with adverse prognosis, particularly when occurring in intermediate risk disease, and these patients appear to benefit from transplant in CR1 [73][74][75][76] . Similarly, TP53 and splicing factor mutations (e.g. SRSF2) have also been associated with independently adverse prognosis 77 . RUNX1, ASXL1 and TP53 mutated disease have been assigned to the adverse risk group in the 2017 ELN classification, except when they occur in otherwise ELN favourable risk disease 30 . Therefore, this mutational information can be helpful in risk stratification. With respect to other mutations (e.g. DNMT3A, IDH, TET2) the data regarding prognosis are less clear.
# Germline mutations
It is now recognized that patients with certain inherited mutations carry a higher risk of developing AML and other myeloid neoplasms; some of these can be detected in standard myeloid panels. These include RUNX1, GATA2 and CEBPA 78 . Detection of one of these mutations in a younger patient should prompt germline mutation testing, using non-hematopoietic tissues such as buccal swabs or cultured fibroblasts.
If a germline mutation is detected, any potential sibling donor should be tested, as this would present a theoretical risk of the donor marrow developing leukemia. TP53 mutations (as seen in Li-Fraumeni syndrome) predispose patients to the early development of a number of solid tumour malignancies; these patients are also at higher risk of developing AML or MDS with exposure to chemotherapy or radiation 78 . Therefore, detection of a TP53 mutation in patients with such a history should also prompt consideration of germline mutation testing. 80 The true prevalence of myeloid neoplasms with germline predisposition is uncertain, based largely on a lack of available population data; the WHO nevertheless describes these as relatively rare 80 . Despite the likely low prevalence of predisposing mutations in the general population, recent next-generation sequencing data suggest that germline mutations may be found in as many as 8.4-11.6% of AMLs and 12.9% of MPNs 81 , which would equate to one in every 5-10 patients with a new diagnosis. There is vast variation in germline mutation prevalence by subgroup, however; Down syndrome associated AML, for example, accounts for up to 14% of pediatric cases of AML 82 , whereas DDX41 germline mutations are observed in an estimated 1.4% 83 . There are also notable differences in malignancy penetrance by germline event: the relative risk of development of a myeloid malignancy in patients with germline CEBPA mutations is estimated to be near complete, for example, whereas the risk of AML in patients with Dyskeratosis Congenita is far lower 80,84 . Finally, variable age of onset of disease may be seen across the entities: patients with bone marrow failure syndromes may develop malignancies in early adulthood, whereas the mean age of onset of disease in patients with germline DDX41 mutations is the seventh decade 80 .
Population-based screening for germline mutations associated with increased risk of myeloid malignancies is not currently feasible, however advanced molecular testing might be considered in certain settings. Clinical suspicion for a myeloid neoplasm with germline predisposition may arise by way of specific clinical features: Personal history of multiple cancers Thrombocytopenia, bleeding propensity or macrocytosis preceding the diagnosis of a myeloid neoplasm by several years A first or second degree relative with a hematological neoplasm A first or second degree relative with a solid tumor suggestive of germline predisposition (e.g. early-onset breast cancer) Physical exam features compatible with an inherited condition Failure of a potential stem cell donor to mobilize using standard protocols Modified from 80,85 The possibility of germline predisposition might also arise in cases of myeloid neoplasia with specific mutational profiles, and some genetic changes cannot be discerned reliably as somatic or germline without confirmatory germline testing 86 . Variants in some genes established as germline predisposing factors may be acquired in the somatic context 86 . In the absence of tumor-normal paired testing (which is typical in hematologic neoplasms), germline variants tend to demonstrate heterozygous range variant burdens that remain fixed over time (and despite changes in tumor burden), tend not to be of high frequency in somatic mutation databases (with the potential for emphasis in germline variant databases), and tend to have specific functional implications 86 . Guidelines published by the American College of Medical Geneticists may be employed to assist in the assessment of a putative germline variant 87 .
Patients considered high risk, either by clinical assessment or tumor-only variant profiling, should have confirmatory testing. In Alberta, comprehensive testing for myeloid neoplasms with germline predisposition is largely unavailable, and therefore the approach to confirmatory testing is mainly dictated by the putative gene or condition under consideration. If a patient is presenting with a possible bone marrow failure syndrome or aplastic anemia, recommended testing approaches are elaborated in a separate CKCM document (https://extranet.ahsnet.ca/teams/policydocuments/1/klink/et-klink-ckv-aplasticanemia-adult-cancer-inpatient.pdf ). These conditions require chromosomal breakage or telomere length studies (the latter performed in British Columbia). Confirmatory testing by next-generation sequencing for possible Fanconi Anemia is available through AHS Genetics & Genomics, however the common genetic variants associated with Dyskeratosis Congenita are not available as part of the AHS Genetics & Genomics comprehensive germline testing panel. Similarly, this panel can provide testing for CEBPA, GATA2 and RUNX1, however the panel does not include test features for DDX41, ANKRD26, or ETV6. Testing using the AHS Genetics & Genomics comprehensive germline testing panel requires a specific requisition (https://www.albertahealthservices.ca/frm-20897.pdf ). Send out testing to address the above genes not interrogable in Alberta must be organized through AHS Genetics & Genomics (https://www.albertahealthservices.ca/frm-18176.pdf ); the University of Chicago offers a comprehensive familial myelodysplastic syndrome/acute leukemia panel (https://dnatesting.uchicago.edu/tests/comprehensive-familial-myelodysplastic-syndromeacute-leukemiapanel )
Patients with an established familial germline predisposition syndrome should not be worked-up using comprehensive panels. Instead, testing tailored to the specific variant of interest should be organized through AHS Genetics & Genomics.
Determining if a genetic abnormality is germline or if a predisposing condition exits is important for genetic counselling with respects to other family members. It becomes particularly important if a hematopoietic stem cell transplant is being considered and donors are being sought within the family. In some rare instances such as Faconi anemia and Li Fraumeni syndrome (germline TP53 mutation) conditioning for the transplant would need to be altered to avoid excessive toxicity.
# Minimal (measurable) residual disease
Early response to therapy is one of the most important prognostic factors in acute leukemia. Evaluation of minimal or measurable residual disease (MRD) is critical to identify patients at elevated risk of relapse which influences clinical decision-making. The leukemia associated immunophenotype (LAIP) of each patient should be established at diagnosis by multiparameter flow cytometry (MPFC), particularly if there is not a molecular abnormality to follow. Analysis of MRD by a properly validated technique performed locally is then recommended to be followed regularly by bone marrow aspirate until negative or the patient proceeds to transplantation.
A study in de novo (n=126) AML evaluated the utility of MRD in predicting relapse. Patients were segregated by their detectable levels of cells with LAIP at the remission determination bone marrow. The patients were split into very low risk (n=8), defined as having fewer than 10 -4 LAP cells per sample, low risk (n=37), defined as having 10 -4 to 10 -3 LAP cells per sample, intermediate risk (n=64), defined as having fewer than 10 -3 to 10 -2 LAP cells per sample, and high risk (n=17), defined as having greater than 10 -2 LAP cells per sample. No patients from the very low risk category relapsed during the time observed, whereas 14%, 50% and 84% of patients in the low, intermediate and high-risk group relapsed after 3 years, respectively (p=0.0001). Additionally, there were significant differences in overall survival (OS) between groups, with 100%, 90%, 62% and 29% rates after 3 years of follow-up (p= 0.003) 88 .
Another study, by Perea and colleagues, evaluated the prognostic value of MRD amongst AML patients with favorable cytogenetics (t(8;21) and inv( 16)) (n=55). MRD was evaluated by tandem RT-PCR (reverse transcription polymerase chain reaction) and flow cytometry. The group found that the mean amount of MRD detected by flow cytometry at the end of treatment in relapsed vs non-relapsed patients was significantly different (0.3% vs 0.08%, respectively; p=0.002) 89 .
In a prospective, blinded study of pediatric patients (n=252) with de novo AML employing a multivariate analysis controlling for allogeneic marrow transplantation, age, sex, white blood count at diagnosis, presence of splenomegaly or hepatomegaly, and presence of more than 15% blasts in the marrow after the first course of induction (by flow cytometry), showed that patients with MRD, defined as ≥0.5% blasts, after one induction and one consolidation were 4.8-fold more likely to relapse (p<0.001) and 3.1-fold more likely to die (p< 0.001) when compared to MRD-negative patients 90 .
A large multi-center prospective study (n=471) was designed to determine cut-off points for MRD in determining relapse rates. MRD was tested after induction cycle 1, cycle 2, and consolidation treatment in age <60 years patients with AML (Dutch-Belgian HOVON-SAKK study) 91 . The study demonstrated that in patients with MRD (reported as % LAIP-positive cells) of >0.1% after induction cycle 1 and after two cycles of chemotherapy, there was a significant increases in relapse rates compared to those with lower or undetectable MRD levels. On multivariate analysis, MRD positivity after cycle 2 remained an independent prognostic factor for relapse 91 .
Another prospective study (n=892) reporting findings from the United Kingdom National Cancer Research Institute AML 16 Trial evaluated the prognostic utility of MRD in elderly patients. MRD negativity amongst patients who achieved CR, was reported in 51% (n=286) of patients after first treatment, and 64% (n= 279) of patients after the second treatment, which was associated with a significantly better 3-year survival (p < 0.001 for both) and a significantly lower relapse rate (p< 0.001 for both) when compared to MRD-positive patients. Higher risk of early relapse was also reported amongst MRD-positive patients (median time to relapse 17.1 vs 8.5 months in MRD-negative patients) 92 .
A retrospective study sought to investigate the prognostic utility of MRD in pre-hematopoietic cell transplant (HCT) patients. The study consecutively enrolled patients (n=99) receiving myeloablative HCT for AML in first morphologic remission. MRD was defined as any detectable level of residual disease. Two-year overall survival was 30.2% amongst MRD-positive patients versus 76.6% in MRD-negative patients and two-year relapse rates were 64.9% amongst MRD-positive patients versus 17.6% in MRDnegative patients. After adjustment for all or a subset of cytogenetic risk, secondary disease, incomplete blood count recovery, and abnormal karyotype pre-HCT, MRD-positive HCT was associated with increased overall mortality (HR 4.05, 95% CI: 1.90 to 8.62; p <0.001) and relapse (HR 8.49, 95% CI 3.67 to 19.65; p <0.001) when compared to MRD-negative HCT 93 . A subsequent report confirmed the poor prognosis and high relapse rate of patients with MRD detectable disease by MPFC just prior to transplant 160 .
Molecular studies by quantitative RT-PCR can also be used for detection of MRD, with a sensitivity of 1 in 10 -4 cells. The value of RT-PCR in core binding factor AML has already been discussed. NPM1 mutations can also be monitored by this technique 94,95 . A study by the UK NRCI found that persistence of detectable NPM1 transcripts after the second cycle of chemotherapy was associated with a higher risk of relapse (82% vs. 30%; hazard ratio, 4.80, P<0.001) and a lower OS (24% vs. 75%; hazard ratio for death, 4.38, P<0.001). This effect was seen even in patients with a co-existing FLT3-ITD mutation 73 . ELN guidelines have now been published 96 , recommending that CRMRD be included as a response designation. These guidelines also recommend that qRT-PCR be available for assessment of response for PML-RARA, RUNX1-RUNX1T1, CBFB-MYH11, and NPM1. For other AML patients, MRD assessment by multiparameter flow cytometry (MPFC) is recommended. Patients that fail to achieve a 3-log reduction in RUNX1-RUNX1T1 or CBFB-MYH11 transcripts, have detectable NPM1 transcripts or have > 0.1% detectable disease by MPFC, following the second cycle of intensive chemotherapy (e.g. one induction and one consolidation) have high relapse rates. In these cases, consideration should be made to altering therapy. It was also recommended that serial monitoring by qRT-PCR be considered for those patients with RUNX1-RUNX1T1, CBFB-MYH11 or NPM1 who are not proceeding to transplant. Not all of these tests are currently routinely available or uniformly reported in Alberta; our goal is to work toward implementing standardized MRD testing, based on these guidelines.
A recent study found that mutational profiling by NGS can also be used for MRD detection postchemotherapy, and can be predictive of relapse 97 , however, this is not currently recommended for MRD assessment outside of clinical trials. Defined by the presence of one single monosomy (excluding loss of X or Y) in association with at least one additional monosomy or structural chromosome abnormality (excluding core-binding factor AML). g. These markers should not be used as an adverse prognostic marker if they co-occur with favorable-risk AML subtypes. h. TP53 mutations are significantly associated with AML with complex and monosomal karyotype.
# Risk Groups as per Cytogenetic and Molecular Status
Treatment 29,98,99 The initial goal of therapy for AML is to achieve a complete remission, given that a complete remission with currently available therapy is requisite, although not sufficient for a cure. It is the sole outcome currently associated with improved survival. Chemotherapy is the mainstay of treatment. Poor performance status and comorbid medical conditions, in addition to age, are factors which influence the ability of an individual to tolerate induction therapy.
In patients undergoing intensive chemotherapy a central venous catheter ideally should be placed.
Supportive care in all patients includes red blood cell transfusions for symptomatic anemia. Platelets should be transfused at a threshold of 10 x 10 9 /L if there is no evidence of bleeding or to keep a platelet level of around 50 x 10 9 /L if there is active bleeding.
Tumor lysis prophylaxis with allopurinol should be initiated in all patients. Monitoring for electrolyte abnormalities and renal function should be ongoing during the first few days of induction chemotherapy particularly in patients with significantly elevated white blood cell count. Rasburicase should be considered in those at high risk of significant tumor lysis.
Antifungal prophylaxis should be considered during all phases of chemotherapy depending on local incidence of invasive fungal infections 29,98 . In a large randomized trial in AML patients receiving induction and post-remission chemotherapy, posaconazole prophylaxis was associated with a lower incidence of invasive Aspergillosis and lower mortality compared with fluconazole or itraconazole 100 . Therapy of febrile neutropenia should include empiric broad spectrum antibiotics according to IDSA guidelines 101 .
The use of growth factor support should be individualized and should be considered in those with documented life-threatening infections. Recent use of G-CSF can increase the blast count in a bone marrow specimen obtained to determine remission status, however immunophentoyping may be useful in this situation if the leukemic cells are known to have an abnormal phenotype. Pegylated growth factors have not been studied in this setting.
Steroid eye drops are recommended during the administration of intermediate to high dose cytarabine to prevent conjunctivitis. These patients should also be screened for cerebellar toxicities before each dose of cytarabine.
Sperm preservation should be discussed with male patients and a serum pregnancy test should be performed in female patients. Women should be given their options regarding fertility preservation.
Rare patients who present with extramedullary disease should be treated with systemic therapy. Local therapy (surgery/radiotherapy may be useful for residual disease).
# Transplant Eligible Patients:
# Induction
Chemotherapy should consist of standard-dose cytarabine with an anthracycline, so called 7&3 chemotherapy (see appendix A for regimens). Studies looking at higher doses of cytarabine in induction have not shown an increased CR rate but have demonstrated an increased treatment related mortality [103][104][105] . At count recovery or about day 28-35 from the start of chemotherapy a bone marrow aspirate should be done to determine remission status. The likelihood of establishing a CR with one cycle of induction chemotherapy varies amongst prognostic groups but overall is in the order of 60-70%. Consider repeating cytogenetic analysis if initially abnormal as part of the remission documentation 29 .Other regimens such as FLAG (fludarabine + high-dose cytarabine + G-CSF) or NOVE (mitoxantrone + etoposide) may need to be considered in the case of significant left ventricular dysfunction.
# Re-induction
If CR is not achieved after one cycle of induction chemotherapy another attempt is appropriate. This may consistent of a repeat of 7&3 chemotherapy or alternatively a different regimen such as NOVE, NOVE-HiDAC 80 , FLAG-Ida (FLAG + idarubicin), or high dose cytarabine (HiDAC) (see appendix A for regimens) may be tried. A bone marrow aspirate and biopsy should be done at count recovery or day 30-35 to document remission status. The likelihood of a second regimen being successful is in the order of 50%. If no remission is achieved after 2 cycles of induction chemotherapy palliation may become the goal of care.
# Consolidation
If CR has been achieved further therapy is necessary for potential cure. The nature of consolidation therapy must be individualized for each patient based on a risk analysis of the risk of relapse of the AML versus the risk of the proposed consolidation therapy. This will depend on prognostic features of the leukemia, response to therapy, performance status and type of hematopoietic stem cell donor available. HiDAC is the mainstay of consolidation chemotherapy as there has been shown to be a dose intensity effect to cytarabine suggesting that HiDAC is beneficial in induction or consolidation 103,104 . Generally at least one cycle is administered in all patients if only to allow for planning of an allogeneic stem cell transplant although the absolute need for this is controversial.
Good risk patients: In patients with AML with t(8;21) or inv 16, data suggests that provided there are no additional risk factors multiple cycles of HiDAC provide higher overall survival than lower doses of cytarabine or stem cell transplant [106][107][108][109] .Our recommendation is 3-4 cycles of HiDAC post induction chemotherapy. A recent retrospective study from Edmonton and Vancouver found similar outcomes with 2 cycles of consolidation compared with 3 110 , but this requires confirmation in a prospective study.
There is also evidence that the addition of gemtuzumab ozogamicin (GO) may produce better outcomes when combined with chemotherapy 111 ; however, this agent is not yet approved in Canada.
Intermediate risk patients: HiDAC has been shown to be preferable over lower dose cytarabine in this cytogenetic group as well 26,107 but its superiority over stem cell transplantation has not been established. It is generally recognized that an allogeneic stem cell transplant provides a decreased relapse rate at a cost of increased treatment related mortality when compared to consolidation chemotherapy or autologous transplantation 109,[112][113][114] . The transplant related mortality gap between matched related and unrelated donors has been shown to be significantly reduced in recent years 115,116 . A suitable hematopoietic stem cell donor should be sought. If a matched sibling donor is found a related myeloablative stem cell transplant should proceed as soon as possible, ideally after one dose of HiDAC. If there are no suitable family donors, the patient should proceed through 3-4 cycles of HiDAC consolidation while a match unrelated donor is sought. If one is found before the third cycle of consolidation chemotherapy, consider matched unrelated donor stem cell transplantation.
High risk patients: All efforts should be undertaken to find a matched donor, related or unrelated for eligible patients. During that time the patient should receive ongoing cycles of HiDAC chemotherapy up to a total of 4 cycles. The patient should proceed to allogeneic stem cell transplantation as soon as a donor is identified. If no fully matched donor is available consideration should be given to a haploidentical related transplant if a suitable donor is available. Finally, unrelated cord blood transplantation is also an option in selected situations.
# FLT3 Mutation Positive Patients:
If not enrolled on a clinical trial with a FLT3 inhibitor, midostaurin should be added for these patients on day 8 of each induction and consolidation treatment cycle, as per the RATIFY clinical trial protocol (midostaurin and standard induction/consolidation chemotherapy). The Phase III RATIFY (CALGB 10603) trial randomized 717 AML patients with FLT3 mutation to receive standard induction and consolidation chemotherapy +/-midostaurin. After a median follow-up of 57 months, patients in the midostaurin arm had a significant improvement in median overall survival vs. placebo (74.7 months vs. 26 months, respectively; p=0.007), representing a 23% reduction in the risk for death 49 . It has now been approved by Health Canada for this indication.
# Relapse:
Re-induction: An attempt at achieving a second CR should be attempted. If the remission was greater than one year 7&3 chemotherapy can be used again. Otherwise other regimens such as FLAG-Ida, NOVE, NOVE-HiDAC, or HiDAC are appropriate. Participation in a clinical trial is encouraged.
Hematopoietic stem cell transplantation: If a stem cell transplant was not done in first CR it should be undertaken once a second CR has been achieved. The ideal donor would be an allogeneic matched related or unrelated donor, or if necessary a related haploidentical donor or cord blood unit.
# Palliation
If comorbid conditions affect the ability to proceed with optimal aggressive therapy, treatment with either low-dose cytarabine (LDAC) or azacitidine (VIDAZA®) is recommended as these have been shown to increase overall survival compared to supportive care alone 117,118 . Azacitidine is recommended for patients with 20-30% marrow blasts with dysplasia and for patients with adverse risk cytogenetics, based on two Phase III randomized trials 119,120 . For patients with >30% blasts and intermediate risk cytogenetics, LDAC and azacitidine have similar survivals 121 ; LDAC has the advantage of lower cost and the potential for athome administration.
The recommended dose of azacitidine is 75 mg/m 2 /day subcutaneously for 7 days, every 28 days, for at least six cycles 122 . This is also an appropriate approach in the setting of primary induction failure not eligible for further intensive therapy, or relapse, particularly after allogeneic stem cell transplantation. It may also be considered in patients in CR after induction where aggressive chemotherapy for consolidation is no longer indicated. The most commonly used dosing for LDAC is 20 mg subcutaneously twice daily for 10 days 117 , repeated every 4-5 weeks; 40 mg once daily may be used for home care administration. At least 4 cycles should be used, unless there is clear evidence of progression earlier. In patients not responding to LDAC, azacitidine may be utilized; however, LDAC does not appear to be effective in azacitidine failures.
For patients not able or willing to receive these treatments, or not responding to these, supportive care alone is appropriate, with hydroxyurea to control circulating blast counts.
Transplant Ineligible Patients: In patients with a normal karyotype, the remission rate on older patients is 50-60% with cytarabine combined with idarubicin, daunorubicin or mitoxantrone. In those with adverse risk cytogenetics the chance of achieving a remission is approximately 25%, with median OS of approximately 6 months 25,26,123 . Attempts to modify this by adjusting the chemotherapy regimens, adding growth factors or multidrug resistance protein regulators have not been successful 17,[124][125][126] . Due to the poor outcomes in this group, clinical trials are particularly important. However, if none are available, azacitidine would be appropriate therapy in older patients with high-risk cytogenetics who are not considered candidates for allogeneic HSCT. In other elderly non-fit patients, low-dose cytarabine would also be appropriate
# Induction
In patients with an ECOG performance status of 2 or less and no prohibitive comorbid conditions, standard 7&3 induction chemotherapy is appropriate 127 , particularly in patients with core-binding factor leukemias. If consideration is being given to consolidation therapy or re-induction in the case of primary induction failure, a bone marrow aspirate should be performed to document remission. If no further therapy is planned this can be omitted.
# Consolidation
Consolidation chemotherapy in this group of patients is controversial. There is evidence to suggest that low-dose, prolonged ambulatory treatment should be preferred to intensive chemotherapy 123 ; however intermediate dose cytarabine can be considered if the patient maintains a good performance status, normal renal function, and has a good or normal karyotype. Consolidation has not been shown to prolong survival in patients with high risk karyotypes. There is limited retrospective data which suggests azacitidine may be appropriate in this setting, although prior cytotoxic therapy was associated with a decreased marrow response rate, azacitidine treatment still prolonged overall survival 128 . LDAC may also be considered in patients in CR who are not suitable candidates for further intensive chemotherapy.
# Relapse
In this age group, if acute leukemia recurs palliation with best supportive care or azacitidine is indicated if there are no available clinical trials.
# Mixed-Phenotype Acute Leukemia:
Mixed-phenotype acute leukemia (MPAL) is rare, accounting for less than 5% of acute leukemia cases 7 . Treatment approaches to MPAL vary, as there is no standard therapy for patients. Typical, treatment may include AML-type induction therapy, ALL-type induction therapy, or a hybrid combination of AML/ALL-type induction regimen 129 . An early allogeneic hematopoietic cell transplant should be considered for these patients. It should be noted that data regarding the treatment of MPAL is largely retrospective in nature, with limited studies available for review.
One international retrospective study of 100 children and adults with MPAL defined by the 2008 WHO classification reported a 5-year survival rate of 37% (median survival 1.5 years) 130 . Treatment was selected by the managing physician and information regarding the treatment choice by age group was not presented. Age >15, Philadelphia chromosome positive leukemia, and AML-type induction treatment approaches were associated with significantly reduced median survival. Data from this study is summarized below. [132][133][134] , however, it remains unclear whether all of these risk factors still apply to patients treated with modern induction regimens.
Symptoms of increased intracranial pressure, cranial nerve palsies, symptoms of CNS hemorrhage, symptoms of spinal cord compression and/or visual changes indicate potential CNS involvement. Mass lesions are uncommon, although reported at a higher frequency in inv( 16) patients 132 . Diagnosis of CNS leukemia is typically confirmed by the identification of leukemic blasts on cytocentrifuge preparations of cerebrospinal fluid after lumber puncture.
No prospective studies comparing intrathecal chemotherapy, systemic chemotherapy and/or cranial radiation have been reported to guide treatment in patients with CNS leukemia. Intrathecal chemotherapy with methotrexate (12 to 15 mg/dose) or cytarabine (50-70 mg/dose) is a common approach. Systemic high dose methotrexate or cytarabine in combination with diaziquone has been shown to achieve clearance of the CNS tumour load 135 , however, even after successful therapy, treatment in this setting is associated with high relapse rates 136 . Patients with cranial nerve involvement or a tumour mass that impinges on important structures may require initial radiation therapy (18 to 25 Gy for the brain) followed by intrathecal chemotherapy 136,137 .
In patients with neurological symptoms imaging should be done to rule out a mass or bleed. If neither of these is present a lumbar puncture should be done and sent for morphology as well as flow cytometry. If this is negative for leukemic cells initially it should be repeated if the symptoms persist. If it is positive, as per the diagnostic criteria in section 3, intrathecal chemotherapy should be administered twice a week concurrently with induction chemotherapy until the cerebrospinal fluid is no longer positive by morphology and flow cytometry. An additional 2 intrathecal treatments should then be administered. Intrathecal chemotherapy should consist of alternating single agent cytarabine and methotrexate or "triple therapy" with cytarabine, methotrexate and hydrocortisone.
In patients with myelomonocytic or monocytic leukemia as well as those with a presenting blast count of greater than 40 x10 9 /L consider a screening lumbar puncture at diagnosis with intrathecal chemotherapy administered at the same time. If the cerebrospinal fluid is positive for leukemic cells the patient should be treated as above.
# Follow Up
Once all therapy is completed no further bone marrow aspirates are indicated unless there is concern of relapse or loss of graft in transplanted patients. Regular complete blood counts should be performed every month for the first few years then every 3 months until 5 years. The risk of recurrence after 5 years is very low and hematological follow up can be stopped at that point. Patients should be reminded of the signs and symptoms of leukemia including those of anemia, thrombocytopenia and infection and instructed to seek medical attention at any point if these develop. If there is concern of a relapse at any point, a bone marrow aspirate and biopsy should be performed and the patient should be sent for all the appropriate diagnostic tests.
# New Therapies
Gemtuzumab ozogamicin (GO) the anti-CD33 antibody carrying a toxic calicheamicin-γ1 derivative, which after intracellular hydrolytic release, induces DNA strand breaks, apoptosis, and cell death was the first anti-cancer immunoconjugate to obtain regulatory approval in the United States. It was subsequently withdrawn from the US by Pfizer after results from the S0106 trial demonstrated no overall survival benefit, while reporting an increased rate of early mortality in the GO arm of patients 18-60 years old with de novo AML receiving 2 cycles of induction chemotherapy with daunorubicin/cytarabine with or without GO (6 mg/m 2 ) 105 . However, emerging data from other well controlled studies did report benefits from the addition of GO to chemotherapy, particularly when used in smaller fractionated doses [138][139][140][141] . A recent metanalysis of 5 randomized trials found an overall survival benefit for GO when added to intensive chemotherapy, most strikingly seen in patients with favourable risk cytogenetics, while those with adverse risk karyotypes did not benefit 111 . In September 2017 GO was approved by the FDA for this indication. It is currently under review by Health Canada (February 2019) and available via compassionate access.
CPX-351 (Vyxeos R ) is a nanoparticle formulation containing a fixed molar ratio of daunorubicin and cytarabine. A phase III randomized trial in previously untreated AML patients with secondary AML age 60-75 found that this agent was superior to standard 3+7 induction therapy 142 , while no benefit was seen in another study in de novo 143 . It has now been FDA approved for the treatment of secondary AML as of August 2017; approval in Canada is pending however it is available on a compassionate basis.
The development of more potent second generation FLT3 inhibitors remains an area of active investigation. The second-generation inhibitors (quizartinib, gilteritinib, crenolanib) have produced CR rates in the 40% range as single agents in relapsed AML 144,145 , but remain investigational. These agents are being actively investigated in combination with chemotherapy, both in the frontline and relapsed setting. Gilteritinib is now available by compassionate access.
Approximately 15-20% of AML patients have IDH1 or IDH2 mutations, which result in aberrant production of an oncoprotein, 5HG, which induces a block in cell differentiation. Enasidenib (AG221) is a selective oral IDH2 inhibitor that inhibits 5HG production and restores normal cell differentiation. Treatment with this agent in relapsed/refractory AML patients with IDH2 mutations has produced CR in approximately 30% of cases; responses may take up to 6 months to be seen 146 . This agent has now been approved by the FDA and Health Canada for this indication but not yet publically funded. It is available on a compassionate basis. Ivosidenib is a selective IDH1 inhibitor which has shown activity in IDH1 mutated disease in early clinical trials 147 .
Another promising agent is venetoclax, a selective oral small molecule BCL-2 inhibitor. Although it has limited activity as a single agent, it has been found to synergize with chemotherapy agents in preclinical models. In a study by Wei et al, venetoclax 600 mg daily was given in combination with low dose cytarabine to patients with newly diagnosed AML not eligible to receive intensive induction chemotherapy 148 . Of the 82 patients evaluable, 44 (54%) achieved CR or CR with incomplete count recovery (CRi), demonstrating that this is an active combination in patients with newly diagnosed AML. Venetoclax in combination with azacitdiine or decitabine was evaluated in older patients with AML unfit to receive intensive chemotherapy. Of the 145 patients enrolled, 67%of patients achieved CR/CRi. The median duration of response was 11.3 months 149 .
These regimens are now under evaluation in Phase III randomized clinical trials. Phase I studies are also ongoing adding it to intensive remission inducing chemotherapy. It has been approved by the FDA in patients over the age of 75 with de novo AML in combination with low dose cytarabine or hypomethylating agents as of November 2018.
Many other novel agents are currently in clinical trials in AML, including agents that target MDM2 (inhibition of which results in upregulation of p53, inducing apoptosis) 150 , DOT1L (associated with MLL overexpression/rearrangements) 151 , Polo-like kinase-1 152,153 , and CXCR4 152,153 . A number of novel immunocongugates are also in clinical trials, targeting antigens expressed on AML stem cells such as CD123 and CLL1. CAR-T (chimeric antigen receptor) cell therapy is a novel form of immunotherapy which has produced remissions in many patients with chemotherapy-refractory ALL and lymphoma; early trials in AML are in progress.
# MAINTENANCE
A formal review will be conducted in 2019, however if new evidence is brought forward before that time, the guideline will be changed accordingly.
# GLOSSARY OF ABBREVIATIONS
Acronym | None | None |
56e343908e89a9d8a3425310485e59ce55364de2 | cma | None | This update of the 2010 International Consensus Recommendations on the Management of Patients With Nonvariceal Upper Gastrointestinal Bleeding (UGIB) refines previous important statements and presents new clinically relevant recommendations. Methods: An international multidisciplinary group of experts developed the recommendations. Data sources included evidence summarized in previous recommendations, as well as systematic reviews and trials identified from a series of literature searches of several electronic bibliographic databases from inception to April 2018. Using an iterative process, group members formulated key questions. Two methodologists prepared evidence profiles and assessed quality (certainty) of evidence relevant to the key questions according to the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. Group members reviewed the evidence profiles and, using a consensus process, voted on recommendations and determined the strength of recommendations as strong or conditional. Recommendations: Preendoscopic management: The group suggests using a Glasgow Blatchford score of 1 or less to identify patients at very low risk for rebleeding, who may not require hospitalization. In patients without cardiovascular disease, the suggested hemoglobin threshold for blood transfusion is less than 80 g/L, with a higher threshold for those with cardiovascular disease. Endoscopic management: The group suggests that patients with acute UGIB undergo endoscopy within 24 hours of presentation. Thermocoagulation and sclerosant injection are recommended, and clips are suggested, for endoscopic therapy in patients with high-risk stigmata. Use of TC-325 (hemostatic powder) was suggested as temporizing therapy, but not as sole treatment, in patients with actively bleeding ulcers. Pharmacologic management: The group recommends that patients with bleeding ulcers with high-risk stigmata who have had successful endoscopic therapy receive high-dose proton-pump inhibitor (PPI) therapy (intravenous loading dose followed by continuous infusion) for 3 days. For these high-risk patients, continued oral PPI therapy is suggested twice daily through 14 days, then once daily for a total duration that depends on the nature of the bleeding lesion. Secondary prophylaxis: The group suggests PPI therapy for patients with previous ulcer bleeding who require antiplatelet or anticoagulant therapy for cardiovascular prophylaxis.#
meeting included up to 20 voting participants for each statement (numbers varied, mainly because of travel difficulties), 2 nonvoting GRADE methodologists, and a nonvoting moderator (J.K.M).
The cochairs, other steering committee members, and methodologists generated a list of new and old statements that were presented to the group through an anonymous, Web-based consensus platform (ECD Solutions). Via teleconference, the steering committee members reached consensus on which statements warranted inclusion in the guideline by focusing on priority areas. Using a modified Delphi process (14), all voting participants modified and finalized the new statements. After reviewing the evidence profiles, the participants anonymously voted on their degree of agreement or disagreement with each statement and submitted comments. Votes were nonbinding and designed to gauge the extent of agreement and the pattern of evidence uncertainty to guide the allotment of time for discussion during the meeting. The Canadian Association of Gastroenterology (CAG) office tabulated the votes and comments and presented the results to the group. Although initially discussed in the form of declarative statements, these were edited into specific PICO questions by the methodologists before the consensus meeting.
At a 2-day consensus meeting in May 2018, the group applied the GRADE Evidence to Decision framework to move from evidence to recommendations by assessing 7 key criteria: the balance between desirable and undesirable effects, quality (certainty) of the evidence, variability in patients' values and preferences, resource requirements, cost-effectiveness, acceptability, and feasibility (Supplement Appendix 2) (15)(16)(17). Participants voted on the direction of the PICO question (for or against) as yes, uncertain, or no. Consensus for or against a specific strategy was reached if at least 75% of the participants voted yes or no, respectively. For PICO questions on which agreement was reached, the group then discussed the strength of the recommendation (strong vs. conditional) by considering the factors in the Evidence to Decision framework (18). In cases of low or very low QoE, unless at least 1 of the other 3 factors was overwhelmingly strong, the strength of the recommendation would default (without a vote) to "conditional" by using the phrase "we suggest." If the statement warranted a vote and at least 75% of the participants voted "strong," then the recommendation would be designated as strong with the phrase "we recommend."
Consensus was not reached on 4 PICO questions (no recommendation A to D), because fewer than 75% of the participants voted either yes or no. No corresponding statements were developed for these questions, but the pertinent evidence and discussions are summarized briefly in the text.
# Oversight and Review
The guideline process was overseen by the CAG clinical affairs committee to ensure methodological quality and a transparent, nonbiased, evidence-based
# CLINICAL GUIDELINE
Management of Upper Gastrointestinal Bleeding decision-making process. Recommendations are based on evidence from the literature and consensus discussion and may not fully reflect the product labeling for a given country.
The manuscript was initially drafted by the cochairs (A.N.B. and M.B.) and the GRADE experts (F.T. and G.I.L.). It was reviewed and revised by the steering committee members (E.J.K., J.S., L.L., and M.A.) before dissemination to the full consensus group for feedback. Finally, the manuscript was posted on the CAG Web site, and members were invited via e-mail to submit comments over a 2-week period.
In accordance with CAG policy, written conflict-ofinterest disclosures for the 24 months preceding the consensus meeting were provided by all participants and made available to the group.
# Role of the Funding Source | This update of the 2010 International Consensus Recommendations on the Management of Patients With Nonvariceal Upper Gastrointestinal Bleeding (UGIB) refines previous important statements and presents new clinically relevant recommendations. Methods: An international multidisciplinary group of experts developed the recommendations. Data sources included evidence summarized in previous recommendations, as well as systematic reviews and trials identified from a series of literature searches of several electronic bibliographic databases from inception to April 2018. Using an iterative process, group members formulated key questions. Two methodologists prepared evidence profiles and assessed quality (certainty) of evidence relevant to the key questions according to the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. Group members reviewed the evidence profiles and, using a consensus process, voted on recommendations and determined the strength of recommendations as strong or conditional. Recommendations: Preendoscopic management: The group suggests using a Glasgow Blatchford score of 1 or less to identify patients at very low risk for rebleeding, who may not require hospitalization. In patients without cardiovascular disease, the suggested hemoglobin threshold for blood transfusion is less than 80 g/L, with a higher threshold for those with cardiovascular disease. Endoscopic management: The group suggests that patients with acute UGIB undergo endoscopy within 24 hours of presentation. Thermocoagulation and sclerosant injection are recommended, and clips are suggested, for endoscopic therapy in patients with high-risk stigmata. Use of TC-325 (hemostatic powder) was suggested as temporizing therapy, but not as sole treatment, in patients with actively bleeding ulcers. Pharmacologic management: The group recommends that patients with bleeding ulcers with high-risk stigmata who have had successful endoscopic therapy receive high-dose proton-pump inhibitor (PPI) therapy (intravenous loading dose followed by continuous infusion) for 3 days. For these high-risk patients, continued oral PPI therapy is suggested twice daily through 14 days, then once daily for a total duration that depends on the nature of the bleeding lesion. Secondary prophylaxis: The group suggests PPI therapy for patients with previous ulcer bleeding who require antiplatelet or anticoagulant therapy for cardiovascular prophylaxis.#
meeting included up to 20 voting participants for each statement (numbers varied, mainly because of travel difficulties), 2 nonvoting GRADE methodologists, and a nonvoting moderator (J.K.M).
The cochairs, other steering committee members, and methodologists generated a list of new and old statements that were presented to the group through an anonymous, Web-based consensus platform (ECD Solutions). Via teleconference, the steering committee members reached consensus on which statements warranted inclusion in the guideline by focusing on priority areas. Using a modified Delphi process (14), all voting participants modified and finalized the new statements. After reviewing the evidence profiles, the participants anonymously voted on their degree of agreement or disagreement with each statement and submitted comments. Votes were nonbinding and designed to gauge the extent of agreement and the pattern of evidence uncertainty to guide the allotment of time for discussion during the meeting. The Canadian Association of Gastroenterology (CAG) office tabulated the votes and comments and presented the results to the group. Although initially discussed in the form of declarative statements, these were edited into specific PICO questions by the methodologists before the consensus meeting.
At a 2-day consensus meeting in May 2018, the group applied the GRADE Evidence to Decision framework to move from evidence to recommendations by assessing 7 key criteria: the balance between desirable and undesirable effects, quality (certainty) of the evidence, variability in patients' values and preferences, resource requirements, cost-effectiveness, acceptability, and feasibility (Supplement Appendix 2) (15)(16)(17). Participants voted on the direction of the PICO question (for or against) as yes, uncertain, or no. Consensus for or against a specific strategy was reached if at least 75% of the participants voted yes or no, respectively. For PICO questions on which agreement was reached, the group then discussed the strength of the recommendation (strong vs. conditional) by considering the factors in the Evidence to Decision framework (18). In cases of low or very low QoE, unless at least 1 of the other 3 factors was overwhelmingly strong, the strength of the recommendation would default (without a vote) to "conditional" by using the phrase "we suggest." If the statement warranted a vote and at least 75% of the participants voted "strong," then the recommendation would be designated as strong with the phrase "we recommend."
Consensus was not reached on 4 PICO questions (no recommendation A to D), because fewer than 75% of the participants voted either yes or no. No corresponding statements were developed for these questions, but the pertinent evidence and discussions are summarized briefly in the text.
# Oversight and Review
The guideline process was overseen by the CAG clinical affairs committee to ensure methodological quality and a transparent, nonbiased, evidence-based
# CLINICAL GUIDELINE
Management of Upper Gastrointestinal Bleeding decision-making process. Recommendations are based on evidence from the literature and consensus discussion and may not fully reflect the product labeling for a given country.
The manuscript was initially drafted by the cochairs (A.N.B. and M.B.) and the GRADE experts (F.T. and G.I.L.). It was reviewed and revised by the steering committee members (E.J.K., J.S., L.L., and M.A.) before dissemination to the full consensus group for feedback. Finally, the manuscript was posted on the CAG Web site, and members were invited via e-mail to submit comments over a 2-week period.
In accordance with CAG policy, written conflict-ofinterest disclosures for the 24 months preceding the consensus meeting were provided by all participants and made available to the group.
# Role of the Funding Source
Funding for the consensus meeting was provided by unrestricted, arms-length grants to the CAG from the Institute of Nutrition, Metabolism and Diabetes of the Canadian Institutes of Health Research and the Saudi Gastroenterology Association. The CAG administered all aspects of the meeting; the funding sources had no involvement in, nor were they made aware of, any part of the process, from the development of search strings and statements to drafting and approving these guidelines.
# RECOMMENDATION STATEMENTS FOR UGIB
Each statement is followed by the strength of evidence based on GRADE analyses and a discussion of the evidence. The voting results are shown in Table 1, along with summaries of the new recommendations established from this consensus, recommendations that were revised from the 2003 and 2010 guidelines (3,4), and recommendations that were unchanged because most of the group believed that they currently did not require revision (3,4).
# Section A: Resuscitation, Risk Assessment, and Preendoscopy Management
# Statement A1
For patients with acute UGIB and hemodynamic instability, resuscitation should be initiated.
(Designated a good practice statement.) Discussion. Fluid resuscitation should be initiated in patients with UGIB and hemodynamic instability, because hemorrhagic shock may lead to multiorgan failure and death. The goals of fluid resuscitation are to restore end-organ perfusion and tissue oxygenation while steps are taken to control bleeding.
Uncertainty remains regarding the type of fluid (colloid vs. crystalloid) and the rate and timing of resuscitation (aggressive vs. restrictive). A Cochrane systematic review including 70 randomized controlled trials found no difference in mortality between critically ill patients who received colloids (albumin or plasma protein fraction, hydroxyethyl starch, modified gelatin, dextran, colloids in hypertonic crystalloid, or colloids in isotonic crystalloid) and those who received crystalloids (normal saline, Ringer lactate, or hypertonic saline) for fluid resuscitation (19). One small randomized trial conducted in patients with UGIB who had hemorrhagic shock found no statistically significant difference in mortality between hypertonic saline dextran and Ringer lactate (relative risk [RR], 0.18 [95% CI, 0.02 to 1.41]) (20). A large trial, published after the systematic review, that included 2857 critically ill patients showed no difference in 28-day mortality between those given colloids and those who received crystalloids (21). The trial found an unexpected borderline reduction in 90-day mortality among patients receiving colloids (RR, 0.92 [CI, 0.86 to 0.99])-a finding that was considered hypothesis generating (21). Because current evidence does not show that colloids increase survival rates compared with crystalloids and because colloids are more expensive, the consensus group agreed that routine use in clinical practice is not justified (19).
Uncertainty also exists regarding the type of crystalloid for use in fluid resuscitation. A recent randomized trial in 15 802 critically ill patients found a small reduction in acute kidney injury (odds ratio [OR], 0.91 [CI, 0.84 to 0.99]) and a possible small reduction in inhospital mortality (10.3% vs. 11.1%; P = 0.08) with balanced crystalloids (such as Ringer lactate) vs. saline (22).
Animal models have shown that early aggressive fluid resuscitation to increase blood pressure to normal values may exacerbate blood loss, disrupt coagulation, and increase mortality (23,24). The alternative is restrictive or hypotensive resuscitation, in which fluid is given but the target end point is less than normotension. A Cochrane systematic review included 6 randomized trials that examined timing and volume of fluid administration in 2128 patients with bleeding. Trials were heterogeneous regarding patient types, clinical settings, types of fluids, and resuscitation protocols (25). None found restrictive fluid resuscitation (with a delayed or smaller volume of fluid) to be inferior to more aggressive fluid resuscitation (with an early or a larger volume of fluid) with regard to mortality (25). Two randomized trials published since the review also found no differences in mortality between restrictive and aggressive resuscitation in patients with trauma and hemorrhagic shock (26,27). The consensus group agreed that the evidence was insufficient to make a recommendation regarding restrictive fluid resuscitation. The important issue in patients with hemorrhagic shock due to trauma or UGIB is to stop the bleeding while minimizing hemodynamic compromise.
# Statement A2a
For patients with acute UGIB, we suggest using a Glasgow Blatchford score of 1 or less to identify patients who are at very low risk for rebleeding or mortality and thus may not require hospitalization or inpatient endoscopy.
(GRADE: conditional recommendation, low-quality evidence)
Management of Upper Gastrointestinal Bleeding CLINICAL GUIDELINE . For patients with acute UGIB, we suggest using a Glasgow Blatchford score of ≤1 to identify patients who are at very low risk for rebleeding or mortality and thus may not require hospitalization or inpatient endoscopy. GRADE: conditional recommendation, low-quality evidence. Vote on PICO question: yes, 76%; uncertain/neutral, 18%; no, 6% (see PICO question 2 in Supplement Appendix 2) A2b. For patients with acute UGIB, we suggest against using the AIMS65 prognostic score to identify patients who are at very low risk for rebleeding or mortality and thus may not require hospitalization or inpatient endoscopy. GRADE: conditional recommendation, low-quality evidence. Vote on PICO question: no, 100% (see PICO question 2 in Supplement Appendix 2) A3. Consider placement of a nasogastric tube in selected patients because the findings may have prognostic value. † A4. In patients with acute UGIB without underlying cardiovascular disease, we suggest giving blood transfusions for those with a hemoglobin level <80 g/L. GRADE: conditional recommendation, low-quality evidence. Vote on PICO question: yes, 75%; uncertain/neutral, 15%; no, 10% (see PICO question 3a in Supplement Appendix 2) A5. In patients with acute UGIB with underlying cardiovascular disease, we suggest giving blood transfusions at a higher hemoglobin threshold than for those without cardiovascular disease. GRADE: conditional recommendation, very low-quality evidence. Vote on PICO question: yes, 80%; uncertain/neutral, 5%; no, 15% (see PICO question 3b in Supplement Appendix 2) A6. In patients with acute UGIB receiving anticoagulants (vitamin K antagonists, DOACs), we suggest not delaying endoscopy (with or without endoscopic hemostatic therapy). GRADE: conditional recommendation, very low-quality evidence. Vote on PICO question: yes, 100% (see PICO question 4 in Supplement Appendix 2) A7. Promotility agents should not be used routinely before endoscopy to increase the diagnostic yield. ‡ A8. Selected patients with acute ulcer bleeding who are at low risk for rebleeding on the basis of clinical and endoscopic criteria may be discharged promptly after endoscopy. ‡ A9. Pre-endoscopic PPI therapy may be considered to downstage the endoscopic lesion and decrease the need for endoscopic intervention but should not delay endoscopy. ‡ B. Endoscopic management B1. Develop institution-specific protocols for multidisciplinary management. Include access to an endoscopist trained in endoscopic hemostasis. † B2. Have support staff trained to assist in endoscopy available on an urgent basis. † B3: For patients admitted with acute UGIB, we suggest performing early endoscopy (within 24 hours of presentation). GRADE: conditional recommendation, very low-quality evidence. Vote on PICO question: yes, 100% (see PICO question 5a in Appendix 2) B4. Endoscopic hemostatic therapy is not indicated for patients with low-risk stigmata (a clean-based ulcer or a nonprotuberant pigmented dot in an ulcer bed). † B5. A finding of a clot in an ulcer bed warrants targeted irrigation in an attempt at dislodgement, with appropriate treatment of the underlying lesion. ‡ B6. The role of endoscopic therapy for ulcers with adherent clots is controversial. Endoscopic therapy may be considered, although intensive PPI therapy alone may be sufficient. ‡ B7. Endoscopic hemostatic therapy is indicated for patients with high-risk stigmata (active bleeding or a visible vessel in an ulcer bed). † B8. Epinephrine injection alone provides suboptimal efficacy and should be used in combination with another method. ‡ B9. No single method of endoscopic thermal coaptive therapy is superior to another. † B10a. For patients with acutely bleeding ulcers with high-risk stigmata, we recommend endoscopic therapy with thermocoagulation or sclerosant injection. GRADE: strong recommendation, low-quality evidence. Vote on PICO question: yes, 94%; uncertain/neutral, 6% (see PICO question 6a1 in Supplement Appendix 2) B10b. For patients with acutely bleeding ulcers with high-risk stigmata, we suggest endoscopic therapy with (through-the-scope) clips. GRADE: conditional recommendation, very low-quality evidence. Vote on PICO question: yes, 94%; uncertain/neutral, 6% (see PICO question 6a2 in Supplement Appendix 2) B11a. In patients with actively bleeding ulcers, we suggest using TC-325 as a temporizing therapy to stop bleeding when conventional endoscopic therapies are not available or fail. GRADE: conditional recommendation, very low-quality evidence. Vote on PICO question: yes, 82%; uncertain/neutral, 18% (see PICO question 6b2 in Supplement Appendix 2) B11b. In patients with actively bleeding ulcers, we suggest against using TC-325 as a single therapeutic strategy vs. conventional endoscopic therapy (clips alone, thermocoagulation alone, or combination therapy). GRADE: conditional recommendation, very low-quality evidence. Vote on PICO question: yes, 12%; uncertain/neutral, 12%; no, 76% (see PICO question 6b1 in Supplement Appendix 2) B12. Routine second-look endoscopy is not recommended. ‡ B13. A second attempt at endoscopic therapy is generally recommended in cases of rebleeding. †
# C. Pharmacologic management
C1. H 2 RAs are not recommended for patients with acute ulcer bleeding. † C2. Somatostatin and octreotide are not routinely recommended for patients with acute ulcer bleeding. † C3. For patients with bleeding ulcers with high-risk stigmata who have undergone successful endoscopic therapy, we recommend using PPI therapy via intravenous loading dose followed by continuous intravenous infusion (as opposed to no treatment or H 2 RAs). GRADE: strong recommendation, moderate-quality evidence. Vote on PICO question: yes, 100% (see PICO question 8a in Supplement Appendix 2) C4. For patients who present with ulcer bleeding at high risk for rebleeding (that is, an ulcer requiring endoscopic therapy followed by 3 days of high-dose PPI therapy), we suggest using twice-daily oral PPIs (vs. once-daily) through 14 days, followed by once daily. GRADE: conditional recommendation, very low-quality evidence. Vote on PICO question: yes, 95%; uncertain/neutral, 5% (see PICO question 10 in Supplement Appendix 2) C5. Patients should be discharged with a prescription for a single daily-dose oral PPI for a duration as dictated by the underlying cause. ‡
# Continued on following page
# CLINICAL GUIDELINE Management of Upper Gastrointestinal Bleeding
# No Recommendation A
For patients with acute UGIB, the consensus group could not make a recommendation for or against using the preendoscopic Rockall prognostic scale to identify patients who are at very low risk for rebleeding or mortality and thus may not require hospitalization or inpatient endoscopy.
(GRADE for PICO: very low-quality evidence)
# Statement A2b
For patients with acute UGIB, we suggest against using the AIMS65 prognostic score to identify patients who are at very low risk for rebleeding or mortality and thus may not require hospitalization or inpatient endoscopy.
(GRADE: conditional recommendation, low-quality evidence) Key Evidence. Evidence profiles for the 3 beststudied prognostic scores (Glasgow Blatchford [GBS], preendoscopic Rockall, and AIMS65) were considered separately. The QoE review focused on studies that assessed the use of preendoscopic scoring systems to identify patients at very low risk for undesirable outcomes. No randomized trials that directly assessed the clinical impact of using versus not using prognostic scales were identified. Therefore, the evidence was derived from "before-after" studies (28) and studies of diagnostic test accuracy that assessed the surrogate outcome of diagnostic (prognostic) accuracy of the scales.
A beforeϪafter study by Stanley and colleagues (28) assessed a strategy of not admitting emergency
# E. Secondary prophylaxis §
E1. In patients with previous ulcer bleeding who require an NSAID, it should be recognized that treatment with a traditional NSAID plus a PPI or COX-2 inhibitor alone is still associated with a clinically important risk for recurrent ulcer bleeding. ‡ E2. In patients with previous ulcer bleeding who require an NSAID, the combination of a PPI and a COX-2 inhibitor is recommended to reduce the risk for recurrent bleeding from that of COX-2 inhibitors alone. ‡ E3. In patients who receive low-dose ASA and develop acute ulcer bleeding, ASA therapy should be restarted as soon as the risk for cardiovascular complication is thought to outweigh the risk for bleeding. ‡ E4. In patients with previous ulcer bleeding receiving cardiovascular prophylaxis with single-or dual-antiplatelet therapy, we suggest using PPI therapy vs.
no PPI therapy. GRADE: conditional recommendation, low-quality evidence. Vote on PICO question (single): yes, 95%; uncertain/neutral: 5%. Vote on PICO question (double): yes, 100% (see PICO questions 9a and 9c in Supplement Appendix 2) E5. In patients with previous ulcer bleeding requiring continued cardiovascular prophylaxis with anticoagulant therapy (vitamin K antagonists, DOACs), we suggest using PPI therapy vs. no PPI therapy. GRADE: conditional recommendation, very low-quality evidence. Vote on PICO question: yes, 85%; uncertain/neutral, 15% (see PICO question 9b in Supplement Appendix 2)
# No recommendation statementsͦͦ
No recommendation A: For patients with acute UGIB, the consensus group could not make a recommendation for or against using the preendoscopic Rockall prognostic scale to identify patients who are at very low risk for rebleeding or mortality and thus may not require hospitalization or inpatient endoscopy. GRADE: no recommendation, very low-quality evidence. Vote on PICO question: yes, 12%; uncertain/neutral, 18%; no, 71% (see PICO question 2 in Supplement Appendix 2) No recommendation B: For patients with acute UGIB at high risk for rebleeding or mortality, the consensus group could not make a recommendation for or against performing endoscopy within 12 hours vs. performing endoscopy later. GRADE: no recommendation, very low-quality evidence. Vote on PICO question: yes, 41%; uncertain/neutral, 47%; no, 12% (see PICO question 5b in Supplement Appendix 2) No recommendation C: In patients with acutely bleeding ulcers who have undergone endoscopic therapy, the consensus group could not make a recommendation for or against using DEP vs. no DEP to assess the need for further endoscopic therapy. GRADE: no recommendation, very low-quality evidence. Vote on PICO question: yes, 47%; uncertain/neutral, 41%; no, 12% (see PICO question 7 in Supplement Appendix 2) No recommendation D: For patients with bleeding ulcers with high-risk stigmata who have undergone successful endoscopic therapy, the consensus group could not make a recommendation for or against using non-high-dose PPI therapy (as opposed to no treatment or H 2 RAs). GRADE: no recommendation, very low-quality evidence. Vote on PICO question: yes, 24%; uncertain/neutral, 47%; no, 29% (see PICO question 8b in Supplement Appendix 2) ASA = acetylsalicylic acid; COX-2 = cyclooxygenase-2; DEP = Doppler endoscopic probe; DOAC = direct oral anticoagulant; GRADE = Grading of Recommendations Assessment, Development and Evaluation; H 2 RA = H 2 -receptor antagonist; NSAID = nonsteroidal anti-inflammatory drug; PICO = patient population, intervention, comparator, and outcome; PPI = proton-pump inhibitor; UGIB = upper gastrointestinal bleeding. * The strength of each recommendation was assigned by the consensus group, according to the GRADE system, as strong ("we recommend...") or conditional ("we suggest...") on the basis of 4 components: QoE, benefit-harm balance, patients' values and preferences, and resource requirements (18). However, when quality of evidence was low or very low, the strength of the recommendation would typically default (without a vote) to conditional, unless at least 1 of the other 3 factors was overwhelmingly strong. † Recommendation unchanged from the 2003 guidelines. See reference 3 for supporting evidence and discussions. ‡ Recommendation unchanged from the 2010 guidelines. See reference 4 for supporting evidence and discussions. § Section was titled "Postdischarge, ASA, and NSAIDs" in the 2010 consensus recommendations (4). ͉͉ Voting threshold of ≥75 for either yes or no was not reached.
# Management of Upper Gastrointestinal Bleeding
# CLINICAL GUIDELINE
department patients with UGIB who were predicted to be at very low risk for undesirable outcomes (GBS of 0). This reduced the number of hospitalization, and no difference was demonstrated in safety outcomes, although the study was not powered for safety outcomes.
The relevant evidence included 2 high-quality systematic reviews and meta-analyses of studies of diagnostic test accuracy (7,29) as well as 2 additional studies notable for their quality and sample sizes (30,31). The sensitivity of low cutoff values for detecting patients at high risk for undesirable clinical outcomes was very good for the GBS (0.99) and preendoscopic Rockall score (range, 0.93 to 0.96, but with more heterogeneity), and lower for AIMS65 (range, 0.78 to 0.82) (Appendix Table 1, available at Annals.org) (7, 29 -31).
For the GBS and AIMS65, the QoE was low, with the evidence being downgraded for indirectness, imprecision, and inconsistency. For the preendoscopic Rockall score, QoE was very low, with the evidence being downgraded for the same reasons plus risk of bias.
Discussion. Use of prognostic scales and early discharge of patients at low risk have the potential to reduce the need for endoscopy, hospital stays, and associated costs without increasing harms. Sensitivity for detecting high-risk patients is a critical outcome, because it is important to avoid incorrectly classifying high risk as low risk when making decisions about early discharge. Specificity is less crucial, because low specificity results in more low-risk patients being hospitalized but not in high-risk patients being discharged. Patient preferences also should be considered; some patients may prefer diagnostic certainty, whereas others may prefer not to be hospitalized. Other factors when considering early discharge include urban versus rural environment, access to hospital or ambulance services, access to out-of-hours endoscopy, and reimbursement issues.
Whether using a prognostic scale results in better patient outcomes than using clinical judgment alone is not known. Because clinical judgment cannot be standardized, the consensus group agreed that use of a prognostic scoring system would help ensure consistent risk assessment and communication. Education is now needed to embed a scoring tool into clinical practice (such as in electronic medical records).
The consensus group suggests the GBS as the preferred prognostic tool because of its high sensitivity (misclassifying ≤1% of high-risk patients as low risk). The preendoscopic Rockall scale has good sensitivity, but it may misclassify 4% to 7% of high-risk patients. Given differing views regarding the threshold sensitivity for discharge, the consensus group could not make a recommendation for or against use of the preendoscopic Rockall score.
The AIMS65 was designed to be used with high cutoff values to identify patients at high risk for death (32) rather than those at low risk for safe discharge. The consensus group suggested not using AIMS65 in this setting, because even at low cutoff values approximately 20% of high-risk patients may be misclassified as low risk.
# Statement A4
In patients with acute UGIB without underlying cardiovascular disease, we suggest giving blood transfusions for those with a hemoglobin level less than 80 g/L.
(GRADE: conditional recommendation, low-quality evidence) Key Evidence. Evidence for a hemoglobin threshold for the effectiveness and safety of red blood cell transfusions was available from a summary of studies comparing restrictive (70 to 80 g/L) versus liberal (90 to 100 g/L) transfusion thresholds for patients with acute UGIB (33).
In the systematic review of 5 randomized controlled trials in patients with UGIB (n = 1965), restrictive transfusion was associated with a lower risk for allcause mortality (RR, 0.65 [CI, 0.45 to 0.97]) and further bleeding (RR, 0.58 [CI, 0.40 to 0.84]) (33) (Appendix Table 2, available at Annals.org). No subgroup differences were found with regard to risks for myocardial infarction, stroke or transient ischemic attack, or acute kidney injury (33), or to the rate of surgical or radiologic intervention between the 2 strategies (34,35). These data were downgraded for serious risk of bias and serious indirectness. However, the QoE for the superiority of the restrictive transfusion strategy is higher (less indirectness) than the QoE for specific thresholds of transfusion.
Two other systematic reviews and meta-analyses that provided supportive data on patients in various clinical settings (cardiac surgery, orthopedic surgery, vascular surgery, acute blood loss or trauma, critical care, acute myocardial infarction, and hematologic cancer) including UGIB, found no difference in 30-day mortality, rebleeding, cardiac events, myocardial infarction, or stroke between the 2 strategies in the combined patient groups (36,37).
Discussion. The data suggest that a restrictive transfusion strategy is beneficial in patients with UGIB (33) and is not associated with adverse events (36,37). The restrictive threshold led to a decrease in the proportion of patients exposed to transfusions (36,37) and in the mean number of units transfused (33). A study assessing direct and indirect costs reported that the total cost per red blood cell unit in 2008 was approximately $760 (38). Although cost per unit may vary greatly across institutions, a restrictive strategy is probably the least expensive.
Only 3 randomized trials provided mortality data in the UGIB-specific review, with 2 high-quality trials providing 98.2% of the weight in the meta-analysis (33). A single-center study found reductions in mortality and rebleeding with a hemoglobin threshold of 70 g/L versus 90 g/L (35), whereas a cluster randomized trial found no reduction in mortality or rebleeding with a threshold of 80 g/L versus 100 g/L (34). Although it did not look at hemoglobin thresholds, 1 trial in UGIB patients with hemodynamic instability found no difference in mortality between early versus delayed blood transfusion; however, the study was underpowered (RR, 5.4 [CI, 0.3 to 107.1]) (39).
Factors that may affect the timing of transfusions include the availability of venipuncture staff, capacity for frequent assessments, timing of blood typing, avail-
# CLINICAL GUIDELINE
Management of Upper Gastrointestinal Bleeding ability of units, hemodilution factors, and degree of hemodynamic stability. In addition, some patients may have underlying, undiagnosed cardiovascular disease, potentially placing them at higher risk for negative outcomes. Therefore, the consensus group suggested that a more conservative hemoglobin threshold of 80 g/L is prudent, with a target of greater than 80 g/L. The threshold recommendation does not apply to patients with exsanguinating bleeding. In the setting of acute blood loss, hemoglobin values may initially remain unchanged from baseline because of plasma equilibrium times. In such situations, transfusion should not be dictated by current hemoglobin level alone but should take into account the predicted drop in hemoglobin and the patient's clinical status.
# Statement A5
In patients with acute UGIB and underlying cardiovascular disease, we suggest giving blood transfusions at a higher hemoglobin threshold than for those without cardiovascular disease.
(GRADE: conditional recommendation, very lowquality evidence) Key Evidence. Two meta-analyses, 1 in patients with UGIB (33) and 1 in patients with cardiovascular disease in various clinical settings (40), included an analysis of 1 randomized trial (34) that provided subgroup data on patients with and without cardiovascular disease. This small, underpowered trial (34) found no significant difference between liberal (hemoglobin threshold, 100 g/L) and restrictive (hemoglobin threshold, 80 g/L) transfusion with regard to mortality (RR, 4.10 [CI, 0.86 to 19.47]) (40) or further bleeding in adults with or without ischemic heart disease (RR, 0.50 [CI, 0.23 to 1.12], and RR, 0.69 [CI, 0.13 to 3.77]) (33). This study was downgraded for serious risk of bias (lack of blinding, possible selection bias) and very serious imprecision (very small sample size).
Reanalysis of the overall data from the metaanalysis of 11 trials in patients with cardiovascular disease (40) found no significant differences between the liberal (90 to 113 g/L) and restrictive (70 to 97 g/L) strategies with regard to 30-day mortality (RR, 0.87 [CI, 0.67 to 1.13]) or acute pulmonary edema (RR, 1.58 [CI, 0.55 to 4.53]) but did find a reduced risk for cardiovascular events with the liberal transfusion strategy (RR, 0.56 [CI, 0.37 to 0.85]). This analysis was downgraded for serious risk of bias, very serious indirectness, and serious imprecision. Because of the variation in outcomes included in the trials as well as in the metaanalyses, several sensitivity analyses were conducted. Although the results became more imprecise, the direction of effect did not change.
Discussion. The data suggest that a more liberal hemoglobin threshold for transfusion may be associated with a lower risk for cardiovascular events in patients with cardiovascular disease. This is based on data from studies in various clinical settings with heterogeneous patient subgroups (such as those with coronary syndromes, ischemic heart disease, congestive heart failure, peripheral vascular disease, or stroke or those with only cardiovascular risk factors, such as hyperten-sion and diabetes). The effects of liberal versus restrictive transfusion strategies may differ among various subgroups. In addition, various definitions were used for the restrictive and liberal groups, including hemoglobin levels and the presence of anemia, and hemoglobin cutoff values varied.
On the basis of these limited data, the consensus group suggested that a higher hemoglobin threshold be considered in patients with cardiovascular disease than in those without it (<80 g/L; statement A4). The group did not recommend a specific cutoff, stating that a cutoff would depend on other factors, including the patient's clinical status, the type and severity of cardiovascular disease, and the severity of bleeding. Guidelines from NICE recommend a higher transfusion level for patients with cardiovascular disease than for those without it, whereas the AABB (formerly known as the American Association of Blood Banks) (41) recommends a hemoglobin threshold of 80 g/L for patients with cardiovascular disease, compared with 70 g/L for those without it. Again, this statement does not apply to patients with exsanguinating bleeding, who may require more liberal transfusion.
# Statement A6
In patients with acute UGIB receiving anticoagulants (vitamin K antagonists, direct oral anticoagulants), we suggest not delaying endoscopy (with or without endoscopic hemostatic therapy).
(GRADE: conditional recommendation, very lowquality evidence) Key Evidence. No systematic reviews, randomized trials, or observational studies that specifically addressed the timing of endoscopy as a primary outcome in patients receiving anticoagulants were found. A retrospective cohort study in patients with acute UGIB (47%) or lower gastrointestinal bleeding compared 157 patients using anticoagulants with 157 matched control participants (42). An international normalized ratio (INR) greater than 2.5 was seen in 22.9% of the patients receiving anticoagulants versus 6.4% of the control participants. No statistically significant differences were observed in rates of rebleeding (13.4% vs. 15.9%; P = 0.52) or thromboembolism (5.7% vs. 3.2%; P = 0.68) between the anticoagulant and control groups. Among the patients receiving anticoagulants, early endoscopy (<24 hours after onset) was not associated with rebleeding (OR, 0.7 [CI, 0.3 to 1.8]), thromboembolic events (OR, 0.5 [CI, 0.1 to 2.1]), or endoscopy-related adverse events (0%). Rebleeding also was not associated with an INR of 2.5 or greater (OR, 0.7 [CI, 0.2 to 2.3]). In contrast, probably because of rapid correction of INR periendoscopically (43,44), thromboembolism was associated with an INR of 2.5 or greater (OR, 7.3 [CI, 1.5 to 35.3]) and the use of a reversal agent (OR, 4.1 [CI, 1.0 to 16.5]) (42).
No differences were found in rebleeding or thromboembolism risks between patients receiving direct oral anticoagulants (DOACs) and those receiving warfarin. However, patients using warfarin had a greater need for transfusion (4.3 ± 5.9 units vs. 2.2 ± 3.1 units; P = 0.046). Periendoscopic use of a reversal agent (vitamin K) was associated with a higher risk for thrombo-Management of Upper Gastrointestinal Bleeding CLINICAL GUIDELINE embolism but not rebleeding, whereas anticoagulant interruption did not affect the risk for either outcome. The results of anticoagulant use in patients with UGIB were not reported separately, but UGIB was associated with a higher rate of endoscopic therapy and transfusions compared with lower gastrointestinal bleeding, suggesting that the combined results may not be entirely generalizable to patients with UGIB (42). This study was downgraded for serious indirectness and imprecision.
Discussion. For patients receiving anticoagulants, the 2010 UGIB guidelines suggested that coagulopathy be corrected but that endoscopy not be delayed (4). This recommendation was made on the basis of cohort studies suggesting that early endoscopy (≤24 hours) may be performed safely in patients using anticoagulants after partial correction of the INR, without an increase in rebleeding rates versus persons not using anticoagulants (45,46). In the study by Nagata and colleagues (42), anticoagulant interruption did not affect risks and no increased risk was found in patients with an INR of 2.5 or greater. The consensus group cannot specify an INR cutoff level that should prompt correction of the INR.
Although available new data were limited, the introduction of DOACs prompted the update to this recommendation. Nagata and colleagues (42) found that patients receiving DOACs had less need for transfusion than those receiving warfarin. The DOACs have a short half-life-8 to 12 hours-and their anticoagulant effect resolves more rapidly than that of warfarin. Reversal agents are now available, although criteria for their use in patients with UGIB are not yet defined and availability may be limited in some areas. Whether the type or extent of anticoagulation would affect the type of endoscopic hemostatic therapy was not addressed.
Other guidelines recommend administration of vitamin K supplemented with intravenous prothrombin complex concentrate (PCC), with use of fresh frozen plasma only if PCC is unavailable (8,9,47). Four-factor PCC has demonstrated efficacy in correcting INR (43,44), as have specifically targeted anticoagulant reversal agents (48,49). Some data suggest a higher risk for thrombosis with rapid reversal of anticoagulation (42,48), but this is beyond the scope of these guidelines.
The consensus group agreed that the degree of coagulopathy should be assessed objectively before therapeutic decisions are made. The anticoagulant agent, patient physiology, and patient compliance with therapy may affect anticoagulation. Because of the recognized benefits of early endoscopy (statement B3), coagulopathy should be treated as necessary but endoscopy should not be delayed.
# Section B: Endoscopic Management
# Statement B3
For patients admitted with acute UGIB, we suggest performing early endoscopy (within 24 hours of presentation).
(GRADE: conditional recommendation, very lowquality evidence) Key Evidence. Evidence for early endoscopy was assessed separately for patients at low and high risk for unfavorable outcomes (death, rebleeding) (Supplement Appendix 2).
Low-risk patients: Two systematic reviews (4, 50) including 3 randomized trials (51)(52)(53) assessed the timing of endoscopy in patients with UGIB. Two of the trials included low-risk patients randomly assigned to early versus later endoscopy (within 1 to 2 hours vs. 1 to 2 days [52], or within 6 hours vs. 48 hours [53]). No differences in mortality or rebleeding were found between groups in either trial (52,53), but 1 study found that early endoscopy reduced length of stay and cost of care (52). The QoE was downgraded for serious risk of bias, indirectness, and very serious imprecision.
Observational studies were seriously confounded by severity of bleeding and comorbidity, which may bias the results in favor or against early endoscopy. Three retrospective cohort studies included exclusively or separately reported data on low-risk patients and adjusted for confounders (54 -56). In 1 study, urgent endoscopy was a predictor of negative outcomes (composite of death; rebleeding; and surgical, radiologic, or endoscopic intervention) among low-risk patients with UGIB (adjusted OR, 0.71 per 6 hours [CI, 0.55 to 0.91]) (54). The definition of low risk in this study was a GBS less than 12, instead of the more common GBS of 2 or less. In another study using the same criterion, time to endoscopy was not associated with in-hospital mortality (55). In the largest study, among low-risk patients endoscopy within 24 hours was associated with lower in-hospital mortality (OR, 0.48 [CI, 0.24 to 0.97]), but not rebleeding, compared with later endoscopy (56). The QoE was downgraded for serious risk of bias and indirectness.
High-risk patients: See text under "No Recommendation B."
Discussion. Safety concerns regarding early endoscopy, including the potential for inadequate resuscitation before the procedure and the need to perform endoscopy during off-hours when fewer endoscopy resources are available, must be weighed against the potential for worse outcomes due to ongoing bleeding. Because such concerns are less of an issue in low-risk patients than in high-risk ones, the decision to perform early endoscopy in those at low risk is driven mainly by cost and length of stay.
The 2010 UGIB guidelines recommended early endoscopy (within 24 hours of presentation) for most patients with acute UGIB (4). This recommendation was based on data suggesting that early endoscopy allowed for safe discharge of low-risk patients, improved outcomes for high-risk patients, and reduced resource use (4).
Although the data were very low quality, they support the conclusion that for low-risk patients, early endoscopy may be performed safely and can reduce resource use. To reduce hospitalization and costs, the endoscopist's recommendations for early discharge of low-risk patients must be embraced by the attending physician. In the trial in which early endoscopy did not reduce resource use, only 21% of eligible patients were discharged early (53). Early endoscopy may also yield
# CLINICAL GUIDELINE
Management of Upper Gastrointestinal Bleeding more high-risk endoscopic stigmata that would have resolved spontaneously (52,53), which may offset benefits in terms of hospitalization.
Availability of endoscopy resources is an important consideration. A meta-analysis of 20 cohort studies found that patients with UGIB hospitalized during offhours were less likely to undergo endoscopy within 24 hours and had higher mortality rates (57). This was not the case in hospitals with formal out-of-hours endoscopy services.
On the basis of the available data, the consensus group suggested that endoscopy be performed within 24 hours of presentation, both for low-and high-risk patients.
For high-risk patients, see the discussion under "No Recommendation B."
# No Recommendation B
For patients with acute UGIB at high risk for rebleeding or mortality, the consensus group could not make a recommendation for or against performing endoscopy within 12 hours versus performing endoscopy later.
(GRADE for PICO: very low-quality evidence) Key Evidence. No randomized trial assessed the timing of endoscopy specifically in high-risk patients with UGIB. One trial in patients with peptic ulcer bleeding, including a high proportion of high-risk patients (44% with shock), found no difference in mortality with endoscopy before or after 12 hours (Appendix Table 3, available at Annals.org) (51). The QoE was downgraded for serious risk of bias and indirectness, and very serious imprecision.
Seven observational studies in high-risk patients with UGIB were assessed (54 -56, 58 -61); however, only 2 provided adjusted results for mortality (Appendix Table 3) (56,58). One study found a reduction in mortality with very early endoscopy (<6 hours) compared with later endoscopy (>6 to ≤48 hours) (58). A large cohort study suggested that among hemodynamically unstable patients, very early endoscopy (≤6 hours) may increase mortality risk, whereas early endoscopy between 6 and 24 hours may reduce mortality risk compared with endoscopy outside that time frame (56). These data were downgraded for serious risk of bias, inconsistency, and imprecision.
Unadjusted results from observational studies were not considered for this guideline. Such results conflict and are difficult to interpret, because the effects of the confounders are bidirectional. More severe bleeding or comorbid conditions are associated with worse outcomes and present a clear bias toward more rapid endoscopy; however, if the severity is too great, then endoscopy might be delayed.
Discussion. Statement B3 recommends endoscopy within 24 hours for patients with UGIB. Whether highrisk patients would benefit from very early endoscopy (within 12 hours) remains unanswered. Although active bleeding is associated with a poor prognosis, patients who are hemodynamically unstable may have more ad-verse outcomes during endoscopy. Therefore, very early endoscopy may be associated with a paradoxical negative effect in high-risk patients (56).
Because of conflicting data, widely variable patient populations (such as those differing in age, bleeding severity, comorbid conditions, or hemodynamic instability), and the potential for harm, the consensus group concluded that insufficient data exist to recommend for or against endoscopy more urgently than the 24-hour window in high-risk patients. Practitioners are reminded that for patients with suspected variceal bleeding, existing recommendations suggest endoscopy within 12 hours of presentation (62,63).
# Statement B10a
For patients with acutely bleeding ulcers with highrisk stigmata, we recommend endoscopic therapy with thermocoagulation or sclerosant injection.
(GRADE: strong recommendation, low-quality evidence)
# Statement B10b
For patients with acutely bleeding ulcers with highrisk stigmata, we suggest endoscopic therapy with (through-the-scope) clips.
(GRADE: conditional recommendation, very lowquality evidence) Key Evidence. Systematic reviews and meta-analyses have assessed the role of endoscopic therapy in patients with UGIB (64 -67). One review looked only at epinephrine injection alone and in combination (66), whereas another was suboptimally reported (67). For this guideline, the evidence was derived mainly from the 2009 reviews by Laine and McQuaid (64) and Barkun and colleagues (65), which were updated via new literature searches from 2006 to 2018. For the comparison of endoscopic treatment with no endoscopic treatment, no new randomized trials were found; therefore, these analyses remain unchanged (64,65).
Compared with pharmacotherapy or no treatment, thermocoagulation (heater probe or bipolar electrocoagulation) or sclerosant injection reduced mortality and rebleeding (64,65). No randomized trials were found comparing hemoclips with no treatment.
The QoE was downgraded for risk of bias (mainly lack of blinding). The QoE for efficacy was moderate for all therapies combined and for sclerosant injection; QoE was low for thermocoagulation and was downgraded further for imprecision.
For comparisons of various active treatments, the meta-analysis by Barkun and colleagues (65) was updated with 3 new trials (68 -70) (Supplement Appendix 2). No differences were found for mortality or rebleeding in comparisons of thermocoagulation, sclerosant injection, hemoclips, and combination therapies (64,65). Meta-analysis of data from 2 trials showed that hemoclips were superior to epinephrine injection alone with regard to rebleeding (RR, 0.17 [CI, 0.05 to 0.55]) but not mortality (RR, 2.15 [CI, 0.59 to 7.78]) (68,71).
Discussion. Endoscopic hemostatic therapy has been well documented to improve outcomes. The con-
# Management of Upper Gastrointestinal Bleeding
# CLINICAL GUIDELINE
sensus group agreed with the prior statements that endoscopic therapy is indicated in patients with high-risk stigmata (active bleeding, visible vessel) and may be considered in patients with an adherent clot (statements B6 and B7). Debate continues with regard to the optimal method. Sclerosant therapy is used less commonly in clinical practice but remains a viable option. Lack of routine PPI therapy and the constantly changing prevalence of Helicobacter pylori may affect the results of older studies. The group chose not to address other endoscopic mechanical techniques, such as over-thescope clips.
On the basis of the available data, a strong recommendation was made for thermocoagulation or sclerosant injections, whereas hemoclips were suggested (conditional recommendation). However, the data generally have failed to show superiority of any one method, and each may be useful depending on location of the bleeding source and patient characteristics.
# Statement B11a
In patients with actively bleeding ulcers, we suggest using TC-325 as a temporizing therapy to stop bleeding when conventional endoscopic therapies are not available or fail.
(GRADE: conditional recommendation, very lowquality evidence)
# Statement B11b
In patients with actively bleeding ulcers, we suggest against using TC-325 as a single therapeutic strategy versus conventional endoscopic therapy (clips alone, thermocoagulation alone, or combination therapy).
(GRADE: conditional recommendation, very lowquality evidence) Key Evidence. Evidence for the efficacy of TC-325 (hemostatic powder spray) was available from 1 small underpowered trial (72) and from observational studies (73,74). The trial randomly assigned 20 patients and found no statistically significant differences in initial hemostasis (90% vs. 100%) or rebleeding (33% vs. 10%) with TC-325 monotherapy versus a conventional combination endoscopic technique (epinephrine injection with either hemoclip or heater probe application) (72). Among 8 patients with actively bleeding (spurting or oozing) ulcers, 4 of 5 in the TC-325 group had successful initial hemostasis, but 3 had rebleeding. In contrast, all 3 in the conventional treatment group achieved initial hemostasis and none had rebleeding.
A systematic review of observational data found an immediate hemostasis rate of 90% but very high rebleeding rates (72-hour, 19%; 7-day, 22%) among 86 patients with ulcer bleeds treated with TC-325 (73). Rebleeding rates (72-hour and 7-day) were highest among patients with active bleeding (spurting, 40% and 60%; oozing, 13% and 16%). Another large prospective cohort study included 202 patients with bleeding treated with TC-325; the rate of initial hemostasis was 97%, with day 8 and day 30 rebleeding rates of 27% and 34%, respectively (74).
Evidence was downgraded for serious risk of bias (lack of blinding) and very serious imprecision (small sample sizes and low total number of events).
Discussion. The success of TC-325 hemostatic powder spray seems to depend on the cause of bleeding and whether the powder is used alone or in combination with other hemostatic therapy. The powder adheres only to actively bleeding lesions (73), its residency time is 24 hours or less (75), and it does not induce tissue healing (73).
TC-325 use in UGIB is associated with a low complication rate, although rare cases of perforation and transient biliary obstruction have been reported (73,76). Additional experience is needed to define the safety profile more clearly.
Decision modeling suggests that a strategy of conventional therapy followed by TC-325 improved the effectiveness and was less costly compared with conventional therapy alone or TC-325 alone in most patient populations with nonvariceal UGIB (77). TC-325 followed by conventional therapy was the most effective strategy for nonulcer high-risk bleeding lesions at low risk for delayed rebleeding.
On the basis of TC-325's mechanism of action and the clinical evidence, the consensus group concluded that TC-325 monotherapy may not adequately treat ulcers with high-risk stigmata, but may be useful as a temporary measure to stop bleeding, and that second-look endoscopy or a second hemostatic technique should be used.
# No Recommendation C
In patients with acutely bleeding ulcers who have undergone endoscopic therapy, the consensus group could not make a recommendation for or against Doppler endoscopic probe (DEP) versus no DEP to assess the need for further endoscopic therapy.
(GRADE for PICO: very low-quality evidence) Key Evidence. Two randomized trials compared DEP-guided versus conventional endoscopic treatment in patients with acute UGIB (78,79). In a 1997 study by Kohler and colleagues (78), all patients had peptic ulcer bleeding, but actively bleeding lesions were excluded. Endoscopic treatment was directed by Doppler findings, injection therapy alone was used, and secondlook endoscopy was performed for all patients. In a 2017 study by Jensen and colleagues (79), most of the 148 patients with severe nonvariceal UGIB (85%) had peptic ulcer bleeding (active bleeding, visible vessel, adherent clot, or flat spot). A meta-analysis of these 2 studies (78, 79) was performed for this guideline (Supplement Appendix 2). However, at the face-to-face meeting, it was decided to focus the evidence profiles on the trial by Jensen and colleagues, which reported data for patients with high-risk lesions (active bleeding, visible vessel) or adherent clot. Data for patients with low-risk lesions (flat spot) were considered indirect, because these lesions are not routinely subjected to endoscopic therapy. In Jensen and colleagues' study (79), DEP reduced rebleeding for all lesions (RR, 0.42 [CI, 0.20 to 0.90]) but not for high-risk lesions (RR, 0.50 [CI, 0.24 to 1.08]).
Overall, the QoE was downgraded for risk of bias, indirectness (population and intervention), and imprecision (moderate sample size).
# CLINICAL GUIDELINE Management of Upper Gastrointestinal Bleeding
Discussion. More studies are needed to determine whether DEP would be useful to guide endoscopic treatment decisions before or after initial therapy or in both settings. One study found only 58% agreement between DEP and findings at index endoscopy (78). Used to determine the need for additional therapy, DEP would be an add-on test with conventional endoscopic treatment for high-risk lesions, which would add cost related to the DEP technology. A cost-minimization analysis found that DEP-directed combination endoscopic therapy was cost-effective compared with combination therapy only for the management of high-risk patients (80).
The consensus group concluded that data suggesting efficacy for DEP is very limited and that lack of availability and expertise in many centers affects feasibility. The group generally agreed that although making a recommendation for or against DEP to manage UGIB is premature, it has the potential to alter the usual approach to visually assessing bleeding lesion risk when evaluating the need for, and adequacy of, endoscopic hemostasis.
# Section C: Pharmacologic Management
# Statement C3
For patients with bleeding ulcers with high-risk stigmata who have undergone successful endoscopic therapy, we recommend using PPI therapy via intravenous loading dose followed by continuous intravenous infusion (as opposed to no treatment or H 2receptor antagonists).
(GRADE: strong recommendation, moderate-quality evidence)
# No Recommendation D
For patients with bleeding ulcers with high-risk stigmata who have undergone successful endoscopic therapy, the consensus group could not make a recommendation for or against non-high-dose PPI therapy (as opposed to no treatment or H 2 -receptor antagonists).
(GRADE for PICO: very low-quality evidence) Key Evidence. Two Cochrane reviews on PPIs in UGIB were updated for this guideline (81,82). The first (81), which included 24 trials comparing PPIs with placebo or H 2 -receptor antagonists (H 2 RAs), was updated with an additional 14 randomized trials. Of these, 12 included data on patients with high-risk stigmata (active bleeding, visible vessel) or adherent clot who had undergone appropriate endoscopic therapy. There was moderate QoE that PPI therapy versus no PPIs or H 2 RAs reduced mortality risk (OR, 0.56 [CI, 0.34 to 0.94]) and high QoE that it reduced rebleeding risk (OR, 0.43 [CI, 0.29 to 0.63]) (Table 2). The evidence for mortality was downgraded because of serious risk of bias (mainly lack of blinding in some trials).
The second meta-analysis (82), which included 22 trials comparing various PPI regimens, was updated with an additional 18 trials. Of these, 25 compared high-dose PPIs (defined as an 80-mg intravenous bolus followed by 72 hours of an 8-mg/h continuous intravenous infusion) with non-high-dose PPIs, and 17 included data on patients with high-risk stigmata or adherent clots who had undergone endoscopic treatment. No differences were found in the risk for mortality or rebleeding between high-dose and nonhigh-dose PPIs (low and moderate QoE) or between high-dose and oral PPIs (very low and low QoE) (Table 2). Indirect comparisons between high-dose PPIs and no treatment or H 2 RAs and between non-high-dose PPIs and no treatment or H 2 RAs yielded very low QoE for the superiority of high-dose PPI therapy (update of [81]). Moderate QoE supported the superiority of non-high-dose PPIs versus no PPIs for the outcome of rebleeding, but the QoE for mortality was low. The evidence was downgraded, mainly because of imprecision and risk of bias for some comparisons.
Adverse effects were poorly reported in most of the studies. Overall, no consistent signal of a difference was found between PPI therapy and placebo or H 2 RAs, between high-dose and non-high-dose PPIs, or between intravenous and oral PPI therapy. The exception was an increased risk for thrombophlebitis with PPIs administered intravenously versus orally.
Discussion. High-dose PPI therapy (that is, an 80-mg intravenous bolus followed by 72 hours of 8-mg/h continuous intravenous infusion) reduces rebleeding and mortality. Because non-high-dose therapy has been associated with a reduction in rebleeding
# Management of Upper Gastrointestinal Bleeding
# CLINICAL GUIDELINE
but not mortality compared with no PPI therapy, a majority of the consensus group did not vote to recommend non-high-dose PPI therapy. The consensus group is not confident that the precision of the estimates of absolute differences between high-and nonhigh-dose PPI therapy regarding mortality and rebleeding is sufficient to consider the 2 therapies equivalent.
Studies of non-high-dose PPI therapy are complicated by different dosing regimens and methods of administration, including continuous intravenous infusion, intravenous bolus, and oral regimens.
Cost-effectiveness studies have suggested that high-dose intravenous PPIs after successful endoscopic hemostasis improve outcomes at a modest cost increase relative to non-high-dose intravenous or oral PPI strategies (83)(84)(85)(86). In addition, the incremental costs of different PPI regimens (continuous or intermittent, before or after endoscopic therapy) are modest compared with total per-patient costs.
The consensus group concluded that the evidence supports a strong recommendation for high-dose PPIs for patients with bleeding ulcers with high-risk stigmata (active bleeding or visible vessel) who have had successful endoscopic therapy. The recommendation for patients with adherent clots remains unchanged (statement B6) and includes endoscopic therapy or consideration of PPI therapy alone (Table 1). Given the demonstrated benefits on rebleeding outcomes and that the costs and availability of intravenous formulations may be issues in some areas, the consensus group also did not make a recommendation against using lower PPI doses.
# Statement C4
For patients who present with ulcer bleeding at high risk for rebleeding (that is, an ulcer requiring endoscopic therapy followed by 3 days of high-dose PPI therapy), we suggest using twice-daily oral PPIs (vs. once daily) through 14 days, followed by once daily.
(GRADE: conditional recommendation, very lowquality evidence) Key Evidence. One trial enrolled patients at highrisk for rebleeding (Rockall scores ≥6) who had undergone successful endoscopic therapy and received 3 days of high-dose PPI therapy (intravenous esomeprazole, 80-mg loading dose followed by 8-mg/h continuous infusion) (87). Patients were randomly assigned to receive oral esomeprazole, 40 mg, either once or twice daily for 11 days (days 3 to 14). All patients received an additional 2 weeks of once-daily PPI therapy. A reduction was found in rebleeding (RR, 0.37 [CI, 0.19 to 0.73]) but not mortality rates (RR, 0.38 [CI, 0.10 to 1.38]) with twice-versus once-daily PPIs. The QoE was downgraded for risk of bias and imprecision.
Discussion. Based on the data suggesting superiority over the standard dosage for rebleeding, the consensus group suggested the use of twice-daily PPIs to complete 2 weeks of PPI therapy, after 3 days of highdose therapy.
# Section D: Nonendoscopic and Nonpharmacologic In-Hospital Management
No updates to the 2010 international UGIB guidelines (4).
# Section E: Secondary Prophylaxis
# Statement E4
In patients with previous ulcer bleeding receiving cardiovascular prophylaxis with single-or dualantiplatelet therapy, we suggest using PPI therapy versus no PPI therapy.
(GRADE: conditional recommendation, low-quality evidence)
Key Evidence. Single-antiplatelet therapy: Evidence for the role of PPI therapy in patients receiving singleagent antiplatelet therapy was available from 5 randomized trials (88 -92) comparing PPIs versus no PPIs in patients requiring continued antiplatelet therapy. Because of heterogeneity in study designs and comparison groups, a meta-analysis of all 5 studies was not done. All 5 trials were conducted in Hong Kong. A history of H pylori infection and eradication treatment was common.
One trial found PPIs to be more effective than placebo in reducing recurrent complications (bleeding, perforation, and obstruction) (RR, 0.11 [CI, 0.01 to 0.84]) in patients with previous ulcer complications who had successful H pylori eradication and required continued antiplatelet therapy (acetylsalicylic acid [ASA]) (88). A meta-analysis of 2 trials showed that PPIs plus ASA reduced rebleeding rates versus clopidogrel alone (RR, 0.07 [CI, 0.01 to 0.34]) in patients with previous ASA-associated ulcer bleeding who did not have H pylori infection or who had it successfully eradicated (90,91). In patients with previous ASA-associated ulcer bleeding, trials found no difference between PPIs and eradication treatment in those with H pylori infection (89), or between PPIs and H 2 RAs in patients without H pylori infection or those in whom H pylori infection was eradicated (92). Two trials found no differences in mortality rates between PPI and placebo groups (88) or between PPIs plus ASA versus clopidogrel (89).
The evidence was downgraded, primarily for very serious imprecision (small studies, very low number of events).
Dual-antiplatelet therapy (DAPT): No randomized trials were found assessing the use of PPIs in patients receiving DAPT who had a history of ulcer bleeding. Two systematic reviews were found in patients receiving DAPT after percutaneous coronary intervention or in the presence of coronary artery disease (93,94). The reporting and methodological quality of both reviews were suboptimal, with inclusion of studies that were not eligible (for example, because of patients not receiving DAPT, incorrect comparisons, or double counting). A meta-analysis conducted for this guideline included 4 randomized trials (n = 4805) comparing PPI versus no PPI therapy in patients receiving prophylactic DAPT (ASA and clopidogrel). The largest study was international ( 95), whereas the other 3 were conducted in China (96 -98). The meta-analysis showed a reduction in gastrointestinal bleeding risk with PPI therapy versus placebo (n = 4 studies; RR, 0. No studies were found that assessed ASA in combination with other antiplatelet drugs, such as prasugrel or ticagrelor. The evidence was downgraded for high or unclear risk of bias in the Chinese studies and for serious indirectness in all 4 trials (most patients did not have a history of ulcer bleeding).
Discussion. The evidence consistently supports a benefit with PPI therapy in patients with previous ulcer bleeding who continue single-or dual-antiplatelet therapy and suggest that PPI therapy is superior to clopidogrel alone in patients receiving ASA.
Most patients in these studies had H pylori infection before PPI therapy, and in 1 study eradication treatment alone was as effective as PPI therapy (89). Observational data suggest that ulcer rebleeding risk in patients receiving low-dose ASA may be reduced among those who had H pylori infection eradicated compared with those who were never infected (99). It is anticipated that PPI therapy should be beneficial in populations with lower rates of H pylori infection, although the magnitude of effect may be decreased. The consensus group suggested that eradication therapy alone may be sufficient to reduce bleeding risk for some patients with H pylori infection, with only incremental benefits associated with additional PPI therapy.
Although various adverse events have been reported with PPI therapy (statement E5), the systematic review and meta-analysis conducted for this guideline found no increased risk for myocardial infarction in patients receiving DAPT.
On the basis of the evidence, the consensus group suggests PPI therapy to prevent rebleeding in most patients who require single-or dual-antiplatelet therapy for a duration consistent with the ongoing need for antiplatelet therapy.
# Statement E5
In patients with previous ulcer bleeding requiring continued cardiovascular prophylaxis with anticoagulant therapy (vitamin K antagonists, DOACs), we suggest using PPI therapy versus no PPI therapy.
(GRADE: conditional recommendation, very lowquality evidence) Key Evidence. Compared with no PPI therapy, the use of PPIs in patients receiving anticoagulant therapy was associated with a reduced risk for rebleeding in 2 large cohort studies (100, 101) but not in 3 casecontrol studies (102)(103)(104). Most patients included in these studies did not have a history of ulcer bleeding. In 1 small case-control study in patients with a history of UGIB, rebleeding risk was not significantly reduced in patients receiving warfarin plus PPIs (RR, 1.93 [CI, 0.23 to 16.28]) compared with those not receiving warfarin (103). In contrast, in 1 of the cohort studies the greatest risk reduction with PPI therapy versus no PPI therapy was seen in patients with a history of peptic ulcers or gastrointestinal bleeding (adjusted incidence rate ratio, 0.14 [CI, 0.06 to 0.30]) (101). None of the included studies assessed mortality.
The evidence was downgraded for indirectness (most patients did not have previous ulcer bleeding).
Discussion. A history of ulcer bleeding is associated with an increased risk for bleeding, and although anticoagulants do not cause ulcer bleeding, they increase the risk for bleeding from sites that have mucosal breaks.
Meta-analyses of primarily observational studies have suggested potential associations between PPI therapy and adverse effects, including communityacquired pneumonia, hip fracture, colorectal cancer, chronic kidney disease, community-acquired enteric infection, and Clostridium difficile infection (105)(106)(107)(108)(109). An analysis of factors, such as consistency, specificity, temporality, and biological plausibility, as well as confounding factors, showed that the evidence for causality is very weak (110). The consensus group concluded that for high-risk patients with an ongoing need for anticoagulants, the evidence suggests that the benefits of secondary prophylaxis outweigh the risks. The unproven potential and rare safety concerns should not prevent treatment for patients at risk for life-threatening consequences.
# ONGOING AND RESEARCH RECOMMENDATIONS
Although UGIB management has improved substantially during the past 2 decades, areas remain in which more data are needed (Appendix Table 4, available at Annals.org). In particular, more studies are needed to define the benefits of specific prognostic scales, the role of a restrictive versus liberal transfusion practice in patients with UGIB and cardiovascular disease, optimal PPI regimens, optimal endoscopic hemostatic therapies, and the role of PPIs in patients receiving antithrombotic therapy. Planned analyses from the COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial may clarify the efficacy and safety of PPIs versus no PPIs in patients receiving anticoagulant therapy (111).
Several pertinent articles that were not available at the time of this consensus have been published since the literature searches were completed (as of May 2018). These include a large randomized trial in patients with cardiovascular disease that compared the efficacy and safety of DOACs or ASA with or without PPI therapy (112,113). Randomized trials have assessed PPIs versus H 2 RAs for recurrent UGIB (114), as well as endoscopic therapy with hemostatic powder and hemoclips (115,116). In addition, the use of DEP to guide hemostasis has been studied further (117). Although a discussion of over-the-scope clips for recurrent peptic ulcer bleeding is beyond the scope of the statements addressed in this guideline, data are emerging (118). These are just some examples of new or ongoing studies that have the potential to affect clinical practice, but they may not do so. The consensus group cannot comment on the results of these trials, because a systematic Management of Upper Gastrointestinal Bleeding CLINICAL GUIDELINE literature search was not performed and the GRADE approach was not applied.
# APPLICABILITY AND IMPLEMENTATION ISSUES
Plans are under way to develop a user-friendly clinical algorithm for UGIB management, slide presentations, short videos, and CAG podcasts. The guidelines and supporting materials will be disseminated to all participating societies and regions through such venues as symposia sessions or workshops at society meetings. Major recommendations will be posted on society and government health Web sites. Finally, we anticipate that these guidelines will continue to be updated as new data become available. Note: This clinical practice guideline (CPG) on UGIB was developed under the direction of Drs. Alan N. Barkun and Marc Bardou, in accordance with the policies and procedures of the CAG and under the direction of CAG Clinical Affairs. It has been reviewed by the CAG Clinical Affairs Committee and the CAG Board of Directors. The CPG was developed after a thorough consideration of the medical literature and the best available evidence and clinical experience. It represents the consensus of a Canadian and international panel comprising experts on this topic. The CPG aims to provide a reasonable and practical approach to care for specialists and allied health professionals who are charged with providing optimal care to patients and their families, and it may be subject to change as scientific knowledge and technology advance and as practice patterns evolve.
# Disclaimer:
The CPG is not intended as a substitute for physicians using their individual judgment in managing clinical care in consultation with the patient, with appropriate regard to all the individual circumstances of the patient, the diagnostic and treatment options available, and the available re-sources. Adherence to these recommendations will not necessarily produce successful outcomes in every case.
#
Diabetes and the Saudi Gastroenterology Association for their generous support of the guideline process. The consensus group thanks Dr. Waleed Alhazzani (McMaster University) for participation in the development of PICO questions and in preliminary discussions and voting; Paul Sinclair, Cindy Roll, and Lesley Marshall (CAG representatives) for administrative and technical support and logistical assistance; and Pauline Lavigne and Steven Portelance for editorial assistance and medical writing services (supported by funds from the CAG).
Financial Support: By an unrestricted grant to the CAG by the CIHR Institute of Nutrition, Metabolism and Diabetes and the Saudi Gastroenterology Association. Disclosures: Dr. Barkun reports grants and consulting fees from and advisory board membership at Pendopharm and At-Gen, and advisory membership at Olympus and Cook, outside the submitted work. Dr | None | None |
96521729de94fa26ef2cb1a3a249e25e484b64e4 | cma | None | # Introduction
This document incorporates recommendations from the 2021 Canadian Thoracic Society (CTS) Guideline -A Focused Update on the Management of Very Mild and Mild Asthma 1 with previous statements and recommendations from the CTS 2010 2 and 2012 3 asthma guidelines and the CTS/ Canadian Pediatric Society 2015 position statement on the diagnosis and management of asthma in preschoolers. 4 For the evidence and rationale informing those recommendations and detailed information about preschool asthma, users should refer to the original documents. Recommendations from previous CTS guidelines were reviewed using the CTS Guideline Update Policy, the review process based on the "living guideline" concept, to determine if the information was still relevant and accurate. 5 The recommendations from the CTS 2017 Severe Asthma Guideline 6 have not been incorporated as severe asthma is typically managed in subspecialty clinics, but may be incorporated in future guideline updates. 1 compared to the 2012 guideline 3 1. Treatment for very mild asthma. Patients on as needed (PRN) use of a SABA with well-controlled asthma at higher risk for asthma exacerbation should have treatment escalated to daily inhaled corticosteroids (ICS) + PRN SABA (all ages) or PRN budesonide/formoterol (bud/form) (≥12 years of age) (Figure 3). Daily ICS (all ages) or PRN bud/form (≥12 years of age) are also options for patients on PRN SABA with well-controlled asthma who are not at higher risk for exacerbation, if they prefer to have better asthma control and to decrease their risk of asthma exacerbation. Previous guidance: Patients with very mild intermittent asthma may be treated with PRN SABA. ICS should be prescribed for those with symptoms even "less than 3 times a week, " those with mild loss of control, or those presenting with an asthma exacerbation requiring systemic steroids. 2. Treatment for mild asthma. Patients on PRN SABA with poorly-controlled asthma (as per updated CTS criteria) should have treatment escalated to daily ICS + PRN SABA. For individuals ≥12 years of age not controlled on PRN SABA who have poor adherence to daily ICS despite substantial asthma education and support, PRN bud/form is recommended over daily ICS + PRN SABA (Figure 3). Previous guidance: Use of an ICS/LABA combination as a reliever in lieu of a fast-acting beta-agonist (FABA) alone was not recommended. 3. Assessing risk of exacerbation in addition to asthma control. When deciding on optimal treatment, in addition to evaluating asthma control, risk of asthma exacerbation should be assessed based on the criteria presented in Table 3. Previous guidance: Exacerbations should be mild and infrequent, and some risk factors for exacerbation were included within the Asthma Control criteria. 4. Change in control criteria for daytime symptoms and frequency of reliever need. Those with well-controlled asthma should have daytime symptoms ≤ 2 days per week and need for reliever (SABA or PRN bud/form) ≤ 2 doses per week. For preschoolers, the frequency of symptoms has been changed from ≥8 days/month to >8 days/month to align with criteria for older patients. Previous guidance: Good asthma control if <4 days per week of daytime symptoms or <4 doses per week of FABA. 5. Clarification for criteria of mild versus severe asthma exacerbation. A severe asthma exacerbation is one that requires either systemic steroids, an emergency department (ED) visit or hospitalization. A mild exacerbation is an increase in asthma symptoms from baseline that does not require systemic steroids, an ED visit or a hospitalization. Previous guidance: Severity of exacerbations was not specifically defined. 6. Update of severity classification. Reclassification of asthma severity to remove the very severe category to align with the Recognition and Management of Severe Asthma Position Statement, 6 and to include other asthma therapies.
# Summary of new features
Previous guidance: Categories such as "mild intermittent" and "mild persistent" asthma were referred to in previous guidelines but are no longer used. This terminology can lead to a misunderstanding of the underlying pathophysiology of asthma as the term "mild intermittent" may suggest to patients that there are times when they do not have asthma when in fact, asthma is a chronic condition and it is only the symptoms that can be intermittent.
# Asthma continuum and ICS dosing table. Reference
ICS for dosing in the continuum has been changed to fluticasone propionate equivalents. SABA or bud/ form as needed has been extended across the bottom of the continuum (Figure 2). Dosing categories and treatments have been expanded in the continuum and ICS dosing table (
# Asthma definition
It is recognized that asthma is a heterogenous disorder compromised of many different phenotypes with an increased understanding of the various endotypes or mechanistic pathways. Although some advocate viewing asthma as a component of its parts or treatable traits, outside of severe asthma, current evidence is not to the point where treatment recommendations can be based on phenotypes or endotypes, although trials utilizing this approach are being conducted. 7,8 The definition of asthma remains unchanged from the previous CTS 2012 Asthma Guideline:
# Asthma is an inflammatory disorder of the airways characterized by paroxysmal or persistent symptoms such as dyspnea, chest tightness, wheezing, sputum production and cough, associated with variable airflow limitation and airway hyper-responsiveness to endogenous or exogenous stimuli. Inflammation and its resultant effects on airway structure and function are considered to be the main mechanisms leading to the development and maintenance of asthma. 3
# Asthma diagnosis
The diagnosis of asthma is based on a compatible clinical history (see previous definition) with objective evidence of reversible airflow obstruction (Table 1). In patients 6 years 13 or exercise challenge with ≥10-15% decrease in feV 1 post-exercise abbreviatons: saBa, short-acting beta-agonist; feV 1 , forced expiratory volume in 1 second; fVC, forced vital capacity; lln, lower limit of normal; iCs, inhaled corticosteroid; pC20, provocative concentration; pd20, provocative dose. a approximate lower limits of normal ratios for children and adults. b in children with mild intermittent symptoms and mild exacerbations, the diagnosis is only suggested because the accuracy of parental report of response to treatment may be unreliable due to misperception and spontaneous improvement of symptoms, which is why confirmation of reversible obstruction by direct observation from a health care provider is preferred. c Comparison of peak expiratory flows should be done on the same device given the variability between devices. d difference between minimum aM pre-bronchodilator value in 1 week and maximum pM value as % of recent maximum.
-f age and over, spirometry demonstrating reversible airflow obstruction is the preferred method of confirming a diagnosis of asthma. Since spirometry has a higher specificity than sensitivity for diagnosing asthma, normal spirometry does not rule out a diagnosis of asthma. 9 The diagnosis of asthma should be considered in children 1 to 5 years of age with recurrent asthma-like symptoms or exacerbations, even if triggered by viral infections. In children under the age of 6, a compatible clinical history, physical exam and trial of treatment are used to make a clinical diagnosis (Table 1, Figure 1). Given that up to 50% of children under the age of 6 outgrow their symptoms, a monitored trial off medication can be attempted when asthma is well-controlled with exposure to the child's typical triggers, including no exacerbations, for at least 3-6 months. 10,11
# Asthma management
The core components of asthma management are highlighted in the asthma management continuum (Figure 2) and include: 1) Assessing asthma control and risk of exacerbation, 2) Providing asthma self-management education including a written action plan, 3) Identifying triggers and discussing environmental control if applicable, and 4) Prescribing a documentation by a physician or trained health care practitioner. b episodes of wheezing with/without difficulty breathing. c severity of an exacerbation documented by clinical assessment of signs of airflow obstruction, preferably with the addition of objective measures such oxygen saturation and respiratory rate, and/or validated score such as the pediatric respiratory assessment Measure (praM) score. d Based on marked improvement in signs of airflow obstruction before and after therapy or a reduction of ≥ 3 points on the praM score, recognizing the expected time response to therapy. e a conclusive therapeutic trial hinges on adequate dose of asthma medication, adequate inhalation technique, diligent documentation of the signs and/or symptoms, and timely medical reassessment; if these conditions are not met, consider repeating the treatment or therapeutic trial. f the diagnosis of asthma is based on recurrent (≥ 2) episodes of asthma-like exacerbations (documented signs) and/or symptoms. in case of a first occurrence of exacerbation with no previous asthma-like symptoms, the diagnostic of asthma is suspected and can be confirmed with re-occurrence of asthma-like symptoms or exacerbations with response to asthma therapy. g >8 days/month with asthma-like symptoms. h severe exacerbations require any of the following: systemic steroids, hospitalization; or an emergency department visit. i in this age group, the diagnostic accuracy of parental report of a short-term response to as-needed short-acting β 2 -agonist (saBa) may be unreliable due to misperception and/or spontaneous improvement of another condition. documentation of airflow obstruction and reversibility when symptomatic, by a physician or trained health care practitioner, is preferred. j Based on 50% fewer severe exacerbations, shorter and milder exacerbations, and fewer, milder symptoms between episodes.
appropriate pharmacologic treatment to achieve and maintain asthma control which includes minimizing exacerbations.
# Asthma control and risk of exacerbation
Asthma control (Table 2) and risk for exacerbation (Table 3) should be assessed at each clinical encounter.
The goal of asthma treatment is to have well-controlled asthma in order to minimize short-and long-term complications, morbidity and mortality. 3 Asthma control is often thought of as symptom control; however, the CTS control criteria incorporate all facets of asthma control including: 1) symptoms and impact on quality of life; 2) exacerbations; 3) lung function; and 4) inflammatory markers for adults with moderate to severe asthma. The use of the fraction of exhaled nitric oxide (FeNO) as a marker of asthma control was assessed in the CTS 2012 asthma guideline 3 and was not recommended as a routine measurement.
For patients with poorly-controlled asthma, potential reasons for poor control should be assessed and corrected Management relies on an accurate diagnosis of asthma and regular reassessment of control and risk of exacerbation. all individuals with asthma should be provided with self-management education, including a written action plan. adherence to treatment, inhaler technique, exposure to environmental triggers, and the presence of comorbidities should be reassessed at each visit and optimized. individuals with well controlled asthma on no medication or prn saBa at lower risk of exacerbation can use prn saBa, daily iCs + prn saBa, and if ≥ 12 years of age prn bud/form*. individuals at higher risk of exacerbation even if well-controlled on prn saBa or no medication, and those with poorly-controlled asthma on prn saBa or no medication should be started on daily iCs + prn saBa. in individuals ≥ 12 years old with poor adherence despite substantial asthma education and support, prn bud/form- can be considered. ltra are second-line monotherapy for asthma. if asthma is not adequately controlled by daily low doses of iCs with good technique and adherence, additional therapy should be considered. in children 1-11 years old, iCs should be increased to medium dose and if still not controlled in children 6-11 years old, the addition of a laBa or ltra should be considered. in individuals 12 years of age and over, a laBa in the same inhaler as an iCs is first line adjunct therapy. if still not controlled, the addition of a ltra or tiotropium should be considered. in children who are not well-controlled on medium dose iCs, a referral to an asthma specialist is recommended. after achieving asthma control, including no severe exacerbations, for at least 3-6 months, medication should be reduced to the minimum necessary dose to maintain asthma control and prevent future exacerbations. Hfa, hydrofluoroalkane; saBa, short-acting beta-agonist, laBa, long-acting beta-agonist, iCs, inhaled corticosteroid, ltra, leukotriene receptor antagonist, bud/ form: budesonide-formoterol in a single inhaler prior to or in conjunction with escalation of pharmacologic therapy. This includes assessment of: adherence, inhalation technique and whether they have been using an empty inhaler, environmental (including occupational) exposures and key comorbidities (eg, rhinosinusitis, gastro-esophageal reflux, paradoxical vocal fold motion, anxiety and depression). 6 Individuals can have well-controlled asthma but still be at risk for exacerbation. Specific risk factors for severe exacerbations should be assessed at each clinical encounter (Table 3). These risk factors are particularly important when deciding on controller therapy for a patient with very mild or mild asthma.
A more complete list of risk factors for severe exacerbations (Table 4) and for near-fatal and fatal asthma (Table 5) are provided to facilitate discussion between clinicians and patients about their individual risk. Patients at risk for near fatal or fatal asthma require careful follow-up, and may benefit from a multi-disciplinary team, given that factors such as non-adherence, substance use and psychiatric illness increase their risk of death from asthma.
# Asthma education and written action plan
Once a diagnosis of asthma is made, it is important that patients and families receive appropriate asthma self-management education. Key components of an asthma education program are listed in Table 6. 2
# Written action plan
Written asthma action plans are an important part of care for all patients with asthma. 2 They have been shown to decrease exacerbations in children and adults. 21,22 There is no clear benefit of peak-flow based action plans in comparison to symptom-based action plans. 23,24 The choice between these 2 types of action plans can be individualized based on patient preference and physician judgment, as there are some circumstances (eg, patients with poor symptom perception) where a peak-flow based action plan may be of benefit.
Action plans should outline recommended daily preventive management strategies to maintain control, when and how to adjust reliever therapy (and controller therapy in adults prone to exacerbations) for loss of control and provide clear instructions regarding when to seek urgent medical attention. 2 Treatment in the yellow zone of an action plan will be discussed in the pharmacologic treatment section. Examples of action plans for children and adults can be found on the CTS website under Guidelines and Resources at y/ knowledge-tools-resources/asthma/
# Environmental control
Environmental factors that trigger a patient's asthma should be identified on history and avoided, if possible. Approximately 36% of adult-onset asthma cases are probably or possibly work-related; 25 therefore, it is important to perform a thorough medical and occupational history to identify work-related asthma.
Evidence for the clinical benefit of specific interventions to reduce exposure to indoor allergens in all patients with asthma is lacking. Given the expense and complexity of these interventions, these are not recommended as a general strategy; however, in patients with asthma symptoms triggered by indoor allergens, it would be prudent to minimize exposure. The current literature suggests that multi-component interventions (eg, use of two or more single-component interventions) are more effective than single-component interventions (eg, HEPA filters, cleaning products, carpet removal, pet removal). 30 First-or secondhand exposure to tobacco smoke is a risk factor for asthma exacerbations and counseling on smoking cessation should be provided. Smoking marijuana and vaping are increasing in prevalence, particularly among adolescents, a patient who meets all of the above criteria would be considered to have well-controlled asthma. - a mild exacerbation is an increase in asthma symptoms from baseline that does not require systemic steroids, an ed visit, or a hospitalization. "infrequent" is not specifically defined, since the frequency of mild exacerbations that patients consider an impairment to quality of life varies. if the patient feels that the frequency of mild exacerbations is impairing their quality of life, then their asthma should be considered poorly-controlled. if a patient is having frequent mild exacerbations, they should be assessed to determine if at baseline, they have poorly-controlled asthma. † there are no established criteria for control when using bud/form as a reliever,; however, use of a reliever often indicates that a patient is having symptoms and is a criterion that can be objectively assessed. # diurnal variation is calculated as the highest peak expiratory flow (pef) minus the lowest divided by the highest peak flow multiplied by 100, for morning and night (determined over a 2-week period). - Consider in adults ≥ 18 years of age with uncontrolled moderate to severe asthma who are assessed in specialist centers. 2. Identify triggers: identification and avoidance of environmental triggers specific to the patients.
Asthma control for all patients: asthma can be controlled and all patients with asthma can lead a normal life. regular symptoms, poor lung function and asthma exacerbations indicate treatment failure. 4. Minimal to no exacerbations for all patients: identify risk factors for asthma exacerbations. 5. Reliever vs. controller: the difference between reliever and controller medications and their use in the written action plan. 6. Written action plan: provision and explanation of a written action plan comprising:
- How and how often to assess asthma control (self-monitoring)
- instructions to maintain good control emphasizing adherence to controller medication and making specific environmental changes - signs and symptoms indicating poorly-controlled asthma, with instructions on what to do during loss of control (medication to add or increase, how much and how long; when and how to seek additional help (eg, when to go to the hospital or call the health care provider) 7. Medication safety and side effects: expected onset of action and potential side effects of medications. 8. Inhaler teaching: teaching and verification of the inhalation technique specific to the devices prescribed for the patient. ensuring patients know how to tell when an inhaler is empty. individuals with any one of these risk factors are at higher risk for asthma exacerbation:
- any history of a previous severe asthma exacerbation (requiring any of the following: systemic steroids, ed visit, or hospitalization) 2. poorly controlled asthma as per Cts criteria 3. overuse of saBa (defined as use of more than 2 inhalers of saBa in a year) 4. current smoker these risk factors were chosen based on or of >1.5 for severe exacerbations, certainty of the effect and ease of use in clinical practice. 1,14 Table 5. Risk factors associated with near-fatal or fatal asthma. 19,20 any previous near-fatal asthma exacerbation (eg, previous intensive care unit (iCu) admission, ventilation, respiratory acidosis) recurrent hospitalizations or ed visits in last year severe asthma overuse of saBa poor adherence to treatment plans failure to attend clinic appointments depression, anxiety or other psychiatric illness alcohol or other substance use obesity severe domestic, marital, employment, local stress denial of illness or severity of illness Note. this table is adapted from siGn 158 -British guideline on the management of asthma by kind permission of the scottish intercollegiate Guidelines network. 15 and these exposures are increasingly recognized as a cause for respiratory symptoms and risk for exacerbation in patients with asthma. 17,18,31 Pharmacologic treatment
# Inhaler device
It is important to consider the type of inhaler device that a patient prefers to use and can use properly before prescribing asthma medication, as most categories of medication come in multiple devices (eg, pressurized meter dose inhaler (pMDI), dry powder inhaler; Table 7). Poor inhaler technique is still seen in up to 70% of patients 32 and is associated with poor asthma control and increased exacerbations. 33 The use of valved holding chambers with pMDIs decreases oropharyngeal deposition of medication, increases lower airway deposition and overcomes issues with actuation-inhalation coordination. 34 Up to 50% of patients have poor actuation-inhalation coordination with pMDIs; 32 thus, valved holding chambers should be recommended for all ages of patients prescribed a pMDI, particularly with inhaled corticosteroids. 35 Dry powder inhalers require a minimal inspiratory pressure, which may be difficult in young children and occasionally in adult patients with low FEV 1 or other comorbid illnesses such as neuromuscular weakness, 36 particularly during asthma exacerbations. For resource with pictures of available asthma medication and videos on proper inhaler technique, see / knowledge-tools-resources/asthma/.
# Reliever therapy
All individuals with asthma should have access to a reliever for use as needed to treat acute symptoms. In Canada, SABAs (salbutamol, terbutaline), and a combination inhaler (bud/form) are approved for this indication. As needed bud/form is approved for use as a reliever in adults and children ≥12 years of age. Bud/form is not studied and should not be used as a reliever when controller medications other than maintenance bud/form are used. The use of bud/form as a reliever in patients not on a daily controller medication (p 8), and in those on a fixed dose of bud/form for maintenance (p 8) will be discussed in the Controller Therapy section.
Regular need for a reliever (more than 2 doses per week) merits reevaluation to identify the reason(s) for poorly-controlled asthma. Frequent use of a SABA reliever is a risk factor for severe exacerbations and asthma-related death, 16 and the use of more than two inhalers of SABA in a year (typically containing 200 doses each) should prompt reevaluation of asthma control.
SABAs should only be used for symptom relief and should not be regularly used "to open the airways" before daily controller therapy administration as this has been shown to increase risk of exacerbations. 1
# Controller therapy
The effectiveness of each treatment should be carefully evaluated for its impact on current control, future risk (in particular asthma exacerbations), and side effects. 3 The safest and minimum effective ICS dose that acheives the goals of current control and eliminates exacerbations, should be prescribed to minimize side effects in all groups, particularly in children to address the concern regarding growth velocity.
Improvement in clinical symptoms occurs within 1-2 weeks of starting daily ICS, 38 although it can take months to see a plateau in improvement. The dosing table provides comparative dosing for the ICS approved for use in Canada (Table 8). There is a plateau in the dose-response curve for ICS in a large number of patients who respond to daily low-to medium-dose ICS that is dose equivalent to 200-250 mcg of fluticasone proprionate. 42,43 For patients with poorly-controlled asthma, potential reasons for poor control should be assessed and corrected prior to or in conjunction with escalation of pharmacologic therapy. This includes assessment of: adherence, inhalation technique and whether they have been using an empty inhaler, environmental (including occupational) exposures and key comorbidities (eg, rhinosinusitis, gastro-esophageal reflux, paradoxical vocal fold motion, anxiety and depression). 6 Patients not on controller therapy (Figure 3)
Patients who are well controlled on PRN SABA or no medication with a lower risk for exacerbations can continue PRN SABA or be switched to either daily ICS + PRN SABA (all ages) or PRN bud/form (≥12 years of age) if they prefer to have better asthma control or reduce their risk for exacerbations. 1 Patients well-controlled on PRN SABA or no medication who are at higher risk for exacerbations should not be on PRN SABA, even if they have minimal symptoms. They should be switched to daily ICS + PRN SABA (all ages) or PRN bud/form (≥ 12 years of age). Daily ICS + PRN SABA is the recommended controller therapy except for patients ≥ 12 years of age with poor adherence to daily medication despite substantial asthma education and support, for whom PRN bud/form is recommended over daily ICS + PRN SABA. 1 Patients who are not controlled on PRN SABA or no medication should be on daily ICS + PRN SABA
The strategy of taking an ICS each time a SABA is taken (PRN ICS-SABA) is not approved for use in Canada, and is only recommended as a harm reduction measure in patients ≥18 years of age at higher risk for exacerbations who are unable to use daily ICS + PRN SABA or PRN bud/ form. 1 The clinical trial that evaluated this strategy in adults using 2 separate inhalers 44 used a regimen of beclomethasone 50 mcg 2 puffs each time salbutamol 100 mcg 2 puffs was used. If clinicians recommend this strategy (off-label), we suggest that the maximum approved daily ICS dose should not be exceeded (see Table 8).
In patients of all ages, leukotriene receptor antagonists (LTRAs) are second line to daily ICS.
# Patients not achieving control on low dose ICS
Children not achieving asthma control despite adherence to low dose ICS should be increased to medium dose ICS (Table 8). Children < 6 years of age, not achieving control on medium dose ICS should be referred to an asthma specialist (section Reasons for Referral).
Children 6-11 years of age not achieving control on medium dose ICS should be started on a second controller medication, either a LABA (in the same inhaler as the ICS) or LTRA. Improvement is overall more likely to be seen with the addition of a LABA; however, individual responses vary and the side effect profile of these medications should also be discussed with patients and parents when making this decision (section Safety of LABA and LTRA). 45 In children 6-11 years of age not controlled on low dose ICS, other guidelines 46,47 recommend either increasing to medium dose ICS or adding a LABA, based on the current evidence not showing clear superiority and safety of one regimen over the other. However, the limited approval of ICS/LABA formulations in Canada for children 6-11 years of age precludes a similar recommendation at this time.
Children ≥12 years of age and adults not achieving control despite adherence to low dose ICS should be started on daily ICS/LABA. Alternative options include adding an LTRA or increasing to a medium dose of ICS.
Individuals ≥12 years of age and adults on an ICS/LABA with poor control or who are prone to exacerbations can be switched to bud/form maintenance and reliever therapy at the same maintenance ICS dose.
# Patients not achieving control on moderate dose ICS + second controller medication
Health care providers are referred to the CTS 2017 position statement on the Recognition and Management of Severe Asthma 6 for further recommendations on assessment and management.
# Safety of LABA and LTRA
The safety of LABA taken in conjunction with ICS has been demonstrated in large trials, 48 and there is no longer a black box warning on LABA medications. They are still, however, not to be used as monotherapy. A new black box warning has been issued for LTRAs due to neuropsychiatric side effects, most commonly irritability, aggressiveness, anxiety and sleep disturbance including suicidal thoughts or actions. 49 These side effects have been reported in up to 16% of pediatric asthma patients started on montelukast and typically occurred within 2 weeks of initiation. 50,51
# Yellow zone management (Table 9)
It is not recommended that children and adults on maintenance ICS double the dose of their ICS with acute loss of asthma control given the lack of benefit of this approach.
In children (<16 years of age and older) it is not recommended that the ICS dose be increased by 4-fold or more given the lack of benefit of this approach. This was recently confirmed in a trial of 5 to 11 year olds examining fluticasone 200 mcg/day versus 1000 mcg/day in the yellow zone, which did not find any decrease in exacerbations. 52 - increase bud/form to a maximum of 8 inhalations per day daily iCs or ltra in individuals ≥16 years of age and older with a history of a severe exacerbation in the last year: - 1 st choice: trial of ≥4 fold increase in iCs for 7 to 14 days - 2 nd choice: prednisone 30-50 mg for at least 5 days- otherwise no step up in controller medication. daily bud/form - 1 st choice: increase bud/form to a maximum of 4 inhalations twice daily for 7 to 14 days (≥16 years of age and older) or use bud/form as reliever and a controller (maximum 8 inhalations per day) (≥12 years of age and older) - 2 nd choice: prednisone 30-50 mg for at least 5 days- daily fluticasone propionate/ salmeterol, mometasone/ formoterol, fluticasone furoate/vilanterol in individuals ≥16 years of age with a history of a severe exacerbation in the last year: - 1 st choice: trial of ≥4 fold increase in iCs (higher iCs strength of iCs/laBa combination or extra iCs) for 7 to 14 days - 2 nd choice: prednisone 30-50 mg for at least 5 days- otherwise no step up in controller medication. - if regular need for step up therapy or need for a course of systemic steroids, address reasons for poor control and reassess/initiate controller therapy. does not apply to preschoolers.
In adults (≥16 years of age) with a history of a severe exacerbation in the last year, a trial of a 4 or 5-fold increase in maintenance ICS dose for 7-14 days is suggested. A pragmatic trial of adults (16 years of age and older) compared quadrupling the dose of ICS in the yellow zone to maintaining the same baseline dose and found a modest improvement in severe exacerbations (45% in the quadrupling group vs 52% in the control group, hazard ratio for time to first exacerbation 0.81, 95% confidence interval 0.71-0.92, p = 0.002) at the expense of increased dysphonia and oral candidiasis in the quadrupling group. 53 In adults (≥16 years of age) on daily bud/form, it is suggested that the dose be increased to a maximum of 4 inhalations twice daily for 7-14 days, as this has been shown to decrease severe exacerbations. 3 Evidence for increasing doses for other ICS/LABA formulations is lacking, and for adult patients on daily ICS/ LABA other than bud/form, a 4-fold or greater increase in ICS dose for 7-14 days or a course of systemic steroids is only suggested for adults that are exacerbation prone. Health care providers should be aware of the maximum daily LABA dose approved for adult use in Canada (salmeterol 100 mcg, formoterol 48 mcg, vilanterol 25 mcg). A tool to assist clinicians prescribe increased doses of ICS or ICS/LABA in the yellow zone is available in the Guidelines and Resources section of the CTS website at /.
It is not recommended to routinely add oral corticosteroids as part of a written action plan in children or adults except in patients with recent severe exacerbations who fail to respond to inhaled SABA as part of their written action plan.
Prednisone dose and duration in adults should be individualized based on previous or current response. A dose of 30 to 50 mg/day for at least 5 days is suggested. For children suggested dose is 1 mg/kg/day (maximum 50 mg) for at least 3 days.
Any severe exacerbation (requiring use of systemic steroids, ED visit or hospitalization) is an indication to start a controller therapy for patients only on PRN SABA (see Figure 3) and for all patients is an indication for a reassessment of asthma mangement. Frequent courses of oral corticosteroid should prompt referral to a specialist (see the Reasons for referral section).
# Asthma severity
Asthma severity is defined by the intensity of medication required to maintain asthma control. Given that it can only be determined once asthma control is achieved, categorization of asthma severity is not useful to guide treatment decisions except when a patient meets the criteria for severe asthma and other therapeutic options are available. 6 This classification (Table 10) is an update to the 1999 criteria and is provided to standardize terminology. It is important to highlight that even those with very mild or mild asthma are at risk for asthma-related morbidity, including exacerbations and mortality. 19
# Reasons for referral
A referral to an asthma specialist for consultation or co-management is recommended for the following reasons:
- Diagnostic uncertainty - Children not controlled on moderate dose ICS with correct inhaler technique and appropriate medication adherence - Suspected or confirmed severe asthma - Life-threatening event such as an admission to the ICU for asthma - Need for allergy testing to assess the possible role of environmental allergens in those with a suggestive clinical history - Confirmed or suspected work-related asthma or - Any asthma hospitalization (all ages), ≥ 2 ED visits (all ages) or ≥ 2 courses of systemic steroids (children)
An asthma specialist includes specialists in asthma, general respirology, pediatrics, and/or allergy/immunology who have access to lung function, certified asthma/respiratory educators/ nurse clinicians +/-FeNO, induced sputum analysis. 6 Questions for future guidelines to address These topics were identified during the update of this guideline as areas where there is differing recommendations in international and national guidelines, or where a specific clinical question has not been addressed in the past or requires updating. Mild exacerbation: an increase in asthma symptoms from baseline that does not require systemic steroids, an emergency department visit or a hospitalization. Differentiating this from chronic poorly-controlled asthma may only occur retrospectively.
Higher risk of exacerbation is defined by presence of any of the following:
- any history of a previous severe asthma exacerbation (requiring either systemic steroids, ED visit or hospitalization);
- poorly-controlled asthma as per CTS criteria; 3. overuse of SABA (using more than 2 inhalers of SABA in 1 year); or 4. being a current smoker.
Individuals without any of these features have a lower risk of exacerbation.
Well-controlled asthma: Asthma in which all criteria for well-controlled asthma are met (Table 3) Poorly-controlled asthma: Asthma in which any one of the criteria for well-controlled are not met (Table 3). | # Introduction
This document incorporates recommendations from the 2021 Canadian Thoracic Society (CTS) Guideline -A Focused Update on the Management of Very Mild and Mild Asthma 1 with previous statements and recommendations from the CTS 2010 2 and 2012 3 asthma guidelines and the CTS/ Canadian Pediatric Society 2015 position statement on the diagnosis and management of asthma in preschoolers. 4 For the evidence and rationale informing those recommendations and detailed information about preschool asthma, users should refer to the original documents. [1][2][3][4] Recommendations from previous CTS guidelines were reviewed using the CTS Guideline Update Policy, the review process based on the "living guideline" concept, to determine if the information was still relevant and accurate. 5 The recommendations from the CTS 2017 Severe Asthma Guideline 6 have not been incorporated as severe asthma is typically managed in subspecialty clinics, but may be incorporated in future guideline updates. 1 compared to the 2012 guideline 3 1. Treatment for very mild asthma. Patients on as needed (PRN) use of a SABA with well-controlled asthma at higher risk for asthma exacerbation should have treatment escalated to daily inhaled corticosteroids (ICS) + PRN SABA (all ages) or PRN budesonide/formoterol (bud/form) (≥12 years of age) (Figure 3). Daily ICS (all ages) or PRN bud/form (≥12 years of age) are also options for patients on PRN SABA with well-controlled asthma who are not at higher risk for exacerbation, if they prefer to have better asthma control and to decrease their risk of asthma exacerbation. Previous guidance: Patients with very mild intermittent asthma may be treated with PRN SABA. ICS should be prescribed for those with symptoms even "less than 3 times a week, " those with mild loss of control, or those presenting with an asthma exacerbation requiring systemic steroids. 2. Treatment for mild asthma. Patients on PRN SABA with poorly-controlled asthma (as per updated CTS criteria) should have treatment escalated to daily ICS + PRN SABA. For individuals ≥12 years of age not controlled on PRN SABA who have poor adherence to daily ICS despite substantial asthma education and support, PRN bud/form is recommended over daily ICS + PRN SABA (Figure 3). Previous guidance: Use of an ICS/LABA combination as a reliever in lieu of a fast-acting beta-agonist (FABA) alone was not recommended. 3. Assessing risk of exacerbation in addition to asthma control. When deciding on optimal treatment, in addition to evaluating asthma control, risk of asthma exacerbation should be assessed based on the criteria presented in Table 3. Previous guidance: Exacerbations should be mild and infrequent, and some risk factors for exacerbation were included within the Asthma Control criteria. 4. Change in control criteria for daytime symptoms and frequency of reliever need. Those with well-controlled asthma should have daytime symptoms ≤ 2 days per week and need for reliever (SABA or PRN bud/form) ≤ 2 doses per week. For preschoolers, the frequency of symptoms has been changed from ≥8 days/month to >8 days/month to align with criteria for older patients. Previous guidance: Good asthma control if <4 days per week of daytime symptoms or <4 doses per week of FABA. 5. Clarification for criteria of mild versus severe asthma exacerbation. A severe asthma exacerbation is one that requires either systemic steroids, an emergency department (ED) visit or hospitalization. A mild exacerbation is an increase in asthma symptoms from baseline that does not require systemic steroids, an ED visit or a hospitalization. Previous guidance: Severity of exacerbations was not specifically defined. 6. Update of severity classification. Reclassification of asthma severity to remove the very severe category to align with the Recognition and Management of Severe Asthma Position Statement, 6 and to include other asthma therapies.
# Summary of new features
Previous guidance: Categories such as "mild intermittent" and "mild persistent" asthma were referred to in previous guidelines but are no longer used. This terminology can lead to a misunderstanding of the underlying pathophysiology of asthma as the term "mild intermittent" may suggest to patients that there are times when they do not have asthma when in fact, asthma is a chronic condition and it is only the symptoms that can be intermittent.
# Asthma continuum and ICS dosing table. Reference
ICS for dosing in the continuum has been changed to fluticasone propionate equivalents. SABA or bud/ form as needed has been extended across the bottom of the continuum (Figure 2). Dosing categories and treatments have been expanded in the continuum and ICS dosing table (
# Asthma definition
It is recognized that asthma is a heterogenous disorder compromised of many different phenotypes with an increased understanding of the various endotypes or mechanistic pathways. Although some advocate viewing asthma as a component of its parts or treatable traits, outside of severe asthma, current evidence is not to the point where treatment recommendations can be based on phenotypes or endotypes, although trials utilizing this approach are being conducted. 7,8 The definition of asthma remains unchanged from the previous CTS 2012 Asthma Guideline:
# Asthma is an inflammatory disorder of the airways characterized by paroxysmal or persistent symptoms such as dyspnea, chest tightness, wheezing, sputum production and cough, associated with variable airflow limitation and airway hyper-responsiveness to endogenous or exogenous stimuli. Inflammation and its resultant effects on airway structure and function are considered to be the main mechanisms leading to the development and maintenance of asthma. 3
# Asthma diagnosis
The diagnosis of asthma is based on a compatible clinical history (see previous definition) with objective evidence of reversible airflow obstruction (Table 1). In patients 6 years 13 or exercise challenge with ≥10-15% decrease in feV 1 post-exercise abbreviatons: saBa, short-acting beta-agonist; feV 1 , forced expiratory volume in 1 second; fVC, forced vital capacity; lln, lower limit of normal; iCs, inhaled corticosteroid; pC20, provocative concentration; pd20, provocative dose. a approximate lower limits of normal ratios for children and adults. b in children with mild intermittent symptoms and mild exacerbations, the diagnosis is only suggested because the accuracy of parental report of response to treatment may be unreliable due to misperception and spontaneous improvement of symptoms, which is why confirmation of reversible obstruction by direct observation from a health care provider is preferred. c Comparison of peak expiratory flows should be done on the same device given the variability between devices. d difference between minimum aM pre-bronchodilator value in 1 week and maximum pM value as % of recent maximum.
of age and over, spirometry demonstrating reversible airflow obstruction is the preferred method of confirming a diagnosis of asthma. Since spirometry has a higher specificity than sensitivity for diagnosing asthma, normal spirometry does not rule out a diagnosis of asthma. 9 The diagnosis of asthma should be considered in children 1 to 5 years of age with recurrent asthma-like symptoms or exacerbations, even if triggered by viral infections. In children under the age of 6, a compatible clinical history, physical exam and trial of treatment are used to make a clinical diagnosis (Table 1, Figure 1). Given that up to 50% of children under the age of 6 outgrow their symptoms, a monitored trial off medication can be attempted when asthma is well-controlled with exposure to the child's typical triggers, including no exacerbations, for at least 3-6 months. 10,11
# Asthma management
The core components of asthma management are highlighted in the asthma management continuum (Figure 2) and include: 1) Assessing asthma control and risk of exacerbation, 2) Providing asthma self-management education including a written action plan, 3) Identifying triggers and discussing environmental control if applicable, and 4) Prescribing a documentation by a physician or trained health care practitioner. b episodes of wheezing with/without difficulty breathing. c severity of an exacerbation documented by clinical assessment of signs of airflow obstruction, preferably with the addition of objective measures such oxygen saturation and respiratory rate, and/or validated score such as the pediatric respiratory assessment Measure (praM) score. d Based on marked improvement in signs of airflow obstruction before and after therapy or a reduction of ≥ 3 points on the praM score, recognizing the expected time response to therapy. e a conclusive therapeutic trial hinges on adequate dose of asthma medication, adequate inhalation technique, diligent documentation of the signs and/or symptoms, and timely medical reassessment; if these conditions are not met, consider repeating the treatment or therapeutic trial. f the diagnosis of asthma is based on recurrent (≥ 2) episodes of asthma-like exacerbations (documented signs) and/or symptoms. in case of a first occurrence of exacerbation with no previous asthma-like symptoms, the diagnostic of asthma is suspected and can be confirmed with re-occurrence of asthma-like symptoms or exacerbations with response to asthma therapy. g >8 days/month with asthma-like symptoms. h severe exacerbations require any of the following: systemic steroids, hospitalization; or an emergency department visit. i in this age group, the diagnostic accuracy of parental report of a short-term response to as-needed short-acting β 2 -agonist (saBa) may be unreliable due to misperception and/or spontaneous improvement of another condition. documentation of airflow obstruction and reversibility when symptomatic, by a physician or trained health care practitioner, is preferred. j Based on 50% fewer severe exacerbations, shorter and milder exacerbations, and fewer, milder symptoms between episodes.
appropriate pharmacologic treatment to achieve and maintain asthma control which includes minimizing exacerbations.
# Asthma control and risk of exacerbation
Asthma control (Table 2) and risk for exacerbation (Table 3) should be assessed at each clinical encounter.
The goal of asthma treatment is to have well-controlled asthma in order to minimize short-and long-term complications, morbidity and mortality. 3 Asthma control is often thought of as symptom control; however, the CTS control criteria incorporate all facets of asthma control including: 1) symptoms and impact on quality of life; 2) exacerbations; 3) lung function; and 4) inflammatory markers for adults with moderate to severe asthma. The use of the fraction of exhaled nitric oxide (FeNO) as a marker of asthma control was assessed in the CTS 2012 asthma guideline 3 and was not recommended as a routine measurement.
For patients with poorly-controlled asthma, potential reasons for poor control should be assessed and corrected Management relies on an accurate diagnosis of asthma and regular reassessment of control and risk of exacerbation. all individuals with asthma should be provided with self-management education, including a written action plan. adherence to treatment, inhaler technique, exposure to environmental triggers, and the presence of comorbidities should be reassessed at each visit and optimized. individuals with well controlled asthma on no medication or prn saBa at lower risk of exacerbation can use prn saBa, daily iCs + prn saBa, and if ≥ 12 years of age prn bud/form*. individuals at higher risk of exacerbation even if well-controlled on prn saBa or no medication, and those with poorly-controlled asthma on prn saBa or no medication should be started on daily iCs + prn saBa. in individuals ≥ 12 years old with poor adherence despite substantial asthma education and support, prn bud/form* can be considered. ltra are second-line monotherapy for asthma. if asthma is not adequately controlled by daily low doses of iCs with good technique and adherence, additional therapy should be considered. in children 1-11 years old, iCs should be increased to medium dose and if still not controlled in children 6-11 years old, the addition of a laBa or ltra should be considered. in individuals 12 years of age and over, a laBa in the same inhaler as an iCs is first line adjunct therapy. if still not controlled, the addition of a ltra or tiotropium should be considered. in children who are not well-controlled on medium dose iCs, a referral to an asthma specialist is recommended. after achieving asthma control, including no severe exacerbations, for at least 3-6 months, medication should be reduced to the minimum necessary dose to maintain asthma control and prevent future exacerbations. Hfa, hydrofluoroalkane; saBa, short-acting beta-agonist, laBa, long-acting beta-agonist, iCs, inhaled corticosteroid, ltra, leukotriene receptor antagonist, bud/ form: budesonide-formoterol in a single inhaler prior to or in conjunction with escalation of pharmacologic therapy. This includes assessment of: adherence, inhalation technique and whether they have been using an empty inhaler, environmental (including occupational) exposures and key comorbidities (eg, rhinosinusitis, gastro-esophageal reflux, paradoxical vocal fold motion, anxiety and depression). 6 Individuals can have well-controlled asthma but still be at risk for exacerbation. Specific risk factors for severe exacerbations should be assessed at each clinical encounter (Table 3). These risk factors are particularly important when deciding on controller therapy for a patient with very mild or mild asthma.
A more complete list of risk factors for severe exacerbations (Table 4) and for near-fatal and fatal asthma (Table 5) are provided to facilitate discussion between clinicians and patients about their individual risk. Patients at risk for near fatal or fatal asthma require careful follow-up, and may benefit from a multi-disciplinary team, given that factors such as non-adherence, substance use and psychiatric illness increase their risk of death from asthma.
# Asthma education and written action plan
Once a diagnosis of asthma is made, it is important that patients and families receive appropriate asthma self-management education. Key components of an asthma education program are listed in Table 6. 2
# Written action plan
Written asthma action plans are an important part of care for all patients with asthma. 2 They have been shown to decrease exacerbations in children and adults. 21,22 There is no clear benefit of peak-flow based action plans in comparison to symptom-based action plans. 23,24 The choice between these 2 types of action plans can be individualized based on patient preference and physician judgment, as there are some circumstances (eg, patients with poor symptom perception) where a peak-flow based action plan may be of benefit.
Action plans should outline recommended daily preventive management strategies to maintain control, when and how to adjust reliever therapy (and controller therapy in adults prone to exacerbations) for loss of control and provide clear instructions regarding when to seek urgent medical attention. 2 Treatment in the yellow zone of an action plan will be discussed in the pharmacologic treatment section. Examples of action plans for children and adults can be found on the CTS website under Guidelines and Resources at https://cts-sct.ca/guideline-librar y/ knowledge-tools-resources/asthma/
# Environmental control
Environmental factors that trigger a patient's asthma should be identified on history and avoided, if possible. Approximately 36% of adult-onset asthma cases are probably or possibly work-related; 25 therefore, it is important to perform a thorough medical and occupational history to identify work-related asthma.
Evidence for the clinical benefit of specific interventions to reduce exposure to indoor allergens in all patients with asthma is lacking. [26][27][28][29] Given the expense and complexity of these interventions, these are not recommended as a general strategy; however, in patients with asthma symptoms triggered by indoor allergens, it would be prudent to minimize exposure. The current literature suggests that multi-component interventions (eg, use of two or more single-component interventions) are more effective than single-component interventions (eg, HEPA filters, cleaning products, carpet removal, pet removal). 30 First-or secondhand exposure to tobacco smoke is a risk factor for asthma exacerbations and counseling on smoking cessation should be provided. Smoking marijuana and vaping are increasing in prevalence, particularly among adolescents, a patient who meets all of the above criteria would be considered to have well-controlled asthma. * a mild exacerbation is an increase in asthma symptoms from baseline that does not require systemic steroids, an ed visit, or a hospitalization. "infrequent" is not specifically defined, since the frequency of mild exacerbations that patients consider an impairment to quality of life varies. if the patient feels that the frequency of mild exacerbations is impairing their quality of life, then their asthma should be considered poorly-controlled. if a patient is having frequent mild exacerbations, they should be assessed to determine if at baseline, they have poorly-controlled asthma. † there are no established criteria for control when using bud/form as a reliever,; however, use of a reliever often indicates that a patient is having symptoms and is a criterion that can be objectively assessed. # diurnal variation is calculated as the highest peak expiratory flow (pef) minus the lowest divided by the highest peak flow multiplied by 100, for morning and night (determined over a 2-week period). • Consider in adults ≥ 18 years of age with uncontrolled moderate to severe asthma who are assessed in specialist centers. 2. Identify triggers: identification and avoidance of environmental triggers specific to the patients.
# 3.
Asthma control for all patients: asthma can be controlled and all patients with asthma can lead a normal life. regular symptoms, poor lung function and asthma exacerbations indicate treatment failure. 4. Minimal to no exacerbations for all patients: identify risk factors for asthma exacerbations. 5. Reliever vs. controller: the difference between reliever and controller medications and their use in the written action plan. 6. Written action plan: provision and explanation of a written action plan comprising:
• How and how often to assess asthma control (self-monitoring)
• instructions to maintain good control emphasizing adherence to controller medication and making specific environmental changes • signs and symptoms indicating poorly-controlled asthma, with instructions on what to do during loss of control (medication to add or increase, how much and how long; when and how to seek additional help (eg, when to go to the hospital or call the health care provider) 7. Medication safety and side effects: expected onset of action and potential side effects of medications. 8. Inhaler teaching: teaching and verification of the inhalation technique specific to the devices prescribed for the patient. ensuring patients know how to tell when an inhaler is empty. individuals with any one of these risk factors are at higher risk for asthma exacerbation:
1. any history of a previous severe asthma exacerbation (requiring any of the following: systemic steroids, ed visit, or hospitalization) 2. poorly controlled asthma as per Cts criteria 3. overuse of saBa (defined as use of more than 2 inhalers of saBa in a year) 4. current smoker these risk factors were chosen based on or of >1.5 for severe exacerbations, certainty of the effect and ease of use in clinical practice. 1,14 Table 5. Risk factors associated with near-fatal or fatal asthma. 19,20 any previous near-fatal asthma exacerbation (eg, previous intensive care unit (iCu) admission, ventilation, respiratory acidosis) recurrent hospitalizations or ed visits in last year severe asthma overuse of saBa poor adherence to treatment plans failure to attend clinic appointments depression, anxiety or other psychiatric illness alcohol or other substance use obesity severe domestic, marital, employment, local stress denial of illness or severity of illness Note. this table is adapted from siGn 158 -British guideline on the management of asthma by kind permission of the scottish intercollegiate Guidelines network. 15 and these exposures are increasingly recognized as a cause for respiratory symptoms and risk for exacerbation in patients with asthma. 17,18,31 Pharmacologic treatment
# Inhaler device
It is important to consider the type of inhaler device that a patient prefers to use and can use properly before prescribing asthma medication, as most categories of medication come in multiple devices (eg, pressurized meter dose inhaler (pMDI), dry powder inhaler; Table 7). Poor inhaler technique is still seen in up to 70% of patients 32 and is associated with poor asthma control and increased exacerbations. 33 The use of valved holding chambers with pMDIs decreases oropharyngeal deposition of medication, increases lower airway deposition and overcomes issues with actuation-inhalation coordination. 34 Up to 50% of patients have poor actuation-inhalation coordination with pMDIs; 32 thus, valved holding chambers should be recommended for all ages of patients prescribed a pMDI, particularly with inhaled corticosteroids. 35 Dry powder inhalers require a minimal inspiratory pressure, which may be difficult in young children and occasionally in adult patients with low FEV 1 or other comorbid illnesses such as neuromuscular weakness, 36 particularly during asthma exacerbations. For resource with pictures of available asthma medication and videos on proper inhaler technique, see https://cts-sct.ca/guideline-library/ knowledge-tools-resources/asthma/.
# Reliever therapy
All individuals with asthma should have access to a reliever for use as needed to treat acute symptoms. In Canada, SABAs (salbutamol, terbutaline), and a combination inhaler (bud/form) are approved for this indication. As needed bud/form is approved for use as a reliever in adults and children ≥12 years of age. Bud/form is not studied and should not be used as a reliever when controller medications other than maintenance bud/form are used. The use of bud/form as a reliever in patients not on a daily controller medication (p 8), and in those on a fixed dose of bud/form for maintenance (p 8) will be discussed in the Controller Therapy section.
Regular need for a reliever (more than 2 doses per week) merits reevaluation to identify the reason(s) for poorly-controlled asthma. Frequent use of a SABA reliever is a risk factor for severe exacerbations and asthma-related death, 16 and the use of more than two inhalers of SABA in a year (typically containing 200 doses each) should prompt reevaluation of asthma control.
SABAs should only be used for symptom relief and should not be regularly used "to open the airways" before daily controller therapy administration as this has been shown to increase risk of exacerbations. 1
# Controller therapy
The effectiveness of each treatment should be carefully evaluated for its impact on current control, future risk (in particular asthma exacerbations), and side effects. 3 The safest and minimum effective ICS dose that acheives the goals of current control and eliminates exacerbations, should be prescribed to minimize side effects in all groups, particularly in children to address the concern regarding growth velocity.
Improvement in clinical symptoms occurs within 1-2 weeks of starting daily ICS, 38 although it can take months to see a plateau in improvement. [39][40][41] The dosing table provides comparative dosing for the ICS approved for use in Canada (Table 8). There is a plateau in the dose-response curve for ICS in a large number of patients who respond to daily low-to medium-dose ICS that is dose equivalent to 200-250 mcg of fluticasone proprionate. 42,43 For patients with poorly-controlled asthma, potential reasons for poor control should be assessed and corrected prior to or in conjunction with escalation of pharmacologic therapy. This includes assessment of: adherence, inhalation technique and whether they have been using an empty inhaler, environmental (including occupational) exposures and key comorbidities (eg, rhinosinusitis, gastro-esophageal reflux, paradoxical vocal fold motion, anxiety and depression). 6 Patients not on controller therapy (Figure 3)
Patients who are well controlled on PRN SABA or no medication with a lower risk for exacerbations can continue PRN SABA or be switched to either daily ICS + PRN SABA (all ages) or PRN bud/form (≥12 years of age) if they prefer to have better asthma control or reduce their risk for exacerbations. 1 Patients well-controlled on PRN SABA or no medication who are at higher risk for exacerbations should not be on PRN SABA, even if they have minimal symptoms. They should be switched to daily ICS + PRN SABA (all ages) or PRN bud/form (≥ 12 years of age). Daily ICS + PRN SABA is the recommended controller therapy except for patients ≥ 12 years of age with poor adherence to daily medication despite substantial asthma education and support, for whom PRN bud/form is recommended over daily ICS + PRN SABA. 1 Patients who are not controlled on PRN SABA or no medication should be on daily ICS + PRN SABA
The strategy of taking an ICS each time a SABA is taken (PRN ICS-SABA) is not approved for use in Canada, and is only recommended as a harm reduction measure in patients ≥18 years of age at higher risk for exacerbations who are unable to use daily ICS + PRN SABA or PRN bud/ form. 1 The clinical trial that evaluated this strategy in adults using 2 separate inhalers 44 used a regimen of beclomethasone 50 mcg 2 puffs each time salbutamol 100 mcg 2 puffs was used. If clinicians recommend this strategy (off-label), we suggest that the maximum approved daily ICS dose should not be exceeded (see Table 8).
In patients of all ages, leukotriene receptor antagonists (LTRAs) are second line to daily ICS.
# Patients not achieving control on low dose ICS
Children not achieving asthma control despite adherence to low dose ICS should be increased to medium dose ICS (Table 8). Children < 6 years of age, not achieving control on medium dose ICS should be referred to an asthma specialist (section Reasons for Referral).
Children 6-11 years of age not achieving control on medium dose ICS should be started on a second controller medication, either a LABA (in the same inhaler as the ICS) or LTRA. Improvement is overall more likely to be seen with the addition of a LABA; however, individual responses vary and the side effect profile of these medications should also be discussed with patients and parents when making this decision (section Safety of LABA and LTRA). 45 In children 6-11 years of age not controlled on low dose ICS, other guidelines 46,47 recommend either increasing to medium dose ICS or adding a LABA, based on the current evidence not showing clear superiority and safety of one regimen over the other. However, the limited approval of ICS/LABA formulations in Canada for children 6-11 years of age precludes a similar recommendation at this time.
Children ≥12 years of age and adults not achieving control despite adherence to low dose ICS should be started on daily ICS/LABA. Alternative options include adding an LTRA or increasing to a medium dose of ICS.
Individuals ≥12 years of age and adults on an ICS/LABA with poor control or who are prone to exacerbations can be switched to bud/form maintenance and reliever therapy at the same maintenance ICS dose.
# Patients not achieving control on moderate dose ICS + second controller medication
Health care providers are referred to the CTS 2017 position statement on the Recognition and Management of Severe Asthma 6 for further recommendations on assessment and management.
# Safety of LABA and LTRA
The safety of LABA taken in conjunction with ICS has been demonstrated in large trials, 48 and there is no longer a black box warning on LABA medications. They are still, however, not to be used as monotherapy. A new black box warning has been issued for LTRAs due to neuropsychiatric side effects, most commonly irritability, aggressiveness, anxiety and sleep disturbance including suicidal thoughts or actions. 49 These side effects have been reported in up to 16% of pediatric asthma patients started on montelukast and typically occurred within 2 weeks of initiation. 50,51
# Yellow zone management (Table 9)
It is not recommended that children and adults on maintenance ICS double the dose of their ICS with acute loss of asthma control given the lack of benefit of this approach.
In children (<16 years of age and older) it is not recommended that the ICS dose be increased by 4-fold or more given the lack of benefit of this approach. This was recently confirmed in a trial of 5 to 11 year olds examining fluticasone 200 mcg/day versus 1000 mcg/day in the yellow zone, which did not find any decrease in exacerbations. 52 • increase bud/form to a maximum of 8 inhalations per day daily iCs or ltra in individuals ≥16 years of age and older with a history of a severe exacerbation in the last year: • 1 st choice: trial of ≥4 fold increase in iCs for 7 to 14 days • 2 nd choice: prednisone 30-50 mg for at least 5 days* otherwise no step up in controller medication. daily bud/form • 1 st choice: increase bud/form to a maximum of 4 inhalations twice daily for 7 to 14 days (≥16 years of age and older) or use bud/form as reliever and a controller (maximum 8 inhalations per day) (≥12 years of age and older) • 2 nd choice: prednisone 30-50 mg for at least 5 days* daily fluticasone propionate/ salmeterol, mometasone/ formoterol, fluticasone furoate/vilanterol in individuals ≥16 years of age with a history of a severe exacerbation in the last year: • 1 st choice: trial of ≥4 fold increase in iCs (higher iCs strength of iCs/laBa combination or extra iCs) for 7 to 14 days • 2 nd choice: prednisone 30-50 mg for at least 5 days* otherwise no step up in controller medication. * if regular need for step up therapy or need for a course of systemic steroids, address reasons for poor control and reassess/initiate controller therapy. ** does not apply to preschoolers.
In adults (≥16 years of age) with a history of a severe exacerbation in the last year, a trial of a 4 or 5-fold increase in maintenance ICS dose for 7-14 days is suggested. A pragmatic trial of adults (16 years of age and older) compared quadrupling the dose of ICS in the yellow zone to maintaining the same baseline dose and found a modest improvement in severe exacerbations (45% in the quadrupling group vs 52% in the control group, hazard ratio for time to first exacerbation 0.81, 95% confidence interval 0.71-0.92, p = 0.002) at the expense of increased dysphonia and oral candidiasis in the quadrupling group. 53 In adults (≥16 years of age) on daily bud/form, it is suggested that the dose be increased to a maximum of 4 inhalations twice daily for 7-14 days, as this has been shown to decrease severe exacerbations. 3 Evidence for increasing doses for other ICS/LABA formulations is lacking, and for adult patients on daily ICS/ LABA other than bud/form, a 4-fold or greater increase in ICS dose for 7-14 days or a course of systemic steroids is only suggested for adults that are exacerbation prone. Health care providers should be aware of the maximum daily LABA dose approved for adult use in Canada (salmeterol 100 mcg, formoterol 48 mcg, vilanterol 25 mcg). A tool to assist clinicians prescribe increased doses of ICS or ICS/LABA in the yellow zone is available in the Guidelines and Resources section of the CTS website at https://cts-sct.ca/guideline-library/knowledge-tools-resources/asthma/.
It is not recommended to routinely add oral corticosteroids as part of a written action plan in children or adults except in patients with recent severe exacerbations who fail to respond to inhaled SABA as part of their written action plan.
Prednisone dose and duration in adults should be individualized based on previous or current response. A dose of 30 to 50 mg/day for at least 5 days is suggested. For children suggested dose is 1 mg/kg/day (maximum 50 mg) for at least 3 days.
Any severe exacerbation (requiring use of systemic steroids, ED visit or hospitalization) is an indication to start a controller therapy for patients only on PRN SABA (see Figure 3) and for all patients is an indication for a reassessment of asthma mangement. Frequent courses of oral corticosteroid should prompt referral to a specialist (see the Reasons for referral section).
# Asthma severity
Asthma severity is defined by the intensity of medication required to maintain asthma control. Given that it can only be determined once asthma control is achieved, categorization of asthma severity is not useful to guide treatment decisions except when a patient meets the criteria for severe asthma and other therapeutic options are available. 6 This classification (Table 10) is an update to the 1999 criteria and is provided to standardize terminology. It is important to highlight that even those with very mild or mild asthma are at risk for asthma-related morbidity, including exacerbations and mortality. 19
# Reasons for referral
A referral to an asthma specialist for consultation or co-management is recommended for the following reasons:
• Diagnostic uncertainty • Children not controlled on moderate dose ICS with correct inhaler technique and appropriate medication adherence • Suspected or confirmed severe asthma • Life-threatening event such as an admission to the ICU for asthma • Need for allergy testing to assess the possible role of environmental allergens in those with a suggestive clinical history • Confirmed or suspected work-related asthma or • Any asthma hospitalization (all ages), ≥ 2 ED visits (all ages) or ≥ 2 courses of systemic steroids (children)
An asthma specialist includes specialists in asthma, general respirology, pediatrics, and/or allergy/immunology who have access to lung function, certified asthma/respiratory educators/ nurse clinicians +/-FeNO, induced sputum analysis. 6 Questions for future guidelines to address These topics were identified during the update of this guideline as areas where there is differing recommendations in international and national guidelines, or where a specific clinical question has not been addressed in the past or requires updating. Mild exacerbation: an increase in asthma symptoms from baseline that does not require systemic steroids, an emergency department visit or a hospitalization. Differentiating this from chronic poorly-controlled asthma may only occur retrospectively.
Higher risk of exacerbation is defined by presence of any of the following:
1. any history of a previous severe asthma exacerbation (requiring either systemic steroids, ED visit or hospitalization);
2. poorly-controlled asthma as per CTS criteria; 3. overuse of SABA (using more than 2 inhalers of SABA in 1 year); or 4. being a current smoker.
Individuals without any of these features have a lower risk of exacerbation.
Well-controlled asthma: Asthma in which all criteria for well-controlled asthma are met (Table 3) Poorly-controlled asthma: Asthma in which any one of the criteria for well-controlled are not met (Table 3).
# Acknowledgments
The authors would like to recognize and thank CTS staff (Anne Van Dam), CTS member (Om Kurmi), CTS Executive members (Dina Brooks, Paul Hernandez, Richard Leigh, Mohit Bhutani, and John Granton), CTS CRGC Executive members (Samir Gupta and Christopher Licskai), and CTS Asthma Assembly Steering Committee members (Diane Lougheed, Francine Ducharme, Dhenuka Radhakrishnan, Andréanne Côté, Tania Samanta) for their input and guidance. We would also like to acknowledge with sincere appreciation our expert reviewers who made valuable contributions to the manu-
# Disclosure statement
Members of the CTS Asthma Guideline Panel declared potential conflicts of interest at the time of appointment and these were updated throughout the process in accordance with the CTS Conflict of Interest Disclosure Policy. Individual member conflict of interest statements are posted on the CTS website. | None | None |
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The National Advisory Committee on Immunization (NACI) is an External Advisory Body that provides the Public Health Agency of Canada (PHAC) with independent, ongoing and timely medical, scientific, and public health advice in response to questions from PHAC relating to immunization.
In addition to burden of disease and vaccine characteristics, PHAC has expanded the mandate of NACI to include the systematic consideration of programmatic factors in developing evidence based recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels.
The additional factors to be systematically considered by NACI include: economics, ethics, equity, feasibility, and acceptability. Not all NACI statements will require in-depth analyses of all programmatic factors. While systematic consideration of programmatic factors will be conducted using evidence-informed tools to identify distinct issues that could impact decision-making for recommendation development, only distinct issues identified as being specific to the vaccine or vaccine-preventable disease will be included.
This statement contains NACI's independent advice and recommendations, which are based upon the best current available scientific knowledge. This document is being disseminated for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph. Recommendations for use and other information set out herein may differ from that set out in the product monographs of the Canadian manufacturers of the vaccines. Manufacturer(s) have sought approval of the vaccines and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of PHAC's Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.
# I. BACKGROUND
On June 10, 2022, in the context of the rapidly evolving monkeypox outbreak, NACI provided options for the use of the Imvamune ® vaccine (Modified vaccinia Ankara-Bavarian Nordic ) for post-exposure vaccination against monkeypox (1) . NACI recommended that a single dose of the Imvamune ® vaccine may be offered to people with high-risk exposures to a probable or confirmed case of monkeypox, or within a setting where transmission is happening. A second dose may be offered after 28 days if an assessment indicates an ongoing risk of exposure. Since NACI issued guidance in early June, the monkeypox pandemic has remained ongoing across numerous Canadian jurisdictions (2) .
As of September 16, 2022, nine Canadian provinces and territories have publicly reported 1,363 cases of monkeypox (3) . Over 95% of confirmed cases with available information self-identified as gay, bisexual, and other men who have sex with men (gbMSM), and 52% as living with human immunodeficiency virus (HIV). In response to the outbreak, PHAC has distributed over 110,000 doses of Imvamune ® vaccine to provinces and territories, and over 70,000 people have been vaccinated with at least one dose as of August 28th (3) .
Canadian jurisdictions experiencing ongoing monkeypox outbreaks have built on the foundation of NACI guidance on the use of Imvamune ® . Specifically, jurisdictions with active monkeypox outbreaks have expanded eligibility for Imvamune ® vaccine administration beyond post-exposure use based on the limited feasibility of case and contact identification. All jurisdictions have shown flexibility in the approach, responding to the reality of the outbreak in their jurisdiction, and leveraging strong partnerships with gbMSM communities to implement their vaccine programs.
In consideration of ongoing community transmission and restricted vaccine supply, Canadian provinces and territories and a number of vaccine stakeholders have indicated the need for national guidance on pre-exposure vaccination, including identification of priority populations for pre-exposure vaccination programs and guidance on the potential use of dose-sparing strategies (i.e., extended dosing intervals and/or fractional intradermal dosing). This follows recent implementation of intradermal (ID) dosefractioning schedules for Imvamune ® (Jynneos ® ) in the US (4) (and Europe (5) ).
While individuals self-identifying as gbMSM who engage in activities associated with higher risk (e.g., multiple and/or anonymous sexual contacts) remain at the highest risk of exposure to monkeypox, there is theoretical concern that other groups may also be at increased risk of disease exposure (such as sex workers independent of biological sex and gender, and people exposed to infectious material such as staff or volunteers in settings where monkeypox may be circulating). In addition to those at increased risk of exposure, other population groups may be at increased risk of disease severity following
# OBJECTIVE
In the context of the evolving multi-country monkeypox outbreak, this rapid response was undertaken to provide additional guidance on the use of the Imvamune® vaccine as pre-exposure vaccination, including the definition of priority populations for pre-exposure vaccination programs, and the relevance of dose-sparing strategies (i.e., extended dosing intervals and fractional dosing).
NACI and PHAC continue to monitor the evolving scientific data recognizing that the trajectory of the current monkeypox outbreak remains unclear, the situation is rapidly evolving and there may be additional considerations in the coming months. DEFINITIONS MSM: Man or Two-Spirit identifying individual who has sex with another person who identifies as a man, including but not limited to individuals who self-identify as transgender, cis-gender, Two-Spirit, gender-queer, intersex, and non-binary and who also identify as gay, bisexual, or pansexual.
Pre-exposure vaccination: Vaccine dose(s) administered prior to any potential exposure to monkeypox; also sometimes referred to as pre-exposure immunization or prophylaxis.
Post-exposure vaccination: Vaccine dose(s) administered shortly following a known exposure to monkeypox, or a setting where transmission is happening; also sometimes referred to as post-exposure prophylaxis.
# II. METHODS
On August 22, 2022 the NACI High Consequence Infectious Disease working group (HCID WG) convened to discuss and review data on the evolving monkeypox outbreak. Input was provided by the Public Health Ethics Consultative Group, Canadian Immunization Committee (CIC), NACI's Vaccine Safety Working Group, and the National Emergency Strategic Stockpile (NESS). That same date, Montreal Public Health and Ontario Ministry of Health presented emerging evidence on the ongoing monkeypox outbreaks, including epidemiological trends and Imvamune® vaccine programs to the HCID WG. The communities and groups considered at higher risk of monkeypox exposure were identified after considering current and projected epidemiology. Three groups representing 2SLGBTQI+ communities and one group representing sex workers were consulted to provide stakeholder input on the acceptability of vaccine strategies. The HCID WG reviewed data on the current status of the monkeypox outbreak in Canada and globally, along with additional evidence included in published scientific literature and from the manufacturer, regarding the safety, immunogenicity and
# III. EVIDENCE SUMMARY
# IV.1 Burden of disease
Since the beginning of 2022 and as of September 5, 59,996 confirmed cases of monkeypox and 18 deaths from monkeypox infection have been reported to the World Health Organization (WHO) from 102 Member States across all 6 WHO regions (6) . Since May 2022, a high proportion of cases have been reported from countries without previously documented monkeypox transmission, including Canada. Due to an unexpectedly large number of cases and continuing transmission, as well as the potential impact of disease spread in affected countries and internationally, the WHO declared the ongoing monkeypox outbreak a Public Health Emergency of International Concern on July 23, 2022 (7) .
The current international outbreak continues to primarily affect men who identify as gbMSM and who have reported recent sex with one or multiple partners (8) . The majority of the individuals self-identifying as gbMSM who are diagnosed with monkeypox have reported no contact with a person known to have a confirmed monkeypox infection (9)(10)(11) . The severity of disease of the current outbreak has generally been low, with fewer reported hospitalizations, intensive care unit (ICU) admissions, and deaths (case fatality rate of <0.1%) compared to historical outbreaks (11)(12)(13)(14) . The majority of hospital admissions have been for pain management or management of disease complications (9,11,14,15) . However, monkeypox infection has additional impacts including risk of functional impairment due to severe pain related to lesions (e.g., difficulties swallowing, urinating and defecating) or scarring, as well as socio-economic impacts (e.g., loss of income/social interaction when isolating).
As of September 14, 2022, 91 cases of monkeypox have been reported among healthcare workers globally in non-endemic countries in 2022, where only three of these cases were reported to have had occupational exposure (16) . In the cases with occupational exposure, the individuals were deemed to have been exposed while collecting diagnostic samples. While actively monitored, no cases among healthcare workers in Canada due to occupational exposure have been reported.
The clinical presentation in the current outbreak differs from the historical symptoms described for monkeypox, with fewer cases experiencing prodromal systemic symptoms and more experiencing genital rashes without spread to other parts of the body (12,13,17) . Systemic symptoms, previously described as prodromal, have also occurred concurrently or after the initial appearance of rash. The most frequently reported symptoms include rash (75%), fever (61%), and lymphadenopathy (18%) (8) . Other less commonly reported atypical clinical presentations include penile edema, secondary bacterial infection, rectal perforation, solitary lesion, and polymorphic lesions (9) . Asymptomatic infections have been described (18,19) , but there is currently no clear evidence of asymptomatic transmission. At least 25% of cases have been reported to have a concomitant sexually transmitted infection (9,13,(20)(21)(22) .
As of September 16, 2022, nine Canadian provinces and territories have publicly reported 1,363 cases of monkeypox (3) , with outbreak characteristics that have been similar to those observed internationally. Over 95% of confirmed cases have been in men 18-44 years of age who self-identify as gbMSM and as having multiple and/or new sex partners. Among those with known HIV status, 52% reported living with HIV. As of September 7, 2022, there have been 35 monkeypox associated hospitalizations, including three ICU admissions, with no reported deaths in Canada (23) .
The monkeypox viruses circulating in Europe, US and Canada are predominantly subvariants of the B.1 strain of Clade II (former West African Clade) (24,25) . A recent case series from India reported two cases of the A.2 strain of Clade II among travellers from the United Arab Emirates (25) . The A.2 strain is similar to the strain associated with monkeypox cases detected in the United States in 2021 (25) , however this strain has not been linked to major clusters (26) . There is currently no evidence to suggest whether either strain is more infectious or virulent.
# IV.2 Emerging evidence on safety and effectiveness of Imvamune ® in the context of ongoing monkeypox outbreaks
# Post-market surveillance data on Imvamune ®
Available post-marketing data on Imvamune ® safety is limited, but suggests that the vaccine is well tolerated. An observational study from France (preprint article) reported that the first dose of Imvamune ® administered as post-exposure vaccination (n=276; median age 19 years ) was well tolerated with no severe adverse events reported (27) . Approximately half reported local pain and 15% reported fatigue (median duration of 4 days); no fever or other systemic symptoms were described. In the United Kingdom, following the identification of a Monkeypox imported case in 2019, 17 contacts received Imvamune ® as post-exposure vaccination, which included infants and young children, with no known adverse events (28) . In Canada, the majority of adverse events following immunization reported to the passive surveillance system were non-serious and primarily include injection site reactions and fatigue (29) .
# Efficacy and Effectiveness of Imvamune ® in the context of a monkeypox outbreak
There is currently no evidence on the efficacy of a two-dose primary series of Imvamune ® (given as either pre-or post-exposure vaccination) against monkeypox infection, transmission or severe disease. However, emerging evidence suggests individuals vaccinated with 1 dose of Imvamune ® and who remain at high risk of exposure following vaccination may be at risk of infection post-vaccination (27,30) . Please see the Appendix A for a summary of evidence on the safety, immunogenicity and effectiveness of MVA-BN when administered off-label using fractional doses or delayed second doses.
For additional information on the safety, immunogenicity, and efficacy of Imvamune ® and related MVA vaccines, please see the June 10, 2022 NACI Rapid Response: Interim guidance on the use of Imvamune ® in the context of monkeypox outbreaks in Canada.
# IV. RECOMMENDATIONS
Following the review of available evidence summarized above, NACI makes the following recommendations for public health level and individual level decision-making.
Please see Table 1 for a more detailed explanation of the strength of NACI recommendations and grade of the body of evidence.
NACI is carefully monitoring the evolving epidemiology, including potential identification of additional risk factors for monkeypox, as well as the scientific developments related to the safety, effectiveness, and duration of protection of Imvamune ® . As the current outbreak evolves and new risk factors or groups at higher risk are identified, the criteria for those who should be vaccinated may change.
# Recommendations
# In the context of the ongoing monkeypox outbreak and limited vaccine supply, dose sparing strategies should be considered in order to expand vaccination coverage to a broader population currently considered for pre-exposure vaccination 1 : (Strong NACI recommendation)
2.1. Among immunocompetent adults currently considered for pre-exposure vaccination 1 , the first dose of Imvamune ® can be prioritised in order to extend the potential protective impact broadly across populations most at risk of exposure.
-Second doses should be offered as soon as demand for first doses among eligible individuals has been met. Individuals should receive their second dose at least 28 days after the first dose, provided they are at ongoing risk of exposure. This may result in an extended interval strategy, where the second dose is offered beyond the minimum authorised interval (28 days).
-Individuals considered moderately to severely immunocompromised and currently eligible for pre-exposure vaccination 1 should be prioritized to receive two doses of the Imvamune ® vaccine administered at the authorized interval (28 days between doses). 1 Based on current epidemiology, NACI recommends the following individuals/groups be considered for pre-exposure vaccination with Imvamune ® : Men who have sex with men (MSM), and individuals who have sex with MSM, AND who meet at least one of the following criteria: 1) Having two or more sexual partners or being in a relationship where at least one of the partners has other sexual partners; 2) Having had a confirmed sexually transmitted infection acquired in the last year, or 3) Engage in sexual contact in sex-onpremises venues. Additionally, regardless of sex or gender, individuals who self-identify as sex workers regardless of self-identified sex/gender and staff or volunteers in sex-onpremises venues where workers may have contact with fomites potentially contaminated with monkeypox without the use of personal protective equipment. Those with a prior documented history of monkeypox infection need not be vaccinated. 3. NACI recommends that, when supply is not constrained, Imvamune ® preexposure vaccination should be offered as a two-dose primary series, with at least 28 days between first and second sub-cutaneous doses, for individuals currently eligible for pre-exposure vaccination 1 .
(Strong NACI recommendation)
# Summary of evidence, rationale and additional considerations for Recommendations 2 and 3:
- At this time, Imvamune ® is the only vaccine authorized for use in Canada under an Extraordinary Use New Drug Submission (EUNDS) for the indication of active immunization against smallpox, monkeypox and related Orthopoxvirus infections, and is currently only available to provinces and territories through PHAC. Domestic supply in response to the ongoing monkeypox outbreaks must consider current/future emergency preparedness (e.g., smallpox preparedness). Considering current and forecasted limitations to both Canadian and global Imvamune ® supply, and the unknown epidemiological trajectory of monkeypox in Canada, NACI explored dose-sparing strategies to maximize vaccine coverage for those at high risk of monkeypox exposure. Although the available evidence is limited, in the short-term, one dose of Imvamune ® vaccine is likely to provide some protection against symptomatic infection when provided as vaccination prior to any exposure. In the current outbreak context, dose-sparing strategies via intradermal administration may be most optimal when used as a second dose. This is in light of feasibility limitations for broad and rapid intradermal vaccine deployment and the greater body of evidence regarding a complete dose. Internal PHAC modelling reviewed by NACI based on Canadian supply projections suggested that expanding vaccine coverage by extending dose intervals of the Imvamune ® vaccine and using 1-full (SC) and 1-fractional (ID) dose could have short-term public health benefits in preventing infections while vaccine supply is constrained as long as three or more fractional doses could be extracted from each vial. There is limited clinical evidence on Imvamune ® when provided as a fractional ID dose, and relative vaccine effectiveness compared to two doses administered via SC injection is unknown. A National Institutes of Health-led Phase 2 clinical trial compared different routes of administration of Imvamune ® among healthy participants. Based on neutralizing antibody levels following vaccination, Imvamune ® given by a fractional ID dose was considered immunologically noninferior to a full dose administered via SC injection. Severe (>3cm) and longlasting (>30 days) local reactions were more frequently reported with ID injection compared to subcutaneous injection however the frequency of systematic reactogenicity did not differ among the two groups. Refer to the Appendix A for additional detail. Improperly administered ID doses should be discussed with an expert in vaccines or local public health authority for guidance on accepting the dose and considering it valid, or repeating the dose. Informed consent should transparently include the known and unknown benefits and risks and acknowledgement of the off-label nature of Imvamune ® administered via intradermal route. As Imvamune ® is formulated as a single dose vial and does not contain preservatives, when used for multiple doses, the vial must be discarded after 6 hours from first puncture in order to reduce the risk of contamination of the vial or infection. In situations where individuals received a first dose of Imvamune using an ID route, then the dose should be considered valid. Individuals with history of a documented infection with monkeypox following the receipt of the initial vaccine dose need not be vaccinated. NACI will continue to review emerging evidence on Imvamune ® vaccine effectiveness, the duration of protection, immunogenicity, and safety, including real-world evidence from jurisdictions that have recommended ID administration as a dose sparing strategy (e.g., US, Europe). -The strength of this recommendation has been updated since initial NACI guidance was published on June 10, 2022, based on accumulating evidence on the safety of Imvamune ® . The recommendation strength is now aligned with the strength of evidence pertaining to pre-exposure vaccination with Imvamune ® .
# Post-exposure vaccination
For additional information, please refer to the NACI rapid response: Interim guidance on the use of Imvamune ® in the context of monkeypox outbreaks in Canada, issued June 10, 2022. a Immunocompetent individuals recommended for Imvamune ® pre-exposure or post-exposure vaccination should receive a single dose if they have previously been vaccinated with a live replicating 1st or 2nd generation smallpox vaccine (i.e., as a booster dose). However, individuals considered moderately to severely immunocompromised should receive two doses, regardless of previous smallpox vaccination.
b Pre-exposure or post-exposure vaccination is not indicated for individuals who meet the definition of suspect, probable or confirmed monkeypox case or with prior history of infection with monkeypox.
In the context of constrained supply, for immunocompetent individuals, the first dose can be prioritised; this may result in an extended interval strategy, where the second dose is offered beyond the minimum authorised interval of 28 days. For post-exposure vaccination, the second dose is only administered if the person is at ongoing risk of exposure.
Imvamune ® given as pre-exposure or post-exposure vaccination should not be delayed due to recent receipt of an mRNA COVID-19 vaccine. If vaccine timing can be planned (i.e., prior to employment within a research laboratory), NACI recommends that Imvamune ® be given at least 4 weeks after or before an mRNA vaccine for COVID-19.
Refer to the June 10, 2022 NACI Statement for details on co-administration guidance.
Please see the PHAC webpage: Quick reference guide on use of Imvamune ® for health care professionals in the context of monkeypox outbreaks in Canada.
Additional information on Imvamune ® is contained within the product monograph available through Health Canada's Drug product database.
# VI. RESEARCH PRIORITIES
- Further study of the protection offered by Imvamune ® vaccine against monkeypox infection, disease and transmission (in pre-exposure and post-exposure vaccination scenarios), including:
- Understanding which immune responses are protective against infection and disease and defining protective thresholds, including the duration of protection 2. Understanding how the impact of previous orthopox infection or vaccination impacts the protection offered by Imvamune ® 3. Real-world evidence on the vaccine effectiveness of Imvamune ® against monkeypox when used as a single SC dose, with extended intervals, and/or in combination with fractional intradermal dosing. 2. Additional studies to further inform on the safety of Imvamune ® vaccine including both clinical trials and post-market safety surveillance. 3. Further studies to assess vaccine efficacy/effectiveness and safety of Imvamune ® in priority populations, including people who are pregnant or breastfeeding, children <18 years of age, and people who are immunocompromised. 4. Further study into the epidemiology of the disease to better understand the modes of transmission, the disease presentation, and to identify the populations at highest risk for severe disease in order to inform and optimize disease prevention strategies. 5. Further study into the optimal immunization strategies for outbreak control (e.g., ring vaccinations, population groups at medium/low risk of infection). 6. Further study into the optimal immunization strategies to reach and enhance vaccine acceptance and uptake in populations at highest risk of infection.
The safety of intradermal (ID) administration of a fractional dose (1/5 th of the standard dose) of MVA-BN vaccine (containing the same virus type and content as Imvamune ® ) was assessed in a Phase II randomized clinical trial among healthy individuals 18 years and older born after 1971. The study compared 2 doses of MVA-BN administered 28 days apart when using subcutaneous (SC) administration of a standard dose (n=167) and ID administration of a fractional dose (n=191) (31) .
ID administration was associated with increased local reactogenicity compared to SC administration, including itchiness, erythema and induration at the infection site. Although severe (>3 cm) and long-lasting (>30 days) local reactions were more frequently reported with ID compared to SC group, there were only three (3/191; 1.6%) individuals in the ID group and none in the SC group who experienced severe local reactions (itchiness) with functional impairment. Compared to the SC group, a higher proportion of individuals in the ID group did not receive a second vaccination due to persistent local reactogenicity (mild or greater) at the time of the second vaccination (20/192 for ID administration and 3/167 for SC administration). However, most local symptoms were not deemed clinically significant by the investigators (31) .
While the reactogenicity of both ID doses was overall similar, dose 2 ID was more reactogenic than dose 1 regarding the size of local reactions. However, the clinical significance of this difference is minimal (31) . Systemic reactogenicity of MVA-BN was consistent for both ID and SC administration (31) .
Given the number of study participants, it is unlikely that rare or very rare adverse events would be detected in this clinical trial. NACI will monitor post-market safety surveillance data as it emerges and update its recommendations as needed.
# Safety precaution relating to single dose vials without preservatives
Please see the PHAC webpage: Quick reference guide on use of Imvamune ® for health care professionals in the context of monkeypox outbreaks in Canada.
# Immunogenicity data on intradermal administration of a fractional dose of MVA-BN
MVA-BN administration at 1/5 th of the standard SC dose was found to be immunologically non-inferior compared to the standard SC dose. After the receipt of the second dose, the peak geometric mean neutralization titres (GMTs) were 49.5 (95% CI: 40 to 61.3%) in the SC and 59.6 (95% CI: 48.1 to 74%) in the ID group, with 95.3% and 94.5% of study participants achieving immune response (based on peak titres) in the SC and ID group, respectively. At six months following the receipt of the second dose GMT values declined to 10.2 (95% CI: 9.4 to 11%) and 10.4 (95% CI: 9.4 to 11.5%), and only 39.2% and 35.2% of study participants remained seropositive in the SC and ID group, respectively (31) . These findings were in line with those previously reported from studies that evaluated the immunogenicity of influenza, rabies and hepatitis B vaccines, and which demonstrated non-inferior immune responses compared to standard dosing when 20% to 60% of antigen was administered using the ID route (32) .
# Vaccine efficacy or effectiveness data on intradermal administration of a fractional dose of MVA-BN
The relative or absolute efficacy or effectiveness of fractional doses of MVA-BN against monkeypox using an ID (versus SC) route of administration remains unknown.
# Subcutaneous administration of MVA-BN using a delayed interval between first and second dose
# Immunogenicity data on a single dose of MVA-BN
Immunogenicity of booster doses following a one or two dose primary vaccine schedule has been reported in one study. Up to 30 weeks following the completion of a one-or two-dose schedule, neutralizing titres were higher in study participants who received two vaccine doses, but these differences disappeared by week 108 (approaching baseline). Following the receipt of a booster dose, there were no differences observed in antibody responses (measured as neutralizing antibody titres) between those who previously received one or two doses of the vaccine when followed up to week 30 post booster immunization (33) . However, at this time, there is no known immunological correlate of protection for Imvamune ® for any outcome associated with monkeypox infection or disease.
# Effectiveness data on a single dose of Imvamune ®
One of the first estimates of one-dose Imvamune ® vaccine effectiveness against symptomatic monkeypox infection were reported as a pre-print by Arbel and others (34) . The observational study using administrative data (i.e., electronic medical records from a healthcare organization that covers approximately 52% of the entire Israeli population) followed over 8,000 individuals who were assessed as being at moderate to high risk for infection and of whom 626 (7.7%) received one dose of the MVA vaccine. All study participants completed at least 7 days of follow-up (study period from July 31 to August 10, 2022 ) during which 14 infections were confirmed only in unimmunized individuals, providing an estimated VE of 100% (95% CI: 100-100%). However, although the results of the study are encouraging, given the very short observational period (e.g., up to 10 days since vaccination, including time prior to mounting an adequate immune response), the small number of infections, and the potential biases that may be associated with the model (e.g., time-varying confounding), the GRADE assessment of the study suggests a low certainty of evidence. The results of the study remain to be validated after an anticipated peer review and the updating of the results using a longer follow-up period post vaccination.
Data from Canadian provinces and territories on breakthrough infections following a single dose of Imvamune ® are emerging. While most infections have been reported during the incubation period (maximum 21 days, with the majority reporting symptoms <14 days following vaccination), there have also been cases where infections were reported beyond 21 days post vaccination (PHAC-compiled data from Alberta, British Columbia, Ontario, Saskatchewan, and the Yukon Territory) (35) .
Breakthrough infections following a single dose of Imvamune ® have been reported to be milder in disease severity compared to those among unvaccinated individuals. A case series analysis from Montreal among monkeypox cases confirmed that between May 12 and August 10, 2022, monkeypox cases where symptom onset occurred ≥21 days since vaccination with Imvamune ® had less severe infections (lesions at fewer anatomical sites) compared to unvaccinated cases (36) .
Similar to findings reported in Canada, several studies from the United States and the UK have also reported instances of breakthrough monkeypox infections following a single dose of Imvamune ® at more than 25 days post vaccination (12,27,37) . However, these reports cannot be used to estimate the vaccine effectiveness of Imvamune ® against monkeypox infection or severe disease, as they do not include a control group.
The absolute or relative efficacy or effectiveness of Imvamune ® against monkeypox infection or severe disease when administered as a single-dose compared to a two-dose primary series is unknown. Considering principles of vaccinology, in general, a longer interval between the first and second doses allows maturation of the memory B cells, resulting in higher and more durable response (38) . 27 Immunocompromised due to solid tumour or hematologic malignancies or treatments for these conditions Solid-organ transplant and taking immunosuppressive therapy Hematopoietic stem cell transplant (within 2 years of transplantation or taking immunosuppression therapy) Immunocompromise due to chimeric antigen receptor (CAR) T cell therapy targeting lymphocytes Moderate to severe primary immunodeficiency with associated humoral and/or cell-mediated immunodeficiency or immune dysregulation HIV with AIDS-defining illness or TB diagnosis in last 12 months before starting vaccine series, or severe immune compromise with CD4<200 cells/uL or CD4%<15%, or without HIV viral suppression Recent treatment with the following categories of immunosuppressive therapies:
anti-B cell therapies (monoclonal antibodies targeting CD19, CD20 and CD22), high-dose systemic corticosteroids, alkylating agents, antimetabolites, or tumornecrosis factor (TNF) inhibitors and other biologic agents that are significantly immunosuppressive Chronic kidney disease on dialysis For guidance on the timing of vaccination for transplant recipients and those requiring immunosuppressive therapies, for a more fulsome list of conditions leading to primary immunodeficiency, and for further information on immunosuppressive therapies, refer to Immunization of Immunocompromised Persons in the Canadian Immunization Guide (CIG), Part 3 -Vaccination of Specific Populations. | Également disponible en français sous le titre : Réponse rapide du CCNI : mise à jour des directives provisoires sur l'Imvamune MD dans le contexte des éclosions actuelles de variole simienne To obtain additional information, please contact:#
The National Advisory Committee on Immunization (NACI) is an External Advisory Body that provides the Public Health Agency of Canada (PHAC) with independent, ongoing and timely medical, scientific, and public health advice in response to questions from PHAC relating to immunization.
In addition to burden of disease and vaccine characteristics, PHAC has expanded the mandate of NACI to include the systematic consideration of programmatic factors in developing evidence based recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels.
The additional factors to be systematically considered by NACI include: economics, ethics, equity, feasibility, and acceptability. Not all NACI statements will require in-depth analyses of all programmatic factors. While systematic consideration of programmatic factors will be conducted using evidence-informed tools to identify distinct issues that could impact decision-making for recommendation development, only distinct issues identified as being specific to the vaccine or vaccine-preventable disease will be included.
This statement contains NACI's independent advice and recommendations, which are based upon the best current available scientific knowledge. This document is being disseminated for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph. Recommendations for use and other information set out herein may differ from that set out in the product monographs of the Canadian manufacturers of the vaccines. Manufacturer(s) have sought approval of the vaccines and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of PHAC's Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.
# I. BACKGROUND
On June 10, 2022, in the context of the rapidly evolving monkeypox outbreak, NACI provided options for the use of the Imvamune ® vaccine (Modified vaccinia Ankara-Bavarian Nordic [MVA-BN]) for post-exposure vaccination against monkeypox (1) . NACI recommended that a single dose of the Imvamune ® vaccine may be offered to people with high-risk exposures to a probable or confirmed case of monkeypox, or within a setting where transmission is happening. A second dose may be offered after 28 days if an assessment indicates an ongoing risk of exposure. Since NACI issued guidance in early June, the monkeypox pandemic has remained ongoing across numerous Canadian jurisdictions (2) .
As of September 16, 2022, nine Canadian provinces and territories have publicly reported 1,363 cases of monkeypox (3) . Over 95% of confirmed cases with available information self-identified as gay, bisexual, and other men who have sex with men (gbMSM), and 52% as living with human immunodeficiency virus (HIV). In response to the outbreak, PHAC has distributed over 110,000 doses of Imvamune ® vaccine to provinces and territories, and over 70,000 people have been vaccinated with at least one dose as of August 28th (3) .
Canadian jurisdictions experiencing ongoing monkeypox outbreaks have built on the foundation of NACI guidance on the use of Imvamune ® . Specifically, jurisdictions with active monkeypox outbreaks have expanded eligibility for Imvamune ® vaccine administration beyond post-exposure use based on the limited feasibility of case and contact identification. All jurisdictions have shown flexibility in the approach, responding to the reality of the outbreak in their jurisdiction, and leveraging strong partnerships with gbMSM communities to implement their vaccine programs.
In consideration of ongoing community transmission and restricted vaccine supply, Canadian provinces and territories and a number of vaccine stakeholders have indicated the need for national guidance on pre-exposure vaccination, including identification of priority populations for pre-exposure vaccination programs and guidance on the potential use of dose-sparing strategies (i.e., extended dosing intervals and/or fractional intradermal dosing). This follows recent implementation of intradermal (ID) dosefractioning schedules for Imvamune ® (Jynneos ® ) in the US (4) (and Europe (5) ).
While individuals self-identifying as gbMSM who engage in activities associated with higher risk (e.g., multiple and/or anonymous sexual contacts) remain at the highest risk of exposure to monkeypox, there is theoretical concern that other groups may also be at increased risk of disease exposure (such as sex workers independent of biological sex and gender, and people exposed to infectious material such as staff or volunteers in settings where monkeypox may be circulating). In addition to those at increased risk of exposure, other population groups may be at increased risk of disease severity following
# OBJECTIVE
In the context of the evolving multi-country monkeypox outbreak, this rapid response was undertaken to provide additional guidance on the use of the Imvamune® vaccine as pre-exposure vaccination, including the definition of priority populations for pre-exposure vaccination programs, and the relevance of dose-sparing strategies (i.e., extended dosing intervals and fractional dosing).
NACI and PHAC continue to monitor the evolving scientific data recognizing that the trajectory of the current monkeypox outbreak remains unclear, the situation is rapidly evolving and there may be additional considerations in the coming months. DEFINITIONS MSM: Man or Two-Spirit identifying individual who has sex with another person who identifies as a man, including but not limited to individuals who self-identify as transgender, cis-gender, Two-Spirit, gender-queer, intersex, and non-binary and who also identify as gay, bisexual, or pansexual.
Pre-exposure vaccination: Vaccine dose(s) administered prior to any potential exposure to monkeypox; also sometimes referred to as pre-exposure immunization or prophylaxis.
Post-exposure vaccination: Vaccine dose(s) administered shortly following a known exposure to monkeypox, or a setting where transmission is happening; also sometimes referred to as post-exposure prophylaxis.
# II. METHODS
On August 22, 2022 the NACI High Consequence Infectious Disease working group (HCID WG) convened to discuss and review data on the evolving monkeypox outbreak. Input was provided by the Public Health Ethics Consultative Group, Canadian Immunization Committee (CIC), NACI's Vaccine Safety Working Group, and the National Emergency Strategic Stockpile (NESS). That same date, Montreal Public Health and Ontario Ministry of Health presented emerging evidence on the ongoing monkeypox outbreaks, including epidemiological trends and Imvamune® vaccine programs to the HCID WG. The communities and groups considered at higher risk of monkeypox exposure were identified after considering current and projected epidemiology. Three groups representing 2SLGBTQI+ communities and one group representing sex workers were consulted to provide stakeholder input on the acceptability of vaccine strategies. The HCID WG reviewed data on the current status of the monkeypox outbreak in Canada and globally, along with additional evidence included in published scientific literature and from the manufacturer, regarding the safety, immunogenicity and
# III. EVIDENCE SUMMARY
# IV.1 Burden of disease
Since the beginning of 2022 and as of September 5, 59,996 confirmed cases of monkeypox and 18 deaths from monkeypox infection have been reported to the World Health Organization (WHO) from 102 Member States across all 6 WHO regions (6) . Since May 2022, a high proportion of cases have been reported from countries without previously documented monkeypox transmission, including Canada. Due to an unexpectedly large number of cases and continuing transmission, as well as the potential impact of disease spread in affected countries and internationally, the WHO declared the ongoing monkeypox outbreak a Public Health Emergency of International Concern on July 23, 2022 (7) .
The current international outbreak continues to primarily affect men who identify as gbMSM and who have reported recent sex with one or multiple partners (8) . The majority of the individuals self-identifying as gbMSM who are diagnosed with monkeypox have reported no contact with a person known to have a confirmed monkeypox infection (9)(10)(11) . The severity of disease of the current outbreak has generally been low, with fewer reported hospitalizations, intensive care unit (ICU) admissions, and deaths (case fatality rate of <0.1%) compared to historical outbreaks (11)(12)(13)(14) . The majority of hospital admissions have been for pain management or management of disease complications (9,11,14,15) . However, monkeypox infection has additional impacts including risk of functional impairment due to severe pain related to lesions (e.g., difficulties swallowing, urinating and defecating) or scarring, as well as socio-economic impacts (e.g., loss of income/social interaction when isolating).
As of September 14, 2022, 91 cases of monkeypox have been reported among healthcare workers globally in non-endemic countries in 2022, where only three of these cases were reported to have had occupational exposure (16) . In the cases with occupational exposure, the individuals were deemed to have been exposed while collecting diagnostic samples. While actively monitored, no cases among healthcare workers in Canada due to occupational exposure have been reported.
The clinical presentation in the current outbreak differs from the historical symptoms described for monkeypox, with fewer cases experiencing prodromal systemic symptoms and more experiencing genital rashes without spread to other parts of the body (12,13,17) . Systemic symptoms, previously described as prodromal, have also occurred concurrently or after the initial appearance of rash. The most frequently reported symptoms include rash (75%), fever (61%), and lymphadenopathy (18%) (8) . Other less commonly reported atypical clinical presentations include penile edema, secondary bacterial infection, rectal perforation, solitary lesion, and polymorphic lesions (9) . Asymptomatic infections have been described (18,19) , but there is currently no clear evidence of asymptomatic transmission. At least 25% of cases have been reported to have a concomitant sexually transmitted infection (9,13,(20)(21)(22) .
As of September 16, 2022, nine Canadian provinces and territories have publicly reported 1,363 cases of monkeypox (3) , with outbreak characteristics that have been similar to those observed internationally. Over 95% of confirmed cases have been in men 18-44 years of age who self-identify as gbMSM and as having multiple and/or new sex partners. Among those with known HIV status, 52% reported living with HIV. As of September 7, 2022, there have been 35 monkeypox associated hospitalizations, including three ICU admissions, with no reported deaths in Canada (23) .
The monkeypox viruses circulating in Europe, US and Canada are predominantly subvariants of the B.1 strain of Clade II (former West African Clade) (24,25) . A recent case series from India reported two cases of the A.2 strain of Clade II among travellers from the United Arab Emirates (25) . The A.2 strain is similar to the strain associated with monkeypox cases detected in the United States in 2021 (25) , however this strain has not been linked to major clusters (26) . There is currently no evidence to suggest whether either strain is more infectious or virulent.
# IV.2 Emerging evidence on safety and effectiveness of Imvamune ® in the context of ongoing monkeypox outbreaks
# Post-market surveillance data on Imvamune ®
Available post-marketing data on Imvamune ® safety is limited, but suggests that the vaccine is well tolerated. An observational study from France (preprint article) reported that the first dose of Imvamune ® administered as post-exposure vaccination (n=276; median age 19 years [interquartile range, 14-25]) was well tolerated with no severe adverse events reported (27) . Approximately half reported local pain and 15% reported fatigue (median duration of 4 days); no fever or other systemic symptoms were described. In the United Kingdom, following the identification of a Monkeypox imported case in 2019, 17 contacts received Imvamune ® as post-exposure vaccination, which included infants and young children, with no known adverse events (28) . In Canada, the majority of adverse events following immunization reported to the passive surveillance system were non-serious and primarily include injection site reactions and fatigue (29) .
# Efficacy and Effectiveness of Imvamune ® in the context of a monkeypox outbreak
There is currently no evidence on the efficacy of a two-dose primary series of Imvamune ® (given as either pre-or post-exposure vaccination) against monkeypox infection, transmission or severe disease. However, emerging evidence suggests individuals vaccinated with 1 dose of Imvamune ® and who remain at high risk of exposure following vaccination may be at risk of infection post-vaccination (27,30) . Please see the Appendix A for a summary of evidence on the safety, immunogenicity and effectiveness of MVA-BN when administered off-label using fractional doses or delayed second doses.
For additional information on the safety, immunogenicity, and efficacy of Imvamune ® and related MVA vaccines, please see the June 10, 2022 NACI Rapid Response: Interim guidance on the use of Imvamune ® in the context of monkeypox outbreaks in Canada.
# IV. RECOMMENDATIONS
Following the review of available evidence summarized above, NACI makes the following recommendations for public health level and individual level decision-making.
Please see Table 1 for a more detailed explanation of the strength of NACI recommendations and grade of the body of evidence.
NACI is carefully monitoring the evolving epidemiology, including potential identification of additional risk factors for monkeypox, as well as the scientific developments related to the safety, effectiveness, and duration of protection of Imvamune ® . As the current outbreak evolves and new risk factors or groups at higher risk are identified, the criteria for those who should be vaccinated may change.
# Recommendations
# In the context of the ongoing monkeypox outbreak and limited vaccine supply, dose sparing strategies should be considered in order to expand vaccination coverage to a broader population currently considered for pre-exposure vaccination 1 : (Strong NACI recommendation)
2.1. Among immunocompetent adults currently considered for pre-exposure vaccination 1 , the first dose of Imvamune ® can be prioritised in order to extend the potential protective impact broadly across populations most at risk of exposure.
-Second doses should be offered as soon as demand for first doses among eligible individuals has been met. Individuals should receive their second dose at least 28 days after the first dose, provided they are at ongoing risk of exposure. This may result in an extended interval strategy, where the second dose is offered beyond the minimum authorised interval (28 days).
-Individuals considered moderately to severely immunocompromised and currently eligible for pre-exposure vaccination 1 should be prioritized to receive two doses of the Imvamune ® vaccine administered at the authorized interval (28 days between doses). 1 Based on current epidemiology, NACI recommends the following individuals/groups be considered for pre-exposure vaccination with Imvamune ® : Men who have sex with men (MSM), and individuals who have sex with MSM, AND who meet at least one of the following criteria: 1) Having two or more sexual partners or being in a relationship where at least one of the partners has other sexual partners; 2) Having had a confirmed sexually transmitted infection acquired in the last year, or 3) Engage in sexual contact in sex-onpremises venues. Additionally, regardless of sex or gender, individuals who self-identify as sex workers regardless of self-identified sex/gender and staff or volunteers in sex-onpremises venues where workers may have contact with fomites potentially contaminated with monkeypox without the use of personal protective equipment. Those with a prior documented history of monkeypox infection need not be vaccinated. 3. NACI recommends that, when supply is not constrained, Imvamune ® preexposure vaccination should be offered as a two-dose primary series, with at least 28 days between first and second sub-cutaneous doses, for individuals currently eligible for pre-exposure vaccination 1 .
(Strong NACI recommendation)
# Summary of evidence, rationale and additional considerations for Recommendations 2 and 3:
At this time, Imvamune ® is the only vaccine authorized for use in Canada under an Extraordinary Use New Drug Submission (EUNDS) for the indication of active immunization against smallpox, monkeypox and related Orthopoxvirus infections, and is currently only available to provinces and territories through PHAC. Domestic supply in response to the ongoing monkeypox outbreaks must consider current/future emergency preparedness (e.g., smallpox preparedness). Considering current and forecasted limitations to both Canadian and global Imvamune ® supply, and the unknown epidemiological trajectory of monkeypox in Canada, NACI explored dose-sparing strategies to maximize vaccine coverage for those at high risk of monkeypox exposure. Although the available evidence is limited, in the short-term, one dose of Imvamune ® vaccine is likely to provide some protection against symptomatic infection when provided as vaccination prior to any exposure. In the current outbreak context, dose-sparing strategies via intradermal administration may be most optimal when used as a second dose. This is in light of feasibility limitations for broad and rapid intradermal vaccine deployment and the greater body of evidence regarding a complete dose. Internal PHAC modelling reviewed by NACI based on Canadian supply projections suggested that expanding vaccine coverage by extending dose intervals of the Imvamune ® vaccine and using 1-full (SC) and 1-fractional (ID) dose could have short-term public health benefits in preventing infections while vaccine supply is constrained as long as three or more fractional doses could be extracted from each vial. There is limited clinical evidence on Imvamune ® when provided as a fractional ID dose, and relative vaccine effectiveness compared to two doses administered via SC injection is unknown. A National Institutes of Health-led Phase 2 clinical trial compared different routes of administration of Imvamune ® among healthy participants. Based on neutralizing antibody levels following vaccination, Imvamune ® given by a fractional ID dose was considered immunologically noninferior to a full dose administered via SC injection. Severe (>3cm) and longlasting (>30 days) local reactions were more frequently reported with ID injection compared to subcutaneous injection however the frequency of systematic reactogenicity did not differ among the two groups. Refer to the Appendix A for additional detail. Improperly administered ID doses should be discussed with an expert in vaccines or local public health authority for guidance on accepting the dose and considering it valid, or repeating the dose. Informed consent should transparently include the known and unknown benefits and risks and acknowledgement of the off-label nature of Imvamune ® administered via intradermal route. As Imvamune ® is formulated as a single dose vial and does not contain preservatives, when used for multiple doses, the vial must be discarded after 6 hours from first puncture in order to reduce the risk of contamination of the vial or infection. In situations where individuals received a first dose of Imvamune using an ID route, then the dose should be considered valid. Individuals with history of a documented infection with monkeypox following the receipt of the initial vaccine dose need not be vaccinated. NACI will continue to review emerging evidence on Imvamune ® vaccine effectiveness, the duration of protection, immunogenicity, and safety, including real-world evidence from jurisdictions that have recommended ID administration as a dose sparing strategy (e.g., US, Europe). -The strength of this recommendation has been updated since initial NACI guidance was published on June 10, 2022, based on accumulating evidence on the safety of Imvamune ® . The recommendation strength is now aligned with the strength of evidence pertaining to pre-exposure vaccination with Imvamune ® .
# Post-exposure vaccination
For additional information, please refer to the NACI rapid response: Interim guidance on the use of Imvamune ® in the context of monkeypox outbreaks in Canada, issued June 10, 2022. a Immunocompetent individuals recommended for Imvamune ® pre-exposure or post-exposure vaccination should receive a single dose if they have previously been vaccinated with a live replicating 1st or 2nd generation smallpox vaccine (i.e., as a booster dose). However, individuals considered moderately to severely immunocompromised should receive two doses, regardless of previous smallpox vaccination.
b Pre-exposure or post-exposure vaccination is not indicated for individuals who meet the definition of suspect, probable or confirmed monkeypox case or with prior history of infection with monkeypox.
In the context of constrained supply, for immunocompetent individuals, the first dose can be prioritised; this may result in an extended interval strategy, where the second dose is offered beyond the minimum authorised interval of 28 days. For post-exposure vaccination, the second dose is only administered if the person is at ongoing risk of exposure.
Imvamune ® given as pre-exposure or post-exposure vaccination should not be delayed due to recent receipt of an mRNA COVID-19 vaccine. If vaccine timing can be planned (i.e., prior to employment within a research laboratory), NACI recommends that Imvamune ® be given at least 4 weeks after or before an mRNA vaccine for COVID-19.
Refer to the June 10, 2022 NACI Statement for details on co-administration guidance.
Please see the PHAC webpage: Quick reference guide on use of Imvamune ® for health care professionals in the context of monkeypox outbreaks in Canada.
Additional information on Imvamune ® is contained within the product monograph available through Health Canada's Drug product database.
# VI. RESEARCH PRIORITIES
1. Further study of the protection offered by Imvamune ® vaccine against monkeypox infection, disease and transmission (in pre-exposure and post-exposure vaccination scenarios), including:
1. Understanding which immune responses are protective against infection and disease and defining protective thresholds, including the duration of protection 2. Understanding how the impact of previous orthopox infection or vaccination impacts the protection offered by Imvamune ® 3. Real-world evidence on the vaccine effectiveness of Imvamune ® against monkeypox when used as a single SC dose, with extended intervals, and/or in combination with fractional intradermal dosing. 2. Additional studies to further inform on the safety of Imvamune ® vaccine including both clinical trials and post-market safety surveillance. 3. Further studies to assess vaccine efficacy/effectiveness and safety of Imvamune ® in priority populations, including people who are pregnant or breastfeeding, children <18 years of age, and people who are immunocompromised. 4. Further study into the epidemiology of the disease to better understand the modes of transmission, the disease presentation, and to identify the populations at highest risk for severe disease in order to inform and optimize disease prevention strategies. 5. Further study into the optimal immunization strategies for outbreak control (e.g., ring vaccinations, population groups at medium/low risk of infection). 6. Further study into the optimal immunization strategies to reach and enhance vaccine acceptance and uptake in populations at highest risk of infection.
#
The safety of intradermal (ID) administration of a fractional dose (1/5 th of the standard dose) of MVA-BN vaccine (containing the same virus type and content as Imvamune ® ) was assessed in a Phase II randomized clinical trial among healthy individuals 18 years and older born after 1971. The study compared 2 doses of MVA-BN administered 28 days apart when using subcutaneous (SC) administration of a standard dose (n=167) and ID administration of a fractional dose (n=191) (31) .
ID administration was associated with increased local reactogenicity compared to SC administration, including itchiness, erythema and induration at the infection site. Although severe (>3 cm) and long-lasting (>30 days) local reactions were more frequently reported with ID compared to SC group, there were only three (3/191; 1.6%) individuals in the ID group and none in the SC group who experienced severe local reactions (itchiness) with functional impairment. Compared to the SC group, a higher proportion of individuals in the ID group did not receive a second vaccination due to persistent local reactogenicity (mild or greater) at the time of the second vaccination (20/192 for ID administration and 3/167 for SC administration). However, most local symptoms were not deemed clinically significant by the investigators (31) .
While the reactogenicity of both ID doses was overall similar, dose 2 ID was more reactogenic than dose 1 regarding the size of local reactions. However, the clinical significance of this difference is minimal (31) . Systemic reactogenicity of MVA-BN was consistent for both ID and SC administration (31) .
Given the number of study participants, it is unlikely that rare or very rare adverse events would be detected in this clinical trial. NACI will monitor post-market safety surveillance data as it emerges and update its recommendations as needed.
# Safety precaution relating to single dose vials without preservatives
Please see the PHAC webpage: Quick reference guide on use of Imvamune ® for health care professionals in the context of monkeypox outbreaks in Canada.
# Immunogenicity data on intradermal administration of a fractional dose of MVA-BN
MVA-BN administration at 1/5 th of the standard SC dose was found to be immunologically non-inferior compared to the standard SC dose. After the receipt of the second dose, the peak geometric mean neutralization titres (GMTs) were 49.5 (95% CI: 40 to 61.3%) in the SC and 59.6 (95% CI: 48.1 to 74%) in the ID group, with 95.3% and 94.5% of study participants achieving immune response (based on peak titres) in the SC and ID group, respectively. At six months following the receipt of the second dose GMT values declined to 10.2 (95% CI: 9.4 to 11%) and 10.4 (95% CI: 9.4 to 11.5%), and only 39.2% and 35.2% of study participants remained seropositive in the SC and ID group, respectively (31) . These findings were in line with those previously reported from studies that evaluated the immunogenicity of influenza, rabies and hepatitis B vaccines, and which demonstrated non-inferior immune responses compared to standard dosing when 20% to 60% of antigen was administered using the ID route (32) .
# Vaccine efficacy or effectiveness data on intradermal administration of a fractional dose of MVA-BN
The relative or absolute efficacy or effectiveness of fractional doses of MVA-BN against monkeypox using an ID (versus SC) route of administration remains unknown.
# Subcutaneous administration of MVA-BN using a delayed interval between first and second dose
# Immunogenicity data on a single dose of MVA-BN
Immunogenicity of booster doses following a one or two dose primary vaccine schedule has been reported in one study. Up to 30 weeks following the completion of a one-or two-dose schedule, neutralizing titres were higher in study participants who received two vaccine doses, but these differences disappeared by week 108 (approaching baseline). Following the receipt of a booster dose, there were no differences observed in antibody responses (measured as neutralizing antibody titres) between those who previously received one or two doses of the vaccine when followed up to week 30 post booster immunization (33) . However, at this time, there is no known immunological correlate of protection for Imvamune ® for any outcome associated with monkeypox infection or disease.
# Effectiveness data on a single dose of Imvamune ®
One of the first estimates of one-dose Imvamune ® vaccine effectiveness against symptomatic monkeypox infection were reported as a pre-print by Arbel and others (34) . The observational study using administrative data (i.e., electronic medical records from a healthcare organization that covers approximately 52% of the entire Israeli population) followed over 8,000 individuals who were assessed as being at moderate to high risk for infection and of whom 626 (7.7%) received one dose of the MVA vaccine. All study participants completed at least 7 days of follow-up (study period from July 31 to August 10, 2022 [last data extraction date, August 15, 2022]) during which 14 infections were confirmed only in unimmunized individuals, providing an estimated VE of 100% (95% CI: 100-100%). However, although the results of the study are encouraging, given the very short observational period (e.g., up to 10 days since vaccination, including time prior to mounting an adequate immune response), the small number of infections, and the potential biases that may be associated with the model (e.g., time-varying confounding), the GRADE assessment of the study suggests a low certainty of evidence. The results of the study remain to be validated after an anticipated peer review and the updating of the results using a longer follow-up period post vaccination.
Data from Canadian provinces and territories on breakthrough infections following a single dose of Imvamune ® are emerging. While most infections have been reported during the incubation period (maximum 21 days, with the majority reporting symptoms <14 days following vaccination), there have also been cases where infections were reported beyond 21 days post vaccination (PHAC-compiled data from Alberta, British Columbia, Ontario, Saskatchewan, and the Yukon Territory) (35) .
Breakthrough infections following a single dose of Imvamune ® have been reported to be milder in disease severity compared to those among unvaccinated individuals. A case series analysis from Montreal among monkeypox cases confirmed that between May 12 and August 10, 2022, monkeypox cases where symptom onset occurred ≥21 days since vaccination with Imvamune ® had less severe infections (lesions at fewer anatomical sites) compared to unvaccinated cases (36) .
Similar to findings reported in Canada, several studies from the United States and the UK have also reported instances of breakthrough monkeypox infections following a single dose of Imvamune ® at more than 25 days post vaccination (12,27,37) . However, these reports cannot be used to estimate the vaccine effectiveness of Imvamune ® against monkeypox infection or severe disease, as they do not include a control group.
The absolute or relative efficacy or effectiveness of Imvamune ® against monkeypox infection or severe disease when administered as a single-dose compared to a two-dose primary series is unknown. Considering principles of vaccinology, in general, a longer interval between the first and second doses allows maturation of the memory B cells, resulting in higher and more durable response (38) . 27 Immunocompromised due to solid tumour or hematologic malignancies or treatments for these conditions Solid-organ transplant and taking immunosuppressive therapy Hematopoietic stem cell transplant (within 2 years of transplantation or taking immunosuppression therapy) Immunocompromise due to chimeric antigen receptor (CAR) T cell therapy targeting lymphocytes Moderate to severe primary immunodeficiency with associated humoral and/or cell-mediated immunodeficiency or immune dysregulation HIV with AIDS-defining illness or TB diagnosis in last 12 months before starting vaccine series, or severe immune compromise with CD4<200 cells/uL or CD4%<15%, or without HIV viral suppression Recent treatment with the following categories of immunosuppressive therapies:
anti-B cell therapies (monoclonal antibodies targeting CD19, CD20 and CD22), high-dose systemic corticosteroids, alkylating agents, antimetabolites, or tumornecrosis factor (TNF) inhibitors and other biologic agents that are significantly immunosuppressive Chronic kidney disease on dialysis For guidance on the timing of vaccination for transplant recipients and those requiring immunosuppressive therapies, for a more fulsome list of conditions leading to primary immunodeficiency, and for further information on immunosuppressive therapies, refer to Immunization of Immunocompromised Persons in the Canadian Immunization Guide (CIG), Part 3 -Vaccination of Specific Populations. | None | None |
b02f098e4541c6d0d02b31c7ee42d87dd6698bd7 | cma | None | # Initial Management of Pediatric Asthma
In Emergent/Urgent Care Settings
This document outlines the methodology used to develop recommendations to support early identification and initial management of children and youth with asthma who present to emergent/urgent care settings across British Columbia. This provincial work was led by Child Heath BC (CHBC) in partnership with clinical and content experts, representing rural and urban centers within the various provincial health authorities. The Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument provided the methodological strategy for the development of this guideline. The following document reviews each component of the AGREE II instrument 23 . The resulting work consists of a package of clinical support documents and educational tools that used together assist the emergency clinician to screen, rapidly assess and begin implementation of interventions in the emergent/urgent care setting. They are not intended for inpatient use.
The provincial resource package includes:
Guideline
# Background Pediatric Asthma
Pediatric asthma has been identified as a significant health issue in British Columbia (BC). It is the most common chronic disease impacting children and is a leading cause of missed school days and hospital visits 12 . As there is no known cure for asthma; efforts are focused on the delivery of timely and appropriate management strategies to minimize the individual and community level impacts. Children and families can be supported to control their asthma and improve their overall quality of life 13 .
Asthma is a chronic health condition characterized by inflammation of the airway walls and narrowing of the air passages leading to the lungs 13 . Symptoms can be episodic or persistent and present in a variety of ways that include: chest tightness, coughing, wheezing and shortness of breath. These symptoms and episodes of severe shortness of breath can be triggered by exposures such as allergens, environmental irritants, viral infections, exercise and strong emotions 8,12,14 . Poor asthma control can negatively impact a child's overall quality of life, impacting their ability to participate in sports, school and other recreational activities 14 .
# Asthma Diagnosis and Management
The majority of children with asthma present with symptom onset in their preschool years. Preschool aged children have the highest rates of emergency department visits and hospitalizations for asthma symptoms when compared to other age groups. There continues to be uncertainty regarding the diagnosis of asthma in this young age group. This uncertainty can result in delayed treatment and contribute to morbidity in both the short and long term; highlighting the need for early diagnosis and treatment 8 . 8,14 . Management strategies include medications, education and environmental controls 15 . "Asthma education is an essential component of asthma management for all patients. Guided self-management, combining asthma education, regular medical review, self-assessment and a written action plan have been shown to reduce hospitalizations, emergency visits, urgent physician visits, missed days at work or school, days of restricted activity, and improved pulmonary function in children" (Canadian Thoracic Society Asthma Committee, 2010, p.18).
Evidence-based management of pediatric patients experiencing acute asthma symptoms includes repeated doses of Salbutamol and Ipratropium, along with oral corticosteroids within the first sixty minutes of care 3 . Lower rates of hospitalization and the improved use of evidence-based medications are associated with the use of a validated and standardized clinical score. The PRAM is a validated scoring tool used to classify the severity of a pediatric patient's respiratory distress and subsequent response to treatment 1, 2, 3 .
# Scope and Purpose
Child Health BC Provincial Asthma Guideline: Initial Management of Pediatric Asthma in Emergent/Urgent Care Settings
# Scope
This guideline is for use with Children ages 1 year of age to 17 years of age less 1 day- presenting with wheezing, or respiratory distress, AND Diagnosed to have asthma, or Treated 2 times prior with a bronchodilator for wheezing *While children less than 1 year of age with their first known episode of wheeze should not be routinely treated as a part of the PRAM pathway, treating physicians may choose to include these children on a case by case basis following their assessment.
# Target User of this Guideline
PRAM scoring is performed in the Emergency Department or Urgent Care Centre by members of the health care team including: Physicians, Nurse Practitioners, Registered Nurses and Respiratory Therapists.
# Purpose
This provincial guideline and related tools outline the recommendations for the initial management of pediatric patients presenting to emergent/urgent care settings across British Columbia (BC) with acute asthma exacerbations. The guideline provides recommended actions based on the use of the Pediatric Respiratory Assessment Measure (PRAM) 1,2 .
The Translating Emergency Knowledge for Kids (TREKK) Bottom Line Recommendations: Asthma (2017) were used as the foundation for building this guideline 3 .
# Methodology
The Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument provided the methodological strategy for the development of this guideline 23 .
# Literature Search Strategy
The provincial working group was aware that TREKK had completed a comprehensive literature review and had developed updated Bottom Line Recommendations for Asthma (2017). The TREKK review included:
- 4 systematic reviews - 2 meta-analysis - 3 key studies - Review of existing guidelines
The TREKK Bottom Line Recommendations were reviewed by the working group and it was determined that these recommendations would be used as the basis for the provincial guideline and care algorithm. As a part of this determination the provincial working group reviewed original papers that were included in the systematic review and other literature as relevant. An additional scoping review was completed to gather and review existing guidelines and explore specific components within the guideline. Specifically additional information was sought to inform medication dosing and teaching recommendations.
# Methods for Formulating Recommendations
Based on the information listed above, pediatric recommendations were accepted by the provincial working group. Recommendations requiring provincial adaptation (e.g. medication calculations for pharmacy) were adapted by seeking advice and consensus from clinical experts across the Health Authorities. A series of provincial meetings were held to review the guideline (Part B) and care algorithm, line by line and seek consensus. Draft documents were distributed to the working group members following each set of revisions and feedback was reviewed at the next meeting. Once a final draft was agreed upon the provincial working group members and the CHBC Regional Coordinators were asked to circulate for wider feedback within the Provincial Health Authorities. Feedback was collected and final revisions were circulated to the group for consensus. Acceptance of the guideline was sought from the CHBC steering committee and the Provincial Emergency Services Advisory Council.
# Procedure for Updating the Guideline
This guideline will be reviewed every three years (or earlier if new evidence is published) by a multidisciplinary provincial advisory group consisting of clinical experts in emergency and respiratory care. This guideline will be reviewed again in 2021.
# Summary of Recommendations with Levels of Evidence
The following section will outline the key recommendations and assign a level of evidence based on the
# Appendix A: Methods
# Appendix A: Acknowledgments
This group would like to acknowledge the many health care professionals who contributed to the development of this guideline by sharing their expert opinion and by acting as reviewers. In addition to the working group members, Connie Yang, MD, FRCP(C), MSc (Clinical Assistant Professor, Division of Respiratory Medicine British Columbia Children's Hospital) and Simi Khangura MD, FRCPC (Clinical Associate Professor Division of Emergency Medicine, Department of Pediatrics, UBC, BC's Children's Hospital) provided significant input into the development of the guideline and accompanying algorithm. Appendix C: Editorial Independence
# Working Group Members
BC
# Appendix C: Editorial Independence
There are no conflicts of interest to report.
# i. Disclaimer
Child Health BC develops evidence-based clinical support documents that include recommendations for the care of children and youth across British Columbia. These documents are intended to give an understanding of a clinical problem, and outline one or more preferred approaches to the investigation and management of the problem. These documents are for guidance only and not intended as a substitute for the advice or professional judgment of a health care professional, nor are they intended to be the only approach to the management of a clinical problem. Healthcare professionals should continue to use their own judgment and take into consideration context, resources and other relevant factors. Neither Provincial Health Services Authority nor Child Health BC assume any responsibility or liability from reliance on or use of the documents. | # Initial Management of Pediatric Asthma
In Emergent/Urgent Care Settings
This document outlines the methodology used to develop recommendations to support early identification and initial management of children and youth with asthma who present to emergent/urgent care settings across British Columbia. This provincial work was led by Child Heath BC (CHBC) in partnership with clinical and content experts, representing rural and urban centers within the various provincial health authorities. The Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument provided the methodological strategy for the development of this guideline. The following document reviews each component of the AGREE II instrument 23 . The resulting work consists of a package of clinical support documents and educational tools that used together assist the emergency clinician to screen, rapidly assess and begin implementation of interventions in the emergent/urgent care setting. They are not intended for inpatient use.
The provincial resource package includes:
Guideline
# Background Pediatric Asthma
Pediatric asthma has been identified as a significant health issue in British Columbia (BC). It is the most common chronic disease impacting children and is a leading cause of missed school days and hospital visits 12 . As there is no known cure for asthma; efforts are focused on the delivery of timely and appropriate management strategies to minimize the individual and community level impacts. Children and families can be supported to control their asthma and improve their overall quality of life 13 .
Asthma is a chronic health condition characterized by inflammation of the airway walls and narrowing of the air passages leading to the lungs 13 . Symptoms can be episodic or persistent and present in a variety of ways that include: chest tightness, coughing, wheezing and shortness of breath. These symptoms and episodes of severe shortness of breath can be triggered by exposures such as allergens, environmental irritants, viral infections, exercise and strong emotions 8,12,14 . Poor asthma control can negatively impact a child's overall quality of life, impacting their ability to participate in sports, school and other recreational activities 14 .
# Asthma Diagnosis and Management
The majority of children with asthma present with symptom onset in their preschool years. Preschool aged children have the highest rates of emergency department visits and hospitalizations for asthma symptoms when compared to other age groups. There continues to be uncertainty regarding the diagnosis of asthma in this young age group. This uncertainty can result in delayed treatment and contribute to morbidity in both the short and long term; highlighting the need for early diagnosis and treatment 8 . 8,14 . Management strategies include medications, education and environmental controls 15 . "Asthma education is an essential component of asthma management for all patients. Guided self-management, combining asthma education, regular medical review, self-assessment and a written action plan have been shown to reduce hospitalizations, emergency visits, urgent physician visits, missed days at work or school, days of restricted activity, and improved pulmonary function in children" (Canadian Thoracic Society Asthma Committee, 2010, p.18).
Evidence-based management of pediatric patients experiencing acute asthma symptoms includes repeated doses of Salbutamol and Ipratropium, along with oral corticosteroids within the first sixty minutes of care 3 . Lower rates of hospitalization and the improved use of evidence-based medications are associated with the use of a validated and standardized clinical score. The PRAM is a validated scoring tool used to classify the severity of a pediatric patient's respiratory distress and subsequent response to treatment 1, 2, 3 .
# Scope and Purpose
Child Health BC Provincial Asthma Guideline: Initial Management of Pediatric Asthma in Emergent/Urgent Care Settings
# Scope
This guideline is for use with Children ages 1 year of age to 17 years of age less 1 day* presenting with wheezing, or respiratory distress, AND Diagnosed to have asthma, or Treated 2 times prior with a bronchodilator for wheezing *While children less than 1 year of age with their first known episode of wheeze should not be routinely treated as a part of the PRAM pathway, treating physicians may choose to include these children on a case by case basis following their assessment.
# Target User of this Guideline
PRAM scoring is performed in the Emergency Department or Urgent Care Centre by members of the health care team including: Physicians, Nurse Practitioners, Registered Nurses and Respiratory Therapists.
# Purpose
This provincial guideline and related tools outline the recommendations for the initial management of pediatric patients presenting to emergent/urgent care settings across British Columbia (BC) with acute asthma exacerbations. The guideline provides recommended actions based on the use of the Pediatric Respiratory Assessment Measure (PRAM) 1,2 .
The Translating Emergency Knowledge for Kids (TREKK) Bottom Line Recommendations: Asthma (2017) were used as the foundation for building this guideline 3 .
# Methodology
The Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument provided the methodological strategy for the development of this guideline 23 .
# Literature Search Strategy
The provincial working group was aware that TREKK had completed a comprehensive literature review and had developed updated Bottom Line Recommendations for Asthma (2017). The TREKK review included:
• 4 systematic reviews • 2 meta-analysis • 3 key studies • Review of existing guidelines
The TREKK Bottom Line Recommendations were reviewed by the working group and it was determined that these recommendations would be used as the basis for the provincial guideline and care algorithm. As a part of this determination the provincial working group reviewed original papers that were included in the systematic review and other literature as relevant. An additional scoping review was completed to gather and review existing guidelines and explore specific components within the guideline. Specifically additional information was sought to inform medication dosing and teaching recommendations.
# Methods for Formulating Recommendations
Based on the information listed above, pediatric recommendations were accepted by the provincial working group. Recommendations requiring provincial adaptation (e.g. medication calculations for pharmacy) were adapted by seeking advice and consensus from clinical experts across the Health Authorities. A series of provincial meetings were held to review the guideline (Part B) and care algorithm, line by line and seek consensus. Draft documents were distributed to the working group members following each set of revisions and feedback was reviewed at the next meeting. Once a final draft was agreed upon the provincial working group members and the CHBC Regional Coordinators were asked to circulate for wider feedback within the Provincial Health Authorities. Feedback was collected and final revisions were circulated to the group for consensus. Acceptance of the guideline was sought from the CHBC steering committee and the Provincial Emergency Services Advisory Council.
# Procedure for Updating the Guideline
This guideline will be reviewed every three years (or earlier if new evidence is published) by a multidisciplinary provincial advisory group consisting of clinical experts in emergency and respiratory care. This guideline will be reviewed again in 2021.
# Summary of Recommendations with Levels of Evidence
The following section will outline the key recommendations and assign a level of evidence based on the
# Appendix A: Methods
# Appendix A: Acknowledgments
This group would like to acknowledge the many health care professionals who contributed to the development of this guideline by sharing their expert opinion and by acting as reviewers. In addition to the working group members, Connie Yang, MD, FRCP(C), MSc (Clinical Assistant Professor, Division of Respiratory Medicine British Columbia Children's Hospital) and Simi Khangura MD, FRCPC (Clinical Associate Professor Division of Emergency Medicine, Department of Pediatrics, UBC, BC's Children's Hospital) provided significant input into the development of the guideline and accompanying algorithm. Appendix C: Editorial Independence
# Working Group Members
BC
# Appendix C: Editorial Independence
There are no conflicts of interest to report.
# i. Disclaimer
Child Health BC develops evidence-based clinical support documents that include recommendations for the care of children and youth across British Columbia. These documents are intended to give an understanding of a clinical problem, and outline one or more preferred approaches to the investigation and management of the problem. These documents are for guidance only and not intended as a substitute for the advice or professional judgment of a health care professional, nor are they intended to be the only approach to the management of a clinical problem. Healthcare professionals should continue to use their own judgment and take into consideration context, resources and other relevant factors. Neither Provincial Health Services Authority nor Child Health BC assume any responsibility or liability from reliance on or use of the documents. | None | None |
af6f69f380ccf531585bfd8353861e8adb8ca162 | cma | None | Updated to reflect use to replace coagulation factors in special populations when frozen plasma is not available or the risk/benefit ratio of frozen plasma is unfavorable NAC Statement on Reversal of Direct Oral Anticoagulants (last revision: October 2018) assimilated into this document with further revisions to incorporate latest evidence Addition of suggested dosing regimen using weight and INR based on randomized clinical trials and suggested pediatric dosing based on observational evidence Addition that adverse reactions to PCCs require mandatory report as per the Protecting Canadians from Unsafe Drugs Act (Vanessa's Law) Updated references, added links to the NAC Statement on Fibrinogen Concentrate Use in Acquired Hypofibrinogenemia where applicable, and further detailed risks associated with PCCs May 2014 Dosing recommendations and use of PCCs in elective situations revised Clarity improved around various recommendations June 2011 Addition of Beriplex as a licensed product Incorporation of two national audits of Octaplex, leading to revision of dosing recommendations V: 20220208 FINAL 5 | P a g eThe National Advisory Committee on Blood and Blood Products (NAC) is an interprovincial medical and technical advisory body to the provincial and territorial health ministries and the blood supplier Canadian Blood Services. Its mandate is to provide professional leadership in assisting and identifying, designing and implementing cost-effective blood utilization management initiatives for the optimization of patient care throughout Canada. Currently available four-factor prothrombin complex concentrates (PCCs) are human plasma derived products that have undergone solvent/detergent treatment and/or nanofiltration for viral, bacterial and parasite inactivation and/or removal. They contain the vitamin K dependent procoagulant factors -II, VII, IX and X as well as the vitamin K dependent natural anticoagulant factors Protein C and Protein S, manufactured with added heparin. The two currently available PCCs (Beriplex®, Octaplex®) are considered interchangeable in practice.#
In 2008, NAC was approached by Canadian Blood Services and the Provinces to develop recommendations for appropriate use of PCCs as they became available in Canada. That led to the "NAC Statement on Recommendations for Use of PCCs", which underwent revisions in 2011 and 2014. Due to new evidence and changes in practice that have occurred since the last revision, a working group was convened in 2021 to revise and update the recommendations. The "NAC Statement on Reversal of Direct Oral Anticoagulants" published in 2018 has also been assimilated into this document.
The working group continues to advocate for the use of this product under the oversight of transfusion medicine services, directed by expertise in thrombosis/hemostasis/transfusion medicine, informed by the evolving medical literature, and in settings with access to appropriate diagnostic and treatment facilities for the identification and management of potential complications. These recommendations consider available literature, audit data and consensus opinion of the working group formed in 2021. Conflict of interest disclosures of the working group members are available on the NAC website (www.nacblood.ca).
# INDICATIONS Recommended Indications:
A. Rapid reversal of oral vitamin K antagonists (VKAs, e.g. warfarin) or deficiency of vitamin K dependent coagulation factors in patients with major bleeding - Major bleeding as defined by the International Society on Thrombosis and Haemostasis (ISTH) bleeding scale includes: 1.
fatal bleeding; 2. symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular, pericardial, or intramuscular with compartment syndrome; 3. bleeding causing a fall in hemoglobin ≥ 20 g/L or leading to transfusion ≥ 2 units of red blood cells. - Critical bleeding following injury or surgical intervention also appropriately qualifies as major bleeding in this context. A. Treatment of bleeding in patients receiving direct factor Xa inhibitor anticoagulants -PCCs should only be considered in patients presenting with severe or life-threatening bleeding.
- Specific reversal agents for direct factor Xa inhibitors (including rivaroxaban, apixaban, and edoxaban), such as andexanet alfa, should be used, if available. At the time of writing, andexanet alfa is not currently approved by Health Canada. - There are no randomized trials published as of writing, evaluating the efficacy and safety of PCCs for treatment of direct factor Xa inhibitor associated bleeding. - The optimal dosing strategy is uncertain with 2000 IU (fixed dose) or 25-50 IU/kg (to a max 3000 IU) being the most commonly recommended dosing strategy. Other considerations for treatment: - Other adjunctive strategies include: holding medications that increase the risk of bleeding (e.g. antiplatelet agents), bleeding source control, and use of tranexamic acid (though tranexamic acid has not been studied in direct factor Xa inhibitor associated bleeding). - Inappropriate approaches to treatment of direct factor Xa inhibitor associated bleeding which are not to be used include: frozen plasma administration, vitamin K (unless concomitant vitamin K deficiency/antagonist is present), and recombinant factor VIIa. - In patients presenting for urgent surgery and/or an invasive procedure taking direct factor Xa inhibitor anticoagulants in whom clinically significant anticoagulant effect is suspected or demonstrated, if it is clinically appropriate to delay the surgery/procedure, then anticoagulants should be discontinued within an appropriate timeframe to ensure minimal residual anticoagulation. o If surgery cannot be delayed in an anticoagulated patient, consultation with expertise from thrombosis/hemostasis/transfusion medicine is strongly recommended to guide pre-procedural lab testing (including an anti-factor Xa level, if available, prior to proceeding especially if the direct factor Xa inhibitor has not been held for an appropriate time frame) and bleeding management. o Although an elevated INR is suggestive of direct factor Xa inhibitor presence, it cannot be used as a quantitative measure for the degree of anticoagulation, or alone provide guidance for administration of PCCs for surgical and/or invasive procedures. The INR may also be normal in patients who are fully anticoagulated. o At the time of writing, there is limited data regarding the efficacy and safety of PCCs for management of factor Xa inhibitor treated patients requiring urgent surgery. - NAC recommends that institutional/regional protocols be developed and implemented, including relevant laboratory testing and hemostatic management.
B. Use in bleeding/massive hemorrhage patients, when plasma is unavailable -Some smaller/remote health service providers may have challenges providing plasma in bleeding patients, given the lack of thawing devices or lack of stocking due to rarity of use. are only to be used for hemophilia patients with inhibitors as per the product monograph (control of spontaneous bleeding episodes, surgical interventions, and/or routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults and children older than 6 years of age).
# ADVERSE EVENTS AND RISKS
- PCC use may be associated with an increased risk of thrombosis and should be used with caution in patients with recent thrombotic events (i.e. venous thromboembolism, myocardial infarction, ischemic stroke, systemic embolism) and DIC. o Risks of thrombosis reported with PCC use in VKA reversal range from 1.4% to 4.2% across studies in systematic reviews. o The risk of thrombosis after VKA reversal with PCC has not been shown to be higher than after VKA reversal with plasma. o If the decision is to use the product off-label in patients with liver dysfunction and DIC, please consult the product monograph for further recommendations (e.g. the need for antithrombin levels or replacement). - PCCs also contain heparin, which can lead to/or exacerbate HIT.
- Other reported reactions can be found in the product monograph, and may include formation of inhibitor antibodies for one or more of the factors, and anaphylactic reactions.
- The Protecting Canadians from Unsafe Drugs Act (Vanessa's Law) introduces amendments to the Food and Drugs Act that mandates reporting of serious adverse drug reactions. This act came into effect December 16th, 2019, applies to purified plasma protein products, and includes the reporting of serious anticoagulant-related bleeds by hospitals. o Serious adverse reactions include those that require in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, is life-threatening, or results in death. o Regulations for mandatory reporting of serious adverse drug reactions apply to all hospital facilities. Any patient or staff member is eligible to submit a severe adverse drug reaction report. Facility/regional policies should be consulted to ensure reporting per local protocol as reporting is not explicitly in the domain of transfusion medicine services. For more information, please consult Health Canada.
# DOSING, ADMINISTRATION & MONITORING
There is significant variability in the dosing used for PCCs across Canada and in the literature.
- The working group felt that there was insufficient published evidence to indicate one dosing regimen for VKAs as superior to another and recommends following local policy with monitoring for efficacy. o Some of the variability in practice and literature stems from different target INRs for various clinical indications and whether or not weight-based and/or INR-based dosing was deemed important by local clinical groups. - The expert consensus recommendation is to target a local INR of 1.5 or less for VKA reversal.
- This is based on the fact that an INR of 1.5 or less has evolved to be the standard of practice across Canada. However, no data clearly supports a relationship between the surrogate outcome of lowering the INR and reduced bleeding in this situation.
- Normal hemostasis does not require 100% factor levels. Although the product monographs recommend correcting factor levels to normal, an INR of 1.5 is likely equivalent to vitamin-K dependent factor levels of at least 30-50% which are adequate for hemostasis. Administration:
- Must be administered intravenously, where medications shall not be added directly to the administration set that contains a blood component or another product. - Should be administered by slow IV infusion (for example: 1000 IU over 5 minutes); or as per product monograph. o Health Canada has approved adult infusion rate recommendations based on the product monograph, though observational literature and experience at Canadian hospitals suggest more rapid infusion rates (such as 1000 IU over 5 minutes) are safe. - Preferentially should be infused through peripheral IV access. Caution should be exercised when infusing centrally and it is prudent to use product monograph recommended infusion rates when administered through a central line.
Vitamin K for VKA Reversal:
- The expert working group recommends IV Vitamin K administration for VKA reversal. When Vitamin K is used as an alternative, the injectable formulation, which can be given orally or intravenously, is preferred. Oral vitamin K has a slower onset of action than IV vitamin K. Intramuscular and subcutaneous routes of Vitamin K administration are not recommended. - Clinicians should not be hesitant to prescribe IV vitamin K as it does not produce the inability to resume oral anticoagulation ("warfarin resistance") when used at appropriate doses. Further, if warfarin resistance is encountered in a rare patient, there are alternative anticoagulants that can be used. - For patients receiving VKAs with INRs of >4.5 but <10 without clinically significant bleeding, the ASH Guidelines for Management of Venous Thromboembolism suggests using temporary cessation of VKAs alone without the addition of vitamin K.
# Post dose monitoring in VKA Reversal:
Since dose effect is not universally applicable, efficacy of dosing in VKA reversal must be determined using the surrogate marker INR post PCC administration.
- If correction to an INR <1.5 has not been achieved and there is insufficient time to wait for Vitamin K to take effect, a subsequent dose of PCC guided by the post-infusion INR may be required if the patient continues to demonstrate clinical bleeding. | Updated to reflect use to replace coagulation factors in special populations when frozen plasma is not available or the risk/benefit ratio of frozen plasma is unfavorable NAC Statement on Reversal of Direct Oral Anticoagulants (last revision: October 2018) assimilated into this document with further revisions to incorporate latest evidence Addition of suggested dosing regimen using weight and INR based on randomized clinical trials and suggested pediatric dosing based on observational evidence Addition that adverse reactions to PCCs require mandatory report as per the Protecting Canadians from Unsafe Drugs Act (Vanessa's Law) Updated references, added links to the NAC Statement on Fibrinogen Concentrate Use in Acquired Hypofibrinogenemia where applicable, and further detailed risks associated with PCCs May 2014 Dosing recommendations and use of PCCs in elective situations revised Clarity improved around various recommendations June 2011 Addition of Beriplex as a licensed product Incorporation of two national audits of Octaplex, leading to revision of dosing recommendations V: 20220208 FINAL 5 | P a g eThe National Advisory Committee on Blood and Blood Products (NAC) is an interprovincial medical and technical advisory body to the provincial and territorial health ministries and the blood supplier Canadian Blood Services. Its mandate is to provide professional leadership in assisting and identifying, designing and implementing cost-effective blood utilization management initiatives for the optimization of patient care throughout Canada. Currently available four-factor prothrombin complex concentrates (PCCs) are human plasma derived products that have undergone solvent/detergent treatment and/or nanofiltration for viral, bacterial and parasite inactivation and/or removal. They contain the vitamin K dependent procoagulant factors -II, VII, IX and X as well as the vitamin K dependent natural anticoagulant factors Protein C and Protein S, manufactured with added heparin. The two currently available PCCs (Beriplex®, Octaplex®) are considered interchangeable in practice.#
In 2008, NAC was approached by Canadian Blood Services and the Provinces to develop recommendations for appropriate use of PCCs as they became available in Canada. That led to the "NAC Statement on Recommendations for Use of PCCs", which underwent revisions in 2011 and 2014. Due to new evidence and changes in practice that have occurred since the last revision, a working group was convened in 2021 to revise and update the recommendations. The "NAC Statement on Reversal of Direct Oral Anticoagulants" published in 2018 has also been assimilated into this document.
The working group continues to advocate for the use of this product under the oversight of transfusion medicine services, directed by expertise in thrombosis/hemostasis/transfusion medicine, informed by the evolving medical literature, and in settings with access to appropriate diagnostic and treatment facilities for the identification and management of potential complications. These recommendations consider available literature, audit data and consensus opinion of the working group formed in 2021. Conflict of interest disclosures of the working group members are available on the NAC website (www.nacblood.ca).
# INDICATIONS Recommended Indications:
A. Rapid reversal of oral vitamin K antagonists (VKAs, e.g. warfarin) or deficiency of vitamin K dependent coagulation factors in patients with major bleeding • Major bleeding as defined by the International Society on Thrombosis and Haemostasis (ISTH) bleeding scale includes: 1.
[potentially] fatal bleeding; 2. symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular, pericardial, or intramuscular with compartment syndrome; 3. bleeding causing a fall in hemoglobin ≥ 20 g/L or leading to transfusion ≥ 2 units of red blood cells. • Critical bleeding following injury or surgical intervention also appropriately qualifies as major bleeding in this context. A. Treatment of bleeding in patients receiving direct factor Xa inhibitor anticoagulants -PCCs should only be considered in patients presenting with severe or life-threatening bleeding.
• Specific reversal agents for direct factor Xa inhibitors (including rivaroxaban, apixaban, and edoxaban), such as andexanet alfa, should be used, if available. At the time of writing, andexanet alfa is not currently approved by Health Canada. • There are no randomized trials published as of writing, evaluating the efficacy and safety of PCCs for treatment of direct factor Xa inhibitor associated bleeding. • The optimal dosing strategy is uncertain with 2000 IU (fixed dose) or 25-50 IU/kg (to a max 3000 IU) being the most commonly recommended dosing strategy. Other considerations for treatment: • Other adjunctive strategies include: holding medications that increase the risk of bleeding (e.g. antiplatelet agents), bleeding source control, and use of tranexamic acid (though tranexamic acid has not been studied in direct factor Xa inhibitor associated bleeding). • Inappropriate approaches to treatment of direct factor Xa inhibitor associated bleeding which are not to be used include: frozen plasma administration, vitamin K (unless concomitant vitamin K deficiency/antagonist is present), and recombinant factor VIIa. • In patients presenting for urgent surgery and/or an invasive procedure taking direct factor Xa inhibitor anticoagulants in whom clinically significant anticoagulant effect is suspected or demonstrated, if it is clinically appropriate to delay the surgery/procedure, then anticoagulants should be discontinued within an appropriate timeframe to ensure minimal residual anticoagulation. o If surgery cannot be delayed in an anticoagulated patient, consultation with expertise from thrombosis/hemostasis/transfusion medicine is strongly recommended to guide pre-procedural lab testing (including an anti-factor Xa level, if available, prior to proceeding especially if the direct factor Xa inhibitor has not been held for an appropriate time frame) and bleeding management. o Although an elevated INR is suggestive of direct factor Xa inhibitor presence, it cannot be used as a quantitative measure for the degree of anticoagulation, or alone provide guidance for administration of PCCs for surgical and/or invasive procedures. The INR may also be normal in patients who are fully anticoagulated. o At the time of writing, there is limited data regarding the efficacy and safety of PCCs for management of factor Xa inhibitor treated patients requiring urgent surgery. • NAC recommends that institutional/regional protocols be developed and implemented, including relevant laboratory testing and hemostatic management.
B. Use in bleeding/massive hemorrhage patients, when plasma is unavailable -Some smaller/remote health service providers may have challenges providing plasma in bleeding patients, given the lack of thawing devices or lack of stocking due to rarity of use. are only to be used for hemophilia patients with inhibitors as per the product monograph (control of spontaneous bleeding episodes, surgical interventions, and/or routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults and children older than 6 years of age).
# ADVERSE EVENTS AND RISKS
• PCC use may be associated with an increased risk of thrombosis and should be used with caution in patients with recent thrombotic events (i.e. venous thromboembolism, myocardial infarction, ischemic stroke, systemic embolism) and DIC. o Risks of thrombosis reported with PCC use in VKA reversal range from 1.4% to 4.2% across studies in systematic reviews. o The risk of thrombosis after VKA reversal with PCC has not been shown to be higher than after VKA reversal with plasma. o If the decision is to use the product off-label in patients with liver dysfunction and DIC, please consult the product monograph for further recommendations (e.g. the need for antithrombin levels or replacement). • PCCs also contain heparin, which can lead to/or exacerbate HIT.
• Other reported reactions can be found in the product monograph, and may include formation of inhibitor antibodies for one or more of the factors, and anaphylactic reactions.
• The Protecting Canadians from Unsafe Drugs Act (Vanessa's Law) introduces amendments to the Food and Drugs Act that mandates reporting of serious adverse drug reactions. This act came into effect December 16th, 2019, applies to purified plasma protein products, and includes the reporting of serious anticoagulant-related bleeds by hospitals. o Serious adverse reactions include those that require in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, is life-threatening, or results in death. o Regulations for mandatory reporting of serious adverse drug reactions apply to all hospital facilities. Any patient or staff member is eligible to submit a severe adverse drug reaction report. Facility/regional policies should be consulted to ensure reporting per local protocol as reporting is not explicitly in the domain of transfusion medicine services. For more information, please consult Health Canada.
# DOSING, ADMINISTRATION & MONITORING
There is significant variability in the dosing used for PCCs across Canada and in the literature.
• The working group felt that there was insufficient published evidence to indicate one dosing regimen for VKAs as superior to another and recommends following local policy with monitoring for efficacy. o Some of the variability in practice and literature stems from different target INRs for various clinical indications and whether or not weight-based and/or INR-based dosing was deemed important by local clinical groups. • The expert consensus recommendation is to target a local INR of 1.5 or less for VKA reversal.
o This is based on the fact that an INR of 1.5 or less has evolved to be the standard of practice across Canada. However, no data clearly supports a relationship between the surrogate outcome of lowering the INR and reduced bleeding in this situation.
o Normal hemostasis does not require 100% factor levels. Although the product monographs recommend correcting factor levels to normal, an INR of 1.5 is likely equivalent to vitamin-K dependent factor levels of at least 30-50% which are adequate for hemostasis. Administration:
• Must be administered intravenously, where medications shall not be added directly to the administration set that contains a blood component or another product. • Should be administered by slow IV infusion (for example: 1000 IU over 5 minutes); or as per product monograph. o Health Canada has approved adult infusion rate recommendations based on the product monograph, though observational literature and experience at Canadian hospitals suggest more rapid infusion rates (such as 1000 IU over 5 minutes) are safe. • Preferentially should be infused through peripheral IV access. Caution should be exercised when infusing centrally and it is prudent to use product monograph recommended infusion rates when administered through a central line.
Vitamin K for VKA Reversal:
• The expert working group recommends IV Vitamin K administration for VKA reversal. When Vitamin K is used as an alternative, the injectable formulation, which can be given orally or intravenously, is preferred. Oral vitamin K has a slower onset of action than IV vitamin K. Intramuscular and subcutaneous routes of Vitamin K administration are not recommended. • Clinicians should not be hesitant to prescribe IV vitamin K as it does not produce the inability to resume oral anticoagulation ("warfarin resistance") when used at appropriate doses. Further, if warfarin resistance is encountered in a rare patient, there are alternative anticoagulants that can be used. • For patients receiving VKAs with INRs of >4.5 but <10 without clinically significant bleeding, the ASH Guidelines for Management of Venous Thromboembolism suggests using temporary cessation of VKAs alone without the addition of vitamin K.
# Post dose monitoring in VKA Reversal:
Since dose effect is not universally applicable, efficacy of dosing in VKA reversal must be determined using the surrogate marker INR post PCC administration.
• If correction to an INR <1.5 has not been achieved and there is insufficient time to wait for Vitamin K to take effect, a subsequent dose of PCC guided by the post-infusion INR may be required if the patient continues to demonstrate clinical bleeding. | None | None |
597a01b2f5c5dc079a1da0563f44cbd61c0f6cfc | cma | None | How does this edition differ from the 2021 Guidelines? Several important content changes have been made and they are highlighted in bold in the text. Some of the more important changes include: - The recommendation that family physician anesthesia providers (FPA) in Canada obtain the Certificate of Added Competence at the enhanced skill level in family practice anesthesia through the College of Family Physicians of Canada. - A completely revised Section 2.3, now entitled Physician Health and Wellness, outlining general guiding principles on the topic including several key anesthesia-related areas to consider with specific recommendations applicable to anesthesia departments of all sizes. - The recommendation, related to difficult airway management and difficult airway kits, that emergency front of neck access (eFONA) airway (e.g., surgical cricothyroidotomy) equipment be immediately available at any location where anesthesia care is delivered. - The recommendation to utilize, when appropriate, low total fresh gas flow techniques (B 1 LÁmin -1 ) when using volatile inhalational anesthetic agents, recognizing the potential environmental, pulmonary, and economic benefits. - Revisions to Section 5.2 Airway Management emphasizing the critical importance of the non-technical and human factors that may act as enablers or barriers to successful airway management. - The recommendation that depth of anesthesia monitoring equipment (e.g., processed EEG-based) be available and considered for use, if clinically indicated, in patients who are at increased risk for intraoperative awareness.#
- Revisions to Section 7 Guidelines for Neuraxial and Peripheral Nerve Block Regional Anesthesia, which now includes specific patient safety recommendations related to peripheral nerve block regional anesthesia techniques.
Comment cet énoncé diffère-t-il des Lignes directrices de 2021? Plusieurs modifications importantes ont été apportées au contenu; elles sont surlignées en gras dans le texte. Parmi les modifications les plus importantes, citons :
- La recommandation selon laquelle les omni-anesthésistes (ou anesthésistes en médecine familiale -AMF) au Canada obtiennent un Certificat de compe´tence additionnelle au niveau de compétence amélioré en anesthésie en médecine familiale par l'entremise du Collège des médecins de famille du Canada.
- Une section 2.3 entièrement révisée, dorénavant intitulée Santé et bien-être des médecins, décrivant des principes directeurs généraux sur le sujet, y compris concernant plusieurs domaines clés liés à l'anesthésie à considérer, avec des recommandations spécifiques applicables aux départements d'anesthésie de toutes tailles.
- En lien avec la prise en charge des voies aériennes difficiles et les trousses d'intubation difficile, la recommandation que le matériel nécessaire à réaliser un abord cervical antérieur d'urgence (eFONA) (p. ex., cricothyroïdotomie chirurgicale) soit à portée immédiate à tout endroit où des soins d'anesthésie sont dispensés.
- La recommandation d'utiliser, s'il y a lieu, des techniques à faible débit total de gaz frais (B 1 LÁmin -1 ) lors de l'utilisation d'agents anesthésiques par inhalation volatils, en reconnaissant les avantages environnementaux, pulmonaires et économiques potentiels.
- Des révisions de la section 5.2 Prise en charge des voies aériennes soulignant l'importance cruciale des facteurs non techniques et humains qui peuvent agir comme catalyseurs ou obstacles à une prise en charge réussie des voies aériennes.
- La recommandation que le matériel de monitorage de la profondeur de l'anesthésie (p. ex., basé sur l'analyse de l'EEG) soit disponible et que son utilisation soit envisagée, si cela est cliniquement indiqué, chez les patients qui présentent un risque accru de mémorisation peropératoire.
- Des révisions apportées à la section 7 Lignes directrices pour l'anesthésie régionale par bloc neuraxial et bloc nerveux périphérique, qui comprend maintenant des recommandations spécifiques en matière de sécurité des patients liées aux techniques d'anesthésie régionale par bloc nerveux périphérique. Lignes directrices pour l'exercice de l'anesthésie dans les lieux isolés 9.1 Soins anesthésiques dispensés dans un établissement médical/chirurgical/dentaire non hospitalier 9.2 Soins anesthésiques dispensés hors de la salle d'opération dans un hôpital ou un établissement non hospitalier Annexe 1 : Association canadienne de normalisation -Normes concernant le matériel Annexe 2 : Classification de l'état de santé des patients, selon l'American Society of Anesthesiologists Annexe 3 : Liste de vérification préanesthésique Annexe 4 : Lignes directrices, normes et autres énoncés officiels disponibles sur l'internet Annexe 5 : Exposé de principe sur les assistants en anesthésie : Un exposé de principe officiel de la Société canadienne des anesthésiologistes Annexe 6 : Sédation procédurale : exposé de principe de la Société canadienne des anesthésiologistes SPECIAL ARTICLE Overview The Guidelines to the Practice of Anesthesia Revised Edition 2022 (the Guidelines) were prepared by the Canadian Anesthesiologists' Society (CAS), which reserves the right to determine their publication and distribution. The Guidelines are subject to revision and updated versions are published annually. The Guidelines to the Practice of Anesthesia Revised Edition 2022 supersedes all previously published versions of this document. Although the CAS encourages Canadian anesthesiologists to adhere to its practice guidelines to ensure high-quality patient care, the CAS cannot guarantee any specific patient outcome. Anesthesiologists should exercise their own professional judgement in determining the proper course of action for any patient's circumstances. The CAS assumes no responsibility or liability for any error or omission arising from the use of any information contained in its Guidelines to the Practice of Anesthesia.
# Table des matières
# Preamble
Anesthesiology is a dynamic specialty of medicine that fosters continuous improvements in anesthetic care for patients undergoing surgical and obstetric procedures in Canada. This document is reviewed annually and revised periodically.
The following recommendations are aimed at providing basic guidelines to anesthetic practice. They are intended as a framework for reasonable and acceptable patient care and should be interpreted as such to allow for some degree of flexibility in different circumstances. Each section of the Guidelines is subject to revision as warranted by the evolution of technology, practice, and the best available evidence.
# Basic Principles
In this document, the term anesthesiologist is used to designate all licensed medical practitioners with privileges to administer anesthetics. An anesthetic is the deliberate performance of any procedure to render a patient temporarily insensitive to pain or to the external environment so that a diagnostic or therapeutic procedure can be performed.
These Guidelines are intended to apply to all anesthesiologists in Canada. The independent practice of anesthesia is a specialized field of medicine, and as such, it should be practiced by physicians with appropriate training in anesthesia. The only route to specialist recognition in anesthesia in Canada is through the certification process of the Royal College of Physicians and Surgeons of Canada. The Canadian Anesthesiologists' Society (CAS) acknowledges the fact that remote communities often Can J Anesth/J Can Anesth
Text approved by the CAS Board for the 2022 Revised Edition.
Texte approuvé par le CA de la SCA pour l'édition révisée 2022.
# Supplementary Information
The online version contains supplementary material available at .
lack the population base to support a specialist anesthesiology practice. In these communities, appropriately trained family physicians may be required to provide anesthesia services. In communities with the clinical volume to support full-time anesthesiologists, fellowship-certified anesthesiologists should provide these services. All anesthesiologists must continue their education in the practice of anesthesia, pain management, perioperative care, and resuscitation and participate in a structured maintenance of competence program (e.g., Royal College MOC).
# Organization of Anesthetic Services
The department of anesthesia should be properly organized, directed, and integrated with other departments in the organization or facility, and it should include all facility staff members who provide anesthetic services to patients for surgical, obstetric, diagnostic, and therapeutic purposes.
The department should be staffed appropriately, bearing in mind the scope and nature of the services it provides, and it should strive to ensure that these services are available as required by the healthcare facility.
The chief of the department should be a physician who has obtained certification or appropriate training in anesthesia. This individual should be appointed in the same manner as other chiefs of clinical departments and should be a member of the senior medical administrative bodies for the facility.
# Responsibilities of the Chief of Anesthesia
- To be aware of the current CAS Guidelines to the Practice of Anesthesia, the requirements of the Canadian Council on Health Services Accreditation, and the requirements of the provincial licensing authority as they relate to anesthesia; 2. To ensure that written policies with respect to the practice of anesthesia are established and enforced; 3. To evaluate the qualifications and abilities of the physicians providing anesthetic care as well as other health professionals providing ancillary care-this includes, but is not restricted to, recommending clinical privileges for physicians with anesthetic responsibilities and annually reviewing these privileges; 4. To employ a systematic approach for monitoring the quality of anesthetic care provided by members of the department of anesthesia throughout the healthcare facility;
Monitoring quality of care may include, but need not be restricted to, the use of chart audits, clinical indicator and outcome monitoring, adverse event reporting systems, morbidity and mortality conferences, and critical incident case reviews. The extent of quality improvement activities will vary depending on the departmental and health facility resources available to the chief. For effective quality improvement, it is strongly encouraged that all department members should actively participate in any such activities. 5. To ensure that records are kept for all anesthetic procedures-these records should allow for evaluation of all anesthetic care in the facility; 6. To carry out such other duties as the governing body of the facility may delegate to ensure safe anesthetic care; 7. To promote institutional compliance with applicable Canadian Standards Association (CSA) Standards (Appendix 1); and 8. To coordinate liaison between the departments of anesthesiology, biomedical engineering, and information management services. Special areas of anesthetic care may have specific concerns. The department of anesthesia in each institution may determine privileges in pediatric anesthesia according to the pediatric population it serves, the child's age, the presence of comorbidities, the physician's specific training and experience in pediatric anesthesia, and the complexity of the procedure involved.
# Privileges in Anesthesia
Physicians with anesthetic privileges should possess the knowledge and technical and non-technical skills necessary for the practice of anesthesia.
Knowledge and technical skills include the ability:
- To provide preanesthetic evaluation of the patient and determine the appropriate anesthetic management;
Guidelines to the Practice of Anesthesia -Revised Edition 2022
- To render the patient insensible to pain for the performance of diagnostic and therapeutic procedures, surgical operations, and obstetric procedures; - To monitor and support the vital organ systems during the perioperative period; - To provide immediate postanesthetic management of the patient; - To provide resuscitation and intensive care when indicated; and - To provide relief from acute and chronic pain.
Non-technical skills include:
- Task management: planning and preparing, prioritizing, providing and maintaining standards, and identifying and utilizing resources; - Teamwork: coordinating activities with team members, exchanging information, using authority and assertiveness, assessing capabilities, supporting others, and supporting the World Health Organization Surgical Safety Checklist; - Situational awareness: anticipating, gathering information, recognizing, and understanding, and;
- Decision-making: identifying options, balancing risks and selecting options, and re-evaluating.
# Physician Health and Wellness
Anesthesia care physicians require a high level of expertise, sound judgement, decision-making skills, alertness and vigilance, and must be able to respond to rapidly changing and often unexpected clinical challenges. Work-related, organizational, and personal factors may all contribute challenges to a provider's ability to function at their highest level of performance. The critical importance of anesthesia physician health must be recognized and adequately considered. Issues such as fatigue, workplace harassment and bullying, personal and mental health issues, stress, inadequate nutrition while working, burnout, and substance use can all contribute adversely to health and well-being and ultimately to patient safety. All anesthesia physicians should monitor themselves and colleagues for signs and symptoms of functional impairment so that impairments can be detected early and support offered. Substance use disorders are common in society and can also affect anesthesia physicians. Opioid abuse is more common in anesthesia than in most other medical specialties. Controlled medication diversion prevention programs are essential as a minimum (see section 3.1, 4a and b) and should be part of broader departmental strategies, policies, and education to assist identification of physicians and anesthesia support staff who may be impaired because of substance use disorders.
Anesthesia and/or facility leadership must be supportive of physician health and well-being through administrative structures that promote and support a healthy workplace and establish mechanisms of peer support. Smaller departments may need to rely on local, provincial, or national physician support programs, and accessing such resources should be promoted for staff. The goal should be creating and sustaining a culture of psychological safety where deviation from manageable and reasonable working conditions are reported and acted upon, and where providers at risk or in difficulty can be identified and appropriately supported without fear of negative repercussions.
Specific areas to consider may include, but need not be restricted to:
# Residents
Residents in anesthesia are registered medical practitioners who participate in the provision of anesthesia services both inside and outside the operating room as part of their training. The Royal College of Physicians and Surgeons of Canada and provincial and local regulatory authorities require that a responsible attending staff anesthesiologist must supervise all resident activities. The degree of this supervision must consider the condition of each patient, the nature of the anesthetic service, and the experience and capabilities of the resident (increasing professional responsibility). At the discretion of the supervising staff anesthesiologist, residents may provide a range of anesthetic care with minimal supervision. In all cases, the supervising attending anesthesiologist must remain readily available to give advice or assist the resident with urgent or routine patient care. Whether supervision is direct or indirect, close communication between the resident and the responsible supervising staff anesthesiologist is essential for safe patient care. Each anesthesia department teaching anesthesia residents should have policies regarding the activities and supervision of residents.
# Ancillary Personnel
The healthcare facility must ensure that ancillary personnel are available as assistants to the anesthesiologist. Such assistants must be available at all times and places where anesthetic services are provided. Ancillary personnel should have the competencies to meet the specific needs of subspecialty areas of anesthesia, reflecting on the need for specific skills in areas such as specialty pediatric anesthesia.
It is recommended that facilities have a formally designated anesthesia assistant with specific training in anesthesia assistance. The department of anesthesia and the appropriate administrative bodies must approve the scope of practice for anesthesia assistants working in a specific institution. Furthermore, anesthesia assistants like other employed health professionals, must be covered by the facility's liability insurance. Duties and tasks delegated to anesthesia assistants must be consistent with existing governmental regulations, the policies and guidelines established by professional regulatory agencies, and the policies of the local facility.
An institution without formal anesthesia assistants must provide other paramedical personnel to assist the anesthesiologist. The tasks that these assistants may perform must be clearly defined. An anesthesiologist must only delegate or assign those tasks for which such personnel have approval or accreditation.
# Anesthetic Equipment and Anesthetizing Location
An anesthetic must be administered in an appropriate facility. All necessary equipment, including emergency equipment, life support systems, medications, and supplies must be readily available. It is strongly recommended that a cognitive aid manual be made available at all anesthetizing locations in support of the management of critical perioperative emergencies. The contents of the manual should be regularly reviewed, updated as required, and periodically practiced as a team.
The healthcare facility, in consultation with the department of anesthesia, is responsible for the design and maintenance of preoperative, postoperative, and anesthetizing locations, as well as the purchase, maintenance, and disposal of anesthetic and ancillary equipment and supplies. The Canadian Standards Association (CSA) and other standards development organizations have published standards and guidance documents for the design, construction, and renovation of healthcare facilities and for the risk management, basic safety, and essential performance of medical equipment (Appendix 1).
# Responsibilities of the Healthcare Facility
The healthcare facility must ensure that:
- The operating rooms, anesthetizing locations, and perioperative care locations comply with at least the minimum design and construction requirements of the national, provincial, and local building, plumbing, electrical, HVAC (heating, ventilation, and air conditioning), fire, and security codes at the time of construction or renovation.
- Medical gas and vacuum systems, waste anesthetic gas scavenging systems, terminal units, head walls, low pressure connecting assemblies, and pressure regulators meet the requirements of the CSA and are certified by a CSA-approved testing agency. 3. Oxygen concentrators that comply with CSA requirements are an acceptable substitute for bulk oxygen supply systems. When such concentrators are installed, users must be aware that:
a. The facility medical oxygen supply may deliver a fraction of inspired oxygen (FiO 2 ) that varies from 0.93 to 0.99; b. Oxygen analyzers must be calibrated against 100% O 2 (FiO 2 0.99) and room air or equivalent (FiO 2 0.21); c. The use of low-flow (less than one litre total fresh gas flow) anesthetic techniques may result in the accumulation of inert gas (argon) and the dilution of nitrous oxide and oxygen in the circuit.
- There is compliance with all safety regulations and best practice with respect to the storage, preparation, identification, labelling, disposal, and use of medical gases, medications, and related materials.
a. General medication safety recommendations include, but need not be restricted to:
- Identifying an anesthesia department lead designated to cooperate with pharmacy to promote medication safety best practice. In recognition of the increased risk of medication errors related to medication brand substitutions and look-alike packaging, departments and pharmacies should consider strategies to reduce this risk. - Requesting that pharmacy staff notify anesthesia staff, with as much notice as possible, of upcoming medication supplier, packaging, or concentration changes such that anesthesia staff can be alerted. - Standardization of drug trays across all locations and during product transitions. Medications with different supplier brands and packaging for a medication should not be mixed in the same anesthesia cart. - Medication substitutions, particularly of a different concentration, should be labelled with highly visible warning labels when any new medication is introduced. - Look-alike medications should be physically separated in the anesthesia carts as much as is possible and identified with warning labels.
- Cautioning physicians and technical support staff that replacement of unopened medications back into anesthesia carts is risky because medication may be put in the incorrect location.
- Reporting any medication-related adverse events through local adverse event reporting systems or CAIRS or both.
b. Through cooperation between the departments of anesthesia and pharmacy, there are policies developed and enforced for the safe handling, storage, and disposal of controlled medications (e.g., opioids) in the operating rooms and postanesthesia care unit (PACU) that are consistent with the law, with any regulatory authority requirements, and established best practice principles. The goals of such policies should be to limit access of unauthorized personnel to controlled medications to minimize the risk of controlled medication diversion, and to establish robust documentation procedures that can be audited, while also protecting patient safety by still permitting anesthesia providers immediate access to any medications required for patient care.
Best practice principles support a variety of specific strategies to achieve these goals. The CAS does not endorse any one specific strategy or policy but strongly recommends that all available options be considered. Robust systems and procedures must be implemented. Due consideration should be given to any limitation in resources available to implement specific security systems and procedures within a facility, particularly for smaller facilities.
Recommendations include, but need not be restricted to:
- Storing controlled substances in a secure lockable safe or locked drawer when the OR is unattended by anesthesia personnel (e.g., between cases). - Never leaving controlled substances (including those drawn up into syringes or bags) unattended in any location. - Emptying the contents of syringes and bags containing controlled substances before disposal. - Adopting disposal and/or destruction systems to dispose of controlled substance waste. - Consideration of a requirement that controlled substance waste be returned to the pharmacy and be subjected to random analysis. - Periodic audits of a healthcare provider's controlled substance utilization records and their anesthesia records.
- Consideration of the implementation of automated anesthesia cabinets or automated medication dispensing cabinets (e.g. PyxisTM).
The operating room, labour and delivery, postanesthesia care unit (PACU), and regional block areas, for example, should all be recognized as high risk areas for controlled medication diversion and therefore must be subject to heightened security, surveillance, and auditing. Anesthesia providers must ensure that potentially infectious materials or agents are not transferred from one patient to another. Special attention in this regard Guidelines to the Practice of Anesthesia -Revised Edition 2022 should be given to syringes, infusion pump administration sets, and multi-dose drug vials.
Training on the safe use of all anesthesia equipment should be provided to all anesthesia department members prior to use. Attendance at these sessions should be documented. These training sessions should be repeated as necessary for new or established department members.
# Waste Gases
Recommendations for reducing occupational exposure to waste anesthetic gases: The department of anesthesia should establish policies regarding preanesthetic assessment. The primary goal of preanesthetic assessment is to obtain the information required to plan anesthetic management. Accordingly, a physician who is knowledgeable about anesthetic management for the proposed diagnostic or therapeutic procedure should document all aspects of the patient's medical and surgical history, findings on physical examination, and laboratory investigations that are relevant to anesthetic management. The patient's history should include past and current medical problems, current and recent drug therapy, unusual reactions or responses to drugs, and any problems or complications associated with previous anesthetics. A family history of adverse reactions associated with anesthesia should also be obtained. Information about the anesthetic that the patient considers relevant should also be documented. An American Society of Anesthesiologists physical status classification (Appendix 2) should be recorded for each patient.
In appropriate cases, the availability of an ''Advance Care Plan'' (representation agreement, advanced directive, ''living will'', ''do not resuscitate'' directive, etc.) should be ascertained, and its applicability to the proposed intervention should be determined and documented on the anesthetic assessment record.
The surgeon may request consultation with an anesthesiologist. Medical consultations should be obtained when indicated.
Preoperative anesthetic assessment or consultation may take place in an outpatient clinic before admission for the operative procedure. Indications for pre-admission assessment include the presence of significant medical problems (comorbidities), the nature of the proposed diagnostic or therapeutic procedure, and patient request. A parent/guardian must be present if the patient is a child or not competent to provide informed consent. All patients should be informed that arrangements will be made to meet with an anesthesiologist if they wish to discuss anesthetic management before admission to the facility. The preoperative assessment clinic should also allow nursing and other healthcare personnel to assess the patient. The attending anesthesiologist is responsible for performing a final preanesthetic assessment in the immediate preoperative period.
# Preoperative Testing
Laboratory testing should not be performed on a routine basis but should be obtained only when results will change perioperative management. Laboratory investigations should be performed when indicated by the patient's medical status, drug therapy, and the nature of the proposed procedure.
Routine laboratory blood testing, electrocardiograms, and chest radiographs are not recommended for asymptomatic patients having low-risk surgery. Examples of low-risk surgery include, but are not restricted to, cataract surgery, minor breast surgery, superficial procedures, and many minor ambulatory procedures. For more detailed definitions of low-risk surgery and for other recommendations related to preoperative testing, visit Choosing Wisely on the CAS website and the associated Internet links.
# Fasting Policies
Fasting policies should vary to account for age and preexisting medical conditions and should apply to all forms of anesthesia, including procedural sedation (see Appendix 6). 1 Emergent or urgent procedures should be undertaken after considering the risk of delaying surgery vs the risk of aspiration of gastric contents. The type and amount of food ingested should be considered in determining the duration of fasting. Before elective procedures, the minimum duration of fasting should be:
- Eight hours after a large meal of solids particularly containing protein (e.g., meat) or fatty foods - Six hours after a light meal (e.g., non-fatty meal such as toast) - Six hours after ingestion of infant formula, non-human milk, or expressed breast milk fortified with additions - Four hours after ingestion of breast milk - Two hours after ingestion of clear fluids for adults - One hour after ingestion of clear fluids for infants and children.
Unless contraindicated, adults and children should be encouraged to drink clear fluids (including water, pulp-free juice, complex carbohydrate beverages, and black tea or coffee) up to two hours before elective surgery. Pediatric patients should also be encouraged to consume clear fluids, as defined, up to one hour before elective procedures.
Conditions that delay gastric emptying require individual patient assessment. These guidelines may be modified at the discretion of the physician.
Premedication, when indicated, should be ordered by the anesthesiologist. Orders should be specific as to dose, time, and route of administration.
An H2 receptor antagonist (oral or intravenous) is recommended for all women presenting for Cesarean delivery.
Thirty mL of oral sodium citrate (0.3 molar) is recommended prior to an emergent Cesarean delivery if general anesthesia is planned. See Section 7.3 for fasting guidelines specific to patients in active labour.
# Additional Regulations
Provincial legislation or facility bylaws may dictate additional regulations governing the conduct of anesthesia.
5 The Anesthetic Period
# Preparation for Anesthesia
Before beginning anesthesia, the anesthesiologist must ensure that 1. An explanation of the planned anesthetic procedure, including recognized risks and alternative techniques, has been provided and documented; 2. An adequate review of the patient's condition has been performed; 3. All equipment that is expected to be required is available and in working order, including the equipment required for supporting core temperature management (patient core temperature 36-37°C); 4. A reserve source of oxygen under pressure is available; 5. All drugs and agents that are expected to be required are correctly identified-user-applied drug labels should conform to the CSA Standard CAN/CSA-Z264.3-98 (R2005) (Appendix 1); 6. If Luer neuraxial connectors are used, both sides of all Luer connections must be labelled. Consideration should be given to the use of neuraxial connectors complying with ISO 80369-6:2016-small bore connectors for neuraxial application (e.g., NRFitÒ connectors) subject to availability from equipment suppliers; and 7. The manufacturers' recommendations concerning the use, handling, and disposal of anesthetic equipment and supplies have been considered.
# Airway Management
Airway management, particularly of the difficult airway, contributes to a significant proportion of anesthesia-related morbidity and mortality. The appropriate management of those patients who have an anticipated or unanticipated difficult tracheal intubation, a failed airway (completed best effort after 3 attempts), where bag-mask ventilation or supraglottic device placement may be difficult, in a ''cannot ventilate, cannot oxygenate'' (CVCO) scenario or who require an eFONA airway procedure is critical for patient safety. This includes, but need not be restricted to, adequate airway assessment, equipment (e.g., difficult airway kits, videolaryngoscopes, bronchoscopes, eFONA equipment), training and simulation, support personnel and the use of protocols and cognitive aids to optimize difficult airway management.
Equipment location and availability, local environment (e.g., remote locations) provider experience, teamwork and communication (e.g., team briefings) and psychological factors are all areas deserving of attention and optimization. It is essential to appreciate the non-technical human factors (individual, team and organizational) that may act as enablers or barriers to successful airway management. The CAS does not endorse any one specific guideline, algorithm or cognitive aid for difficult and failed airway management but strongly recommends that readers refer to Appendix 4 for up to date publications related to this topic.
# Delegation of Patient Care
The anesthesiologist's primary responsibility is to the patient receiving care. The anesthesiologist or an anesthesia assistant supervised by the anesthesiologist must remain with the patient at all times throughout the conduct of all general and major regional anesthetics and for procedural sedation until the patient is transferred to the care of personnel in an appropriate care unit.
If the attending anesthesiologist leaves the operating room temporarily, he/she must delegate care of the patient to another anesthesiologist, a resident in anesthesia, or an anesthesia assistant. When the attending anesthesiologist delegates care to a resident in anesthesia or an anesthesia assistant, the attending anesthesiologist remains responsible for the anesthetic management of the patient. Before delegating care of the patient to an anesthesia assistant, the anesthesiologist must ensure that the patient's condition is stable and that the anesthesia assistant is familiar with the operative procedure and the operating room environment and equipment. The attending anesthesiologist must remain immediately available when care is delegated to an anesthesia assistant.
An anesthesiologist may briefly delegate routine care of a stable patient to a competent person who is not an anesthesia assistant only under the most exceptional circumstances, e.g., to provide life-saving emergency care to another patient. That person's only responsibility would be to monitor the patient during the anesthesiologist's absence and to keep the anesthesiologist informed until he/ she returns. In this situation, the anesthesiologist remains responsible for the care of the patient and must inform the operating room team.
An intraoperative handover of care between two anesthesiologists should be documented in the anesthesia record and follow a structured protocol.
It is unacceptable for one anesthesiologist to simultaneously administer general anesthesia, major regional anesthesia (spinal, epidural, or other), or deep procedural sedation (see Appendix 6) 1 for concurrent surgical, diagnostic, or therapeutic procedures on more than one patient. Nevertheless, it may be appropriate in specific circumstances for one anesthesiologist to supervise more than one patient where only minimal to moderate sedation is administered, provided an appropriately trained, qualified, and accredited individual approved by the department of anesthesiology, and the healthcare institution is in constant attendance with each patient receiving care. In an obstetric unit, however, it is acceptable to supervise more than one patient receiving regional analgesia for labour. Due care must be taken to ensure that a suitably trained person adequately observes each patient following an established protocol. When an anesthesiologist is providing anesthetic care for an obstetric delivery, a second appropriately trained person should be available to provide neonatal resuscitation.
It is unacceptable for a single physician to administer an anesthetic, including deep procedural sedation, and simultaneously perform a diagnostic or therapeutic procedure, except for procedures done with only infiltration of local anesthetic and/or minimal sedation.
# Patient Monitoring
The only indispensable monitor is the presence, at all times, of a physician or an anesthesia assistant who is under the immediate supervision of an anesthesiologist and has appropriate training and experience. Mechanical and electronic monitors are aids to vigilance. Such devices assist the anesthesiologist to ensure the integrity of the vital organs and, in particular, the adequacy of tissue perfusion and oxygenation. Monitoring equipment must be used as intended by the manufacturer and approved by Health Canada for the specific application.
The healthcare facility is responsible for the provision and maintenance of monitoring equipment that meets current published equipment standards.
The chief of anesthesia is responsible for advising the healthcare facility regarding the procurement of monitoring equipment and for establishing policies for monitoring to help ensure patient safety.
The anesthesiologist is responsible for monitoring the patient receiving care and for ensuring that appropriate monitoring equipment is available and working correctly. A preanesthetic checklist (Appendix 3 or equivalent) must be completed prior to initiation of anesthesia.
Cautious dosing, vigilant monitoring, and the appropriate reversal of neuromuscular blocking drugs are all essential for patient safety. Neuromuscular monitoring must be utilized when neuromuscular blocking agents are administered.
It is recommended that depth of anesthesia monitoring (e.g., processed EEG-based) be available and be considered for use, if clinically indicated, for patients who are at increased risk for intraoperative anesthesia awareness.
Monitoring guidelines for standard patient care apply to all patients receiving general anesthesia, regional anesthesia, or procedural sedation.
# Required Monitoring Equipment
Monitoring equipment is classified as follows:
- Required: These monitors must be in continuous use throughout the administration of all anesthetics. - Exclusively available for each patient: These monitors must be available at each anesthetic work station so that they can be used with no delay. - Immediately available: These monitors must be available to facilitate their use without undue delay.
The following monitoring equipment is required:
- Pulse oximeter;
- Apparatus to measure blood pressure, either directly or noninvasively; - Electrocardiography; - Neuromuscular blockade monitor when neuromuscular blocking drugs are used; - Capnography for general anesthesia and to assess the adequacy of ventilation for moderate or deep procedural sedation; and - Agent-specific anesthetic gas monitor, when inhalational anesthetic agents are used.
The following monitoring equipment must be exclusively available for each patient:
- Apparatus to measure temperature; - Stethoscope; - Appropriate lighting to visualize an exposed portion of the patient.
The following monitoring equipment must be immediately available:
- Spirometer to measure tidal volume; - Manometer to measure endotracheal tube cuff pressure;
- Equipment for invasive hemodynamic monitoring if indicated (e.g., arterial, central venous).
The anesthesiologist must remain constantly vigilant, understanding that brief interruptions in continuous monitoring may be unavoidable and there are certain circumstances in which a monitor may fail.
Audible and visual alarms for oximetry and capnography should not be indefinitely disabled during the conduct of an anesthetic except during unusual circumstances. The variable pitch, pulse tone, and lowthreshold alarm of the pulse oximeter and the capnograph apnea alarm must give an audible and visual warning.
# Perioperative Temperature Management
Monitoring patient core temperature is strongly recommended during cases of general and neuraxial regional anesthesia lasting 30 min or longer. In the absence of surgical or patient indications for intraoperative hypothermia, active patient warming systems, control of the operating room ambient temperature, and other methods, should be used to target a central core temperature of 36-37°C.
# Patient Positioning
Patient positioning for procedures requiring anesthesia is an operating room team responsibility and demands a high level of attention to avoid complications. It is recognized, however, that positioning-related complications can still occur despite best practice and vigilance. Risks related to patient positioning will vary and depend on the type and duration of surgery, the specific position utilized, and patient factors such as BMI and other comorbidities. Therefore, the considerations and planning for positioning best practice should be discussed by the surgical team ideally before anesthesia induction, for example during part 1 of the Surgical Safety Checklist. All members of the team, including the anesthesiologist, should be encouraged to voice concerns related to any aspect of positioning (e.g., specific risk factors and availability, condition and appropriateness of OR tables and other positioning equipment), and strategies to mitigate these risks should be considered. Patient positioning should be documented and also rechecked regularly by the anesthesiologist to be sure positioning conditions remain ideal. Patients should be informed preoperatively of any specific risks that may be associated with the position planned for their procedure.
# Records
All monitored physiologic variables should be charted at intervals appropriate to the clinical circumstances. Heart rate and blood pressure should be recorded at least every five minutes. Oxygen saturation must be monitored continuously and should be recorded at frequent intervals, at a minimum of every five minutes, for all patients. End-tidal carbon dioxide concentration must be monitored continuously and recorded at frequent intervals if the trachea is intubated or a supraglottic device is in situ. Reasons for deviation from these charting guidelines should be documented in the anesthetic record. Monitors, equipment, and techniques, as well as time, dose, and route of all drugs and intravenous fluids should be recorded. All other relevant intraoperative anesthesia care and events, including unexpected or adverse events, should also be recorded.
The patient health record should include the patient's level of consciousness, heart rate, blood pressure, oxygen saturation, and respiratory rate as first determined in the PACU. These recommendations apply to both manually created (handwritten) and electronic anesthesia information management system (AIMS) created anesthesia records. At present, there are no practice standards for what additional data (e.g., gas analysis, ventilator, and respiratory data) that can potentially be collected by an AIMS charting system should become part of a patient's permanent health record.
AIMS have been shown to have potential benefits over handwritten records in several key areas, including improved legibility, precision and reliability of anesthesia records, providing searchable data for quality improvement, outcome and performance reporting and translational research, enhanced medication safety and tracking and real-time clinical decision support for users. The anesthesia patient safety literature supports the use of AIMS. Importantly, AIMS maintain a longitudinal patient database so historical patient encounters should be easily retrievable for review and this should be considered an important feature of any system. The CAS does not promote or endorse any one specific vendor or product but acknowledges that there may be potential benefits of a well designed and implemented AIMS over manually charted records where facility and anesthesia department resources permit the consideration of an AIMS. Ideally it should be implemented and supported in cooperation with the facility information technology department including communication with other facility electronic patient databases wherever possible.
6 The Postanesthetic Period
# Recovery Facility
A PACU must be available in any facility that provides anesthetic services. Administrative policies to coordinate medical and nursing care responsibilities must be enforced in accordance with facility bylaws.
The department of anesthesia should have overall medical administrative responsibility for the PACU. There should be a PACU policy manual approved by appropriate medical, nursing, and administrative authorities.
The anesthesiologist should accompany the patient to the PACU, communicate necessary information to the PACU nurse(s) as part of a structured handover of care protocol, and write appropriate orders. Continuous monitoring of patients is recommended during the perioperative period appropriate to the clinical situation. If clinically indicated, supplemental oxygen, portable pulse oximetry, and other appropriate monitoring devices should be applied during transport to the PACU or intensive care unit. If supplemental oxygen is applied during transport or in PACU to patients who are intubated, it is strongly recommended that it only be provided using devices approved for that specific application to minimize any risk of barotrauma. The anesthesiologist should delegate care to the PACU nurse only when assured that nursing staff may safely observe and care for the patient. The anesthesiologist or designated alternate is responsible for providing anesthetic-related care in the PACU. Discharge from the PACU is the responsibility of the anesthesiologist; this responsibility may be delegated in accordance with facility policy.
Supplemental oxygen and suction must be available for every patient in the PACU. Emergency equipment for airway management, resuscitation, and life support must be available in the PACU. Equipment for management of the difficult airway must be immediately available to the PACU. The monitoring used in the PACU should be appropriate to the patient's condition, and a full range of monitoring devices should be available. Monitor alarms should be enabled with alarm settings appropriate to the condition and age of the patient. The use of continuous pulse oximetry is required in the initial phase of recovery. Capnography is required for intubated and deeply sedated patients and is recommended for unconscious patients with in situ supraglottic airway devices. An apnea monitor is recommended for preterm infants with a gestational age of less than 50 weeks.
An accurate record of the immediate recovery period must be maintained. This must include a record of vital signs together with other aspects of treatment and observation. The recovery record must form a part of the permanent medical record. Any complications that bear any relation to the anesthetic should be recorded either on the recovery record or on the progress notes on the patient's chart.
In some circumstances, it may be considered acceptable to transfer a patient directly to other care units or to bypass the PACU if the appropriate level of care is available in another unit in the facility and the suitability of the patient for this transfer is documented on the anesthetic record.
# Discharge of Patients After Day Surgery
Discharge of patients after day surgery must utilize a formal care plan approved by the institution and be documented in the patient care notes. Patients should meet the facility discharge to home criteria using a validated assessment tool (e.g., Post Anesthetic Discharge Scoring System). Specific written instructions should include management of pain and postoperative complications, and both routine and emergency followup. The patient should be advised regarding the additive effects of alcohol and other sedative drugs, the danger of driving or operating other hazardous machinery during the postoperative period (most commonly 24 hr postoperatively), and the necessity for attention by a competent adult during the postoperative period (most commonly 24 hr postoperatively).
7 Guidelines for Neuraxial and Peripheral Nerve Block Regional Anesthesia 7.1 Peripheral Nerve Block Regional Anesthesia It is strongly recommended that a preperipheral nerve block checklist (''pause'') be developed, implemented, and administered in all areas where peripheral blocks are performed. This should include, but need not be restricted to:
- Confirmation that informed consent has been obtained. - Confirmation of patient identity, allergies, surgical procedure, block type and location, and correct side of the block in the presence of an alert patient or substitute decision maker. - Review of coagulation status.
- Marking of the correct side to be blocked if applicable. - Discussion of planned and maximum safe local anesthestic dosages to be administered. - Confirmation of the availability of appropriate resuscitation equipment (cf. below). - Communication and timing of the block in coordination with operating room availability.
Patient monitoring should, at a minimum, include non-invasive blood pressure and oxygen saturation. Supplemental oxygen and equipment for airway management must be immediately available. Delegation of monitoring patients must be consistent with existing CAS Guidelines.
In areas where peripheral nerve block regional anesthesia techniques are performed and/or local anesthetic infusions are delivered, cognitive aids and medications (e.g., lipid emulsion 20%) for the treatment of local anesthetic systemic toxicity (LAST) must be immediately available.
# Obstetric Neuraxial Regional Anesthesia
Anesthesia services for parturients include obstetric analgesia for labour-for both uncomplicated and complicated deliveries-or for operative deliveries. All guidelines regarding provision of anesthesia for other diagnostic or therapeutic procedures also apply to the provision of obstetric anesthesia. The guidelines in this section pertain to epidural and spinal analgesia during labour. The term ''regional analgesia'' includes epidural, spinal, and combined spinal-epidural analgesia.
These guidelines are reviewed annually by the Obstetric Anesthesia Section of CAS and updated as indicated. Each facility may choose to develop additional guidelines or policies for specific situations in which obstetric regional analgesia is provided.
Under the direction of an anesthesiologist, some aspects of monitoring and management of obstetric regional analgesia may be delegated to other healthcare personnel. Each facility should ensure that such other personnel receive the same training, certification, continuing education, and recertification in obstetric regional analgesia.
# Initiation of Obstetric Regional Analgesia
Before introducing obstetric regional analgesia, the facility should have appropriate monitoring protocols in place. These protocols should outline the types of monitoring required and the frequency of monitoring. In addition, they should clearly state how to manage common problems and emergencies and indicate whom to contact if assistance is required.
- Obstetric regional analgesia should be provided only by physicians with training, facility privileges, and licence to provide these services. This includes trainees with appropriate supervision. 2. Regional analgesia should be initiated and maintained only in locations where appropriate resuscitation equipment and drugs are immediately available. 3. Informed consent should be obtained and documented in the medical record. 4. Intravenous access must be established before initiating regional analgesia, and it should be maintained throughout the administration of regional analgesia. 5. The anesthesiologist should be immediately available until analgesia is established and the patient's vital signs are stable. 1. there are appropriate protocols for management of patients receiving CEI, PIEB, and PCEA; and 2. the anesthesiologist can be contacted for the purpose of obtaining advice and direction.
When initial and top-up bolus epidural local anesthetics are administered, the anesthesiologist must be immediately available to intervene appropriately recognizing that these techniques can cause immediate life-threatening complications.
Individual departments of anesthesiology should establish their own policies regarding the appropriate availability of an anesthesiologist to manage the potential complications of regional analgesia for labour and delivery. Safety systems must be in place to secure epidural local anesthetic mixtures and supplies containing controlled substances (e.g., opioids) to minimize the risk of diversion.
# Oral Intake During Labour
Gastric emptying of solids is delayed during labour and opioid analgesics may further delay gastric emptying.
Therefore, parturients should generally be discouraged from ingesting solid foods when in active labour. In contrast to solid food, clear fluids are emptied relatively rapidly from the stomach during labour. Therefore, in general, women should be permitted clear fluids as desired during active labour. Individual facilities should develop protocols regarding the intake of solids and clear fluids by women in active labour.
# Guidelines for Acute Pain Management Using Neuraxial Analgesia
When neuraxial analgesia is managed by anesthesiologists, the incidence of side effects is no higher than when alternative techniques of pain management are used. Accordingly, when its use is appropriate, neuraxial analgesia should be managed by anesthesiologists.
For the purposes of these guidelines, neuraxial analgesia is defined as intrathecal or epidural administration of opioids and/or local anesthetics for treatment of postoperative pain or other acute pain problems. These guidelines are to provide anesthesiologists with the principles of management to maximize the benefit-risk ratio of providing neuraxial analgesia.
# Administrative and Educational Policies
The department of anesthesia should establish an acute pain service that is responsible for:
# Policies for Drug Administration
Each facility should use a limited number of standard solutions. A preprinted order sheet listing the standard solutions for the facility is strongly recommended. Before any solution that is not standard in the facility is dispensed, the anesthesiologist should verify the order with nursing and pharmacy personnel and discuss its indications and all concerns relating to its use with the nurses responsible for administering the drug and monitoring the patient.
The risk of errors due to incorrect route of drug injection must be minimized. For continuous infusions or PCEA, the use of unique tamper-proof pumps that are distinct from the pumps used for intravenous fluid or drug administration is strongly recommended. The tubing between neuraxial analgesia infusion pumps and catheters should not have ports that could permit unintentional injection of intravenous drugs (see section 5.1-6).
Preparation of solutions should follow a standardized procedure. All analgesic drug solutions should be labeled with the composition of the solution (opioid, local anesthetic, or both) and its intended route of administration. For epidural administration, this should include the date and time of preparation and the name of the individual who prepared it.
# Patient Monitoring and Management of Adverse Events
Patients receiving neuraxial analgesia should be in a room equipped with oxygen and suction. Resuscitation drugs and equipment must be immediately available. Before initiating neuraxial analgesia, intravenous access must be secured, and after discontinuing neuraxial analgesia, intravenous access must be maintained for the expected duration of drug effects.
Epidural catheter dressings should permit examination for catheter movement and daily inspection of the catheter entry site for any signs of infection.
Standardized policies for patient management should be established. The parameters to be assessed, frequency of assessments, documentation, and procedures for management of complications should be specified. Adequate nursing personnel must be available to assess and manage patients receiving neuraxial analgesia. Monitoring should continue after discontinuation of neuraxial analgesia until its effects have dissipated.
An anesthesiologist must be readily available to advise nursing personnel on such issues as dose titration and management of adverse effects. Each facility with an acute pain service should ensure that an anesthesiologist is available to attend directly to patients receiving neuraxial analgesia within an appropriate time depending on the clinical situation. Each facility should also specify procedures for emergent management of any lifethreatening complications.
Other drugs, particularly benzodiazepines or parenteral opioids, may cause severe respiratory depression in patients receiving neuraxial analgesia. For this reason, other physicians should not order sedatives or analgesics for any patient receiving neuraxial analgesia. The acute pain service should direct analgesic and sedative therapy until the effects of neuraxial analgesia have dissipated.
# Epidurals and Anticoagulation
Patients with epidural catheters may receive prophylactic low-dose anticoagulant therapy if appropriate precautions are taken:
- To minimize the risk of epidural hematoma, catheter insertion and removal and the timing of anticoagulant administration must be coordinated so that no clinically significant anticoagulant effect is present at these times. - Use of nonsteroidal anti-inflammatory drugs in patients receiving neuraxial analgesia is appropriate, but concurrent administration of these drugs or other antiplatelet medication and an anticoagulant may increase the risk of epidural hematoma.
- Where neuraxial analgesia is used for prolonged postoperative pain management, every effort should be made to avoid lower extremity motor blockade. - Nursing staff should be aware of the signs and symptoms of epidural hematoma. Any change in neurologic status or new-onset back pain must be investigated immediately.
If therapeutic anticoagulation or low molecular weight heparin are indicated in a patient with an epidural catheter, the anesthesiologist should be consulted so that the timing of catheter removal and initiation of alternative analgesic management can be coordinated safely.
# Guidelines for the Practice of Anesthesia in Remote Locations
The basic principles, training requirements, techniques, equipment, and medications used for the practice of anesthesia in remote locations are as outlined in other sections of these Guidelines. They apply equally to anesthesia care, including procedural sedation (see Appendix 6) delivered by anesthesiologists in any operating room or out-of-operating room locations both within a hospital facility and outside of a hospital facility (e.g., offices, clinics). 9.1 Anesthesia Care Delivered in a Non-Hospital Medical/Surgical/Dental Facility
# Patient Selection
The physical status of patients should be classified using the American Society of Anesthesiologists physical status (ASA) score. Typically, only patients with ASA classifications of I and II should be considered for procedures. Patients with ASA III classification may be accepted under certain circumstances but only at the discretion of the attending anesthesiologist. Caution should be exercised when booking patients with a known difficult airway.
# Preoperative Considerations
The patient must have had a recent and documented health history, physical examination including an airway examination, and any appropriate laboratory investigations. This may be carried out by another physician (e.g., proceduralist) but it is strongly recommended that there be a screening process that is developed and supported by the anesthesia leadershipproviding services. The duration of fasting should be consistent with section 4.2 Fasting Guidelines.
# Conduct of Anesthesia
The anesthetic and recovery facilities must conform to facility standards established by the CSA (see Appendix 1) and all CAS guidelines established for patient care. The patient should be discharged home from the facility using a validated scoring system for fitness to discharge (e.g., Post Anesthetic Discharge Scoring System). Patients should be provided with written instructions for the preoperative and postoperative periods. The demand for the delivery of anesthesia care services outside of an operating room (e.g., endoscopy, interventional radiology, cardiac catheterization) is growing because of technological advances and the growth in the availability of less invasive, yet potentially painful, procedures. The delivery of anesthesia care in these remote procedural units can present unique challenges to the anesthesia care team (e.g., patients may have an ASA status of III-IV and have significant comorbidities) and they may be some distance from the operating rooms and support staff or outside of a hospital facility. Procedural units where anesthesiologists have been asked to provide care should comply with the same CSA standards (Appendix 1), equipment guidelines (see section 3.0), and general CAS guidelines as an operating room to the greatest extent possible. This includes, but need not be restricted to, patient selection and assessment, pre-procedural testing, fasting guidelines, equipment and electrical outlets, oxygen and suction, ventilation and scavenging if inhalational agents will be utilized, medications and equipment required for resuscitation, patient monitoring, the recovery facility and anesthesia support personnel. Any location outside of an operating room where anesthesiologists provide care must be approved by the anesthesia leadership of the facility. Appropriately trained and experienced anesthesia support personnel, for example an Anesthesia Assistant (see section 2.5) or other staff with experience supporting anesthesia should be present or immediately available to assist the anesthesiologist in remote locations. It is not appropriate to rely solely on procedural unit staff to support anesthesia unless they have had training and experience in the direct support of the delivery of anesthesia care and are approved by anesthesia leadership. There must be reliable two-way communication available to call for assistance and support of the anesthesia provider as it may be required.
provided solely for the convenience of CAS members. The CAS is not responsible for the accuracy, currency, or reliability of the content. The CAS does not offer any guarantee in this regard. It is not responsible for the information found through these links and does not necessarily endorse the sites or their content. This list includes sites that are updated periodically. Les recommandations suivantes ont pour objectif de proposer des lignes directrices de base touchant l'exercice de l'anesthésie. Leur but est de constituer un cadre pour la prestation de soins aux patients qui soient raisonnables et acceptables, et c'est ainsi qu'elles devraient être interprétées, ce qui permet une certaine flexibilité selon les circonstances. Chaque partie du Guide peut faire l'objet de révision au besoin, selon l'évolution de la technologie, de la pratique et des meilleures données probantes disponibles.
1 Principes de base Dans le présent document, le mot anesthésiologiste est utilisé pour désigner toute personne qui a un permis d'exercer la médecine avec privilège d'administrer l'anesthésie. L'anesthésie est la réalisation délibérée de toute intervention visant à rendre un patient temporairement insensible à la douleur ou à l'environnement externe dans le but d'exécuter une intervention diagnostique ou thérapeutique.
Le présent Guide s'adresse à tous les anesthésiologistes du Canada. L'exercice indépendant de l'anesthésie est une spécialité médicale et, à ce titre, elle doit être exercée par des médecins ayant une formation appropriée en anesthésie. Le processus de certification du Collège royal des médecins et chirurgiens du Canada constitue la seule voie de reconnaissance comme spécialiste en anesthésie au Canada.
La Société canadienne des anesthésiologistes (SCA) reconnaît que la population dans les collectivités éloignées n'est souvent pas suffisamment nombreuse pour justifier une pratique d'anesthésiologie spécialisée. Dans ces collectivités, des médecins de famille ayant reçu une formation adéquate pourraient être appelés à dispenser les services d'anesthésie. Dans les communautés où le volume clinique est suffisamment important pour justifier l'emploi d'anesthésiologistes à temps plein, des anesthésiologistes ayant complété leur spécialisation devraient offrir ces services. Tous les anesthésiologistes doivent poursuivre une formation continue dans la pratique de l'anesthésie, de la prise en charge de la douleur, des soins périopératoires et de la réanimation, et participer à un programme structuré de maintien des compétences (par ex., MDC du Collège royal).
# Organisation des services d'anesthésie
Le département d'anesthésie devrait être organisé, dirigé et intégré de façon appropriée aux autres départements de l'organisme ou de l'établissement, et devrait regrouper tous les membres du personnel de l'établissement qui assurent des soins anesthésiques aux patients, aussi bien à des fins chirurgicales, obstétricales, diagnostiques ou thérapeutiques.
Compte tenu de l'ampleur et de la nature des services offerts, le département devrait comporter le personnel nécessaire et s'efforcer d'assurer que ces services soient disponibles comme l'établissement de soins de santé le requiert.
Le chef du département devrait être un médecin certifié en anesthésie ou encore possédant une formation adéquate en anesthésie. Cette personne devrait être nommée de la même manière que les autres chefs de départements cliniques et devrait faire partie des entités administratives médicales supérieures de l'établissement. Certains domaines spécifiques des soins anesthésiques peuvent avoir des préoccupations qui leur sont propres. Le département d'anesthésie de chaque institution peut déterminer les privilèges en anesthésie pédiatrique, selon la population pédiatrique que l'institution dessert, l'âge de l'enfant, la présence de comorbidités, la formation spécifique du médecin et son expérience en anesthésie pédiatrique, ainsi que la complexité de l'intervention en question.
Les médecins qui obtiennent le privilège d'exercer l'anesthésie devraient posséder les connaissances ainsi que les habiletés techniques et non techniques indispensables à la pratique de l'anesthésie. Des problèmes tels que la fatigue, le harcèlement et l'intimidation en milieu de travail, les problèmes de santé personnelle et mentale, le stress, une nutrition inadéquate au travail, l'épuisement professionnel et la consommation de substances peuvent tous contribuer négativement à la santé et au bien-être et, en fin de compte, à la sécurité des patients. Tous les médecins en anesthésie devraient demeurer vigilants pour détecter, chez eux-mêmes et leurs collègues, tout signe ou symptôme d'une déficience fonctionnelle, afin que toute déficience puisse être dépistée rapidement et qu'un soutien puisse être proposé. Les troubles liés à l'utilisation de substances sont courants dans la société et peuvent également affecter les médecins en anesthésie. L'abus d'opioïdes est plus fréquent en anesthésie que dans la plupart des autres spécialités médicales. Au minimum, les programmes de prévention du détournement de médicaments contrôlés sont essentiels (voir les sections 3.1, 4 a et b) et devraient faire partie des stratégies, des politiques et de la formation départementales plus larges pour aider à identifier les médecins et le personnel de soutien à l'anesthésie qui pourraient avoir leurs facultés affaiblies en raison de troubles liés à l'utilisation de substances.
La direction du département d'anesthésie et/ou de l'établissement a le devoir de soutenir la santé et le bien-être des médecins, notamment au moyen de structures administratives qui favorisent et encouragent un milieu de travail sain et créent des mécanismes de soutien par les pairs. Les départements plus petits pourraient avoir besoin de s'appuyer sur des programmes locaux, provinciaux ou nationaux de soutien aux médecins, et l'accès à ces ressources devrait être encouragé auprès du personnel. L'objectif devrait être de créer et de maintenir une culture de sécurité psychologique dans laquelle les écarts par rapport à des conditions de travail gérables et raisonnables sont signalés et réglés, et dans laquelle les fournisseurs de soins à risque ou en difficulté peuvent être identifiés et soutenus de manière appropriée, sans crainte de répercussions négatives.
Les domaines spécifiques à considérer peuvent inclure, sans toutefois s'y limiter : 2.5 Personnel de soutien L'établissement de soins de santé doit s'assurer de la disponibilité de personnel de soutien pour remplir un rôle d'assistance auprès de l'anesthésiologiste. Cette assistance doit être disponible en tout temps et en tout lieu où des services d'anesthésie sont offerts. Le personnel de soutien doit posséder les compétences nécessaires à répondre aux besoins spécifiques des domaines de surspécialité de l'anesthésie, ce qui se répercute sur le besoin de compétences spécifiques dans des domaines tels que l'anesthésie spécialisée en pédiatrie.
On recommande aux établissements de disposer d'un assistant en anesthésie formellement désigné qui aura reçu une formation spécifique en assistance en anesthésie. Le département d'anesthésie et les autorités administratives compétentes doivent approuver l'étendue des tâches des assistants en anesthésie travaillant dans un établissement en particulier. En outre, les assistants en anesthésie, tout comme les autres professionnels de la santé employés par l'établissement, doivent être protégés par l'assuranceresponsabilité de l'établissement. Les responsabilités et les tâches déléguées aux assistants en anesthésie doivent être conformes aux règlements gouvernementaux en vigueur, aux politiques et lignes directrices édictées par les organismes de règlementation de la profession, et aux politiques de l'établissement local.
Un établissement ne disposant pas d'assistants en anesthésie en bonne et due forme doit mettre à disposition de l'anesthésiologiste du personnel paramédical afin de l'assister. Les tâches incombant à ces assistants doivent être clairement définies. Un anesthésiologiste ne doit leur déléguer ou impartir que les tâches pour lesquelles ils ont été autorisés ou approuvés.
3 Matériel d'anesthésie et lieux convenant à l'anesthésie L'anesthésie doit se pratiquer dans un établissement adapté. Tout le matériel nécessaire, y compris le matériel d'urgence, les systèmes de soutien des fonctions vitales, les médicaments et les autres fournitures, doit être à portée de main. Il est fortement recommandé qu'un manuel de listes de contrôle et d'aides cognitives soit disponible dans tous les lieux où l'anesthésie est pratiquée afin de soutenir la prise en charge des urgences périopératoires critiques. Le contenu de ce manuel devrait être révisé et mis à jour régulièrement selon les besoins et répété de façon périodique en équipe.
L'établissement de soins de santé, en consultation avec le département d'anesthésie, est responsable de l'aménagement et de l'entretien des lieux servant aux soins préopératoires, postopératoires et anesthésiques, ainsi que de l'achat, de l'entretien et du traitement après utilisation du matériel et des fournitures servant à l'anesthésie et aux autres fonctions connexes. L'Association canadienne de normalisation (CSA) et d'autres organismes d'élaboration de normes ont publié des normes et des recommandations se rapportant à la conception, la construction et la rénovation des établissements de santé, ainsi que concernant la gestion du risque, la sécurité de base et les performances essentielles du matériel médical (Annexe 1).
# Responsabilités de l'établissement de santé
Il incombe à l'établissement de soins de santé de veiller à l'application des mesures suivantes : Le personnel qui administre l'anesthésie doit s'assurer qu'on ne transmet pas de substances ou d'agents potentiellement infectieux d'un patient à un autre. À cet égard, une attention particulière doit être portée aux seringues, aux tubulures des pompes à perfusion et aux fioles de médicaments multidoses.
Avant d'introduire tout nouvel appareil en anesthésie, tous les membres du département d'anesthésie doivent recevoir une formation concernant son utilisation sécuritaire. La participation à ces séances doit être documentée. Ces séances de formation doivent être répétées aussi souvent que nécessaire pour les nouveaux et anciens membres du département.
# Gaz résiduels
Recommandations visant à diminuer l'exposition professionnelle aux gaz anesthésiques résiduels : Le principal objet de l'évaluation préanesthésique est d'obtenir les renseignements requis pour planifier la prise en charge anesthésique. Par conséquent, un médecin bien informé quant à la prise en charge anesthésique pour la procédure diagnostique ou thérapeutique proposée devrait documenter tous les aspects des antécédents médicochirurgicaux du patient, le bilan de l'examen physique et les résultats des analyses de laboratoire pertinents à la prise en charge anesthésique. Les antécédents du patient devraient inclure les problèmes médicaux passés et actuels, la prise de médicaments récente et actuelle, les réactions ou réponses inhabituelles aux médicaments et tous les problèmes et complications associés aux anesthésies administrées antérieurement. Il y a lieu de connaître également les antécédents familiaux de réactions indésirables associées à l'anesthésie. Tout renseignement concernant l'anesthésie que le patient juge pertinent de signaler devrait également être noté. Il convient enfin d'inscrire au dossier médical de chaque patient le code de classification de l'American Society of Anesthesiologists (Annexe 2).
Dans les cas adaptés, la disponibilité d'un « Plan de soins avancés » (accord de représentation, directive préalable, « testament biologique », directive « ne pas réanimer », etc.) doit être vérifiée et son applicabilité à l'intervention proposée déterminée et documentée au dossier d'évaluation anesthésique.
Le chirurgien peut solliciter une consultation avec un anesthésiologiste. Les consultations médicales devraient être obtenues lorsque cela est indiqué.
Le bilan ou la consultation anesthésique préopératoire peut avoir lieu en clinique externe avant l'admission pour l'opération. Les indications concernant l'évaluation préalable à l'admission comprennent l'existence de problèmes médicaux importants (comorbidités), la nature de la procédure diagnostique ou thérapeutique proposée, et la demande du patient. La présence d'un parent/tuteur légal est nécessaire si le patient est un enfant ou n'est pas apte à fournir un consentement éclairé. Tous les patients devraient être informés que des dispositions seront prises pour rencontrer un anesthésiologiste s'ils souhaitent s'entretenir de leur prise en charge anesthésique avant leur admission à l'établissement. La clinique d'évaluation préopératoire devrait également permettre au personnel infirmier et aux autres membres du personnel de santé d'évaluer le patient. L'anesthésiologiste en charge du patient est responsable de l'évaluation préanesthésique finale durant la période préopératoire immédiate.
# Examens préopératoires
Les examens de laboratoire ne devraient pas être réalisés sur une base régulière mais uniquement lorsque les résultats modifieront la prise en charge périopératoire. Les analyses de laboratoire devraient être réalisées lorsque l'état du patient, le traitement médicamenteux et la nature de l'intervention proposée les justifient. Les tests sanguins de laboratoire, les électrocardiogrammes et les radiographies du poumon de routine ne sont pas recommandés chez les patients asymptomatiques subissant une chirurgie à faible risque.
# Lignes directrices concernant le jeûne
Les règles concernant le jeûne devraient varier en fonction de l'âge du patient et de ses antécédents médicaux et s'appliquer à toutes les formes d'anesthésie, incluant la sédation procédurale (voir Annexe 6). 1 Les interventions très urgentes ou urgentes doivent être réalisées après avoir examiné les risques qu'entraînerait leur report comparativement au risque d'aspiration du contenu de l'estomac. Le type et la quantité de nourriture absorbée doivent être pris en considération pour déterminer la durée du jeûne. Avant une intervention non urgente, la durée minimale du jeûne devrait être de :
- Huit heures après un repas copieux comportant des aliments solides, particulièrement s'il contenait des protéines (par ex. de la viande) ou des aliments gras; - Six heures après un repas léger (par ex. repas faible en gras tel une tartine); - Six heures après l'ingestion de lait maternisé, de lait non humain ou de lait maternel tiré et fortifié avec des adjuvants; - Quatre heures après l'ingestion de lait maternel;
- Deux heures après l'ingestion de liquides clairs pour un adulte; - Une heure après l'ingestion de liquides clairs pour les nourrissons ou les enfants.
Sauf contre-indication, il convient d'encourager les adultes et les enfants à boire des liquides clairs (eau, jus sans pulpe, boissons à base de sucres complexes et thé ou café noir) jusqu'à deux heures avant une chirurgie non urgente. Les patients pédiatriques devraient également être encouragés à boire des liquides clairs, tels que définis, jusqu'à une heure avant une chirurgie non urgente.
Les conditions retardant la vidange gastrique nécessitent une évaluation au cas par cas du patient. Ces recommandations peuvent être modifiées à la discrétion du médecin.
Lorsqu'elle est indiquée, la prémédication devrait être ordonnée par l'anesthésiologiste. Les ordonnances doivent spécifier la dose, le moment et la voie d'administration.
Un antagoniste des récepteurs H2 (par voie orale ou intraveineuse) est recommandé pour toutes les femmes devant subir un accouchement par césarienne.
Trente (30) mL de citrate de sodium (0,3 molaire) sont recommandés avant un accouchement par césarienne urgent si l'on planifie une anesthésie générale.
Voir la Section 7.3 pour les recommandations de jeûne spécifiques aux patientes en travail actif.
# Règlementations supplémentaires
Des lois provinciales ou la règlementation de l'établissement pourraient prescrire d'autres directives régissant l'administration de l'anesthésie.
5 La période anesthésique
# Préparation à l'anesthésie
Avant le début de l'anesthésie, l'anesthésiologiste doit s'assurer que 1. La procédure anesthésique prévue a été expliquée au patient, y compris les risques reconnus et les techniques alternatives, et on a documenté cette explication; 2. Une évaluation adaptée de l'état du patient a été réalisée; 3. Tout le matériel qu'on prévoit nécessaire est accessible et en bon état de fonctionnement, y compris le matériel nécessaire au maintien de la température centrale (température centrale du patient 36-37°C); 4. On a accès à une source de réserve d'oxygène sous pression; 5. Tous les médicaments et agents qu'on prévoit nécessaires sont correctement identifiés -les étiquettes de médicament apposées par l'usager doivent être conformes à la norme de la CSA CAN/ CSA -Z264.3-98 (R2005) (Annexe 1); 6. Si des connecteurs Luer neuraxiaux sont utilisés, les deux côtés des raccords Luer doivent être étiquetés. Il faut envisager l'utilisation de connecteurs neuraxiaux conformes à la norme ISO 80369-6:2016connecteurs de petit diamètre interne pour application neuraxiale (raccords NRFitÒ) en fonction des disponibilités des fournisseurs de matériel; et 7. On a tenu compte des indications du fabricant quant à l'utilisation, à la manipulation et à la disposition de l'équipement et du matériel d'anesthésie.
# Prise en charge des voies aériennes
La prise en charge des voies aériennes, particulièrement en cas de voies aériennes difficiles, contribue significativement à la morbidité et à la mortalité liées à l'anesthésie. Chez les patients pour lesquels une intubation trachéale difficile est anticipée ou non anticipée, ou si l'intubation a échoué, ou lorsque la ventilation au masque ou le positionnement d'un dispositif supraglottique pourrait être difficile, et/ou dans les situations « impossible de ventiler, impossible d'oxygéner » (CVCOcannot ventilate, cannot oxygenate), et/ou lorsqu'un abord cervical antérieur d'urgence (eFONA) est nécessaire, une prise en charge appropriée des voies aériennes est essentielle à la sécurité des patients. Cette prise en charge comprend, sans nécessairement s'y limiter, une évaluation adaptée des voies aériennes, du matériel (par ex. trousses pour les voies aériennes difficiles, vidéolaryngoscopes, bronchoscopes, matériel d'abord cervical antérieur ou de cricothyroïdotomie d'urgence), une formation et des exercices de simulation appropriés, du personnel de soutien et le recours aux protocoles et listes de contrôle adéquats afin de prendre en charge au mieux des voies aériennes difficiles. Une attention et une optimisation particulières sont nécessaires dans divers domaines, notamment : l'emplacement et la disponibilité du matériel, le contexte local (p. ex., les lieux isolés), l'expérience du fournisseur de soins, le travail d'équipe et la communication (p. ex., les séances d'information de l'équipe), ainsi que les facteurs psychologiques. Il est essentiel de tenir compte des facteurs non techniques et humains (au niveau de l'individu, de l'équipe et de l'organisation) qui peuvent agir comme des catalyseurs ou des obstacles à une prise en charge des voies aériennes réussie. La SCA ne recommande pas une ligne directrice, un algorithme ou une liste de contrôle en particulier pour la prise en charge des voies aériennes difficiles ou lors d'un échec d'intubation, mais elle encourage fortement les lecteurs à se référer à l'Annexe 4 pour accéder aux publications les plus récentes sur le sujet.
# Délégation des soins aux patients
L'anesthésiologiste est avant tout responsable du patient qu'il a sous ses soins. L'anesthésiologiste ou un assistant en anesthésie supervisé par l'anesthésiologiste doit demeurer constamment aux côtés du patient pour toute la durée d'une anesthésie générale, régionale majeure et intraveineuse monitorée, jusqu'à ce que le patient ait été confié aux soins du personnel de l'unité de soins compétente.
Si l'anesthésiologiste traitant quitte temporairement la salle d'opération, il doit confier les soins du patient à un autre anesthésiologiste, à un résident en anesthésie ou à un assistant en anesthésie. Lorsque l'anesthésiologiste traitant délègue les soins à un résident en anesthésie ou à un assistant en anesthésie, il demeure responsable de la prise en charge anesthésique du patient. Avant de déléguer les soins du patient à un assistant en anesthésie, l'anesthésiologiste doit s'assurer que l'état du patient est stable et que l'assistant en anesthésie est familier avec l'intervention chirurgicale ainsi qu'avec l'environnement et le matériel de la salle d'opération. L'anesthésiologiste traitant doit demeurer immédiatement disponible lorsque les soins sont délégués à un assistant en anesthésie.
Un anesthésiologiste peut brièvement confier les soins courants d'un patient dont l'état est stable à une personne compétente qui n'est pas un assistant en anesthésie qu'en cas de circonstances particulièrement exceptionnelles, pour se porter par exemple au secours d'un autre patient dont la vie est en danger. L'unique responsabilité de cette personne devrait être de surveiller le patient en l'absence de l'anesthésiologiste et de tenir l'anesthésiologiste informé jusqu'à son retour. Dans de telles circonstances, l'anesthésiologiste demeure responsable des soins prodigués au patient et se doit de tenir l'équipe de la salle d'opération au courant.
Le transfert peropératoire des soins entre deux anesthésiologistes doit être noté au dossier d'anesthésie et se conformer à un protocole structuré.
Il est inacceptable qu'un anesthésiologiste administre simultanément une anesthésie générale, une anesthésie régionale majeure (rachidienne, péridurale ou autre) ou une sédation procédurale profonde (voir Annexe 6) 1 pour des interventions chirurgicales, diagnostiques ou thérapeutiques concomitantes pratiquées sur plus d'un patient à la fois. Toutefois, il peut être admis, dans des circonstances particulières, qu'un anesthésiologiste supervise plus d'un patient chez lequel une sédation minime à modérée est administrée, à condition qu'un individu ayant reçu une formation adéquate, qualifié, accrédité et approuvé par le service d'anesthésiologie et l'établissement de santé, soit constamment présent auprès de chaque patient recevant des soins. Il sera par contre admis, dans un service d'obstétrique, de surveiller simultanément plus d'une patiente à laquelle est administrée une analgésie régionale pour le travail. Chaque parturiente devra cependant être surveillée adéquatement par une personne compétente, suivant un protocole établi. Lorsqu'un anesthésiologiste dispense des soins anesthésiques en vue d'un accouchement, une deuxième personne dûment formée doit se tenir prête à intervenir pour pratiquer la réanimation néonatale.
Il est inacceptable qu'un seul médecin administre une anesthésie y compris la sédation procédurale profonde simultanément à la réalisation d'une procédure diagnostique ou thérapeutique, exception faite des interventions réalisées par seule infiltration d'anesthésiques locaux et/ou une sédation minimale.
# Monitorage du patient
Le seul moniteur indispensable est la présence, à tous les instants, d'un médecin ou d'un assistant en anesthésie placé sous la supervision immédiate d'un anesthésiologiste et détenant la formation et l'expérience appropriées. Les moniteurs mécaniques et électroniques ne sont que des aides à la vigilance. Ces appareils aident l'anesthésiologiste à s'assurer de l'intégrité des organes vitaux et, en particulier, de la perfusion et de l'oxygénation satisfaisantes des tissus. Le matériel de monitorage doit être utilisé comme prévu par le fabricant et approuvé par Santé Canada pour l'application spécifique.
Il incombe à l'établissement de soins de santé de fournir et d'entretenir un équipement de monitorage qui respecte les normes en vigueur.
Il incombe au chef du département d'anesthésie de conseiller l'établissement de soins de santé au sujet de l'acquisition de l'équipement de monitorage et d'établir les normes de monitorage qui aideront à assurer la sécurité du patient.
Il incombe à l'anesthésiologiste de monitorer le patient qui est sous ses soins et de s'assurer que l'équipement de monitorage approprié soit disponible et fonctionne correctement. Une feuille de vérification préanesthésique (Annexe 3 ou équivalent) doit être remplie avant l'amorce de l'anesthésie.
Une posologie prudente, un monitorage vigilant et la neutralisation adéquate des bloqueurs neuromusculaires sont des éléments essentiels à la sécurité des patients. Un monitorage neuromusculaire doit être utilisé lors de l'administration de bloqueurs neuromusculaires.
Il est recommandé qu'un monitorage de la profondeur de l'anesthésie (p. ex., basé sur l'analyse de l'EEG) soit disponible et que son utilisation soit envisagée, si cela est cliniquement indiqué, chez les patients qui présentent un risque accru de mémorisation peropératoire.
Les directives de monitorage pour les soins standard aux patients s'appliquent à tous les patients recevant une anesthésie générale, une anesthésie régionale ou une sédation intraveineuse.
# Matériel de monitorage requis
Le matériel de monitorage est catégorisé comme suit :
- Requis : Ces moniteurs doivent être utilisés sans interruption pendant toute la durée de l'administration de toute anesthésie. - Accessible en exclusivité pour chaque patient : Ces moniteurs doivent être accessibles à chaque poste de travail d'anesthésie, de sorte qu'ils puissent être utilisés sans délai. - À portée immédiate : Ces moniteurs doivent être accessibles afin de faciliter leur utilisation sans délai indu.
Le matériel de monitorage suivant est requis :
- Un saturomètre;
- Un appareil permettant de mesurer la tension artérielle, directement ou sans effraction; - Un électrocardiographe; - Un moniteur de bloc neuromusculaire lors de l'utilisation de bloqueurs neuromusculaires; - Un capnographe, pour l'anesthésie générale et pour évaluer le caractère adéquat de la ventilation pour une sédation modérée ou une sédation procédurale profonde; et - Un moniteur de gaz anesthésiques spécifique à l'agent, lorsque des agents anesthésiques par inhalation sont utilisés.
Le matériel de monitorage suivant doit être accessible en exclusivité pour chaque patient :
- Un appareil pour mesurer la température; - Un stéthoscope;
- Un éclairage suffisant pour visualiser une partie exposée du patient.
Le matériel de monitorage suivant sera à portée immédiate :
- Un spiromètre pour mesurer le volume respiratoire;
- Un manomètre pour mesurer la pression du ballonnet du tube endotrachéal; - Le matériel pour un monitorage hémodynamique invasif si indiqué (p. ex., ligne artérielle, cathéter veineux central).
L'anesthésiologiste doit demeurer vigilant en tout temps, étant conscient que de brèves interruptions du monitorage continu peuvent être inévitables et que, dans certaines circonstances, un moniteur pourrait faire défaut. Les alarmes audibles et visuelles du saturomètre et du capnographe ne devraient pas être désactivées indéfiniment pendant le déroulement d'une anesthésie, sauf en cas de circonstances inhabituelles. L'alarme à tonalité variable, celle des pulsations cardiaques et l'alarme de seuil inférieur du saturomètre ainsi que l'alarme d'apnée du capnographe doivent émettre un signal audible et visible.
# Dossiers
Toutes les variables physiologiques monitorées doivent être enregistrées à intervalles réguliers en fonction des circonstances cliniques. La fréquence cardiaque et la tension artérielle doivent être enregistrées au minimum toutes les cinq minutes. La saturation en oxygène doit être monitorée en continu et devrait être enregistrée à intervalles fréquents, au minimum toutes les cinq minutes, chez tous les patients. La concentration en dioxyde de carbone (PCO 2 ) télé-expiratoire doit être monitorée en continu et enregistrée à intervalles fréquents en cas d'intubation trachéale ou si un dispositif supraglottique est en place. On doit documenter au dossier anesthésique toute raison pour laquelle on déroge à ces directives de tenue de dossier. Les types de moniteurs, le matériel et les techniques, ainsi que l'heure, la posologie et la voie d'administration de tout médicament et liquide devraient être notés. Tous les autres soins et événements anesthésiques peropératoires pertinents, y compris les événements imprévus ou indésirables, devraient également être enregistrés.
Le dossier de santé du patient doit inclure le niveau de conscience du patient, sa fréquence cardiaque, sa tension artérielle, sa saturation en oxygène et sa fréquence respiratoire tels que mesurés à l'arrivée en salle de réveil. Ces recommandations s'appliquent tant aux dossiers anesthésiques manuscrits qu'à ceux créés via des systèmes électroniques de gestion de l'information en anesthésie (SGIA). À l'heure actuelle, il n'existe aucune norme de pratique indiquant quelles données supplémentaires (par ex. données d'analyse de gaz, de ventilation et respiratoires) potentiellement récoltées par un système de dossier de SGIA devraient faire partie du dossier de santé permanent d'un patient.
Il a été démontré que les SGIA pouvaient avoir des avantages potentiels par rapport aux dossiers rédigés à la main dans plusieurs domaines clés, notamment en augmentant la lisibilité, la précision et la fiabilité des dossiers anesthésiques, en créant des données interrogeables favorisant l'amélioration de la qualité, la communication des résultats et de la performance, la recherche translationnelle, une meilleure innocuité et un meilleur suivi des médicaments, ainsi qu'un suivi et un soutien à la décision clinique en temps réel pour les utilisateurs. La littérature sur la sécurité des patients en anesthésie appuie l'utilisation des SGIA. Il est important de mentionner que les SGIA permettent de créer une base de données de patients longitudinale, de telle manière que les antécédents anesthésiques importants des patients soient facilement trouvables si l'on veut les passer en revue, ce qui devrait être considéré comme une propriété importante pour tout système. La SCA ne promeut ni n'endosse un fournisseur ou un produit en particulier, mais elle reconnaît les avantages potentiels d'un SGIA bien conçu et mis en oeuvre par rapport à des dossiers complétés manuellement là où les ressources institutionnelles et du département d'anesthésie permettent d'envisager l'implantation d'un SGIA. Dans l'idéal, ce système devrait être mis en oeuvre et géré en coopération avec le département des technologies de l'information de l'établissement, et devrait permettre la communication avec les autres bases de données électroniques de patients de l'établissement dans la mesure du possible.
6 La période postanesthésique 6.1 La salle de réveil Une salle de réveil doit être disponible dans tout établissement offrant des services anesthésiques. Des politiques administratives conformes aux règlements de l'établissement devront être appliquées de façon à coordonner les responsabilités des soins médicaux et infirmiers.
Le département d'anesthésie devrait endosser l'ensemble de la responsabilité administrative médicale pour la salle de réveil. Il devrait exister un manuel des politiques de la salle de réveil approuvé par les autorités médicales, infirmières et administratives compétentes.
L'anesthésiologiste devrait accompagner le patient en salle de réveil, transmettre les renseignements nécessaires au personnel infirmier de la salle de réveil dans le cadre d'un transfert structuré du protocole de soins, et rédiger les ordonnances nécessaires. Le monitorage continu des patients est recommandé pendant la phase périopératoire en fonction de la situation clinique. Si cliniquement indiqué, de l'oxygène supplémentaire, une oxymétrie de pouls portable et d'autres dispositifs de monitorage adaptés doivent être utilisés pendant le transfert vers la salle de réveil ou l'USI. Si de l'oxygène supplémentaire est administré à des patients intubés pendant le transport ou en salle de réveil, afin de minimiser tout risque de barotraumatisme, il est fortement recommandé de ne le fournir qu'avec des dispositifs approuvés pour cette application spécifique. L'anesthésiologiste ne devrait déléguer les soins du patient à l'infirmier ou l'infirmière de la salle de réveil que lorsqu'il est assuré que le personnel infirmier pourra adéquatement observer et prendre soin du patient. L'anesthésiologiste ou un anesthésiologiste remplaçant désigné est responsable des soins postanesthésiques en salle de réveil. Le congé de la salle de réveil est sous la responsabilité de l'anesthésiologiste; cette responsabilité peut être déléguée en accord avec les politiques de l'établissement.
Une source d'oxygène d'appoint et une succion doivent être disponibles pour chaque patient en salle de réveil. Le matériel d'urgence nécessaire à la prise en charge des voies aériennes, la réanimation et au soutien des fonctions vitales doit être disponible en salle de réveil. Le matériel pour la prise en charge de voies aériennes difficiles doit être à portée immédiate en salle de réveil. Le monitorage utilisé en salle de réveil doit être adapté à l'état du patient et un éventail complet d'appareils de monitorage doit être disponible. Les alarmes des moniteurs doivent être en fonction, avec des paramètres d'alarme adaptés à l'état et à l'âge du patient. L'utilisation continue d'un saturomètre est requise pendant la phase initiale de récupération. Un capnographe est requis pour les patients intubés ou sous sédation profonde et est recommandé pour les patients inconscients ayant des dispositifs supraglottiques in situ dans les voies aériennes. Un moniteur d'apnée est recommandé chez les nourrissons prématurés et ayant un âge gestationnel de moins de 50 semaines.
Un dossier détaillé de la période immédiate de réveil doit être tenu. Celui-ci doit inclure un enregistrement des signes vitaux ainsi que des autres aspects du traitement et de l'observation. Cette feuille d'observation fait partie du dossier médical permanent. Toute complication ayant un lien avec l'anesthésie doit être notée sur la feuille de la salle de réveil ou dans les notes d'évolution du dossier du patient. Dans certaines situations, il peut être acceptable de transférer un patient directement vers d'autres unités de soins ou de passer outre la salle de réveil si un niveau de soins adapté est disponible dans une autre unité de l'établissement et s'il est noté au dossier anesthésique que le patient est jugé apte à ce transfert.
# Congé des patients après chirurgie d'un jour
Le congé des patients après une chirurgie ambulatoire doit se faire en utilisant un plan formel de soins approuvé par l'institution et documenté dans les notes de soins prodigués aux patients. Les patients doivent satisfaire les critères de congé au domicile en utilisant un outil d'évaluation validé (p. ex., le système de cotation de congé post-anesthésie ). La prise en charge de la douleur et des complications postopératoires, ainsi que le suivi de routine et d'urgence, doivent tous faire l'objet d'instructions écrites spécifiques. Le patient doit être averti au sujet des synergies additives qu'il existe entre l'alcool et d'autres sédatifs, du danger de conduire ou d'utiliser des machines dangereuses dans la période postopératoire (dans la plupart des cas durant les 24 heures suivant l'opération), et de la nécessité d'attention de la part d'un adulte compétent dans la période postopératoire (dans la plupart des cas durant les 24 heures suivant l'opération).
# Anesthésie régionale neuraxiale obstétricale
Les services d'anesthésie destinés aux parturientes comprennent l'analgésie obstétricale pour le travail -pour l'accouchement avec ou sans complication -ou pour les césariennes. Toutes les directives visant l'anesthésie administrée pour toute autre intervention diagnostique ou thérapeutique s'appliquent également à l'anesthésie obstétricale. Les directives de la présente section portent sur l'analgésie péridurale et la rachianesthésie pendant le travail. L'expression « analgésie régionale » désigne l'analgésie péridurale, la rachianesthésie et la combinaison des deux.
Ces directives sont passées en revue chaque année par la Section d'anesthésie obstétricale de la SCA et mises à jour au besoin. Chaque établissement peut décider d'élaborer des directives ou politiques supplémentaires pour des situations spécifiques dans lesquelles une analgésie régionale obstétricale est dispensée.
Sous la direction d'un anesthésiologiste, certains aspects du monitorage et de la prise en charge de l'analgésie régionale obstétricale peuvent être délégués à d'autres membres du personnel de santé. Chaque établissement doit s'assurer que ces personnes reçoivent les mêmes formation, certification, formation continue et recertification en analgésie régionale en obstétrique. Chaque département d'anesthésiologie devrait établir ses propres politiques concernant la disponibilité jugée adaptée d'un anesthésiologiste pour prendre en charge les complications potentielles liées à l'analgésie régionale pour le travail obstétrical et l'accouchement.
Des systèmes de sécurité doivent exister pour protéger les mélanges d'anesthésiques locaux périduraux contenant des substances contrôlées (par ex. des opioïdes) de façon à minimiser les risques de détournement.
# Absorption orale pendant le travail
La vidange gastrique des aliments solides est retardée pendant le travail, et les analgésiques opioïdes peuvent la retarder encore davantage. Par conséquent, on devrait généralement décourager les parturientes d'ingérer des aliments solides pendant le travail actif. Contrairement aux aliments solides, les liquides clairs sont éliminés relativement rapidement de l'estomac pendant le travail. Ainsi, en règle générale, on devrait permettre aux parturientes d'ingérer des liquides clairs comme elles le souhaitent pendant le travail actif. Chaque établissement devrait élaborer des protocoles concernant l'absorption d'aliments solides et de liquides clairs par les femmes en travail actif.
8 Lignes directrices pour la prise en charge de la douleur aiguë à l'aide de l'analgésie neuraxiale Lorsque l'analgésie neuraxiale est prise en charge par des anesthésiologistes, l'incidence d'effets secondaires n'est pas plus élevée que lorsque des techniques alternatives de prise en charge de la douleur sont utilisées. En conséquence, lorsque son utilisation est indiquée, l'analgésie neuraxiale devrait être prise en charge par les anesthésiologistes.
Aux fins de ce guide, l'analgésie neuraxiale se définit comme l'administration intrathécale ou péridurale d'opioïdes et/ou d'anesthésiques locaux en vue du traitement de la douleur postopératoire ou d'autres problèmes de douleur aiguë. Ce guide vise à fournir aux anesthésiologistes les principes de prise en charge afin que l'analgésie neuraxiale soit pratiquée de manière à en maximiser les avantages et en minimiser les risques.
# Politiques administratives et éducatives
Le département d'anesthésie devrait mettre sur pied un service de traitement de la douleur aiguë responsable de; Un programme de formation standardisécomprenant la formation initiale, la certification et le maintien continu de la compétence -devrait être établi pour le personnel infirmier dispensant des soins aux patients recevant une analgésie neuraxiale.
Le personnel infirmier doit comprendre:
- Le risque de dépression respiratoire, y compris la dépression respiratoire tardive, lors de l'administration d'opioïdes hydrophiles; Le risque d'erreurs attribuables à une voie impropre d'injection du médicament doit être minimisé. Pour des perfusions continues ou une APCP, l'emploi de pompes inviolables distinctes de celles utilisées pour l'administration de solutés ou de médicaments est vivement recommandé. La tubulure entre les pompes de perfusion de l'analgésie neuraxiale et les cathéters ne devrait comporter aucun orifice susceptible de permettre une injection non intentionnelle de médicaments intraveineux (voir section 5.1-6).
La préparation des solutions devrait suivre une procédure standardisée. Toutes les solutions analgésiques devraient porter une étiquette indiquant la composition de la solution (opioïdes, anesthésique local, ou les deux) ainsi que la voie d'administration appropriée. Dans le cas d'une administration péridurale, cela doit inclure la date et l'heure de la préparation ainsi que le nom de la personne l'ayant préparée.
# Monitorage des patients et prise en charge des évènements indésirables
Les patients auxquels est administrée une analgésie neuraxiale devraient être placés dans une chambre équipée d'oxygène et de succion. Des médicaments et du matériel de réanimation doivent être à portée immédiate. L'accès intraveineux doit être établi avant d'amorcer l'analgésie neuraxiale et, après cessation de l'analgésie neuraxiale, maintenu pendant toute la durée prévue des effets médicamenteux.
Le pansement qui maintient en place le cathéter péridural doit permettre l'examen du cathéter pour détecter tout mouvement et permettre l'inspection quotidienne du point d'entrée afin de déceler tout signe d'infection.
L'adoption de politiques standardisées au chapitre de la prise en charge des patients est préconisée. Les paramètres qu'il convient d'évaluer, la fréquence des évaluations, la documentation et les procédures de prise en charge des complications devraient être précisés. Un personnel de soins infirmiers en nombre suffisant doit être présent pour évaluer et prendre en charge les patients recevant une analgésie neuraxiale. Le monitorage devrait se poursuivre après cessation de l'analgésie neuraxiale jusqu'à ce que ses effets se soient dissipés.
Un anesthésiologiste doit être immédiatement disponible afin de conseiller le personnel infirmier sur des aspects tels que le titrage de la dose et la prise en charge des effets indésirables. Chaque établissement doté d'un service de traitement de la douleur aiguë doit veiller à ce qu'un anesthésiologiste soit disponible pour s'occuper directement des patients recevant une analgésie neuraxiale dans un délai approprié en fonction de la situation clinique. Chaque établissement devrait également déterminer les procédures en vue d'une prise en charge urgente de toute complication menaçant le pronostic vital. D'autres médicaments, notamment les benzodiazépines ou les opioïdes parentéraux, peuvent causer une dépression respiratoire majeure chez les patients recevant une analgésie neuraxiale. Pour cette raison, les autres médecins ne devraient pas prescrire de sédatifs ou d'analgésiques à tout patient recevant une analgésie neuraxiale. Le service de traitement de la douleur aiguë devrait demeurer en charge de la thérapeutique analgésique et sédative jusqu'à dissipation des effets de l'analgésie neuraxiale. Si une anticoagulation thérapeutique ou de l'héparine de bas poids moléculaire sont indiquées chez un patient muni d'un cathéter péridural, l'anesthésiologiste devrait être consulté afin que le moment de retrait du cathéter et l'amorce d'un traitement analgésique de substitution puissent être coordonnés de manière sécuritaire.
9 Lignes directrices pour l'exercice de l'anesthésie dans les lieux isolés Les principes fondamentaux, les exigences de formation, les techniques, le matériel et les médicaments utilisés pour la pratique de l'anesthésie dans les lieux isolés ont été documentés dans d'autres sections de ce Guide. Ils s'appliquent également aux soins anesthésiques, notamment à la sédation procédurale (voir Annexe 6) dispensée par un anesthésiologiste dans toute salle d'opération ou emplacement hors de la salle d'opération, tant à l'intérieur d'un établissement hospitalier qu'à l'extérieur (par ex. bureaux, cliniques).
# Soins anesthésiques dispensés dans un établissement médical/chirurgical/dentaire non hospitalier
# Se´lection des patients
Le statut physique des patients devrait être catégorisé selon le score de l'American Society of Anesthesiologists (ASA). D'une manière générale, seuls les patients des classes ASA I et II devraient être retenus pour subir une intervention. Les patients de statut ASA III pourraient être acceptés sous certaines conditions, mais seulement à la discrétion de l'anesthésiologiste en charge. Il faut faire preuve de prudence lors de la sélection de patients présentant des voies aériennes difficiles connues.
# Conside´rations pre´ope´ratoires
Une histoire de cas et un examen physique récents, incluant un examen des voies aériennes, devraient paraître au dossier du patient, ainsi que les résultats des examens de laboratoire appropriés. Ces examens peuvent être exécutés par un autre médecin (par ex. un 'procéduraliste', soit un médecin/chirurgien compétent pour réaliser des interventions diagnostiques ou thérapeutiques), mais l'existence d'un processus de sélection mis au point et endossé par les services anesthésiques est fortement recommandée. La durée du jeûne devrait être conforme à la section 4.2 Lignes directrices concernant le jeuˆne.
# Conduite de l'anesthe´sie
Les installations des salles d'anesthésie et de réveil doivent être conformes aux normes hospitalières établies par la CSA (voir Annexe 1) et à toutes les lignes directrices de la SCA établies pour les soins aux patients. Le patient devrait recevoir son congé de l'hôpital pour rentrer à la maison en utilisant un système de notation validé évaluant son aptitude au congé (par. ex. Système de cotation de congé post-anesthésique). Les patients devraient recevoir des instructions écrites concernant les périodes préopératoire et postopératoire.
# Soins anesthésiques dispensés hors de la salle d'opération dans un hôpital ou un établissement non hospitalier
En raison des avancées technologiques et de la plus grande disponibilité d'interventions moins invasives mais potentiellement douloureuses, la demande pour la fourniture de soins anesthésiques à l'extérieur de la salle d'opération (par ex., endoscopie, radiologie interventionnelle, cathétérisation cardiaque) croît. La fourniture de soins anesthésiques dans ces unités interventionnelles éloignées peut s'accompagner de défis particuliers pour l'équipe de soins anesthésiques (p. ex., les patients pourraient avoir un statut ASA III-IV et d'importantes comorbidités), et ces unités pourraient se trouver à une certaine distance des salles d'opération et du personnel de soutien, voire à l'extérieur d'un établissement hospitalier. Les unités d'intervention dans lesquelles les anesthésiologistes sont appelés à fournir des soins devraient se conformer, dans la mesure du possible, aux mêmes normes de la CSA (Annexe 1), lignes directrices concernant le matériel d'anesthésie (voir section 3.0), et lignes directrices générales de la SCA qu'une salle d'opération. Cela comprend, sans s'y limiter, la sélection et l'évaluation des patients, les examens pré-procéduraux, les lignes directrices concernant le jeûne, le matériel et les prises électriques, l'oxygène et la succion, la ventilation et l'évacuation des agents volatils si utilisés, les médicaments et le matériel nécessaires à la réanimation, le monitorage du patient, les installations de rétablissement et le personnel de soutien en anesthésie. Tout lieu où des anesthésiologistes fournissent des soins en dehors d'une salle d'opération doit être approuvé par la direction de l'anesthésie dans l'établissement. Du personnel de soutien en anesthésie adéquatement formé et expérimenté, par exemple un assistant en anesthésie (voir section 2.5) ou d'autres personnes ayant de l'expérience dans le soutien en anesthésie, devrait être présent ou immédiatement disponible pour assister l'anesthésiologiste dans les lieux isolés. Il ne convient pas de dépendre exclusivement du personnel de l'unité chirurgicale pour soutenir l'anesthésie, à moins que ce personnel ne soit formé et ait de l'expérience dans le soutien direct de la fourniture de soins anesthésiques et qu'il ait reçu l'aval de la direction de l'anesthésie. Une communication bidirectionnelle fiable doit être disponible pour que le prestataire d'anesthésie ait accès à de l'aide et du soutien si nécessaire.
Remerciements Nous tenons à remercier les anciens membres du Comité des normes de pratique de l'anesthésie qui ont apporté leurs contributions à des versions antérieures de ce Guide. Le Comité tient à remercier sincèrement le Bureau de rédaction du JCA pour son aide inestimable.
Conflits d'intérêt Tous les auteurs de cet article font partie du Comité des normes de la Société canadienne des anesthésiologistes (SCA). Aucun des auteurs n'a un quelconque intérêt financier ou commercial lié aux sociétés ou fabricants d'appareils médicaux dont il est fait mention dans cet article ou dans les annexes associées. Dr Gregory Dobson est président du Comité des normes de la SCA. Annexe 4: Lignes directrices, normes et autres énoncés officiels disponibles sur l'internet L'Annexe 4 (disponible au : / Guide-d-exercice) offre une liste non exhaustive de sites contenant des déclarations officielles promulguées par d'autres associations médicales au Canada et ailleurs dans le monde. Cette liste est fournie aux membres de la SCA uniquement à des fins pratiques. La SCA n'est pas responsable de l'exactitude, de la mise à jour ou de la fiabilité du contenu de ces sites. La SCA n'offre aucune garantie à cet effet. Elle se dégage de toute responsabilité concernant l'information trouvée par le biais de ces liens et n'endosse pas nécessairement ces sites ou leur contenu. Cette liste contient l'adresse de sites qui sera mise à jour de façon périodique.
Annexe 5: Exposé de principe sur les assistants en anesthésie : exposé de principe officiel de la Société canadienne des anesthésiologistes Disponible en matériel électronique supplémentaire.
Annexe 6: Exposé de principe sur la sédation procédurale : exposé de principe officiel de la Société canadienne des anesthésiologistes Disponible en matériel électronique supplémentaire.
Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | How does this edition differ from the 2021 Guidelines? Several important content changes have been made and they are highlighted in bold in the text. Some of the more important changes include: • The recommendation that family physician anesthesia providers (FPA) in Canada obtain the Certificate of Added Competence at the enhanced skill level in family practice anesthesia through the College of Family Physicians of Canada. • A completely revised Section 2.3, now entitled Physician Health and Wellness, outlining general guiding principles on the topic including several key anesthesia-related areas to consider with specific recommendations applicable to anesthesia departments of all sizes. • The recommendation, related to difficult airway management and difficult airway kits, that emergency front of neck access (eFONA) airway (e.g., surgical cricothyroidotomy) equipment be immediately available at any location where anesthesia care is delivered. • The recommendation to utilize, when appropriate, low total fresh gas flow techniques (B 1 LÁmin -1 ) when using volatile inhalational anesthetic agents, recognizing the potential environmental, pulmonary, and economic benefits. • Revisions to Section 5.2 Airway Management emphasizing the critical importance of the non-technical and human factors that may act as enablers or barriers to successful airway management. • The recommendation that depth of anesthesia monitoring equipment (e.g., processed EEG-based) be available and considered for use, if clinically indicated, in patients who are at increased risk for intraoperative awareness.#
• Revisions to Section 7 Guidelines for Neuraxial and Peripheral Nerve Block Regional Anesthesia, which now includes specific patient safety recommendations related to peripheral nerve block regional anesthesia techniques.
Comment cet énoncé diffère-t-il des Lignes directrices de 2021? Plusieurs modifications importantes ont été apportées au contenu; elles sont surlignées en gras dans le texte. Parmi les modifications les plus importantes, citons :
• La recommandation selon laquelle les omni-anesthésistes (ou anesthésistes en médecine familiale -AMF) au Canada obtiennent un Certificat de compe´tence additionnelle au niveau de compétence amélioré en anesthésie en médecine familiale par l'entremise du Collège des médecins de famille du Canada.
• Une section 2.3 entièrement révisée, dorénavant intitulée Santé et bien-être des médecins, décrivant des principes directeurs généraux sur le sujet, y compris concernant plusieurs domaines clés liés à l'anesthésie à considérer, avec des recommandations spécifiques applicables aux départements d'anesthésie de toutes tailles.
• En lien avec la prise en charge des voies aériennes difficiles et les trousses d'intubation difficile, la recommandation que le matériel nécessaire à réaliser un abord cervical antérieur d'urgence (eFONA) (p. ex., cricothyroïdotomie chirurgicale) soit à portée immédiate à tout endroit où des soins d'anesthésie sont dispensés.
• La recommandation d'utiliser, s'il y a lieu, des techniques à faible débit total de gaz frais (B 1 LÁmin -1 ) lors de l'utilisation d'agents anesthésiques par inhalation volatils, en reconnaissant les avantages environnementaux, pulmonaires et économiques potentiels.
• Des révisions de la section 5.2 Prise en charge des voies aériennes soulignant l'importance cruciale des facteurs non techniques et humains qui peuvent agir comme catalyseurs ou obstacles à une prise en charge réussie des voies aériennes.
• La recommandation que le matériel de monitorage de la profondeur de l'anesthésie (p. ex., basé sur l'analyse de l'EEG) soit disponible et que son utilisation soit envisagée, si cela est cliniquement indiqué, chez les patients qui présentent un risque accru de mémorisation peropératoire.
• Des révisions apportées à la section 7 Lignes directrices pour l'anesthésie régionale par bloc neuraxial et bloc nerveux périphérique, qui comprend maintenant des recommandations spécifiques en matière de sécurité des patients liées aux techniques d'anesthésie régionale par bloc nerveux périphérique. Lignes directrices pour l'exercice de l'anesthésie dans les lieux isolés 9.1 Soins anesthésiques dispensés dans un établissement médical/chirurgical/dentaire non hospitalier 9.2 Soins anesthésiques dispensés hors de la salle d'opération dans un hôpital ou un établissement non hospitalier Annexe 1 : Association canadienne de normalisation -Normes concernant le matériel Annexe 2 : Classification de l'état de santé des patients, selon l'American Society of Anesthesiologists Annexe 3 : Liste de vérification préanesthésique Annexe 4 : Lignes directrices, normes et autres énoncés officiels disponibles sur l'internet Annexe 5 : Exposé de principe sur les assistants en anesthésie : Un exposé de principe officiel de la Société canadienne des anesthésiologistes Annexe 6 : Sédation procédurale : exposé de principe de la Société canadienne des anesthésiologistes SPECIAL ARTICLE Overview The Guidelines to the Practice of Anesthesia Revised Edition 2022 (the Guidelines) were prepared by the Canadian Anesthesiologists' Society (CAS), which reserves the right to determine their publication and distribution. The Guidelines are subject to revision and updated versions are published annually. The Guidelines to the Practice of Anesthesia Revised Edition 2022 supersedes all previously published versions of this document. Although the CAS encourages Canadian anesthesiologists to adhere to its practice guidelines to ensure high-quality patient care, the CAS cannot guarantee any specific patient outcome. Anesthesiologists should exercise their own professional judgement in determining the proper course of action for any patient's circumstances. The CAS assumes no responsibility or liability for any error or omission arising from the use of any information contained in its Guidelines to the Practice of Anesthesia.
# Table des matières
# Preamble
Anesthesiology is a dynamic specialty of medicine that fosters continuous improvements in anesthetic care for patients undergoing surgical and obstetric procedures in Canada. This document is reviewed annually and revised periodically.
The following recommendations are aimed at providing basic guidelines to anesthetic practice. They are intended as a framework for reasonable and acceptable patient care and should be interpreted as such to allow for some degree of flexibility in different circumstances. Each section of the Guidelines is subject to revision as warranted by the evolution of technology, practice, and the best available evidence.
# Basic Principles
In this document, the term anesthesiologist is used to designate all licensed medical practitioners with privileges to administer anesthetics. An anesthetic is the deliberate performance of any procedure to render a patient temporarily insensitive to pain or to the external environment so that a diagnostic or therapeutic procedure can be performed.
These Guidelines are intended to apply to all anesthesiologists in Canada. The independent practice of anesthesia is a specialized field of medicine, and as such, it should be practiced by physicians with appropriate training in anesthesia. The only route to specialist recognition in anesthesia in Canada is through the certification process of the Royal College of Physicians and Surgeons of Canada. The Canadian Anesthesiologists' Society (CAS) acknowledges the fact that remote communities often Can J Anesth/J Can Anesth https://doi.org/10.1007/s12630-021-02135-7
Text approved by the CAS Board for the 2022 Revised Edition.
Texte approuvé par le CA de la SCA pour l'édition révisée 2022.
# Supplementary Information
The online version contains supplementary material available at https://doi.org/10.1007/s12630-021-02135-7.
lack the population base to support a specialist anesthesiology practice. In these communities, appropriately trained family physicians may be required to provide anesthesia services. In communities with the clinical volume to support full-time anesthesiologists, fellowship-certified anesthesiologists should provide these services. All anesthesiologists must continue their education in the practice of anesthesia, pain management, perioperative care, and resuscitation and participate in a structured maintenance of competence program (e.g., Royal College MOC).
# Organization of Anesthetic Services
The department of anesthesia should be properly organized, directed, and integrated with other departments in the organization or facility, and it should include all facility staff members who provide anesthetic services to patients for surgical, obstetric, diagnostic, and therapeutic purposes.
The department should be staffed appropriately, bearing in mind the scope and nature of the services it provides, and it should strive to ensure that these services are available as required by the healthcare facility.
The chief of the department should be a physician who has obtained certification or appropriate training in anesthesia. This individual should be appointed in the same manner as other chiefs of clinical departments and should be a member of the senior medical administrative bodies for the facility.
# Responsibilities of the Chief of Anesthesia
1. To be aware of the current CAS Guidelines to the Practice of Anesthesia, the requirements of the Canadian Council on Health Services Accreditation, and the requirements of the provincial licensing authority as they relate to anesthesia; 2. To ensure that written policies with respect to the practice of anesthesia are established and enforced; 3. To evaluate the qualifications and abilities of the physicians providing anesthetic care as well as other health professionals providing ancillary care-this includes, but is not restricted to, recommending clinical privileges for physicians with anesthetic responsibilities and annually reviewing these privileges; 4. To employ a systematic approach for monitoring the quality of anesthetic care provided by members of the department of anesthesia throughout the healthcare facility;
Monitoring quality of care may include, but need not be restricted to, the use of chart audits, clinical indicator and outcome monitoring, adverse event reporting systems, morbidity and mortality conferences, and critical incident case reviews. The extent of quality improvement activities will vary depending on the departmental and health facility resources available to the chief. For effective quality improvement, it is strongly encouraged that all department members should actively participate in any such activities. 5. To ensure that records are kept for all anesthetic procedures-these records should allow for evaluation of all anesthetic care in the facility; 6. To carry out such other duties as the governing body of the facility may delegate to ensure safe anesthetic care; 7. To promote institutional compliance with applicable Canadian Standards Association (CSA) Standards (Appendix 1); and 8. To coordinate liaison between the departments of anesthesiology, biomedical engineering, and information management services. Special areas of anesthetic care may have specific concerns. The department of anesthesia in each institution may determine privileges in pediatric anesthesia according to the pediatric population it serves, the child's age, the presence of comorbidities, the physician's specific training and experience in pediatric anesthesia, and the complexity of the procedure involved.
# Privileges in Anesthesia
Physicians with anesthetic privileges should possess the knowledge and technical and non-technical skills necessary for the practice of anesthesia.
Knowledge and technical skills include the ability:
• To provide preanesthetic evaluation of the patient and determine the appropriate anesthetic management;
Guidelines to the Practice of Anesthesia -Revised Edition 2022
• To render the patient insensible to pain for the performance of diagnostic and therapeutic procedures, surgical operations, and obstetric procedures; • To monitor and support the vital organ systems during the perioperative period; • To provide immediate postanesthetic management of the patient; • To provide resuscitation and intensive care when indicated; and • To provide relief from acute and chronic pain.
Non-technical skills include:
• Task management: planning and preparing, prioritizing, providing and maintaining standards, and identifying and utilizing resources; • Teamwork: coordinating activities with team members, exchanging information, using authority and assertiveness, assessing capabilities, supporting others, and supporting the World Health Organization Surgical Safety Checklist; • Situational awareness: anticipating, gathering information, recognizing, and understanding, and;
• Decision-making: identifying options, balancing risks and selecting options, and re-evaluating.
# Physician Health and Wellness
Anesthesia care physicians require a high level of expertise, sound judgement, decision-making skills, alertness and vigilance, and must be able to respond to rapidly changing and often unexpected clinical challenges. Work-related, organizational, and personal factors may all contribute challenges to a provider's ability to function at their highest level of performance. The critical importance of anesthesia physician health must be recognized and adequately considered. Issues such as fatigue, workplace harassment and bullying, personal and mental health issues, stress, inadequate nutrition while working, burnout, and substance use can all contribute adversely to health and well-being and ultimately to patient safety. All anesthesia physicians should monitor themselves and colleagues for signs and symptoms of functional impairment so that impairments can be detected early and support offered. Substance use disorders are common in society and can also affect anesthesia physicians. Opioid abuse is more common in anesthesia than in most other medical specialties. Controlled medication diversion prevention programs are essential as a minimum (see section 3.1, 4a and b) and should be part of broader departmental strategies, policies, and education to assist identification of physicians and anesthesia support staff who may be impaired because of substance use disorders.
Anesthesia and/or facility leadership must be supportive of physician health and well-being through administrative structures that promote and support a healthy workplace and establish mechanisms of peer support. Smaller departments may need to rely on local, provincial, or national physician support programs, and accessing such resources should be promoted for staff. The goal should be creating and sustaining a culture of psychological safety where deviation from manageable and reasonable working conditions are reported and acted upon, and where providers at risk or in difficulty can be identified and appropriately supported without fear of negative repercussions.
Specific areas to consider may include, but need not be restricted to:
•
# Residents
Residents in anesthesia are registered medical practitioners who participate in the provision of anesthesia services both inside and outside the operating room as part of their training. The Royal College of Physicians and Surgeons of Canada and provincial and local regulatory authorities require that a responsible attending staff anesthesiologist must supervise all resident activities. The degree of this supervision must consider the condition of each patient, the nature of the anesthetic service, and the experience and capabilities of the resident (increasing professional responsibility). At the discretion of the supervising staff anesthesiologist, residents may provide a range of anesthetic care with minimal supervision. In all cases, the supervising attending anesthesiologist must remain readily available to give advice or assist the resident with urgent or routine patient care. Whether supervision is direct or indirect, close communication between the resident and the responsible supervising staff anesthesiologist is essential for safe patient care. Each anesthesia department teaching anesthesia residents should have policies regarding the activities and supervision of residents.
# Ancillary Personnel
The healthcare facility must ensure that ancillary personnel are available as assistants to the anesthesiologist. Such assistants must be available at all times and places where anesthetic services are provided. Ancillary personnel should have the competencies to meet the specific needs of subspecialty areas of anesthesia, reflecting on the need for specific skills in areas such as specialty pediatric anesthesia.
It is recommended that facilities have a formally designated anesthesia assistant with specific training in anesthesia assistance. The department of anesthesia and the appropriate administrative bodies must approve the scope of practice for anesthesia assistants working in a specific institution. Furthermore, anesthesia assistants like other employed health professionals, must be covered by the facility's liability insurance. Duties and tasks delegated to anesthesia assistants must be consistent with existing governmental regulations, the policies and guidelines established by professional regulatory agencies, and the policies of the local facility.
An institution without formal anesthesia assistants must provide other paramedical personnel to assist the anesthesiologist. The tasks that these assistants may perform must be clearly defined. An anesthesiologist must only delegate or assign those tasks for which such personnel have approval or accreditation.
# Anesthetic Equipment and Anesthetizing Location
An anesthetic must be administered in an appropriate facility. All necessary equipment, including emergency equipment, life support systems, medications, and supplies must be readily available. It is strongly recommended that a cognitive aid manual be made available at all anesthetizing locations in support of the management of critical perioperative emergencies. The contents of the manual should be regularly reviewed, updated as required, and periodically practiced as a team.
The healthcare facility, in consultation with the department of anesthesia, is responsible for the design and maintenance of preoperative, postoperative, and anesthetizing locations, as well as the purchase, maintenance, and disposal of anesthetic and ancillary equipment and supplies. The Canadian Standards Association (CSA) and other standards development organizations have published standards and guidance documents for the design, construction, and renovation of healthcare facilities and for the risk management, basic safety, and essential performance of medical equipment (Appendix 1).
# Responsibilities of the Healthcare Facility
The healthcare facility must ensure that:
1. The operating rooms, anesthetizing locations, and perioperative care locations comply with at least the minimum design and construction requirements of the national, provincial, and local building, plumbing, electrical, HVAC (heating, ventilation, and air conditioning), fire, and security codes at the time of construction or renovation.
2. Medical gas and vacuum systems, waste anesthetic gas scavenging systems, terminal units, head walls, low pressure connecting assemblies, and pressure regulators meet the requirements of the CSA and are certified by a CSA-approved testing agency. 3. Oxygen concentrators that comply with CSA requirements are an acceptable substitute for bulk oxygen supply systems. When such concentrators are installed, users must be aware that:
a. The facility medical oxygen supply may deliver a fraction of inspired oxygen (FiO 2 ) that varies from 0.93 to 0.99; b. Oxygen analyzers must be calibrated against 100% O 2 (FiO 2 0.99) and room air or equivalent (FiO 2 0.21); c. The use of low-flow (less than one litre total fresh gas flow) anesthetic techniques may result in the accumulation of inert gas (argon) and the dilution of nitrous oxide and oxygen in the circuit.
4. There is compliance with all safety regulations and best practice with respect to the storage, preparation, identification, labelling, disposal, and use of medical gases, medications, and related materials.
a. General medication safety recommendations include, but need not be restricted to:
• Identifying an anesthesia department lead designated to cooperate with pharmacy to promote medication safety best practice. In recognition of the increased risk of medication errors related to medication brand substitutions and look-alike packaging, departments and pharmacies should consider strategies to reduce this risk. • Requesting that pharmacy staff notify anesthesia staff, with as much notice as possible, of upcoming medication supplier, packaging, or concentration changes such that anesthesia staff can be alerted. • Standardization of drug trays across all locations and during product transitions. Medications with different supplier brands and packaging for a medication should not be mixed in the same anesthesia cart. • Medication substitutions, particularly of a different concentration, should be labelled with highly visible warning labels when any new medication is introduced. • Look-alike medications should be physically separated in the anesthesia carts as much as is possible and identified with warning labels.
• Cautioning physicians and technical support staff that replacement of unopened medications back into anesthesia carts is risky because medication may be put in the incorrect location.
• Reporting any medication-related adverse events through local adverse event reporting systems or CAIRS or both.
b. Through cooperation between the departments of anesthesia and pharmacy, there are policies developed and enforced for the safe handling, storage, and disposal of controlled medications (e.g., opioids) in the operating rooms and postanesthesia care unit (PACU) that are consistent with the law, with any regulatory authority requirements, and established best practice principles. The goals of such policies should be to limit access of unauthorized personnel to controlled medications to minimize the risk of controlled medication diversion, and to establish robust documentation procedures that can be audited, while also protecting patient safety by still permitting anesthesia providers immediate access to any medications required for patient care.
Best practice principles support a variety of specific strategies to achieve these goals. The CAS does not endorse any one specific strategy or policy but strongly recommends that all available options be considered. Robust systems and procedures must be implemented. Due consideration should be given to any limitation in resources available to implement specific security systems and procedures within a facility, particularly for smaller facilities.
Recommendations include, but need not be restricted to:
• Storing controlled substances in a secure lockable safe or locked drawer when the OR is unattended by anesthesia personnel (e.g., between cases). • Never leaving controlled substances (including those drawn up into syringes or bags) unattended in any location. • Emptying the contents of syringes and bags containing controlled substances before disposal. • Adopting disposal and/or destruction systems to dispose of controlled substance waste. • Consideration of a requirement that controlled substance waste be returned to the pharmacy and be subjected to random analysis. • Periodic audits of a healthcare provider's controlled substance utilization records and their anesthesia records.
• Consideration of the implementation of automated anesthesia cabinets or automated medication dispensing cabinets (e.g. PyxisTM).
The operating room, labour and delivery, postanesthesia care unit (PACU), and regional block areas, for example, should all be recognized as high risk areas for controlled medication diversion and therefore must be subject to heightened security, surveillance, and auditing. Anesthesia providers must ensure that potentially infectious materials or agents are not transferred from one patient to another. Special attention in this regard Guidelines to the Practice of Anesthesia -Revised Edition 2022 should be given to syringes, infusion pump administration sets, and multi-dose drug vials.
Training on the safe use of all anesthesia equipment should be provided to all anesthesia department members prior to use. Attendance at these sessions should be documented. These training sessions should be repeated as necessary for new or established department members.
# Waste Gases
Recommendations for reducing occupational exposure to waste anesthetic gases: The department of anesthesia should establish policies regarding preanesthetic assessment. The primary goal of preanesthetic assessment is to obtain the information required to plan anesthetic management. Accordingly, a physician who is knowledgeable about anesthetic management for the proposed diagnostic or therapeutic procedure should document all aspects of the patient's medical and surgical history, findings on physical examination, and laboratory investigations that are relevant to anesthetic management. The patient's history should include past and current medical problems, current and recent drug therapy, unusual reactions or responses to drugs, and any problems or complications associated with previous anesthetics. A family history of adverse reactions associated with anesthesia should also be obtained. Information about the anesthetic that the patient considers relevant should also be documented. An American Society of Anesthesiologists physical status classification (Appendix 2) should be recorded for each patient.
In appropriate cases, the availability of an ''Advance Care Plan'' (representation agreement, advanced directive, ''living will'', ''do not resuscitate'' directive, etc.) should be ascertained, and its applicability to the proposed intervention should be determined and documented on the anesthetic assessment record.
The surgeon may request consultation with an anesthesiologist. Medical consultations should be obtained when indicated.
Preoperative anesthetic assessment or consultation may take place in an outpatient clinic before admission for the operative procedure. Indications for pre-admission assessment include the presence of significant medical problems (comorbidities), the nature of the proposed diagnostic or therapeutic procedure, and patient request. A parent/guardian must be present if the patient is a child or not competent to provide informed consent. All patients should be informed that arrangements will be made to meet with an anesthesiologist if they wish to discuss anesthetic management before admission to the facility. The preoperative assessment clinic should also allow nursing and other healthcare personnel to assess the patient. The attending anesthesiologist is responsible for performing a final preanesthetic assessment in the immediate preoperative period.
# Preoperative Testing
Laboratory testing should not be performed on a routine basis but should be obtained only when results will change perioperative management. Laboratory investigations should be performed when indicated by the patient's medical status, drug therapy, and the nature of the proposed procedure.
Routine laboratory blood testing, electrocardiograms, and chest radiographs are not recommended for asymptomatic patients having low-risk surgery. Examples of low-risk surgery include, but are not restricted to, cataract surgery, minor breast surgery, superficial procedures, and many minor ambulatory procedures. For more detailed definitions of low-risk surgery and for other recommendations related to preoperative testing, visit Choosing Wisely on the CAS website and the associated Internet links.
# Fasting Policies
Fasting policies should vary to account for age and preexisting medical conditions and should apply to all forms of anesthesia, including procedural sedation (see Appendix 6). 1 Emergent or urgent procedures should be undertaken after considering the risk of delaying surgery vs the risk of aspiration of gastric contents. The type and amount of food ingested should be considered in determining the duration of fasting. Before elective procedures, the minimum duration of fasting should be:
• Eight hours after a large meal of solids particularly containing protein (e.g., meat) or fatty foods • Six hours after a light meal (e.g., non-fatty meal such as toast) • Six hours after ingestion of infant formula, non-human milk, or expressed breast milk fortified with additions • Four hours after ingestion of breast milk • Two hours after ingestion of clear fluids for adults • One hour after ingestion of clear fluids for infants and children.
Unless contraindicated, adults and children should be encouraged to drink clear fluids (including water, pulp-free juice, complex carbohydrate beverages, and black tea or coffee) up to two hours before elective surgery. Pediatric patients should also be encouraged to consume clear fluids, as defined, up to one hour before elective procedures.
Conditions that delay gastric emptying require individual patient assessment. These guidelines may be modified at the discretion of the physician.
Premedication, when indicated, should be ordered by the anesthesiologist. Orders should be specific as to dose, time, and route of administration.
An H2 receptor antagonist (oral or intravenous) is recommended for all women presenting for Cesarean delivery.
Thirty mL of oral sodium citrate (0.3 molar) is recommended prior to an emergent Cesarean delivery if general anesthesia is planned. See Section 7.3 for fasting guidelines specific to patients in active labour.
# Additional Regulations
Provincial legislation or facility bylaws may dictate additional regulations governing the conduct of anesthesia.
5 The Anesthetic Period
# Preparation for Anesthesia
Before beginning anesthesia, the anesthesiologist must ensure that 1. An explanation of the planned anesthetic procedure, including recognized risks and alternative techniques, has been provided and documented; 2. An adequate review of the patient's condition has been performed; 3. All equipment that is expected to be required is available and in working order, including the equipment required for supporting core temperature management (patient core temperature 36-37°C); 4. A reserve source of oxygen under pressure is available; 5. All drugs and agents that are expected to be required are correctly identified-user-applied drug labels should conform to the CSA Standard CAN/CSA-Z264.3-98 (R2005) (Appendix 1); 6. If Luer neuraxial connectors are used, both sides of all Luer connections must be labelled. Consideration should be given to the use of neuraxial connectors complying with ISO 80369-6:2016-small bore connectors for neuraxial application (e.g., NRFitÒ connectors) subject to availability from equipment suppliers; and 7. The manufacturers' recommendations concerning the use, handling, and disposal of anesthetic equipment and supplies have been considered.
# Airway Management
Airway management, particularly of the difficult airway, contributes to a significant proportion of anesthesia-related morbidity and mortality. The appropriate management of those patients who have an anticipated or unanticipated difficult tracheal intubation, a failed airway (completed best effort after 3 attempts), where bag-mask ventilation or supraglottic device placement may be difficult, in a ''cannot ventilate, cannot oxygenate'' (CVCO) scenario or who require an eFONA airway procedure is critical for patient safety. This includes, but need not be restricted to, adequate airway assessment, equipment (e.g., difficult airway kits, videolaryngoscopes, bronchoscopes, eFONA equipment), training and simulation, support personnel and the use of protocols and cognitive aids to optimize difficult airway management.
Equipment location and availability, local environment (e.g., remote locations) provider experience, teamwork and communication (e.g., team briefings) and psychological factors are all areas deserving of attention and optimization. It is essential to appreciate the non-technical human factors (individual, team and organizational) that may act as enablers or barriers to successful airway management. The CAS does not endorse any one specific guideline, algorithm or cognitive aid for difficult and failed airway management but strongly recommends that readers refer to Appendix 4 for up to date publications related to this topic.
# Delegation of Patient Care
The anesthesiologist's primary responsibility is to the patient receiving care. The anesthesiologist or an anesthesia assistant supervised by the anesthesiologist must remain with the patient at all times throughout the conduct of all general and major regional anesthetics and for procedural sedation until the patient is transferred to the care of personnel in an appropriate care unit.
If the attending anesthesiologist leaves the operating room temporarily, he/she must delegate care of the patient to another anesthesiologist, a resident in anesthesia, or an anesthesia assistant. When the attending anesthesiologist delegates care to a resident in anesthesia or an anesthesia assistant, the attending anesthesiologist remains responsible for the anesthetic management of the patient. Before delegating care of the patient to an anesthesia assistant, the anesthesiologist must ensure that the patient's condition is stable and that the anesthesia assistant is familiar with the operative procedure and the operating room environment and equipment. The attending anesthesiologist must remain immediately available when care is delegated to an anesthesia assistant.
An anesthesiologist may briefly delegate routine care of a stable patient to a competent person who is not an anesthesia assistant only under the most exceptional circumstances, e.g., to provide life-saving emergency care to another patient. That person's only responsibility would be to monitor the patient during the anesthesiologist's absence and to keep the anesthesiologist informed until he/ she returns. In this situation, the anesthesiologist remains responsible for the care of the patient and must inform the operating room team.
An intraoperative handover of care between two anesthesiologists should be documented in the anesthesia record and follow a structured protocol.
It is unacceptable for one anesthesiologist to simultaneously administer general anesthesia, major regional anesthesia (spinal, epidural, or other), or deep procedural sedation (see Appendix 6) 1 for concurrent surgical, diagnostic, or therapeutic procedures on more than one patient. Nevertheless, it may be appropriate in specific circumstances for one anesthesiologist to supervise more than one patient where only minimal to moderate sedation is administered, provided an appropriately trained, qualified, and accredited individual approved by the department of anesthesiology, and the healthcare institution is in constant attendance with each patient receiving care. In an obstetric unit, however, it is acceptable to supervise more than one patient receiving regional analgesia for labour. Due care must be taken to ensure that a suitably trained person adequately observes each patient following an established protocol. When an anesthesiologist is providing anesthetic care for an obstetric delivery, a second appropriately trained person should be available to provide neonatal resuscitation.
It is unacceptable for a single physician to administer an anesthetic, including deep procedural sedation, and simultaneously perform a diagnostic or therapeutic procedure, except for procedures done with only infiltration of local anesthetic and/or minimal sedation.
# Patient Monitoring
The only indispensable monitor is the presence, at all times, of a physician or an anesthesia assistant who is under the immediate supervision of an anesthesiologist and has appropriate training and experience. Mechanical and electronic monitors are aids to vigilance. Such devices assist the anesthesiologist to ensure the integrity of the vital organs and, in particular, the adequacy of tissue perfusion and oxygenation. Monitoring equipment must be used as intended by the manufacturer and approved by Health Canada for the specific application.
The healthcare facility is responsible for the provision and maintenance of monitoring equipment that meets current published equipment standards.
The chief of anesthesia is responsible for advising the healthcare facility regarding the procurement of monitoring equipment and for establishing policies for monitoring to help ensure patient safety.
The anesthesiologist is responsible for monitoring the patient receiving care and for ensuring that appropriate monitoring equipment is available and working correctly. A preanesthetic checklist (Appendix 3 or equivalent) must be completed prior to initiation of anesthesia.
Cautious dosing, vigilant monitoring, and the appropriate reversal of neuromuscular blocking drugs are all essential for patient safety. Neuromuscular monitoring must be utilized when neuromuscular blocking agents are administered.
It is recommended that depth of anesthesia monitoring (e.g., processed EEG-based) be available and be considered for use, if clinically indicated, for patients who are at increased risk for intraoperative anesthesia awareness.
Monitoring guidelines for standard patient care apply to all patients receiving general anesthesia, regional anesthesia, or procedural sedation.
# Required Monitoring Equipment
Monitoring equipment is classified as follows:
• Required: These monitors must be in continuous use throughout the administration of all anesthetics. • Exclusively available for each patient: These monitors must be available at each anesthetic work station so that they can be used with no delay. • Immediately available: These monitors must be available to facilitate their use without undue delay.
The following monitoring equipment is required:
• Pulse oximeter;
• Apparatus to measure blood pressure, either directly or noninvasively; • Electrocardiography; • Neuromuscular blockade monitor when neuromuscular blocking drugs are used; • Capnography for general anesthesia and to assess the adequacy of ventilation for moderate or deep procedural sedation; and • Agent-specific anesthetic gas monitor, when inhalational anesthetic agents are used.
The following monitoring equipment must be exclusively available for each patient:
• Apparatus to measure temperature; • Stethoscope; • Appropriate lighting to visualize an exposed portion of the patient.
The following monitoring equipment must be immediately available:
• Spirometer to measure tidal volume; • Manometer to measure endotracheal tube cuff pressure;
• Equipment for invasive hemodynamic monitoring if indicated (e.g., arterial, central venous).
The anesthesiologist must remain constantly vigilant, understanding that brief interruptions in continuous monitoring may be unavoidable and there are certain circumstances in which a monitor may fail.
Audible and visual alarms for oximetry and capnography should not be indefinitely disabled during the conduct of an anesthetic except during unusual circumstances. The variable pitch, pulse tone, and lowthreshold alarm of the pulse oximeter and the capnograph apnea alarm must give an audible and visual warning.
# Perioperative Temperature Management
Monitoring patient core temperature is strongly recommended during cases of general and neuraxial regional anesthesia lasting 30 min or longer. In the absence of surgical or patient indications for intraoperative hypothermia, active patient warming systems, control of the operating room ambient temperature, and other methods, should be used to target a central core temperature of 36-37°C.
# Patient Positioning
Patient positioning for procedures requiring anesthesia is an operating room team responsibility and demands a high level of attention to avoid complications. It is recognized, however, that positioning-related complications can still occur despite best practice and vigilance. Risks related to patient positioning will vary and depend on the type and duration of surgery, the specific position utilized, and patient factors such as BMI and other comorbidities. Therefore, the considerations and planning for positioning best practice should be discussed by the surgical team ideally before anesthesia induction, for example during part 1 of the Surgical Safety Checklist. All members of the team, including the anesthesiologist, should be encouraged to voice concerns related to any aspect of positioning (e.g., specific risk factors and availability, condition and appropriateness of OR tables and other positioning equipment), and strategies to mitigate these risks should be considered. Patient positioning should be documented and also rechecked regularly by the anesthesiologist to be sure positioning conditions remain ideal. Patients should be informed preoperatively of any specific risks that may be associated with the position planned for their procedure.
# Records
All monitored physiologic variables should be charted at intervals appropriate to the clinical circumstances. Heart rate and blood pressure should be recorded at least every five minutes. Oxygen saturation must be monitored continuously and should be recorded at frequent intervals, at a minimum of every five minutes, for all patients. End-tidal carbon dioxide concentration must be monitored continuously and recorded at frequent intervals if the trachea is intubated or a supraglottic device is in situ. Reasons for deviation from these charting guidelines should be documented in the anesthetic record. Monitors, equipment, and techniques, as well as time, dose, and route of all drugs and intravenous fluids should be recorded. All other relevant intraoperative anesthesia care and events, including unexpected or adverse events, should also be recorded.
The patient health record should include the patient's level of consciousness, heart rate, blood pressure, oxygen saturation, and respiratory rate as first determined in the PACU. These recommendations apply to both manually created (handwritten) and electronic anesthesia information management system (AIMS) created anesthesia records. At present, there are no practice standards for what additional data (e.g., gas analysis, ventilator, and respiratory data) that can potentially be collected by an AIMS charting system should become part of a patient's permanent health record.
AIMS have been shown to have potential benefits over handwritten records in several key areas, including improved legibility, precision and reliability of anesthesia records, providing searchable data for quality improvement, outcome and performance reporting and translational research, enhanced medication safety and tracking and real-time clinical decision support for users. The anesthesia patient safety literature supports the use of AIMS. Importantly, AIMS maintain a longitudinal patient database so historical patient encounters should be easily retrievable for review and this should be considered an important feature of any system. The CAS does not promote or endorse any one specific vendor or product but acknowledges that there may be potential benefits of a well designed and implemented AIMS over manually charted records where facility and anesthesia department resources permit the consideration of an AIMS. Ideally it should be implemented and supported in cooperation with the facility information technology department including communication with other facility electronic patient databases wherever possible.
6 The Postanesthetic Period
# Recovery Facility
A PACU must be available in any facility that provides anesthetic services. Administrative policies to coordinate medical and nursing care responsibilities must be enforced in accordance with facility bylaws.
The department of anesthesia should have overall medical administrative responsibility for the PACU. There should be a PACU policy manual approved by appropriate medical, nursing, and administrative authorities.
The anesthesiologist should accompany the patient to the PACU, communicate necessary information to the PACU nurse(s) as part of a structured handover of care protocol, and write appropriate orders. Continuous monitoring of patients is recommended during the perioperative period appropriate to the clinical situation. If clinically indicated, supplemental oxygen, portable pulse oximetry, and other appropriate monitoring devices should be applied during transport to the PACU or intensive care unit. If supplemental oxygen is applied during transport or in PACU to patients who are intubated, it is strongly recommended that it only be provided using devices approved for that specific application to minimize any risk of barotrauma. The anesthesiologist should delegate care to the PACU nurse only when assured that nursing staff may safely observe and care for the patient. The anesthesiologist or designated alternate is responsible for providing anesthetic-related care in the PACU. Discharge from the PACU is the responsibility of the anesthesiologist; this responsibility may be delegated in accordance with facility policy.
Supplemental oxygen and suction must be available for every patient in the PACU. Emergency equipment for airway management, resuscitation, and life support must be available in the PACU. Equipment for management of the difficult airway must be immediately available to the PACU. The monitoring used in the PACU should be appropriate to the patient's condition, and a full range of monitoring devices should be available. Monitor alarms should be enabled with alarm settings appropriate to the condition and age of the patient. The use of continuous pulse oximetry is required in the initial phase of recovery. Capnography is required for intubated and deeply sedated patients and is recommended for unconscious patients with in situ supraglottic airway devices. An apnea monitor is recommended for preterm infants with a gestational age of less than 50 weeks.
An accurate record of the immediate recovery period must be maintained. This must include a record of vital signs together with other aspects of treatment and observation. The recovery record must form a part of the permanent medical record. Any complications that bear any relation to the anesthetic should be recorded either on the recovery record or on the progress notes on the patient's chart.
In some circumstances, it may be considered acceptable to transfer a patient directly to other care units or to bypass the PACU if the appropriate level of care is available in another unit in the facility and the suitability of the patient for this transfer is documented on the anesthetic record.
# Discharge of Patients After Day Surgery
Discharge of patients after day surgery must utilize a formal care plan approved by the institution and be documented in the patient care notes. Patients should meet the facility discharge to home criteria using a validated assessment tool (e.g., Post Anesthetic Discharge Scoring System). Specific written instructions should include management of pain and postoperative complications, and both routine and emergency followup. The patient should be advised regarding the additive effects of alcohol and other sedative drugs, the danger of driving or operating other hazardous machinery during the postoperative period (most commonly 24 hr postoperatively), and the necessity for attention by a competent adult during the postoperative period (most commonly 24 hr postoperatively).
7 Guidelines for Neuraxial and Peripheral Nerve Block Regional Anesthesia 7.1 Peripheral Nerve Block Regional Anesthesia It is strongly recommended that a preperipheral nerve block checklist (''pause'') be developed, implemented, and administered in all areas where peripheral blocks are performed. This should include, but need not be restricted to:
• Confirmation that informed consent has been obtained. • Confirmation of patient identity, allergies, surgical procedure, block type and location, and correct side of the block in the presence of an alert patient or substitute decision maker. • Review of coagulation status.
• Marking of the correct side to be blocked if applicable. • Discussion of planned and maximum safe local anesthestic dosages to be administered. • Confirmation of the availability of appropriate resuscitation equipment (cf. below). • Communication and timing of the block in coordination with operating room availability.
Patient monitoring should, at a minimum, include non-invasive blood pressure and oxygen saturation. Supplemental oxygen and equipment for airway management must be immediately available. Delegation of monitoring patients must be consistent with existing CAS Guidelines.
In areas where peripheral nerve block regional anesthesia techniques are performed and/or local anesthetic infusions are delivered, cognitive aids and medications (e.g., lipid emulsion 20%) for the treatment of local anesthetic systemic toxicity (LAST) must be immediately available.
# Obstetric Neuraxial Regional Anesthesia
Anesthesia services for parturients include obstetric analgesia for labour-for both uncomplicated and complicated deliveries-or for operative deliveries. All guidelines regarding provision of anesthesia for other diagnostic or therapeutic procedures also apply to the provision of obstetric anesthesia. The guidelines in this section pertain to epidural and spinal analgesia during labour. The term ''regional analgesia'' includes epidural, spinal, and combined spinal-epidural analgesia.
These guidelines are reviewed annually by the Obstetric Anesthesia Section of CAS and updated as indicated. Each facility may choose to develop additional guidelines or policies for specific situations in which obstetric regional analgesia is provided.
Under the direction of an anesthesiologist, some aspects of monitoring and management of obstetric regional analgesia may be delegated to other healthcare personnel. Each facility should ensure that such other personnel receive the same training, certification, continuing education, and recertification in obstetric regional analgesia.
# Initiation of Obstetric Regional Analgesia
Before introducing obstetric regional analgesia, the facility should have appropriate monitoring protocols in place. These protocols should outline the types of monitoring required and the frequency of monitoring. In addition, they should clearly state how to manage common problems and emergencies and indicate whom to contact if assistance is required.
1. Obstetric regional analgesia should be provided only by physicians with training, facility privileges, and licence to provide these services. This includes trainees with appropriate supervision. 2. Regional analgesia should be initiated and maintained only in locations where appropriate resuscitation equipment and drugs are immediately available. 3. Informed consent should be obtained and documented in the medical record. 4. Intravenous access must be established before initiating regional analgesia, and it should be maintained throughout the administration of regional analgesia. 5. The anesthesiologist should be immediately available until analgesia is established and the patient's vital signs are stable. 1. there are appropriate protocols for management of patients receiving CEI, PIEB, and PCEA; and 2. the anesthesiologist can be contacted for the purpose of obtaining advice and direction.
When initial and top-up bolus epidural local anesthetics are administered, the anesthesiologist must be immediately available to intervene appropriately recognizing that these techniques can cause immediate life-threatening complications.
Individual departments of anesthesiology should establish their own policies regarding the appropriate availability of an anesthesiologist to manage the potential complications of regional analgesia for labour and delivery. Safety systems must be in place to secure epidural local anesthetic mixtures and supplies containing controlled substances (e.g., opioids) to minimize the risk of diversion.
# Oral Intake During Labour
Gastric emptying of solids is delayed during labour and opioid analgesics may further delay gastric emptying.
Therefore, parturients should generally be discouraged from ingesting solid foods when in active labour. In contrast to solid food, clear fluids are emptied relatively rapidly from the stomach during labour. Therefore, in general, women should be permitted clear fluids as desired during active labour. Individual facilities should develop protocols regarding the intake of solids and clear fluids by women in active labour.
# Guidelines for Acute Pain Management Using Neuraxial Analgesia
When neuraxial analgesia is managed by anesthesiologists, the incidence of side effects is no higher than when alternative techniques of pain management are used. Accordingly, when its use is appropriate, neuraxial analgesia should be managed by anesthesiologists.
For the purposes of these guidelines, neuraxial analgesia is defined as intrathecal or epidural administration of opioids and/or local anesthetics for treatment of postoperative pain or other acute pain problems. These guidelines are to provide anesthesiologists with the principles of management to maximize the benefit-risk ratio of providing neuraxial analgesia.
# Administrative and Educational Policies
The department of anesthesia should establish an acute pain service that is responsible for:
# Policies for Drug Administration
Each facility should use a limited number of standard solutions. A preprinted order sheet listing the standard solutions for the facility is strongly recommended. Before any solution that is not standard in the facility is dispensed, the anesthesiologist should verify the order with nursing and pharmacy personnel and discuss its indications and all concerns relating to its use with the nurses responsible for administering the drug and monitoring the patient.
The risk of errors due to incorrect route of drug injection must be minimized. For continuous infusions or PCEA, the use of unique tamper-proof pumps that are distinct from the pumps used for intravenous fluid or drug administration is strongly recommended. The tubing between neuraxial analgesia infusion pumps and catheters should not have ports that could permit unintentional injection of intravenous drugs (see section 5.1-6).
Preparation of solutions should follow a standardized procedure. All analgesic drug solutions should be labeled with the composition of the solution (opioid, local anesthetic, or both) and its intended route of administration. For epidural administration, this should include the date and time of preparation and the name of the individual who prepared it.
# Patient Monitoring and Management of Adverse Events
Patients receiving neuraxial analgesia should be in a room equipped with oxygen and suction. Resuscitation drugs and equipment must be immediately available. Before initiating neuraxial analgesia, intravenous access must be secured, and after discontinuing neuraxial analgesia, intravenous access must be maintained for the expected duration of drug effects.
Epidural catheter dressings should permit examination for catheter movement and daily inspection of the catheter entry site for any signs of infection.
Standardized policies for patient management should be established. The parameters to be assessed, frequency of assessments, documentation, and procedures for management of complications should be specified. Adequate nursing personnel must be available to assess and manage patients receiving neuraxial analgesia. Monitoring should continue after discontinuation of neuraxial analgesia until its effects have dissipated.
An anesthesiologist must be readily available to advise nursing personnel on such issues as dose titration and management of adverse effects. Each facility with an acute pain service should ensure that an anesthesiologist is available to attend directly to patients receiving neuraxial analgesia within an appropriate time depending on the clinical situation. Each facility should also specify procedures for emergent management of any lifethreatening complications.
Other drugs, particularly benzodiazepines or parenteral opioids, may cause severe respiratory depression in patients receiving neuraxial analgesia. For this reason, other physicians should not order sedatives or analgesics for any patient receiving neuraxial analgesia. The acute pain service should direct analgesic and sedative therapy until the effects of neuraxial analgesia have dissipated.
# Epidurals and Anticoagulation
Patients with epidural catheters may receive prophylactic low-dose anticoagulant therapy if appropriate precautions are taken:
• To minimize the risk of epidural hematoma, catheter insertion and removal and the timing of anticoagulant administration must be coordinated so that no clinically significant anticoagulant effect is present at these times. • Use of nonsteroidal anti-inflammatory drugs in patients receiving neuraxial analgesia is appropriate, but concurrent administration of these drugs or other antiplatelet medication and an anticoagulant may increase the risk of epidural hematoma.
• Where neuraxial analgesia is used for prolonged postoperative pain management, every effort should be made to avoid lower extremity motor blockade. • Nursing staff should be aware of the signs and symptoms of epidural hematoma. Any change in neurologic status or new-onset back pain must be investigated immediately.
If therapeutic anticoagulation or low molecular weight heparin are indicated in a patient with an epidural catheter, the anesthesiologist should be consulted so that the timing of catheter removal and initiation of alternative analgesic management can be coordinated safely.
# Guidelines for the Practice of Anesthesia in Remote Locations
The basic principles, training requirements, techniques, equipment, and medications used for the practice of anesthesia in remote locations are as outlined in other sections of these Guidelines. They apply equally to anesthesia care, including procedural sedation (see Appendix 6) delivered by anesthesiologists in any operating room or out-of-operating room locations both within a hospital facility and outside of a hospital facility (e.g., offices, clinics). 9.1 Anesthesia Care Delivered in a Non-Hospital Medical/Surgical/Dental Facility
# Patient Selection
The physical status of patients should be classified using the American Society of Anesthesiologists physical status (ASA) score. Typically, only patients with ASA classifications of I and II should be considered for procedures. Patients with ASA III classification may be accepted under certain circumstances but only at the discretion of the attending anesthesiologist. Caution should be exercised when booking patients with a known difficult airway.
# Preoperative Considerations
The patient must have had a recent and documented health history, physical examination including an airway examination, and any appropriate laboratory investigations. This may be carried out by another physician (e.g., proceduralist) but it is strongly recommended that there be a screening process that is developed and supported by the anesthesia leadershipproviding services. The duration of fasting should be consistent with section 4.2 Fasting Guidelines.
# Conduct of Anesthesia
The anesthetic and recovery facilities must conform to facility standards established by the CSA (see Appendix 1) and all CAS guidelines established for patient care. The patient should be discharged home from the facility using a validated scoring system for fitness to discharge (e.g., Post Anesthetic Discharge Scoring System). Patients should be provided with written instructions for the preoperative and postoperative periods. The demand for the delivery of anesthesia care services outside of an operating room (e.g., endoscopy, interventional radiology, cardiac catheterization) is growing because of technological advances and the growth in the availability of less invasive, yet potentially painful, procedures. The delivery of anesthesia care in these remote procedural units can present unique challenges to the anesthesia care team (e.g., patients may have an ASA status of III-IV and have significant comorbidities) and they may be some distance from the operating rooms and support staff or outside of a hospital facility. Procedural units where anesthesiologists have been asked to provide care should comply with the same CSA standards (Appendix 1), equipment guidelines (see section 3.0), and general CAS guidelines as an operating room to the greatest extent possible. This includes, but need not be restricted to, patient selection and assessment, pre-procedural testing, fasting guidelines, equipment and electrical outlets, oxygen and suction, ventilation and scavenging if inhalational agents will be utilized, medications and equipment required for resuscitation, patient monitoring, the recovery facility and anesthesia support personnel. Any location outside of an operating room where anesthesiologists provide care must be approved by the anesthesia leadership of the facility. Appropriately trained and experienced anesthesia support personnel, for example an Anesthesia Assistant (see section 2.5) or other staff with experience supporting anesthesia should be present or immediately available to assist the anesthesiologist in remote locations. It is not appropriate to rely solely on procedural unit staff to support anesthesia unless they have had training and experience in the direct support of the delivery of anesthesia care and are approved by anesthesia leadership. There must be reliable two-way communication available to call for assistance and support of the anesthesia provider as it may be required.
provided solely for the convenience of CAS members. The CAS is not responsible for the accuracy, currency, or reliability of the content. The CAS does not offer any guarantee in this regard. It is not responsible for the information found through these links and does not necessarily endorse the sites or their content. This list includes sites that are updated periodically. Les recommandations suivantes ont pour objectif de proposer des lignes directrices de base touchant l'exercice de l'anesthésie. Leur but est de constituer un cadre pour la prestation de soins aux patients qui soient raisonnables et acceptables, et c'est ainsi qu'elles devraient être interprétées, ce qui permet une certaine flexibilité selon les circonstances. Chaque partie du Guide peut faire l'objet de révision au besoin, selon l'évolution de la technologie, de la pratique et des meilleures données probantes disponibles.
1 Principes de base Dans le présent document, le mot anesthésiologiste est utilisé pour désigner toute personne qui a un permis d'exercer la médecine avec privilège d'administrer l'anesthésie. L'anesthésie est la réalisation délibérée de toute intervention visant à rendre un patient temporairement insensible à la douleur ou à l'environnement externe dans le but d'exécuter une intervention diagnostique ou thérapeutique.
Le présent Guide s'adresse à tous les anesthésiologistes du Canada. L'exercice indépendant de l'anesthésie est une spécialité médicale et, à ce titre, elle doit être exercée par des médecins ayant une formation appropriée en anesthésie. Le processus de certification du Collège royal des médecins et chirurgiens du Canada constitue la seule voie de reconnaissance comme spécialiste en anesthésie au Canada.
La Société canadienne des anesthésiologistes (SCA) reconnaît que la population dans les collectivités éloignées n'est souvent pas suffisamment nombreuse pour justifier une pratique d'anesthésiologie spécialisée. Dans ces collectivités, des médecins de famille ayant reçu une formation adéquate pourraient être appelés à dispenser les services d'anesthésie. Dans les communautés où le volume clinique est suffisamment important pour justifier l'emploi d'anesthésiologistes à temps plein, des anesthésiologistes ayant complété leur spécialisation devraient offrir ces services. Tous les anesthésiologistes doivent poursuivre une formation continue dans la pratique de l'anesthésie, de la prise en charge de la douleur, des soins périopératoires et de la réanimation, et participer à un programme structuré de maintien des compétences (par ex., MDC du Collège royal).
# Organisation des services d'anesthésie
Le département d'anesthésie devrait être organisé, dirigé et intégré de façon appropriée aux autres départements de l'organisme ou de l'établissement, et devrait regrouper tous les membres du personnel de l'établissement qui assurent des soins anesthésiques aux patients, aussi bien à des fins chirurgicales, obstétricales, diagnostiques ou thérapeutiques.
Compte tenu de l'ampleur et de la nature des services offerts, le département devrait comporter le personnel nécessaire et s'efforcer d'assurer que ces services soient disponibles comme l'établissement de soins de santé le requiert.
Le chef du département devrait être un médecin certifié en anesthésie ou encore possédant une formation adéquate en anesthésie. Cette personne devrait être nommée de la même manière que les autres chefs de départements cliniques et devrait faire partie des entités administratives médicales supérieures de l'établissement. Certains domaines spécifiques des soins anesthésiques peuvent avoir des préoccupations qui leur sont propres. Le département d'anesthésie de chaque institution peut déterminer les privilèges en anesthésie pédiatrique, selon la population pédiatrique que l'institution dessert, l'âge de l'enfant, la présence de comorbidités, la formation spécifique du médecin et son expérience en anesthésie pédiatrique, ainsi que la complexité de l'intervention en question.
Les médecins qui obtiennent le privilège d'exercer l'anesthésie devraient posséder les connaissances ainsi que les habiletés techniques et non techniques indispensables à la pratique de l'anesthésie. Des problèmes tels que la fatigue, le harcèlement et l'intimidation en milieu de travail, les problèmes de santé personnelle et mentale, le stress, une nutrition inadéquate au travail, l'épuisement professionnel et la consommation de substances peuvent tous contribuer négativement à la santé et au bien-être et, en fin de compte, à la sécurité des patients. Tous les médecins en anesthésie devraient demeurer vigilants pour détecter, chez eux-mêmes et leurs collègues, tout signe ou symptôme d'une déficience fonctionnelle, afin que toute déficience puisse être dépistée rapidement et qu'un soutien puisse être proposé. Les troubles liés à l'utilisation de substances sont courants dans la société et peuvent également affecter les médecins en anesthésie. L'abus d'opioïdes est plus fréquent en anesthésie que dans la plupart des autres spécialités médicales. Au minimum, les programmes de prévention du détournement de médicaments contrôlés sont essentiels (voir les sections 3.1, 4 a et b) et devraient faire partie des stratégies, des politiques et de la formation départementales plus larges pour aider à identifier les médecins et le personnel de soutien à l'anesthésie qui pourraient avoir leurs facultés affaiblies en raison de troubles liés à l'utilisation de substances.
La direction du département d'anesthésie et/ou de l'établissement a le devoir de soutenir la santé et le bien-être des médecins, notamment au moyen de structures administratives qui favorisent et encouragent un milieu de travail sain et créent des mécanismes de soutien par les pairs. Les départements plus petits pourraient avoir besoin de s'appuyer sur des programmes locaux, provinciaux ou nationaux de soutien aux médecins, et l'accès à ces ressources devrait être encouragé auprès du personnel. L'objectif devrait être de créer et de maintenir une culture de sécurité psychologique dans laquelle les écarts par rapport à des conditions de travail gérables et raisonnables sont signalés et réglés, et dans laquelle les fournisseurs de soins à risque ou en difficulté peuvent être identifiés et soutenus de manière appropriée, sans crainte de répercussions négatives.
Les domaines spécifiques à considérer peuvent inclure, sans toutefois s'y limiter : 2.5 Personnel de soutien L'établissement de soins de santé doit s'assurer de la disponibilité de personnel de soutien pour remplir un rôle d'assistance auprès de l'anesthésiologiste. Cette assistance doit être disponible en tout temps et en tout lieu où des services d'anesthésie sont offerts. Le personnel de soutien doit posséder les compétences nécessaires à répondre aux besoins spécifiques des domaines de surspécialité de l'anesthésie, ce qui se répercute sur le besoin de compétences spécifiques dans des domaines tels que l'anesthésie spécialisée en pédiatrie.
On recommande aux établissements de disposer d'un assistant en anesthésie formellement désigné qui aura reçu une formation spécifique en assistance en anesthésie. Le département d'anesthésie et les autorités administratives compétentes doivent approuver l'étendue des tâches des assistants en anesthésie travaillant dans un établissement en particulier. En outre, les assistants en anesthésie, tout comme les autres professionnels de la santé employés par l'établissement, doivent être protégés par l'assuranceresponsabilité de l'établissement. Les responsabilités et les tâches déléguées aux assistants en anesthésie doivent être conformes aux règlements gouvernementaux en vigueur, aux politiques et lignes directrices édictées par les organismes de règlementation de la profession, et aux politiques de l'établissement local.
Un établissement ne disposant pas d'assistants en anesthésie en bonne et due forme doit mettre à disposition de l'anesthésiologiste du personnel paramédical afin de l'assister. Les tâches incombant à ces assistants doivent être clairement définies. Un anesthésiologiste ne doit leur déléguer ou impartir que les tâches pour lesquelles ils ont été autorisés ou approuvés.
3 Matériel d'anesthésie et lieux convenant à l'anesthésie L'anesthésie doit se pratiquer dans un établissement adapté. Tout le matériel nécessaire, y compris le matériel d'urgence, les systèmes de soutien des fonctions vitales, les médicaments et les autres fournitures, doit être à portée de main. Il est fortement recommandé qu'un manuel de listes de contrôle et d'aides cognitives soit disponible dans tous les lieux où l'anesthésie est pratiquée afin de soutenir la prise en charge des urgences périopératoires critiques. Le contenu de ce manuel devrait être révisé et mis à jour régulièrement selon les besoins et répété de façon périodique en équipe.
L'établissement de soins de santé, en consultation avec le département d'anesthésie, est responsable de l'aménagement et de l'entretien des lieux servant aux soins préopératoires, postopératoires et anesthésiques, ainsi que de l'achat, de l'entretien et du traitement après utilisation du matériel et des fournitures servant à l'anesthésie et aux autres fonctions connexes. L'Association canadienne de normalisation (CSA) et d'autres organismes d'élaboration de normes ont publié des normes et des recommandations se rapportant à la conception, la construction et la rénovation des établissements de santé, ainsi que concernant la gestion du risque, la sécurité de base et les performances essentielles du matériel médical (Annexe 1).
# Responsabilités de l'établissement de santé
Il incombe à l'établissement de soins de santé de veiller à l'application des mesures suivantes : Le personnel qui administre l'anesthésie doit s'assurer qu'on ne transmet pas de substances ou d'agents potentiellement infectieux d'un patient à un autre. À cet égard, une attention particulière doit être portée aux seringues, aux tubulures des pompes à perfusion et aux fioles de médicaments multidoses.
Avant d'introduire tout nouvel appareil en anesthésie, tous les membres du département d'anesthésie doivent recevoir une formation concernant son utilisation sécuritaire. La participation à ces séances doit être documentée. Ces séances de formation doivent être répétées aussi souvent que nécessaire pour les nouveaux et anciens membres du département.
# Gaz résiduels
Recommandations visant à diminuer l'exposition professionnelle aux gaz anesthésiques résiduels : Le principal objet de l'évaluation préanesthésique est d'obtenir les renseignements requis pour planifier la prise en charge anesthésique. Par conséquent, un médecin bien informé quant à la prise en charge anesthésique pour la procédure diagnostique ou thérapeutique proposée devrait documenter tous les aspects des antécédents médicochirurgicaux du patient, le bilan de l'examen physique et les résultats des analyses de laboratoire pertinents à la prise en charge anesthésique. Les antécédents du patient devraient inclure les problèmes médicaux passés et actuels, la prise de médicaments récente et actuelle, les réactions ou réponses inhabituelles aux médicaments et tous les problèmes et complications associés aux anesthésies administrées antérieurement. Il y a lieu de connaître également les antécédents familiaux de réactions indésirables associées à l'anesthésie. Tout renseignement concernant l'anesthésie que le patient juge pertinent de signaler devrait également être noté. Il convient enfin d'inscrire au dossier médical de chaque patient le code de classification de l'American Society of Anesthesiologists (Annexe 2).
Dans les cas adaptés, la disponibilité d'un « Plan de soins avancés » (accord de représentation, directive préalable, « testament biologique », directive « ne pas réanimer », etc.) doit être vérifiée et son applicabilité à l'intervention proposée déterminée et documentée au dossier d'évaluation anesthésique.
Le chirurgien peut solliciter une consultation avec un anesthésiologiste. Les consultations médicales devraient être obtenues lorsque cela est indiqué.
Le bilan ou la consultation anesthésique préopératoire peut avoir lieu en clinique externe avant l'admission pour l'opération. Les indications concernant l'évaluation préalable à l'admission comprennent l'existence de problèmes médicaux importants (comorbidités), la nature de la procédure diagnostique ou thérapeutique proposée, et la demande du patient. La présence d'un parent/tuteur légal est nécessaire si le patient est un enfant ou n'est pas apte à fournir un consentement éclairé. Tous les patients devraient être informés que des dispositions seront prises pour rencontrer un anesthésiologiste s'ils souhaitent s'entretenir de leur prise en charge anesthésique avant leur admission à l'établissement. La clinique d'évaluation préopératoire devrait également permettre au personnel infirmier et aux autres membres du personnel de santé d'évaluer le patient. L'anesthésiologiste en charge du patient est responsable de l'évaluation préanesthésique finale durant la période préopératoire immédiate.
# Examens préopératoires
Les examens de laboratoire ne devraient pas être réalisés sur une base régulière mais uniquement lorsque les résultats modifieront la prise en charge périopératoire. Les analyses de laboratoire devraient être réalisées lorsque l'état du patient, le traitement médicamenteux et la nature de l'intervention proposée les justifient. Les tests sanguins de laboratoire, les électrocardiogrammes et les radiographies du poumon de routine ne sont pas recommandés chez les patients asymptomatiques subissant une chirurgie à faible risque.
# Lignes directrices concernant le jeûne
Les règles concernant le jeûne devraient varier en fonction de l'âge du patient et de ses antécédents médicaux et s'appliquer à toutes les formes d'anesthésie, incluant la sédation procédurale (voir Annexe 6). 1 Les interventions très urgentes ou urgentes doivent être réalisées après avoir examiné les risques qu'entraînerait leur report comparativement au risque d'aspiration du contenu de l'estomac. Le type et la quantité de nourriture absorbée doivent être pris en considération pour déterminer la durée du jeûne. Avant une intervention non urgente, la durée minimale du jeûne devrait être de :
• Huit heures après un repas copieux comportant des aliments solides, particulièrement s'il contenait des protéines (par ex. de la viande) ou des aliments gras; • Six heures après un repas léger (par ex. repas faible en gras tel une tartine); • Six heures après l'ingestion de lait maternisé, de lait non humain ou de lait maternel tiré et fortifié avec des adjuvants; • Quatre heures après l'ingestion de lait maternel;
• Deux heures après l'ingestion de liquides clairs pour un adulte; • Une heure après l'ingestion de liquides clairs pour les nourrissons ou les enfants.
Sauf contre-indication, il convient d'encourager les adultes et les enfants à boire des liquides clairs (eau, jus sans pulpe, boissons à base de sucres complexes et thé ou café noir) jusqu'à deux heures avant une chirurgie non urgente. Les patients pédiatriques devraient également être encouragés à boire des liquides clairs, tels que définis, jusqu'à une heure avant une chirurgie non urgente.
Les conditions retardant la vidange gastrique nécessitent une évaluation au cas par cas du patient. Ces recommandations peuvent être modifiées à la discrétion du médecin.
Lorsqu'elle est indiquée, la prémédication devrait être ordonnée par l'anesthésiologiste. Les ordonnances doivent spécifier la dose, le moment et la voie d'administration.
Un antagoniste des récepteurs H2 (par voie orale ou intraveineuse) est recommandé pour toutes les femmes devant subir un accouchement par césarienne.
Trente (30) mL de citrate de sodium (0,3 molaire) sont recommandés avant un accouchement par césarienne urgent si l'on planifie une anesthésie générale.
Voir la Section 7.3 pour les recommandations de jeûne spécifiques aux patientes en travail actif.
# Règlementations supplémentaires
Des lois provinciales ou la règlementation de l'établissement pourraient prescrire d'autres directives régissant l'administration de l'anesthésie.
5 La période anesthésique
# Préparation à l'anesthésie
Avant le début de l'anesthésie, l'anesthésiologiste doit s'assurer que 1. La procédure anesthésique prévue a été expliquée au patient, y compris les risques reconnus et les techniques alternatives, et on a documenté cette explication; 2. Une évaluation adaptée de l'état du patient a été réalisée; 3. Tout le matériel qu'on prévoit nécessaire est accessible et en bon état de fonctionnement, y compris le matériel nécessaire au maintien de la température centrale (température centrale du patient 36-37°C); 4. On a accès à une source de réserve d'oxygène sous pression; 5. Tous les médicaments et agents qu'on prévoit nécessaires sont correctement identifiés -les étiquettes de médicament apposées par l'usager doivent être conformes à la norme de la CSA CAN/ CSA -Z264.3-98 (R2005) (Annexe 1); 6. Si des connecteurs Luer neuraxiaux sont utilisés, les deux côtés des raccords Luer doivent être étiquetés. Il faut envisager l'utilisation de connecteurs neuraxiaux conformes à la norme ISO 80369-6:2016connecteurs de petit diamètre interne pour application neuraxiale (raccords NRFitÒ) en fonction des disponibilités des fournisseurs de matériel; et 7. On a tenu compte des indications du fabricant quant à l'utilisation, à la manipulation et à la disposition de l'équipement et du matériel d'anesthésie.
# Prise en charge des voies aériennes
La prise en charge des voies aériennes, particulièrement en cas de voies aériennes difficiles, contribue significativement à la morbidité et à la mortalité liées à l'anesthésie. Chez les patients pour lesquels une intubation trachéale difficile est anticipée ou non anticipée, ou si l'intubation a échoué, ou lorsque la ventilation au masque ou le positionnement d'un dispositif supraglottique pourrait être difficile, et/ou dans les situations « impossible de ventiler, impossible d'oxygéner » (CVCOcannot ventilate, cannot oxygenate), et/ou lorsqu'un abord cervical antérieur d'urgence (eFONA) est nécessaire, une prise en charge appropriée des voies aériennes est essentielle à la sécurité des patients. Cette prise en charge comprend, sans nécessairement s'y limiter, une évaluation adaptée des voies aériennes, du matériel (par ex. trousses pour les voies aériennes difficiles, vidéolaryngoscopes, bronchoscopes, matériel d'abord cervical antérieur ou de cricothyroïdotomie d'urgence), une formation et des exercices de simulation appropriés, du personnel de soutien et le recours aux protocoles et listes de contrôle adéquats afin de prendre en charge au mieux des voies aériennes difficiles. Une attention et une optimisation particulières sont nécessaires dans divers domaines, notamment : l'emplacement et la disponibilité du matériel, le contexte local (p. ex., les lieux isolés), l'expérience du fournisseur de soins, le travail d'équipe et la communication (p. ex., les séances d'information de l'équipe), ainsi que les facteurs psychologiques. Il est essentiel de tenir compte des facteurs non techniques et humains (au niveau de l'individu, de l'équipe et de l'organisation) qui peuvent agir comme des catalyseurs ou des obstacles à une prise en charge des voies aériennes réussie. La SCA ne recommande pas une ligne directrice, un algorithme ou une liste de contrôle en particulier pour la prise en charge des voies aériennes difficiles ou lors d'un échec d'intubation, mais elle encourage fortement les lecteurs à se référer à l'Annexe 4 pour accéder aux publications les plus récentes sur le sujet.
# Délégation des soins aux patients
L'anesthésiologiste est avant tout responsable du patient qu'il a sous ses soins. L'anesthésiologiste ou un assistant en anesthésie supervisé par l'anesthésiologiste doit demeurer constamment aux côtés du patient pour toute la durée d'une anesthésie générale, régionale majeure et intraveineuse monitorée, jusqu'à ce que le patient ait été confié aux soins du personnel de l'unité de soins compétente.
Si l'anesthésiologiste traitant quitte temporairement la salle d'opération, il doit confier les soins du patient à un autre anesthésiologiste, à un résident en anesthésie ou à un assistant en anesthésie. Lorsque l'anesthésiologiste traitant délègue les soins à un résident en anesthésie ou à un assistant en anesthésie, il demeure responsable de la prise en charge anesthésique du patient. Avant de déléguer les soins du patient à un assistant en anesthésie, l'anesthésiologiste doit s'assurer que l'état du patient est stable et que l'assistant en anesthésie est familier avec l'intervention chirurgicale ainsi qu'avec l'environnement et le matériel de la salle d'opération. L'anesthésiologiste traitant doit demeurer immédiatement disponible lorsque les soins sont délégués à un assistant en anesthésie.
Un anesthésiologiste peut brièvement confier les soins courants d'un patient dont l'état est stable à une personne compétente qui n'est pas un assistant en anesthésie qu'en cas de circonstances particulièrement exceptionnelles, pour se porter par exemple au secours d'un autre patient dont la vie est en danger. L'unique responsabilité de cette personne devrait être de surveiller le patient en l'absence de l'anesthésiologiste et de tenir l'anesthésiologiste informé jusqu'à son retour. Dans de telles circonstances, l'anesthésiologiste demeure responsable des soins prodigués au patient et se doit de tenir l'équipe de la salle d'opération au courant.
Le transfert peropératoire des soins entre deux anesthésiologistes doit être noté au dossier d'anesthésie et se conformer à un protocole structuré.
Il est inacceptable qu'un anesthésiologiste administre simultanément une anesthésie générale, une anesthésie régionale majeure (rachidienne, péridurale ou autre) ou une sédation procédurale profonde (voir Annexe 6) 1 pour des interventions chirurgicales, diagnostiques ou thérapeutiques concomitantes pratiquées sur plus d'un patient à la fois. Toutefois, il peut être admis, dans des circonstances particulières, qu'un anesthésiologiste supervise plus d'un patient chez lequel une sédation minime à modérée est administrée, à condition qu'un individu ayant reçu une formation adéquate, qualifié, accrédité et approuvé par le service d'anesthésiologie et l'établissement de santé, soit constamment présent auprès de chaque patient recevant des soins. Il sera par contre admis, dans un service d'obstétrique, de surveiller simultanément plus d'une patiente à laquelle est administrée une analgésie régionale pour le travail. Chaque parturiente devra cependant être surveillée adéquatement par une personne compétente, suivant un protocole établi. Lorsqu'un anesthésiologiste dispense des soins anesthésiques en vue d'un accouchement, une deuxième personne dûment formée doit se tenir prête à intervenir pour pratiquer la réanimation néonatale.
Il est inacceptable qu'un seul médecin administre une anesthésie y compris la sédation procédurale profonde simultanément à la réalisation d'une procédure diagnostique ou thérapeutique, exception faite des interventions réalisées par seule infiltration d'anesthésiques locaux et/ou une sédation minimale.
# Monitorage du patient
Le seul moniteur indispensable est la présence, à tous les instants, d'un médecin ou d'un assistant en anesthésie placé sous la supervision immédiate d'un anesthésiologiste et détenant la formation et l'expérience appropriées. Les moniteurs mécaniques et électroniques ne sont que des aides à la vigilance. Ces appareils aident l'anesthésiologiste à s'assurer de l'intégrité des organes vitaux et, en particulier, de la perfusion et de l'oxygénation satisfaisantes des tissus. Le matériel de monitorage doit être utilisé comme prévu par le fabricant et approuvé par Santé Canada pour l'application spécifique.
Il incombe à l'établissement de soins de santé de fournir et d'entretenir un équipement de monitorage qui respecte les normes en vigueur.
Il incombe au chef du département d'anesthésie de conseiller l'établissement de soins de santé au sujet de l'acquisition de l'équipement de monitorage et d'établir les normes de monitorage qui aideront à assurer la sécurité du patient.
Il incombe à l'anesthésiologiste de monitorer le patient qui est sous ses soins et de s'assurer que l'équipement de monitorage approprié soit disponible et fonctionne correctement. Une feuille de vérification préanesthésique (Annexe 3 ou équivalent) doit être remplie avant l'amorce de l'anesthésie.
Une posologie prudente, un monitorage vigilant et la neutralisation adéquate des bloqueurs neuromusculaires sont des éléments essentiels à la sécurité des patients. Un monitorage neuromusculaire doit être utilisé lors de l'administration de bloqueurs neuromusculaires.
Il est recommandé qu'un monitorage de la profondeur de l'anesthésie (p. ex., basé sur l'analyse de l'EEG) soit disponible et que son utilisation soit envisagée, si cela est cliniquement indiqué, chez les patients qui présentent un risque accru de mémorisation peropératoire.
Les directives de monitorage pour les soins standard aux patients s'appliquent à tous les patients recevant une anesthésie générale, une anesthésie régionale ou une sédation intraveineuse.
# Matériel de monitorage requis
Le matériel de monitorage est catégorisé comme suit :
• Requis : Ces moniteurs doivent être utilisés sans interruption pendant toute la durée de l'administration de toute anesthésie. • Accessible en exclusivité pour chaque patient : Ces moniteurs doivent être accessibles à chaque poste de travail d'anesthésie, de sorte qu'ils puissent être utilisés sans délai. • À portée immédiate : Ces moniteurs doivent être accessibles afin de faciliter leur utilisation sans délai indu.
Le matériel de monitorage suivant est requis :
• Un saturomètre;
• Un appareil permettant de mesurer la tension artérielle, directement ou sans effraction; • Un électrocardiographe; • Un moniteur de bloc neuromusculaire lors de l'utilisation de bloqueurs neuromusculaires; • Un capnographe, pour l'anesthésie générale et pour évaluer le caractère adéquat de la ventilation pour une sédation modérée ou une sédation procédurale profonde; et • Un moniteur de gaz anesthésiques spécifique à l'agent, lorsque des agents anesthésiques par inhalation sont utilisés.
Le matériel de monitorage suivant doit être accessible en exclusivité pour chaque patient :
• Un appareil pour mesurer la température; • Un stéthoscope;
• Un éclairage suffisant pour visualiser une partie exposée du patient.
Le matériel de monitorage suivant sera à portée immédiate :
• Un spiromètre pour mesurer le volume respiratoire;
• Un manomètre pour mesurer la pression du ballonnet du tube endotrachéal; • Le matériel pour un monitorage hémodynamique invasif si indiqué (p. ex., ligne artérielle, cathéter veineux central).
L'anesthésiologiste doit demeurer vigilant en tout temps, étant conscient que de brèves interruptions du monitorage continu peuvent être inévitables et que, dans certaines circonstances, un moniteur pourrait faire défaut. Les alarmes audibles et visuelles du saturomètre et du capnographe ne devraient pas être désactivées indéfiniment pendant le déroulement d'une anesthésie, sauf en cas de circonstances inhabituelles. L'alarme à tonalité variable, celle des pulsations cardiaques et l'alarme de seuil inférieur du saturomètre ainsi que l'alarme d'apnée du capnographe doivent émettre un signal audible et visible.
# Dossiers
Toutes les variables physiologiques monitorées doivent être enregistrées à intervalles réguliers en fonction des circonstances cliniques. La fréquence cardiaque et la tension artérielle doivent être enregistrées au minimum toutes les cinq minutes. La saturation en oxygène doit être monitorée en continu et devrait être enregistrée à intervalles fréquents, au minimum toutes les cinq minutes, chez tous les patients. La concentration en dioxyde de carbone (PCO 2 ) télé-expiratoire doit être monitorée en continu et enregistrée à intervalles fréquents en cas d'intubation trachéale ou si un dispositif supraglottique est en place. On doit documenter au dossier anesthésique toute raison pour laquelle on déroge à ces directives de tenue de dossier. Les types de moniteurs, le matériel et les techniques, ainsi que l'heure, la posologie et la voie d'administration de tout médicament et liquide devraient être notés. Tous les autres soins et événements anesthésiques peropératoires pertinents, y compris les événements imprévus ou indésirables, devraient également être enregistrés.
Le dossier de santé du patient doit inclure le niveau de conscience du patient, sa fréquence cardiaque, sa tension artérielle, sa saturation en oxygène et sa fréquence respiratoire tels que mesurés à l'arrivée en salle de réveil. Ces recommandations s'appliquent tant aux dossiers anesthésiques manuscrits qu'à ceux créés via des systèmes électroniques de gestion de l'information en anesthésie (SGIA). À l'heure actuelle, il n'existe aucune norme de pratique indiquant quelles données supplémentaires (par ex. données d'analyse de gaz, de ventilation et respiratoires) potentiellement récoltées par un système de dossier de SGIA devraient faire partie du dossier de santé permanent d'un patient.
Il a été démontré que les SGIA pouvaient avoir des avantages potentiels par rapport aux dossiers rédigés à la main dans plusieurs domaines clés, notamment en augmentant la lisibilité, la précision et la fiabilité des dossiers anesthésiques, en créant des données interrogeables favorisant l'amélioration de la qualité, la communication des résultats et de la performance, la recherche translationnelle, une meilleure innocuité et un meilleur suivi des médicaments, ainsi qu'un suivi et un soutien à la décision clinique en temps réel pour les utilisateurs. La littérature sur la sécurité des patients en anesthésie appuie l'utilisation des SGIA. Il est important de mentionner que les SGIA permettent de créer une base de données de patients longitudinale, de telle manière que les antécédents anesthésiques importants des patients soient facilement trouvables si l'on veut les passer en revue, ce qui devrait être considéré comme une propriété importante pour tout système. La SCA ne promeut ni n'endosse un fournisseur ou un produit en particulier, mais elle reconnaît les avantages potentiels d'un SGIA bien conçu et mis en oeuvre par rapport à des dossiers complétés manuellement là où les ressources institutionnelles et du département d'anesthésie permettent d'envisager l'implantation d'un SGIA. Dans l'idéal, ce système devrait être mis en oeuvre et géré en coopération avec le département des technologies de l'information de l'établissement, et devrait permettre la communication avec les autres bases de données électroniques de patients de l'établissement dans la mesure du possible.
6 La période postanesthésique 6.1 La salle de réveil Une salle de réveil doit être disponible dans tout établissement offrant des services anesthésiques. Des politiques administratives conformes aux règlements de l'établissement devront être appliquées de façon à coordonner les responsabilités des soins médicaux et infirmiers.
Le département d'anesthésie devrait endosser l'ensemble de la responsabilité administrative médicale pour la salle de réveil. Il devrait exister un manuel des politiques de la salle de réveil approuvé par les autorités médicales, infirmières et administratives compétentes.
L'anesthésiologiste devrait accompagner le patient en salle de réveil, transmettre les renseignements nécessaires au personnel infirmier de la salle de réveil dans le cadre d'un transfert structuré du protocole de soins, et rédiger les ordonnances nécessaires. Le monitorage continu des patients est recommandé pendant la phase périopératoire en fonction de la situation clinique. Si cliniquement indiqué, de l'oxygène supplémentaire, une oxymétrie de pouls portable et d'autres dispositifs de monitorage adaptés doivent être utilisés pendant le transfert vers la salle de réveil ou l'USI. Si de l'oxygène supplémentaire est administré à des patients intubés pendant le transport ou en salle de réveil, afin de minimiser tout risque de barotraumatisme, il est fortement recommandé de ne le fournir qu'avec des dispositifs approuvés pour cette application spécifique. L'anesthésiologiste ne devrait déléguer les soins du patient à l'infirmier ou l'infirmière de la salle de réveil que lorsqu'il est assuré que le personnel infirmier pourra adéquatement observer et prendre soin du patient. L'anesthésiologiste ou un anesthésiologiste remplaçant désigné est responsable des soins postanesthésiques en salle de réveil. Le congé de la salle de réveil est sous la responsabilité de l'anesthésiologiste; cette responsabilité peut être déléguée en accord avec les politiques de l'établissement.
Une source d'oxygène d'appoint et une succion doivent être disponibles pour chaque patient en salle de réveil. Le matériel d'urgence nécessaire à la prise en charge des voies aériennes, la réanimation et au soutien des fonctions vitales doit être disponible en salle de réveil. Le matériel pour la prise en charge de voies aériennes difficiles doit être à portée immédiate en salle de réveil. Le monitorage utilisé en salle de réveil doit être adapté à l'état du patient et un éventail complet d'appareils de monitorage doit être disponible. Les alarmes des moniteurs doivent être en fonction, avec des paramètres d'alarme adaptés à l'état et à l'âge du patient. L'utilisation continue d'un saturomètre est requise pendant la phase initiale de récupération. Un capnographe est requis pour les patients intubés ou sous sédation profonde et est recommandé pour les patients inconscients ayant des dispositifs supraglottiques in situ dans les voies aériennes. Un moniteur d'apnée est recommandé chez les nourrissons prématurés et ayant un âge gestationnel de moins de 50 semaines.
Un dossier détaillé de la période immédiate de réveil doit être tenu. Celui-ci doit inclure un enregistrement des signes vitaux ainsi que des autres aspects du traitement et de l'observation. Cette feuille d'observation fait partie du dossier médical permanent. Toute complication ayant un lien avec l'anesthésie doit être notée sur la feuille de la salle de réveil ou dans les notes d'évolution du dossier du patient. Dans certaines situations, il peut être acceptable de transférer un patient directement vers d'autres unités de soins ou de passer outre la salle de réveil si un niveau de soins adapté est disponible dans une autre unité de l'établissement et s'il est noté au dossier anesthésique que le patient est jugé apte à ce transfert.
# Congé des patients après chirurgie d'un jour
Le congé des patients après une chirurgie ambulatoire doit se faire en utilisant un plan formel de soins approuvé par l'institution et documenté dans les notes de soins prodigués aux patients. Les patients doivent satisfaire les critères de congé au domicile en utilisant un outil d'évaluation validé (p. ex., le système de cotation de congé post-anesthésie [PADSS]). La prise en charge de la douleur et des complications postopératoires, ainsi que le suivi de routine et d'urgence, doivent tous faire l'objet d'instructions écrites spécifiques. Le patient doit être averti au sujet des synergies additives qu'il existe entre l'alcool et d'autres sédatifs, du danger de conduire ou d'utiliser des machines dangereuses dans la période postopératoire (dans la plupart des cas durant les 24 heures suivant l'opération), et de la nécessité d'attention de la part d'un adulte compétent dans la période postopératoire (dans la plupart des cas durant les 24 heures suivant l'opération).
# Anesthésie régionale neuraxiale obstétricale
Les services d'anesthésie destinés aux parturientes comprennent l'analgésie obstétricale pour le travail -pour l'accouchement avec ou sans complication -ou pour les césariennes. Toutes les directives visant l'anesthésie administrée pour toute autre intervention diagnostique ou thérapeutique s'appliquent également à l'anesthésie obstétricale. Les directives de la présente section portent sur l'analgésie péridurale et la rachianesthésie pendant le travail. L'expression « analgésie régionale » désigne l'analgésie péridurale, la rachianesthésie et la combinaison des deux.
Ces directives sont passées en revue chaque année par la Section d'anesthésie obstétricale de la SCA et mises à jour au besoin. Chaque établissement peut décider d'élaborer des directives ou politiques supplémentaires pour des situations spécifiques dans lesquelles une analgésie régionale obstétricale est dispensée.
Sous la direction d'un anesthésiologiste, certains aspects du monitorage et de la prise en charge de l'analgésie régionale obstétricale peuvent être délégués à d'autres membres du personnel de santé. Chaque établissement doit s'assurer que ces personnes reçoivent les mêmes formation, certification, formation continue et recertification en analgésie régionale en obstétrique. Chaque département d'anesthésiologie devrait établir ses propres politiques concernant la disponibilité jugée adaptée d'un anesthésiologiste pour prendre en charge les complications potentielles liées à l'analgésie régionale pour le travail obstétrical et l'accouchement.
Des systèmes de sécurité doivent exister pour protéger les mélanges d'anesthésiques locaux périduraux contenant des substances contrôlées (par ex. des opioïdes) de façon à minimiser les risques de détournement.
# Absorption orale pendant le travail
La vidange gastrique des aliments solides est retardée pendant le travail, et les analgésiques opioïdes peuvent la retarder encore davantage. Par conséquent, on devrait généralement décourager les parturientes d'ingérer des aliments solides pendant le travail actif. Contrairement aux aliments solides, les liquides clairs sont éliminés relativement rapidement de l'estomac pendant le travail. Ainsi, en règle générale, on devrait permettre aux parturientes d'ingérer des liquides clairs comme elles le souhaitent pendant le travail actif. Chaque établissement devrait élaborer des protocoles concernant l'absorption d'aliments solides et de liquides clairs par les femmes en travail actif.
8 Lignes directrices pour la prise en charge de la douleur aiguë à l'aide de l'analgésie neuraxiale Lorsque l'analgésie neuraxiale est prise en charge par des anesthésiologistes, l'incidence d'effets secondaires n'est pas plus élevée que lorsque des techniques alternatives de prise en charge de la douleur sont utilisées. En conséquence, lorsque son utilisation est indiquée, l'analgésie neuraxiale devrait être prise en charge par les anesthésiologistes.
Aux fins de ce guide, l'analgésie neuraxiale se définit comme l'administration intrathécale ou péridurale d'opioïdes et/ou d'anesthésiques locaux en vue du traitement de la douleur postopératoire ou d'autres problèmes de douleur aiguë. Ce guide vise à fournir aux anesthésiologistes les principes de prise en charge afin que l'analgésie neuraxiale soit pratiquée de manière à en maximiser les avantages et en minimiser les risques.
# Politiques administratives et éducatives
Le département d'anesthésie devrait mettre sur pied un service de traitement de la douleur aiguë responsable de; Un programme de formation standardisécomprenant la formation initiale, la certification et le maintien continu de la compétence -devrait être établi pour le personnel infirmier dispensant des soins aux patients recevant une analgésie neuraxiale.
Le personnel infirmier doit comprendre:
• Le risque de dépression respiratoire, y compris la dépression respiratoire tardive, lors de l'administration d'opioïdes hydrophiles; Le risque d'erreurs attribuables à une voie impropre d'injection du médicament doit être minimisé. Pour des perfusions continues ou une APCP, l'emploi de pompes inviolables distinctes de celles utilisées pour l'administration de solutés ou de médicaments est vivement recommandé. La tubulure entre les pompes de perfusion de l'analgésie neuraxiale et les cathéters ne devrait comporter aucun orifice susceptible de permettre une injection non intentionnelle de médicaments intraveineux (voir section 5.1-6).
La préparation des solutions devrait suivre une procédure standardisée. Toutes les solutions analgésiques devraient porter une étiquette indiquant la composition de la solution (opioïdes, anesthésique local, ou les deux) ainsi que la voie d'administration appropriée. Dans le cas d'une administration péridurale, cela doit inclure la date et l'heure de la préparation ainsi que le nom de la personne l'ayant préparée.
# Monitorage des patients et prise en charge des évènements indésirables
Les patients auxquels est administrée une analgésie neuraxiale devraient être placés dans une chambre équipée d'oxygène et de succion. Des médicaments et du matériel de réanimation doivent être à portée immédiate. L'accès intraveineux doit être établi avant d'amorcer l'analgésie neuraxiale et, après cessation de l'analgésie neuraxiale, maintenu pendant toute la durée prévue des effets médicamenteux.
Le pansement qui maintient en place le cathéter péridural doit permettre l'examen du cathéter pour détecter tout mouvement et permettre l'inspection quotidienne du point d'entrée afin de déceler tout signe d'infection.
L'adoption de politiques standardisées au chapitre de la prise en charge des patients est préconisée. Les paramètres qu'il convient d'évaluer, la fréquence des évaluations, la documentation et les procédures de prise en charge des complications devraient être précisés. Un personnel de soins infirmiers en nombre suffisant doit être présent pour évaluer et prendre en charge les patients recevant une analgésie neuraxiale. Le monitorage devrait se poursuivre après cessation de l'analgésie neuraxiale jusqu'à ce que ses effets se soient dissipés.
Un anesthésiologiste doit être immédiatement disponible afin de conseiller le personnel infirmier sur des aspects tels que le titrage de la dose et la prise en charge des effets indésirables. Chaque établissement doté d'un service de traitement de la douleur aiguë doit veiller à ce qu'un anesthésiologiste soit disponible pour s'occuper directement des patients recevant une analgésie neuraxiale dans un délai approprié en fonction de la situation clinique. Chaque établissement devrait également déterminer les procédures en vue d'une prise en charge urgente de toute complication menaçant le pronostic vital. D'autres médicaments, notamment les benzodiazépines ou les opioïdes parentéraux, peuvent causer une dépression respiratoire majeure chez les patients recevant une analgésie neuraxiale. Pour cette raison, les autres médecins ne devraient pas prescrire de sédatifs ou d'analgésiques à tout patient recevant une analgésie neuraxiale. Le service de traitement de la douleur aiguë devrait demeurer en charge de la thérapeutique analgésique et sédative jusqu'à dissipation des effets de l'analgésie neuraxiale. Si une anticoagulation thérapeutique ou de l'héparine de bas poids moléculaire sont indiquées chez un patient muni d'un cathéter péridural, l'anesthésiologiste devrait être consulté afin que le moment de retrait du cathéter et l'amorce d'un traitement analgésique de substitution puissent être coordonnés de manière sécuritaire.
9 Lignes directrices pour l'exercice de l'anesthésie dans les lieux isolés Les principes fondamentaux, les exigences de formation, les techniques, le matériel et les médicaments utilisés pour la pratique de l'anesthésie dans les lieux isolés ont été documentés dans d'autres sections de ce Guide. Ils s'appliquent également aux soins anesthésiques, notamment à la sédation procédurale (voir Annexe 6) dispensée par un anesthésiologiste dans toute salle d'opération ou emplacement hors de la salle d'opération, tant à l'intérieur d'un établissement hospitalier qu'à l'extérieur (par ex. bureaux, cliniques).
# Soins anesthésiques dispensés dans un établissement médical/chirurgical/dentaire non hospitalier
# Se´lection des patients
Le statut physique des patients devrait être catégorisé selon le score de l'American Society of Anesthesiologists (ASA). D'une manière générale, seuls les patients des classes ASA I et II devraient être retenus pour subir une intervention. Les patients de statut ASA III pourraient être acceptés sous certaines conditions, mais seulement à la discrétion de l'anesthésiologiste en charge. Il faut faire preuve de prudence lors de la sélection de patients présentant des voies aériennes difficiles connues.
# Conside´rations pre´ope´ratoires
Une histoire de cas et un examen physique récents, incluant un examen des voies aériennes, devraient paraître au dossier du patient, ainsi que les résultats des examens de laboratoire appropriés. Ces examens peuvent être exécutés par un autre médecin (par ex. un 'procéduraliste', soit un médecin/chirurgien compétent pour réaliser des interventions diagnostiques ou thérapeutiques), mais l'existence d'un processus de sélection mis au point et endossé par les services anesthésiques est fortement recommandée. La durée du jeûne devrait être conforme à la section 4.2 Lignes directrices concernant le jeuˆne.
# Conduite de l'anesthe´sie
Les installations des salles d'anesthésie et de réveil doivent être conformes aux normes hospitalières établies par la CSA (voir Annexe 1) et à toutes les lignes directrices de la SCA établies pour les soins aux patients. Le patient devrait recevoir son congé de l'hôpital pour rentrer à la maison en utilisant un système de notation validé évaluant son aptitude au congé (par. ex. Système de cotation de congé post-anesthésique). Les patients devraient recevoir des instructions écrites concernant les périodes préopératoire et postopératoire.
# Soins anesthésiques dispensés hors de la salle d'opération dans un hôpital ou un établissement non hospitalier
En raison des avancées technologiques et de la plus grande disponibilité d'interventions moins invasives mais potentiellement douloureuses, la demande pour la fourniture de soins anesthésiques à l'extérieur de la salle d'opération (par ex., endoscopie, radiologie interventionnelle, cathétérisation cardiaque) croît. La fourniture de soins anesthésiques dans ces unités interventionnelles éloignées peut s'accompagner de défis particuliers pour l'équipe de soins anesthésiques (p. ex., les patients pourraient avoir un statut ASA III-IV et d'importantes comorbidités), et ces unités pourraient se trouver à une certaine distance des salles d'opération et du personnel de soutien, voire à l'extérieur d'un établissement hospitalier. Les unités d'intervention dans lesquelles les anesthésiologistes sont appelés à fournir des soins devraient se conformer, dans la mesure du possible, aux mêmes normes de la CSA (Annexe 1), lignes directrices concernant le matériel d'anesthésie (voir section 3.0), et lignes directrices générales de la SCA qu'une salle d'opération. Cela comprend, sans s'y limiter, la sélection et l'évaluation des patients, les examens pré-procéduraux, les lignes directrices concernant le jeûne, le matériel et les prises électriques, l'oxygène et la succion, la ventilation et l'évacuation des agents volatils si utilisés, les médicaments et le matériel nécessaires à la réanimation, le monitorage du patient, les installations de rétablissement et le personnel de soutien en anesthésie. Tout lieu où des anesthésiologistes fournissent des soins en dehors d'une salle d'opération doit être approuvé par la direction de l'anesthésie dans l'établissement. Du personnel de soutien en anesthésie adéquatement formé et expérimenté, par exemple un assistant en anesthésie (voir section 2.5) ou d'autres personnes ayant de l'expérience dans le soutien en anesthésie, devrait être présent ou immédiatement disponible pour assister l'anesthésiologiste dans les lieux isolés. Il ne convient pas de dépendre exclusivement du personnel de l'unité chirurgicale pour soutenir l'anesthésie, à moins que ce personnel ne soit formé et ait de l'expérience dans le soutien direct de la fourniture de soins anesthésiques et qu'il ait reçu l'aval de la direction de l'anesthésie. Une communication bidirectionnelle fiable doit être disponible pour que le prestataire d'anesthésie ait accès à de l'aide et du soutien si nécessaire.
Remerciements Nous tenons à remercier les anciens membres du Comité des normes de pratique de l'anesthésie qui ont apporté leurs contributions à des versions antérieures de ce Guide. Le Comité tient à remercier sincèrement le Bureau de rédaction du JCA pour son aide inestimable.
Conflits d'intérêt Tous les auteurs de cet article font partie du Comité des normes de la Société canadienne des anesthésiologistes (SCA). Aucun des auteurs n'a un quelconque intérêt financier ou commercial lié aux sociétés ou fabricants d'appareils médicaux dont il est fait mention dans cet article ou dans les annexes associées. Dr Gregory Dobson est président du Comité des normes de la SCA. Annexe 4: Lignes directrices, normes et autres énoncés officiels disponibles sur l'internet L'Annexe 4 (disponible au : http://www.cas.ca/Francais/ Guide-d-exercice) offre une liste non exhaustive de sites contenant des déclarations officielles promulguées par d'autres associations médicales au Canada et ailleurs dans le monde. Cette liste est fournie aux membres de la SCA uniquement à des fins pratiques. La SCA n'est pas responsable de l'exactitude, de la mise à jour ou de la fiabilité du contenu de ces sites. La SCA n'offre aucune garantie à cet effet. Elle se dégage de toute responsabilité concernant l'information trouvée par le biais de ces liens et n'endosse pas nécessairement ces sites ou leur contenu. Cette liste contient l'adresse de sites qui sera mise à jour de façon périodique.
Annexe 5: Exposé de principe sur les assistants en anesthésie : exposé de principe officiel de la Société canadienne des anesthésiologistes Disponible en matériel électronique supplémentaire.
Annexe 6: Exposé de principe sur la sédation procédurale : exposé de principe officiel de la Société canadienne des anesthésiologistes Disponible en matériel électronique supplémentaire.
Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
#
Acknowledgements Contributions to earlier versions of the Guidelines from former members of the Committee on Standards to the Practice of Anesthesia are gratefully acknowledged. The Committee wishes to gratefully acknowledge the tremendous support provided by the editorial staff at the CJA. | None | None |
28ae071f1bc9af18186e25378e841644fe9ce63b | cma | None | December 15, 2020 -Care in Pediatric and Adolescent Gynecology (PAG) throughout Canada has been significantly impacted since the COVID-19 pandemic caused wide shut-downs of elective services and shifts to virtual care since March 2020. Access to elective services has differed across the country, and some service areas are better suited to care virtually than others. This statement serves to guide practice in the gynecologic care of young girls and adolescents during and after the pandemic and is based on available evidence and opinion of best practice from the CANPAGO committee members and PAG expertise across the country.# Maintenance of Services
PAG care is inclusive of essential services and access to care for these essential services needs to be prioritized and maintained in a similar fashion to all other essential services. Emergency and priority areas for in-person care requiring access to immediate in-person services include but are not limited to: Confirmed or suspected ovarian torsion Ovarian masses and suspected malignancies Genital trauma Heavy menstrual bleeding with anemia Per the SOGC statement on Contraception in the pandemic 1 , and based in human rights requirements, contraceptive care likewise requires access for our younger patients to contraception counselling and services, IUD insertion and medical and surgical abortion and this needs to be available in a confidential fashion which includes in-person care when required either to provide a confidential environment or for procedures.
Multidisciplinary clinics, which bring together multiple providers in a single space (against current recommendations for gathering or crossing multiple disciplines who may be making different choices about in-person care), are particularly challenging in a virtual environment. Multidisciplinary care clinics, which often note a synergy to the environment for both patients and care providers, may need to be adapted and virtual during the pandemic, but should do their best to maintain their multiple perspectives on care and should resume in their usual format as soon as they are able.
# Virtual Care
As with many other areas of medical care, PAG providers are being required to see many patients virtually through videoconference or telephone call and are needing to adapt and innovate their techniques and experiences. Provincial agencies financing health care across the country are strongly recommended to reimburse appropriately for virtual care and to continue to do so after the pandemic so that virtual care can continue to be used in circumstances in which it provides benefits over and above in-person care.
Explicit consent for virtual care, including that it may limit confidentiality, is recommended and should be documented.
# Special Considerations and Populations in Virtual Care
Some populations are well suited to virtual care and, as in all areas of medicine, may well continue to prefer virtual care long after the pandemic has settled. Patients experiencing cognitive and physical disabilities, for whom clinic attendance in person can often provide challenges in transport and waiting for themselves and their parents and guardians, are one such example. These patients are sometimes seen for menstrual suppression where a physical exam may not be required. Some populations of patients may well prefer virtual care and should be given this option and their choice in virtual or inperson care should be respected. Blood pressure as needed may be attained at required in-person visits to any service.
Other marginalized populations or those with limited access to transportation may also prefer virtual care. Patient preferences should be acknowledged and respected where possible. Virtual care may therefore have future potential to increase the reach of PAG care into marginalized populations or geographically through virtual care where subspecialists are not regularly available. Populations who require translation services can be managed through virtual care with services such as language line offering three-way phone translation. Non-English/French speakers should not be disadvantaged in virtual care.
# Confidentiality During Virtual Care
Care in the adolescent population requires confidentiality and the opportunity for the young patient to converse alone with the care provider for HEEADSSS 2 or SSHADESS 3 history and discussion of any items which the patient prefers to keep confidential from their parent or guardian at that moment. This is clearly easier to do in an in-person encounter where the parent/guardian can be asked to step out of the room and this can be confirmed visually.
In virtual care, the same request of the parent/guardian can be made with explanation of the reason and description of the limits of confidentiality. A parent/guardian can be asked to step out of the room or a phone/computer can be turned off of speaker mode, or the patient can move to a room where they are alone and they can let the care provider know when they are alone. Experience to date suggests this can work well although rapport is more difficult to establish virtually and it cannot be guaranteed that the patient is alone.
# Consent Process in Virtual Care
At times, it may be appropriate to consent for procedures during virtual care. Institutional policies will likely guide the requirement for written consent but flexibility to patient need is encouraged. It may therefore be possible to adopt novel policies for consent, such as the presence of two staff to document consent during a virtual encounter (which may work well for smaller procedures such as IUD insertions), or to delay the signing of a consent form for the day of the procedure if the process and risks/benefits/alternatives relevant to the consent are documented during a virtual encounter or to send documents electronically for e-signature. These solutions may enable the surgical process to proceed without delay and without in-person visits merely for the signing of a form.
# Teaching and Learner Engagement in Virtual Care
As a mostly academic group of providers, we continue to have a duty to teach our trainees (undergraduate and postgraduate medical, nursing, midwifery and allied health professionals). As we ourselves negotiate this changing care environment and virtual care, we should continue to do so with and in guidance of our trainees. Trainees can fit well into virtual clinics and call or video call patients either ahead of their staff provider or with the faculty listening in as they might observe an in-person encounter. Clinics need to adapt their space to safely accommodate care providers and learners who can be socially distant in the clinic space. Virtual care can be provided from outside the main clinic space (such as from home) so long as the learner and staff can each maintain a confidential environment and communicate with one another to conclude the patient encounter. Use of technology, as recommended by the institution for the maintenance of safety and security, should be used at all times. Remote access to electronic records allows for documentation and communication.
# Tools and Resources for PAG providers of virtual care and during Pandemic times
It is recommended that tools and resources to assist, guide and simulate virtual care in children and adolescents, be developed by educators and teaching faculty over time. PAG providers and SOGC and CANPAGO members are encouraged to apply their expertise to this area to support our best care to our patient population at all times. These would best exist in a centralized location (such as the SOGC website) for ease and equality of access).
# Advocacy
It is recommended that providers of care to young girls and adolescents avail themselves of opportunities to remain strong advocates for their patients and their patients' care within their health care organizations, locally, provincially and nationally -through direct care, publications, research, appropriate online and social media presence -to ensure a strong voice for the imperative to provide comprehensive gynecologic care to our patient populations during these pandemic times and in general. | December 15, 2020 -Care in Pediatric and Adolescent Gynecology (PAG) throughout Canada has been significantly impacted since the COVID-19 pandemic caused wide shut-downs of elective services and shifts to virtual care since March 2020. Access to elective services has differed across the country, and some service areas are better suited to care virtually than others. This statement serves to guide practice in the gynecologic care of young girls and adolescents during and after the pandemic and is based on available evidence and opinion of best practice from the CANPAGO committee members and PAG expertise across the country.# Maintenance of Services
PAG care is inclusive of essential services and access to care for these essential services needs to be prioritized and maintained in a similar fashion to all other essential services. Emergency and priority areas for in-person care requiring access to immediate in-person services include but are not limited to: Confirmed or suspected ovarian torsion Ovarian masses and suspected malignancies Genital trauma Heavy menstrual bleeding with anemia Per the SOGC statement on Contraception in the pandemic 1 , and based in human rights requirements, contraceptive care likewise requires access for our younger patients to contraception counselling and services, IUD insertion and medical and surgical abortion and this needs to be available in a confidential fashion which includes in-person care when required either to provide a confidential environment or for procedures.
Multidisciplinary clinics, which bring together multiple providers in a single space (against current recommendations for gathering or crossing multiple disciplines who may be making different choices about in-person care), are particularly challenging in a virtual environment. Multidisciplinary care clinics, which often note a synergy to the environment for both patients and care providers, may need to be adapted and virtual during the pandemic, but should do their best to maintain their multiple perspectives on care and should resume in their usual format as soon as they are able.
# Virtual Care
As with many other areas of medical care, PAG providers are being required to see many patients virtually through videoconference or telephone call and are needing to adapt and innovate their techniques and experiences. Provincial agencies financing health care across the country are strongly recommended to reimburse appropriately for virtual care and to continue to do so after the pandemic so that virtual care can continue to be used in circumstances in which it provides benefits over and above in-person care.
Explicit consent for virtual care, including that it may limit confidentiality, is recommended and should be documented.
# Special Considerations and Populations in Virtual Care
Some populations are well suited to virtual care and, as in all areas of medicine, may well continue to prefer virtual care long after the pandemic has settled. Patients experiencing cognitive and physical disabilities, for whom clinic attendance in person can often provide challenges in transport and waiting for themselves and their parents and guardians, are one such example. These patients are sometimes seen for menstrual suppression where a physical exam may not be required. Some populations of patients may well prefer virtual care and should be given this option and their choice in virtual or inperson care should be respected. Blood pressure as needed may be attained at required in-person visits to any service.
Other marginalized populations or those with limited access to transportation may also prefer virtual care. Patient preferences should be acknowledged and respected where possible. Virtual care may therefore have future potential to increase the reach of PAG care into marginalized populations or geographically through virtual care where subspecialists are not regularly available. Populations who require translation services can be managed through virtual care with services such as language line offering three-way phone translation. Non-English/French speakers should not be disadvantaged in virtual care.
# Confidentiality During Virtual Care
Care in the adolescent population requires confidentiality and the opportunity for the young patient to converse alone with the care provider for HEEADSSS 2 or SSHADESS 3 history and discussion of any items which the patient prefers to keep confidential from their parent or guardian at that moment. This is clearly easier to do in an in-person encounter where the parent/guardian can be asked to step out of the room and this can be confirmed visually.
In virtual care, the same request of the parent/guardian can be made with explanation of the reason and description of the limits of confidentiality. A parent/guardian can be asked to step out of the room or a phone/computer can be turned off of speaker mode, or the patient can move to a room where they are alone and they can let the care provider know when they are alone. Experience to date suggests this can work well although rapport is more difficult to establish virtually and it cannot be guaranteed that the patient is alone.
# Consent Process in Virtual Care
At times, it may be appropriate to consent for procedures during virtual care. Institutional policies will likely guide the requirement for written consent but flexibility to patient need is encouraged. It may therefore be possible to adopt novel policies for consent, such as the presence of two staff to document consent during a virtual encounter (which may work well for smaller procedures such as IUD insertions), or to delay the signing of a consent form for the day of the procedure if the process and risks/benefits/alternatives relevant to the consent are documented during a virtual encounter or to send documents electronically for e-signature. These solutions may enable the surgical process to proceed without delay and without in-person visits merely for the signing of a form.
# Teaching and Learner Engagement in Virtual Care
As a mostly academic group of providers, we continue to have a duty to teach our trainees (undergraduate and postgraduate medical, nursing, midwifery and allied health professionals). As we ourselves negotiate this changing care environment and virtual care, we should continue to do so with and in guidance of our trainees. Trainees can fit well into virtual clinics and call or video call patients either ahead of their staff provider or with the faculty listening in as they might observe an in-person encounter. Clinics need to adapt their space to safely accommodate care providers and learners who can be socially distant in the clinic space. Virtual care can be provided from outside the main clinic space (such as from home) so long as the learner and staff can each maintain a confidential environment and communicate with one another to conclude the patient encounter. Use of technology, as recommended by the institution for the maintenance of safety and security, should be used at all times. Remote access to electronic records allows for documentation and communication.
# Tools and Resources for PAG providers of virtual care and during Pandemic times
It is recommended that tools and resources to assist, guide and simulate virtual care in children and adolescents, be developed by educators and teaching faculty over time. PAG providers and SOGC and CANPAGO members are encouraged to apply their expertise to this area to support our best care to our patient population at all times. These would best exist in a centralized location (such as the SOGC website) for ease and equality of access).
# Advocacy
It is recommended that providers of care to young girls and adolescents avail themselves of opportunities to remain strong advocates for their patients and their patients' care within their health care organizations, locally, provincially and nationally -through direct care, publications, research, appropriate online and social media presence -to ensure a strong voice for the imperative to provide comprehensive gynecologic care to our patient populations during these pandemic times and in general. | None | None |
f2010ce5b111f48d83b3910c2f1a8a92112bb6cd | cma | None | Background: Recent evidence suggests that biologic therapy with targeted activity within the Type 2 inflammatory pathway can improve the clinical signs and symptoms of chronic rhinosinusitis with nasal polyposis (CRSwNP). There remains a population in CRSwNP that despite medical therapy and endoscopic sinus surgery have persistent signs and symptoms of disease. Therefore, biologics, monoclonal antibody agents, could be beneficial therapeutic treatments for these patients. There have been eight randomized, double-blind, placebo-controlled trails performed for CRSwNP targeted components of the Type 2 inflammatory pathway, notably interleukin (IL)-4, IL-5 and IL-13, IL-5R, IL-33, and immunoglobulin (Ig)E. However, there are no formal recommendations for the optimal use of biologics in managing Chronic Rhinosinusitis (CRS) within the Canadian health care environment. Methods: A Delphi Method process was utilized involving three rounds of questionnaires in which the first two were completed individually online and the third was discussed on a virtual platform with all the panelists. 17 fellowship trained rhinologists across Canada evaluated the 28 original statements on a scale of 1-10 and provided comments. A rating within 1-3 indicated disagreement, 8-10 demonstrated agreement and 4-7 represented being neutral towards a statement. All ratings were quantitively reviewed by mean, median, mode, range and standard deviation. Consensus was defined by removing the highest and lowest of the scores and using the "3 point relaxed system". Results: After three rounds, a total of 11 statements achieved consensus. This white paper only contains the final agreed upon statements and clear rationale and support for the statements regarding the use of biologics in patients with CRS.This white paper provides guidance to Canadian physicians on the use of biologic therapy for the management of patients with CRS, but the medical and surgical regimen should ultimately be individualized to the patient. As more biologics become available and additional trials are published we will provide updated versions of this white paper every few years.# Background
The Canadian clinical practice guideline for the management of chronic rhinosinusitis (CRS) provides the framework for the medical and surgical management of patients with CRS . Recent developments in the medical management of CRS have occurred due to an improved understanding of the disease pathophysiology, including Type 2 inflammation, which has led to therapy that is able to modulate the immune response present in CRS. Despite improvements in delivery methods (budesonide irrigation , Xhance delivery device (Optinose®, Yardley, PA.) , etc.), compliance strategies, and refinements in surgical technique, there continues to be a CRS patient population that has a limited response to currently available strategies. Recent clinical trial data has suggested that biologic therapy with targeted activity within the Type 2 inflammatory pathway can improve the clinical signs and symptoms of chronic rhinosinusitis with nasal polyposis (CRSwNP) in patients with medically and/or surgically recalcitrant disease. This has given rise to an interest in biologic monoclonal antibody agents as therapeutic treatments for CRS. However, until now, high-quality evidence for the use of biologic therapies in managing CRS has not been available and thus no formal recommendations exist for their optimal use within the Canadian health care environment. This white paper aims to fill this knowledge gap by offering guidance to Canadian physicians on the use of biologic therapy for the management of patients with CRS as of September 2020.
In the current environment, patients with CRSwNP whose disease is poorly responsive to medical therapy, with persistent signs and symptoms of disease, may undergo endoscopic sinus surgery (ESS). In general, the objective of this surgery is not curative, but rather to decrease the inflammatory load, thereby increasing nasal airflow and sinus drainage, and to improve access for facilitation of topical medication delivery to the paranasal sinuses. Although this approach is successful in the majority of patients, there remains a population in whom lasting disease control remains elusive. Despite advances in surgical techniques and expertise, and combined with preventative postoperative treatments, recurrence of disease may be seen in some patients within six months. Furthermore, within five years, up to 10-30% of patients with nasal polyps require a revision surgery . After surgery, patients rely on off-label use of saline and steroid combination irrigations, topical intranasal corticosteroid sprays, oral corticosteroids and antibiotics for control of symptoms which may be followed by additional surgery if symptoms persist. While beneficial in most cases, in patient groups with more severe disease, these medical therapies may offer control for only a short period of time, and thus the quality of life continues to be considerably impaired. In the face of persistent paranasal sinus disease, management of comorbid asthma may be more difficult, leading to increased use of oral corticosteroids for polyp or asthma control . Repeated and prolonged use of short-courses of oral prednisone have additive systemic adverse effects , and repeated courses of antibiotics may promote the development of bacterial resistance. Oral antibiotics are not routinely considered for CRSwNP but can be provided when patients experience purulence.
# Rationale for use of biologics in CRS
Biologic agents, or biologics, are created to target specific immune cells or mediators in an inflammatory cascade that are responsible for the progression of a disease . In CRS, agents currently approved or under assessment for CRSwNP target components of the Type 2 inflammatory pathway, notably interleukin (IL)-4, IL-5 and IL-13, IL-5R, IL-33, and immunoglobulin (Ig)E . All studies that have been conducted to date have been trialed in CRSwNP populations, except for one study that also included chronic rhinosinusitis without nasal polyposis (CRSsNP) patients . As of September 2020, there have been eight randomized, double-blind, placebo-controlled trails performed using biologics that target the previously mentioned inflammatory mediators and one trial still underway that targets IL-33. The details of the eight completed trials are summarized in Table 1.
This white paper is meant to provide guidance in the use of biologic treatments for physicians trained in and experienced in providing both medical and surgical treatments for patients with CRS.
# Methods
The panel consisted of 17 fellowship trained rhinologists across Canada who are a part of the Canadian Rhinology Working Group within the Canadian Society of Otolaryngology-Head and Neck Surgery. Decisions were made from evidence-based recommendations but also reflected clinical expertise; therefore, a systematic literature search of all randomized control trials involving CRS and biologics were first obtained (Table 1) and disseminated to the group in order for the discussion and decisions to be driven by the evidence. The development of the recommendations were established through a Delphi model process.
This process involved three rounds of questionnaires in which the first two were completed individually online and the third was discussed on a virtual platform with all the panelists. The Round 1 questionnaire consisted of 28 provided statements that were established by AT, MD, IW, SK and are referred as the provided statements in the subsequent rounds. To remove bias, all participants were able to add new statements to fill in knowledge gaps that were not covered by the provided statements. The new statement additions were referred as panelist statements in the subsequent rounds. The 28 provided statements were evaluated on a scale of 1 to 10 in terms of a participant's agreement with the statement.
A rating within 1-3 indicated disagreement while a rating of 8-10 demonstrated agreement. A rating between 4 and 7 represented being neutral towards a statement. In addition to providing a rating, participants were encouraged to provide comments and add new statements as they deemed fit. All ratings were quantitively reviewed by mean, median, mode, range and standard deviation. Consensus was defined by removing the highest and lowest of the scores after both round 1 and 2 and using the "3 point relaxed system" . This means, in order for a statement to reach consensus, all panelists' ratings for the statement must fall within a 3point region on the scale of 10. Statements that did not reach consensus were removed from the next round of statements but all results were shown to the panelists between each round.
# Results
After three rounds, a total of 11 statements achieved consensus. The statements that were removed throughout the Delphi process are not included here as this document only contains final agreed upon statements to provide the reader with clear statements regarding the use of biologics in patients with CRS. We expect this white paper to evolve over time and will require updating as additional clinical trials become available and clinical experience increases. Updated versions of this white paper will be available on www.entcanada.org.
# Discussion
Consensus statements
- Patients must have both subjective and objective findings consistent with the diagnosis of CRSwNP to qualify for biologic therapy. All endotypes of CRSwNP are considered eligible except for primary ciliary dyskinesia and cystic fibrosis.
Biologics have been largely studied in patients with CRSwNP. Therefore, patients who have been diagnosed with CRSwNP, based on the current Canadian clinical practice guidelines for CRSwNP, would be eligible . CRSwNP is defined as having 2 or more of the following symptoms lasting at least 8 to 12 weeks :
Facial congestion/fullness Facial pain/pressure/fullness Nasal obstruction/blockage Purulent anterior/posterior nasal drainage Hyposmia/anosmia Nasal endoscopy must show bilateral polyps within the nasal cavity to be considered for biologic therapy. Specialists must be cognisant that unilateral polyp disease can be caused by localized pathology such as fungal ball, antrochoanal polyps, odontogenic sinusitis or a tumor, both benign or malignant, and these diagnoses do not benefit from the use of biologic therapy . For patients with primary ciliary dyskinesia or cystic fibrosis, these diseases are considered to have a disease pathophysiology that is not due to Type 2 inflammation; therefore, there is no perceived benefit in using currently available biologics that target Type 2 inflammation .
# Patients with CRSwNP do not need another Type 2
inflammatory condition such as asthma to be considered for biologic therapy.
Historically, clinicians would provide biologics for patients suffering from asthma or atopic dermatitis and patients with CRSwNP indirectly benefited in this way. Both asthma and atopic dermatitis are Type 2 inflammatory diseases that have current indications for the use of biologics in Canada. However, currently there is clear evidence that patients with CRSwNP without asthma or atopic dermatitis benefit from biologic therapy. For instance, the efficacy of dupilumab was investigated in patients with CRSwNP regardless if they had any other Type 2 mediated diseases . Dupilumab is a fully human monoclonal antibody to interleukin 4 receptor α inhibiting IL-4 and IL-13, which both play a central role in Type 2 inflammation. Individuals without asthma treated with dupilumab had a significant improvement in the secondary endpoints: total Sino-Nasal Outcome Test-22 (SNOT-22) scores, Lund-Mackay score, and objective olfactory scores compared to the placebo . There was clinical improvement but no statistical significant improvement found in the primary endpoint of endoscopic nasal polyp score. However, those on dupilumab with comorbid asthma, having a more severe Type 2 disease, did have a significant improvement in nasal polyp score compared to the placebo . These results are similar to those of the other three randomized control trials that included an asthma cohort but did not consider asthma as a criteria to participate .
There is insufficient evidence to make a recommendation for providing biologics to patients with CRSsNP.
There are no studies investigating the use of biologics in CRSsNP for the panel to consider. CRSsNP has not been studied, but the diversity of inflammatory profiles in CRSsNP suggests Type 2 inflammation may play a role in a subset of patients and trials are currently underway to assess the efficacy of this therapy.
Biologics should not be provided to those suffering with recurrent acute bacterial sinusitis.
There were no studies for the panel to consider that assesses the outcomes of biologics in the setting of recurrent acute bacterial sinusitis (RABRS) which is not considered a Type 2 inflammatory disease. Consequently, there is currently no recognized benefit for the use of biologic therapies in this patient group.
The severity of subjective CRS symptoms needs to be moderate to severe based on the clinicians choosing of a validated patient reported outcome measure for chronic sinus disease.
Examples of frequently used outcome measures for assessing subjective symptoms include, but are not limited to, the Chronic Sinusitis Survey (CSS), SNOT-22, Rhinosinusitis Disability Index (RSDI) and Visual Analogue Scale (VAS) . In the eight randomized control trials that have been conducted on biologics targeting Type 2 inflammation in CRSwNP, most studies used the validated patient reported outcome, SNOT-22 . Otherwise a Visual Analogue Scale (VAS) score was used in combination or on its own . Other studies used a "total symptom score" with a scale range of 0 to 9 points but this is not a validated outcome measure.
- Biologics should only be considered for those who have undergone adequate sinus surgery and failed appropriate medical therapy (AMT) following surgery. Patients unfit for surgery who have failed AMT may also be considered candidates for biologic therapy.
Adequate sinus surgery that promotes ventilation, addresses mucostasis and facilitates topical medical therapy are essential goals in sinus surgery . Following surgery, CRS patients should continue AMT. AMT is a term that has not been used in the current Canadian guidelines but in more recent guidelines from Europe have highlighted the importance of AMT . The majority of CRSwNP patients will derive prolonged benefit from adequate surgery and AMT. As such, the panel recommends that ESS be used as an initial treatment modality in unoperated patients with CRSwNP who have failed AMT, as this provides a majority of patients with long-term disease control. However, patients who have already undergone ESS with minimal, or short-term improvement are at high risk of recurrence following subsequent surgery is performed. CRSwNP patients who have significant recurrence following ESS should be evaluated again to see if adequate surgery was performed and whether further surgery is required. Following this, they can then be considered for alternative therapies, such as biologics. Additionally, patients who cannot undergo surgery due to medical comorbidities but fail AMT may benefit from biologic therapies, as they cannot receive the full benefits of topical medical therapy due to unopened paranasal sinuses.
Surgery as a primary treatment modality remains costeffective. In the United States it has been shown that for patients without a history of previous sinus surgery, ESS followed by AMT is more cost effective than primary dupilumab for CRSwNP patients . This will likely be true for other biologics approved for CRSwNP given current suggested patient/drug plan costs. With the lower cost of routine outpatient sinus surgery in Canada (estimated to be approximately $3510.31 Canadian (CAD) per patient compared to an estimated annual cost for dupilumab of $25,918 CAD ), this proposition continues to hold and informs this recommendation.
However, while fixing a dollar value for the first surgery and associated medical and work issues is relatively simple, it will be more difficult to fix a value for the repeated cycles of ESS and steroids accompanied by persistent symptoms these patients undergo otherwise. Thus, while the short-term costs of biologics exceed the costs of ESS for unoperated patients, for refractory patients with multiple recurrences the long-term value still remains to be determined.
A question emerges as to whether certain groups of patients may have demographic features or biochemical markers that could help identify those most likely to fail surgery in order to facilitate case selection for biologic therapy. Whether the biologic is best provided only after surgery despite these predictive features and/or marker or pre-emptively administered without surgery is unknown at this time. "Treatable traits" such as aspirin exacerbated respiratory disease (AERD) or markers such as peripheral eosinophils have been discussed but further research in this area is clearly still required.
Option: A CT sinus scan performed prior to administration of biologics may determine if adequate sinus surgery was performed and to objectively confirm global mucosal inflammation.
In patients unfamiliar to the clinician or in cases of uncertainty, a CT scan can help determine if adequate surgery was performed, or to rule out complications leading to diagnoses such as mucocele. Moreover, if on endoscopy it is unclear if the inflammation is isolated to a certain sinus or sinuses, a CT scan would help differentiate this. Biologics seem most beneficial for those patients with global mucosal inflammation. Inflammatory sinus disease of an isolated paranasal sinus may better benefit from corrective or extended surgical approaches to the site of interest for treatment.
# Response to biologics is based on subjective and
-bjective improvement. Patients should experience an improvement to some or all of their major symptoms which include sense of smell, nasal obstruction, nasal discharge and facial pain. By 16 weeks, there should also be objective improvement on endoscopy or CT scan and this should be reevaluated at 1 year.
The definition of response is complex but requires subjective and objective improvement within a particular time frame. From completed trials, sixteen weeks appears to provide sufficient time to determine if the biologic therapy had a positive impact subjectively and objectively on a patient's CRSwNP disease. The clinician may use the patient reported outcome measures used initially to define severity of symptoms to compare if there was a minimally important clinical difference in subjective symptoms. As for objective measures, the committee supports the use of endoscopy over CT scan. Clinicians are recommended to use a validated endoscopy grading rubric to help compare endoscopy findings before and after the 16 weeks of treatment. There is an appreciation for the limitation of polyp grading scales where there is a significant reduction in the size of the polyp and symptomatic improvement despite the polyp grade not improving with treatment, and this discordance needs to be considered in conjunction with the raw polyp grading score. There must be a discussion between the clinician and the patient to determine if the improvements achieved subjectively and objectively are worthy of continuing with biologic therapy.
# Providers have the option of providing another
biologic therapy if patients fail to respond to one biologic agent but continue to fit the inclusion criteria for biologic therapy. At this time, there are no biological markers to determine the best biological agent to use.
As of September 2020, there is only one biologic approved for use in Canada for CRSwNP and there are no studies that investigate outcomes following a switch in biologic therapy if a patient fails to improve with their first prescribed biologic agent. Since biologics target different inflammatory receptors and cytokines, patients may benefit from a biologic with a different target. The second biologic agent should be evaluated at 16 weeks for efficacy in the similar manner as the first biologic.
Cost of biologics matters in the decision making of the use of biologics for CRS patients.
In a single payer health care system, the cost of biologic therapy should be considered. Surgery remains a cost-effective option for most cases of CRSwNP. As the annual cost of biologics are high, their use should be restricted to appropriate cases where other options have been exhausted. Generally, biologics in Canada indicated for asthma can range between $600 to $4000 per vial/ syringe, dependent on the drug . A cost utility analysis has shown that upfront surgery for CRSwNP is a more cost-effective option than dupilumab .
However, it is clearly evident that those who require revision surgery more than once will likely require it again and the time between surgeries diminishes with each surgery. Therefore, a cost utility analysis in this clinical scenario is required to address this question .
- The short-term use of biologics (12 months) in CRSwNP is considered safe. In other Type 2 inflammatory conditions, biologics have been shown to be safe long term.
At this time, there is evidence from published studies that the use of biologics in CRSwNP are considered safe for short-term use up to 52 weeks. The most common adverse events reported include headache, nasopharyngitis, upper respiratory tract infection, oropharyngeal pain, and injection-site reactions . No serious adverse events related to the use of biologics were reported . However, the safety of biologics for other indications such as asthma and atopic dermatitis have been researched more widely and demonstrate that they are safe for long-term use over years of use, and millions of injections .
# Conclusion
Management options for patients with CRSwNP now includes biologics. While biologics have been used for several years in other Type 2 conditions, they are novel in the management of CRSwNP. Discussion of biologic therapy for CRS treatment should be undertaken by a physician trained in and able to provide both medical and surgical treatments for CRS; who is able to undertake an informed discussion of the risks, benefits and possible complications of all of the treatment options with an affected patient. This white paper provides guidance to clinicians considering biologic therapies for CRSwNP, but the medical and surgical regimen should ultimately be individualized to the patient. As more biologics become available and additional trials are published, this white paper will be updated on www. entcanada.org with a revised published version every few years. | Background: Recent evidence suggests that biologic therapy with targeted activity within the Type 2 inflammatory pathway can improve the clinical signs and symptoms of chronic rhinosinusitis with nasal polyposis (CRSwNP). There remains a population in CRSwNP that despite medical therapy and endoscopic sinus surgery have persistent signs and symptoms of disease. Therefore, biologics, monoclonal antibody agents, could be beneficial therapeutic treatments for these patients. There have been eight randomized, double-blind, placebo-controlled trails performed for CRSwNP targeted components of the Type 2 inflammatory pathway, notably interleukin (IL)-4, IL-5 and IL-13, IL-5R, IL-33, and immunoglobulin (Ig)E. However, there are no formal recommendations for the optimal use of biologics in managing Chronic Rhinosinusitis (CRS) within the Canadian health care environment. Methods: A Delphi Method process was utilized involving three rounds of questionnaires in which the first two were completed individually online and the third was discussed on a virtual platform with all the panelists. 17 fellowship trained rhinologists across Canada evaluated the 28 original statements on a scale of 1-10 and provided comments. A rating within 1-3 indicated disagreement, 8-10 demonstrated agreement and 4-7 represented being neutral towards a statement. All ratings were quantitively reviewed by mean, median, mode, range and standard deviation. Consensus was defined by removing the highest and lowest of the scores and using the "3 point relaxed system". Results: After three rounds, a total of 11 statements achieved consensus. This white paper only contains the final agreed upon statements and clear rationale and support for the statements regarding the use of biologics in patients with CRS.This white paper provides guidance to Canadian physicians on the use of biologic therapy for the management of patients with CRS, but the medical and surgical regimen should ultimately be individualized to the patient. As more biologics become available and additional trials are published we will provide updated versions of this white paper every few years.# Background
The Canadian clinical practice guideline for the management of chronic rhinosinusitis (CRS) provides the framework for the medical and surgical management of patients with CRS [1]. Recent developments in the medical management of CRS have occurred due to an improved understanding of the disease pathophysiology, including Type 2 inflammation, which has led to therapy that is able to modulate the immune response present in CRS. Despite improvements in delivery methods (budesonide irrigation [2], Xhance delivery device (Optinose®, Yardley, PA.) [3], etc.), compliance strategies, and refinements in surgical technique, there continues to be a CRS patient population that has a limited response to currently available strategies. Recent clinical trial data has suggested that biologic therapy with targeted activity within the Type 2 inflammatory pathway can improve the clinical signs and symptoms of chronic rhinosinusitis with nasal polyposis (CRSwNP) in patients with medically and/or surgically recalcitrant disease. This has given rise to an interest in biologic monoclonal antibody agents as therapeutic treatments for CRS. However, until now, high-quality evidence for the use of biologic therapies in managing CRS has not been available and thus no formal recommendations exist for their optimal use within the Canadian health care environment. This white paper aims to fill this knowledge gap by offering guidance to Canadian physicians on the use of biologic therapy for the management of patients with CRS as of September 2020.
In the current environment, patients with CRSwNP whose disease is poorly responsive to medical therapy, with persistent signs and symptoms of disease, may undergo endoscopic sinus surgery (ESS). In general, the objective of this surgery is not curative, but rather to decrease the inflammatory load, thereby increasing nasal airflow and sinus drainage, and to improve access for facilitation of topical medication delivery to the paranasal sinuses. Although this approach is successful in the majority of patients, there remains a population in whom lasting disease control remains elusive. Despite advances in surgical techniques and expertise, and combined with preventative postoperative treatments, recurrence of disease may be seen in some patients within six months. Furthermore, within five years, up to 10-30% of patients with nasal polyps require a revision surgery [4][5][6]. After surgery, patients rely on off-label use of saline and steroid combination irrigations, topical intranasal corticosteroid sprays, oral corticosteroids and antibiotics for control of symptoms which may be followed by additional surgery if symptoms persist. While beneficial in most cases, in patient groups with more severe disease, these medical therapies may offer control for only a short period of time, and thus the quality of life continues to be considerably impaired. In the face of persistent paranasal sinus disease, management of comorbid asthma may be more difficult, leading to increased use of oral corticosteroids for polyp or asthma control [7]. Repeated and prolonged use of short-courses of oral prednisone have additive systemic adverse effects [8], and repeated courses of antibiotics may promote the development of bacterial resistance. Oral antibiotics are not routinely considered for CRSwNP but can be provided when patients experience purulence.
# Rationale for use of biologics in CRS
Biologic agents, or biologics, are created to target specific immune cells or mediators in an inflammatory cascade that are responsible for the progression of a disease [9]. In CRS, agents currently approved or under assessment for CRSwNP target components of the Type 2 inflammatory pathway, notably interleukin (IL)-4, IL-5 and IL-13, IL-5R, IL-33, and immunoglobulin (Ig)E [9]. All studies that have been conducted to date have been trialed in CRSwNP populations, except for one study that also included chronic rhinosinusitis without nasal polyposis (CRSsNP) patients [10]. As of September 2020, there have been eight randomized, double-blind, placebo-controlled trails performed using biologics that target the previously mentioned inflammatory mediators and one trial still underway that targets IL-33. The details of the eight completed trials are summarized in Table 1.
This white paper is meant to provide guidance in the use of biologic treatments for physicians trained in and experienced in providing both medical and surgical treatments for patients with CRS.
# Methods
The panel consisted of 17 fellowship trained rhinologists across Canada who are a part of the Canadian Rhinology Working Group within the Canadian Society of Otolaryngology-Head and Neck Surgery. Decisions were made from evidence-based recommendations but also reflected clinical expertise; therefore, a systematic literature search of all randomized control trials involving CRS and biologics were first obtained (Table 1) and disseminated to the group in order for the discussion and decisions to be driven by the evidence. The development of the recommendations were established through a Delphi model process.
This process involved three rounds of questionnaires in which the first two were completed individually online and the third was discussed on a virtual platform with all the panelists. The Round 1 questionnaire consisted of 28 provided statements that were established by AT, MD, IW, SK and are referred as the provided statements in the subsequent rounds. To remove bias, all participants were able to add new statements to fill in knowledge gaps that were not covered by the provided statements. The new statement additions were referred as panelist statements in the subsequent rounds. The 28 provided statements were evaluated on a scale of 1 to 10 in terms of a participant's agreement with the statement.
A rating within 1-3 indicated disagreement while a rating of 8-10 demonstrated agreement. A rating between 4 and 7 represented being neutral towards a statement. In addition to providing a rating, participants were encouraged to provide comments and add new statements as they deemed fit. All ratings were quantitively reviewed by mean, median, mode, range and standard deviation. Consensus was defined by removing the highest and lowest of the scores after both round 1 and 2 and using the "3 point relaxed system" [20]. This means, in order for a statement to reach consensus, all panelists' ratings for the statement must fall within a 3point region on the scale of 10. Statements that did not reach consensus were removed from the next round of statements but all results were shown to the panelists between each round.
# Results
After three rounds, a total of 11 statements achieved consensus. The statements that were removed throughout the Delphi process are not included here as this document only contains final agreed upon statements to provide the reader with clear statements regarding the use of biologics in patients with CRS. We expect this white paper to evolve over time and will require updating as additional clinical trials become available and clinical experience increases. Updated versions of this white paper will be available on www.entcanada.org.
# Discussion
Consensus statements
1. Patients must have both subjective and objective findings consistent with the diagnosis of CRSwNP to qualify for biologic therapy. All endotypes of CRSwNP are considered eligible except for primary ciliary dyskinesia and cystic fibrosis.
Biologics have been largely studied in patients with CRSwNP. Therefore, patients who have been diagnosed with CRSwNP, based on the current Canadian clinical practice guidelines for CRSwNP, would be eligible [1]. CRSwNP is defined as having 2 or more of the following symptoms lasting at least 8 to 12 weeks [1]:
Facial congestion/fullness Facial pain/pressure/fullness Nasal obstruction/blockage Purulent anterior/posterior nasal drainage Hyposmia/anosmia Nasal endoscopy must show bilateral polyps within the nasal cavity to be considered for biologic therapy. Specialists must be cognisant that unilateral polyp disease can be caused by localized pathology such as fungal ball, antrochoanal polyps, odontogenic sinusitis or a tumor, both benign or malignant, and these diagnoses do not benefit from the use of biologic therapy [21]. For patients with primary ciliary dyskinesia or cystic fibrosis, these diseases are considered to have a disease pathophysiology that is not due to Type 2 inflammation; therefore, there is no perceived benefit in using currently available biologics that target Type 2 inflammation [21].
# Patients with CRSwNP do not need another Type 2
inflammatory condition such as asthma to be considered for biologic therapy.
Historically, clinicians would provide biologics for patients suffering from asthma or atopic dermatitis and patients with CRSwNP indirectly benefited in this way. Both asthma and atopic dermatitis are Type 2 inflammatory diseases that have current indications for the use of biologics in Canada. However, currently there is clear evidence that patients with CRSwNP without asthma or atopic dermatitis benefit from biologic therapy. For instance, the efficacy of dupilumab was investigated in patients with CRSwNP regardless if they had any other Type 2 mediated diseases [15]. Dupilumab is a fully human monoclonal antibody to interleukin 4 receptor α inhibiting IL-4 and IL-13, which both play a central role in Type 2 inflammation. Individuals without asthma treated with dupilumab had a significant improvement in the secondary endpoints: total Sino-Nasal Outcome Test-22 (SNOT-22) scores, Lund-Mackay score, and objective olfactory scores compared to the placebo [15]. There was clinical improvement but no statistical significant improvement found in the primary endpoint of endoscopic nasal polyp score. However, those on dupilumab with comorbid asthma, having a more severe Type 2 disease, did have a significant improvement in nasal polyp score compared to the placebo [15]. These results are similar to those of the other three randomized control trials that included an asthma cohort but did not consider asthma as a criteria to participate [11,13,15].
# 3.
There is insufficient evidence to make a recommendation for providing biologics to patients with CRSsNP.
There are no studies investigating the use of biologics in CRSsNP for the panel to consider. CRSsNP has not been studied, but the diversity of inflammatory profiles in CRSsNP suggests Type 2 inflammation may play a role in a subset of patients and trials are currently underway to assess the efficacy of this therapy.
# 4.
Biologics should not be provided to those suffering with recurrent acute bacterial sinusitis.
There were no studies for the panel to consider that assesses the outcomes of biologics in the setting of recurrent acute bacterial sinusitis (RABRS) which is not considered a Type 2 inflammatory disease. Consequently, there is currently no recognized benefit for the use of biologic therapies in this patient group.
# 5.
The severity of subjective CRS symptoms needs to be moderate to severe based on the clinicians choosing of a validated patient reported outcome measure for chronic sinus disease.
Examples of frequently used outcome measures for assessing subjective symptoms include, but are not limited to, the Chronic Sinusitis Survey (CSS), SNOT-22, Rhinosinusitis Disability Index (RSDI) and Visual Analogue Scale (VAS) [22]. In the eight randomized control trials that have been conducted on biologics targeting Type 2 inflammation in CRSwNP, most studies used the validated patient reported outcome, SNOT-22 [12,[15][16][17][18]. Otherwise a Visual Analogue Scale (VAS) score was used in combination or on its own [12][13][14][15][16][17][18]. Other studies used a "total symptom score" with a scale range of 0 to 9 points but this is not a validated outcome measure.
6. Biologics should only be considered for those who have undergone adequate sinus surgery and failed appropriate medical therapy (AMT) following surgery. Patients unfit for surgery who have failed AMT may also be considered candidates for biologic therapy.
Adequate sinus surgery that promotes ventilation, addresses mucostasis and facilitates topical medical therapy are essential goals in sinus surgery [21]. Following surgery, CRS patients should continue AMT. AMT is a term that has not been used in the current Canadian guidelines but in more recent guidelines from Europe have highlighted the importance of AMT [21]. The majority of CRSwNP patients will derive prolonged benefit from adequate surgery and AMT. As such, the panel recommends that ESS be used as an initial treatment modality in unoperated patients with CRSwNP who have failed AMT, as this provides a majority of patients with long-term disease control. However, patients who have already undergone ESS with minimal, or short-term improvement are at high risk of recurrence following subsequent surgery is performed. CRSwNP patients who have significant recurrence following ESS should be evaluated again to see if adequate surgery was performed and whether further surgery is required. Following this, they can then be considered for alternative therapies, such as biologics. Additionally, patients who cannot undergo surgery due to medical comorbidities but fail AMT may benefit from biologic therapies, as they cannot receive the full benefits of topical medical therapy due to unopened paranasal sinuses.
Surgery as a primary treatment modality remains costeffective. In the United States it has been shown that for patients without a history of previous sinus surgery, ESS followed by AMT is more cost effective than primary dupilumab for CRSwNP patients [23]. This will likely be true for other biologics approved for CRSwNP given current suggested patient/drug plan costs. With the lower cost of routine outpatient sinus surgery in Canada (estimated to be approximately $3510.31 Canadian (CAD) per patient compared to an estimated annual cost for dupilumab of $25,918 CAD [24,25]), this proposition continues to hold and informs this recommendation.
However, while fixing a dollar value for the first surgery and associated medical and work issues is relatively simple, it will be more difficult to fix a value for the repeated cycles of ESS and steroids accompanied by persistent symptoms these patients undergo otherwise. Thus, while the short-term costs of biologics exceed the costs of ESS for unoperated patients, for refractory patients with multiple recurrences the long-term value still remains to be determined.
A question emerges as to whether certain groups of patients may have demographic features or biochemical markers that could help identify those most likely to fail surgery in order to facilitate case selection for biologic therapy. Whether the biologic is best provided only after surgery despite these predictive features and/or marker or pre-emptively administered without surgery is unknown at this time. "Treatable traits" such as aspirin exacerbated respiratory disease (AERD) or markers such as peripheral eosinophils have been discussed but further research in this area is clearly still required.
# 7.
Option: A CT sinus scan performed prior to administration of biologics may determine if adequate sinus surgery was performed and to objectively confirm global mucosal inflammation.
In patients unfamiliar to the clinician or in cases of uncertainty, a CT scan can help determine if adequate surgery was performed, or to rule out complications leading to diagnoses such as mucocele. Moreover, if on endoscopy it is unclear if the inflammation is isolated to a certain sinus or sinuses, a CT scan would help differentiate this. Biologics seem most beneficial for those patients with global mucosal inflammation. Inflammatory sinus disease of an isolated paranasal sinus may better benefit from corrective or extended surgical approaches to the site of interest for treatment.
# Response to biologics is based on subjective and
objective improvement. Patients should experience an improvement to some or all of their major symptoms which include sense of smell, nasal obstruction, nasal discharge and facial pain. By 16 weeks, there should also be objective improvement on endoscopy or CT scan and this should be reevaluated at 1 year.
The definition of response is complex but requires subjective and objective improvement within a particular time frame. From completed trials, sixteen weeks appears to provide sufficient time to determine if the biologic therapy had a positive impact subjectively and objectively on a patient's CRSwNP disease. The clinician may use the patient reported outcome measures used initially to define severity of symptoms to compare if there was a minimally important clinical difference in subjective symptoms. As for objective measures, the committee supports the use of endoscopy over CT scan. Clinicians are recommended to use a validated endoscopy grading rubric to help compare endoscopy findings before and after the 16 weeks of treatment. There is an appreciation for the limitation of polyp grading scales where there is a significant reduction in the size of the polyp and symptomatic improvement despite the polyp grade not improving with treatment, and this discordance needs to be considered in conjunction with the raw polyp grading score. There must be a discussion between the clinician and the patient to determine if the improvements achieved subjectively and objectively are worthy of continuing with biologic therapy.
# Providers have the option of providing another
biologic therapy if patients fail to respond to one biologic agent but continue to fit the inclusion criteria for biologic therapy. At this time, there are no biological markers to determine the best biological agent to use.
As of September 2020, there is only one biologic approved for use in Canada for CRSwNP and there are no studies that investigate outcomes following a switch in biologic therapy if a patient fails to improve with their first prescribed biologic agent. Since biologics target different inflammatory receptors and cytokines, patients may benefit from a biologic with a different target. The second biologic agent should be evaluated at 16 weeks for efficacy in the similar manner as the first biologic.
# 10.
Cost of biologics matters in the decision making of the use of biologics for CRS patients.
In a single payer health care system, the cost of biologic therapy should be considered. Surgery remains a cost-effective option for most cases of CRSwNP. As the annual cost of biologics are high, their use should be restricted to appropriate cases where other options have been exhausted. Generally, biologics in Canada indicated for asthma can range between $600 to $4000 per vial/ syringe, dependent on the drug [26,27]. A cost utility analysis has shown that upfront surgery for CRSwNP is a more cost-effective option than dupilumab [23].
However, it is clearly evident that those who require revision surgery more than once will likely require it again and the time between surgeries diminishes with each surgery. Therefore, a cost utility analysis in this clinical scenario is required to address this question [6].
11. The short-term use of biologics (12 months) in CRSwNP is considered safe. In other Type 2 inflammatory conditions, biologics have been shown to be safe long term.
At this time, there is evidence from published studies that the use of biologics in CRSwNP are considered safe for short-term use up to 52 weeks. The most common adverse events reported include headache, nasopharyngitis, upper respiratory tract infection, oropharyngeal pain, and injection-site reactions [10]. No serious adverse events related to the use of biologics were reported [10]. However, the safety of biologics for other indications such as asthma and atopic dermatitis have been researched more widely and demonstrate that they are safe for long-term use over years of use, and millions of injections [28,29].
# Conclusion
Management options for patients with CRSwNP now includes biologics. While biologics have been used for several years in other Type 2 conditions, they are novel in the management of CRSwNP. Discussion of biologic therapy for CRS treatment should be undertaken by a physician trained in and able to provide both medical and surgical treatments for CRS; who is able to undertake an informed discussion of the risks, benefits and possible complications of all of the treatment options with an affected patient. This white paper provides guidance to clinicians considering biologic therapies for CRSwNP, but the medical and surgical regimen should ultimately be individualized to the patient. As more biologics become available and additional trials are published, this white paper will be updated on www. entcanada.org with a revised published version every few years.
# Acknowledgements
We thank Laura Samson and Enoch Lee for their coordination.
# Funding
Not applicable.
# Availability of data and materials
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
# Ethics approval and consent to participate
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee (University of British Columbia -Providence Health Research Ethics Board H20-00335 and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
# Consent for publication
Not applicable.
# Competing interests
| None | None |
d8b04fbd62c4662cb0495b5d73b0130e04a9addf | cma | None | To provide an approach to the perioperative management of warfarin-treated patients who require an elective or urgent surgery/procedure. - To provide an approach for bridging anticoagulation, if needed, during warfarin interruption. For guidance on management of patients who require an urgent or emergency surgery/procedure, please refer to the Perioperative Anticoagulant Management Algorithm found on the Thrombosis Canada website under the "Tools" tab.Bridging anticoagulation refers to giving a short-acting anticoagulant, typically a low molecular weight heparin (LWMH), before and after surgery or invasive procedure to minimize the time that warfarintreated patients are not anticoagulated. This is different from providing routine thromboprophylaxis in the post-operative setting.# BRIDGING ANTICOAGULATION OPTIONS:
Pre-and post-operative dosing:
- Subcutaneous (SC) therapeutic-dose LMWH: enoxaparin 1 mg/kg twice daily or 1.5 mg/kg once daily, dalteparin 100 IU/kg twice daily or 200 IU/kg once daily, or tinzaparin 175 IU/kg once daily. - Intravenous (IV) unfractionated heparin (UFH) to achieve a therapeutic activated partial thromboplastin time (aPTT) defined according to local laboratory parameters is not commonly used.
Alternative post-operative dosing:
- In patients having a high-bleed-risk surgery/procedure, an alternate post-operative management option should be considered with a prophylactic dose of SC LMWH: enoxaparin 40 mg once daily, dalteparin 5000 IU once daily or tinzaparin 4500 IU once daily. - In patients having a high-bleed-risk surgery/procedure that is cardiac, spinal or intracranial, postoperative therapeutic-dose LMWH bridging should be avoided; alternate options are low-dose prophylactic LMWH, delaying anticoagulation until the bleed risk decreases or resuming warfarin alone.
# MONITORING:
There is no need for laboratory monitoring with SC LMWH bridging. Monitoring of the aPTT is required for bridging with IV UFH.
# ADVERSE EFFECTS:
Bridging is associated with a 2% increase in risk for major bleeding and a 10-15% risk for minor bleeding. Bridging should be used carefully to minimize this bleeding risk.
# PERI-PROCEDURE MANAGEMENT QUESTIONS AND ANSWERS:
Is peri-procedure warfarin interruption always needed? Deciding if warfarin interruption is needed is based on the bleeding risk of the surgery/procedure (see Table 1). Most surgeries/procedures require warfarin interruption but, in general, minimal-bleed-risk procedures (e.g. dental, cataract surgery, minor skin procedures) do not need warfarin interruption. - Chronic atrial fibrillation with a CHADS2 score- of 3-4 - Newer generation (bileaflet) mechanical aortic valve - Prior arterial or venous thromboembolism within last 3-12 months
# LOW-RISK (BRIDGING ANTICOAGULATION IS NOT RECOMMENDED):
- Chronic atrial fibrillation (valvular or non-valvular) with a CHADS2 score- of 0-2 - Prior venous thromboembolism over 12 months ago - Bioprosthetic heart valve *CHADS2 score estimates the risk of stroke in patients with non-valvular atrial fibrillation. The score is the total points for the presence of congestive heart failure (1), hypertension (1), age > 75 yrs (1), diabetes (1), stroke, transient ischemic attack or systemic embolism (2). †Consider a temporary inferior vena cava filter to be inserted after warfarin interruption and prior to surgery for patients in whom surgery is necessary within 1 month of a proximal DVT; filter can be left in situ for 1-2 weeks until therapeutic anticoagulation is re-established. Elective surgery within 3 months after a diagnosis of deep vein thrombosis or pulmonary embolism should generally be avoided.
# What is the perioperative anticoagulant management after warfarin interruption for elective procedures?
A suggested management algorithm is shown in the Figure below.
# FIGURE 1. PERIOPERATIVE MANAGEMENT OF WARFARIN-TREATED PATIENTS BEFORE AND AFTER SURGERY/PROCEDURE
When is it safe to resume bridging anticoagulation after surgery/procedure?
The timing of post-procedure resumption of bridging depends on: a) the bleeding risk of the procedure (see Table 1), b) whether there has been adequate post-operative hemostasis (based on wound inspection and drainage tubes to detect bleeding), and c) the class of anticoagulant used.
Minimizing bleeding is important because of associated morbidity; a delay in warfarin resumption because of bleeding also exposes patients to an increased thromboembolic risk.
# Is interruption of anticoagulation needed?
Continue anticoagulation: see Table 1 Stop warfarin 5 days before procedure and check INR day -1 to ensure 1.5 or less. If INR >1.5 administer vitamin K1 1-2 mg orally. Use therapeutic LMWH ~3 days before surgery. Last preoperative dose 24 h before surgery (1/2 of daily). Resume therapeutic dose LMWH according to bleeding risk as outlined in Table 3 after surgery. Resume warfarin postoperatively when patient drinking fluids, consider bolus dose.
# Yes TABLE 3. POST-OPERATIVE RESUMPTION OF BRIDGING ANTICOAGULATION
Resumption of therapeutic doses of any anticoagulant should not occur earlier than the time periods suggested below.
# LOW/MODERATE-BLEED-RISK PROCEDURE:
- Therapeutic-dose LMWH/UFH, starting approximately 24 hours after surgery (i.e. day after surgery)
# HIGH-BLEED-RISK PROCEDURE:
- Therapeutic-dose LMWH/UFH, starting 48-72 hours after surgery - Alternate management: prophylactic LMWH, starting 12-24 hours after surgery (i.e. day after surgery) or resume warfarin alone with no post-operative LMWH/UFH
# SPECIAL CONSIDERATIONS:
Dental procedures: In patients having 1-2 dental extractions or endodontic (root canal) procedures, warfarin can be safely continued. To reduce the incidence of gingival bleeding, patients can take oral tranexamic acid mouthwash (5 mL just before the procedure, and 2-3 times daily after the procedure until bleeding subsides).
# Eye procedures:
In patients having a cataract extraction, especially if done with topical and not retrobulbar anesthesia, warfarin can be safely continued. For other eye procedures, warfarin is generally interrupted but consultation with an ophthalmologist is advised.
Colonoscopy & gastroscopy: Warfarin interruption will be needed for most patients who undergo colonoscopy because the potential for polyp removal cannot always be determined beforehand. Caution is warranted after removal of large (>1 cm) polyps since bleeding can occur 2-7 days after polypectomy due to dislodgement of eschar. Polyp-related bleeding may be reduced with endoscopic application of clips to the polyp stalk.
OTHER RELEVANT THROMBOSIS CANADA CLINICAL GUIDES:
- Unfractionated Heparin, Low Molecular Weight Heparin and Fondaparinux - Warfarin
# Date of version: 04Sept2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein. | To provide an approach to the perioperative management of warfarin-treated patients who require an elective or urgent surgery/procedure. • To provide an approach for bridging anticoagulation, if needed, during warfarin interruption. For guidance on management of patients who require an urgent or emergency surgery/procedure, please refer to the Perioperative Anticoagulant Management Algorithm found on the Thrombosis Canada website under the "Tools" tab.Bridging anticoagulation refers to giving a short-acting anticoagulant, typically a low molecular weight heparin (LWMH), before and after surgery or invasive procedure to minimize the time that warfarintreated patients are not anticoagulated. This is different from providing routine thromboprophylaxis in the post-operative setting.# BRIDGING ANTICOAGULATION OPTIONS:
Pre-and post-operative dosing:
• Subcutaneous (SC) therapeutic-dose LMWH: enoxaparin 1 mg/kg twice daily or 1.5 mg/kg once daily, dalteparin 100 IU/kg twice daily or 200 IU/kg once daily, or tinzaparin 175 IU/kg once daily. • Intravenous (IV) unfractionated heparin (UFH) to achieve a therapeutic activated partial thromboplastin time (aPTT) defined according to local laboratory parameters is not commonly used.
Alternative post-operative dosing:
• In patients having a high-bleed-risk surgery/procedure, an alternate post-operative management option should be considered with a prophylactic dose of SC LMWH: enoxaparin 40 mg once daily, dalteparin 5000 IU once daily or tinzaparin 4500 IU once daily. • In patients having a high-bleed-risk surgery/procedure that is cardiac, spinal or intracranial, postoperative therapeutic-dose LMWH bridging should be avoided; alternate options are low-dose prophylactic LMWH, delaying anticoagulation until the bleed risk decreases or resuming warfarin alone.
# MONITORING:
There is no need for laboratory monitoring with SC LMWH bridging. Monitoring of the aPTT is required for bridging with IV UFH.
# ADVERSE EFFECTS:
Bridging is associated with a 2% increase in risk for major bleeding and a 10-15% risk for minor bleeding. Bridging should be used carefully to minimize this bleeding risk.
# PERI-PROCEDURE MANAGEMENT QUESTIONS AND ANSWERS:
Is peri-procedure warfarin interruption always needed? Deciding if warfarin interruption is needed is based on the bleeding risk of the surgery/procedure (see Table 1). Most surgeries/procedures require warfarin interruption but, in general, minimal-bleed-risk procedures (e.g. dental, cataract surgery, minor skin procedures) do not need warfarin interruption. • Chronic atrial fibrillation with a CHADS2 score* of 3-4 • Newer generation (bileaflet) mechanical aortic valve • Prior arterial or venous thromboembolism within last 3-12 months
# LOW-RISK (BRIDGING ANTICOAGULATION IS NOT RECOMMENDED):
• Chronic atrial fibrillation (valvular or non-valvular) with a CHADS2 score* of 0-2 • Prior venous thromboembolism over 12 months ago • Bioprosthetic heart valve *CHADS2 score estimates the risk of stroke in patients with non-valvular atrial fibrillation. The score is the total points for the presence of congestive heart failure (1), hypertension (1), age > 75 yrs (1), diabetes (1), stroke, transient ischemic attack or systemic embolism (2). †Consider a temporary inferior vena cava filter to be inserted after warfarin interruption and prior to surgery for patients in whom surgery is necessary within 1 month of a proximal DVT; filter can be left in situ for 1-2 weeks until therapeutic anticoagulation is re-established. Elective surgery within 3 months after a diagnosis of deep vein thrombosis or pulmonary embolism should generally be avoided.
# What is the perioperative anticoagulant management after warfarin interruption for elective procedures?
A suggested management algorithm is shown in the Figure below.
# FIGURE 1. PERIOPERATIVE MANAGEMENT OF WARFARIN-TREATED PATIENTS BEFORE AND AFTER SURGERY/PROCEDURE
When is it safe to resume bridging anticoagulation after surgery/procedure?
The timing of post-procedure resumption of bridging depends on: a) the bleeding risk of the procedure (see Table 1), b) whether there has been adequate post-operative hemostasis (based on wound inspection and drainage tubes to detect bleeding), and c) the class of anticoagulant used.
Minimizing bleeding is important because of associated morbidity; a delay in warfarin resumption because of bleeding also exposes patients to an increased thromboembolic risk.
# Is interruption of anticoagulation needed?
Continue anticoagulation: see Table 1 Stop warfarin 5 days before procedure and check INR day -1 to ensure 1.5 or less. If INR >1.5 administer vitamin K1 1-2 mg orally. Use therapeutic LMWH ~3 days before surgery. Last preoperative dose 24 h before surgery (1/2 of daily). Resume therapeutic dose LMWH according to bleeding risk as outlined in Table 3 after surgery. Resume warfarin postoperatively when patient drinking fluids, consider bolus dose.
# Yes TABLE 3. POST-OPERATIVE RESUMPTION OF BRIDGING ANTICOAGULATION
Resumption of therapeutic doses of any anticoagulant should not occur earlier than the time periods suggested below.
# LOW/MODERATE-BLEED-RISK PROCEDURE:
• Therapeutic-dose LMWH/UFH, starting approximately 24 hours after surgery (i.e. day after surgery)
# HIGH-BLEED-RISK PROCEDURE:
• Therapeutic-dose LMWH/UFH, starting 48-72 hours after surgery • Alternate management: prophylactic LMWH, starting 12-24 hours after surgery (i.e. day after surgery) or resume warfarin alone with no post-operative LMWH/UFH
# SPECIAL CONSIDERATIONS:
Dental procedures: In patients having 1-2 dental extractions or endodontic (root canal) procedures, warfarin can be safely continued. To reduce the incidence of gingival bleeding, patients can take oral tranexamic acid mouthwash (5 mL just before the procedure, and 2-3 times daily after the procedure until bleeding subsides).
# Eye procedures:
In patients having a cataract extraction, especially if done with topical and not retrobulbar anesthesia, warfarin can be safely continued. For other eye procedures, warfarin is generally interrupted but consultation with an ophthalmologist is advised.
Colonoscopy & gastroscopy: Warfarin interruption will be needed for most patients who undergo colonoscopy because the potential for polyp removal cannot always be determined beforehand. Caution is warranted after removal of large (>1 cm) polyps since bleeding can occur 2-7 days after polypectomy due to dislodgement of eschar. Polyp-related bleeding may be reduced with endoscopic application of clips to the polyp stalk.
#
OTHER RELEVANT THROMBOSIS CANADA CLINICAL GUIDES:
• Unfractionated Heparin, Low Molecular Weight Heparin and Fondaparinux • Warfarin
# Date of version: 04Sept2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein. | None | None |
dbf281710a0242f504d15e7b2a2bcb6414e06d9f | cma | None | Pharmacologic and non-pharmacologic COVID-19 therapeutic recommendations which incorporates implementation and logistic considerations for long-term care (LTC) home residents.) NUMBER OF VACCINE DOSES RISK FACTORS 0 doses 1 dose 2 doses 3 or more doses Currently not recommended -SARS-CoV-2 neutralizing antibodies and nirmatrelvir/ ritonavir (Paxlovid) Version 1.# Severely immunocompromised 1 individuals of any age
High risk: Therapeutics should always be recommended for immunocompromised individuals not expected to mount an adequate immune response to COVID-19 vaccination or SARS-CoV-2 infection due to their underlying immune status, regardless of age or vaccine status. 1
- Examples of immunocompromised or immunosuppressed individuals include receipt of treatment for solid tumors and hematologic malignancies (including individuals with lymphoid malignancies who are being monitored without active treatment), receipt of solid-organ transplant and taking immunosuppressive therapy, receipt of chimeric antigen receptor (CAR)-T-cell or hematopoietic stem cell transplant (within 2 years of transplantation or taking immunosuppression therapy), moderate or severe primary immunodeficiency (e.g., DiGeorge syndrome, Wiskott-Aldrich syndrome, common variable immunodeficiency, Good's syndrome, hyper IgE syndrome), advanced or untreated HIV infection, active treatment with high-dose corticosteroids (i.e., ≥20 mg prednisone or equivalent per day when administered for ≥2 weeks), alkylating agents, antimetabolites, transplant-related immunosuppressive drugs, cancer chemotherapeutic agents classified as severely immunosuppressive, tumor-necrosis factor (TNF) blockers, and other biologic agents that are immunosuppressive or immunomodulatory. 2. Acceptable hospitalization risk of individuals at younger end of age band is at least 1-2%.
# SEVERITY OF ILLNESS RECOMMENDATIONS
- Higher risk residents are those who have a ≥3% risk of hospitalization if they develop COVID-19. Standard risk residents are those who have a <3% risk of hospitalization - Despite high rates of COVID-19 vaccination, there continues to be COVID-19-associated morbidity and mortality in LTC home residents due to advanced age, multiple comorbidities and frailty - Racialized people, particularly those who are Indigenous and Black, may be at increased risk of disease progression due to disparate rates of comorbidities, increased barriers to vaccination, and other social determinants associated with worse health. They should be considered priority populations for access to COVID-19 drugs and therapeutics - COVID-19 therapeutic management advanced planning should consider goals of care, obtaining needed bloodwork, medication reviews for drug-drug interactions and consent where applicable ▶Pharmacological therapy is recommended for mildly-symptomatic residents at higher risk of disease progression and should be considered for nirmatrelvir/ritonavir (Paxlovid) or remdesivir. The choice of drug depends on availability, contraindications, ease of administration and goals of care.
- Nirmatrelvir/ Ritonavir (Paxlovid) is recommended at a dose of 300 mg nirmatrelvir and 100 mg ritonavir given together PO BID x 5 days. Dose-adjust to 150/100mg PO BID x 5 days if eGFR 30-59 mL/min. Not recommended if eGFR <30 mL/min. (Order Creatinine prior to administration if no recent results available (< 30 days). If results available within 30 days, can start therapy and order a repeat Creatinine as soon as possible).
- Indicated for mild COVID-19 throughout (not requiring new or increased oxygen) meeting eligibility criteria within 5 days of symptom onset - Lack of efficacy and side effect data in the LTC population - High potential for drug-drug interactions due to ritonavir; requires a pharmacist review for drug-drug interactions prior to prescribing - Cannot be crushed, limiting administration in some LTC residents - Consider whether goals of care are in line with life-prolonging treatment of acute medical conditions
- Remdesivir is recommended at a dose of 200 mg IV on day 1, then 100 mg IV per day on days 2-3. Contraindicated in residents with renal dysfunction (eGFR 5x upper limit of normal. (Order Creatinine and ALT prior to administration if no recent results available (< 30 days). If results available within 30 days, can start therapy and order a repeat Creatinine and ALT as soon as possible).
- Indicated for mild COVID-19 throughout (not requiring new or increased oxygen) meeting eligibility criteria within 7 days of symptom onset - Need for IV access, and daily infusion x 3 make the logistics of administering remdesivir challenging for some LTC homes unless performed by an external provider - Consider whether goals of care are in line with life-prolonging treatment of acute medical conditions ▶Pharmacological therapy for mildly symptomatic residents in LTC, regardless of risk ▲ Budesonide may be considered at a dose of 800 mcg inhaled BID for 14 days.
- Evidence of reduction in duration of symptoms (very low certainty evidence)
- Low risk of harm - Can be considered in addition to other COVID-19 therapies when residents have bothersome respiratory symptoms - May be a class effect; other inhaled steroids that can be administered via an aerochamber (e.g., ciclesonide) rather than a turbuhaler may also be considered
# Risk of Disease Progression
# CURRENTLY NOT RECOMMENDED*
There is insufficient evidence to support the use of the following therapies in the treatment of COVID-19 outside of clinical trials or where other indications would justify its use: ▲ Fluvoxamine may be considered at a dose of 50 mg PO daily, titrated up to 100 mg PO BID for 10-15 days. (If the drug is well tolerated, increase the dose to 100 mg PO BID on day 2. If the drug is less well tolerated, consider a dose of 50 mg PO BID on day 2, and increase the dose to 100 mg PO BID on day 3).
- Indicated for mild COVID-19 throughout (not requiring new or increased oxygen) within 7 days of symptom onset and not receiving Paxlovid or remdesivir - Evidence of benefit is not very strong. Not believed to be a class effect - Side effect profile of high dose fluvoxamine and high potential for drug-drug interactions makes this treatment challenging for most LTC residents, recommend pharmacist review for drug-drug interactions prior to prescribing - Limited clinical experience in LTC population - Older adults may experience fluvoxamine concentrations that are 2-to 3-fold higher than younger adults - Risks in this population may outweigh the benefits There is currently insufficient evidence to make a recommendation around aspirin or anticoagulation for mildly ill residents The following therapies are not recommended for mildly ill residents: dexamethasone, tocilizumab, sarilumab and baricitinib ▶Supportive therapy
# Fluids
Consider fluid intake as LTC residents with COVID-19 are at risk of volume depletion. For those with decreased oral intake, encourage oral fluids or consider initiating hypodermoclysis as a temporary measure, as needed, through the acute illness. (Hypodermoclysis up to a rate of approximately 50 cc/hour using an isotonic solution (e.g., normal saline)).
Patients with moderate COVID-19 will need to have a clinical assessment and decision made around need for transfer to hospital
The following therapies may be offered to residents in homes where moderate COVID-19 can be managed - These therapies may also be offered to residents who do not wish to be transferred to acute care, in accordance with their goals of care ▶Pharmacologic therapy
- Dexamethasone is recommended at a dose of 6 mg PO daily for 10 days (IM dexamethasone 10 mg per day or SC dexamethasone 6 mg per day may be alternative options for people with poor swallowing).
- Monitor closely for delirium (including hypoactive delirium); consider early discontinuation if harms outweigh the benefits for the resident after considering their goals of care - Monitor blood glucose in all residents with diabetes - No reason to withhold dexamethasone regardless of the administration of remdesivir - Remdesivir is recommended at a dose of 200 mg IV on day 1, then 100 mg IV per day for 4 days. Contraindicated in patients with renal dysfunction (eGFR5x upper limit of normal. (Order Creatinine and ALT prior to administration if no recent results available (< 30 days). If results available within 30 days, can start therapy and order a repeat Creatinine and ALT as soon as possible).
- Need for IV access, and daily infusion x5 make the logistics of administering remdesivir challenging for some LTC settings unless performed by an external provider - Consider whether goals of care are in line with life-prolonging treatment of acute medical conditions ▶Supportive therapies
# Fluids
Consider fluid intake as LTC residents with COVID-19 are at risk of volume depletion. For those with decreased oral intake, encourage oral fluids or consider initiating hypodermoclysis as a temporary measure as needed, through the acute illness.
(Hypodermoclysis up to a rate of approximately 50 cc/hour using an isotonic solution (e.g., normal saline)).
Oxygen -supplemental oxygen up to 5L/min via nasal prongs. Target SpO2 > 92% (unless prior chronic lung disease, where lower SpO2 levels could be targeted) ▲ Anticoagulation -therapeutic dose anticoagulation with low molecular weight heparin (LMWH) may be considered.
- Therapeutic dose anticoagulation with LMWH for residents not already anticoagulated who are felt to be at low risk of bleeding - Residents on therapeutic doses of anticoagulation (regardless of type) for other pre-COVID-19 reasons should continue to take anticoagulation as previously prescribed - If residents have a bleeding risk, consider no anticoagulation or prophylactic dose LMWH
- Tocilizumab is recommended at a dose of 400 mg one time IV.
- For residents on supplemental oxygen, only given if they have not shown improvement with dexamethasone after 24-48 hours and their CRP>75 - Illness severity, need for evaluation of CRP, IV route of admission, and drug availability make tocilizumab administration very challenging in LTC, and so would require acute care transfer if consistent with goals of care | Pharmacologic and non-pharmacologic COVID-19 therapeutic recommendations which incorporates implementation and logistic considerations for long-term care (LTC) home residents.) NUMBER OF VACCINE DOSES RISK FACTORS 0 doses 1 dose 2 doses 3 or more doses ■ Currently not recommended -SARS-CoV-2 neutralizing antibodies and nirmatrelvir/ ritonavir (Paxlovid) Version 1.# Severely immunocompromised 1 individuals of any age
High risk: Therapeutics should always be recommended for immunocompromised individuals not expected to mount an adequate immune response to COVID-19 vaccination or SARS-CoV-2 infection due to their underlying immune status, regardless of age or vaccine status. 1
1. Examples of immunocompromised or immunosuppressed individuals include receipt of treatment for solid tumors and hematologic malignancies (including individuals with lymphoid malignancies who are being monitored without active treatment), receipt of solid-organ transplant and taking immunosuppressive therapy, receipt of chimeric antigen receptor (CAR)-T-cell or hematopoietic stem cell transplant (within 2 years of transplantation or taking immunosuppression therapy), moderate or severe primary immunodeficiency (e.g., DiGeorge syndrome, Wiskott-Aldrich syndrome, common variable immunodeficiency, Good's syndrome, hyper IgE syndrome), advanced or untreated HIV infection, active treatment with high-dose corticosteroids (i.e., ≥20 mg prednisone or equivalent per day when administered for ≥2 weeks), alkylating agents, antimetabolites, transplant-related immunosuppressive drugs, cancer chemotherapeutic agents classified as severely immunosuppressive, tumor-necrosis factor (TNF) blockers, and other biologic agents that are immunosuppressive or immunomodulatory. 2. Acceptable hospitalization risk of individuals at younger end of age band is at least 1-2%.
# SEVERITY OF ILLNESS RECOMMENDATIONS
• Higher risk residents are those who have a ≥3% risk of hospitalization if they develop COVID-19. Standard risk residents are those who have a <3% risk of hospitalization • Despite high rates of COVID-19 vaccination, there continues to be COVID-19-associated morbidity and mortality in LTC home residents due to advanced age, multiple comorbidities and frailty • Racialized people, particularly those who are Indigenous and Black, may be at increased risk of disease progression due to disparate rates of comorbidities, increased barriers to vaccination, and other social determinants associated with worse health. They should be considered priority populations for access to COVID-19 drugs and therapeutics • COVID-19 therapeutic management advanced planning should consider goals of care, obtaining needed bloodwork, medication reviews for drug-drug interactions and consent where applicable ▶Pharmacological therapy is recommended for mildly-symptomatic residents at higher risk of disease progression and should be considered for nirmatrelvir/ritonavir (Paxlovid) or remdesivir. The choice of drug depends on availability, contraindications, ease of administration and goals of care.
• Nirmatrelvir/ Ritonavir (Paxlovid) is recommended at a dose of 300 mg nirmatrelvir and 100 mg ritonavir given together PO BID x 5 days. Dose-adjust to 150/100mg PO BID x 5 days if eGFR 30-59 mL/min. Not recommended if eGFR <30 mL/min. (Order Creatinine prior to administration if no recent results available (< 30 days). If results available within 30 days, can start therapy and order a repeat Creatinine as soon as possible).
• Indicated for mild COVID-19 throughout (not requiring new or increased oxygen) meeting eligibility criteria within 5 days of symptom onset • Lack of efficacy and side effect data in the LTC population • High potential for drug-drug interactions due to ritonavir; requires a pharmacist review for drug-drug interactions prior to prescribing • Cannot be crushed, limiting administration in some LTC residents • Consider whether goals of care are in line with life-prolonging treatment of acute medical conditions
• Remdesivir is recommended at a dose of 200 mg IV on day 1, then 100 mg IV per day on days 2-3. Contraindicated in residents with renal dysfunction (eGFR <30 mL/ min), ALT>5x upper limit of normal. (Order Creatinine and ALT prior to administration if no recent results available (< 30 days). If results available within 30 days, can start therapy and order a repeat Creatinine and ALT as soon as possible).
• Indicated for mild COVID-19 throughout (not requiring new or increased oxygen) meeting eligibility criteria within 7 days of symptom onset • Need for IV access, and daily infusion x 3 make the logistics of administering remdesivir challenging for some LTC homes unless performed by an external provider • Consider whether goals of care are in line with life-prolonging treatment of acute medical conditions ▶Pharmacological therapy for mildly symptomatic residents in LTC, regardless of risk ▲ Budesonide may be considered at a dose of 800 mcg inhaled BID for 14 days.
• Evidence of reduction in duration of symptoms (very low certainty evidence)
• Low risk of harm • Can be considered in addition to other COVID-19 therapies when residents have bothersome respiratory symptoms • May be a class effect; other inhaled steroids that can be administered via an aerochamber (e.g., ciclesonide) rather than a turbuhaler may also be considered
# Risk of Disease Progression
# CURRENTLY NOT RECOMMENDED*
There is insufficient evidence to support the use of the following therapies in the treatment of COVID-19 outside of clinical trials or where other indications would justify its use: ▲ Fluvoxamine may be considered at a dose of 50 mg PO daily, titrated up to 100 mg PO BID for 10-15 days. (If the drug is well tolerated, increase the dose to 100 mg PO BID on day 2. If the drug is less well tolerated, consider a dose of 50 mg PO BID on day 2, and increase the dose to 100 mg PO BID on day 3).
◆
• Indicated for mild COVID-19 throughout (not requiring new or increased oxygen) within 7 days of symptom onset and not receiving Paxlovid or remdesivir • Evidence of benefit is not very strong. Not believed to be a class effect • Side effect profile of high dose fluvoxamine and high potential for drug-drug interactions makes this treatment challenging for most LTC residents, recommend pharmacist review for drug-drug interactions prior to prescribing • Limited clinical experience in LTC population • Older adults may experience fluvoxamine concentrations that are 2-to 3-fold higher than younger adults • Risks in this population may outweigh the benefits ◆ There is currently insufficient evidence to make a recommendation around aspirin or anticoagulation for mildly ill residents ■ The following therapies are not recommended for mildly ill residents: dexamethasone, tocilizumab, sarilumab and baricitinib ▶Supportive therapy
# Fluids
Consider fluid intake as LTC residents with COVID-19 are at risk of volume depletion. For those with decreased oral intake, encourage oral fluids or consider initiating hypodermoclysis as a temporary measure, as needed, through the acute illness. (Hypodermoclysis up to a rate of approximately 50 cc/hour using an isotonic solution (e.g., normal saline)).
# •
Patients with moderate COVID-19 will need to have a clinical assessment and decision made around need for transfer to hospital •
The following therapies may be offered to residents in homes where moderate COVID-19 can be managed • These therapies may also be offered to residents who do not wish to be transferred to acute care, in accordance with their goals of care ▶Pharmacologic therapy
• Dexamethasone is recommended at a dose of 6 mg PO daily for 10 days (IM dexamethasone 10 mg per day or SC dexamethasone 6 mg per day may be alternative options for people with poor swallowing).
• Monitor closely for delirium (including hypoactive delirium); consider early discontinuation if harms outweigh the benefits for the resident after considering their goals of care • Monitor blood glucose in all residents with diabetes • No reason to withhold dexamethasone regardless of the administration of remdesivir • Remdesivir is recommended at a dose of 200 mg IV on day 1, then 100 mg IV per day for 4 days. Contraindicated in patients with renal dysfunction (eGFR<30 mL/ min) or ALT>5x upper limit of normal. (Order Creatinine and ALT prior to administration if no recent results available (< 30 days). If results available within 30 days, can start therapy and order a repeat Creatinine and ALT as soon as possible).
• Need for IV access, and daily infusion x5 make the logistics of administering remdesivir challenging for some LTC settings unless performed by an external provider • Consider whether goals of care are in line with life-prolonging treatment of acute medical conditions ▶Supportive therapies
# Fluids
Consider fluid intake as LTC residents with COVID-19 are at risk of volume depletion. For those with decreased oral intake, encourage oral fluids or consider initiating hypodermoclysis as a temporary measure as needed, through the acute illness.
(Hypodermoclysis up to a rate of approximately 50 cc/hour using an isotonic solution (e.g., normal saline)).
Oxygen -supplemental oxygen up to 5L/min via nasal prongs. Target SpO2 > 92% (unless prior chronic lung disease, where lower SpO2 levels could be targeted) ▲ Anticoagulation -therapeutic dose anticoagulation with low molecular weight heparin (LMWH) may be considered.
• Therapeutic dose anticoagulation with LMWH for residents not already anticoagulated who are felt to be at low risk of bleeding • Residents on therapeutic doses of anticoagulation (regardless of type) for other pre-COVID-19 reasons should continue to take anticoagulation as previously prescribed • If residents have a bleeding risk, consider no anticoagulation or prophylactic dose LMWH
• Tocilizumab is recommended at a dose of 400 mg one time IV.
• For residents on supplemental oxygen, only given if they have not shown improvement with dexamethasone after 24-48 hours and their CRP>75 • Illness severity, need for evaluation of CRP, IV route of admission, and drug availability make tocilizumab administration very challenging in LTC, and so would require acute care transfer if consistent with goals of care | None | None |
7f11f1820bef78b05c41ec2c6eec1bfad84f6479 | cma | None | Colorectal cancer (CRC) is the second leading cause of cancer deaths in Canada and the United States. A positive family history (FH) significantly increases the risk of developing CRC, and screening programs can substantially reduce CRC incidence and mortality. These consensus recommendations were developed by the Canadian Association of Gastroenterology (CAG), with US and Canadian experts, and endorsed by the American Gastroenterological Association. The purpose was to systematically and critically review the literature and provide specific recommendations See editorial on page 1298.#
BACKGROUND & AIMS: A family history (FH) of colorectal cancer (CRC) increases the risk of developing CRC. These consensus recommendations developed by the Canadian Association of Gastroenterology and endorsed by the American Gastroenterological Association, aim to provide guidance on screening these high-risk individuals. METHODS: Multiple parallel systematic review streams, informed by 10 literature searches, assembled evidence on 5 principal questions around the effect of an FH of CRC or adenomas on the risk of CRC, the age to initiate screening, and the optimal tests and testing intervals. The GRADE (Grading of Recommendation Assessment, Development and Evaluation) approach was used to develop the recommendations. RESULTS: Based on the evidence, the Consensus Group was able to strongly recommend CRC screening for all individuals with an FH of CRC or documented adenoma. However, because most of the evidence was very-low quality, the majority of the remaining statements were conditional ("we suggest"). Colonoscopy is suggested (recommended in individuals with 2 first-degree relatives ), with fecal immunochemical test as an alternative. The elevated risk associated with an FH of 1 FDRs with CRC or documented advanced adenoma suggests initiating screening at a younger age (eg, 40-50 years or 10 years younger than age of diagnosis of FDR). In addition, a shorter interval of every 5 years between screening tests was suggested for individuals with 2 FDRs, and every 5-10 years for those with FH of 1 FDR with CRC or documented advanced adenoma compared to average-risk individuals. Choosing screening parameters for an individual patient should consider the age of the affected FDR and local resources. It is suggested that individuals with an FH of 1 second-degree relatives only, or of nonadvanced adenoma or polyp of unknown histology, be screened according to averagerisk guidelines. CONCLUSIONS: The increased risk of CRC associated with an FH of CRC or advanced adenoma warrants more intense screening for CRC. Well-designed prospective studies are needed in order to make definitive evidence-based recommendations about the age to commence screening and appropriate interval between screening tests.
for CRC screening of individuals with an FH of nonhereditary CRC or adenoma. This is the first guideline to use systematic reviews and the GRADE (Grading of Recommendation Assessment, Development and Evaluation) approach to make recommendations for screening for CRC in this high-risk population. Multiple parallel systematic review streams, informed by 10 literature searches, assembled evidence on 5 principal questions: (1) effect of an FH of CRC on an individual's risk of CRC, (2) effect of an FH of adenoma on an individual's risk of CRC, (3) age at which screening should begin, (4) optimal screening tests, and (5) optimal testing intervals for individuals with an FH of CRC or adenoma. The GRADE approach was used to assess the quality of evidence. Questions were developed through an iterative online platform, and then statements were developed and voted on by a group of specialists.
Consensus was reached on 19 statements addressing 5 main patient risk categories, including individuals with 2 or more first-degree relative (FDRs) with CRC, 1 FDR with CRC, 1 or more FDRs with advanced adenoma, 1 or more seconddegree relatives (SDRs) with CRC, and 1 or more FDR with any non-advanced adenoma (Table 1).
Because of the lack of high-quality data, the majority of statements are conditional recommendations ("we suggest"). However, based on moderate-quality evidence, the Consensus Group is able to strongly recommend CRC screening over no screening for all individuals with an FH of CRC or documented adenoma. In addition, despite very-lowquality evidence, colonoscopy is recommended in individuals with 2 or more FDRs with CRC, because of the high-risk of life-threatening negative consequences of missed lesions.
Based on available data and consensus, Table 2 provides a concise summary of the preferred and secondchoice screening tests, the age at which screening should begin, and the interval for screening according to the level of elevated CRC risk for each patient subgroup. For individual at highest risk (2 or more FDRs with a history of CRC), we recommend screening with colonoscopy, which we suggest begin at age 40-50 years or 10 years younger than the age of diagnosis of the FDR (whichever is earlier), at an interval of every 5 years. For individuals with 1 FDR with a history of CRC or advanced adenoma, we suggest commencing CRC screening at age 40-50 years or 10 years younger than the age of diagnosis of the FDR (whichever is earlier), at an interval of every 5-10 years. For those with an FH of CRC, colonoscopy is suggested with fecal immunochemical test (FIT) as an alternative, while both tests are suggested options for those with an FH of advanced adenoma. Finally, it is suggested that individuals with an FH of 1 or more SDRs only, or of nonadvanced adenoma or polyp of unknown histology be screened according to average-risk guidelines.
Except for the statements for those at the highest risk, age ranges are provided. The relationship between the age at which an affected FDR was diagnosed with CRC and an individual's risk of developing CRC is difficult to define. The evidence shows that the risk falls on a continuum, and that there is no clearly defined age above or below which a clear inflection in risk can be recognized. The Consensus Group carefully considered the issue of recommending a range of years, acknowledging that some clinicians and programs may wish for greater precision. However, the evidence in cases where a range was recommended does not support a specific age point. Definitive statements in these circumstances are misleading and imply a degree of certainty that does not currently exist. Furthermore, specifying a range allows some flexibility, including consideration of the age of the affected FDR and local resources, and underscores the need for further data, which will hopefully lead to greater clarity in the future.
The Consensus Group acknowledged that heritable cancers tend to occur at an earlier age and that this heritable risk decreases with advancing age of the diagnosis of the CRC in the FDR. That being the case, the age of the affected relative should be considered when making clinical decisions regarding screening. For example, having an FDR diagnosed at 75-90 years of age is unlikely to seriously impact an individual's risk of CRC, while an FDR diagnosed at age 35 years is probably highly relevant. Therefore, we acknowledge that national or provincial programs may wish to set specific FDR age cutoffs for screening, based on additional factors, including feasibility, cost, and cost-effectiveness. From an evidence perspective, we are, unfortunately, not able to provide clear guidance at this time. Future research should prioritize prospective studies that assess the optimal time to initiate screening and appropriate intervals between screening tests.
# Introduction
Colorectal cancer (CRC) is the second leading cause of cancer in Canada, and the fourth leading cause in the United States. 1,2 It is the second leading cause of cancer deaths in both countries, with approximately 9400 Canadians, and 50,260 Americans dying of the disease annually. The 2017 estimated incidence of new cases CRC was 26,800 Canadians, and 135,430 Americans, and the prevalence of individuals living with CRC was 105,195 Canadians (2009) and 1.3 million Americans (2014). 1,2 A systematic review (SR) estimated the prevalence of an individual having 1 or more first-degree relatives (FDRs) with CRC to be 3%-10%, and of having 2 or more FDRs with CRC to be about 0.3%. 3 Many of these individuals with a positive family history (FH) are at an increased risk of developing CRC. However, the magnitude of the individual's increased risk appears to be dependent on the degree of relationship to the affected relative, age of the affected relative at time of diagnosis, and the age of the individual. Overall CRC burden in a family (ie, total number of individuals with CRC on the same side of the family) also increases the magnitude of the individual's CRC risk. This may be a red flag for an inherited CRC syndrome. 4 CRC usually develops from premalignant polyps, and CRC screening can be used to detect and remove these polyps or localized cancer. Evidence from studies conducted in individuals primarily at "average risk" for CRC shows that screening (with endoscopy or occult blood tests) can reduce CRC mortality and incidence. Guidelines and the introduction of population-based screening programs have led to substantially increased uptake of CRC screening. Rates in the United States and Canada were about 25%-35% before 2003, but have increased to 55%-60% in 2012-2013 surveys. 8,9 Individuals with an FH of CRC are more likely to adhere to CRC screening recommendations compared to those with no FH. 3 But even among this higher-risk population, participation rates remain less than optimal. 3, While a variety of guidelines for screening individuals for CRC are available, the majority apply to patients at average risk, or those at highest risk due to inherited germline mutations associated with CRC and polyposis. 4,23,24 The few guidelines that make detailed recommendations for screening individuals with an FH of CRC or adenoma have not systematically reviewed the literature in this specific population. 17,19,20 Recent guidelines from the US Multi-Society Task Force on CRC screening used a modified process to systematically review published literature on this topic, however, systematic assessments of the methodological quality of the individual studies were not presented, and the paper was published after our consensus meeting. 22 For this guideline, systematic literature searches were conducted and the quality of evidence (QoE) and strength of recommendations were rated using the Grading of Recommendation Assessment, Development, and Evaluation (GRADE) approach. 25 This guideline specifically excludes individuals with hereditary syndromes, such as Lynch syndrome, familial adenomatous polyposis, attenuated familial adenomatous polyposis, MUTYH-associated polyposis, Peutz-Jeghers syndrome, juvenile polyposis syndrome, Cowden syndrome, serrated (hyperplastic) polyposis syndrome, hereditary pancreatic cancer, and hereditary gastric cancer. However, hereditary CRCs occurring due to mutations and defects in certain genes account for about 5% of all CRC. 4 Given the substantial risk of CRC and extracolonic cancers warranting specific screening strategies, it is important to identify these patients with hereditary syndromes. The National Comprehensive Cancer Network proposed 9 recommendations (summarized in Table 3) for patients who should be referred to a genetics provider for further assessment of a hereditary cancer syndrome. In addition, many jurisdictions and hospitals have implemented universal screening programs for CRC and endometrial cancers that include microsatellite instability or immunohistochemistry to identify patients at risk of Lynch syndrome. These individuals should be managed according to appropriate guidelines for individuals with hereditary gastrointestinal cancer syndromes. 4,23,24 The purpose of this guideline was to systematically and critically review the literature and provide specific recommendations for CRC screening of individuals with an FH of nonhereditary CRC or adenoma.
# Methods
# Scope and Purpose
Questions around screening for CRC in individuals with an FH of nonhereditary CRC or adenomas were identified and discussed by the participants, aided by evidence derived from review of the literature on CRC screening. Specifically, the processes focused on 5 principal questions.
# Sources, Literature Searches, and Systematic Reviews
Evidence for these consensus guidelines was gathered via multiple parallel SR streams. The SRs were informed by a series of 10 literature searches. The scope, search strategy, and yield of each literature search are shown in Supplementary Table 1. All SRs (and the corresponding metaanalyses, where applicable) were performed by the 2 GRADE methodologists (GL and FT), with one exception, an SR of prospective studies on the risk of CRC among individuals with an FH of CRC/adenoma vs those without, which was led by Ahmed M. Abou-Setta, with the data being independently confirmed by the GRADE methodologists. All searches, data extractions, and analyses were performed by 1 investigator and double-checked by a second investigator, with any disagreements resolved by consensus. Most of the literature searches supported more than 1 of the SRs, and most SRs depended on 2 or more literature searches. The streams of evidence and the research questions they addressed are briefly summarized in Table 4. The results of the SRs (along with the assessments of the QoE) were forwarded to the Consensus Group members 1 week before the face-to-face meeting.
All analyses were performed using the Cochrane Collaboration's Review Manager (RevMan).
# Assessment of the Quality of Evidence
The GRADE approach 25 was used by 2 nonvoting methodologists (GL, FT) to assess the following: risk of bias (of individual studies and overall, across studies), indirectness, inconsistency, imprecision, and other aspects (including publication bias) in order to determine the overall quality (trustworthiness) of evidence for each statement. As is described in GRADE 25,26 and used in prior Canadian Association of Gastroenterology (CAG) consensus documents, the descriptors of high, moderate, low, or very low were used to grade the QoE for each statement. One week before the face-to-face meeting, the voting members of the CRC Consensus Group had access to the GRADE assessments (including evidence profiles, the results of the SRs and meta-analyses conducted for this guideline,
# Consensus Process
The Consensus Group included 8 voting members: the meeting chair (DL), and 6 other gastroenterologists and clinical epidemiologists, as well as a family physician. The voting group included 2 participants from the United States (NJS, DAL). Nonvoting members included the moderator (JKM) and 2 GRADE methodologists (GIL, FT), 1 of whom acted as a co-moderator (GIL). The meeting was observed by members of the CAG and the Canadian Partnership Against Cancer. A patient advocate provided valuable insight during the initial guideline development.
A web-based platform (ECD solutions, Atlanta, GA) was used by the CAG to facilitate the consensus process before the 2-day face-to-face meeting held in Banff, Alberta, Canada in March 2017. Voting members used the platform to answer the principal questions to be addressed during the meeting and provided valuable comments, feedback, and suggested sources of evidence. All participants had access to the results of literature searches and relevant references.
At the meeting, the GRADE methodologists presented the data and provided the group with a review of the GRADE evaluations leading to the QoE determination for each of the questions. A modification of the Evidence-to-Decision (EtD) framework was applied to facilitate ranking of multiple screening methods for each specific population. The EtD framework is a formalized approach that enables a structured and transparent discussion on 12 criteria (is the problem a priority; how substantial are the desirable anticipated effects; how substantial are the undesirable anticipated effects; what is the overall certainty of the evidence on effects; is there important uncertainty about or variability in how much individuals value the main outcomes; do the desirable effects outweigh the undesirable effects; how large are the resource requirements; what is the certainty of evidence for the resource requirements; are the net benefits worth the incremental cost; what would be the impact on health equity; is the intervention/ option acceptable to key stakeholders; and is the intervention feasible to implement). 31 Recommendation statements were developed that were subsequently voted on anonymously via touchpads. If 75% of participants voted 4 (agree) or 5 Table 3.National Comprehensive Cancer Network Criteria for Further Genetic Risk Evaluation 4 Criteria Individuals meeting the revised Bethesda Guidelines Individuals with a family history that meets Amsterdam Criteria Individuals with colorectal (or endometrial) cancer with microsatellite instability or immunohistochemistry consistent with Lynch syndrome Individuals with papillary thyroid cancer that is the cribriform-morular variant, or hepatoblastoma Individuals with a diagnosis of CRC and >10 colorectal adenomas Individuals with a personal history of 20 adenomas Individuals with multiple gastrointestinal hamartomatous polyps or serrated polyposis syndrome Individuals from a family with a known hereditary syndrome associated with CRC with or without a known mutation Individuals with a desmoid tumor, multifocal or bilateral CHRPE CHRPE, congenital hypertrophy of retinal pigment epithelium. (strongly agree) on a scale of 1 to 5 (with 1, 2, and 3 indicating disagree strongly, disagree, and uncertain, respectively), a statement was then accepted. Once accepted, the "strength" of the recommendation (strong vs conditional) was determined based on 4 components: (1) QoE, (2) benefit-to-harm balance, (3) patients' values/preferences, and (4) resource requirements. 32 When the QoE was low or very low, unless at least 1 of the other 3 factors was overwhelmingly strong, the strength of the recommendation would typically default (without a vote) to "conditional," using the phrasing, "we suggest." If the QoE was moderate or high, the statement's strength was determined by an anonymous vote; if 75% of participants voted "strong, then the recommendation would be designated as "strong" and the phrasing was "we recommend."
The GRADE approach notes that a conditional recommendation should prompt clinicians to ". . . recognize that different choices will be appropriate for different patients and that they must help each patient to arrive at a management decision consistent with her or his values and preferences," whereas a strong recommendation is indicative of a more broadly applicable statement ("most patients should receive the recommended course of action"). 32 In accordance with CAG policy, written disclosures of any potential conflicts of interest for the 24 months before the consensus meeting were provided by all participants, reviewed by the CAG ethics committee, and made available to all group members.
# Canadian Association of Gastroenterology Approval and American Gastroenterological Association Endorsement
The chair (DL) and 1 of the GRADE methodologists (GL) initially drafted the manuscript, which was then reviewed and revised by the remaining members of the Consensus Group, both individually and jointly during a teleconference. The manuscript was then made available to all CAG members for comments for a 2-week period before submission for publication, as per CAG policy for all clinical practice guidelines.
Finally, the recommendations were reviewed, commented on, and endorsed by the American Gastroenterological Association.
# Role of the Funding Sources | Colorectal cancer (CRC) is the second leading cause of cancer deaths in Canada and the United States. A positive family history (FH) significantly increases the risk of developing CRC, and screening programs can substantially reduce CRC incidence and mortality. These consensus recommendations were developed by the Canadian Association of Gastroenterology (CAG), with US and Canadian experts, and endorsed by the American Gastroenterological Association. The purpose was to systematically and critically review the literature and provide specific recommendations See editorial on page 1298.#
BACKGROUND & AIMS: A family history (FH) of colorectal cancer (CRC) increases the risk of developing CRC. These consensus recommendations developed by the Canadian Association of Gastroenterology and endorsed by the American Gastroenterological Association, aim to provide guidance on screening these high-risk individuals. METHODS: Multiple parallel systematic review streams, informed by 10 literature searches, assembled evidence on 5 principal questions around the effect of an FH of CRC or adenomas on the risk of CRC, the age to initiate screening, and the optimal tests and testing intervals. The GRADE (Grading of Recommendation Assessment, Development and Evaluation) approach was used to develop the recommendations. RESULTS: Based on the evidence, the Consensus Group was able to strongly recommend CRC screening for all individuals with an FH of CRC or documented adenoma. However, because most of the evidence was very-low quality, the majority of the remaining statements were conditional ("we suggest"). Colonoscopy is suggested (recommended in individuals with 2 first-degree relatives [FDRs]), with fecal immunochemical test as an alternative. The elevated risk associated with an FH of 1 FDRs with CRC or documented advanced adenoma suggests initiating screening at a younger age (eg, 40-50 years or 10 years younger than age of diagnosis of FDR). In addition, a shorter interval of every 5 years between screening tests was suggested for individuals with 2 FDRs, and every 5-10 years for those with FH of 1 FDR with CRC or documented advanced adenoma compared to average-risk individuals. Choosing screening parameters for an individual patient should consider the age of the affected FDR and local resources. It is suggested that individuals with an FH of 1 second-degree relatives only, or of nonadvanced adenoma or polyp of unknown histology, be screened according to averagerisk guidelines. CONCLUSIONS: The increased risk of CRC associated with an FH of CRC or advanced adenoma warrants more intense screening for CRC. Well-designed prospective studies are needed in order to make definitive evidence-based recommendations about the age to commence screening and appropriate interval between screening tests.
for CRC screening of individuals with an FH of nonhereditary CRC or adenoma. This is the first guideline to use systematic reviews and the GRADE (Grading of Recommendation Assessment, Development and Evaluation) approach to make recommendations for screening for CRC in this high-risk population. Multiple parallel systematic review streams, informed by 10 literature searches, assembled evidence on 5 principal questions: (1) effect of an FH of CRC on an individual's risk of CRC, (2) effect of an FH of adenoma on an individual's risk of CRC, (3) age at which screening should begin, (4) optimal screening tests, and (5) optimal testing intervals for individuals with an FH of CRC or adenoma. The GRADE approach was used to assess the quality of evidence. Questions were developed through an iterative online platform, and then statements were developed and voted on by a group of specialists.
Consensus was reached on 19 statements addressing 5 main patient risk categories, including individuals with 2 or more first-degree relative (FDRs) with CRC, 1 FDR with CRC, 1 or more FDRs with advanced adenoma, 1 or more seconddegree relatives (SDRs) with CRC, and 1 or more FDR with any non-advanced adenoma (Table 1).
Because of the lack of high-quality data, the majority of statements are conditional recommendations ("we suggest"). However, based on moderate-quality evidence, the Consensus Group is able to strongly recommend CRC screening over no screening for all individuals with an FH of CRC or documented adenoma. In addition, despite very-lowquality evidence, colonoscopy is recommended in individuals with 2 or more FDRs with CRC, because of the high-risk of life-threatening negative consequences of missed lesions.
Based on available data and consensus, Table 2 provides a concise summary of the preferred and secondchoice screening tests, the age at which screening should begin, and the interval for screening according to the level of elevated CRC risk for each patient subgroup. For individual at highest risk (2 or more FDRs with a history of CRC), we recommend screening with colonoscopy, which we suggest begin at age 40-50 years or 10 years younger than the age of diagnosis of the FDR (whichever is earlier), at an interval of every 5 years. For individuals with 1 FDR with a history of CRC or advanced adenoma, we suggest commencing CRC screening at age 40-50 years or 10 years younger than the age of diagnosis of the FDR (whichever is earlier), at an interval of every 5-10 years. For those with an FH of CRC, colonoscopy is suggested with fecal immunochemical test (FIT) as an alternative, while both tests are suggested options for those with an FH of advanced adenoma. Finally, it is suggested that individuals with an FH of 1 or more SDRs only, or of nonadvanced adenoma or polyp of unknown histology be screened according to average-risk guidelines.
Except for the statements for those at the highest risk, age ranges are provided. The relationship between the age at which an affected FDR was diagnosed with CRC and an individual's risk of developing CRC is difficult to define. The evidence shows that the risk falls on a continuum, and that there is no clearly defined age above or below which a clear inflection in risk can be recognized. The Consensus Group carefully considered the issue of recommending a range of years, acknowledging that some clinicians and programs may wish for greater precision. However, the evidence in cases where a range was recommended does not support a specific age point. Definitive statements in these circumstances are misleading and imply a degree of certainty that does not currently exist. Furthermore, specifying a range allows some flexibility, including consideration of the age of the affected FDR and local resources, and underscores the need for further data, which will hopefully lead to greater clarity in the future.
The Consensus Group acknowledged that heritable cancers tend to occur at an earlier age and that this heritable risk decreases with advancing age of the diagnosis of the CRC in the FDR. That being the case, the age of the affected relative should be considered when making clinical decisions regarding screening. For example, having an FDR diagnosed at 75-90 years of age is unlikely to seriously impact an individual's risk of CRC, while an FDR diagnosed at age 35 years is probably highly relevant. Therefore, we acknowledge that national or provincial programs may wish to set specific FDR age cutoffs for screening, based on additional factors, including feasibility, cost, and cost-effectiveness. From an evidence perspective, we are, unfortunately, not able to provide clear guidance at this time. Future research should prioritize prospective studies that assess the optimal time to initiate screening and appropriate intervals between screening tests.
# Introduction
Colorectal cancer (CRC) is the second leading cause of cancer in Canada, and the fourth leading cause in the United States. 1,2 It is the second leading cause of cancer deaths in both countries, with approximately 9400 Canadians, and 50,260 Americans dying of the disease annually. The 2017 estimated incidence of new cases CRC was 26,800 Canadians, and 135,430 Americans, and the prevalence of individuals living with CRC was 105,195 Canadians (2009) and 1.3 million Americans (2014). 1,2 A systematic review (SR) estimated the prevalence of an individual having 1 or more first-degree relatives (FDRs) with CRC to be 3%-10%, and of having 2 or more FDRs with CRC to be about 0.3%. 3 Many of these individuals with a positive family history (FH) are at an increased risk of developing CRC. However, the magnitude of the individual's increased risk appears to be dependent on the degree of relationship to the affected relative, age of the affected relative at time of diagnosis, and the age of the individual. Overall CRC burden in a family (ie, total number of individuals with CRC on the same side of the family) also increases the magnitude of the individual's CRC risk. This may be a red flag for an inherited CRC syndrome. 4 CRC usually develops from premalignant polyps, and CRC screening can be used to detect and remove these polyps or localized cancer. Evidence from studies conducted in individuals primarily at "average risk" for CRC shows that screening (with endoscopy or occult blood tests) can reduce CRC mortality and incidence. [5][6][7] Guidelines and the introduction of population-based screening programs have led to substantially increased uptake of CRC screening. Rates in the United States and Canada were about 25%-35% before 2003, but have increased to 55%-60% in 2012-2013 surveys. 8,9 Individuals with an FH of CRC are more likely to adhere to CRC screening recommendations compared to those with no FH. 3 But even among this higher-risk population, participation rates remain less than optimal. 3,[10][11][12] While a variety of guidelines for screening individuals for CRC are available, the majority apply to patients at average risk, [13][14][15][16][17][18][19][20][21][22] or those at highest risk due to inherited germline mutations associated with CRC and polyposis. 4,23,24 The few guidelines that make detailed recommendations for screening individuals with an FH of CRC or adenoma have not systematically reviewed the literature in this specific population. 17,19,20 Recent guidelines from the US Multi-Society Task Force on CRC screening used a modified process to systematically review published literature on this topic, however, systematic assessments of the methodological quality of the individual studies were not presented, and the paper was published after our consensus meeting. 22 For this guideline, systematic literature searches were conducted and the quality of evidence (QoE) and strength of recommendations were rated using the Grading of Recommendation Assessment, Development, and Evaluation (GRADE) approach. 25 This guideline specifically excludes individuals with hereditary syndromes, such as Lynch syndrome, familial adenomatous polyposis, attenuated familial adenomatous polyposis, MUTYH-associated polyposis, Peutz-Jeghers syndrome, juvenile polyposis syndrome, Cowden syndrome, serrated (hyperplastic) polyposis syndrome, hereditary pancreatic cancer, and hereditary gastric cancer. However, hereditary CRCs occurring due to mutations and defects in certain genes account for about 5% of all CRC. 4 Given the substantial risk of CRC and extracolonic cancers warranting specific screening strategies, it is important to identify these patients with hereditary syndromes. The National Comprehensive Cancer Network proposed 9 recommendations (summarized in Table 3) for patients who should be referred to a genetics provider for further assessment of a hereditary cancer syndrome. In addition, many jurisdictions and hospitals have implemented universal screening programs for CRC and endometrial cancers that include microsatellite instability or immunohistochemistry to identify patients at risk of Lynch syndrome. These individuals should be managed according to appropriate guidelines for individuals with hereditary gastrointestinal cancer syndromes. 4,23,24 The purpose of this guideline was to systematically and critically review the literature and provide specific recommendations for CRC screening of individuals with an FH of nonhereditary CRC or adenoma.
# Methods
# Scope and Purpose
Questions around screening for CRC in individuals with an FH of nonhereditary CRC or adenomas were identified and discussed by the participants, aided by evidence derived from review of the literature on CRC screening. Specifically, the processes focused on 5 principal questions.
# Sources, Literature Searches, and Systematic Reviews
Evidence for these consensus guidelines was gathered via multiple parallel SR streams. The SRs were informed by a series of 10 literature searches. The scope, search strategy, and yield of each literature search are shown in Supplementary Table 1. All SRs (and the corresponding metaanalyses, where applicable) were performed by the 2 GRADE methodologists (GL and FT), with one exception, an SR of prospective studies on the risk of CRC among individuals with an FH of CRC/adenoma vs those without, which was led by Ahmed M. Abou-Setta, with the data being independently confirmed by the GRADE methodologists. All searches, data extractions, and analyses were performed by 1 investigator and double-checked by a second investigator, with any disagreements resolved by consensus. Most of the literature searches supported more than 1 of the SRs, and most SRs depended on 2 or more literature searches. The streams of evidence and the research questions they addressed are briefly summarized in Table 4. The results of the SRs (along with the assessments of the QoE) were forwarded to the Consensus Group members 1 week before the face-to-face meeting.
All analyses were performed using the Cochrane Collaboration's Review Manager (RevMan).
# Assessment of the Quality of Evidence
The GRADE approach 25 was used by 2 nonvoting methodologists (GL, FT) to assess the following: risk of bias (of individual studies and overall, across studies), indirectness, inconsistency, imprecision, and other aspects (including publication bias) in order to determine the overall quality (trustworthiness) of evidence for each statement. As is described in GRADE 25,26 and used in prior Canadian Association of Gastroenterology (CAG) consensus documents, [27][28][29][30] the descriptors of high, moderate, low, or very low were used to grade the QoE for each statement. One week before the face-to-face meeting, the voting members of the CRC Consensus Group had access to the GRADE assessments (including evidence profiles, the results of the SRs and meta-analyses conducted for this guideline,
# Consensus Process
The Consensus Group included 8 voting members: the meeting chair (DL), and 6 other gastroenterologists and clinical epidemiologists, as well as a family physician. The voting group included 2 participants from the United States (NJS, DAL). Nonvoting members included the moderator (JKM) and 2 GRADE methodologists (GIL, FT), 1 of whom acted as a co-moderator (GIL). The meeting was observed by members of the CAG and the Canadian Partnership Against Cancer. A patient advocate provided valuable insight during the initial guideline development.
A web-based platform (ECD solutions, Atlanta, GA) was used by the CAG to facilitate the consensus process before the 2-day face-to-face meeting held in Banff, Alberta, Canada in March 2017. Voting members used the platform to answer the principal questions to be addressed during the meeting and provided valuable comments, feedback, and suggested sources of evidence. All participants had access to the results of literature searches and relevant references.
At the meeting, the GRADE methodologists presented the data and provided the group with a review of the GRADE evaluations leading to the QoE determination for each of the questions. A modification of the Evidence-to-Decision (EtD) framework was applied to facilitate ranking of multiple screening methods for each specific population. The EtD framework is a formalized approach that enables a structured and transparent discussion on 12 criteria (is the problem a priority; how substantial are the desirable anticipated effects; how substantial are the undesirable anticipated effects; what is the overall certainty of the evidence on effects; is there important uncertainty about or variability in how much individuals value the main outcomes; do the desirable effects outweigh the undesirable effects; how large are the resource requirements; what is the certainty of evidence for the resource requirements; are the net benefits worth the incremental cost; what would be the impact on health equity; is the intervention/ option acceptable to key stakeholders; and is the intervention feasible to implement). 31 Recommendation statements were developed that were subsequently voted on anonymously via touchpads. If 75% of participants voted 4 (agree) or 5 Table 3.National Comprehensive Cancer Network Criteria for Further Genetic Risk Evaluation 4 Criteria Individuals meeting the revised Bethesda Guidelines Individuals with a family history that meets Amsterdam Criteria Individuals with colorectal (or endometrial) cancer with microsatellite instability or immunohistochemistry consistent with Lynch syndrome Individuals with papillary thyroid cancer that is the cribriform-morular variant, or hepatoblastoma Individuals with a diagnosis of CRC and >10 colorectal adenomas Individuals with a personal history of 20 adenomas Individuals with multiple gastrointestinal hamartomatous polyps or serrated polyposis syndrome Individuals from a family with a known hereditary syndrome associated with CRC with or without a known mutation Individuals with a desmoid tumor, multifocal or bilateral CHRPE CHRPE, congenital hypertrophy of retinal pigment epithelium. (strongly agree) on a scale of 1 to 5 (with 1, 2, and 3 indicating disagree strongly, disagree, and uncertain, respectively), a statement was then accepted. Once accepted, the "strength" of the recommendation (strong vs conditional) was determined based on 4 components: (1) QoE, (2) benefit-to-harm balance, (3) patients' values/preferences, and (4) resource requirements. 32 When the QoE was low or very low, unless at least 1 of the other 3 factors was overwhelmingly strong, the strength of the recommendation would typically default (without a vote) to "conditional," using the phrasing, "we suggest." If the QoE was moderate or high, the statement's strength was determined by an anonymous vote; if 75% of participants voted "strong, then the recommendation would be designated as "strong" and the phrasing was "we recommend."
The GRADE approach notes that a conditional recommendation should prompt clinicians to ". . . recognize that different choices will be appropriate for different patients and that they must help each patient to arrive at a management decision consistent with her or his values and preferences," whereas a strong recommendation is indicative of a more broadly applicable statement ("most patients should receive the recommended course of action"). 32 In accordance with CAG policy, written disclosures of any potential conflicts of interest for the 24 months before the consensus meeting were provided by all participants, reviewed by the CAG ethics committee, and made available to all group members.
# Canadian Association of Gastroenterology Approval and American Gastroenterological Association Endorsement
The chair (DL) and 1 of the GRADE methodologists (GL) initially drafted the manuscript, which was then reviewed and revised by the remaining members of the Consensus Group, both individually and jointly during a teleconference. The manuscript was then made available to all CAG members for comments for a 2-week period before submission for publication, as per CAG policy for all clinical practice guidelines.
Finally, the recommendations were reviewed, commented on, and endorsed by the American Gastroenterological Association.
# Role of the Funding Sources
Funding for the consensus meeting was provided by an unrestricted, arms-length grant to the CAG by the Canadian Partnership Against Cancer. The CAG administered all aspects of the meeting. A member of the Canadian Partnership Against Cancer observed the meeting, but the organization had no involvement in developing the statements, conducting the SRs, drafting the manuscript, or approving this guideline.
# Principal Questions
Q1. For an individual, what is the effect of an FH of CRC (including the number and family connection of affected relatives, for example, 1 FDR, ‡2 FDRs, ‡1 SDRs) on his/her own risk of CRC?
Evidence regarding this principal question was gathered via 4 streams (presented in detail in Supplementary Table 2 and summarized in Figure 1): a new SR&MA of prospective studies (eligible prospective studies from previous SRs were included); an SR of published SRs (of prospective or retrospective studies); an assessment of studies on the risk of CRC among twins; and a new SR of retrospective studies (eligible retrospective studies from previous SRs were included). All studies reported relative risk (RR) of CRC (individuals with vs without FH of CRC) with a highly variable timeframe for risk reporting among studies; absolute risks (eg, 10-year risk or life-time risk) were not reported.
An SR&MA of prospective studies assessing the effect of FH on the RR of CRC (and adenomas) conducted specifically for this guideline found that the risk of CRC was significantly elevated in individuals with 1 or more FDRs with CRC (13 studies; RR, 1.31; 95% confidence interval [CI], 1.11-1.55). The risk was elevated among those with 1 or more SDRs with CRC (3 studies; RR, 6.11; 95% CI, 0.38-98.00) compared to those without FH, but this was not significant. The quality of the evidence was very low (observational data with high risk of bias with/without serious imprecision). The results of this SR are presented in detail in Supplementary Table 2.
Our SR of SRs included 4 SR&MAs [33][34][35][36] and 1 SR (without meta-analysis). 37 The data consistently show that individuals with 1 or more FDRs diagnosed with CRC have an approximately 2-fold increased risk of developing CRC compared to those without an FH of CRC.
Additional evidence of the risk associated with an FH comes from a study of twins. 38 The Nordic Twin Study, including more than 100,000 twins and more than 3000 CRCs, reported familial RRs of CRC among co-twins of 3.1 (95% CI, 2.4-3.8) for monozygotic twins and 2.2 (95% CI, 1.7-2.7) for dizygotic twins relative to the cohort risk. Given the shared DNA profile, and potentially high rates of shared environmental factors, the RR for dizygotic twins likely represents the upper plausible limit of the RR of CRC in individuals with 1 FDR with CRC.
Modeling studies suggest that results of observational studies are unlikely to be explained by confounding alone when the RR is >2, and very unlikely when the RR is >5. 39 Therefore, taking the data altogether, the Consensus Group agreed that an RR of 2 or more was a reasonable cutoff point to define a clinically significant increased risk of CRC, and that an individual with an FH of 1 FDR with CRC was likely at a 2-fold higher risk of CRC compared to those without (Figure 1).
In addition, an individual's CRC risk increases with an increasing number of affected FDRs. 37 In 1 SR&MA, the pooled RR of developing CRC was 2.24 (95% CI, 2.06-2.43) among those with 1 or more FDRs with a history of CRC, and increased to 3.97 (95% CI, 2.60-6.06) for those with 2 or more FDRs. 35 The large, retrospective, population-registry cohort study by Taylor et al 40 reported an increased risk of CRC among individuals with an FH of 2 FDRs with CRC (RR, 3.01; 95% CI, 2.66-3.38). 40 We conducted a pooled analysis of 4 subgroups (2, 3, 4, 5 FDRs) included in that study and found an even greater risk of CRC among those with 2 or more FDRs with a history of CRC (RR, 5.77; 95% CI, 3.3-10.1). The Consensus Group concluded that the risk of CRC increased with an increasing number of FDRs with CRC.
The degree of the relationship also impacts the risk of CRC, with the elevated risk being driven largely by the presence of 1 or more FDRs, rather than 1 or more SDRs. An SR&MA has reported a more modest elevated risk of CRC among individuals with 1 or more SDRs with a history of CRC (RR, 1.73; 95% CI, 1.02-2.94). 35 In addition, an SR&MA of large retrospective database studies that we conducted for this guideline included 3 studies (Samadder et al, 41 Taylor et al, 40 and Andrieu et al 42 ) and revealed that the RR associated with 1 or more SDRs with a history of CRC was 1.37 (95% CI, 1.24-1.51). However, because the studies included in both of these meta-analyses did not control for the presence of an FDR with CRC, an important confounder, we conducted a sensitivity analysis of the data reported in Taylor et al 40 and found that the RR associated with 1 or more SDRs and no affected FDRs was 1.18 (95% CI, 1.00-1.38), while the RR among those with 1 or more SDRs and an affected FDR was significantly higher (P ¼ .03 for subgroup differences) at 2.37 (95% CI, 1.92-2.92). These results suggest that the apparent increase in risk of CRC in individuals with an affected SDR, and the apparent additive risk associated with multiple affected SDRs are probably driven by concomitant FDRs with CRC. Therefore, the Consensus Group concluded that individuals whose FH includes only SDRs with CRC can be regarded as average-risk individuals; if they have an increased risk for CRC this would be too small to be clinically relevant. However, the Consensus Group stressed the need to take a thorough family history and the use of clinical judgment in this population. Germline genetic testing should be considered in those with a high burden of CRC among relatives. 4 Q2. For an individual, what is the effect of an FH of adenoma (including advanced and nonadvanced adenoma) on his/her own risk of CRC or adenoma?
Data from average-risk individuals suggest that small adenomas are generally not malignant, but that malignant potential increases with increasing adenoma size (see Question 5). 43,44 Histology and number of adenomas also affect the risk of developing CRC. [44][45][46][47] In North American adults older than 50 years of age, the overall prevalence of adenomas has been estimated to be 20%-30%, with the prevalence increasing with increasing age. 48,49 In contrast, the prevalence of advanced adenomas is much lower, at about 6%-7%. 48,49 Advanced adenomas have generally been defined as adenomas that exhibit any of the following: size 10 mm, or high-grade dysplasia, or villous/tubulovillous histology, 45,47,50,51 but, the definition can differ between countries, or even between provinces within a country. While the presence of multiple polyps also affects the risk of CRC and adenoma, we did not examine the relationship between FH, the number of adenomas, and the risk of CRC. Evidence for an increased risk of CRC in individuals with an FH of adenoma is very limited (summarized in Table 5). Most studies have assessed whether individuals with an FDR with CRC have a higher risk of adenoma, not whether individuals with an FDR with an adenoma have a higher risk for CRC. 33,52 One SR of studies through 2011 52 found only 2 studies 53,54 specifically addressing the latter question. However, both studies are confounded by inclusion of individuals with an FH of CRC, which may be responsible for some or all of the elevated risk of CRC when an FDR is diagnosed with adenoma. In a Japanese study, the RR of CRC in individuals who had an FDR with adenomas was 4.36 (95% CI, 1.6-10.21). 53 In the other study (from France), there was an increased risk for the combined outcome of CRC or advanced adenoma (odds ratio [OR], 2.27; 95% CI, 1.01-5.09), but not for CRC alone (OR, 3.90; 95% CI, 0.89-17.01). 54 When individuals with an FDR with CRC were excluded, the ORs were no longer significant for the combined outcome of CRC or advanced adenoma (OR, 2.09; 95% CI, 0.86-5.13) or the other outcomes; however, sample sizes were small.
A large cohort study found a 35% increase in the risk of CRC in the FDRs of individuals with adenomas (RR, 1.35; 95% CI, 1.25-1.46) and an almost 70% increase in risk of CRC in the FDRs of individuals with advanced adenomas (RR, 1.68; 95% CI, 1.29-2.18). 55 The risks of developing similar adenomas in FDRs of individuals with adenoma and advanced adenoma were also elevated (RR, 1.33; 95% CI, 1.26-1.40; and RR, 1.65; 95% CI, 1.28-2.14, respectively). However, similar to other studies, this analysis did not control for an FH of CRC. 55 Additional evidence shows that FH of advanced adenomas is associated with increased risk of developing advanced adenomas, from a study that did exclude individuals with an FH of CRC or hereditary CRC. 50 Siblings of individuals with at least 1 advanced adenoma had 6fold (OR, 6.05; 95% CI, 2.74-13.36) increased odds of advanced adenoma and 3-fold (OR, 3.29; 2.16-5.03) increased odds of any adenoma compared with individuals whose sibling did not have adenomas. The elevated risks were higher in individuals with an FDR diagnosed with the advanced adenoma at aged <60 years, but was also elevated in individuals with an FDR diagnosed at >60 years.
Over time, an FH of adenomas will become increasingly important in populations that have established effective CRC screening programs. When screening modalities that reduce the incidence of CRC are used, there will be significantly fewer diagnoses of CRC and more diagnoses of adenomas (some of which would have progressed to cancers had they not been resected as adenomas). In more recent and in future studies, the elevated risk of CRC in individuals with an FH of advanced adenoma may actually reflect the elevated risk associated with an FH of CRC observed in older studies that predate the increasing use of screening programs.
Because of the high prevalence of adenomas, having an FH of adenomas affects more individuals than having an FH of CRC. Although there are limited data available, individuals with an FH of an advanced adenoma appear to be at increased risk of CRC, regardless of the age at diagnosis of the relative. In clinical practice, given that individuals cannot reliably recall histologic information regarding their own polyps, 56 we recognize many will not be able to describe the polyps of a relative. However, because the evidence is for advanced adenomas, the Consensus Group agreed that the recommendations for high-risk screening of individuals with an FH of advanced adenoma should be restricted to those with an FH of "documented advanced adenoma." Clinicians should also inquire about an FH of multiple polyps, and consider the possibility of a polyposis phenotype, especially in individuals with a high polyp burden. There is no evidence that individuals with an FH of Impact of the Age of the Affected Relative
Our SR&MA of prospective studies found only 1 eligible study with extractable data that assessed the effect of the age at which the FDR was diagnosed with CRC. 57 Compared to individuals without an FH, the adjusted hazard ratio (HR) for CRC in individuals with an FDR diagnosed with CRC at age 60 years was 1.46 (95% CI, 1.17-1.81), which was not significantly different from the adjusted HR for those with FDR diagnosed at age >60 years (HR, 1.25; 95% CI, 1.07-1.45; pooled estimate from 2 age subgroups).
Evidence from retrospective studies was available from a well-conducted SR&MA, which included 3 retrospective cohort studies and 1 cross-sectional study, and reported RRs for CRC (individuals with affected FDRs vs those without FH) stratified by age of the affected FDR (withinstudy comparisons). 35 The RR for CRC for individuals with FDR diagnosed at age <50 years was 3.55 (95% CI, 1.84-6.83); this was numerically, but not significantly, higher than the RR in individuals with FDR diagnosed at age 50 years (2.18; 95% CI, 1.56-3.04).
Since the publication of the SR&MA mentioned, 3 large database studies have been published (Andrieu et al, 42 Samadder et al, 41 and Taylor et al, 2010 40 ) with a possible small overlap among the populations of the latter 2 studies. We pooled these 3 studies and found that the RR (compared to individuals without FH of CRC) was 2.35 (95% CI, 1.92-2.86) for individuals with an FDR diagnosed at <60 years and 1.79 (95% CI, 1.58-2.03) for individuals with an FDR diagnosed at 60 years (P ¼ .02 for subgroup difference). The RR was large enough to be considered clinically important for individuals with an FDR diagnosed at younger ages, and was statistically significant in both subgroups.
The most recent of the large database studies reported detailed results on the HR for CRC according to the age of the affected FDR, and found that the HR decreased as the age at diagnosis of the FDR increased, but remained elevated among all individuals with an FDR of any age compared to those with no FH. HR point estimates ranged from 1.69 to 2.53, but the 95% CIs were widely overlapping among all FDR age groups (10-year intervals from <40 to 80 years). 41 The Consensus Group agreed that the bulk of the evidence supports a continuum for increased RR based on the age of the CRC diagnosis for the FDR, and that a cutoff of age 50 years or 60 years is rather arbitrary. The age of the affected relative should be considered when making clinical decisions regarding screening.
# Impact of the Age of the Individual
Data assessing the age of the individual to be screened for CRC have clearly shown that the risk of CRC increases with age in both the average-risk and high-risk populations. 58 In the prospective study by Fuchs et al, 58 the cumulative incidence curves for CRC for individuals with and without an FH were parallel, with the individuals with an FH being at higher risk in all age groups. In fact, the CRC risk for an individual at age 40 years who had an FH was similar to the risk at age 50 years for an individual without an FH. 58 Similarly, in the Nordic Twin Study, the risk of CRC for the co-twin of an affected twin was elevated at every age compared to the risk in the control twin population. 38 There are few prospective data assessing the effectiveness of initiating a screening program in individuals of different ages. Three SRs [59][60][61] have summarized retrospective data on the effectiveness of screening programs according to age of the screened individuals among averagerisk individuals. These analyses suggest that guaiac fecal occult blood test (gFOBT) or flexible sigmoidoscopy (FS) screening programs can reduce the rate of CRC mortality both in individuals who are 60 years and those <60 years, but did not demonstrate significant differences in RR reductions between the age groups. In 1 large database study from Utah, the risk of CRC in individuals with 1 affected FDR was 2.28 (95% CI, 1.86-2.80) among those age <50 years, and 1.81 (95% CI, 1.71-1.92) among those 50 years, with no statistically significant difference among the 2 subgroups. 41 The Consensus Group agreed that the bulk of the evidence supports an elevated risk of CRC for all individuals with an FH, and screening programs are likely effective in all age subgroups. However, consideration of cost and the need to prioritize resource use should be included in screening decisions. Younger individuals have lower absolute rates of CRC, 58 and screening in this population has a lower diagnostic yield, 62,63 but the potentially larger benefit in qualityadjusted life years saved for a younger individual vs an older one should also be considered.
In the Utah study, the highest RR for CRC was found in younger individuals (age <50 years) who had an FDR with early-onset CRC (age <40 years) (HR, 7.0; 95% CI, 2.86-17.09) compared to individuals aged <50 years without FH of CRC. 41 Initiating screening at age 40 years (or 10 years younger than the age of diagnosis of the FDR) among individuals with an FH of CRC has been associated with a low CRC miss rate of only 3%. 64
# Impact of Age in Individuals With a Family History of Adenoma
No studies were found that assessed the age-specific risk of CRC, or the effectiveness of initiating screening programs at different starting ages in individuals with an FH of adenoma (or advanced adenoma).
# Summary
Therefore, the Consensus Group agreed that the clinical decision to initiate early screening should consider both the age of the individual and the age of the affected relative, while being aware that the age-specific risk of CRC falls on a continuum and is elevated at all ages compared to those with no FH. No randomized controlled trials (RCTs) or large observational studies were found that assessed the comparative efficacy of screening tests in individuals with an FH of CRC or adenomas, with the exception of 1 RCT 65 comparing FIT and colonoscopy. Therefore, evidence was largely extrapolated from studies in individuals at average risk or unselected populations. In general, the quality of evidence was not downgraded for indirectness of population because substantial differences in the direction of effects were not expected in individuals with FH of CRC, if it is assumed that the pathophysiology and natural history of CRC is the same in familial and sporadic cancers. If the only difference between these populations is the higher underlying risk of CRC in individuals with FH, testing strategies would be expected to have the same RRs, but larger absolute benefits with regard to CRC/adenoma detection rates and also larger absolute numbers of complications in populations with an FH compared to those at average risk. The participation rate and cost-effectiveness of a given strategy may not necessarily be the same as in average-risk populations and, in fact, evidence suggests that the importance of these considerations may be amplified in populations with FH of CRC.
The 4 main testing strategies that were considered were colonoscopy, FS, gFOBT, and FIT. The Consensus Group agreed that the most relevant outcomes were all-cause and CRC mortality, and (long-term) incidence of CRC. The evidence for the 4 testing options is summarized here and a detailed description of the quality of evidence profiles is included in Supplementary Table 3 (CRC screening strategies for individuals with FH of CRC or adenoma) and a summary in Supplementary Table 4 (summary of GRADE evidence profiles for CRC screening).
# Colonoscopy
No relevant studies were found assessing the efficacy of screening with colonoscopy vs no screening specifically in individuals with an FH of CRC or adenoma; therefore, evidence was extrapolated from studies in average-risk populations. An SR&MA of 6 large, observational trials found a significant reduction in the risk of CRC incidence (reported by 5 studies; RR, 0.31; 95% CI, 0.12-0.77) and, most importantly, a significant reduction in CRC mortality (reported by 3 studies; RR, 0.32; 95% CI, 0.23-0.43) with colonoscopy vs no screening. 5 One subsequently published large cohort study showed even stronger benefits for colonoscopy vs no screening, with a standardized mortality ratio of 0.11 (95% CI, 0.03-0.26), and a standardized incidence ratio of 0.17 (95% CI, 0.10-0.27). 6 The overall quality of evidence on the benefits of screening colonoscopy compared to no screening was very low (Supplementary Tables 3 and 4).
No studies have directly compared colonoscopy vs FS for CRC screening. However, the Consensus Group agreed that the reductions in all-cause and CRC mortality with colonoscopy for individuals with FH of CRC would be expected to be similar or greater than that seen with FS (see evidence below), because of the significant reduction in the incidence of both distal and proximal CRC with colonoscopy, but only distal CRC with FS, and the likely significantly greater reduction in mortality due to proximal CRC with colonoscopy compared to FS (RR, 0.49; 95% CI, 0.29-0.85, indirect comparison from a network meta-analysis of observational studies). 5 However, this is very-low-quality evidence, and does not consider the potentially increased risk of harms with colonoscopy over FS.
Compared to gFOBT, there was no significant difference in participation rates between colonoscopy and gFOBT in a meta-analysis of 2 RCTs in individuals at average risk. 7 Meta-analysis of studies in average-risk individuals reported that one-time FIT had lower rates of colorectal neoplasia detection (RR, 0.30; 95% CI, 0.14-0.67) and higher rates of participation compared to colonoscopy (RR, 1.50; 95% CI, 1.08-2.10). 7 The only RCT assessing screening strategies in individuals with an FH of CRC compared single colonoscopy to annual FIT for 3 years and found no significant difference in the detection of advanced neoplasia (OR, 1.41; 95% CI, 0.88-2.26). 65 However, this study was at unusually high risk of bias for allocation concealment and was seriously underpowered.
Complication rates with colonoscopy screening (perforations, bleeds, or deaths) were assessed in an SR of 15 observational studies. 60 In 9 studies that included patients with an FH of CRC, the risk of complications was <1%, with the risk of perforations ranging from 0% to 0.22% and bleeding ranging from 0% to 0.19%. 60
# Flexible Sigmoidoscopy
Three SRs comparing the use of FS vs no screening in average-risk populations 7,59,66 all pooled the same 4 RCTs. FS was associated with significant reductions in all-cause mortality (RR, 0.97; 95% CI, 0.96-0.99), CRC mortality (RR, 0.72; 95% CI, 0.65-0.80), and CRC incidence (RR, 0.78; 95% CI, 0.74-0.83) compared to no screening. 7 An SR&MA of RCTs in average-risk individuals reported that FS had significantly higher colorectal neoplasia detection rates and no significant difference in participation rates compared to one-time FIT or one-time gFOBT. 7 The rate of major complications (bleeding, perforation, or death within 30 days of screening, follow-up colonoscopy, or surgery) with screening FS was 0.08% in an SR&MA of 5 RCTs. 67
# Guaiac Fecal Occult Blood Test
Three SRs have assessed studies comparing the use of gFOBT (with colonoscopy offered for positive tests) vs no screening in average-risk populations. 7,59,66 These SRs pooled 4 RCTs with 9 to 30 years of follow-up and showed a significant reduction in CRC mortality (RR, 0.87; 95% CI, 0.82-0.92), but not in all-cause mortality (RR, 1.00; 95% CI, 0.99-1.10) or CRC incidence (RR, 0.96; 95% CI, 0.90-1.02) with gFOBT vs no screening. 7 One subsequently published RCT with only a short follow-up period (median 4.5 years) reported nonsignificant differences between gFOBT screening and no screening for all 3 of these outcomes. 68 As mentioned, gFOBT was significantly less effective for colorectal neoplasia detection than FS. 7 In a Cochrane SR&MA, no complications were reported after gFOBT itself, however, 0.03% of patients experienced major complications (bleeding, perforation, or death) within 30 days of screening, which were related to colonoscopy or surgical procedures after a positive screening test. 67
# Fecal Immunochemical Test
No studies were found assessing FIT compared to no screening, but studies have shown FIT to have superior diagnostic accuracy compared to gFOBT. An SR&MA of 6 RCTs in average-risk populations found a superior colorectal neoplasia detection rate (RR, 2.15; 95% CI, 1.58-2.94) and a higher uptake rate (RR, 1.16; 95% CI, 1.05-1.28) with FIT vs gFOBT. 7 FIT has been associated with lower rates of colorectal neoplasia detection compared to colonoscopy or FS, but higher rates of participation compared to colonoscopy in meta-analyses of studies in average-risk individuals. 7 There was only 1 RCT in individuals with an FH of CRC that compared FIT and colonoscopy, but as mentioned in the discussion regarding colonoscopy, its results are not reliable due to high risk of bias and serious imprecision. 65 A recent SR&MA, that was not available at the time of the consensus meeting, assessed the diagnostic accuracy of FIT in individuals with FH of CRC (vs colonoscopy as reference standard) and found high sensitivity (86%; 95% CI, 31%-99%) and specificity (91%; 95% CI, 89%-93%) for detection of CRC; for detection of advanced neoplasia (composite outcome of either CRC or advanced adenomas) specificity remained high (93%; 95% CI, 90%-95%), but sensitivity was disappointingly low (46%; 95% CI, 37%-56%). 69 No data on all-cause or CRC mortality with FIT were found, however, long-term follow-up of ongoing RCTs in average-risk individuals will provide more information on these outcomes. 70,71 In the interim, the Consensus Group agreed that the reduction in CRC-related mortality with FIT would be expected to be greater than that seen with gFOBT. Data assessing gFOBT can be extrapolated to FIT because FIT is a more specific and sensitive test for FOB. 51 Compared to gFOBT, FIT has higher sensitivity for the detection of neoplasia and higher adherence rates. 7 SR&MA of studies conducted mainly in individual at average risk (excluding discontinued FITs) reported high sensitivity (0.82; 95% CI, 0.73-0.89) and specificity (0.94; 95% CI, 0.92-0.95). 72 The greater adherence to screening with FIT may be the result of fewer dietary restrictions, easier sample collection, and the requirement for fewer samples compared to gFOBT. 18 Higher sensitivity will result in more positive tests requiring colonoscopy, 18 which could result in higher costs and more frequent complications than with gFOBT; however, FIT has been shown to be more costeffective than gFOBT. 73
# Patient Preferences
During the last 2 decades, guidelines recommending CRC screening for adults >50 years and the introduction of population-based screening programs have led to substantially increased uptake of CRC screening. Rates in the United States and Canada were about 25%-35% before 2003, but have increased to 55%-60% in 2012-2013 surveys. 8,9 To help maximize uptake, patient acceptability (adherence) and satisfaction are important when making recommendations for a specific screening test. Overall, individuals with an FH of CRC have been shown to be more likely to adhere to CRC screening recommendations compared to those with no FH. 3 Among individuals with an FH of 1 or more FDRs with CRC, 71%-83% had ever undergone screening (FOBT, FS, or colonoscopy), but only 46% had undergone colonoscopy within 10 years, and 41% within 5 years. 3,[10][11][12] Studies assessing preferences for specific types of CRC screening tests were identified from an SR, 74 with no additional studies found by our updated literature search to January 2017. The 9 studies assessed all used a statedpreference method (eg, conjoint analysis or discrete-choice experiments) and compared 3 or more different CRC screening methods. [75][76][77][78][79][80][81][82][83] All 9 studies included individuals at average risk for CRC, and 7 also included individuals with an FH of CRC. The findings of the included studies were generally consistent and are summarized in Table 6.
Other studies in average-risk populations suggest there is some variation in preferences. While accuracy was typically considered the most important factor, some individuals may be more concerned with other factors, such as the potential inconvenience, pain, or discomfort related to testing. [84][85][86][87] Individuals have reported that bowel preparation was the most unpleasant aspect of colonoscopy, and that the procedure was less painful than anticipated. 87 This reinforces the need for proper counseling. In fact, an RCT found that a tailored intervention with FDRs of individuals
# Cost-Effectiveness
Direct evidence supporting the cost-effectiveness of screening in those with a positive FH was not found. CRC screening has been shown to be cost-effective compared to no screening, but no single screening test has emerged as consistently more cost-effective in the average-risk population. 73,[89][90][91][92] Because of the higher risk for CRC and the potential need for earlier and more frequent testing, data in average-risk individuals may not be applicable to individuals with an FH of CRC.
In the absence of data in individuals with an FH of CRC, an SR of analyses using simulation models to assess the cost-effectiveness of screening strategies in individuals with an FH of CRC was conducted for this guideline. Four costeffectiveness modeling studies were identified (1 US study, 93 1 Australian study, 94 and 2 European studies 95,96 ) Three analyses were from the third-party payer perspective and considered direct costs only (ie, costs of screening, diagnostic tests, and treatment), [94][95][96] while 1 was from a societal cost perspective and included both direct and indirect costs (ie, those associated with attendance for screening, diagnostic, or surveillance procedures, or for treatment of cancer). 93 The screening strategies included various combinations of FIT every 2 or 5 years and colonoscopy every 5 or 10 years, generally beginning at age 40 or 50 years.
Overall, all 4 studies determined that colonoscopy performed every 5 years was cost-effective compared to no screening, FIT every 2 or 5 years, or colonoscopy every 10 years in individuals with an FH of 1 or more FDRs with CRC. [93][94][95][96] The incremental cost-effectiveness ratio of performing colonoscopy every 5 years was approximately US$50,000/life-year gained in 2 studies, 93,95 AU$12,405/ life-year gained in a third study, 94 and V7250/life-year gained in the fourth study. 96 There were no direct comparisons of different starting ages for initiating screening.
Because all modeling studies made various assumptions, the most cost-effective strategy for screening individuals with an FH of CRC cannot be stated definitively. The available data suggested that the more intensive screening strategies for these high-risk populations using colonoscopy were cost-effective. The optimal interval of such screening may vary according to number and age at diagnosis of the affected FDRs.
No studies were found that assessed the effectiveness of various screening specifically in individuals with an FH of adenoma.
In summary, the Consensus Group agreed that the efficacy, patient preference, and cost-effectiveness data support the choice of colonoscopy as the preferred test for individuals at highest risk, but that FIT was an acceptable alternative depending on the individual's specific risk level, other patient factors, and the availability of resources.
Counseling and shared decision-making is critical to maximize uptake of CRC screening.
# Q5. For an individual with an FH of CRC or adenoma, what are the recommended testing intervals?
The interval for screening was extrapolated, in part, from data describing the natural history of adenomas in unselected individuals undergoing screening. The risks of advanced adenomas or CRC after a negative colonoscopy are low, particularly during the first 10 years of follow-up. 97,98 In addition, small adenomas are generally not malignant, and are unlikely to become invasive cancers within 5 years. 43,44 The malignant potential of adenomas increases with increasing size. 43,44 A study estimating the time to progression from normal, through adenoma, to invasive carcinoma, estimated 26 years for diminutive adenoma, 8 years for small adenoma, and 5 years for large adenoma. 99 Because of the high potential for malignant transformation of large adenomas, the efficacy of polypectomy decreases with increasing follow-up years. 99 The risk of developing CRC is also affected by the number and histology of the adenomas. [44][45][46] Therefore, based on the natural history of adenomas, guidelines recommend a 10-year interval for surveillance after a negative colonoscopy for individuals at average risk. 17,18,47 There is currently little evidence to suggest that the natural progression of adenomas in individuals with an FH would differ from those without an FH. In one study, although individuals with a recurrence of adenomas (especially advanced adenomas) were more likely to have an FDR with CRC compared to those without recurrence, this was not statistically significant. 100 Evidence does suggest that the rate of progression from adenoma to CRC may be accelerated in individuals with some, but not other hereditary syndromes. 101 Currently, it is unknown whether an FH of nonhereditary CRC/adenomas would impact the natural history of adenomas in these individuals. If new evidence emerges confirming that the natural history remains the same, this would strengthen the current guideline. However, if emerging evidence shows that the pathophysiology of CRC is unique in individuals with an FH, this would weaken the confidence in the evidence, and would suggest the need to update the guidelines.
RCTs to determine the optimal interval for CRC screening are very limited. In an RCT in unselected, healthy individuals, both annual and biennial screening gFOBT resulted in significant reductions in the incidence of CRC (annual RR, 0.80; 95% CI, 0.70-0.90; biennial RR, 0.83; 95% CI, 0.73-0.94), as well as statistically lower CRC mortality (annual RR, 0.68; 95% CI, 0.56-0.82; biennial RR, 0.78; 95% CI, 0.65-0.93) compared with the control group. 102,103 The 2 approaches appeared to have similar efficacy, although, they were not compared statistically. Similarly, a populationbased RCT evaluating FIT compared screening at 1-, 2-, or 3-year intervals, and found higher participation rates with biennial and triennial screening compared to annual screening, but there was no difference in detection of advanced neoplasms or CRC. 104 Overall, the data assessing screening intervals for an FIT-type screening test are verylow quality and there remains substantial uncertainty as to whether 1-, 2-, or 3-year intervals would have the same efficacy or not.
In addition to the testing interval, the cutoff value for a positive FIT is also important. A diagnostic accuracy SR&MA of studies in average-risk individuals found that using a lower cut-off value (eg, <20 mg/g) significantly increased the sensitivity of FIT, but with a corresponding significant decrease in specificity. 72 One study compared 2 different screening intervals for colonoscopy (1 follow-up colonoscopy at 6 years vs 2 follow-up colonoscopies, 1 at 3 years and the other at 6 years) in individuals with an FH of CRC, 105 but no definitive conclusions can be drawn from that study. Although it was described as an RCT, it was not truly randomized, was underpowered, and did not report cumulative incidence of advanced adenomas at the end of the study. 105 Subgroup analyses of a large cohort study found that among individuals with an FH of CRC, a follow-up colonoscopy within 5 years significantly reduced the risk of CRC (HR, 0.44; 95% CI, 0.30-0.66 compared with no colonoscopy), but was not significant when follow-up colonoscopy took place beyond 5 years (HR, 0.91; 95% CI, 0.55-1.52, compared with no colonoscopy). In contrast, in individuals without an FH, the risk of CRC was significantly reduced (compared with no colonoscopy) in both subgroups, ie, follow up colonoscopy in <5 years and in 5 years. However, these were subgroup analyses and the sample size for those with an FH of CRC was small. 106 No studies were found that assessed the effectiveness of various testing intervals specifically in individuals with an FH of adenoma. Overall, the Consensus Group agreed that the elevated risk warrants consideration of shorter intervals for repeat FIT and colonoscopy among some individuals with an FH of CRC or advanced adenoma compared to those at average risk. However, consideration should be given to the degree of elevated risk (eg, age and number of FDRs, and age of the individual) the quality of screening colonoscopy, and the findings at screening colonoscopy (eg, size, number, and histology of polyps) when considering the timing of subsequent testing.
# Clinical Recommendations
The individual recommendation statements are provided and include the strength of recommendation and quality of supporting evidence (according to the GRADE approach), and the voting result. This is followed by a discussion of the evidence considered for the specific statement. A summary of the recommendation statements is provided in Tables 1 and 2. 1. For an individual with 1 or more FDR with a history of CRC, we recommend screening over no screening. GRADE: Strong recommendation, moderate-quality evidence. Vote: strongly agree, 100% Key evidence. As discussed in Question 1, individuals with 1 or more FDRs are highly likely to have at least a 2fold greater risk of CRC compared to those without an FH. Moderate-quality evidence has demonstrated the efficacy of screening programs in individuals at average risk (see Question 4), and this was extrapolated to individuals at elevated risk.
Discussion. The Consensus Group agreed that screening programs are effective in average-risk individuals, and that individuals at higher risk of CRC related to an FH of 1 or more FDRs with CRC would benefit at least as much, if not more, from screening programs over no screening.
# Individuals With a Family History of 1 First-Degree Relative With Colorectal Cancer
The scenario of an individual with an FH of 1 FDR diagnosed with CRC was used as the base case for initial discussions because the majority of data on the effects of FH are focused on this subgroup. Based on the evidence presented (see principal Question 4 and Supplementary Tables 3 and 4), the Consensus Group ranked the attributes of the 4 main testing strategies on a scale of 1 to 4 (with 1 being the preferred test for the given characteristic) (Table 7). When 2 or more tests were considered largely equivalent for a given characteristic, they were given the same rank. The results of this exercise are shown in Table 7 for the scenario of an FH of 1 FDR with CRC. Based on the evidence for an increased risk of CRC for individuals in this subgroup, colonoscopy was identified as the preferred strategy, followed by FIT. This exercise allowed consideration of factors such as patient preferences, resource use, and feasibility, and was used to help guide decisions on the recommendation statements for this subgroup.
Table 7 was created in the setting of North American subjects, with the Canadian and US gastroenterologists discussing whether differences in testing availability, cost, would impact the rankings. For the subgroup of individuals shown in Table 7, the ranking remained the same for both Canada and the United States. It was suggested that these recommendations could be customized to other countries by using this approach and adjusting the relative rankings of the tests in different settings.
2. For an individual with 1 FDR with a history of CRC, we suggest colonoscopy as the preferred screening test over no screening or all other screening modalities. GRADE: Conditional recommendation, very-low-quality evidence. Vote: strongly agree, 88%; agree, 13% Key evidence. See Question 4. Compared to no screening, the evidence for colonoscopy was determined to be of very-low quality (observational studies at high risk of bias). There was very sparse data comparing colonoscopy to other testing modalities in this population, making this evidence of very-low quality as well.
Discussion. Based on the ranking of attributes (Table 7), colonoscopy was determined to be the overall preferred screening test for individuals with 1 FDR with CRC. Colonoscopy offers the greatest efficacy, and while the RR of complications is highest with this test, the absolute risk of complications remains very low. In addition, although the resources required were ranked as high, the superior efficacy, which leads to better cost-effectiveness and patient acceptability, make colonoscopy the preferred option for individuals at elevated risk.
3. For an individual with 1 FDR with a history of CRC, we suggest FIT as a second-line screening option. GRADE: Conditional recommendation, moderate-quality evidence. Vote: strongly agree, 50%; agree, 38%; uncertain, 13% Key evidence. See Question 4. No RCT data were found comparing FIT to no screening, so evidence was mainly extrapolated from studies comparing FIT with gFOBT, colonoscopy, and FS; however, these studies only accessed diagnostic accuracy and participation rates; no direct data are available on long-term clinical outcomes.
Discussion. Based on the ranking of attributes (Table 7), FIT was ranked second overall as a screening test for individuals with 1 FDR with CRC. While the Consensus Group agreed that colonoscopy is the preferred test for this subgroup, it was deemed necessary to offer an alternative test. With acceptable efficacy and adverse event profiles, FIT is a reasonable option in cases where an individual refuses colonoscopy, has higher than average risks of complications from colonoscopy, or if colonoscopy availability or wait times are an issue. In addition, equitable access can be an issue with colonoscopy and FS in geographic areas where these tests are not readily available. natural history of adenomas in unselected individuals undergoing screening. While data suggest the rate of progression from adenoma to CRC in patients with some hereditary syndromes may be accelerated, it is unknown whether the rate of progression is affected by an FH of nonhereditary CRC. Data assessing different testing intervals for colonoscopy or FIT are very limited, especially in individuals with an FH. Discussion. The Consensus Group agreed that the elevated risk associated with an FH of CRC in 1 FDR may warrant shorter intervals for repeat FIT and colonoscopy compared to those recommended for individuals at average risk. Again, clinical judgment is important when making decisions to shorten the screening interval, and should consider the degree of elevated risk (eg, age and number of FDRs, and age of the individual), the quality of screening colonoscopy, and the findings at screening colonoscopy (eg, size, number, and histology of polyps).
# Two or More First-Degree Relatives With Colorectal Cancer
As discussed in Question 1, an individual's CRC risk increases with an increasing number of affected FDRs. Individuals with 2 or more FDRs with CRC likely have a 4-to 6-fold greater risk than the general population. Although these individuals are at higher risk, the ranking of the attributes of the 4 main testing strategies remained unchanged compared to individuals with an FH of 1 FDR with CRC (Table 7), and colonoscopy continued to be the preferred strategy. As outlined in Statement 1, screening was strongly recommended over no screening in this subgroup of individuals.
8. For an individual with 2 or more FDRs with a history of CRC, we recommend colonoscopy as the preferred screening test over no screening or all other screening modalities. GRADE: Strong recommendation, very-low-quality evidence. Vote: strongly agree, 63%; agree, 38% Key evidence. See Question 4 and Statement 2. Discussion. Colonoscopy was recommended as the preferred screening test for all individuals in this subgroup because of the high efficacy rates and the very high risk of CRC associated with having 2 or more FDRs with CRC. This subgroup of individuals is much smaller than the subgroup with 1 FDR; therefore, it is likely feasible to screen all individuals in this group with colonoscopy. In unusual circumstances, such as when an individual refuses colonoscopy, another screening test should be performed, rather than no test, but all efforts should be made to perform colonoscopy.
Despite very-low QoE, the Consensus Group was given the option to vote on the strength of recommendation for colonoscopy because of the high-risk of life-threatening negative consequences of missed lesions, and agreed that this should be a strong recommendation. 9. For an individual with 2 or more FDRs with a history of CRC undergoing colonoscopy, we suggest commencing CRC screening at age 40 years or 10 years younger than the age of diagnosis of the earliest diagnosed FDR, whichever is earlier. GRADE: Conditional recommendation, very-low-quality evidence. Vote: strongly agree, 63%; agree, 38% Key evidence. See Question 3 and Statement 4. Discussion. The Consensus Group agreed that in light of the very high risk associated with 2 or more FDRs, initiating screening at a young age is clearly warranted in this group of individuals. In addition, screening should begin 10 years younger than the age of diagnosis of the earliest diagnosed FDR. However, again clinical judgment is important; if the FDRs are much older at time of diagnosis, initiating colonoscopies at age 40 years may not be warranted, and genetic testing should be considered in those with a high CRC burden in a family.
10. For an individual with 2 or more FDRs with a history of CRC undergoing screening with colonoscopy, we suggest 5-year screening intervals. GRADE: Conditional recommendation, very-low-quality evidence. Vote: strongly agree, 38%; agree, 63% Key evidence. See Question 5. Evidence for screening intervals was extrapolated, in part, from data describing the natural history of adenomas in unselected individuals and those with hereditary syndromes. Data suggest the rate of progression from adenoma to CRC in patients with Lynch syndrome is accelerated. 101 Observational studies have found cancers, even advanced-stage cancers, that have occurred within intervals of 3 years or fewer, [108][109][110] although it is not clear whether these cancers result from missed lesions at the first colonoscopy or a rapid rate of progression from adenoma to CRC. Currently, it is unknown whether the adenomas in individuals with an FH in multiple relatives lay on a continuum in terms of rate of progression compared to the adenomas found in individuals with hereditary syndromes or those at average risk.
Discussion. The Consensus Group agreed that the very high risk associated with multiple FDRs with CRC warrants a shorter interval for repeat colonoscopy compared to those recommended for individuals at average risk. It is important to investigate these individuals for an inherited syndrome (eg, Lynch syndrome, familial adenomatous polyposis), including a detailed personal and FH incorporating at least 3 generations and potentially genetic testing. Individuals found to have an FH of an inherited syndrome should undergo screening according to appropriate published guidelines. 24 One or More Second-Degree Relatives with Colorectal Cancer
As discussed in Question 1, an individual's CRC risk is associated with the degree of the relationship between the family member and the individual. Risk decreases with increasing distance from the affect relative. Among those with an affected SDR, reported elevations in CRC risk appears to be largely driven by the presence of a concomitant FDR. Although these individuals are likely at lower risk than those with 1 or more FDRs, the ranking of the attributes of the 4 main testing strategies remained unchanged compared to individuals with an FH of 1 FDR with CRC (Table 7). Although colonoscopy was still considered the overall best option, FIT continued to be ranked second overall.
11. For an individual with 1 or more SDRs with a history of CRC, we recommend screening over no screening. GRADE: Strong recommendation, moderate-quality evidence. Vote: strongly agree, 88%; agree, 13% Key evidence. See Question 1 and Statement 1. Studies suggest that individuals with an affected SDR, without an affected FDR, may be at marginally increased risk for CRC, but these data do not appear to be statistically or clinically relevant. Risk appears to increase with increasing number of affected SDRs and decreases with the distance of the relative. Moderate-quality evidence has demonstrated the efficacy of screening programs in individuals at average risk (see Question 4), and this was extrapolated to individuals with SDRs with CRC, whose risk of CRC is at least that of average-risk individuals.
Discussion. The Consensus Group concluded that these individuals are likely at average risk. However, risk appears to fall on a biologic gradient, therefore, a thorough history should be taken. As per guidelines for screening individuals at average risk, screening is strongly recommended over no screening. 14,15,[17][18][19][20] 12. For an individual with 1 or more SDRs with a history of CRC, we suggest commencing CRC screening at age 50 years. GRADE: Conditional recommendation, low-quality evidence.
Vote: strongly agree, 50%; agree, 50% Key evidence. See Questions 1 and 3. It has been clearly shown that the incidence and mortality of CRC increases with age, with a sharp increase at age 50 years. 1,2,58 For this reason, guidelines for individuals at average risk recommend screening for CRC starting at age 50 years. 14,15,[17][18][19][20] Discussion. Based on evidence suggesting individuals with an FH of CRC in 1 or more SDRs are at average or mildly elevated risk, the Consensus Group agreed with the 50-year age of initiation as per guidelines for individuals at average risk. 14,15,[17][18][19][20] 13. For an individual with 1 or more SDRs with a history of CRC, we suggest screening tests and intervals in accordance with average-risk guidelines. GRADE: Conditional recommendation, very-low-quality evidence.
Vote: strongly agree, 38%; agree, 63% Key evidence. See Questions 1 and 3, and Statement 12.
Discussion. Based on the likelihood that these individuals are at average or minimally elevated risk for CRC, screening tests and the interval for screening should be chosen according to locally applicable average-risk guidelines. 14,15,[17][18][19][20] One or More First-Degree Relatives With Advanced Adenoma
As discussed in Question 2, individuals may be unreliable in describing the histology of the polyp, adenoma, or advanced adenoma experienced by a relative; therefore, the Consensus Group defined this subgroup as individuals with an FH of "documented advanced adenoma." The Consensus Group emphasized the importance of the documentation in their recommendation; polyps without documentation should be considered "nonadvanced," see Statement 19. These individuals appear to be at increased risk of CRC and adenomas. When ranking the attributes of the 4 main testing strategies, the Consensus Group acknowledged that patient preferences, cost-effectiveness, and feasibility are different in this subgroup (Table 8) compared to individuals with an FH of 1 FDR with CRC (Table 7). The Consensus Group agreed that the advantages of colonoscopy over FIT in terms of cost-effectiveness and patient acceptability would be decreased in this subgroup. In addition, the high prevalence of adenomas would substantially impact the feasibility of performing colonoscopy or FS on all relatives of individuals with adenomas. Although the overall ranking continued to position colonoscopy first and FIT second overall, almost 40% of the Consensus Group advocated in favor of ranking these 2 options equally. Although colonoscopy would likely be a preferred strategy in the United States for this subgroup of individuals, the ranking remained the same for both Canada and the United States (Table 8).
14. For an individual with 1 or more FDRs with a history of a documented advanced adenoma, we recommend screening over no screening. GRADE: Strong recommendation, moderate-quality evidence. Vote: strongly agree, 63%; agree, 38% No recommendation. For an individual with 1 or more FDRs with a history of a documented advanced adenoma, the Consensus Group was not able to make a recommendation (neither for nor against) on the use of colonoscopy as the preferred screening test over no screening or all other screening modalities.
15. For an individual with 1 or more FDRs with a history of a documented advanced adenoma, we suggest colonoscopy or FIT over no screening or all other screening modalities. GRADE: Conditional recommendation, very-low-quality evidence. Vote: strongly agree, 63%; agree, 38% Key evidence. See Questions 2 and 4. While individuals with an FH of an advanced adenoma appear to be at marginally increased risk for CRC, data are sparse, and it is not clear whether the risk would meet the level of clinically relevant increased risk of 2-fold.
Discussion. The Consensus Group recommended some form of screening over no screening, based on the proven benefits of screening. However, the Consensus Group could not make a recommendation for or against the use of colonoscopy as a "preferred test." Although the group agreed that colonoscopy is the most accurate test, some participants argued screening colonoscopy for all individuals with an FH of an FDR with an advanced adenoma (who may not be at elevated risk), would yield a high number of colonoscopies and likely would not be feasible in Canada. In contrast, the consensus participants from the United States argued that colonoscopy would be the preferred test for this subgroup in the United States.
FIT was considered to be a reasonable option, with acceptable sensitivity and specificity (see Question 4). In addition, while patient preference in individuals at elevated risk because of an FH of CRC is for the most accurate test (colonoscopy), this has not been shown in individuals with an FH of adenoma, and FIT is likely to be more acceptable. 16. For an individual with 1 or more FDRs with a history of a documented advanced adenoma undergoing screening with colonoscopy or FIT, we suggest commencing CRC screening at age 40-50 years or 10 years younger than the age of diagnosis of the earliest diagnosed FDR, whichever is earlier. GRADE: Conditional recommendation, very-low-quality evidence. Vote: strongly agree, 38%; agree, 38%; uncertain, 25% 17. For an individual with 1 or more FDRs with a history of a documented advanced adenoma undergoing screening with colonoscopy, we suggest 5-10 year screening intervals. GRADE: Conditional recommendation, very-low-quality evidence. Vote: strongly agree, 13%; agree, 75%; uncertain, 13% 18. For an individual with 1 or more FDRs with a history of a documented advanced adenoma undergoing screening with FIT, we suggest 1-2 year screening intervals. GRADE: Conditional recommendation, very-low-quality evidence. Vote: strongly agree, 38%; agree, 63% Key evidence. See Questions 3 and 5. Individuals with an FH of an advanced adenoma appear to be at marginally increased risk of CRC.
Discussion. There was substantial discussion around whether the potential modest increase in CRC risk warranted either initiating testing at an earlier age or performing more frequent testing compared to average-risk individuals. Because of the uncertainty around the magnitude of increased risk, the Consensus Group agreed to provide ranges for the starting age and testing interval, with clinical judgment and other risk factors being considered in screening decisions. The group stressed that the interval for colonoscopy in most cases should not be fewer than 5 years, but as for average-risk individuals should not be more than 10 years. The US consensus participants argued that based on natural history data suggesting high-grade dysplasia has a high risk of developing into CRC, the preferred screening for these individuals in the United States would be colonoscopy every 5 years.
One or More First-Degree Relatives With Any Adenoma 19. For an individual with 1 or more FDRs with a history of a nonadvanced adenoma or polyp of unknown histology, we suggest screening in accordance with average-risk guidelines. GRADE: Conditional recommendation, low-quality evidence.
Vote: strongly agree, 63%; agree, 38% Key evidence. See Questions 2 and 5. There was no evidence that individuals with an FH of nonadvanced adenomas are at increased risk of CRC. Discussion. The Consensus Group agreed that this subgroup (usually defined as those with 2 non-advanced adenomas that are <10 mm in size and those without neoplasia), should be screened according to guidelines for average-risk individuals. 14,15,[17][18][19][20] Persons whose polyp is of unknown histology should be screened according to guidelines for average-risk individuals (please also refer to the discussion for Statements 11-13).
# Future Directions
There is a need for well-designed, large. prospective. and retrospective observational studies that will accurately quantify how an FH of CRC or adenoma affects the risk of CRC. Specifically, prospective studies that assess the optimal time to initiate screening and appropriate intervals between screening should be a priority. These studies should strive to avoid the limitations of the existing studies.
There is also a need for well-designed RCTs assessing the effects of FIT compared to gFOBT or colonoscopy on critical clinical outcomes (long-term CRC incidence and mortality) in this patient population. Similarly, the results of ongoing follow-up of RCTs in average-risk individuals, assessing critical long-term outcomes (eg, CRC mortality and incidence) with colonoscopy compared to no screening or FIT should help inform future guidelines. 70,71,111 Finally, while there are some studies suggesting that patient preferences and values, as well as barriers and facilitators to CRC screening, may differ in average-risk vs high-risk populations, this needs to be more clearly defined in both populations.
# Canadian Association of Gastroenterology Statement
This CPG on screening for CRC in individuals with a family history of nonhereditary CRC or adenoma was developed under the direction of Drs Desmond Leddin and David A. Lieberman, in accordance with the policies and procedures of the CAG and under the direction of CAG Clinical Affairs. It has been reviewed by the CAG Practice Affairs and Clinical Affairs Committees and the CAG Board of Directors. The CPG was developed following a thorough consideration of medical literature and the best available evidence and clinical experience. It represents the consensus of a Canadian and International panel composed of experts on this topic. The CPG aims to provide a reasonable and practical approach to care for specialists and allied health professionals charged with the duty of providing optimal care to patients and families, and can be subject to change as scientific knowledge and technology advance and as practice patterns evolve. The CPG is not intended to be a substitute for physicians using their individual judgment in managing clinical care in consultation with the patient, with appropriate regard to all the individual circumstances of the patient, diagnostic and treatment options available, and available resources. Adherence to these recommendations will not necessarily produce successful outcomes in every case.
# Acknowledgments
The Canadian Association of Gastroenterology (CAG) would like to thank the Canadian Partnership Against Cancer (CPAC) for their generous support of the guideline process. The Consensus Group would like to thank the following people for their contributions: Paul Sinclair and Lesley Marshall
# Supplementary Material
Note: To access the supplementary material accompanying this article, visit the online version of Gastroenterology at www.gastrojournal.org, and at https://doi.org/10.1053/ j.gastro.2018.08.017.
# Funding
This guideline was supported through an unrestricted grant to the Canadian Association of Gastroenterology (CAG) by the Canadian Partnership Against Cancer.
Supplementary Table 1 Field: title and abstract Search string: ("colorectal cancer*" OR "colon cancer*" OR "rectal cancer*") AND (fecal OR faecal OR FOBT OR gFOBT OR FIT OR sigmoidoscopy OR colonoscopy) AND (screened OR screening OR surveillance) AND ("cost-effectiveness" OR "cost effectiveness" OR "quality of life" OR "quality-of-life" OR "QALY" OR "Quality Adjusted Life Year*" OR "Cost Utility Analysis" OR "Cost Benefit Analysis" OR "Cost Efficiency Analysis" OR "Cost-Utility Analysis" OR "Cost-Benefit Analysis" OR "Cost-Efficiency Analysis") Results: 188 Highly focused search for cost-effectiveness studies in people with FH of CRC Database: PubMed Language: English Species: Humans Publication dates: January 31, 2010 to January 31, 2017 Field: title and abstract Search string: ("colorectal cancer*" OR "colon cancer*" OR "rectal cancer*") AND (fecal OR faecal OR FOBT OR gFOBT OR FIT OR sigmoidoscopy OR colonoscopy) AND (screened OR screening OR surveillance) AND ("cost-effectiveness" OR "cost effectiveness" OR "quality of life" OR "quality-of-life" OR "QALY" OR "Quality Adjusted Life Year*" OR "Cost Utility Analysis" OR "Cost Benefit Analysis" OR "Cost Efficiency Analysis" OR "Cost-Utility Analysis" OR "Cost-Benefit Analysis" OR "Cost-Efficiency Analysis") AND family Results: 19 Search for prospective studies on the risk of CRC of asymptomatic individuals with an FH of CRC/adenoma vs those without an FH Database: MEDLINE, EMBASE, EBM Reviews-Cochrane Central Register of Controlled Trials, EBM Reviews-Cochrane Database of Systematic Reviews Language: English Publication dates: 1 January 1996 to Oct 8, 2016 | None | None |
31778c9adbf72d51570daf1d684c3421a001d699 | cma | None | In Canada, rates of hospital admission from opioid overdose are higher for older adults (≥ 65) than younger adults, and opioid use disorder (OUD) is a growing concern. In response, Health Canada commissioned the Canadian Coalition of Seniors' Mental Health to create guidelines for the prevention, screening, assessment, and treatment of OUD in older adults.A systematic review of English language literature from 2008-2018 regarding OUD in adults was conducted. Previously published guidelines were evaluated using AGREE II, and key guidelines updated using ADAPTE method, by drawing on current literature. Recommendations were created and assessed using the GRADE method.Thirty-two recommendations were created. Prevention recommendations: it is key to prioritize non-pharmacological and non-opioid strategies to treat acute and chronic noncancer pain. Assessment recommendations: a comprehensive assessment is important to help discern contributions of other medical conditions. Treatment recommendations: buprenorphine is first line for both withdrawal management and maintenance therapy, while methadone, slow-release oral morphine, or naltrexone can be used as alternatives under certain circumstances; non-pharmacological treatments should be offered as an integrated part of care.These guidelines provide practical and timely clinical recommendations on the prevention, assessment, and treatment of OUD in older adults within the Canadian context.# INTRODUCTION
According to the World Health Organization (WHO), people over the age of 50 accounted for 39% of deaths from drug use worldwide by 2015, and of those deaths in older adults (age ≥ 65), approximately 75% were linked to the use of opioids. (1,2) Despite these numbers, there is a paucity of data about the many ways opioids specifically affect older adults and about how to care for those who develop an addiction, also referred to as an opioid use disorder (OUD). (3) There are two primary cohorts of older adults who develop OUD. The first group is made up of those who have been exposed to opioids for many years through drug experimentation, often beginning in adolescence. Some have been identified with and treated for an OUD, and many have had adverse health consequences. (4)(5)(6) The second group of older adults who may develop OUD is made up of those individuals who were prescribed opioids by a health-care provider for a pain condition. (7,8) Some of these individuals may have turned to the illicit market in order to maintain an ongoing supply of opioids following discontinuation of their prescription by Canadian Guidelines on Opioid Use Disorder Among Older Adults a health-care professional. Opioid withdrawal pain can perpetuate the unintended long-term use of opioids for chronic non-cancer pain or due to an OUD, with underlying drivers being opioid-induced hyperalgesia and withdrawal-associated injury-site pain. (9,(10)(11)(12) In Canada, 43.9% of adults > 55 years of age have used a prescription opioid and 1.1% of that group have done so daily (or almost daily) in the last year. (13) Though the proportion of people starting opioid therapy in Canada has trended down from 2013 to 2018, those over 65 have consistently received more new opioid prescriptions and have a higher proportion that go on to long-term opioid therapy (24.8%) than any other age group. (14) From 2007 to 2015, hospitalizations for opioid overdose (referred to as poisonings) in Canada were consistently higher in older adults than in any other age cohort: At over 20 per 100,000, older-adult admissions are almost double that of 15 to 24-year-olds, and represent 30% of all admissions to hospital for opioid poisoning. (15) Only recently by 2017 have younger adults in Canada started to equal and just surpass older adults in hospitalizations related to opioid poisonings. Most opioid poisonings in adults in Canada are accidental; however, 30% are intentional. (16) A recent study found that in older adults, opioid misuse was associated with increased odds of suicidal ideation. (17) According to a US national survey in 2016, 0.8% of adults surveyed met Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV) criteria for OUD in the past year. (18) There are no comparable Canadian studies that use DSM criteria. However one used WHO criteria and estimated a past year prevalence of OUD in Canadian adults to be 0.9% for drug abuse, and 0.5% for drug dependence. Yet reporting of prevalence data is lacking specific to those over 65 using opioids. (19,20) OUD may present more subtly in older adults than their younger counterparts and require a more nuanced approach. (21) OUD may overlap with physiologic tolerance alone and may be mistaken for or masked by other medical conditions. Consequences from opioid use may not be recognized in older adults who have stopped work and who have restricted social networks. Social stigma and cognitive impairment may each play a role in under-identification.
Adults entering older age are having an effect on the changing demographics of substance use and the need for treatment, its utilization, and its cost. For example, one study from New York City found that, as of 2012, adults > 60 years of age comprised 13.1% of those in opioid treatment programs, up from 1.7% in 2006. (22) This study also noted a shift from illicit drugs to those obtained by prescription as the primary type of opioid used. Additionally, when compared to their younger counterparts, older US veterans with OUD have higher rates of comorbid mood disorder, post-traumatic stress disorder, hepatitis C, human immunodeficiency virus, and chronic pain, including neuropathy, which has notably increased the cost of care. (23) The purpose of this article is to outline the issues facing older adults with, or at risk for, an OUD, and to provide a summary of recommendations for the prevention, screening, assessment, and treatment of an OUD in those ≥ 65 years of age. The full guidelines can be accessed electronically (www.ccsmh.ca).
# METHODS
An experienced librarian and research assistants conducted a systematic literature search for relevant studies related to opioid use and opioid use disorder in adults and older adults. The databases searched included the Cochrane Library, EMBASE, PsychInfo, International Guideline Library, and PubMed. Included studies for the recommendations were restricted to human and written in English, with publications dates from 2008 through March 2018. The date limitation of the literature was decided a priori based on the changes observed in the last decade related to the opioid crisis in Canada. More recent literature was included in the introduction and discussion.
An interdisciplinary guideline development committee was set up through the Canadian Coalition of Seniors' Mental Health, consisting of two addiction medicine specialists, two psychiatrists, a physical medicine and rehabilitation specialist, a nurse practitioner, a pharmacist, a family physician with expertise in care of the elderly, as well as a person with lived experience. The committee members identified the top quality guidelines on OUD published using the Appraisal of Guidelines for Research & Evaluation Instrument (AGREE II). (24) We then modified the existing key guidelines using the ADAPTE collaboration process (25) in order to customize the selected guidelines for older adults and the Canadian context. We formulated questions in the PICOT format (Population, Intervention, Comparator, Outcome and Time) as a working group, and populated the questions with answers obtained from the previously chosen key guidelines, then supplemented this information with evidence from current literature.
Working group members drafted recommendations and provided the evidence for each of the recommendations. The person with lived experience provided views and preferences of the target population. The draft recommendations were then reviewed by the whole working group, feedback integrated, so that the final wording of each recommendation was the result of full consensus. Each recommendation was then evaluated using the GRADE system (Grades of Recommendation Assessment, Development, and Evaluation). (26,27) GRADE scores the quality of the evidence as high, moderate, low or very low. It was agreed that "low" and "very low" scores would be amalgamated as "low". The strength of the recommendations was scored as strong or weak. (26,27) We continued to discuss each recommendation and evaluation until we reached 100% consensus on each recommendation. The final recommendations were then sent for external peer review. The working group members integrated the majority of the comments from external reviewers into the guidelines after discussion.
# RESULTS
# Selection of the Previous Guidelines for Adaptation
Only one previous guideline published by the Royal College of Psychiatrists (United Kingdom) in the last 10 years for the prevention, assessment, and treatment of OUD specific to older adults was identified in the English language literature searched. (28) We chose to include this guideline for its direct relevance to older adults, despite a low-quality rating on the AGREE II tool.
We closely reviewed the top four rated OUD guidelines focused on adults in general (not just older adults) published in the last 10 years. (29)(30)(31)(32) We chose the US Veterans' Affairs and Department of Defense's guideline (2015) as the best rated guideline to use as a starting point, per the AGREE II tool. We also relied on elements of the Canadian Clinical Practice Guideline for Opioid Use Disorder for its applicability to our local context. (32) Recommendations from less robust guidelines and clinical practice tips on OUD were considered when the selected guidelines did not address an issue fully or supporting evidence was needed. (33)(34)(35)(36)(37)(38)(39)(40)(41) We considered costs, benefits, and harms when we were drafting the recommendations.
No published randomized, controlled trials were identified on the prevention, assessment, or treatment of OUD in older adults. Therefore, the main evidence used to generate the recommendations was based on the above guidelines, along with systematic and narrative reviews on older adults since 2015. (42)(43)(44)(45)(46)(47)(48)(49) In addition, numerous clinical and observational studies extrapolated from younger adults, some observational cohorts in older adults, as well as clinical expertise, informed these guidelines. For the section on prevention, key Canadian and US guidelines were identified for the treatment of chronic non-cancer pain (CNCP). (50)(51)(52)
# RECOMMENDATIONS Prevention of Opioid Use Disorder Among Older Adults
To curb opioid poisonings and the development of OUD, measures need to be implemented for both primary and secondary prevention. These issues are outlined in the questions (A & B) and addressed in the recommendations (1-9) listed below.
# Question A: In older adults, what measures can reduce the risk of developing an OUD?
# Recommendation 1
In order to avoid the risk of developing an OUD, older adults with acute pain in whom opioids are being considered should receive the lowest effective dose of the least potent immediate release opioid for a duration of ≤ 3 days and rarely > 7 days. (44,(51)(52)(53)(54)(55)
# Recommendation 2
In most circumstances, avoid prescribing opioids for older adults with CNCP. For severe pain that is not responsive to non-opioid therapy in patients without a history of substance use disorder and without active mental illness, a trial of opioid treatment may be considered. Consider obtaining a second opinion before prescribing long-term opioid therapy. After explaining the risks and benefits to the patient, prescribe only in accordance with published guidelines for adults, initiate and maintain opioids at lower doses than for younger adults, and discontinue if function does not improve or if adverse effects arise. (50,51,53,(56)(57)(58)
# Recommendation 3
Patients and their families should be advised to store opioids safely, never to share their medication, and to return unused medication to the pharmacist for disposal. (50,59,60)
# Recommendation 4
Pharmacists and nursing staff are advised to inform the prescriber if there are concerns with co-prescribing, adherence to treatment, or intoxication. (61,51)
# Recommendation 5
In older adults with polypharmacy or comorbidities that increase the risk of opioid overdose (e.g., benzodiazepine use, renal failure, sleep apnea), the lowest effective opioid dose should be used and tapering the opioid and/or other medications should be considered. (50,51,(62)(63)(64)
# Recommendation 6
Once the decision is made to reduce the opioid dose, a slow outpatient tapering schedule (e.g., 5% drop every 2-8 weeks with rest periods) is preferable to more rapid tapering. A faster taper schedule may be attempted under special circumstances of medical need, if the patient is in a treatment setting with medical supervision. (32,9,(65)(66)(67) GRADE: Quality: Low; Strength: Weak
# Recommendation 7
Dispense naloxone kits to anyone using opioids regularly for any reason (CNCP, OUD, etc.), and train household members and support staff on use. (68,69)
# Recommendation 8
Include skilled pharmacists and/or nurses on teams to educate patients on appropriate use of opioids and other medications. (70)(71)(72) GRADE Quality: Low; Strength: Weak
# Recommendation 9
Older adults with, or at risk for, an OUD should be given advice on strategies to reduce the risk of opioid overdose, and information on supervised consumption sites, if available in the community. (73)(74)(75)
# Screening for and Assessment of Opioid Use Disorder Among Older Adults
Screening and assessment are the starting points for care of a person with an OUD, and many effective approaches to both exist for adults. (76) Listed below are questions (C-E) along with recommendations (10-12) for screening and assessment of OUD specific to older adults: Question C: In older adults, when and how should one screen for an OUD?
# Recommendation 10
Older adults should be screened for an OUD using validated tools, if appropriate (e.g., CAGE-AID, ASSIST, PDUQp, ORT, POMI, COMM). Medication reviews and urine drug screens should be utilized if the patient is taking opioids for CNCP or an OUD. (30,41,(77)(78)(79)(80)
# Recommendation 11
Identify a diagnosis of an OUD through completion of a comprehensive assessment, including substance use, medical, pain, psychiatric, cognitive, and psychosocial history within a cultural context, and conduct a brief functional assessment. The use of validated assessment tools may be useful in this process. In addition, a detailed physical examination must be conducted, with an emphasis on signs of intoxication or withdrawal and the sequelae of substance use. Laboratory and other investigations (including urine drug tests) should be performed as appropriate for the medical conditions identified. Reassessment is essential and should be conducted episodically throughout long-term care. (28,33,41,76,81,82)
# Recommendation 12
A full explanation of findings and diagnosis must be shared with the patient and, if appropriate, caregivers. Therapeutic optimism should be provided (i.e., hope given that addiction is a treatable disorder and that older adults, and especially older women, typically have better treatment outcomes than younger adults). (42,83) GRADE: Consensus
# Treatment of Opioid Use DisorderAmong Older Adults
# Pharmacological Treatment
Issues related to pharmacological treatments are asked in questions (F-H) and answered in recommendations (13-26) listed below.
Question F: In older adults with an OUD, what approaches and medications are safe and effective for opioid withdrawal management?
# Recommendation 13
Opioid withdrawal management should only be offered in the context of connection to long-term addiction treatment. (30)(31)(32)41,(43)(44)(45)(46)(47)(84)(85)(86)
# Recommendation 14
Induction onto an opioid agonist is recommended over a nonopioid treatment withdrawal management in older adults with an OUD. If a trial of tapering is attempted, there should be the option to initiate longer-term opioid agonist therapy or opioid antagonist therapy. (30)(31)(32)41,(43)(44)(45)(46)(47)(84)(85)(86)(87)(88)(89)(90)(91)
# Recommendation 15
Buprenorphine-naloxone should be considered first line for opioid withdrawal management in older adults. Methadone is an alternative that may be used, however consider the added risk of adverse events. (30)(31)(32)44,(91)(92)(93) GRADE Quality: Moderate; Strength: Weak
# Recommendation 16
For symptom control during opioid withdrawal management, adjuvant medications can be used in a time-limited fashion, but with caution due to medical comorbidities, side effect risk, and other concerns related to older age. (28,(30)(31)(32)(94)(95)(96)
# Question G: What medications and protocol adjustments are safe and effective in the treatment of an OUD in older adults to improve outcomes?
# Recommendation 17
Buprenorphine maintenance should be considered a first-line treatment for an OUD in older adults. (
# Recommendation 18
Methadone maintenance treatment may be considered for those older adults who cannot tolerate buprenorphine maintenance or in whom it has been ineffective. (4,22,(28)(29)(30)(31)(32)(33)(41)(42)(43)(44)(45)101,(109)(110)(111)(112)(113)(114) GRADE Quality: Moderate; Strength: Strong
# Recommendation 19
If renal function is adequate, daily witnessed ingestion of slow-release oral morphine may be considered with caution for those older adults in whom buprenorphine and methadone maintenance have been ineffective or could not be tolerated. Careful supervision of initiation onto short-acting morphine first is recommended, prior to transition to maintenance with the long-acting 24-hour formulation. (32,99,115)
# Recommendation 20
For older adults with an OUD for whom opioid agonist treatment is contraindicated, unacceptable, unavailable, or discontinued and who have established abstinence for a sufficient period of time, naltrexone may be offered. (30,32,(43)(44)(45)47,100,101,(116)(117)(118)(119)(120) GRADE Quality: Moderate; Strength: Weak
# Recommendation 21
Offer medications for an OUD in the context of connection to long-term addiction, mental health, and primary care treatment, where careful monitoring and dose titration can occur. (18,28,31,39,44,121)
# Recommendation 22
Advise patients that the use of alcohol, benzodiazepines, and other sedative-hypnotics is hazardous when combined with opioid agonist treatment. If the older adult is living in the community and is already physiologically dependent on one of these substances, then slow tapering of the substance(s) (to elimination, if possible), rather than abrupt cessation, is recommended. If the patient is in hospital, residential treatment, or a longterm care setting and medically managed by an experienced provider, detoxification can progress more rapidly, concurrent with the initiation or stabilization on medications for OUD. (30,32,36,45,122,123)
# Recommendation 23
Early take-home dosing for buprenorphine maintenance treatment may be considered, including home induction in patients who are low risk, if they find it difficult to attend the office in withdrawal and if the patient has social supports at home. This approach should not be considered for methadone initiation unless supervised (e.g., reliable caregiver or medical personal administration). (32,124)
# Recommendation 24
Reduce initial doses of medications for treatment of an OUD (e.g., by 25-50%); slow dose escalation frequency (e.g., by 25-50%); use the lowest effective dose to suppress craving, withdrawal symptoms and drug use; and monitor closely (especially for sleep apnea, sedation, cognitive impairment, and falls with opioid agonists). (28,43,(124)(125)(126)(127)(128)
# Recommendation 25
The threshold to admit an older adult with social, psychological, or physical comorbidities to either residential or hospital care for opioid withdrawal management or induction onto medications for an OUD should be lower than for a younger adult. (41,129)
# Recommendation 26
In older adults on medication for an OUD requiring management of mild-to-moderate acute pain or CNCP, non-medication and non-opioid strategies are recommended. For those on an opioid agonist for an OUD who have severe acute pain that has been unresponsive to non-opioid strategies, a short-acting opioid may be considered for a short duration (1-7 days) along with a taper, if necessary (1-7 days). (30,32,36,39,50,51,62,(130)(131)(132) GRADE Quality: Moderate; Strength: Weak
# Other Comments on Medications for OUD
In younger adults, for the palliative end of the OUD spectrum in whom all other modalities have been unsuccessful, there is currently available in Canada injectable opioid agonist treatment (iOAT). No data on iOAT in older adults were identified. The risk of adverse events with injectable medications rises with age, as does immunosuppression and mobility issues for accessing the three-times-daily visit to a clinic needed for iOAT. BC is currently the only province providing and paying for iOAT, and the cost is higher than with all other opioid agonist and antagonist treatments. Due to all of the above issues, we cannot endorse iOAT treatment in older adults at this time and thus have not included it in these guidelines.
# Psychosocial Treatment
Although robust data on behavioural interventions in older adults with OUD are lacking, an understanding of the importance of incorporating psychosocial supports is clear: Older adults may have an accumulation of losses (job, spouse, family, friends, role, home), and may struggle with lack of social support. (133,134) The key question (Question I) regarding psychosocial interventions in older adults with an OUD is outlined below, along with related recommendations (27)(28)(29)(30)(31).
# Question I: In older adults, what psychosocial interventions are effective in the treatment of an OUD to improve outcomes?
# Recommendation 27
Psychosocial interventions should be offered concurrently with medications for an OUD, at a pace appropriate for age and patient needs, but they should not be viewed as a mandatory requirement for accessing pharmacotherapy. (135)(136)(137)(138)(139)
# Recommendation 28
Contingency management may be offered as part of opioid treatment programs and used if accepted by the patient. (140)(141)(142)(143)(144)(145)(146)(147) GRADE Quality: Moderate; Strength: Weak Question J: For older adults with an OUD, what are the treatment considerations for special populations (specifically Indigenous peoples)?
# Recommendation 29
Traditional healing practices used by Indigenous communities can be integrated with buprenorphine treatment to improve outcomes for an OUD. (148) GRADE Quality: Low; Strength: Weak
# Setting
Setting can refer to treatment setting and also the living situation of the older adult.
# Question K: For older adults with an OUD, what specific treatment recommendations are suggested for non-community-based facilities?
# Recommendation 30
If experienced, clinicians may manage older adults with a mild-to-moderate OUD; however, for patients with more severe or complex disorders, it is recommended that personnel or teams with advanced substance use disorder management skills be accessible to support clinicians and to enhance their capacity to care for patients in all settings. The threshold for an admission to hospital or drug and alcohol treatment facility under the care of an Addiction Medicine Specialist is lower than for younger adults, and closer follow-up is needed on discharge to ensure appropriate community-based support. (44,(149)(150)(151)
# Recommendation 31
Older adults with an OUD who are admitted to a hospital, drug and alcohol treatment facility, or non-medical facility with access to medical care (e.g., prisons and shelters) should be offered opioid agonist treatment at the onset of withdrawal (advisable within 1-3 days), with bridging pharmacological treatment on discharge with confirmed transfer of care. (31,98,109,,152-159)
# Recommendation 32
The cost of medically-recommended pharmacological and non-pharmacological treatment for an OUD in older adults should be covered by the public health plan. (28,31,32,36,160) GRADE Quality: Moderate; Strength: Strong
# DISCUSSION
No previous guidelines or clinical trials for the prevention, screening or management of OUD have been undertaken in adults over 65 despite the increasing prevalence of OUD in this age group. Our guidelines represent a systematic effort to identify evidence from literature, taking into consideration the context, the expertise of individuals working with older adults, the input from individuals with lived experience, and the multidisciplinary guideline team. These guidelines provide 32 recommendations covering aspects of opioid management from prevention, screening, assessment, pharmacological treatment, psychosocial interventions, treatment setting, and steps to recovery. Many of the recommendations are in alignment with the other two recent Canadian guidelines on OUD treatment in adults. (32,161) The challenges and limitations in writing these guidelines were many, most important of which was the lack of direct evidence to inform the guidelines of the efficacy or effectiveness of current treatment approaches in this population. Other limitations include lack of a consistent definition for older adults and successful treatment outcome measures for OUD. Finally, there are limited data and empirical evidence for the management of OUD in special populations of older adults related to sex, gender, and ethnic group.
Studies with a focus on older adults are needed to provide empirical evidence for the effectiveness of pharmacological and psychosocial treatments. The deliberate inclusion of subgroups in these studies will provide data for future guidelines to improve their external validity. Future studies to define meaningful and patient-centered treatment outcomes targets are needed. Also, the role of other interventions that are less studied, including self-help groups, is yet to be delineated. Canadian-based data are needed on the rates of opioid use and OUD in older adults, as well as rates of overdose and mortality, in order to design targeted prevention strategies and test the effectiveness of OUD treatment and opioid overdose mitigation.
# Facilitators and Barriers for the Application of These Recommendations
In Canada, the need for expanded resources for treatment of older adults with OUD will likely rise in the coming years. Evidence-based treatment for OUD in adults in general is costeffective and decreases both morbidity and mortality. (162) The lifetime savings to provincial and national health care based on this model could be substantial. All components of the Canadian health-care system must prepare to provide addiction treatment to older adults, including those affected by an OUD.
The uptake of these guidelines will be monitored through tracking CCSMH website visits, orders of print version, distribution of office handouts, and journal article reads. There are plans to update the guidelines approximately every five years, as needed, if new literature becomes available that may significantly change management.
# CONCLUSION
Older adults are susceptible to adverse health consequences of opioid use. There is a growing need for opioid management guidelines for older adults as the population in Canada ages. The current recommendations are intended to provide healthcare workers and policy-makers with evidence-informed, clinically relevant direction and advice on the prevention, screening, assessment, and treatment of OUD in older adults. We hope practitioners will find them both a practical and useful clinical aide, and that community members will find them a helpful education resource. The expanded version of these guidelines can be accessed electronically (www.ccsmh.ca). | In Canada, rates of hospital admission from opioid overdose are higher for older adults (≥ 65) than younger adults, and opioid use disorder (OUD) is a growing concern. In response, Health Canada commissioned the Canadian Coalition of Seniors' Mental Health to create guidelines for the prevention, screening, assessment, and treatment of OUD in older adults.A systematic review of English language literature from 2008-2018 regarding OUD in adults was conducted. Previously published guidelines were evaluated using AGREE II, and key guidelines updated using ADAPTE method, by drawing on current literature. Recommendations were created and assessed using the GRADE method.Thirty-two recommendations were created. Prevention recommendations: it is key to prioritize non-pharmacological and non-opioid strategies to treat acute and chronic noncancer pain. Assessment recommendations: a comprehensive assessment is important to help discern contributions of other medical conditions. Treatment recommendations: buprenorphine is first line for both withdrawal management and maintenance therapy, while methadone, slow-release oral morphine, or naltrexone can be used as alternatives under certain circumstances; non-pharmacological treatments should be offered as an integrated part of care.These guidelines provide practical and timely clinical recommendations on the prevention, assessment, and treatment of OUD in older adults within the Canadian context.# INTRODUCTION
According to the World Health Organization (WHO), people over the age of 50 accounted for 39% of deaths from drug use worldwide by 2015, and of those deaths in older adults (age ≥ 65), approximately 75% were linked to the use of opioids. (1,2) Despite these numbers, there is a paucity of data about the many ways opioids specifically affect older adults and about how to care for those who develop an addiction, also referred to as an opioid use disorder (OUD). (3) There are two primary cohorts of older adults who develop OUD. The first group is made up of those who have been exposed to opioids for many years through drug experimentation, often beginning in adolescence. Some have been identified with and treated for an OUD, and many have had adverse health consequences. (4)(5)(6) The second group of older adults who may develop OUD is made up of those individuals who were prescribed opioids by a health-care provider for a pain condition. (7,8) Some of these individuals may have turned to the illicit market in order to maintain an ongoing supply of opioids following discontinuation of their prescription by Canadian Guidelines on Opioid Use Disorder Among Older Adults a health-care professional. Opioid withdrawal pain can perpetuate the unintended long-term use of opioids for chronic non-cancer pain or due to an OUD, with underlying drivers being opioid-induced hyperalgesia and withdrawal-associated injury-site pain. (9,(10)(11)(12) In Canada, 43.9% of adults > 55 years of age have used a prescription opioid and 1.1% of that group have done so daily (or almost daily) in the last year. (13) Though the proportion of people starting opioid therapy in Canada has trended down from 2013 to 2018, those over 65 have consistently received more new opioid prescriptions and have a higher proportion that go on to long-term opioid therapy (24.8%) than any other age group. (14) From 2007 to 2015, hospitalizations for opioid overdose (referred to as poisonings) in Canada were consistently higher in older adults than in any other age cohort: At over 20 per 100,000, older-adult admissions are almost double that of 15 to 24-year-olds, and represent 30% of all admissions to hospital for opioid poisoning. (15) Only recently by 2017 have younger adults in Canada started to equal and just surpass older adults in hospitalizations related to opioid poisonings. Most opioid poisonings in adults in Canada are accidental; however, 30% are intentional. (16) A recent study found that in older adults, opioid misuse was associated with increased odds of suicidal ideation. (17) According to a US national survey in 2016, 0.8% of adults surveyed met Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV) criteria for OUD in the past year. (18) There are no comparable Canadian studies that use DSM criteria. However one used WHO criteria and estimated a past year prevalence of OUD in Canadian adults to be 0.9% for drug abuse, and 0.5% for drug dependence. Yet reporting of prevalence data is lacking specific to those over 65 using opioids. (19,20) OUD may present more subtly in older adults than their younger counterparts and require a more nuanced approach. (21) OUD may overlap with physiologic tolerance alone and may be mistaken for or masked by other medical conditions. Consequences from opioid use may not be recognized in older adults who have stopped work and who have restricted social networks. Social stigma and cognitive impairment may each play a role in under-identification.
Adults entering older age are having an effect on the changing demographics of substance use and the need for treatment, its utilization, and its cost. For example, one study from New York City found that, as of 2012, adults > 60 years of age comprised 13.1% of those in opioid treatment programs, up from 1.7% in 2006. (22) This study also noted a shift from illicit drugs to those obtained by prescription as the primary type of opioid used. Additionally, when compared to their younger counterparts, older US veterans with OUD have higher rates of comorbid mood disorder, post-traumatic stress disorder, hepatitis C, human immunodeficiency virus, and chronic pain, including neuropathy, which has notably increased the cost of care. (23) The purpose of this article is to outline the issues facing older adults with, or at risk for, an OUD, and to provide a summary of recommendations for the prevention, screening, assessment, and treatment of an OUD in those ≥ 65 years of age. The full guidelines can be accessed electronically (www.ccsmh.ca).
# METHODS
An experienced librarian and research assistants conducted a systematic literature search for relevant studies related to opioid use and opioid use disorder in adults and older adults. The databases searched included the Cochrane Library, EMBASE, PsychInfo, International Guideline Library, and PubMed. Included studies for the recommendations were restricted to human and written in English, with publications dates from 2008 through March 2018. The date limitation of the literature was decided a priori based on the changes observed in the last decade related to the opioid crisis in Canada. More recent literature was included in the introduction and discussion.
An interdisciplinary guideline development committee was set up through the Canadian Coalition of Seniors' Mental Health, consisting of two addiction medicine specialists, two psychiatrists, a physical medicine and rehabilitation specialist, a nurse practitioner, a pharmacist, a family physician with expertise in care of the elderly, as well as a person with lived experience. The committee members identified the top quality guidelines on OUD published using the Appraisal of Guidelines for Research & Evaluation Instrument (AGREE II). (24) We then modified the existing key guidelines using the ADAPTE collaboration process (25) in order to customize the selected guidelines for older adults and the Canadian context. We formulated questions in the PICOT format (Population, Intervention, Comparator, Outcome and Time) as a working group, and populated the questions with answers obtained from the previously chosen key guidelines, then supplemented this information with evidence from current literature.
Working group members drafted recommendations and provided the evidence for each of the recommendations. The person with lived experience provided views and preferences of the target population. The draft recommendations were then reviewed by the whole working group, feedback integrated, so that the final wording of each recommendation was the result of full consensus. Each recommendation was then evaluated using the GRADE system (Grades of Recommendation Assessment, Development, and Evaluation). (26,27) GRADE scores the quality of the evidence as high, moderate, low or very low. It was agreed that "low" and "very low" scores would be amalgamated as "low". The strength of the recommendations was scored as strong or weak. (26,27) We continued to discuss each recommendation and evaluation until we reached 100% consensus on each recommendation. The final recommendations were then sent for external peer review. The working group members integrated the majority of the comments from external reviewers into the guidelines after discussion.
# RESULTS
# Selection of the Previous Guidelines for Adaptation
Only one previous guideline published by the Royal College of Psychiatrists (United Kingdom) in the last 10 years for the prevention, assessment, and treatment of OUD specific to older adults was identified in the English language literature searched. (28) We chose to include this guideline for its direct relevance to older adults, despite a low-quality rating on the AGREE II tool.
We closely reviewed the top four rated OUD guidelines focused on adults in general (not just older adults) published in the last 10 years. (29)(30)(31)(32) We chose the US Veterans' Affairs and Department of Defense's guideline (2015) as the best rated guideline to use as a starting point, per the AGREE II tool. We also relied on elements of the Canadian Clinical Practice Guideline for Opioid Use Disorder for its applicability to our local context. (32) Recommendations from less robust guidelines and clinical practice tips on OUD were considered when the selected guidelines did not address an issue fully or supporting evidence was needed. (33)(34)(35)(36)(37)(38)(39)(40)(41) We considered costs, benefits, and harms when we were drafting the recommendations.
No published randomized, controlled trials were identified on the prevention, assessment, or treatment of OUD in older adults. Therefore, the main evidence used to generate the recommendations was based on the above guidelines, along with systematic and narrative reviews on older adults since 2015. (42)(43)(44)(45)(46)(47)(48)(49) In addition, numerous clinical and observational studies extrapolated from younger adults, some observational cohorts in older adults, as well as clinical expertise, informed these guidelines. For the section on prevention, key Canadian and US guidelines were identified for the treatment of chronic non-cancer pain (CNCP). (50)(51)(52)
# RECOMMENDATIONS Prevention of Opioid Use Disorder Among Older Adults
To curb opioid poisonings and the development of OUD, measures need to be implemented for both primary and secondary prevention. These issues are outlined in the questions (A & B) and addressed in the recommendations (1-9) listed below.
# Question A: In older adults, what measures can reduce the risk of developing an OUD?
# Recommendation 1
In order to avoid the risk of developing an OUD, older adults with acute pain in whom opioids are being considered should receive the lowest effective dose of the least potent immediate release opioid for a duration of ≤ 3 days and rarely > 7 days. (44,(51)(52)(53)(54)(55)
# Recommendation 2
In most circumstances, avoid prescribing opioids for older adults with CNCP. For severe pain that is not responsive to non-opioid therapy in patients without a history of substance use disorder and without active mental illness, a trial of opioid treatment may be considered. Consider obtaining a second opinion before prescribing long-term opioid therapy. After explaining the risks and benefits to the patient, prescribe only in accordance with published guidelines for adults, initiate and maintain opioids at lower doses than for younger adults, and discontinue if function does not improve or if adverse effects arise. (50,51,53,(56)(57)(58)
# Recommendation 3
Patients and their families should be advised to store opioids safely, never to share their medication, and to return unused medication to the pharmacist for disposal. (50,59,60)
# Recommendation 4
Pharmacists and nursing staff are advised to inform the prescriber if there are concerns with co-prescribing, adherence to treatment, or intoxication. (61,51)
# Recommendation 5
In older adults with polypharmacy or comorbidities that increase the risk of opioid overdose (e.g., benzodiazepine use, renal failure, sleep apnea), the lowest effective opioid dose should be used and tapering the opioid and/or other medications should be considered. (50,51,(62)(63)(64)
# Recommendation 6
Once the decision is made to reduce the opioid dose, a slow outpatient tapering schedule (e.g., 5% drop every 2-8 weeks with rest periods) is preferable to more rapid tapering. A faster taper schedule may be attempted under special circumstances of medical need, if the patient is in a treatment setting with medical supervision. (32,9,(65)(66)(67) GRADE: Quality: Low; Strength: Weak
# Recommendation 7
Dispense naloxone kits to anyone using opioids regularly for any reason (CNCP, OUD, etc.), and train household members and support staff on use. (68,69)
# Recommendation 8
Include skilled pharmacists and/or nurses on teams to educate patients on appropriate use of opioids and other medications. (70)(71)(72) GRADE Quality: Low; Strength: Weak
# Recommendation 9
Older adults with, or at risk for, an OUD should be given advice on strategies to reduce the risk of opioid overdose, and information on supervised consumption sites, if available in the community. (73)(74)(75)
# Screening for and Assessment of Opioid Use Disorder Among Older Adults
Screening and assessment are the starting points for care of a person with an OUD, and many effective approaches to both exist for adults. (76) Listed below are questions (C-E) along with recommendations (10-12) for screening and assessment of OUD specific to older adults: Question C: In older adults, when and how should one screen for an OUD?
# Recommendation 10
Older adults should be screened for an OUD using validated tools, if appropriate (e.g., CAGE-AID, ASSIST, PDUQp, ORT, POMI, COMM). Medication reviews and urine drug screens should be utilized if the patient is taking opioids for CNCP or an OUD. (30,41,(77)(78)(79)(80)
# Recommendation 11
Identify a diagnosis of an OUD through completion of a comprehensive assessment, including substance use, medical, pain, psychiatric, cognitive, and psychosocial history within a cultural context, and conduct a brief functional assessment. The use of validated assessment tools may be useful in this process. In addition, a detailed physical examination must be conducted, with an emphasis on signs of intoxication or withdrawal and the sequelae of substance use. Laboratory and other investigations (including urine drug tests) should be performed as appropriate for the medical conditions identified. Reassessment is essential and should be conducted episodically throughout long-term care. (28,33,41,76,81,82)
# Recommendation 12
A full explanation of findings and diagnosis must be shared with the patient and, if appropriate, caregivers. Therapeutic optimism should be provided (i.e., hope given that addiction is a treatable disorder and that older adults, and especially older women, typically have better treatment outcomes than younger adults). (42,83) GRADE: Consensus
# Treatment of Opioid Use DisorderAmong Older Adults
# Pharmacological Treatment
Issues related to pharmacological treatments are asked in questions (F-H) and answered in recommendations (13-26) listed below.
Question F: In older adults with an OUD, what approaches and medications are safe and effective for opioid withdrawal management?
# Recommendation 13
Opioid withdrawal management should only be offered in the context of connection to long-term addiction treatment. (30)(31)(32)41,(43)(44)(45)(46)(47)(84)(85)(86)
# Recommendation 14
Induction onto an opioid agonist is recommended over a nonopioid treatment withdrawal management in older adults with an OUD. If a trial of tapering is attempted, there should be the option to initiate longer-term opioid agonist therapy or opioid antagonist therapy. (30)(31)(32)41,(43)(44)(45)(46)(47)(84)(85)(86)(87)(88)(89)(90)(91)
# Recommendation 15
Buprenorphine-naloxone should be considered first line for opioid withdrawal management in older adults. Methadone is an alternative that may be used, however consider the added risk of adverse events. (30)(31)(32)44,(91)(92)(93) GRADE Quality: Moderate; Strength: Weak
# Recommendation 16
For symptom control during opioid withdrawal management, adjuvant medications can be used in a time-limited fashion, but with caution due to medical comorbidities, side effect risk, and other concerns related to older age. (28,(30)(31)(32)(94)(95)(96)
# Question G: What medications and protocol adjustments are safe and effective in the treatment of an OUD in older adults to improve outcomes?
# Recommendation 17
Buprenorphine maintenance should be considered a first-line treatment for an OUD in older adults. (
# Recommendation 18
Methadone maintenance treatment may be considered for those older adults who cannot tolerate buprenorphine maintenance or in whom it has been ineffective. (4,22,(28)(29)(30)(31)(32)(33)(41)(42)(43)(44)(45)101,(109)(110)(111)(112)(113)(114) GRADE Quality: Moderate; Strength: Strong
# Recommendation 19
If renal function is adequate, daily witnessed ingestion of slow-release oral morphine may be considered with caution for those older adults in whom buprenorphine and methadone maintenance have been ineffective or could not be tolerated. Careful supervision of initiation onto short-acting morphine first is recommended, prior to transition to maintenance with the long-acting 24-hour formulation. (32,99,115)
# Recommendation 20
For older adults with an OUD for whom opioid agonist treatment is contraindicated, unacceptable, unavailable, or discontinued and who have established abstinence for a sufficient period of time, naltrexone may be offered. (30,32,(43)(44)(45)47,100,101,(116)(117)(118)(119)(120) GRADE Quality: Moderate; Strength: Weak
# Recommendation 21
Offer medications for an OUD in the context of connection to long-term addiction, mental health, and primary care treatment, where careful monitoring and dose titration can occur. (18,28,31,39,44,121)
# Recommendation 22
Advise patients that the use of alcohol, benzodiazepines, and other sedative-hypnotics is hazardous when combined with opioid agonist treatment. If the older adult is living in the community and is already physiologically dependent on one of these substances, then slow tapering of the substance(s) (to elimination, if possible), rather than abrupt cessation, is recommended. If the patient is in hospital, residential treatment, or a longterm care setting and medically managed by an experienced provider, detoxification can progress more rapidly, concurrent with the initiation or stabilization on medications for OUD. (30,32,36,45,122,123)
# Recommendation 23
Early take-home dosing for buprenorphine maintenance treatment may be considered, including home induction in patients who are low risk, if they find it difficult to attend the office in withdrawal and if the patient has social supports at home. This approach should not be considered for methadone initiation unless supervised (e.g., reliable caregiver or medical personal administration). (32,124)
# Recommendation 24
Reduce initial doses of medications for treatment of an OUD (e.g., by 25-50%); slow dose escalation frequency (e.g., by 25-50%); use the lowest effective dose to suppress craving, withdrawal symptoms and drug use; and monitor closely (especially for sleep apnea, sedation, cognitive impairment, and falls with opioid agonists). (28,43,(124)(125)(126)(127)(128)
# Recommendation 25
The threshold to admit an older adult with social, psychological, or physical comorbidities to either residential or hospital care for opioid withdrawal management or induction onto medications for an OUD should be lower than for a younger adult. (41,129)
# Recommendation 26
In older adults on medication for an OUD requiring management of mild-to-moderate acute pain or CNCP, non-medication and non-opioid strategies are recommended. For those on an opioid agonist for an OUD who have severe acute pain that has been unresponsive to non-opioid strategies, a short-acting opioid may be considered for a short duration (1-7 days) along with a taper, if necessary (1-7 days). (30,32,36,39,50,51,62,(130)(131)(132) GRADE Quality: Moderate; Strength: Weak
# Other Comments on Medications for OUD
In younger adults, for the palliative end of the OUD spectrum in whom all other modalities have been unsuccessful, there is currently available in Canada injectable opioid agonist treatment (iOAT). No data on iOAT in older adults were identified. The risk of adverse events with injectable medications rises with age, as does immunosuppression and mobility issues for accessing the three-times-daily visit to a clinic needed for iOAT. BC is currently the only province providing and paying for iOAT, and the cost is higher than with all other opioid agonist and antagonist treatments. Due to all of the above issues, we cannot endorse iOAT treatment in older adults at this time and thus have not included it in these guidelines.
# Psychosocial Treatment
Although robust data on behavioural interventions in older adults with OUD are lacking, an understanding of the importance of incorporating psychosocial supports is clear: Older adults may have an accumulation of losses (job, spouse, family, friends, role, home), and may struggle with lack of social support. (133,134) The key question (Question I) regarding psychosocial interventions in older adults with an OUD is outlined below, along with related recommendations (27)(28)(29)(30)(31).
# Question I: In older adults, what psychosocial interventions are effective in the treatment of an OUD to improve outcomes?
# Recommendation 27
Psychosocial interventions should be offered concurrently with medications for an OUD, at a pace appropriate for age and patient needs, but they should not be viewed as a mandatory requirement for accessing pharmacotherapy. (135)(136)(137)(138)(139)
# Recommendation 28
Contingency management may be offered as part of opioid treatment programs and used if accepted by the patient. (140)(141)(142)(143)(144)(145)(146)(147) GRADE Quality: Moderate; Strength: Weak Question J: For older adults with an OUD, what are the treatment considerations for special populations (specifically Indigenous peoples)?
# Recommendation 29
Traditional healing practices used by Indigenous communities can be integrated with buprenorphine treatment to improve outcomes for an OUD. (148) GRADE Quality: Low; Strength: Weak
# Setting
Setting can refer to treatment setting and also the living situation of the older adult.
# Question K: For older adults with an OUD, what specific treatment recommendations are suggested for non-community-based facilities?
# Recommendation 30
If experienced, clinicians may manage older adults with a mild-to-moderate OUD; however, for patients with more severe or complex disorders, it is recommended that personnel or teams with advanced substance use disorder management skills be accessible to support clinicians and to enhance their capacity to care for patients in all settings. The threshold for an admission to hospital or drug and alcohol treatment facility under the care of an Addiction Medicine Specialist is lower than for younger adults, and closer follow-up is needed on discharge to ensure appropriate community-based support. (44,(149)(150)(151)
# Recommendation 31
Older adults with an OUD who are admitted to a hospital, drug and alcohol treatment facility, or non-medical facility with access to medical care (e.g., prisons and shelters) should be offered opioid agonist treatment at the onset of withdrawal (advisable within 1-3 days), with bridging pharmacological treatment on discharge with confirmed transfer of care. (31,98,109,,152-159)
# Recommendation 32
The cost of medically-recommended pharmacological and non-pharmacological treatment for an OUD in older adults should be covered by the public health plan. (28,31,32,36,160) GRADE Quality: Moderate; Strength: Strong
# DISCUSSION
No previous guidelines or clinical trials for the prevention, screening or management of OUD have been undertaken in adults over 65 despite the increasing prevalence of OUD in this age group. Our guidelines represent a systematic effort to identify evidence from literature, taking into consideration the context, the expertise of individuals working with older adults, the input from individuals with lived experience, and the multidisciplinary guideline team. These guidelines provide 32 recommendations covering aspects of opioid management from prevention, screening, assessment, pharmacological treatment, psychosocial interventions, treatment setting, and steps to recovery. Many of the recommendations are in alignment with the other two recent Canadian guidelines on OUD treatment in adults. (32,161) The challenges and limitations in writing these guidelines were many, most important of which was the lack of direct evidence to inform the guidelines of the efficacy or effectiveness of current treatment approaches in this population. Other limitations include lack of a consistent definition for older adults and successful treatment outcome measures for OUD. Finally, there are limited data and empirical evidence for the management of OUD in special populations of older adults related to sex, gender, and ethnic group.
Studies with a focus on older adults are needed to provide empirical evidence for the effectiveness of pharmacological and psychosocial treatments. The deliberate inclusion of subgroups in these studies will provide data for future guidelines to improve their external validity. Future studies to define meaningful and patient-centered treatment outcomes targets are needed. Also, the role of other interventions that are less studied, including self-help groups, is yet to be delineated. Canadian-based data are needed on the rates of opioid use and OUD in older adults, as well as rates of overdose and mortality, in order to design targeted prevention strategies and test the effectiveness of OUD treatment and opioid overdose mitigation.
# Facilitators and Barriers for the Application of These Recommendations
In Canada, the need for expanded resources for treatment of older adults with OUD will likely rise in the coming years. Evidence-based treatment for OUD in adults in general is costeffective and decreases both morbidity and mortality. (162) The lifetime savings to provincial and national health care based on this model could be substantial. All components of the Canadian health-care system must prepare to provide addiction treatment to older adults, including those affected by an OUD.
The uptake of these guidelines will be monitored through tracking CCSMH website visits, orders of print version, distribution of office handouts, and journal article reads. There are plans to update the guidelines approximately every five years, as needed, if new literature becomes available that may significantly change management.
# CONCLUSION
Older adults are susceptible to adverse health consequences of opioid use. There is a growing need for opioid management guidelines for older adults as the population in Canada ages. The current recommendations are intended to provide healthcare workers and policy-makers with evidence-informed, clinically relevant direction and advice on the prevention, screening, assessment, and treatment of OUD in older adults. We hope practitioners will find them both a practical and useful clinical aide, and that community members will find them a helpful education resource. The expanded version of these guidelines can be accessed electronically (www.ccsmh.ca).
# ACKNOWLEDGEMENTS
Funding was provided by Health Canada, Substance Use and Addictions Program. In addition, we would like to thank the Canadian Centre of Substance Use and Addiction (CCSA) and the Behavioral Supports Ontario Substance Use Collaborative for their support, Dr. Meldon Kahan for early guidance, and for external review along with Dr. Ashok Krishnamoorthy, and Dr. John Fraser. Thanks goes to Tonya Mahar for her assistance with literature searches. Finally, we would like to acknowledge the continued dedication of our steering committee, particularly the Co-Lead Dr. David Conn, along with the contribution of our Director, Claire Checkland, and our coordinators: Indira Fernando, Natasha Kachan, and Marc-André LeBlanc.
# DISCLAIMER
This publication is intended for information purposes only, and is not intended to be interpreted or used as a standard of medical practice. Best efforts were used to ensure that the information in this publication is accurate; however, the publisher and every person involved in the creation of this publication disclaim any warranty as to the accuracy, completeness or currency of the contents of this publication. This publication is distributed with the understanding that neither the publisher nor any person involved in the creation of this publication is rendering professional advice. Physicians and other readers must determine the appropriate clinical care for each individual patient on the basis of all the clinical data available for the individual case. The publisher and every person involved in the creation of this publication disclaim any liability arising from contract, negligence, or any other cause of action, to any party, for the publication contents or any consequences arising from its use.
# CONFLICT OF INTEREST DISCLOSURES
The project was funded by Health Canada (Substance Use and Addictions Program). The funder had no role in the creation or approval of the recommendations. Authors received an honorarium for their work. A rigorous process was undertaken to ensure that members of the working group did not have any significant conflict of interest. | None | None |
51741f21fd32d7ceb6a4811504e51c5f7fb8bdb1 | cma | None | To aid practitioners in prescribing unfractionated heparin (UFH), low molecular weight heparin (LMWH), and fondaparinux to patients.UFH and LMWH act as anticoagulants by forming complexes with and substantially increasing the activity of antithrombin (AT). The AT-UFH or AT-LMWH complexes catalyze the inhibition of several activated blood coagulation factors, especially thrombin (factor IIa) and factor Xa, as well as factors IXa, XIa, and XIIa. This ultimately reduces the formation of thrombin and fibrin.#
LMWH is derived by chemical or enzymatic depolymerization of UFH. These smaller molecules retain the ability to inactivate Factor Xa but have substantially reduced inhibitory activity against thrombin. LMWH has more predictable pharmacokinetic properties compared with UFH; this allows LMWH to be administered in fixed doses based on patient weight, without the need for adjustment based on laboratory monitoring.
Fondaparinux is a synthetic and specific inhibitor of factor Xa. It also acts by potentiating antithrombin's activity. AT-fondaparinux complexes selectively inhibit factor Xa. Neutralization of factor Xa reduces the formation of thrombin and fibrin. Fondaparinux does not inactivate thrombin.
# USES FOR UFH AND LMWH:
- Prevention Intravenous (IV) UFH must be adjusted to maintain a therapeutic activated partial thromboplastin time (aPTT). See below for details.
- VTE prophylaxis: 5,000 units (U) subcutaneously (SC) q8h or q12h.
- Acute VTE treatment: IV bolus 5,000 U (or 80 U/kg) followed by a rate of 20 U/kg/hour, adjusted to maintain a therapeutic aPTT or anti-factor Xa assay (follow institutional guidelines).
# DOSING OF LMWH:
Dosing of LMWH depends on the drug used. In Canada, the four commonly used LMWHs are dalteparin (Fragmin ), enoxaparin (Lovenox ), nadroparin (Fraxiparine ), and tinzaparin (Innohep ).
Note: Therapeutic dosing of LMWH is based on actual body weight and should not be capped; there is currently no established maximum dose in VTE treatment.
- enoxaparin: <75 years -30 mg IV x 1, then enoxaparin 1 mg/kg SC BID ≥75 years -0.75 mg/kg SC BID
# DOSING OF FONDAPARINUX:
- VTE prophylaxis: 2.5 mg once daily - VTE treatment: 5 mg once daily for weight 100 kg - Acute coronary syndromes: 2.5 mg once daily
# MONITORING OF UFH, LMWH AND FONDAPARINUX:
- IV UFH: Inadequate UFH therapy in the initial 24-48 hours of treatment predisposes to progressive and/or recurrent VTE. The use of a standardized UFH dosing nomogram is encouraged to help achieve and maintain the aPTT in the therapeutic range efficiently. As aPTT reagents vary in their sensitivity to UFH, each laboratory should establish a therapeutic range locally.
Prior to starting IV UFH, a baseline complete blood count (CBC), prothrombin time (PT)/international normalized ratio (INR) and aPTT should be drawn. Monitoring of the aPTT is initially required q6h to guide adjustment of the infusion rate. Once a therapeutic range is achieved, the aPTT can be checked once daily. Monitoring of the platelet count in patients receiving IV UFH is advised if the infusion will be given for ≥4 days, due to the risk of developing HIT (see Clinical Guide: Heparin-induced Thrombocytopenia).
- LMWH: Prior to starting LMWH, a baseline CBC and creatinine should be checked. Laboratory monitoring is not generally required in patients receiving LMWH. In patients receiving therapeutic LMWH with moderate-to-severe renal insufficiency or during pregnancy, laboratory monitoring with anti-factor Xa levels may be warranted, although target ranges are uncertain. Usual therapeutic doses of tinzaparin, without anti-factor Xa monitoring, have been used effectively and safely in patients with renal failure (down to a creatinine clearance of 20 mL/min).
- Fondaparinux: Laboratory monitoring of fondaparinux should be done in consultation with a specialist. Specific calibrators are required, and a universal therapeutic target has not been established.
# ADVERSE EFFECTS:
- Bleeding is the most common adverse effect of UFH, LMWH and fondaparinux.
- HIT is an immune-mediated platelet activation has been reported in up to 5% of patients who receive UFH depending on the patient population. It may be associated with life-threatening or fatal arterial or venous thrombosis. Onset is generally between 5 and 10 days after commencing therapy, unless there has been a recent prior exposure to UFH or LMWH, in which case HIT can occur earlier. HIT occurs far less frequently in patients receiving LMWH. If HIT is suspected or diagnosed, all sources of heparin must be stopped (e.g. flushes, prothrombin complex concentrate, some total parenteral nutrition), and an alternative "HIT-safe" anticoagulant such as argatroban, danaparoid, bivalirudin, fondaparinux, or a direct oral anticoagulant should generally be started. There is some evidence to support the safety of direct oral anticoagulants for treatment of HIT, but their use for this purpose is still considered off-label, as is that of bivalirudin and fondaparinux (see Clinical Guide: Heparin-induced Thrombocytopenia). - Osteoporosis is an uncommon side-effect associated with prolonged use of high doses of UFH.
Three months of UFH treatment at a moderate dose (20,000 U/day) is rarely associated with clinically significant osteoporosis. - Hyperkalemia is a rare complication of UFH and is caused by aldosterone suppression.
# - Mildly increased levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT)
with no evidence of clinical liver dysfunction may occur in patients who receive UFH or LMWH. This does not appear to be clinically significant. Transaminase values generally return to normal within 15-30 days.
# PERI-PROCEDURE MANAGEMENT:
- For therapeutic IV UFH, stop heparin infusion 4-6 hours prior to a procedure; consideration should be given to re-checking the aPTT to ensure normalization, particularly before procedures with higher bleeding risk.
- There is no need to stop prophylactic doses of UFH prior to most procedures; however, anesthetic guidelines and local anesthetic practices should be followed for patients receiving neuroaxial anesthesia (e.g. epidurals). - For once-daily therapeutic LMWH, stop at least 24 hours prior to procedure depending on renal function, risk of bleeding, and indication for anticoagulation. For twice-daily LMWH, stop at least 12 hours prior to the procedure. For patients receiving neuroaxial anesthesia, anesthetic guidelines and local anesthetic practices should be followed. - There is no need to stop prophylactic doses of LMWH prior to most procedures; however, anesthetic guidelines and local anesthetic practices should be followed for patients receiving neuraxial anesthesia. - The half-life of fondaparinux is approximately 17-21 hours in patients with normal renal function.
Stopping at least 24 hours prior to most procedures is suggested. Anesthetic guidelines and local anesthetic practices should be followed for patients receiving neuraxial anesthesia.
# BLEEDING MANAGEMENT OR EMERGENCY SURGERY:
UFH, LMWH, and fondaparinux should be stopped in case of serious bleeding. When reversal of IV UFH is required, protamine sulfate can be used to reverse the anticoagulant effect (1 mg of protamine reverses 100 U of UFH). One approach to determine the required dose of protamine is to take 100% of the UFH dose given in the previous hour + 50% of the UFH dose given in the hour before + 25% of the UFH dose given in the hour before that; this is an estimate of the amount of UFH to be reversed. The usual initial dose of protamine is 20-50 mg by slow IV infusion over 15-20 minutes due to the risk of anaphylactoid reactions.
LMWH rarely needs to be reversed acutely, and protamine is much less effective than for UFH.
No reversal agent is currently available in Canada for fondaparinux.
Andexanet alfa, an antidote that rapidly reverses the anticoagulant activity of all factor Xa inhibitors (UFH, LMWH, fondaparinux, and direct factor Xa inhibitors such as rivaroxaban, apixaban and edoxaban) has shown efficacy in clinical trials, but is not yet approved by Health Canada.
# SPECIAL CONSIDERATIONS:
# Overlap with warfarin
In most cases, warfarin can be started on the same day as UFH, LMWH or fondaparinux. Warfarin and UFH, LMWH or fondaparinux should overlap for at least 5 days and until the INR value is within therapeutic range for 2 consecutive days.
# Pregnancy
The management of thromboembolism during pregnancy requires LMWH or, less commonly, UFH. Consultation with a specialist is advised. Peripartum management of anticoagulation requires advanced planning. Secondary prevention in the postpartum period can be achieved with LMWH or warfarin. Women can breastfeed while being treated with LMWH or warfarin therapy. There are very limited clinical data available on the use of fondaparinux in pregnant women(see Clinical Guides: Pregnancy: Venous Thromboembolism Treatment and Pregnancy: Thromboprophylaxis).
# Renal Impairment
LMWHs are renally excreted and thus bioaccumulation may occur in patients with renal impairment. There are data to suggest differences exist in the rate of accumulation among various LMWH agents. CrCl should be calculated using the Cockcroft-Gault equation in all patients receiving LMWH. In patients receiving therapeutic doses of LMWH who have a CrCl 0.4 IU/mL; however, good data showing a correlation between these levels and poor clinical outcomes are lacking. Fondaparinux is excreted unchanged in the urine and bioaccumulation is expected to occur in patients with renal impairment, and is contraindicated in patients with a CrCl <30 mL/min.
# Pediatrics
In children, studies have demonstrated age-dependent dosing of UFH and LMWH. Therapeutic UFH is titrated to achieve a target anti-Xa range of 0.35-0.7 U/mL or an aPTT range that correlates with this anti-Xa range. If UFH boluses are used to initiate therapy, the bolus should be no greater than 75-100 U/kg, and boluses should be withheld or reduced if there are significant bleeding risks. Where possible, pediatricians with expertise in thromboembolism should manage pediatric patients with thromboembolism. When this is not possible, coordinated care by a neonatologist/pediatrician and an adult hematologist, supported by consultation with an experienced pediatric hematologist, is recommended.
OTHER RELEVANT THROMBOSIS CANADA CLINICAL GUIDES:
# Date of Version: 10November2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein. | To aid practitioners in prescribing unfractionated heparin (UFH), low molecular weight heparin (LMWH), and fondaparinux to patients.UFH and LMWH act as anticoagulants by forming complexes with and substantially increasing the activity of antithrombin (AT). The AT-UFH or AT-LMWH complexes catalyze the inhibition of several activated blood coagulation factors, especially thrombin (factor IIa) and factor Xa, as well as factors IXa, XIa, and XIIa. This ultimately reduces the formation of thrombin and fibrin.#
LMWH is derived by chemical or enzymatic depolymerization of UFH. These smaller molecules retain the ability to inactivate Factor Xa but have substantially reduced inhibitory activity against thrombin. LMWH has more predictable pharmacokinetic properties compared with UFH; this allows LMWH to be administered in fixed doses based on patient weight, without the need for adjustment based on laboratory monitoring.
Fondaparinux is a synthetic and specific inhibitor of factor Xa. It also acts by potentiating antithrombin's activity. AT-fondaparinux complexes selectively inhibit factor Xa. Neutralization of factor Xa reduces the formation of thrombin and fibrin. Fondaparinux does not inactivate thrombin.
# USES FOR UFH AND LMWH:
1. Prevention Intravenous (IV) UFH must be adjusted to maintain a therapeutic activated partial thromboplastin time (aPTT). See below for details.
• VTE prophylaxis: 5,000 units (U) subcutaneously (SC) q8h or q12h.
• Acute VTE treatment: IV bolus 5,000 U (or 80 U/kg) followed by a rate of 20 U/kg/hour, adjusted to maintain a therapeutic aPTT or anti-factor Xa assay (follow institutional guidelines).
# DOSING OF LMWH:
Dosing of LMWH depends on the drug used. In Canada, the four commonly used LMWHs are dalteparin (Fragmin ), enoxaparin (Lovenox ), nadroparin (Fraxiparine ), and tinzaparin (Innohep ).
Note: Therapeutic dosing of LMWH is based on actual body weight and should not be capped; there is currently no established maximum dose in VTE treatment.
• enoxaparin: <75 years -30 mg IV x 1, then enoxaparin 1 mg/kg SC BID ≥75 years -0.75 mg/kg SC BID
# DOSING OF FONDAPARINUX:
• VTE prophylaxis: 2.5 mg once daily • VTE treatment: 5 mg once daily for weight <50 kg 7.5 mg once daily for weight 50 -100 kg 10 mg once daily for weight >100 kg • Acute coronary syndromes: 2.5 mg once daily
# MONITORING OF UFH, LMWH AND FONDAPARINUX:
• IV UFH: Inadequate UFH therapy in the initial 24-48 hours of treatment predisposes to progressive and/or recurrent VTE. The use of a standardized UFH dosing nomogram is encouraged to help achieve and maintain the aPTT in the therapeutic range efficiently. As aPTT reagents vary in their sensitivity to UFH, each laboratory should establish a therapeutic range locally.
Prior to starting IV UFH, a baseline complete blood count (CBC), prothrombin time (PT)/international normalized ratio (INR) and aPTT should be drawn. Monitoring of the aPTT is initially required q6h to guide adjustment of the infusion rate. Once a therapeutic range is achieved, the aPTT can be checked once daily. Monitoring of the platelet count in patients receiving IV UFH is advised if the infusion will be given for ≥4 days, due to the risk of developing HIT (see Clinical Guide: Heparin-induced Thrombocytopenia).
• LMWH: Prior to starting LMWH, a baseline CBC and creatinine should be checked. Laboratory monitoring is not generally required in patients receiving LMWH. In patients receiving therapeutic LMWH with moderate-to-severe renal insufficiency or during pregnancy, laboratory monitoring with anti-factor Xa levels may be warranted, although target ranges are uncertain. Usual therapeutic doses of tinzaparin, without anti-factor Xa monitoring, have been used effectively and safely in patients with renal failure (down to a creatinine clearance [CrCl] of 20 mL/min).
• Fondaparinux: Laboratory monitoring of fondaparinux should be done in consultation with a specialist. Specific calibrators are required, and a universal therapeutic target has not been established.
# ADVERSE EFFECTS:
• Bleeding is the most common adverse effect of UFH, LMWH and fondaparinux.
• HIT is an immune-mediated platelet activation has been reported in up to 5% of patients who receive UFH depending on the patient population. It may be associated with life-threatening or fatal arterial or venous thrombosis. Onset is generally between 5 and 10 days after commencing therapy, unless there has been a recent prior exposure to UFH or LMWH, in which case HIT can occur earlier. HIT occurs far less frequently in patients receiving LMWH. If HIT is suspected or diagnosed, all sources of heparin must be stopped (e.g. flushes, prothrombin complex concentrate, some total parenteral nutrition), and an alternative "HIT-safe" anticoagulant such as argatroban, danaparoid, bivalirudin, fondaparinux, or a direct oral anticoagulant should generally be started. There is some evidence to support the safety of direct oral anticoagulants for treatment of HIT, but their use for this purpose is still considered off-label, as is that of bivalirudin and fondaparinux (see Clinical Guide: Heparin-induced Thrombocytopenia). • Osteoporosis is an uncommon side-effect associated with prolonged use of high doses of UFH.
Three months of UFH treatment at a moderate dose (20,000 U/day) is rarely associated with clinically significant osteoporosis. • Hyperkalemia is a rare complication of UFH and is caused by aldosterone suppression.
# • Mildly increased levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT)
with no evidence of clinical liver dysfunction may occur in patients who receive UFH or LMWH. This does not appear to be clinically significant. Transaminase values generally return to normal within 15-30 days.
# PERI-PROCEDURE MANAGEMENT:
• For therapeutic IV UFH, stop heparin infusion 4-6 hours prior to a procedure; consideration should be given to re-checking the aPTT to ensure normalization, particularly before procedures with higher bleeding risk.
• There is no need to stop prophylactic doses of UFH prior to most procedures; however, anesthetic guidelines and local anesthetic practices should be followed for patients receiving neuroaxial anesthesia (e.g. epidurals). • For once-daily therapeutic LMWH, stop at least 24 hours prior to procedure depending on renal function, risk of bleeding, and indication for anticoagulation. For twice-daily LMWH, stop at least 12 hours prior to the procedure. For patients receiving neuroaxial anesthesia, anesthetic guidelines and local anesthetic practices should be followed. • There is no need to stop prophylactic doses of LMWH prior to most procedures; however, anesthetic guidelines and local anesthetic practices should be followed for patients receiving neuraxial anesthesia. • The half-life of fondaparinux is approximately 17-21 hours in patients with normal renal function.
Stopping at least 24 hours prior to most procedures is suggested. Anesthetic guidelines and local anesthetic practices should be followed for patients receiving neuraxial anesthesia.
# BLEEDING MANAGEMENT OR EMERGENCY SURGERY:
UFH, LMWH, and fondaparinux should be stopped in case of serious bleeding. When reversal of IV UFH is required, protamine sulfate can be used to reverse the anticoagulant effect (1 mg of protamine reverses 100 U of UFH). One approach to determine the required dose of protamine is to take 100% of the UFH dose given in the previous hour + 50% of the UFH dose given in the hour before + 25% of the UFH dose given in the hour before that; this is an estimate of the amount of UFH to be reversed. The usual initial dose of protamine is 20-50 mg by slow IV infusion over 15-20 minutes due to the risk of anaphylactoid reactions.
LMWH rarely needs to be reversed acutely, and protamine is much less effective than for UFH.
No reversal agent is currently available in Canada for fondaparinux.
Andexanet alfa, an antidote that rapidly reverses the anticoagulant activity of all factor Xa inhibitors (UFH, LMWH, fondaparinux, and direct factor Xa inhibitors such as rivaroxaban, apixaban and edoxaban) has shown efficacy in clinical trials, but is not yet approved by Health Canada.
# SPECIAL CONSIDERATIONS:
# Overlap with warfarin
In most cases, warfarin can be started on the same day as UFH, LMWH or fondaparinux. Warfarin and UFH, LMWH or fondaparinux should overlap for at least 5 days and until the INR value is within therapeutic range for 2 consecutive days.
# Pregnancy
The management of thromboembolism during pregnancy requires LMWH or, less commonly, UFH. Consultation with a specialist is advised. Peripartum management of anticoagulation requires advanced planning. Secondary prevention in the postpartum period can be achieved with LMWH or warfarin. Women can breastfeed while being treated with LMWH or warfarin therapy. There are very limited clinical data available on the use of fondaparinux in pregnant women(see Clinical Guides: Pregnancy: Venous Thromboembolism Treatment and Pregnancy: Thromboprophylaxis).
# Renal Impairment
LMWHs are renally excreted and thus bioaccumulation may occur in patients with renal impairment. There are data to suggest differences exist in the rate of accumulation among various LMWH agents. CrCl should be calculated using the Cockcroft-Gault equation in all patients receiving LMWH. In patients receiving therapeutic doses of LMWH who have a CrCl <30 mL/min, consultation with a specialist is advised. For tinzaparin, available evidence demonstrates no accumulation in patients with CrCl levels down to 20 mL/min. There are limited data available in patients with an estimated CrCl <20 mL/min. If therapeutic doses of LMWH are used in patients with severe renal dysfunction (<30 mL/min), testing anti-factor Xa levels to monitor for accumulation should be considered. Some suggest dose-reduction be considered if the trough anti-Xa level is >0.4 IU/mL; however, good data showing a correlation between these levels and poor clinical outcomes are lacking. Fondaparinux is excreted unchanged in the urine and bioaccumulation is expected to occur in patients with renal impairment, and is contraindicated in patients with a CrCl <30 mL/min.
# Pediatrics
In children, studies have demonstrated age-dependent dosing of UFH and LMWH. Therapeutic UFH is titrated to achieve a target anti-Xa range of 0.35-0.7 U/mL or an aPTT range that correlates with this anti-Xa range. If UFH boluses are used to initiate therapy, the bolus should be no greater than 75-100 U/kg, and boluses should be withheld or reduced if there are significant bleeding risks. Where possible, pediatricians with expertise in thromboembolism should manage pediatric patients with thromboembolism. When this is not possible, coordinated care by a neonatologist/pediatrician and an adult hematologist, supported by consultation with an experienced pediatric hematologist, is recommended.
OTHER RELEVANT THROMBOSIS CANADA CLINICAL GUIDES:
# Date of Version: 10November2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein. | None | None |
3fb4152726c26948e58eefe2405958060640f4f6 | cma | None | To provide recommendations for the prevention of venous thromboembolism (VTE) during pregnancy (antepartum) and the postpartum period.VTE complicates 1-2 per 1,000 deliveries. The daily risk of VTE is increased 5-to 10-fold during pregnancy and 15-to 35-fold in the early postpartum period compared to the non-pregnant, agematched population. Although most studies have reported that the elevated risk of VTE returns to baseline by the end of the sixth postpartum week, a small increase in risk may persist for 12 weeks after delivery.#
The absolute risk of pregnancy-related VTE in most women with thrombophilia without a prior thrombotic event or family history remains low (1% or less). However, women who have factor V Leiden homozygosity, prothrombin gene mutation homozygosity, a deficiency of protein C, S or antithrombin (with a positive family history) or who have combined thrombophilia have a higher risk of VTE. The risk of pregnancy-related VTE in thrombophilic women with a positive family history appears to be 2-4 times greater than that in thrombophilic women without a positive family history of VTE.
Previous VTE increases the risk of pregnancy-related deep vein thrombosis (DVT) and pulmonary embolism (PE). Women with one prior episode of VTE associated with a transient risk factor not related to pregnancy or hormone use appear to be at low risk of antepartum recurrence (≤5%) compared with those with an unprovoked, pregnancy-related or estrogen-related VTE (5-10%). The impact of thrombophilia on the risk of recurrent VTE in pregnancy is unclear.
In recent studies, uncomplicated nonemergent caesarean section has not been associated with an increased risk of VTE, compared with vaginal delivery.
Additional clinical risk factors that also appear to increase the risk of pregnancy-associated VTE include: obesity or increased body mass index (BMI), age ≥ 40 years, pre-eclampsia with intrauterine growth restriction, strict antepartum bed rest for at least 7 days, smoking >5 cigarettes/day prior to pregnancy, systemic lupus erythematosus (SLE), sickle cell disease, cancer, cardiac disease, severe ovarian hyperstimulation syndrome post assisted reproduction, serious postpartum infection, major postpartum hemorrhage requiring surgery, and emergency caesarean section. The magnitude of the risk increases with these factors and how they interact remain uncertain. However, predictive models for assessing individual patient risk of thrombosis are currently under evaluation and may prove helpful in the near future.
# AGENTS AND DOSING:
During pregnancy, the risks of anticoagulant therapy to the fetus must be considered, in addition to maternal safety and the efficacy of the anticoagulant. Evidence extrapolated from observational studies suggest that pharmacologic VTE thromboprophylaxis is associated with about a 75% relative risk reduction in pregnancy-related VTE. Thus, women with a higher baseline risk of VTE will derive more benefit than those with a lower baseline risk of VTE.
Low molecular weight heparin (LMWH) and unfractionated heparin (UFH) do not cross the placenta and, therefore, are safe for the fetus. The potential for bleeding in pregnant women receiving LMWH or UFH prophylaxis is low and does not appear to be different from that reported in non-pregnant patients. LMWH has a better safety profile than UFH; therefore, LMWH is the drug of choice for prevention of VTE during pregnancy.
- The optimal dose of LMWH for antepartum and postpartum prophylaxis to prevent pregnancyrelated VTE is unknown. In general, either standard once daily prophylaxis or intermediate dosing (either twice daily prophylaxis dosing or once daily intermediate dose) is recommended; in women ≥100-120 kg, use of intermediate dosing is suggested. Specific recommendations for VTE prophylaxis are contained in Table 1 below.
- Maternal weight gain and increased renal clearance of LMWH during pregnancy has led to a suggestion that the anticoagulant effect of LMWH prophylaxis be monitored using anti-Xa levels. However, there are no high quality studies showing that dose adjustment to attain specific anti-Xa levels increases the safety or efficacy of prophylaxis. Anti-Xa monitoring for prophylactic anticoagulation with LMWH is not routinely recommended.
- LMWH is safe for the breast-fed infant when administered to the nursing mother.
Vitamin K antagonists (such as warfarin) cross the placenta and can lead to teratogenicity (warfarin embryopathy and central nervous system anomalies), as well as pregnancy loss and fetal bleeding. However, warfarin is safe for the breast-fed infant when administered to the nursing mother.
Direct oral anticoagulants should NOT be used in pregnant or breastfeeding women. Pregnant women were excluded from clinical trials evaluating the oral direct thrombin inhibitors (dabigatran) and anti-Xa inhibitors (rivaroxaban, apixaban, edoxaban), so the human reproductive risks of these medications are unknown. However, these small molecules are known to cross the placenta. Therefore, at present, the direct oral anticoagulants should not be used during pregnancy. We also recommend against using these agents while breastfeeding. Rivaroxaban and dabigatran have been demonstrated in breast milk samples; other drugs in this group may also be excreted into breast milk.
# Starting thromboprophylaxis:
If the decision to use antepartum prophylaxis is taken, it should be initiated early in pregnancy.
# Labour and delivery:
The risk of maternal hemorrhage and epidural hematoma at the time of delivery can be minimized with careful planning. Delivery options include both planned delivery and spontaneous labor with discontinuation of prophylaxis when labor commences, in consultation with obstetrics and anesthesiology.
The choice of delivery mode may be influenced by the desire for epidural anesthesia. Epidural placement should occur no sooner than 12 hours after standard prophylactic LMWH and 24 hours after higher doses of LMWH. If prophylactic UFH is substituted for LMWH close to term, practice guidelines suggest that neuraxial block occur 4 to 6 hours after heparin administration (in patients receiving UFH 5,000 units BID or TID), although individual anesthesiologists may differ in their practice. Typically, resumption of prophylaxis should be delayed until adequate hemostasis is assured and generally at least 12 hours post-delivery or epidural removal.
# Duration of postpartum thromboprophylaxis:
For most women receiving pregnancy thromboprophylaxis, the prophylaxis should continue for 6 weeks postpartum since this is the highest risk period for VTE. Extending postpartum prophylaxis from 6 weeks to 12 weeks is likely only to benefit those women at highest risk of delayed VTE (e.g. those with a prior late postpartum event or those with multiple VTE risk factors persisting beyond 6 weeks).
# Suspected VTE during pregnancy:
Women at risk of VTE should be educated about the need to seek urgent medical attention should they develop symptoms or signs suggestive of DVT or PE. Objective testing is mandatory if symptoms suspicious of DVT or PE occur as there is limited validation of standard clinical diagnostic algorithms in the setting of pregnancy.
# Pediatrics:
In adolescents who are pregnant, the above adult recommendations for thromboprophylaxis should be followed.
# Date of Version: 22Feb2022
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein. | To provide recommendations for the prevention of venous thromboembolism (VTE) during pregnancy (antepartum) and the postpartum period.VTE complicates 1-2 per 1,000 deliveries. The daily risk of VTE is increased 5-to 10-fold during pregnancy and 15-to 35-fold in the early postpartum period compared to the non-pregnant, agematched population. Although most studies have reported that the elevated risk of VTE returns to baseline by the end of the sixth postpartum week, a small increase in risk may persist for 12 weeks after delivery.#
The absolute risk of pregnancy-related VTE in most women with thrombophilia without a prior thrombotic event or family history remains low (1% or less). However, women who have factor V Leiden homozygosity, prothrombin gene mutation homozygosity, a deficiency of protein C, S or antithrombin (with a positive family history) or who have combined thrombophilia have a higher risk of VTE. The risk of pregnancy-related VTE in thrombophilic women with a positive family history appears to be 2-4 times greater than that in thrombophilic women without a positive family history of VTE.
Previous VTE increases the risk of pregnancy-related deep vein thrombosis (DVT) and pulmonary embolism (PE). Women with one prior episode of VTE associated with a transient risk factor not related to pregnancy or hormone use appear to be at low risk of antepartum recurrence (≤5%) compared with those with an unprovoked, pregnancy-related or estrogen-related VTE (5-10%). The impact of thrombophilia on the risk of recurrent VTE in pregnancy is unclear.
In recent studies, uncomplicated nonemergent caesarean section has not been associated with an increased risk of VTE, compared with vaginal delivery.
Additional clinical risk factors that also appear to increase the risk of pregnancy-associated VTE include: obesity or increased body mass index (BMI), age ≥ 40 years, pre-eclampsia with intrauterine growth restriction, strict antepartum bed rest for at least 7 days, smoking >5 cigarettes/day prior to pregnancy, systemic lupus erythematosus (SLE), sickle cell disease, cancer, cardiac disease, severe ovarian hyperstimulation syndrome post assisted reproduction, serious postpartum infection, major postpartum hemorrhage requiring surgery, and emergency caesarean section. The magnitude of the risk increases with these factors and how they interact remain uncertain. However, predictive models for assessing individual patient risk of thrombosis are currently under evaluation and may prove helpful in the near future.
# AGENTS AND DOSING:
During pregnancy, the risks of anticoagulant therapy to the fetus must be considered, in addition to maternal safety and the efficacy of the anticoagulant. Evidence extrapolated from observational studies suggest that pharmacologic VTE thromboprophylaxis is associated with about a 75% relative risk reduction in pregnancy-related VTE. Thus, women with a higher baseline risk of VTE will derive more benefit than those with a lower baseline risk of VTE.
Low molecular weight heparin (LMWH) and unfractionated heparin (UFH) do not cross the placenta and, therefore, are safe for the fetus. The potential for bleeding in pregnant women receiving LMWH or UFH prophylaxis is low and does not appear to be different from that reported in non-pregnant patients. LMWH has a better safety profile than UFH; therefore, LMWH is the drug of choice for prevention of VTE during pregnancy.
• The optimal dose of LMWH for antepartum and postpartum prophylaxis to prevent pregnancyrelated VTE is unknown. In general, either standard once daily prophylaxis or intermediate dosing (either twice daily prophylaxis dosing or once daily intermediate dose) is recommended; in women ≥100-120 kg, use of intermediate dosing is suggested. Specific recommendations for VTE prophylaxis are contained in Table 1 below.
• Maternal weight gain and increased renal clearance of LMWH during pregnancy has led to a suggestion that the anticoagulant effect of LMWH prophylaxis be monitored using anti-Xa levels. However, there are no high quality studies showing that dose adjustment to attain specific anti-Xa levels increases the safety or efficacy of prophylaxis. Anti-Xa monitoring for prophylactic anticoagulation with LMWH is not routinely recommended.
• LMWH is safe for the breast-fed infant when administered to the nursing mother.
Vitamin K antagonists (such as warfarin) cross the placenta and can lead to teratogenicity (warfarin embryopathy and central nervous system anomalies), as well as pregnancy loss and fetal bleeding. However, warfarin is safe for the breast-fed infant when administered to the nursing mother.
Direct oral anticoagulants should NOT be used in pregnant or breastfeeding women. Pregnant women were excluded from clinical trials evaluating the oral direct thrombin inhibitors (dabigatran) and anti-Xa inhibitors (rivaroxaban, apixaban, edoxaban), so the human reproductive risks of these medications are unknown. However, these small molecules are known to cross the placenta. Therefore, at present, the direct oral anticoagulants should not be used during pregnancy. We also recommend against using these agents while breastfeeding. Rivaroxaban and dabigatran have been demonstrated in breast milk samples; other drugs in this group may also be excreted into breast milk.
# Starting thromboprophylaxis:
If the decision to use antepartum prophylaxis is taken, it should be initiated early in pregnancy.
# Labour and delivery:
The risk of maternal hemorrhage and epidural hematoma at the time of delivery can be minimized with careful planning. Delivery options include both planned delivery and spontaneous labor with discontinuation of prophylaxis when labor commences, in consultation with obstetrics and anesthesiology.
The choice of delivery mode may be influenced by the desire for epidural anesthesia. Epidural placement should occur no sooner than 12 hours after standard prophylactic LMWH and 24 hours after higher doses of LMWH. If prophylactic UFH is substituted for LMWH close to term, practice guidelines suggest that neuraxial block occur 4 to 6 hours after heparin administration (in patients receiving UFH 5,000 units BID or TID), although individual anesthesiologists may differ in their practice. Typically, resumption of prophylaxis should be delayed until adequate hemostasis is assured and generally at least 12 hours post-delivery or epidural removal.
# Duration of postpartum thromboprophylaxis:
For most women receiving pregnancy thromboprophylaxis, the prophylaxis should continue for 6 weeks postpartum since this is the highest risk period for VTE. Extending postpartum prophylaxis from 6 weeks to 12 weeks is likely only to benefit those women at highest risk of delayed VTE (e.g. those with a prior late postpartum event or those with multiple VTE risk factors persisting beyond 6 weeks).
# Suspected VTE during pregnancy: [See Clinical Guide Pregnancy: Diagnosis of DVT and PE]
Women at risk of VTE should be educated about the need to seek urgent medical attention should they develop symptoms or signs suggestive of DVT or PE. Objective testing is mandatory if symptoms suspicious of DVT or PE occur as there is limited validation of standard clinical diagnostic algorithms in the setting of pregnancy.
# Pediatrics:
In adolescents who are pregnant, the above adult recommendations for thromboprophylaxis should be followed.
# Date of Version: 22Feb2022
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein. | None | None |
b0c5826ecf93eeb8e087bed35f091b2a88a86e91 | cma | None | This position statement aims to provide rapid guidance for Canadian physicians treating patients with asthma during the COVID-19 pandemic. The recommendations are informed by a very limited body of direct published data, inference from the indirect data, and recommendations from other international guideline bodies. As such, these recommendations are primarily based on expert opinion and we recommend that treatment decisions be individualized.Clinic' prepared by specialists in areas of allergy, asthma and clinical immunology from Canada and the United States. The article is referenced below 1 and is available on the Canadian Society of Allergy and Clinical Immunology website and is currently 'in press' with the The Journal of Allergy and Clinical Immunology: In Practice.# Asthma Management -General Statement
In the absence of direct or indirect data that SARS-CoV-2 impacts the safety and efficacy of current asthma therapies, we recommend that maintenance and exacerbation management for asthma be continued according to current national and international asthma treatment guidelines. Optimal asthma control is expected to be the best protection against a SARS-CoV-2 exacerbation. 2,3,4,5 The primary goal of asthma management is to control the disease and, by doing so, prevent or minimize the risk of short-and long-term complications, morbidity and mortality. 2,3,4,5
# Risk of acquiring SARS-CoV-2 infection (COVID 19) by patients with asthma
# There does not appear to be an increased risk for asthma patients to acquire SARS-CoV-2 infection (COVID-19) compared to the general population.
Rationale: Two studies from China and one from Korea did not find that hospitalized patients with asthma were over-represented in the COVID-19 populations studied. 6,7,8 Risk and severity of asthma exacerbation caused by SARS-CoV-2 (COVID 19)
# We suggest that patients with asthma be advised to restart or continue their prescribed inhaled corticosteroid or inhaled corticosteroid steroid plus long-acting beta2-agonist maintenance therapy to improve disease control and to reduce the severity of viral-induced exacerbations including exacerbations that may be caused by SARS-CoV-2.
Rationale: There are no direct data to evaluate the risk of having an exacerbation or the severity of exacerbation associated with SARS-CoV-2. Risk: It is probable that SARS-CoV-2 can trigger asthma exacerbations. Viral respiratory tract infections are a common cause of asthma exacerbations. 9 Exacerbations requiring emergency department visits and hospitalizations increase annually at times when viral infections increase, typically week 38 on the calendar. 10 Non-pandemic coronaviruses have been associated with asthma exacerbations. 11,12 Improving asthma disease control is expected to reduce the frequency and severity of exacerbations. Severity: As above, two studies from China and one from Korea did not find that hospitalized patients with asthma were over-represented in the COVID-19 populations studied. 6,7,8 One report from Italy reporting 481 deaths and one from China reporting 54 deaths did not identify asthma as a co-morbid risk factor. 13,14
# Safety of using systemic corticosteroids (prednisone) to treat asthma exacerbations during the SARS-CoV-2 (COVID 19) pandemic
# We suggest using prednisone to treat severe asthma exacerbations as recommended in current national and international asthma guidelines during the SARS-CoV-2 (COVID 19) pandemic, whether or not the exacerbation is triggered by SARS-CoV-2.
Rationale: A) Use of prednisone to treat an asthma exacerbation 'not suspected' to be caused by SARS-CoV-2. Prednisone is recommended for the treatment of severe asthma exacerbations in international asthma guidelines including in viral induced exacerbations. 2,3,4,5,15,16 Non-pandemic coronavirus infection contributes to these exacerbations. 9,12 If prednisone-requiring exacerbations are not treated, patients may require an avoidable emergency department visit or hospitalization (which could also expose them to SARS-CoV-2). There is no available evidence of harm caused by using prednisone to treat asthma exacerbations during the pandemic. The brief course of prednisone used to treat acute asthma exacerbation is not expected to compromise the immune system sufficiently to increase chances of acquiring SARS-CoV-2 and/or developing COVID-19. B) Use of prednisone to treat an asthma exacerbation 'suspected' to be caused by SARS-CoV-2. There is a concern that prednisone may prolong viral replication. 17 It remains unclear as to whether prednisone is helpful or harmful in the treatment of COVID-19. Russel and colleagues reviewed observational data and concluded there was no benefit to using prednisone to treat SARS-CoV-2 lung injury. 18 Front-line physicians from the Chinese Thoracic Society challenge this assertion and take the position that since the evidence is inconclusive and since SARS-CoV-2 lung injury is profoundly inflammatory that corticosteroids make play an important role. They recommend that physicians should follow basic principles when using corticosteroids: "(1) the benefits and harms should be carefully weighed before using corticosteroids; (2) corticosteroids should be used prudently in critically ill patients with 2019-nCoV pneumonia; (3) for patients with hypoxemia due to underlying diseases or who regularly use corticosteroids for chronic diseases, further use of corticosteroids should be cautious; and (4) the dosage should be low to-moderate (≤05-1 mg/kg per day methylprednisolone or equivalent) and the duration should be short (≤7 days)." 19 Arabi and colleagues found that after adjusting for confounders, there was no mortality signal associated with prednisone use in the Middle East Respiratory Syndrome. 20 In the absence of evidence of harm and an expectation of a low risk of harm, we prioritized the high value of current evidence-based care recommendations to treat asthma exacerbations with prednisone to reduce the need for urgent health service utilization.
# Safety of using inhaled steroids
# We suggest that patients with asthma restart or continue to use their inhaled asthma controller medications during the COVID-19 epidemic.
Rationale: There is no current evidence that inhaled corticosteroids increase the risk of acquiring SARS-CoV-2 infection (COVID- 19) or that inhaled corticosteroids increase the severity of infection. To the contrary, it is likely that the SARS-CoV-2 could cause an asthma exacerbation, making it a high priority to achieve well controlled asthma as protection against a severe asthma exacerbation. In the absence of evidence of harm and an expectation of a very low risk of harm from inhaled corticosteroids, we prioritized the high value of asthma control to reduce the frequency and severity of exacerbations.
# Use of biologics to manage severe asthma
# We suggest that anti-IgE and anti-IL5 monoclonal antibodies (biologics) be continued during the COVID-19 pandemic. If biologic therapies are interrupted temporarily, we suggest stepping-up other controller therapies on an individualized basis which may include adding low dose prednisone, a high or very high dose inhaled corticosteroid with long-acting beta2-agonist therapy, or long-acting antimuscarinic therapy. Where available, providers may consider switching patients to selfadministration of biologics at home.
Rationale: Anti-IgE and anti-IL5 monoclonal antibodies are currently approved for use in Canada to treat severe allergic and severe eosinophilic asthma. 3 A primary benefit of biologic agents is to reduce the frequency of severe asthma exacerbations. Discontinuing these medications during the COVID-19 pandemic would be expected to increase the frequency of severe exacerbations and increase the likelihood that patients would need to enter the health system through an urgent physician visit, emergency department visit, or hospitalization. Further, the loss of asthma control associated with discontinuing medications may make the patient more vulnerable to a severe exacerbation associated with a viral infection. Mechanistically and based on the published literature on biologic agents, including long-term follow-up studies, we do not expect that the immune response to viral infection would be impaired by these agents. Notably, Esquivel and colleagues identify that Omalizumab may protect against viral induced exacerbations. 21 In the absence of evidence of harm and an expectation of a low risk of harm, in high risk severe asthma patients, we prioritized the high value of biologic agents to treat severe asthma to improve control and to reduce exacerbations including the need for urgent health service utilization.
# Safety of nebulizer use in asthma
We suggest that nebulizers be replaced by metered dose inhalers with spacing devices or dry powder inhalers to administer inhaled-corticosteroids and short-acting bronchodilators inside healthcare facilities including nursing homes to reduce the risk of aerosol spread of virus particles. Patients who are already using nebulizers to administer therapy at home should continue until such time as their provider can discuss switching to metered dose inhalers with a spacing device or dry powder inhalers.
Rationale: Metered dose inhalers with spacing devices are more effective than nebulization and the preferred method of delivery even for acute exacerbations in the emergency department and hospital, and even under non-pandemic circumstances. Dry powder inhalers are another alternate. A recent nebulization experiment elevates concern that clinical nebulization devices pose a risk of aerosolization of SARS-CoV-2, placing healthcare workers and caregivers at risk for infection. 22 The recommendation to avoid nebulization applies to all patients, not only to patients that have confirmed or suspected COVID-19. We placed a high value on selecting the most effective method of delivery while reducing any potential risk of disease transmission.
# Physical distancing for asthma patients
# We suggest that all patients with asthma follow current local, national public and global health advisories with respect to the indications for physical distancing and isolation. Patients with mildmoderate asthma should work from home if feasible. Patients with severe asthma should also work from home if feasible, and if not feasible, should remain off work for medical reasons until such time as the WHO or local public health authorities declare that physical distancing is no longer necessary.
Rationale: Longitudinal experience with seasonal influenza has been extended to infer that patients with chronic lung disease are at risk for severe complications of SARS-CoV-2 infection (COVID-19). Physical distancing is an important public health measure to 'flatten the curve' of community spread of the virus. The workplace is a social environment which may expose patients to others in their community, particularly if physical distancing in the workplace setting is difficult to implement. Until we fully understand the risks associated with SARS-CoV-2 infection in patients with chronic lung disease we have placed a high value on limiting exposure based on prior experience with influenza.
# We will review our recommendations at least every two weeks and as more information becomes available
The pandemic is a rapidly evolving situation. Clinicians are advised to look to the Canadian Thoracic Society website for resources and links to asthma action plans and tutorial videos for children and adults for the proper use of inhalers and puffers as well as further updates on COVID-19 and lung diseases. | This position statement aims to provide rapid guidance for Canadian physicians treating patients with asthma during the COVID-19 pandemic. The recommendations are informed by a very limited body of direct published data, inference from the indirect data, and recommendations from other international guideline bodies. As such, these recommendations are primarily based on expert opinion and we recommend that treatment decisions be individualized.Clinic' prepared by specialists in areas of allergy, asthma and clinical immunology from Canada and the United States. The article is referenced below 1 and is available on the Canadian Society of Allergy and Clinical Immunology website and is currently 'in press' with the The Journal of Allergy and Clinical Immunology: In Practice.# Asthma Management -General Statement
In the absence of direct or indirect data that SARS-CoV-2 impacts the safety and efficacy of current asthma therapies, we recommend that maintenance and exacerbation management for asthma be continued according to current national and international asthma treatment guidelines. Optimal asthma control is expected to be the best protection against a SARS-CoV-2 exacerbation. 2,3,4,5 The primary goal of asthma management is to control the disease and, by doing so, prevent or minimize the risk of short-and long-term complications, morbidity and mortality. 2,3,4,5
# Risk of acquiring SARS-CoV-2 infection (COVID 19) by patients with asthma
# There does not appear to be an increased risk for asthma patients to acquire SARS-CoV-2 infection (COVID-19) compared to the general population.
Rationale: Two studies from China and one from Korea did not find that hospitalized patients with asthma were over-represented in the COVID-19 populations studied. 6,7,8 Risk and severity of asthma exacerbation caused by SARS-CoV-2 (COVID 19)
# We suggest that patients with asthma be advised to restart or continue their prescribed inhaled corticosteroid or inhaled corticosteroid steroid plus long-acting beta2-agonist maintenance therapy to improve disease control and to reduce the severity of viral-induced exacerbations including exacerbations that may be caused by SARS-CoV-2.
Rationale: There are no direct data to evaluate the risk of having an exacerbation or the severity of exacerbation associated with SARS-CoV-2. Risk: It is probable that SARS-CoV-2 can trigger asthma exacerbations. Viral respiratory tract infections are a common cause of asthma exacerbations. 9 Exacerbations requiring emergency department visits and hospitalizations increase annually at times when viral infections increase, typically week 38 on the calendar. 10 Non-pandemic coronaviruses have been associated with asthma exacerbations. 11,12 Improving asthma disease control is expected to reduce the frequency and severity of exacerbations. Severity: As above, two studies from China and one from Korea did not find that hospitalized patients with asthma were over-represented in the COVID-19 populations studied. 6,7,8 One report from Italy reporting 481 deaths and one from China reporting 54 deaths did not identify asthma as a co-morbid risk factor. 13,14
# Safety of using systemic corticosteroids (prednisone) to treat asthma exacerbations during the SARS-CoV-2 (COVID 19) pandemic
# We suggest using prednisone to treat severe asthma exacerbations as recommended in current national and international asthma guidelines during the SARS-CoV-2 (COVID 19) pandemic, whether or not the exacerbation is triggered by SARS-CoV-2.
Rationale: A) Use of prednisone to treat an asthma exacerbation 'not suspected' to be caused by SARS-CoV-2. Prednisone is recommended for the treatment of severe asthma exacerbations in international asthma guidelines including in viral induced exacerbations. 2,3,4,5,15,16 Non-pandemic coronavirus infection contributes to these exacerbations. 9,12 If prednisone-requiring exacerbations are not treated, patients may require an avoidable emergency department visit or hospitalization (which could also expose them to SARS-CoV-2). There is no available evidence of harm caused by using prednisone to treat asthma exacerbations during the pandemic. The brief course of prednisone used to treat acute asthma exacerbation is not expected to compromise the immune system sufficiently to increase chances of acquiring SARS-CoV-2 and/or developing COVID-19. B) Use of prednisone to treat an asthma exacerbation 'suspected' to be caused by SARS-CoV-2. There is a concern that prednisone may prolong viral replication. 17 It remains unclear as to whether prednisone is helpful or harmful in the treatment of COVID-19. Russel and colleagues reviewed observational data and concluded there was no benefit to using prednisone to treat SARS-CoV-2 lung injury. 18 Front-line physicians from the Chinese Thoracic Society challenge this assertion and take the position that since the evidence is inconclusive and since SARS-CoV-2 lung injury is profoundly inflammatory that corticosteroids make play an important role. They recommend that physicians should follow basic principles when using corticosteroids: "(1) the benefits and harms should be carefully weighed before using corticosteroids; (2) corticosteroids should be used prudently in critically ill patients with 2019-nCoV pneumonia; (3) for patients with hypoxemia due to underlying diseases or who regularly use corticosteroids for chronic diseases, further use of corticosteroids should be cautious; and (4) the dosage should be low to-moderate (≤0•5-1 mg/kg per day methylprednisolone or equivalent) and the duration should be short (≤7 days)." 19 Arabi and colleagues found that after adjusting for confounders, there was no mortality signal associated with prednisone use in the Middle East Respiratory Syndrome. 20 In the absence of evidence of harm and an expectation of a low risk of harm, we prioritized the high value of current evidence-based care recommendations to treat asthma exacerbations with prednisone to reduce the need for urgent health service utilization.
# Safety of using inhaled steroids
# We suggest that patients with asthma restart or continue to use their inhaled asthma controller medications during the COVID-19 epidemic.
Rationale: There is no current evidence that inhaled corticosteroids increase the risk of acquiring SARS-CoV-2 infection (COVID- 19) or that inhaled corticosteroids increase the severity of infection. To the contrary, it is likely that the SARS-CoV-2 could cause an asthma exacerbation, making it a high priority to achieve well controlled asthma as protection against a severe asthma exacerbation. In the absence of evidence of harm and an expectation of a very low risk of harm from inhaled corticosteroids, we prioritized the high value of asthma control to reduce the frequency and severity of exacerbations.
# Use of biologics to manage severe asthma
# We suggest that anti-IgE and anti-IL5 monoclonal antibodies (biologics) be continued during the COVID-19 pandemic. If biologic therapies are interrupted temporarily, we suggest stepping-up other controller therapies on an individualized basis which may include adding low dose prednisone, a high or very high dose inhaled corticosteroid with long-acting beta2-agonist therapy, or long-acting antimuscarinic therapy. Where available, providers may consider switching patients to selfadministration of biologics at home.
Rationale: Anti-IgE and anti-IL5 monoclonal antibodies are currently approved for use in Canada to treat severe allergic and severe eosinophilic asthma. 3 A primary benefit of biologic agents is to reduce the frequency of severe asthma exacerbations. Discontinuing these medications during the COVID-19 pandemic would be expected to increase the frequency of severe exacerbations and increase the likelihood that patients would need to enter the health system through an urgent physician visit, emergency department visit, or hospitalization. Further, the loss of asthma control associated with discontinuing medications may make the patient more vulnerable to a severe exacerbation associated with a viral infection. Mechanistically and based on the published literature on biologic agents, including long-term follow-up studies, we do not expect that the immune response to viral infection would be impaired by these agents. Notably, Esquivel and colleagues identify that Omalizumab may protect against viral induced exacerbations. 21 In the absence of evidence of harm and an expectation of a low risk of harm, in high risk severe asthma patients, we prioritized the high value of biologic agents to treat severe asthma to improve control and to reduce exacerbations including the need for urgent health service utilization.
# Safety of nebulizer use in asthma
We suggest that nebulizers be replaced by metered dose inhalers with spacing devices or dry powder inhalers to administer inhaled-corticosteroids and short-acting bronchodilators inside healthcare facilities including nursing homes to reduce the risk of aerosol spread of virus particles. Patients who are already using nebulizers to administer therapy at home should continue until such time as their provider can discuss switching to metered dose inhalers with a spacing device or dry powder inhalers.
Rationale: Metered dose inhalers with spacing devices are more effective than nebulization and the preferred method of delivery even for acute exacerbations in the emergency department and hospital, and even under non-pandemic circumstances. Dry powder inhalers are another alternate. A recent nebulization experiment elevates concern that clinical nebulization devices pose a risk of aerosolization of SARS-CoV-2, placing healthcare workers and caregivers at risk for infection. 22 The recommendation to avoid nebulization applies to all patients, not only to patients that have confirmed or suspected COVID-19. We placed a high value on selecting the most effective method of delivery while reducing any potential risk of disease transmission.
# Physical distancing for asthma patients
# We suggest that all patients with asthma follow current local, national public and global health advisories with respect to the indications for physical distancing and isolation. Patients with mildmoderate asthma should work from home if feasible. Patients with severe asthma should also work from home if feasible, and if not feasible, should remain off work for medical reasons until such time as the WHO or local public health authorities declare that physical distancing is no longer necessary.
Rationale: Longitudinal experience with seasonal influenza has been extended to infer that patients with chronic lung disease are at risk for severe complications of SARS-CoV-2 infection (COVID-19). Physical distancing is an important public health measure to 'flatten the curve' of community spread of the virus. The workplace is a social environment which may expose patients to others in their community, particularly if physical distancing in the workplace setting is difficult to implement. Until we fully understand the risks associated with SARS-CoV-2 infection in patients with chronic lung disease we have placed a high value on limiting exposure based on prior experience with influenza.
# We will review our recommendations at least every two weeks and as more information becomes available
The pandemic is a rapidly evolving situation. Clinicians are advised to look to the Canadian Thoracic Society website for resources and links to asthma action plans and tutorial videos for children and adults for the proper use of inhalers and puffers as well as further updates on COVID-19 and lung diseases. | None | None |
2b058d36e8b26033ca3a10ab4caebd141d200289 | cma | None | # Background
Charged particle radiotherapy uses beams of protons or other particles such as helium or carbon instead of photons. In contrast to conventional photon radiotherapy, in which the greatest energy release is at the surface of the tissue and decreases exponentially the deeper the radiation travels, the energy of a proton beam is released near the end of its path, resulting in a sharp and localized dose peak, referred to as the Bragg peak. This allows for better dose distribution when compared to photon beam radiotherapy, thereby decreasing the dose to normal surrounding tissues, and reducing the risk of both acute and long-term side effects 1,2 . To date, there are no published controlled comparative studies describing outcomes from patients treated with proton beam radiotherapy versus other therapies; thus, the advantage of protons over conventional photon therapy is based on the dosimetric advantage of protons over photons for tumours that are in immediate proximity to critical structures. Most of the published literature is in the form of prospective or retrospective case series and cohort studies; there is also significant variation in the types and stages of cancer for which treatment with proton beam radiotherapy has been reported, as well as the reported doses and fractionation schedules. Published reports focus mainly on toxicity, and include pediatric, adolescent, and adult patients treated with proton beam radiotherapy primarily for ocular cancers, spine or skull base chordomas and chondrosarcomas, spinal and paraspinal bone and soft tissue sarcomas, head and neck cancers, and brain tumours. In addition, there is some literature reporting the use of proton beam radiotherapy for patients with lymphoma, non-small cell lung cancer, prostate cancer, and some gastrointestinal cancers.
By December 2017, 170,556 patients worldwide had been treated with proton beam radiotherapy 3 . Historically, the high capital cost of proton facilities equipped with rotational gantries has limited the number of facilities in operation; however, that number is now increasing rapidly. Between 2004 and 2014, the number of facilities in the United States alone grew to 13 from 2 and from 13 to 32 between 2014 and 2017 3 . Compact single-room cyclotron centres have drastically reduced the capital cost and account for 10 of the 22 facilities under construction worldwide 3 . Gantry-equipped facilities capable of treating a broad range of tumour sites are not currently available in Canada.
In early 2012, the Cancer Care Alberta Proton Therapy Guideline Working Group and Guideline Advisory Group met to evaluate the most current evidence for the use of proton beam radiotherapy in pediatric and adult patients with cancer, and to develop a de novo guideline with recommendations based on an expert review of the available literature. The resulting evidence review, guideline document, and accompanying documents were presented to the out of country Health Services Committee, which operates at arm's length from Alberta Health, to establish a process to identify which patients are appropriate candidates to receive out of country treatment with proton beam radiation therapy. In 2019, the evidence was reviewed, and this guideline was updated. In 2021, the Alberta Health working group set up a special program unit to review proton beam radiation therapy requests, which means the requests no longer go through the out of country Health Services Committee.
Guideline Questions 1. What is the evidence for the use of proton beam radiation therapy for the management of patients with cancer? 2. What are the published recommendations for the selection of patients most likely to benefit from treatment with proton beam radiation therapy? 3. What are the steps involved in referring a patient for out of country proton beam radiation therapy?
# Development
The Cancer Care Alberta Proton Therapy Guideline Advisory Group took the following steps in producing this guideline:
- The Guideline Advisory Group members individually reviewed the results of an environmental scan and literature review conducted by a Knowledge Management Specialist from the Guideline Resource Unit. Members of this group include representatives from Alberta Health, as well as the departments of medical oncology, radiation oncology, and pediatric neurosurgery at the two tertiary cancer centres in Alberta. For a detailed description of the methodology followed during the guideline development process, please refer to the Guideline Resource Unit Handbook. 2. Based on this review, the Guideline Advisory Group gave support to the Guideline Working Group to draft a guideline containing the recommendations and supporting evidence about the selection of patients most likely to benefit from treatment with proton beam radiation therapy. 3. The Guideline Working Group then distributed the draft document via an anonymous electronic survey to 17 healthcare professionals from various disciplines within the province for review and comment. The response rate was 59%. 4. The comments from the external review were incorporated into the guideline draft by the Guideline Working Group. 5. The final guideline was reviewed and endorsed in February 2013 by the Cancer Care Alberta Proton Therapy Guideline Advisory Group and Guideline Working Group and was posted on the external website in March 2013. 6. The updated guideline was reviewed and endorsed in 2019 by members of the Guideline Working Group and Guideline Advisory Group. 7. The out of country process was updated in 2022 by the Alberta Health working group.
# Search Strategy
Medical journals were searched using the MEDLINE, EMBASE, PubMed, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials; the references and bibliographies of studies identified through these searches were scanned for additional sources. The search terms were: Protons (MeSH term) AND Radiotherapy (MeSH term), proton therapy (MeSH term), proton beam (keyword), particle beam therapy (keyword), and charged particle therapy (keyword). The search was limited to studies published in the English language between the years 2000 and 2014. There were no limitations by study design. A search for new or updated guidelines, health technology assessments, and medical policies was conducted by accessing the websites of guideline developers and the National Guidelines Clearinghouse database, and by searching the grey literature using online search engines. A search for ongoing trials at .
# Target Population
The recommendations in this guideline are for pediatric, adolescent, young adult and adult patients who are residents of Alberta and may qualify to receive proton beam radiotherapy at a facility outside of Canada for treatment of their cancer.
# Discussion
# I. Indications and Evidence for Proton Beam Therapy
# Pediatric Tumours
Radiation therapy has played an important role in the treatment and cure of children diagnosed with malignant tumours over the past 30 years; given that approximately 70% of children with malignancies can now expect to be cured, the late effects of treatment have now become a major focus 4 . Proton beam therapy is associated with a reduction in acute and long-term toxicities, as well as lower rates of radiation-induced second malignancies, and potentially less acute and long-term damage to developing organs in pediatric and adolescent patients with cancer ; therefore, the benefits of proton beam radiotherapy are potentially the greatest in this population. Although limited, published reports of pediatric and adolescent patients treated with proton beam radiotherapy have mostly addressed tumours arising on or near critical structures, as well as tumours where organs in the exit path of photon radiotherapy present significant secondary malignancy risk or risk of impaired development and function; such tumours include medulloblastomas, gliomas, ependymomas, retinoblastomas, rhabdomyosarcomas, and pelvic sarcomas 4,7 .
In one of the larger pediatric series published to date, MacDonald and colleagues reported the results of 17 pediatric patients with WHO grade II or III intracranial ependymomas treated with 3-dimensional conformal proton beam radiotherapy 8 . At a median follow-up of 26 months, the rates of local control, progression free survival, and overall survival rates were 86%, 80%, and 89%, respectively. Similarly, Amsbaugh and colleagues published the results of a prospective case series of eight pediatric patients with WHO grade I or II spinal ependymomas treated with proton beam radiotherapy 9 . Five patients were treated with proton beam radiotherapy as part of their primary management, while three were treated for recurrence of their disease. The entire vertebral body was treated in all but two patients, with a mean dose of 51.1 cobalt grey equivalents (CGE). The rates of local control, eventfree survival, and overall survival were all 100% at a mean follow-up of 26 months, and the investigators reported minimal acute side effects.
In a case series of three pediatric patients with medulloblastoma, Yuh and colleagues reported minimal acute side effects, excellent sparing of surrounding critical structures, and no treatment disruptions when the patients were treated with 36 CGE to the craniospinal axis and 18 CGE to the posterior fossa 10 . Similarly, St. Clair and colleagues compared treatment plans from standard photon therapy to intensity modulated radiotherapy (IMRT) and proton beam radiotherapy for craniospinal axis irradiation and posterior fossa boost in a pediatric patient with medulloblastoma. They reported substantial normal-tissue dose sparing with IMRT and proton treatment of the posterior fossa and spinal column, and also that protons were superior to IMRT in this case 11 . In another case series, six pediatric medulloblastoma patients were treated with vertebral-body-sparing proton craniospinal irradiation after maximal safe resection 12 . These patients received a dose of 23.4 Gy or 36 Gy to the craniospinal axis followed by a boost to the posterior fossa and any metastatic lesions. After a median follow-up of 13.6 years, the overall survival and disease-free survival were 83%, treatment did not increase spinal abnormalities compared with historical data, and it allowed for vertebral body growth outside of radiation field and bone marrow sparing. In a modeling study evaluating the consequences of radiotherapy in five year old patients with medulloblastoma, Lundkvist and colleagues reported that proton radiation therapy was cost-effective and was associated with an additional 0.68 qualityadjusted life-years per patient compared with conventional photon radiotherapy 13 . Reductions in IQ loss and growth hormone deficiency contributed most to the cost savings and were the most important parameters for cost-effectiveness. This analysis suggests that proton beam radiotherapy may be cost saving in comparison to photon radiotherapy for pediatric patients with medulloblastoma due to the reduction of late side-effects. A reduction in side-effects for pediatric patients with medulloblastoma treated with proton beam radiotherapy was also demonstrated in a prospective study of 23 pediatric patients who were followed for high-grade ototoxicity 14 , although a cost-benefit analysis was not reported for this trial.
# Young Adult Tumours
Adolescent and young adult patients (age range 19-40) can be particularly vulnerable to complications from radiotherapy. With increased survival, the long term complications of treatment can have a major impact on growth, fertility, and emotional well-being 15 . Particularly the risk of radiation-induced secondary cancer is of concern in these patients. Zhang and colleagues reported on 17 medulloblastoma patients treated with passively scattered proton or field-in-field photon craniospinal irradiation (CSI) 16 . They found that proton CSI reduced the predicted risks of radiogenic second cancer incidence and cardiac mortality by six times compared with photon CSI. Yoon et al. retrospectively review 10 randomly selected cancer patients treated with either photon or proton radiotherapy 17 . The secondary cancer risks to lungs, stomach, liver and pancreas were at least five fold higher in patients treated with photon therapy compared to proton beam therapy. Another retrospective review studied 86 patients with retinoblastoma treated with proton or photon radiotherapy 18 . The 10-year cumulative incidence of radiation-induced or in-field second malignancies was 0% for patients treated with proton beam therapy versus 14% for patients treated with photon therapy (p=0.015). The 10-years cumulative incidence of all second malignancies was 5 % after proton therapy and 14% after photon therapy (p=0.120). Chung and colleagues performed a retrospective cohort study where they matched 558 proton patients with 558 photon patients 19 . Secondary malignancies occurred in 42 (7.5%) photon patients versus only 29 (5.2%) proton patients. They found that proton therapy was not associated with an increased risk of secondary cancer with an adjusted hazard ratio of 0.52 ; p=0.009.
# Central Nervous System Tumours
Similar to pediatric patients with favourable prognoses, adult patients with benign lesions and indolent malignant tumours also benefit from proton beam radiotherapy due to a decreased risk of late neurologic toxicities.
Meningiomas. Meningiomas are the second most common intracranial tumour reported in adults, accounting for 13 to 26% of all primary brain tumours in this population 20,21 . The management of a patient with a meningioma depends on the signs and symptoms produced by the tumour, the age of the patient, and the location and size of the tumour 22 . In the Meningiomas clinical practice guideline, the Alberta Provincial CNS Tumour Team members recommend surgery as the primary treatment for patients who are not candidates for management by watch-and-wait. This guideline also states that radiotherapy offers reasonable control for patients who are not candidates for surgery, patients whose tumour location or shape is not amenable to surgery (such as a cavernous sinus meningioma), patients who have symptomatic residual disease, or for the treatment of recurrence. Boskos and colleagues reported on 24 patients with either atypical or metastatic meningioma treated at the Centre Protonthérapie d'Orsay with a postoperative combination of proton and photon radiotherapy 23 .
The mean local relapse-free survival was 28.3 months (range 10-50) for atypical meningioma and 23 months (range 13-33) for malignant meningioma; ten tumours recurred locally. Overall survival rates were 100% at one year, 80.4% ± 8.8% at three years, 53.2% ± 11.6% at five years, and 42.6% ± 13% at eight years. Noël et al. also reported on the outcomes of 51 patients treated for base of skull meningiomas with a combination of proton and photon radiotherapy 24 . The four-year local control rate was 98%, and the four-year overall survival rate was 100%. The investigators reported tumour stabilization in 38 patients (72%), volume reduction in ten patients (20%), and intra-tumour necrosis in three patients; grade three side effects were observed in two patients. Similarly, Wenkel et al. reported on 46 patients with partially resected, biopsied, or recurrent meningiomas who were treated with combined proton and photon radiotherapy at the Massachusetts General Hospital and the Harvard Cyclotron Laboratory 25 . Five-and ten-year overall survival rates were 93% and 77%, respectively, and the five-and ten-year recurrence-free rates were 100% and 88%, respectively. Survival without severe toxicity was 80% at both five and ten years. The use of stereotactic and hypofractionated stereotactic proton beam radiotherapy were reported by Vernimmen and colleagues in a study of 27 patients with large or complex intracranial meningiomas 26 . Of the 18 patients treated with hypofractionated stereotactic proton beam radiotherapy, 16 remained clinically stable or improved. Of the five patients treated with stereotactic proton beam radiotherapy, two showed clinical improvement and three remained clinically stable. The radiologic control rate was 88% for the patients treated with hypofractionation, and 100% for patients treated without hypofractionation. In a study investigating the use of spot-scanning proton beam radiotherapy, Weber and colleagues reported on 13 patients treated postoperatively for incomplete resection or recurrence and three patients treated radically after presumptive diagnosis based on imaging 27 32 . Similarly, in 59 patients with high-risk cerebral AVMs treated with two-fraction proton stereotactic radiosurgery because of large tumour size or eloquent brain location, the median time to total obliteration was 62 months and the five-year actuarial total obliteration rate was 33% 33 . Complications associated with radiosurgery include radiation necrosis, seizures, and new neurologic deficits, therefore the efficacy of radiosurgery must be weighed against the potential toxicities of treatment 34 .
Acoustic neuromas. Acoustic neuromas, also known as vestibular schwannomas, are benign slowgrowing tumours that commonly arise from the vestibular portion of the eighth cranial nerve and account for approximately 8% of intracranial tumours in adults 35 . Options for treatment depend on tumour size, tumour growth rate, symptoms, health status, and patient preference, and may include observation, single-session stereotactic radiosurgery, fractionated conventional radiotherapy, fractionated stereotactic radiotherapy, proton beam radiotherapy, or surgery 36,37 . Although a distinct advantage of proton therapy over photon therapy for acoustic neuromas has not been demonstrated to date, larger tumours may benefit from proton beam radiotherapy because of the reduction of exit dose to the non-targeted brain and surrounding normal tissues 34 . In a review of 88 patients treated with proton beam radiotherapy at the Harvard Cyclotron Laboratory, Weber and colleagues reported two-and five-year actuarial control rates of 95.3% and 93.6% respectively in patients treated with stereotactic proton beam radiotherapy 38 . Facial and trigeminal nerve function was preserved in 91% and 89% of patients, respectively, and the five-year cumulative radiologic response rate was 94.7%. Salvage therapy was required in five patients post-radiotherapy. In a trial of 30 patients with acoustic neuromas treated with fractionated proton beam radiotherapy at the Loma Linda Medical Center, Bush et al. reported no disease progression at a mean follow-up of 34 months, and radiographic regression in 11 patients 39 . The rate of hearing preservation was 31%, however only 13 patients had useful hearing prior to radiotherapy. No transient or permanent treatment-related trigeminal or facial nerve dysfunction was observed.
# Spinal and Skull Base Chordomas and Chondrosarcomas
Chordomas are slow growing, locally aggressive bone tumours arising from the remnants of the notochord and most frequently occurring in the sacrococcygeal region or at the base of the skull near the sphenooccipital region 40,41 . Chordomas are rare in both adults and children, accounting for only three to four percent of all primary bone tumours 41 . Chondrosarcomas are malignant cartilaginous tumours that can occur anywhere in the skeletal system, and most commonly in the long bones and pelvis; in the skull base, chondrosarcomas account for six percent of all tumours, and most commonly occur in the middle, posterior, or anterior fossae 42 . The clinical features of chordomas and chondrosarcomas are quite similar, as is the optimal treatment strategy, which involves maximal surgical resection . Adjuvant postoperative radiotherapy is commonly used for patients with chordomas, and high doses have been associated with lower rates of local recurrence or treatment failure 44,45 . Postoperative radiotherapy has also been reported for the management of patients with chondrosarcomas. As a result of their proximity to critical neural structures, however, chordomas and chondrosarcomas of the skull base and spine are difficult to manage with conventional radiotherapy techniques, therefore making these tumours one of the main applications for proton beam radiotherapy. Despite the relative rarity of these tumours, the results of over 1,700 patients with spinal and skull base chordomas and chondrosarcomas treated with proton beam radiotherapy have been reported worldwide since the early 1970's 34 . Ares and colleagues recently reported the results of a long-term follow-up study of 64 patients with skull base chordomas or chondrosarcomas treated with spot-scanning proton beam radiotherapy at the Paul Scherrer Institute 46 . The five-year overall survival rate was 91% for patients with chondrosarcomas, and 62% for patients with chordomas; the five-year local control rate was 94% for patients with chondrosarcoma, and 81% for patients with chordomas. Adverse events included grade III (N=1) and grade IV (N=1) unilateral optic neuropathy, grade III temporal lobe parenchyma (N=2) and grade I leukoencephalopathy (N=5). In the largest series published to date, Munzenrider and Liebsch retrospectively reviewed 621 patients with spinal and skull base chordomas or chondrosarcomas treated between 1975 and 1998 at the Harvard Cyclotron Laboratory 47 . Treatment involved combined proton and photon irradiation, with a dose range of 66 to 83 CGE. For patients with skull base tumours, the five-year overall survival rates were 91% for chondrosarcomas and 80% for chordomas (p=0.010), and the ten-year overall survival rates were 88% for chondrosarcomas and 54% for chordomas (p<0.0001). Local recurrence rates were also better for chondrosarcomas versus chordomas at five years (98% versus 73%, p<0.0001) and ten years (94% versus 54%, p<0.0001). For patients with cervical spine tumours, the five-year overall survival rates were 48% for chondrosarcomas and 80% for chordomas (p=0.008), and the ten-year overall survival rates were 48% for chondrosarcomas and 33% for chordomas (p=0.109). Local recurrence rates for chondrosarcomas and chordomas were 54% and 69% at five years, and 54% and 48% at ten years, with no significant differences between the two groups of patients. In a systematic review of seven studies involving 416 adult and pediatric patients with inoperable or incompletely resected chordomas of the skull who were treated with proton beam radiotherapy, Amichetti et al. reported an average five-year overall survival rate of 79.8% (range 66.7-80.5%) and an average five-year local control rate of 69.2% (range 46-73%) 41 . Late toxicity was reported in the range of 5-17%, with some grade III and IV toxicities reported. Similarly, in another systematic review of four studies involving 254 patients with chondrosarcomas of the skull base treated post-operatively with proton beam radiotherapy, Amichetti and colleagues reported a five-year overall survival rate of 99-100% and a five-year local control rate of 75-99% 42 .
The use of proton beam radiotherapy has also been described for soft tissue sarcomas of the spine. DeLaney and colleagues reported the results of a prospective phase II trial involving 50 patients mostly with spinal and paraspinal chordomas and chondrosarcomas, but patients with liposarcoma, osteosarcoma, Ewing's sarcoma, giant cell tumour, angiosarcoma, malignant schwannoma, and spindle cell sarcoma were also included 4 . Patients were treated post-operatively with high-dose proton-photon radiotherapy at a median dose of 76.6 CGE and select patients with high-grade tumours also received chemotherapy. Thirty-six patients were treated for primary tumours, and 14 for recurrent disease. With 7.3-year median follow-up, the respective five-and eight-year actuarial local control rates were 94% and 85% for primary tumours and 81% and 74% for the entire group. Local recurrence was less common for primary tumours, compared to recurrent tumours, (11% vs. 50%, p=0.002). The eight-year actuarial risk of grade 3-4 late RT morbidity was 13% 48 . Guttmann and colleagues studied 23 recurrent soft tissue sarcoma patients treated with proton reirradiation, prospectively 49 . All sarcomas were in a previously irradiated field. The three-year progression-free survival was found to be 43% (95% CI 21-62%) and the three-year overall survival was 64% (95% CI 39-81%). Weber et al. retrospectively reviewed 38 Ewing sarcoma patients treated with pencil beam scanning proton therapy 50 . The five-year actuarial rate of local control, distant metastasis-free survival and overall survival were 81.5%, 76.4% and 83.0% respectively. This treatment was associated with a low rate of high -grade late toxicity. Demizu and colleagues retrospectively reviewed 91 patients with unresectable or incompletely resected bone and soft tissue sarcomas, treated with 70.4 GyRBE proton or carbon ion particle therapy in 16 or 32 fractions 51 . They found that particle therapy was effective with a 3-year overall survival of 83%, a 3-year progression free survival of 72% and a 3-year local control of 92%. The 16 fractions protocol was associated with significantly (p<0.001) more late grade ≥ 3 toxicities.
# Ocular Melanoma
Uveal melanoma, which includes tumours in the iris, ciliary body, and choroid, is the most common type of primary ocular tumour in adults, accounting for 95% of all cases 52,53 . Depending on the size and location of the tumour, treatment can range from local ablative treatments to complete removal of the eye. The use of proton beam radiation therapy for larger tumours has been reported extensively in the literature, with five recent comparative studies and numerous non-comparative studies showing high rates of local control and minimal adverse effects . However, a publication based on data from the SEER database in the United States reported that survival rates for patients with uveal melanoma have not improved from 1973 to 2008, despite a shift toward more conservative treatments such as proton beam radiotherapy during this time period 69 .
# Head and Neck Tumours
Tumours of the paranasal sinuses and nasal cavity are rare, accounting for 2-3% of all head and neck tumours 70 . Optimal treatment involves surgical resection and postoperative radiotherapy; chemotherapy, either alone or in combination with radiotherapy and/or surgery, is also an option for patients who are at high risk of recurrence or for patients with inoperable tumours 71,72 . For patients with paranasal sinus and nasal cavity tumours who are good candidates, proton beam radiotherapy is the ideal form of radiotherapy, owing to the irregular shape of many of these tumours, the relative radioresistance of some of these tumours, requiring high physical and biologically effective doses, the high risk of recurrence associated with these tumours, and the proximity to critical normal tissues in the ocular globes, optic nerves, and brain 34 . Resto et al. retrospectively reviewed the outcomes of 102 patients with locally advanced sinonasal tumours of varying histologies treated at the Harvard Cyclotron Laboratory, the Francis Burr Proton Center, or the Massachusetts General Hospital between 1991 and 2002 73 . Combined photon and proton beam radiotherapy was given as definitive treatment in 32 patients, as adjuvant treatment after partial resection in 50 patients, and as adjuvant treatment after complete resection in 20 patients. Five-year local control rates were 95% for patients with a complete resection, 82% for patients with a partial resection, and 87% for patients with biopsy only. Five-year overall survival rates were 90% for patients with a complete resection, 53% for patients with a partial resection, and 49% for patients with a biopsy only. Also from the Massachusetts General Hospital, Truong and colleagues described 20 patients with primary sphenoid sinus tumours treated with proton beam radiotherapy at a median dose of 76 CGE 74 . The two-year rates of local control, regional control, and freedom from distant metastasis were 86%, 86%, and 50%, respectively. The two-year disease-free and overall-survival rates were 31% and 53%, respectively. The investigators identified brain invasion and involvement of the oropharynx and anterior cranial fossa as important prognostic factors. In a systematic review and meta-analysis which included the Resto et al. study, Ramaekers and colleagues reported a significantly higher pooled estimated five-year local control rate for patients with paranasal and sinonasal tumours treated with proton beam radiotherapy compared to intensity modulated photon therapy (88% vs. 66%;p=0.035) 75 .
Tokuuye and colleagues reported the results of a retrospective review of 33 patients with head and neck tumours and no history of surgery who were treated with proton beam radiotherapy with or without photon beam radiotherapy at the University of Tsukuba Hospital in Japan 76 . The five-year overall survival rate was 44%, and the five-year local control rate was 74%; acute toxicity greater than grade III was reported in one patient, and late toxicity greater than grade III was reported in six patients. Similarly, in a retrospective analysis of 39 adult patients with unresectable malignant tumours of the nasal cavity, paranasal sinus, or skull base who were treated with proton beam radiotherapy at a dose of 60 CGE or higher at the National Cancer Center Hospital East in Japan, Zenda and colleagues reported a one-year local control rate of 77%, and three-year progression-free and overall survival rates of 49.1% and 59.3%, respectively 77 . Acute toxicity included grade II dermatitis; long-term grade III-IV toxicity was reported in five patients, and one treatment-related death was reported. Romesser and colleagues retrospectively reviewed 92 patients with recurrent head and neck cancer treated with proton beam therapy at a median dose of 60.6 GyRBE 78 . The actuarial 12 month freedom-from-distance metastasis and overall survival rates were 84% and 65.2% respectively. Grade III or greater toxicities were noted in 10.8% of patients.
# II. Potential Indications and Evidence for Proton Beam Therapy
# Lymphoma
Cure rates of early Hodgkin lymphoma are high, and the avoidance of late complications and second malignancies has become increasingly important for these patients; proton beam radiotherapy may therefore offer an advantage over conventional methods for patients with lymphoma requiring radiotherapy. In a study of ten consecutive patients with mediastinal masses from lymphoma who were treated with three-dimensional proton beam radiotherapy, Li et al. reported a complete metabolic response rate of 86% 79 . The patients ranged in age from 26 to 45 years of age; eight of these patients had nodular sclerosing stage II Hodgkin lymphoma, one had stage II diffuse large B cell lymphoma, and one had disseminated T-cell lymphoblastic lymphoma. At the time of referral for proton beam radiotherapy, seven patients had either primary refractory disease or recurrent disease. When compared to conventional radiotherapy, proton beam radiotherapy resulted in mean lower doses to the lungs, esophagus, and heart, but not to the breasts 79 . Hoppe and colleagues also recently reported the results of a phase II trial involving dosimetric comparisons of three-dimensional conformal radiotherapy, intensity modulated radiotherapy, and proton beam radiotherapy for ten patients with stage IA-IIIB Hodgkin lymphoma with mediastinal (bulky or nonbulky) involvement after chemotherapy 80 . Proton beam radiotherapy resulted in the lowest mean dose to the heart, lungs, and breasts for all ten patients compared with both the three-dimensional and intensity modulated radiotherapy.
# Prostate Cancer
Several studies have suggested that proton beam radiotherapy may be beneficial for patients with locally advanced prostate cancer, due to the low rate of radiation scattering to adjacent structures. The largest report to date comes from an analysis of 1255 patients treated with either proton beam radiotherapy alone or in combination with photons between 1991 and 1997 at Loma Linda University 81 . The authors reported minimal morbidity, and a 5-year overall biochemical disease-free survival rate of 73%, which is comparable to rates reported with other modalities in this population of patients. The long-term results of the only randomized trial examining proton beam radiotherapy comparing conventional and high-dose radiotherapy were recently published by Zietman and colleagues 82,83 . Three hundred and ninety three patients with stage T1b through T2b prostate cancer and PSA levels less than or equal 15 ng/mL received photon beam radiotherapy at a fixed dose 50.4 Gy, and were then randomized to receive boost proton beam radiotherapy to a total dose of either 70.2 Gy (conventional dose) or 79.2 Gy (high dose). For patients with low-risk disease (N=228), the 10-year biochemical failure rate was significantly different between the two treatment groups (28.2% conventional dose versus 7.1% high dose, p<0.0001). There were no differences in the 10-year overall survival rates among the treatment arms (78.4% versus 83.4%; p=0.41). Treatment with higher-dose radiotherapy was not associated with an increase in acute or late patient-reported prostate cancer symptoms 84 . Although these results are promising, this trial was not designed to test whether proton beam radiotherapy is more or less efficacious than other conformal techniques or brachytherapy for the treatment of patients with prostate cancer. In an analysis of data from the Surveillance, Epidemiology and End Results (SEER) database, patients treated for primary prostate cancer with IMRT (N=684) were compared to patients treated with proton beam radiotherapy (N=684) 85 . Patients treated with IMRT had a lower rate of gastrointestinal morbidity (relative risk=0.66, 95% CI=0.55-0.79), but there were no significant differences in rates of other morbidities between IMRT and proton therapy. AIM Specialty Health published proton bean therapy clinical appropriateness guidelines in 2019 86 . After reviewing the evidence, it was concluded that proton beam therapy is not medically necessary for the treatment of prostate cancer. The evidence quality is low and insufficient to determine how proton therapy and photon-based therapies differ.
# Non-Small Cell Lung Cancer
A limited number of studies have reported an 80-90% rate of local control for patients with stage I non-small cell lung cancer (NSCLC) treated with hypofractionated proton beam radiotherapy . However, in a meta-analysis comparing photon, proton, and carbon-ion radiotherapy for patients with inoperable stage I NSCLC, Grutters and colleagues concluded that proton beam radiotherapy did not offer a statistically significant improvement in overall survival when compared to photon-based stereotactic radiotherapy, although both modalities were significantly better than conventional photon radiotherapy 91 . Proton beam radiotherapy may offer an advantage for patients with advanced inoperable NSCLC, and may spare lung volumes from receiving low-dose irradiation from exiting photon beams. In a retrospective review by Nakayama et al., the progression-free survival rate of 35 patients with stage II and III NSCLC was 59.6% at one year and 29.2% at two years, and the overall survival rate was 81.8% at one year and 58.9% at two years 92 . Similarly, in a retrospective review of 57 patients with inoperable stage IIIA-IIIB NSCLC, Oshiro and colleagues reported one-and two-year progression-free survival rates of 36.2% and 24.9% respectively, and one-and two-year overall survival rates of 65.5% and 39.4%, respectively 93 . While these results are promising, it is important to note that proton beam radiotherapy planning is particularly challenging for lung tumours, owing to organ motion and changes to lung density during respiration 94 .
Members of the working group do not currently recommend that patients with prostate cancer, nonsmall cell lung cancer, or most lymphomas be referred for proton beam radiotherapy, due to an insufficient evidence base. However, individual patient cases should be discussed by the multidisciplinary team during a Tumour Board meeting.
# III. Referral and Funding Process for Out of Country Treatment
A standalone document outlining this process, in Alberta, is available on Insite on the Cancer Care Alberta resource page.
# Patient Selection Criteria.
Health care providers must take into account a wide range of factors in assessing if proton beam radiotherapy will confer a significant advantage for the patient over standard radiotherapy -the diagnosis alone is often not sufficient 95 . Based on the data published to date, combined with the expert clinical experiences of the working group members, we recommend proton beam radiotherapy be considered for pediatric, adolescent, young adult and adult patients who are residents of Alberta, are covered by the Alberta Health Care Insurance Plan (AHCIP), and meet the criteria outlined in the table below.
# Referral Process (Appendix A).
The Radiation Oncologist presents the patient case, which meets the criteria in Table 1, at the Proton Therapy Referral Rounds. A patient deemed borderline for meeting the criteria, requires the referring Radiation Oncologist to contact the Florida Proton Beam Program and request a comparative protonphoton plan. The borderline patient's case and comparative plan is then discussed by members of the Proton Therapy Referral Rounds.
The Proton Therapy Referral Rounds is a multidisciplinary tumour board meeting. At this meeting, all members can provide input on patient cases presented. The team also discusses possible additional treatments, travel arrangements and follow-up care. If a referral is recommended, a summary note of the meeting is generated (checklist in Appendix B), and the Radiation Oncologist contacts the Florida Proton Beam Program to confirm if they have capacity. If the Florida Proton Beam Program does not have capacity, a referral to a non-contracted vendor is required. The Radiation Oncologist must make the request through the out of country Health Services Committee.
Once capacity is confirmed, the referring Radiation Oncologist completes the Request for Approval Form (available on Insite on the Cancer Care Alberta Resource page), which is then sent, along with all items on the Alberta Health Checklist (Appendix C), via FAX or mail to the Senior Medical Director of Cancer Care Alberta. If approved, the Senior Medical Director's office sends the referral via FAX or mail to the Alberta Health Special Program Unit. The referral letter must include the following:
- Referring physician's contact information: name, specialty, facility address, cell phone, email, fax - Patient information: name, date of birth, address, email, phone, Alberta personal health card number, and if the patient is pediatric-parent's/guardians contact information - Approved diagnosis - Proton Therapy Referral Rounds date, summary note and treatment recommendation - Notification of access to Proton Beam Therapy-standard process or expediated process and the rationale behind the choice The Alberta Health Special Program Unit does not have access to any electronic medical records. All details on the case must be included in the referral letter. The application is considered complete when all the required information has been submitted, and the Alberta Health Special Program Unit Chair notifies the referring Radiation Oncologist, in writing, that the application has been scheduled for review at an upcoming meeting. The Alberta Health Special Program Unit will assess the application and decide within 30 days. If the Alberta Health Special Program Unit has any additional questions regarding the referral, they will direct them to the lead of the Proton Beam Therapy Referral Rounds.
Once decided, the Alberta Health Special Program Unit will contact the referring Radiation Oncologist. The approval letter will: 1. Stipulate approval for payment of the services requested 2. Outline the required next steps for the patient 3. Provide details on what services are covered (all medical treatment and transportation to and from) and what is not covered (all accommodation and special costs).
The patient must complete two release forms and return them to the manager of the Alberta Health Special Program Unit. These releases allow the medical management company to assist both the patient and the referring physician with the details of the approved medical treatment. The referral letter to the proton beam radiotherapy centre should clearly state that the patient has been approved by the Alberta Health Special Program Unit.
# Development and Revision History
This guideline was reviewed and endorsed by the Cancer Care Alberta Proton Therapy Guideline Advisory Group. Members of the Cancer Care Alberta Proton Therapy Guideline Advisory Group include surgical oncologists, radiation oncologists, medical oncologists, dermatologists, nurses, pathologists, and pharmacists. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook.
This guideline was originally developed in 2019.
# Maintenance
A formal review of the guideline will be conducted in 2024. If critical new evidence is brought forward before that time, however, the guideline working group members will revise and update the document accordingly.
# Abbreviations | # Background
Charged particle radiotherapy uses beams of protons or other particles such as helium or carbon instead of photons. In contrast to conventional photon radiotherapy, in which the greatest energy release is at the surface of the tissue and decreases exponentially the deeper the radiation travels, the energy of a proton beam is released near the end of its path, resulting in a sharp and localized dose peak, referred to as the Bragg peak. This allows for better dose distribution when compared to photon beam radiotherapy, thereby decreasing the dose to normal surrounding tissues, and reducing the risk of both acute and long-term side effects 1,2 . To date, there are no published controlled comparative studies describing outcomes from patients treated with proton beam radiotherapy versus other therapies; thus, the advantage of protons over conventional photon therapy is based on the dosimetric advantage of protons over photons for tumours that are in immediate proximity to critical structures. Most of the published literature is in the form of prospective or retrospective case series and cohort studies; there is also significant variation in the types and stages of cancer for which treatment with proton beam radiotherapy has been reported, as well as the reported doses and fractionation schedules. Published reports focus mainly on toxicity, and include pediatric, adolescent, and adult patients treated with proton beam radiotherapy primarily for ocular cancers, spine or skull base chordomas and chondrosarcomas, spinal and paraspinal bone and soft tissue sarcomas, head and neck cancers, and brain tumours. In addition, there is some literature reporting the use of proton beam radiotherapy for patients with lymphoma, non-small cell lung cancer, prostate cancer, and some gastrointestinal cancers.
By December 2017, 170,556 patients worldwide had been treated with proton beam radiotherapy 3 . Historically, the high capital cost of proton facilities equipped with rotational gantries has limited the number of facilities in operation; however, that number is now increasing rapidly. Between 2004 and 2014, the number of facilities in the United States alone grew to 13 from 2 and from 13 to 32 between 2014 and 2017 3 . Compact single-room cyclotron centres have drastically reduced the capital cost and account for 10 of the 22 facilities under construction worldwide 3 . Gantry-equipped facilities capable of treating a broad range of tumour sites are not currently available in Canada.
In early 2012, the Cancer Care Alberta Proton Therapy Guideline Working Group and Guideline Advisory Group met to evaluate the most current evidence for the use of proton beam radiotherapy in pediatric and adult patients with cancer, and to develop a de novo guideline with recommendations based on an expert review of the available literature. The resulting evidence review, guideline document, and accompanying documents were presented to the out of country Health Services Committee, which operates at arm's length from Alberta Health, to establish a process to identify which patients are appropriate candidates to receive out of country treatment with proton beam radiation therapy. In 2019, the evidence was reviewed, and this guideline was updated. In 2021, the Alberta Health working group set up a special program unit to review proton beam radiation therapy requests, which means the requests no longer go through the out of country Health Services Committee.
Guideline Questions 1. What is the evidence for the use of proton beam radiation therapy for the management of patients with cancer? 2. What are the published recommendations for the selection of patients most likely to benefit from treatment with proton beam radiation therapy? 3. What are the steps involved in referring a patient for out of country proton beam radiation therapy?
# Development
The Cancer Care Alberta Proton Therapy Guideline Advisory Group took the following steps in producing this guideline:
1. The Guideline Advisory Group members individually reviewed the results of an environmental scan and literature review conducted by a Knowledge Management Specialist from the Guideline Resource Unit. Members of this group include representatives from Alberta Health, as well as the departments of medical oncology, radiation oncology, and pediatric neurosurgery at the two tertiary cancer centres in Alberta. For a detailed description of the methodology followed during the guideline development process, please refer to the Guideline Resource Unit Handbook. 2. Based on this review, the Guideline Advisory Group gave support to the Guideline Working Group to draft a guideline containing the recommendations and supporting evidence about the selection of patients most likely to benefit from treatment with proton beam radiation therapy. 3. The Guideline Working Group then distributed the draft document via an anonymous electronic survey to 17 healthcare professionals from various disciplines within the province for review and comment. The response rate was 59%. 4. The comments from the external review were incorporated into the guideline draft by the Guideline Working Group. 5. The final guideline was reviewed and endorsed in February 2013 by the Cancer Care Alberta Proton Therapy Guideline Advisory Group and Guideline Working Group and was posted on the external website in March 2013. 6. The updated guideline was reviewed and endorsed in 2019 by members of the Guideline Working Group and Guideline Advisory Group. 7. The out of country process was updated in 2022 by the Alberta Health working group.
# Search Strategy
Medical journals were searched using the MEDLINE, EMBASE, PubMed, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials; the references and bibliographies of studies identified through these searches were scanned for additional sources. The search terms were: Protons (MeSH term) AND Radiotherapy (MeSH term), proton therapy (MeSH term), proton beam (keyword), particle beam therapy (keyword), and charged particle therapy (keyword). The search was limited to studies published in the English language between the years 2000 and 2014. There were no limitations by study design. A search for new or updated guidelines, health technology assessments, and medical policies was conducted by accessing the websites of guideline developers and the National Guidelines Clearinghouse database, and by searching the grey literature using online search engines. A search for ongoing trials at http://www.clinicaltrials.
# Target Population
The recommendations in this guideline are for pediatric, adolescent, young adult and adult patients who are residents of Alberta and may qualify to receive proton beam radiotherapy at a facility outside of Canada for treatment of their cancer.
# Discussion
# I. Indications and Evidence for Proton Beam Therapy
# Pediatric Tumours
Radiation therapy has played an important role in the treatment and cure of children diagnosed with malignant tumours over the past 30 years; given that approximately 70% of children with malignancies can now expect to be cured, the late effects of treatment have now become a major focus 4 . Proton beam therapy is associated with a reduction in acute and long-term toxicities, as well as lower rates of radiation-induced second malignancies, and potentially less acute and long-term damage to developing organs in pediatric and adolescent patients with cancer [4][5][6] ; therefore, the benefits of proton beam radiotherapy are potentially the greatest in this population. Although limited, published reports of pediatric and adolescent patients treated with proton beam radiotherapy have mostly addressed tumours arising on or near critical structures, as well as tumours where organs in the exit path of photon radiotherapy present significant secondary malignancy risk or risk of impaired development and function; such tumours include medulloblastomas, gliomas, ependymomas, retinoblastomas, rhabdomyosarcomas, and pelvic sarcomas 4,7 .
In one of the larger pediatric series published to date, MacDonald and colleagues reported the results of 17 pediatric patients with WHO grade II or III intracranial ependymomas treated with 3-dimensional conformal proton beam radiotherapy 8 . At a median follow-up of 26 months, the rates of local control, progression free survival, and overall survival rates were 86%, 80%, and 89%, respectively. Similarly, Amsbaugh and colleagues published the results of a prospective case series of eight pediatric patients with WHO grade I or II spinal ependymomas treated with proton beam radiotherapy 9 . Five patients were treated with proton beam radiotherapy as part of their primary management, while three were treated for recurrence of their disease. The entire vertebral body was treated in all but two patients, with a mean dose of 51.1 cobalt grey equivalents (CGE). The rates of local control, eventfree survival, and overall survival were all 100% at a mean follow-up of 26 months, and the investigators reported minimal acute side effects.
In a case series of three pediatric patients with medulloblastoma, Yuh and colleagues reported minimal acute side effects, excellent sparing of surrounding critical structures, and no treatment disruptions when the patients were treated with 36 CGE to the craniospinal axis and 18 CGE to the posterior fossa 10 . Similarly, St. Clair and colleagues compared treatment plans from standard photon therapy to intensity modulated radiotherapy (IMRT) and proton beam radiotherapy for craniospinal axis irradiation and posterior fossa boost in a pediatric patient with medulloblastoma. They reported substantial normal-tissue dose sparing with IMRT and proton treatment of the posterior fossa and spinal column, and also that protons were superior to IMRT in this case 11 . In another case series, six pediatric medulloblastoma patients were treated with vertebral-body-sparing proton craniospinal irradiation after maximal safe resection 12 . These patients received a dose of 23.4 Gy or 36 Gy to the craniospinal axis followed by a boost to the posterior fossa and any metastatic lesions. After a median follow-up of 13.6 years, the overall survival and disease-free survival were 83%, treatment did not increase spinal abnormalities compared with historical data, and it allowed for vertebral body growth outside of radiation field and bone marrow sparing. In a modeling study evaluating the consequences of radiotherapy in five year old patients with medulloblastoma, Lundkvist and colleagues reported that proton radiation therapy was cost-effective and was associated with an additional 0.68 qualityadjusted life-years per patient compared with conventional photon radiotherapy 13 . Reductions in IQ loss and growth hormone deficiency contributed most to the cost savings and were the most important parameters for cost-effectiveness. This analysis suggests that proton beam radiotherapy may be cost saving in comparison to photon radiotherapy for pediatric patients with medulloblastoma due to the reduction of late side-effects. A reduction in side-effects for pediatric patients with medulloblastoma treated with proton beam radiotherapy was also demonstrated in a prospective study of 23 pediatric patients who were followed for high-grade ototoxicity 14 , although a cost-benefit analysis was not reported for this trial.
# Young Adult Tumours
Adolescent and young adult patients (age range 19-40) can be particularly vulnerable to complications from radiotherapy. With increased survival, the long term complications of treatment can have a major impact on growth, fertility, and emotional well-being 15 . Particularly the risk of radiation-induced secondary cancer is of concern in these patients. Zhang and colleagues reported on 17 medulloblastoma patients treated with passively scattered proton or field-in-field photon craniospinal irradiation (CSI) 16 . They found that proton CSI reduced the predicted risks of radiogenic second cancer incidence and cardiac mortality by six times compared with photon CSI. Yoon et al. retrospectively review 10 randomly selected cancer patients treated with either photon or proton radiotherapy 17 . The secondary cancer risks to lungs, stomach, liver and pancreas were at least five fold higher in patients treated with photon therapy compared to proton beam therapy. Another retrospective review studied 86 patients with retinoblastoma treated with proton or photon radiotherapy 18 . The 10-year cumulative incidence of radiation-induced or in-field second malignancies was 0% for patients treated with proton beam therapy versus 14% for patients treated with photon therapy (p=0.015). The 10-years cumulative incidence of all second malignancies was 5 % after proton therapy and 14% after photon therapy (p=0.120). Chung and colleagues performed a retrospective cohort study where they matched 558 proton patients with 558 photon patients 19 . Secondary malignancies occurred in 42 (7.5%) photon patients versus only 29 (5.2%) proton patients. They found that proton therapy was not associated with an increased risk of secondary cancer with an adjusted hazard ratio of 0.52 [95% confidence interval, 0.32-0.85]; p=0.009.
# Central Nervous System Tumours
Similar to pediatric patients with favourable prognoses, adult patients with benign lesions and indolent malignant tumours also benefit from proton beam radiotherapy due to a decreased risk of late neurologic toxicities.
Meningiomas. Meningiomas are the second most common intracranial tumour reported in adults, accounting for 13 to 26% of all primary brain tumours in this population 20,21 . The management of a patient with a meningioma depends on the signs and symptoms produced by the tumour, the age of the patient, and the location and size of the tumour 22 . In the Meningiomas clinical practice guideline, the Alberta Provincial CNS Tumour Team members recommend surgery as the primary treatment for patients who are not candidates for management by watch-and-wait. This guideline also states that radiotherapy offers reasonable control for patients who are not candidates for surgery, patients whose tumour location or shape is not amenable to surgery (such as a cavernous sinus meningioma), patients who have symptomatic residual disease, or for the treatment of recurrence. Boskos and colleagues reported on 24 patients with either atypical or metastatic meningioma treated at the Centre Protonthérapie d'Orsay with a postoperative combination of proton and photon radiotherapy 23 .
The mean local relapse-free survival was 28.3 months (range 10-50) for atypical meningioma and 23 months (range 13-33) for malignant meningioma; ten tumours recurred locally. Overall survival rates were 100% at one year, 80.4% ± 8.8% at three years, 53.2% ± 11.6% at five years, and 42.6% ± 13% at eight years. Noël et al. also reported on the outcomes of 51 patients treated for base of skull meningiomas with a combination of proton and photon radiotherapy 24 . The four-year local control rate was 98%, and the four-year overall survival rate was 100%. The investigators reported tumour stabilization in 38 patients (72%), volume reduction in ten patients (20%), and intra-tumour necrosis in three patients; grade three side effects were observed in two patients. Similarly, Wenkel et al. reported on 46 patients with partially resected, biopsied, or recurrent meningiomas who were treated with combined proton and photon radiotherapy at the Massachusetts General Hospital and the Harvard Cyclotron Laboratory 25 . Five-and ten-year overall survival rates were 93% and 77%, respectively, and the five-and ten-year recurrence-free rates were 100% and 88%, respectively. Survival without severe toxicity was 80% at both five and ten years. The use of stereotactic and hypofractionated stereotactic proton beam radiotherapy were reported by Vernimmen and colleagues in a study of 27 patients with large or complex intracranial meningiomas 26 . Of the 18 patients treated with hypofractionated stereotactic proton beam radiotherapy, 16 remained clinically stable or improved. Of the five patients treated with stereotactic proton beam radiotherapy, two showed clinical improvement and three remained clinically stable. The radiologic control rate was 88% for the patients treated with hypofractionation, and 100% for patients treated without hypofractionation. In a study investigating the use of spot-scanning proton beam radiotherapy, Weber and colleagues reported on 13 patients treated postoperatively for incomplete resection or recurrence and three patients treated radically after presumptive diagnosis based on imaging 27 32 . Similarly, in 59 patients with high-risk cerebral AVMs treated with two-fraction proton stereotactic radiosurgery because of large tumour size or eloquent brain location, the median time to total obliteration was 62 months and the five-year actuarial total obliteration rate was 33% 33 . Complications associated with radiosurgery include radiation necrosis, seizures, and new neurologic deficits, therefore the efficacy of radiosurgery must be weighed against the potential toxicities of treatment 34 .
Acoustic neuromas. Acoustic neuromas, also known as vestibular schwannomas, are benign slowgrowing tumours that commonly arise from the vestibular portion of the eighth cranial nerve and account for approximately 8% of intracranial tumours in adults 35 . Options for treatment depend on tumour size, tumour growth rate, symptoms, health status, and patient preference, and may include observation, single-session stereotactic radiosurgery, fractionated conventional radiotherapy, fractionated stereotactic radiotherapy, proton beam radiotherapy, or surgery 36,37 . Although a distinct advantage of proton therapy over photon therapy for acoustic neuromas has not been demonstrated to date, larger tumours may benefit from proton beam radiotherapy because of the reduction of exit dose to the non-targeted brain and surrounding normal tissues 34 . In a review of 88 patients treated with proton beam radiotherapy at the Harvard Cyclotron Laboratory, Weber and colleagues reported two-and five-year actuarial control rates of 95.3% and 93.6% respectively in patients treated with stereotactic proton beam radiotherapy 38 . Facial and trigeminal nerve function was preserved in 91% and 89% of patients, respectively, and the five-year cumulative radiologic response rate was 94.7%. Salvage therapy was required in five patients post-radiotherapy. In a trial of 30 patients with acoustic neuromas treated with fractionated proton beam radiotherapy at the Loma Linda Medical Center, Bush et al. reported no disease progression at a mean follow-up of 34 months, and radiographic regression in 11 patients 39 . The rate of hearing preservation was 31%, however only 13 patients had useful hearing prior to radiotherapy. No transient or permanent treatment-related trigeminal or facial nerve dysfunction was observed.
# Spinal and Skull Base Chordomas and Chondrosarcomas
Chordomas are slow growing, locally aggressive bone tumours arising from the remnants of the notochord and most frequently occurring in the sacrococcygeal region or at the base of the skull near the sphenooccipital region 40,41 . Chordomas are rare in both adults and children, accounting for only three to four percent of all primary bone tumours 41 . Chondrosarcomas are malignant cartilaginous tumours that can occur anywhere in the skeletal system, and most commonly in the long bones and pelvis; in the skull base, chondrosarcomas account for six percent of all tumours, and most commonly occur in the middle, posterior, or anterior fossae 42 . The clinical features of chordomas and chondrosarcomas are quite similar, as is the optimal treatment strategy, which involves maximal surgical resection [41][42][43] . Adjuvant postoperative radiotherapy is commonly used for patients with chordomas, and high doses have been associated with lower rates of local recurrence or treatment failure 44,45 . Postoperative radiotherapy has also been reported for the management of patients with chondrosarcomas. As a result of their proximity to critical neural structures, however, chordomas and chondrosarcomas of the skull base and spine are difficult to manage with conventional radiotherapy techniques, therefore making these tumours one of the main applications for proton beam radiotherapy. Despite the relative rarity of these tumours, the results of over 1,700 patients with spinal and skull base chordomas and chondrosarcomas treated with proton beam radiotherapy have been reported worldwide since the early 1970's 34 . Ares and colleagues recently reported the results of a long-term follow-up study of 64 patients with skull base chordomas or chondrosarcomas treated with spot-scanning proton beam radiotherapy at the Paul Scherrer Institute 46 . The five-year overall survival rate was 91% for patients with chondrosarcomas, and 62% for patients with chordomas; the five-year local control rate was 94% for patients with chondrosarcoma, and 81% for patients with chordomas. Adverse events included grade III (N=1) and grade IV (N=1) unilateral optic neuropathy, grade III temporal lobe parenchyma (N=2) and grade I leukoencephalopathy (N=5). In the largest series published to date, Munzenrider and Liebsch retrospectively reviewed 621 patients with spinal and skull base chordomas or chondrosarcomas treated between 1975 and 1998 at the Harvard Cyclotron Laboratory 47 . Treatment involved combined proton and photon irradiation, with a dose range of 66 to 83 CGE. For patients with skull base tumours, the five-year overall survival rates were 91% for chondrosarcomas and 80% for chordomas (p=0.010), and the ten-year overall survival rates were 88% for chondrosarcomas and 54% for chordomas (p<0.0001). Local recurrence rates were also better for chondrosarcomas versus chordomas at five years (98% versus 73%, p<0.0001) and ten years (94% versus 54%, p<0.0001). For patients with cervical spine tumours, the five-year overall survival rates were 48% for chondrosarcomas and 80% for chordomas (p=0.008), and the ten-year overall survival rates were 48% for chondrosarcomas and 33% for chordomas (p=0.109). Local recurrence rates for chondrosarcomas and chordomas were 54% and 69% at five years, and 54% and 48% at ten years, with no significant differences between the two groups of patients. In a systematic review of seven studies involving 416 adult and pediatric patients with inoperable or incompletely resected chordomas of the skull who were treated with proton beam radiotherapy, Amichetti et al. reported an average five-year overall survival rate of 79.8% (range 66.7-80.5%) and an average five-year local control rate of 69.2% (range 46-73%) 41 . Late toxicity was reported in the range of 5-17%, with some grade III and IV toxicities reported. Similarly, in another systematic review of four studies involving 254 patients with chondrosarcomas of the skull base treated post-operatively with proton beam radiotherapy, Amichetti and colleagues reported a five-year overall survival rate of 99-100% and a five-year local control rate of 75-99% 42 .
The use of proton beam radiotherapy has also been described for soft tissue sarcomas of the spine. DeLaney and colleagues reported the results of a prospective phase II trial involving 50 patients mostly with spinal and paraspinal chordomas and chondrosarcomas, but patients with liposarcoma, osteosarcoma, Ewing's sarcoma, giant cell tumour, angiosarcoma, malignant schwannoma, and spindle cell sarcoma were also included 4 . Patients were treated post-operatively with high-dose proton-photon radiotherapy at a median dose of 76.6 CGE and select patients with high-grade tumours also received chemotherapy. Thirty-six patients were treated for primary tumours, and 14 for recurrent disease. With 7.3-year median follow-up, the respective five-and eight-year actuarial local control rates were 94% and 85% for primary tumours and 81% and 74% for the entire group. Local recurrence was less common for primary tumours, compared to recurrent tumours, (11% vs. 50%, p=0.002). The eight-year actuarial risk of grade 3-4 late RT morbidity was 13% 48 . Guttmann and colleagues studied 23 recurrent soft tissue sarcoma patients treated with proton reirradiation, prospectively 49 . All sarcomas were in a previously irradiated field. The three-year progression-free survival was found to be 43% (95% CI 21-62%) and the three-year overall survival was 64% (95% CI 39-81%). Weber et al. retrospectively reviewed 38 Ewing sarcoma patients treated with pencil beam scanning proton therapy 50 . The five-year actuarial rate of local control, distant metastasis-free survival and overall survival were 81.5%, 76.4% and 83.0% respectively. This treatment was associated with a low rate of high -grade late toxicity. Demizu and colleagues retrospectively reviewed 91 patients with unresectable or incompletely resected bone and soft tissue sarcomas, treated with 70.4 GyRBE proton or carbon ion particle therapy in 16 or 32 fractions 51 . They found that particle therapy was effective with a 3-year overall survival of 83%, a 3-year progression free survival of 72% and a 3-year local control of 92%. The 16 fractions protocol was associated with significantly (p<0.001) more late grade ≥ 3 toxicities.
# Ocular Melanoma
Uveal melanoma, which includes tumours in the iris, ciliary body, and choroid, is the most common type of primary ocular tumour in adults, accounting for 95% of all cases 52,53 . Depending on the size and location of the tumour, treatment can range from local ablative treatments to complete removal of the eye. The use of proton beam radiation therapy for larger tumours has been reported extensively in the literature, with five recent comparative studies and numerous non-comparative studies showing high rates of local control and minimal adverse effects [54][55][56][57][58][59][60][61][62][63][64][65][66][67][68] . However, a publication based on data from the SEER database in the United States reported that survival rates for patients with uveal melanoma have not improved from 1973 to 2008, despite a shift toward more conservative treatments such as proton beam radiotherapy during this time period 69 .
# Head and Neck Tumours
Tumours of the paranasal sinuses and nasal cavity are rare, accounting for 2-3% of all head and neck tumours 70 . Optimal treatment involves surgical resection and postoperative radiotherapy; chemotherapy, either alone or in combination with radiotherapy and/or surgery, is also an option for patients who are at high risk of recurrence or for patients with inoperable tumours 71,72 . For patients with paranasal sinus and nasal cavity tumours who are good candidates, proton beam radiotherapy is the ideal form of radiotherapy, owing to the irregular shape of many of these tumours, the relative radioresistance of some of these tumours, requiring high physical and biologically effective doses, the high risk of recurrence associated with these tumours, and the proximity to critical normal tissues in the ocular globes, optic nerves, and brain 34 . Resto et al. retrospectively reviewed the outcomes of 102 patients with locally advanced sinonasal tumours of varying histologies treated at the Harvard Cyclotron Laboratory, the Francis Burr Proton Center, or the Massachusetts General Hospital between 1991 and 2002 73 . Combined photon and proton beam radiotherapy was given as definitive treatment in 32 patients, as adjuvant treatment after partial resection in 50 patients, and as adjuvant treatment after complete resection in 20 patients. Five-year local control rates were 95% for patients with a complete resection, 82% for patients with a partial resection, and 87% for patients with biopsy only. Five-year overall survival rates were 90% for patients with a complete resection, 53% for patients with a partial resection, and 49% for patients with a biopsy only. Also from the Massachusetts General Hospital, Truong and colleagues described 20 patients with primary sphenoid sinus tumours treated with proton beam radiotherapy at a median dose of 76 CGE 74 . The two-year rates of local control, regional control, and freedom from distant metastasis were 86%, 86%, and 50%, respectively. The two-year disease-free and overall-survival rates were 31% and 53%, respectively. The investigators identified brain invasion and involvement of the oropharynx and anterior cranial fossa as important prognostic factors. In a systematic review and meta-analysis which included the Resto et al. study, Ramaekers and colleagues reported a significantly higher pooled estimated five-year local control rate for patients with paranasal and sinonasal tumours treated with proton beam radiotherapy compared to intensity modulated photon therapy (88% vs. 66%;p=0.035) 75 .
Tokuuye and colleagues reported the results of a retrospective review of 33 patients with head and neck tumours and no history of surgery who were treated with proton beam radiotherapy with or without photon beam radiotherapy at the University of Tsukuba Hospital in Japan 76 . The five-year overall survival rate was 44%, and the five-year local control rate was 74%; acute toxicity greater than grade III was reported in one patient, and late toxicity greater than grade III was reported in six patients. Similarly, in a retrospective analysis of 39 adult patients with unresectable malignant tumours of the nasal cavity, paranasal sinus, or skull base who were treated with proton beam radiotherapy at a dose of 60 CGE or higher at the National Cancer Center Hospital East in Japan, Zenda and colleagues reported a one-year local control rate of 77%, and three-year progression-free and overall survival rates of 49.1% and 59.3%, respectively 77 . Acute toxicity included grade II dermatitis; long-term grade III-IV toxicity was reported in five patients, and one treatment-related death was reported. Romesser and colleagues retrospectively reviewed 92 patients with recurrent head and neck cancer treated with proton beam therapy at a median dose of 60.6 GyRBE 78 . The actuarial 12 month freedom-from-distance metastasis and overall survival rates were 84% and 65.2% respectively. Grade III or greater toxicities were noted in 10.8% of patients.
# II. Potential Indications and Evidence for Proton Beam Therapy
# Lymphoma
Cure rates of early Hodgkin lymphoma are high, and the avoidance of late complications and second malignancies has become increasingly important for these patients; proton beam radiotherapy may therefore offer an advantage over conventional methods for patients with lymphoma requiring radiotherapy. In a study of ten consecutive patients with mediastinal masses from lymphoma who were treated with three-dimensional proton beam radiotherapy, Li et al. reported a complete metabolic response rate of 86% 79 . The patients ranged in age from 26 to 45 years of age; eight of these patients had nodular sclerosing stage II Hodgkin lymphoma, one had stage II diffuse large B cell lymphoma, and one had disseminated T-cell lymphoblastic lymphoma. At the time of referral for proton beam radiotherapy, seven patients had either primary refractory disease or recurrent disease. When compared to conventional radiotherapy, proton beam radiotherapy resulted in mean lower doses to the lungs, esophagus, and heart, but not to the breasts 79 . Hoppe and colleagues also recently reported the results of a phase II trial involving dosimetric comparisons of three-dimensional conformal radiotherapy, intensity modulated radiotherapy, and proton beam radiotherapy for ten patients with stage IA-IIIB Hodgkin lymphoma with mediastinal (bulky or nonbulky) involvement after chemotherapy 80 . Proton beam radiotherapy resulted in the lowest mean dose to the heart, lungs, and breasts for all ten patients compared with both the three-dimensional and intensity modulated radiotherapy.
# Prostate Cancer
Several studies have suggested that proton beam radiotherapy may be beneficial for patients with locally advanced prostate cancer, due to the low rate of radiation scattering to adjacent structures. The largest report to date comes from an analysis of 1255 patients treated with either proton beam radiotherapy alone or in combination with photons between 1991 and 1997 at Loma Linda University 81 . The authors reported minimal morbidity, and a 5-year overall biochemical disease-free survival rate of 73%, which is comparable to rates reported with other modalities in this population of patients. The long-term results of the only randomized trial examining proton beam radiotherapy comparing conventional and high-dose radiotherapy were recently published by Zietman and colleagues 82,83 . Three hundred and ninety three patients with stage T1b through T2b prostate cancer and PSA levels less than or equal 15 ng/mL received photon beam radiotherapy at a fixed dose 50.4 Gy, and were then randomized to receive boost proton beam radiotherapy to a total dose of either 70.2 Gy (conventional dose) or 79.2 Gy (high dose). For patients with low-risk disease (N=228), the 10-year biochemical failure rate was significantly different between the two treatment groups (28.2% conventional dose versus 7.1% high dose, p<0.0001). There were no differences in the 10-year overall survival rates among the treatment arms (78.4% versus 83.4%; p=0.41). Treatment with higher-dose radiotherapy was not associated with an increase in acute or late patient-reported prostate cancer symptoms 84 . Although these results are promising, this trial was not designed to test whether proton beam radiotherapy is more or less efficacious than other conformal techniques or brachytherapy for the treatment of patients with prostate cancer. In an analysis of data from the Surveillance, Epidemiology and End Results (SEER) database, patients treated for primary prostate cancer with IMRT (N=684) were compared to patients treated with proton beam radiotherapy (N=684) 85 . Patients treated with IMRT had a lower rate of gastrointestinal morbidity (relative risk=0.66, 95% CI=0.55-0.79), but there were no significant differences in rates of other morbidities between IMRT and proton therapy. AIM Specialty Health published proton bean therapy clinical appropriateness guidelines in 2019 86 . After reviewing the evidence, it was concluded that proton beam therapy is not medically necessary for the treatment of prostate cancer. The evidence quality is low and insufficient to determine how proton therapy and photon-based therapies differ.
# Non-Small Cell Lung Cancer
A limited number of studies have reported an 80-90% rate of local control for patients with stage I non-small cell lung cancer (NSCLC) treated with hypofractionated proton beam radiotherapy [87][88][89][90] . However, in a meta-analysis comparing photon, proton, and carbon-ion radiotherapy for patients with inoperable stage I NSCLC, Grutters and colleagues concluded that proton beam radiotherapy did not offer a statistically significant improvement in overall survival when compared to photon-based stereotactic radiotherapy, although both modalities were significantly better than conventional photon radiotherapy 91 . Proton beam radiotherapy may offer an advantage for patients with advanced inoperable NSCLC, and may spare lung volumes from receiving low-dose irradiation from exiting photon beams. In a retrospective review by Nakayama et al., the progression-free survival rate of 35 patients with stage II and III NSCLC was 59.6% at one year and 29.2% at two years, and the overall survival rate was 81.8% at one year and 58.9% at two years 92 . Similarly, in a retrospective review of 57 patients with inoperable stage IIIA-IIIB NSCLC, Oshiro and colleagues reported one-and two-year progression-free survival rates of 36.2% and 24.9% respectively, and one-and two-year overall survival rates of 65.5% and 39.4%, respectively 93 . While these results are promising, it is important to note that proton beam radiotherapy planning is particularly challenging for lung tumours, owing to organ motion and changes to lung density during respiration 94 .
Members of the working group do not currently recommend that patients with prostate cancer, nonsmall cell lung cancer, or most lymphomas be referred for proton beam radiotherapy, due to an insufficient evidence base. However, individual patient cases should be discussed by the multidisciplinary team during a Tumour Board meeting.
# III. Referral and Funding Process for Out of Country Treatment
A standalone document outlining this process, in Alberta, is available on Insite on the Cancer Care Alberta resource page.
# Patient Selection Criteria.
Health care providers must take into account a wide range of factors in assessing if proton beam radiotherapy will confer a significant advantage for the patient over standard radiotherapy -the diagnosis alone is often not sufficient 95 . Based on the data published to date, combined with the expert clinical experiences of the working group members, we recommend proton beam radiotherapy be considered for pediatric, adolescent, young adult and adult patients who are residents of Alberta, are covered by the Alberta Health Care Insurance Plan (AHCIP), and meet the criteria outlined in the table below.
# Referral Process (Appendix A).
The Radiation Oncologist presents the patient case, which meets the criteria in Table 1, at the Proton Therapy Referral Rounds. A patient deemed borderline for meeting the criteria, requires the referring Radiation Oncologist to contact the Florida Proton Beam Program and request a comparative protonphoton plan. The borderline patient's case and comparative plan is then discussed by members of the Proton Therapy Referral Rounds.
The Proton Therapy Referral Rounds is a multidisciplinary tumour board meeting. At this meeting, all members can provide input on patient cases presented. The team also discusses possible additional treatments, travel arrangements and follow-up care. If a referral is recommended, a summary note of the meeting is generated (checklist in Appendix B), and the Radiation Oncologist contacts the Florida Proton Beam Program to confirm if they have capacity. If the Florida Proton Beam Program does not have capacity, a referral to a non-contracted vendor is required. The Radiation Oncologist must make the request through the out of country Health Services Committee.
Once capacity is confirmed, the referring Radiation Oncologist completes the Request for Approval Form (available on Insite on the Cancer Care Alberta Resource page), which is then sent, along with all items on the Alberta Health Checklist (Appendix C), via FAX or mail to the Senior Medical Director of Cancer Care Alberta. If approved, the Senior Medical Director's office sends the referral via FAX or mail to the Alberta Health Special Program Unit. The referral letter must include the following:
• Referring physician's contact information: name, specialty, facility address, cell phone, email, fax • Patient information: name, date of birth, address, email, phone, Alberta personal health card number, and if the patient is pediatric-parent's/guardians contact information • Approved diagnosis • Proton Therapy Referral Rounds date, summary note and treatment recommendation • Notification of access to Proton Beam Therapy-standard process or expediated process and the rationale behind the choice The Alberta Health Special Program Unit does not have access to any electronic medical records. All details on the case must be included in the referral letter. The application is considered complete when all the required information has been submitted, and the Alberta Health Special Program Unit Chair notifies the referring Radiation Oncologist, in writing, that the application has been scheduled for review at an upcoming meeting. The Alberta Health Special Program Unit will assess the application and decide within 30 days. If the Alberta Health Special Program Unit has any additional questions regarding the referral, they will direct them to the lead of the Proton Beam Therapy Referral Rounds.
Once decided, the Alberta Health Special Program Unit will contact the referring Radiation Oncologist. The approval letter will: 1. Stipulate approval for payment of the services requested 2. Outline the required next steps for the patient 3. Provide details on what services are covered (all medical treatment and transportation to and from) and what is not covered (all accommodation and special costs).
The patient must complete two release forms and return them to the manager of the Alberta Health Special Program Unit. These releases allow the medical management company to assist both the patient and the referring physician with the details of the approved medical treatment. The referral letter to the proton beam radiotherapy centre should clearly state that the patient has been approved by the Alberta Health Special Program Unit.
# Development and Revision History
This guideline was reviewed and endorsed by the Cancer Care Alberta Proton Therapy Guideline Advisory Group. Members of the Cancer Care Alberta Proton Therapy Guideline Advisory Group include surgical oncologists, radiation oncologists, medical oncologists, dermatologists, nurses, pathologists, and pharmacists. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook.
This guideline was originally developed in 2019.
# Maintenance
A formal review of the guideline will be conducted in 2024. If critical new evidence is brought forward before that time, however, the guideline working group members will revise and update the document accordingly.
# Abbreviations
# Disclaimer
The recommendations contained in this guideline are a consensus of the Alberta Provincial Palliative Tumour Team and are a synthesis of currently accepted approaches to management, derived from a review of relevant scientific literature. Clinicians applying these guidelines should, in consultation with the patient, use independent medical judgment in the context of individual clinical circumstances to direct care.
# Copyright © (2022) Alberta Health Services
This copyright work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivative 4.0 International license. You are free to copy and distribute the work including in other media and formats for noncommercial purposes, as long as you attribute the work to Alberta Health Services, do not adapt the work, and abide by the other license terms. To view a copy of this license, see https://creativecommons.org/licenses/by-ncnd/4.0/. The license does not apply to AHS trademarks, logos or content for which Alberta Health Services is not the copyright owner.
# Funding Source
Financial support for the development of Cancer Care Alberta's evidence-based clinical practice guidelines and supporting materials comes from the Cancer Care Alberta operating budget; no outside commercial funding was received to support the development of this document.
All cancer drugs described in the guidelines are funded in accordance with the Outpatient Cancer Drug Benefit Program, at no charge, to eligible residents of Alberta, unless otherwise explicitly stated. For a complete list of funded drugs, specific indications, and approved prescribers, please refer to the Outpatient Cancer Drug Benefit Program Master List.
# Conflict of Interest Statements
Dr. Keith Aronyk has nothing to disclose Dr. Salman Faruqi has nothing to disclose.
Dr. Gerald Lim has nothing to disclose. | None | None |
792950d1f2dab5c73dfb8a0380d599b767f75bc7 | cma | None | To assist health care professionals in the management of cerebral venous thrombosis (CVT). For information related to CVT in the context of Vaccine-induced Thrombotic Thrombocytopenia (VITT), please consult Clinical Guide Vaccine-induced Prothrombotic Immune Thrombocytopenia (VIPIT/VITT).The cerebral venous system is comprised of the dural venous sinuses, deep and cortical cerebral veins, cavernous sinuses, and internal jugular veins. CVT refers to thrombosis affecting any of these sites. CVT is rare, with an incidence of approximately 10-20 per million person-years and accounting for approximately 1% of all strokes. In contrast with pulmonary embolism (PE) and deep vein thrombosis (DVT), CVT primarily affects younger individuals, with approximately 80% of cases occurring in individuals under the age of 55. Women are predominantly affected, with 75% of cases affecting females, and over 50% of cases associated with oral contraceptive use or the puerperium. However, these sex differences attenuate after the age of 50. The presenting symptoms associated with CVT can be secondary to increased intracranial pressure (ICP; headache, nausea, vomiting, blurred vision, diplopia), parenchymal injury secondary to edema or hemorrhage (focal deficits, decreased level of consciousness or encephalopathy), or cortical irritation (seizures). The most common presenting symptom is headache (90%), with seizures occurring in approximately 40% and focal deficits in 20-40%. Approximately 30% of individuals will present with some amount of intracranial bleeding secondary to parenchymal injury. Intracerebral blood is most common, with subarachnoid or subdural blood less frequently.#
General risk factors for CVT include hormonal therapy, pregnancy, heritable and acquired thrombophilias, malignancy (especially hematologic malignancies), systemic infections, collagen vascular diseases, including vasculitic disorders (e.g. systemic lupus erythematosus, granulomatosis with polyangiitis, and Behcet's disease) and inflammatory bowel disease. Local risk factors include head trauma, neurosurgery, spinal procedures, and head and neck infection (e.g. meningitis, otitis, mastoiditis). In less than one quarter of cases, no apparent cause is found.
While most CVT survivors (approximately 85%) will be functionally independent following their event, 5-10% will die, and over half may experience persisting issues related to headache, fatigue, mood or cognition affecting quality of life. Longer-term prognostic data on VTE recurrence is limited. The existing literature suggests that risk of any recurrent VTE is approximately 2-4% per year, with higher rates of recurrence in those with identified thrombophilia, malignancy, and unprovoked events.
# DIAGNOSIS OF CEREBRAL VENOUS THROMBOSIS:
In most cases, non-contrast CT head is not sufficiently sensitive to diagnose CVT. CT venography or contrast-enhanced MR venography should be performed to in individuals being assessed for possible CVT. Imaging with non-contrast CT or MRI will help to assess for the presence of parenchymal injury, including venous edema, intracranial bleeding, and signs of mass effect.
# MANAGEMENT OF CEREBRAL VENOUS THROMBOSIS:
Given the uncommon nature of CVT, recommendations are based on limited randomized data and observational cohort studies. The primary purpose of treatment is to prevent secondary brain injury and mortality from venous infarction, intracerebral hemorrhage or malignant (ie. life-threatening) mass effect. The general management approach consists of: 1) anticoagulant therapy, 2) management of increased ICP, 3) seizures and 4) headache. Some patients with CVT may be at risk of neurological deterioration with depressed level of consciousness or new onset of focal deficits due to intracranial bleeding, increased ICP or seizures. Therefore, the need for initial management in an intensive care/high-acuity setting should be assessed early, with recommended early involvement of Neurology and Hematology/Thrombosis services.
# Anticoagulant therapy
Anticoagulation, even in the presence of intracranial blood, is the standard-of-care treatment for CVT. Unlike primary intracerebral hemorrhage, the mechanism of intracranial bleeding in CVT is usually due to increased venous pressure, therefore improvement of venous obstruction generally reduces the impetus for bleeding. There may be rare cases where there are concerns regarding the safety of anticoagulation (e.g. large or rapidly expanding intracranial hemorrhage, anticipated emergent surgical decompression) that will require case-by-case collaborative decision-making by neurology and hematology/thrombosis. Usually, either parenteral anticoagulation with unfractionated heparin (UFH) or low-molecular weight heparin (LMWH) is initiated, with subsequent transition to oral anticoagulation once the patient is stable (see "duration of therapy" for considerations regarding longer-term anticoagulation). In patients not forecasted to require early neurosurgical intervention or those deemed to not have a high risk of life-threatening bleeding we favour the use of LMWH over UFH for a more reliable quality of anticoagulation.
Current guideline-recommended oral anticoagulation is with a Vitamin K antagonist (VKA) with INR target 2.0-3.0. However, the recent RESPECT-CVT trial, (published subsequent to the most recent guideline updates from the American Heart Association/American Stroke Association and the European Stroke Organization) found no differences in rates of major bleeding (one GI bleed in the dabigatran arm, 2 ICH in the warfarin arm) or venous recanalization between dose-adjusted warfarin and dabigatran 150 mg bid, initiated 5-14 days after parenteral anticoagulation and continued for 6 months. The trial, which enrolled 120 participants, was exploratory and not powered for efficacy or safety outcomes. A substudy of the EINSTEIN-Jr trial examined use of rivaroxaban for CVT in 114 children. The trial randomized children with VTE after 5-9 days of parenteral anticoagulation 2:1 to three months of rivaroxaban 20 mg-equivalent dosing versus vitamin K antagonist or parenteral anticoagulation. There was one recurrent VTE in the standard therapy group and one major bleeding event (ICH), whereas in the rivaroxaban arm there were 5 clinically relevant non-major bleeding events with no VTE recurrence and no major hemorrhage. There are other ongoing trials currently investigating DOACs for CVT (Clinicaltrials.gov -NCT03178864, NCT03191305, NCT03217448, NCT03747081), which will contribute additional information to inform the use of these agents in CVT.
# Deterioration despite anticoagulation
Some patients may deteriorate despite use of anticoagulation, either due to mass effect (secondary to venous infarction and/or hemorrhage) or thrombus extension. In cases of life-threatening mass effect, urgent neurosurgical consultation is warranted for decompressive hemicraniectomy.
Mechanical thrombectomy may be appropriate in cases where neurological deterioration is secondary to thrombus extension. Interdisciplinary collaboration may be required to determine what the best course of action may be for severe cases. The TO-ACT trial examined routine use of neurointervention (endovascular therapy, intradural thrombolytic or both as per local practice) versus conservative management in patients with severe CVT (decreased level of consciousness or mental status disorder, intracranial bleeding, and/or deep venous involvement). The trial, which was terminated early for futility after 67 patients of a target of 164 were recruited, found no difference in the rates of favourable neurological outcome at 12 months. Three of 33 interventional patients experienced intraprocedural venous sinus perforation. Thus routine use of neurointervention is not recommended, with case-by-case decision making as needed for severe presentations.
# Management of increased intracranial pressure (ICP)
Increased intracranial pressure is commonly seen in CVT. In individuals with ICP associated with optic nerve changes (papilledema, enlarged blind spots or other visual loss) or diplopia, acetazolamide may be considered alongside involvement of the ophthalmology service for monitoring.
Acetazolamide may also be considered for management of intracranial hypertension without visual changes on a case-by-case basis, in addition to conservative measures such as head of bed elevated to 30 degrees or above.
Surgical treatment such as shunting or optic nerve fenestration may be warranted in refractory cases, or in cases where the consequence of CVT results in significant hemorrhage and mass effect requiring neurosurgical intervention.
# Seizure management
Approximately 30-40% of patients with CVT will experience seizures, with over 10% experiencing seizures after the acute stage. Referral to a neurologist is indicated. Clinicians should be aware of the drug-drug interactions that exist between several common antiseizure medications and oral anticoagulants (both vitamin K antagonists as well as DOACs).
There is no evidence supporting the use of prophylactic antiseizure therapy in those without seizures.
# Headache
Approximately 90% of patients with cerebral venous thrombosis will present with headache, which may be severe in some cases. Appropriate analgesia is important both for patient comfort in addition to the fact that severe pain and vomiting can contribute to increased ICP. While headache generally improves with initiation of therapy for CVT and ICP management, some may have ongoing chronic headache that may impact quality of life. Referral for ongoing pain management in the outpatient setting is indicated in these cases.
# Risk factor management
- Provoking factors, including hormonal therapies, should be discontinued. Lifestyle modifications including smoking cessation should also be encouraged. - Heritable and acquired thrombophilias are risk factors for CVT although the implications for choice and duration of anticoagulation therapy are uncertain in most cases. Routine testing is thus not currently recommended. - In patients with a known history of antiphospholipid antibody syndrome (APLAS), use of DOACs is not recommended. The TRAPS trial, which randomized individuals with tripleantibody-positive APLAS and a history or arterial or venous thromboembolism to a switch to rivaroxaban versus continuing Vitamin K antagonist anticoagulation, was stopped early due to an excess of recurrent arterial thromboembolic events in the rivaroxaban arm. Other trials investigating DOACs in lower-risk individuals with APLAS are ongoing (clinicaltrials.gov NCT02295475).
# DURATION OF THERAPY:
- The optimal duration of anticoagulation in CVT has not been established. As mentioned, the observational data on longer-term recurrence is limited but risk of recurrence in those without an indication for permanent anticoagulation appears to be higher in men, in individuals with inherited thrombophilias and in those with cryptogenic events. Recommendations for duration have been extrapolated from data for DVT and PE and should be based on the patient's individual circumstances. - CVT in the context of a reversible provoking factor should generally be treated for 3-6 months.
In individuals in whom CVT was unprovoked, at least 6-12 months of anticoagulation is suggested. Individuals who have recurrent CVT, prior venous thromboembolism or in whom there is an ongoing provoking factor should be considered for extended anticoagulant therapy with periodic reassessment for bleeding risk, as should those without high risk features for bleeding but are uncomfortable with estimated risks of recurrence associated with anticoagulant discontinuation.
- Data about the risk of CVT during a subsequent pregnancy and the impact of thrombosis prophylaxis on that risk are limited. Systematic review data suggests that in women with a history of CVT the relative risk of non-cerebral VTE is 16-fold and risk of recurrent CVT 80-fold than the baseline risk in the general population. In the absence of robust data, it is reasonable to prescribe antepartum and postpartum prophylaxis to pregnant women with a prior history of CVT and no contraindication for anticoagulation.
OTHER RELEVANT THROMBOSIS CANADA CLINICAL GUIDES:
- Dabigatran (Pradaxa®)
# Date of version: 29November2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein. | To assist health care professionals in the management of cerebral venous thrombosis (CVT). For information related to CVT in the context of Vaccine-induced Thrombotic Thrombocytopenia (VITT), please consult Clinical Guide Vaccine-induced Prothrombotic Immune Thrombocytopenia (VIPIT/VITT).The cerebral venous system is comprised of the dural venous sinuses, deep and cortical cerebral veins, cavernous sinuses, and internal jugular veins. CVT refers to thrombosis affecting any of these sites. CVT is rare, with an incidence of approximately 10-20 per million person-years and accounting for approximately 1% of all strokes. In contrast with pulmonary embolism (PE) and deep vein thrombosis (DVT), CVT primarily affects younger individuals, with approximately 80% of cases occurring in individuals under the age of 55. Women are predominantly affected, with 75% of cases affecting females, and over 50% of cases associated with oral contraceptive use or the puerperium. However, these sex differences attenuate after the age of 50. The presenting symptoms associated with CVT can be secondary to increased intracranial pressure (ICP; headache, nausea, vomiting, blurred vision, diplopia), parenchymal injury secondary to edema or hemorrhage (focal deficits, decreased level of consciousness or encephalopathy), or cortical irritation (seizures). The most common presenting symptom is headache (90%), with seizures occurring in approximately 40% and focal deficits in 20-40%. Approximately 30% of individuals will present with some amount of intracranial bleeding secondary to parenchymal injury. Intracerebral blood is most common, with subarachnoid or subdural blood less frequently.#
General risk factors for CVT include hormonal therapy, pregnancy, heritable and acquired thrombophilias, malignancy (especially hematologic malignancies), systemic infections, collagen vascular diseases, including vasculitic disorders (e.g. systemic lupus erythematosus, granulomatosis with polyangiitis, and Behcet's disease) and inflammatory bowel disease. Local risk factors include head trauma, neurosurgery, spinal procedures, and head and neck infection (e.g. meningitis, otitis, mastoiditis). In less than one quarter of cases, no apparent cause is found.
While most CVT survivors (approximately 85%) will be functionally independent following their event, 5-10% will die, and over half may experience persisting issues related to headache, fatigue, mood or cognition affecting quality of life. Longer-term prognostic data on VTE recurrence is limited. The existing literature suggests that risk of any recurrent VTE is approximately 2-4% per year, with higher rates of recurrence in those with identified thrombophilia, malignancy, and unprovoked events.
# DIAGNOSIS OF CEREBRAL VENOUS THROMBOSIS:
In most cases, non-contrast CT head is not sufficiently sensitive to diagnose CVT. CT venography or contrast-enhanced MR venography should be performed to in individuals being assessed for possible CVT. Imaging with non-contrast CT or MRI will help to assess for the presence of parenchymal injury, including venous edema, intracranial bleeding, and signs of mass effect.
# MANAGEMENT OF CEREBRAL VENOUS THROMBOSIS:
Given the uncommon nature of CVT, recommendations are based on limited randomized data and observational cohort studies. The primary purpose of treatment is to prevent secondary brain injury and mortality from venous infarction, intracerebral hemorrhage or malignant (ie. life-threatening) mass effect. The general management approach consists of: 1) anticoagulant therapy, 2) management of increased ICP, 3) seizures and 4) headache. Some patients with CVT may be at risk of neurological deterioration with depressed level of consciousness or new onset of focal deficits due to intracranial bleeding, increased ICP or seizures. Therefore, the need for initial management in an intensive care/high-acuity setting should be assessed early, with recommended early involvement of Neurology and Hematology/Thrombosis services.
# Anticoagulant therapy
Anticoagulation, even in the presence of intracranial blood, is the standard-of-care treatment for CVT. Unlike primary intracerebral hemorrhage, the mechanism of intracranial bleeding in CVT is usually due to increased venous pressure, therefore improvement of venous obstruction generally reduces the impetus for bleeding. There may be rare cases where there are concerns regarding the safety of anticoagulation (e.g. large or rapidly expanding intracranial hemorrhage, anticipated emergent surgical decompression) that will require case-by-case collaborative decision-making by neurology and hematology/thrombosis. Usually, either parenteral anticoagulation with unfractionated heparin (UFH) or low-molecular weight heparin (LMWH) is initiated, with subsequent transition to oral anticoagulation once the patient is stable (see "duration of therapy" for considerations regarding longer-term anticoagulation). In patients not forecasted to require early neurosurgical intervention or those deemed to not have a high risk of life-threatening bleeding we favour the use of LMWH over UFH for a more reliable quality of anticoagulation.
Current guideline-recommended oral anticoagulation is with a Vitamin K antagonist (VKA) with INR target 2.0-3.0. However, the recent RESPECT-CVT trial, (published subsequent to the most recent guideline updates from the American Heart Association/American Stroke Association and the European Stroke Organization) found no differences in rates of major bleeding (one GI bleed in the dabigatran arm, 2 ICH in the warfarin arm) or venous recanalization between dose-adjusted warfarin and dabigatran 150 mg bid, initiated 5-14 days after parenteral anticoagulation and continued for 6 months. The trial, which enrolled 120 participants, was exploratory and not powered for efficacy or safety outcomes. A substudy of the EINSTEIN-Jr trial examined use of rivaroxaban for CVT in 114 children. The trial randomized children with VTE after 5-9 days of parenteral anticoagulation 2:1 to three months of rivaroxaban 20 mg-equivalent dosing versus vitamin K antagonist or parenteral anticoagulation. There was one recurrent VTE in the standard therapy group and one major bleeding event (ICH), whereas in the rivaroxaban arm there were 5 clinically relevant non-major bleeding events with no VTE recurrence and no major hemorrhage. There are other ongoing trials currently investigating DOACs for CVT (Clinicaltrials.gov -NCT03178864, NCT03191305, NCT03217448, NCT03747081), which will contribute additional information to inform the use of these agents in CVT.
# Deterioration despite anticoagulation
Some patients may deteriorate despite use of anticoagulation, either due to mass effect (secondary to venous infarction and/or hemorrhage) or thrombus extension. In cases of life-threatening mass effect, urgent neurosurgical consultation is warranted for decompressive hemicraniectomy.
Mechanical thrombectomy may be appropriate in cases where neurological deterioration is secondary to thrombus extension. Interdisciplinary collaboration may be required to determine what the best course of action may be for severe cases. The TO-ACT trial examined routine use of neurointervention (endovascular therapy, intradural thrombolytic or both as per local practice) versus conservative management in patients with severe CVT (decreased level of consciousness or mental status disorder, intracranial bleeding, and/or deep venous involvement). The trial, which was terminated early for futility after 67 patients of a target of 164 were recruited, found no difference in the rates of favourable neurological outcome at 12 months. Three of 33 interventional patients experienced intraprocedural venous sinus perforation. Thus routine use of neurointervention is not recommended, with case-by-case decision making as needed for severe presentations.
# Management of increased intracranial pressure (ICP)
Increased intracranial pressure is commonly seen in CVT. In individuals with ICP associated with optic nerve changes (papilledema, enlarged blind spots or other visual loss) or diplopia, acetazolamide may be considered alongside involvement of the ophthalmology service for monitoring.
Acetazolamide may also be considered for management of intracranial hypertension without visual changes on a case-by-case basis, in addition to conservative measures such as head of bed elevated to 30 degrees or above.
Surgical treatment such as shunting or optic nerve fenestration may be warranted in refractory cases, or in cases where the consequence of CVT results in significant hemorrhage and mass effect requiring neurosurgical intervention.
# Seizure management
Approximately 30-40% of patients with CVT will experience seizures, with over 10% experiencing seizures after the acute stage. Referral to a neurologist is indicated. Clinicians should be aware of the drug-drug interactions that exist between several common antiseizure medications and oral anticoagulants (both vitamin K antagonists as well as DOACs).
There is no evidence supporting the use of prophylactic antiseizure therapy in those without seizures.
# Headache
Approximately 90% of patients with cerebral venous thrombosis will present with headache, which may be severe in some cases. Appropriate analgesia is important both for patient comfort in addition to the fact that severe pain and vomiting can contribute to increased ICP. While headache generally improves with initiation of therapy for CVT and ICP management, some may have ongoing chronic headache that may impact quality of life. Referral for ongoing pain management in the outpatient setting is indicated in these cases.
# Risk factor management
• Provoking factors, including hormonal therapies, should be discontinued. Lifestyle modifications including smoking cessation should also be encouraged. • Heritable and acquired thrombophilias are risk factors for CVT although the implications for choice and duration of anticoagulation therapy are uncertain in most cases. Routine testing is thus not currently recommended. • In patients with a known history of antiphospholipid antibody syndrome (APLAS), use of DOACs is not recommended. The TRAPS trial, which randomized individuals with tripleantibody-positive APLAS and a history or arterial or venous thromboembolism to a switch to rivaroxaban versus continuing Vitamin K antagonist anticoagulation, was stopped early due to an excess of recurrent arterial thromboembolic events in the rivaroxaban arm. Other trials investigating DOACs in lower-risk individuals with APLAS are ongoing (clinicaltrials.gov NCT02295475).
# DURATION OF THERAPY:
• The optimal duration of anticoagulation in CVT has not been established. As mentioned, the observational data on longer-term recurrence is limited but risk of recurrence in those without an indication for permanent anticoagulation appears to be higher in men, in individuals with inherited thrombophilias and in those with cryptogenic events. Recommendations for duration have been extrapolated from data for DVT and PE and should be based on the patient's individual circumstances. • CVT in the context of a reversible provoking factor should generally be treated for 3-6 months.
In individuals in whom CVT was unprovoked, at least 6-12 months of anticoagulation is suggested. Individuals who have recurrent CVT, prior venous thromboembolism or in whom there is an ongoing provoking factor should be considered for extended anticoagulant therapy with periodic reassessment for bleeding risk, as should those without high risk features for bleeding but are uncomfortable with estimated risks of recurrence associated with anticoagulant discontinuation.
• Data about the risk of CVT during a subsequent pregnancy and the impact of thrombosis prophylaxis on that risk are limited. Systematic review data suggests that in women with a history of CVT the relative risk of non-cerebral VTE is 16-fold and risk of recurrent CVT 80-fold than the baseline risk in the general population. In the absence of robust data, it is reasonable to prescribe antepartum and postpartum prophylaxis to pregnant women with a prior history of CVT and no contraindication for anticoagulation.
OTHER RELEVANT THROMBOSIS CANADA CLINICAL GUIDES:
• Dabigatran (Pradaxa®)
•
# Date of version: 29November2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein. | None | None |
900ccecdfa6ecf36e4e72f3220f9b2986b4303b3 | cma | None | Sickle Cell Disease (SCD) is an inherited blood cell disorder predominantly affecting persons of African ancestry with an estimated prevalence of 1/500 African Canadians. Patients with SCD often have underlying cardiopulmonary comorbidities that may predispose them to poor outcomes if they become infected with SARS-CoV-2. The majority of adult sickle cell patients also have functional asplenia which contributes to infection severity and adverse outcomes. Is COVID-19 immunization recommended for people with sickle cell disease? COVID-19 vaccines should be encouraged for adults and youth with sickle cell disease and are not contraindicated, including those who have had COVID-19 infection. This recommendation is based on the following review: - In a UK cohort study, persons with SCD and SARS-CoV-2 infection have increased hazard ratios of hospitalization (4.87 in men and 6.68 in women) and death (4.41 in men and 5.94 in women). 1 - In an American registry study of 784 patients with SCD and SARS-CoV-2 infection (average age 22 years), 50.5% were hospitalized, 8.2% admitted to ICU, 3.1% required ventilatory support, and the death rate was 2.4%. 2 - A retrospective electronic medical record study identified 312 patients with COVID-19 and SCD between January and September 2020. Those with SCD had higher 2.0 times higher risk of hospitalization, 2.4 times higher risk of pneumonia, and 3.4 times higher risk of pain crisis compared to matched individuals without SCD. 3 - The U.S. Centers for Disease Control (CDC) identifies SCD among the medical conditions at high risk for severe COVID-19 disease. 4 - Children with SCD may be at higher risk of morbidity with COVID-19 infection including acute vaso-occlusive events and severe acute chest syndrome requiring exchange transfusion. 5 - The American Society of Hematology recommends that given the high levels of efficacy for vaccines and the low rates of vaccine-related adverse reactions, providers should encourage SCD patients to receive COVID-19 vaccinations as soon as possible. 6 There are data to suggest that the currently available COVID-19 vaccines have efficacy. 7 While data specific to the safety and efficacy of COMIRNATY (Pfizer-BioNTech), SPIKEVAX (Moderna), and VAXZEVRIA (AstraZeneca) vaccines in people with sickle cell disease is currently limited, trials studying vaccine efficacy in people with sickle cell disease are ongoing. 8 COVID-19 Vaccines for People with Sickle Cell Disease#
The authors of this guidance agree that the benefits of COVID-19 immunization with these vaccines outweigh any theoretical risks of immunization. 9 Are COVID-19 vaccines efficacious and safe for people with sickle cell disease?
As sickle cell disease is considered to be a severe underlying medical condition, persons with sickle cell disease were excluded from the Pfizer-BioNTech and Moderna COVID-19 vaccine clinical trials. While data collection is ongoing 10 , it is currently unknown if COVID-19 vaccines are as efficacious for patients with sickle cell disease as they were found to be for the clinical trial participants.
Due to the functional asplenia of the majority of people with SCD, persons with SCD are immunocompromised. 6 As with most vaccines, there is a potential for blunted immune response in individuals who are immunocompromised due to their disease or treatment. 9,11 It is therefore possible that persons with SCD may not respond as well to COVID-19 vaccines as the general population and should continue to follow local public health guidelines and adhere to precautionary infection prevention procedures following immunization for as long as SARS-CoV-2 continues to circulate at high rates in the community.
While not specific to COVID-19 vaccines, persons with SCD may be at risk for developing vaso-occlusive pain crises within a few days of immunization with any vaccine and should be counselled to monitor for symptoms and advise their SCD care providers in the event that they develop symptoms.
Currently, there are no serious safety warnings or precautions associated with the COMIRNATY (Pfizer-BioNTech), SPIKEVAX (Moderna), and VAXZEVRIA (AstraZeneca) vaccines in persons with SCD beyond those of the general population. If vaccination with the VAXZEVRIA (AstraZeneca) vaccine is considered, clinicians should be aware of the rare potential for development of venous or arterial thrombosis accompanied by thrombocytopenia 4 to 30 days after vaccination. 4 Are there any specific contraindications or exceptions for people with sickle cell disease?
Individuals who have had a severe allergic reaction to an ingredient of one type of COVID-19 vaccine are still able to receive future doses of the other type of vaccine. 12 BCCDC has a list of the individual components and their purpose in the vaccines. For a complete list of components in the vaccine, consult the vaccine monographs found at: www.bccdc.ca/health-info/diseases-conditions/covid-19/covid-19-vaccine/vaccines-for-covid-19.
For individuals with a history of anaphylactic reaction to a previous dose of an mRNA COVID-19 vaccine, re-vaccination (i.e., administration of a subsequent dose in the series when indicated) may be offered with the same vaccine or the same mRNA platform if a risk assessment deems that the benefits outweigh the potential risks for the individual and if informed consent is provided. Prior to revaccination, consultation with an allergist or another appropriate physician COVID-19 Vaccines for People with Sickle Cell Disease Updated: April 18, 2023 (e.g., Medical Health Officer) is advised. If re-vaccination is going ahead, vaccine administration should be done in a controlled setting with expertise and equipment to manage anaphylaxis, with an extended period of observation of at least 30 minutes after re-vaccination.
Health Canada continues to monitor any adverse events following immunization through their post-authorization surveillance process.
Otherwise, there are no contraindications or exceptions to immunization for individuals within the SCD population beyond those for the general population.
COVID-19 vaccines can be given concomitantly with, or any time before or after any other indicated vaccine. Are there specific recommendations or considerations for safe and/or most effective administration? SCD patients receiving chronic red blood cell exchange should be vaccinated within 10 days following exchange to minimize the potential for developing vaso-occlusive pain crises. Otherwise, there are no additional timing considerations for the administration of the COVID-19 vaccine in SCD patients. | Sickle Cell Disease (SCD) is an inherited blood cell disorder predominantly affecting persons of African ancestry with an estimated prevalence of 1/500 African Canadians. Patients with SCD often have underlying cardiopulmonary comorbidities that may predispose them to poor outcomes if they become infected with SARS-CoV-2. The majority of adult sickle cell patients also have functional asplenia which contributes to infection severity and adverse outcomes. Is COVID-19 immunization recommended for people with sickle cell disease? COVID-19 vaccines should be encouraged for adults and youth with sickle cell disease and are not contraindicated, including those who have had COVID-19 infection. This recommendation is based on the following review: • In a UK cohort study, persons with SCD and SARS-CoV-2 infection have increased hazard ratios of hospitalization (4.87 in men and 6.68 in women) and death (4.41 in men and 5.94 in women). 1 • In an American registry study of 784 patients with SCD and SARS-CoV-2 infection (average age 22 years), 50.5% were hospitalized, 8.2% admitted to ICU, 3.1% required ventilatory support, and the death rate was 2.4%. 2 • A retrospective electronic medical record study identified 312 patients with COVID-19 and SCD between January and September 2020. Those with SCD had higher 2.0 times higher risk of hospitalization, 2.4 times higher risk of pneumonia, and 3.4 times higher risk of pain crisis compared to matched individuals without SCD. 3 • The U.S. Centers for Disease Control (CDC) identifies SCD among the medical conditions at high risk for severe COVID-19 disease. 4 • Children with SCD may be at higher risk of morbidity with COVID-19 infection including acute vaso-occlusive events and severe acute chest syndrome requiring exchange transfusion. 5 • The American Society of Hematology recommends that given the high levels of efficacy for vaccines and the low rates of vaccine-related adverse reactions, providers should encourage SCD patients to receive COVID-19 vaccinations as soon as possible. 6 There are data to suggest that the currently available COVID-19 vaccines have efficacy. 7 While data specific to the safety and efficacy of COMIRNATY (Pfizer-BioNTech), SPIKEVAX (Moderna), and VAXZEVRIA (AstraZeneca) vaccines in people with sickle cell disease is currently limited, trials studying vaccine efficacy in people with sickle cell disease are ongoing. 8 COVID-19 Vaccines for People with Sickle Cell Disease#
The authors of this guidance agree that the benefits of COVID-19 immunization with these vaccines outweigh any theoretical risks of immunization. 9 Are COVID-19 vaccines efficacious and safe for people with sickle cell disease?
As sickle cell disease is considered to be a severe underlying medical condition, persons with sickle cell disease were excluded from the Pfizer-BioNTech and Moderna COVID-19 vaccine clinical trials. While data collection is ongoing 10 , it is currently unknown if COVID-19 vaccines are as efficacious for patients with sickle cell disease as they were found to be for the clinical trial participants.
Due to the functional asplenia of the majority of people with SCD, persons with SCD are immunocompromised. 6 As with most vaccines, there is a potential for blunted immune response in individuals who are immunocompromised due to their disease or treatment. 9,11 It is therefore possible that persons with SCD may not respond as well to COVID-19 vaccines as the general population and should continue to follow local public health guidelines and adhere to precautionary infection prevention procedures following immunization for as long as SARS-CoV-2 continues to circulate at high rates in the community.
While not specific to COVID-19 vaccines, persons with SCD may be at risk for developing vaso-occlusive pain crises within a few days of immunization with any vaccine and should be counselled to monitor for symptoms and advise their SCD care providers in the event that they develop symptoms.
Currently, there are no serious safety warnings or precautions associated with the COMIRNATY (Pfizer-BioNTech), SPIKEVAX (Moderna), and VAXZEVRIA (AstraZeneca) vaccines in persons with SCD beyond those of the general population. If vaccination with the VAXZEVRIA (AstraZeneca) vaccine is considered, clinicians should be aware of the rare potential for development of venous or arterial thrombosis accompanied by thrombocytopenia 4 to 30 days after vaccination. 4 Are there any specific contraindications or exceptions for people with sickle cell disease?
Individuals who have had a severe allergic reaction to an ingredient of one type of COVID-19 vaccine are still able to receive future doses of the other type of vaccine. 12 BCCDC has a list of the individual components and their purpose in the vaccines. For a complete list of components in the vaccine, consult the vaccine monographs found at: www.bccdc.ca/health-info/diseases-conditions/covid-19/covid-19-vaccine/vaccines-for-covid-19.
For individuals with a history of anaphylactic reaction to a previous dose of an mRNA COVID-19 vaccine, re-vaccination (i.e., administration of a subsequent dose in the series when indicated) may be offered with the same vaccine or the same mRNA platform if a risk assessment deems that the benefits outweigh the potential risks for the individual and if informed consent is provided. Prior to revaccination, consultation with an allergist or another appropriate physician COVID-19 Vaccines for People with Sickle Cell Disease Updated: April 18, 2023 (e.g., Medical Health Officer) is advised. If re-vaccination is going ahead, vaccine administration should be done in a controlled setting with expertise and equipment to manage anaphylaxis, with an extended period of observation of at least 30 minutes after re-vaccination.
Health Canada continues to monitor any adverse events following immunization through their post-authorization surveillance process.
Otherwise, there are no contraindications or exceptions to immunization for individuals within the SCD population beyond those for the general population.
COVID-19 vaccines can be given concomitantly with, or any time before or after any other indicated vaccine. [13][14][15][16] Are there specific recommendations or considerations for safe and/or most effective administration? SCD patients receiving chronic red blood cell exchange should be vaccinated within 10 days following exchange to minimize the potential for developing vaso-occlusive pain crises. Otherwise, there are no additional timing considerations for the administration of the COVID-19 vaccine in SCD patients. | None | None |
d8293276633fb5bda6b6bd477a12604a2f51ce13 | cma | None | Background: During the early part of the COVID-19 pandemic, the Canadian Society of Otolaryngology -Head & Neck Surgery (CSO-HNS) task force published recommendations on performance of tracheotomy. Since then, our understanding of the virus has evolved with ongoing intensive research efforts. New literature has helped us better understand various aspects including patient outcomes and health care worker (HCW) risks associated with tracheotomy during the COVID-19 pandemic. Accordingly, the task force has re-evaluated and revised some of the previous recommendations. Main body: Based on recent evidence, a negative reverse transcription polymerase chain reaction (RT-PCR) COVID-19 swab status is no longer the main deciding factor in the timing of tracheotomy. Instead, tracheotomy may be considered as soon as COVID-19 swab positive patients are greater than 20 days beyond initial symptoms and 2 weeks of mechanical ventilation. Furthermore, both open and percutaneous surgical techniques may be considered with both techniques showing similar safety and outcome profiles. Additional recommendations with discussion of current evidence are presented.These revised recommendations apply new evidence in optimizing patient and health care system outcomes as well as minimizing risks of COVID-19 transmission during aerosol-generating tracheotomy procedures. As previously noted, additional evidence may lead to further evolution of these and other similar recommendations.# Introduction
In April 2020, the CSO-HNS (Canadian Society of Otolaryngology-Head & Neck Surgery) taskforce published recommendations on performance of tracheotomy during the COVID-19 pandemic . Tracheotomy is considered an AGMP (aerosol generating medical procedure) with significant risks of viral transmission . Since then, there has been a growing body of evidence that has helped guide management decisions, however, some issues such as mutant viral strains continue to evolve while others remain unclear.
# Utility of performing tracheotomy in the critical care COVID-19 population
Recent systematic reviews have attempted to assess the utility of performing tracheotomy in the critically ill COVID-19 patient population . While these suggest some potential benefits in terms of decreased ICU (intensive care unit) stay and overall mortality, the level of heterogeneity and possible selection bias leave interpretation of these results open. There is likely a significant subgroup of patients with respiratory failure to wean and few other comorbidities that would potentially benefit from this intervention. Similarly, risks of tracheal/laryngeal injury with prolonged intubation of greater than 2-3 weeks need to be considered . To date, there is insufficient evidence to suggest COVID 19 patients are substantially different in their risk for glottic injury than other ARDS (acute respiratory distress syndrome) prolonged intubated patients. Given the often delayed timing of tracheotomy in COVID 19 patients, it is possible that there is increased risk of laryngeal complications as a long-term sequelae .
# Changes to previous recommendations
# Defining COVID-19 positive status
The most significant changes in these recommendations pertain to reliance on a negative RT-PCR (reverse transcription polymerase chain reaction) test prior to proceeding with tracheotomy. In the earlier version of the recommendations, the consensus specified awaiting conversion to negative RT-PCR COVID-19 status. Since that time, several studies have described viral load dynamics as evidenced by a comparison of duration of viral shedding assessed by RT-PCR (viral fragments) vs detection of viable virus from time of symptom onset . This evaluation of pooled data indicates that RT-PCR may remain positive for a mean of 17 days after onset of symptoms and has even been reported up to 83 days. Recent viral culture studies have confirmed that viable virus has not been recovered in mild to moderate cases after 10 days, and in severe cases after 20 days with the risk of viral shedding dropping below 5% after 15.2 days . Only rarely, in severely immunocompromised individuals, viable virus has been detected after 20 or more days .
We thus recommend a time-based evaluation of disease progression to define COVID-19 positivity and help guide decision making regarding performance of tracheotomy. Based on the recent CDC (Centers for Disease Control and Prevention) guidelines , a COVID-19 positive patient with severe to critical illness has been defined as cleared of the COVID-19 virus if it has been more than 20 days since (the earlier of) symptom onset or first positive diagnostic test. Prolonged RT-PCR can continue to be positive for up to 3 months after illness onset and does not necessarily denote transmissible disease and may represent inactive viral particles .
# COVID-19 RT-PCR positive (< 20 days)
If a patient is COVID-19 positive and it has been less than 20 days since symptom onset or first positive RT-PCR, we recommend against performing a tracheotomy in this group of patients who are potentially still infectious . This should only generally be considered in this situation if the endotracheal tube is proving insufficient to provide an adequate airway, or an emergent procedure is required . Enhanced PPE and environmental precautions are advised in these situations. In these patients, requests for tracheotomy should be considered in exceptional circumstances on a case-by-case basis with thorough discussion of the risks and benefits between the ICU staff and the attending surgeon.
# COVID-19 RT-PCR positive (> 20 days)
If a patient is COVID-19 positive and it has been more than 20 days since symptom onset or first positive diagnostic test, a tracheotomy can be performed if otherwise clinically indicated. In general, patients undergoing consideration for tracheotomy should be mechanically ventilated/ intubated for over 14 days. These patients may be considered "COVID-19 negative" for the purposes of tracheotomy, and the recommendations below should be followed. Postoperatively, these patients may be cared for as per local institution/regional protocols which may depend on COVID-19 RT-PCR testing with associated PPE and precautions.
# COVID-19 RT-PCR negative
We are recommending (at minimum) N95 masks and full face/eye protection to be worn by the surgical team due to the possibility of false negative COVID-19 testing . A negative result does not exclude the possibility of COVID-19 . However, local epidemiology should be considered, and in time periods of low local epidemiology, the risk of a random patient to be unknowingly COVID-19 positive becomes negligible. Additionally, any other upper airway surgery that must proceed should have the requirement of COVID-19 testing/clearance of the patient before initiating surgery.
# COVID-19 unknown status
For emergent tracheotomy with unknown COVID-19 status, our recommendations remain generally unchanged from previous. This includes the use of full aerosol PPE including N95 masks with full face/ eye protection. Powered air purifying respirator (PAPR)/N99- equipment or equivalent is an option if available. ○ *Although there is limited evidence to suggest possible superiority of PAPRs in limiting HCW exposures with other respiratory viruses (ie. influenza virus) as compared to N95 masks , there is currently a lack of field observational studies to suggest a difference in transmission risks to HCWs between the two types of PPE when performing AGMPs in patients with SARS-CoV-2 . Negative pressure rooms may be preferable if available. Intubation rather than tracheotomy is highly preferable if achievable. Caution is urged with the use of high flow oxygen/ high flow nasal cannula, as well as unsealed noninvasive ventilation/bilevel positive airway pressure (BIPAP) as these are considered potential AGMPs and risk further transmission of disease . Intubation and/or tracheotomy should be performed by the most skilled person present to maximize initial attempt success , and minimize aerosolization risks. Awake tracheotomy and cricothyroidotomy are to be considered high risk for viral plume spread and should be avoided if possible. Only in extenuating circumstances should this be considered. A discussion between team members (e.g., anesthesia, otolaryngology, general/thoracic surgery, trauma team leader, emergency physician, critical care physician) should be undertaken to determine the risk/benefit profile for each situation.
# COVID-19 positive (> 90 days)
If a patient is COVID-19 positive and it has been more than 3-6 months since initial positive result,
# Surgical technique
Preference for open tracheotomy Open or percutaneous tracheotomy appear to have similar outcomes and risks to the patient and HCWs involved.
RT-PCR reverse transcription polymerase chain reaction, HCW healthcare workers Positive (> 20 DAYS) Tracheotomy can be performed if clinically indicated with full aerosol PPE (at least N95 and full face/eye protection for the surgical team).
Positive (> 90 DAYS) Patients should be retested for COVID-19 and if positive, the patient should be considered potentially infectious (for 20 days). If the patient is retested for COVID-19 and if negative, should be treated as COVID-19 negative.
# Negative
Tracheotomy can be performed if clinically indicated with full PPE (N95 and full face/eye protection for the surgical team).
# Unknown status emergent
Recommend use of full aerosol PPE including (at least N95 masks with full face/eye protection). Option to use PAPR/N99 equipment or equivalent if available.
PPE personal protective equipment, PAPR powered air purifying respirator there is the possibility of reinfection . This may become an increasing issue with the emergence of new variants of SARS-CoV-2.
In this situation, the patient should be retested for COVID-19 and if positive, the patient should be considered potentially re-infected, and if so, considered positive for < 20 days. If the patient is retested for COVID-19 and if negative, should be treated as COVID-19 negative.
# Health care team
The recommendation to limit the number of team members during tracheotomy to reduce potential spread of disease remains. Furthermore, the surgical/anesthesia team providing care to the tracheotomy patient is to be fully vaccinated if possible.
A review of evidence surrounding HCW transmission revealed a relatively low-rate risk of viral transmission overall
# Surgical technique
Regarding type of tracheotomy, either a percutaneous or open tracheotomy may be performed if clinically indicated. Based on recent evidence , outcomes and risk to the patient and healthcare workers appear to be similar for performance of both percutaneous tracheotomy and open tracheotomy .
# Caveats
As previously noted, the COVID-19 pandemic has been fraught with a continuously changing situation. While the improved availability of PPE, treatments and both patient and HCW vaccine status may herald a possible light at the end of the tunnel, opposing factors such as more contagious/virulent viral variants and vaccine fears threaten this progress. Such aspects as well as further evidence may lead to further evolution of these and other similar recommendations. Although patient vaccination status and similar aforementioned factors likely affect disease course and health care worker transmission risk in these cases, data is still too limited at this time and further analysis is warranted.
# Summary of changes
The taskforce recommends that it is reasonable to consider tracheotomy after (the greater of) 2 weeks duration of mechanical ventilation or greater than 20 days after symptoms emerge/first positive RT-PCR test. However, we recommend this decision is made on a case-by-case basis based on the overall trajectory of the patient's outcome and comorbidities whereby performance of a tracheotomy will be more likely to provide a benefit to the patient's outcome. This should be weighed alongside ICU capacity, resources and surgical considerations. Open surgical and percutaneous techniques appear to have similar safety and outcome profiles. These recommendations are not meant to supersede local governmental or institutional guidelines. See Table 1 for a summary of the main changes comparing the previous and current version. See Table 2 for a summary of the current recommendations based on COVID RT-PCR positivity. | Background: During the early part of the COVID-19 pandemic, the Canadian Society of Otolaryngology -Head & Neck Surgery (CSO-HNS) task force published recommendations on performance of tracheotomy. Since then, our understanding of the virus has evolved with ongoing intensive research efforts. New literature has helped us better understand various aspects including patient outcomes and health care worker (HCW) risks associated with tracheotomy during the COVID-19 pandemic. Accordingly, the task force has re-evaluated and revised some of the previous recommendations. Main body: Based on recent evidence, a negative reverse transcription polymerase chain reaction (RT-PCR) COVID-19 swab status is no longer the main deciding factor in the timing of tracheotomy. Instead, tracheotomy may be considered as soon as COVID-19 swab positive patients are greater than 20 days beyond initial symptoms and 2 weeks of mechanical ventilation. Furthermore, both open and percutaneous surgical techniques may be considered with both techniques showing similar safety and outcome profiles. Additional recommendations with discussion of current evidence are presented.These revised recommendations apply new evidence in optimizing patient and health care system outcomes as well as minimizing risks of COVID-19 transmission during aerosol-generating tracheotomy procedures. As previously noted, additional evidence may lead to further evolution of these and other similar recommendations.# Introduction
In April 2020, the CSO-HNS (Canadian Society of Otolaryngology-Head & Neck Surgery) taskforce published recommendations on performance of tracheotomy during the COVID-19 pandemic [1]. Tracheotomy is considered an AGMP (aerosol generating medical procedure) with significant risks of viral transmission [2][3][4]. Since then, there has been a growing body of evidence that has helped guide management decisions, however, some issues such as mutant viral strains continue to evolve while others remain unclear.
# Utility of performing tracheotomy in the critical care COVID-19 population
Recent systematic reviews have attempted to assess the utility of performing tracheotomy in the critically ill COVID-19 patient population [2,4]. While these suggest some potential benefits in terms of decreased ICU (intensive care unit) stay and overall mortality, the level of heterogeneity and possible selection bias leave interpretation of these results open. There is likely a significant subgroup of patients with respiratory failure to wean and few other comorbidities that would potentially benefit from this intervention. Similarly, risks of tracheal/laryngeal injury with prolonged intubation of greater than 2-3 weeks need to be considered [5]. To date, there is insufficient evidence to suggest COVID 19 patients are substantially different in their risk for glottic injury than other ARDS (acute respiratory distress syndrome) prolonged intubated patients. Given the often delayed timing of tracheotomy in COVID 19 patients, it is possible that there is increased risk of laryngeal complications as a long-term sequelae [6].
# Changes to previous recommendations
# Defining COVID-19 positive status
The most significant changes in these recommendations pertain to reliance on a negative RT-PCR (reverse transcription polymerase chain reaction) test prior to proceeding with tracheotomy. In the earlier version of the recommendations, the consensus specified awaiting conversion to negative RT-PCR COVID-19 status. Since that time, several studies have described viral load dynamics as evidenced by a comparison of duration of viral shedding assessed by RT-PCR (viral fragments) vs detection of viable virus from time of symptom onset [7]. This evaluation of pooled data indicates that RT-PCR may remain positive for a mean of 17 days after onset of symptoms and has even been reported up to 83 days. Recent viral culture studies [8] have confirmed that viable virus has not been recovered in mild to moderate cases after 10 days, and in severe cases after 20 days with the risk of viral shedding dropping below 5% after 15.2 days [9]. Only rarely, in severely immunocompromised individuals, viable virus has been detected after 20 or more days [8,10].
We thus recommend a time-based evaluation of disease progression to define COVID-19 positivity and help guide decision making regarding performance of tracheotomy. Based on the recent CDC (Centers for Disease Control and Prevention) guidelines [8], a COVID-19 positive patient with severe to critical illness has been defined as cleared of the COVID-19 virus if it has been more than 20 days since (the earlier of) symptom onset or first positive diagnostic test. Prolonged RT-PCR can continue to be positive for up to 3 months after illness onset and does not necessarily denote transmissible disease and may represent inactive viral particles [9].
# COVID-19 RT-PCR positive (< 20 days)
If a patient is COVID-19 positive and it has been less than 20 days since symptom onset or first positive RT-PCR, we recommend against performing a tracheotomy in this group of patients who are potentially still infectious [2,3,11,12]. This should only generally be considered in this situation if the endotracheal tube is proving insufficient to provide an adequate airway, or an emergent procedure is required [1]. Enhanced PPE and environmental precautions are advised in these situations. In these patients, requests for tracheotomy should be considered in exceptional circumstances on a case-by-case basis with thorough discussion of the risks and benefits between the ICU staff and the attending surgeon.
# COVID-19 RT-PCR positive (> 20 days)
If a patient is COVID-19 positive and it has been more than 20 days since symptom onset or first positive diagnostic test, a tracheotomy can be performed if otherwise clinically indicated. In general, patients undergoing consideration for tracheotomy should be mechanically ventilated/ intubated for over 14 days. These patients may be considered "COVID-19 negative" for the purposes of tracheotomy, and the recommendations below should be followed. Postoperatively, these patients may be cared for as per local institution/regional protocols which may depend on COVID-19 RT-PCR testing with associated PPE and precautions.
# COVID-19 RT-PCR negative
We are recommending (at minimum) N95 masks and full face/eye protection to be worn by the surgical team due to the possibility of false negative COVID-19 testing [13]. A negative result does not exclude the possibility of COVID-19 [14]. However, local epidemiology should be considered, and in time periods of low local epidemiology, the risk of a random patient to be unknowingly COVID-19 positive becomes negligible. Additionally, any other upper airway surgery that must proceed should have the requirement of COVID-19 testing/clearance of the patient before initiating surgery.
# COVID-19 unknown status
For emergent tracheotomy with unknown COVID-19 status, our recommendations remain generally unchanged from previous. This includes the use of full aerosol PPE including N95 masks with full face/ eye protection. Powered air purifying respirator (PAPR)/N99* equipment or equivalent is an option if available. ○ *Although there is limited evidence to suggest possible superiority of PAPRs in limiting HCW exposures with other respiratory viruses (ie. influenza virus) as compared to N95 masks [15], there is currently a lack of field observational studies to suggest a difference in transmission risks to HCWs between the two types of PPE when performing AGMPs in patients with SARS-CoV-2 [16]. Negative pressure rooms may be preferable if available. Intubation rather than tracheotomy is highly preferable if achievable. Caution is urged with the use of high flow oxygen/ high flow nasal cannula, as well as unsealed noninvasive ventilation/bilevel positive airway pressure (BIPAP) as these are considered potential AGMPs and risk further transmission of disease [14]. Intubation and/or tracheotomy should be performed by the most skilled person present to maximize initial attempt success [17], and minimize aerosolization risks. Awake tracheotomy and cricothyroidotomy are to be considered high risk for viral plume spread and should be avoided if possible. Only in extenuating circumstances should this be considered. A discussion between team members (e.g., anesthesia, otolaryngology, general/thoracic surgery, trauma team leader, emergency physician, critical care physician) should be undertaken to determine the risk/benefit profile for each situation.
# COVID-19 positive (> 90 days)
If a patient is COVID-19 positive and it has been more than 3-6 months since initial positive result,
# Surgical technique
Preference for open tracheotomy Open or percutaneous tracheotomy appear to have similar outcomes and risks to the patient and HCWs involved.
RT-PCR reverse transcription polymerase chain reaction, HCW healthcare workers Positive (> 20 DAYS) Tracheotomy can be performed if clinically indicated with full aerosol PPE (at least N95 and full face/eye protection for the surgical team).
Positive (> 90 DAYS) Patients should be retested for COVID-19 and if positive, the patient should be considered potentially infectious (for 20 days). If the patient is retested for COVID-19 and if negative, should be treated as COVID-19 negative.
# Negative
Tracheotomy can be performed if clinically indicated with full PPE (N95 and full face/eye protection for the surgical team).
# Unknown status emergent
Recommend use of full aerosol PPE including (at least N95 masks with full face/eye protection). Option to use PAPR/N99 equipment or equivalent if available.
PPE personal protective equipment, PAPR powered air purifying respirator there is the possibility of reinfection [8,18,19]. This may become an increasing issue with the emergence of new variants of SARS-CoV-2.
In this situation, the patient should be retested for COVID-19 and if positive, the patient should be considered potentially re-infected, and if so, considered positive for < 20 days. If the patient is retested for COVID-19 and if negative, should be treated as COVID-19 negative.
# Health care team
The recommendation to limit the number of team members during tracheotomy to reduce potential spread of disease remains. Furthermore, the surgical/anesthesia team providing care to the tracheotomy patient is to be fully vaccinated if possible.
A review of evidence surrounding HCW transmission revealed a relatively low-rate risk of viral transmission overall
# Surgical technique
Regarding type of tracheotomy, either a percutaneous or open tracheotomy may be performed if clinically indicated. Based on recent evidence [2], outcomes and risk to the patient and healthcare workers appear to be similar for performance of both percutaneous tracheotomy and open tracheotomy [20,21].
# Caveats
As previously noted, the COVID-19 pandemic has been fraught with a continuously changing situation. While the improved availability of PPE, treatments and both patient and HCW vaccine status may herald a possible light at the end of the tunnel, opposing factors such as more contagious/virulent viral variants and vaccine fears threaten this progress. Such aspects as well as further evidence may lead to further evolution of these and other similar recommendations. Although patient vaccination status and similar aforementioned factors likely affect disease course and health care worker transmission risk in these cases, data is still too limited at this time and further analysis is warranted.
# Summary of changes
The taskforce recommends that it is reasonable to consider tracheotomy after (the greater of) 2 weeks duration of mechanical ventilation or greater than 20 days after symptoms emerge/first positive RT-PCR test. However, we recommend this decision is made on a case-by-case basis based on the overall trajectory of the patient's outcome and comorbidities whereby performance of a tracheotomy will be more likely to provide a benefit to the patient's outcome. This should be weighed alongside ICU capacity, resources and surgical considerations. Open surgical and percutaneous techniques appear to have similar safety and outcome profiles. These recommendations are not meant to supersede local governmental or institutional guidelines. See Table 1 for a summary of the main changes comparing the previous and current version. See Table 2 for a summary of the current recommendations based on COVID RT-PCR positivity.
# Acknowledgements
Not applicable.
# Disclaimer
The Canadian Society of Otolaryngology -Head & Neck Surgery (CSO-HNS) has developed this information as guidance for its members. This is based on information available at the time of writing (March 30, 2020) and the Society recognizes that the situation is evolving rapidly, so recommendations may change. The guidance included in this document does not replace regular standards of care, nor do they replace the application of clinical judgement to each individual presentation, nor variations due to jurisdiction or facility type. The views expressed in this presentation are those of the author(s) and do not reflect the official policy or position of the U.S. Army, Department of Defense, or the U.S. Government. The CSO-HNS is not liable for the accuracy or completeness of the information in this document. The information in this document cannot replace professional advice.
Authors' contributions DDS and PTE devised the project. IJW and DDS organized and coordinated group consensus discussions. All authors contributed substantially to the manuscript and reviewed and approved the final version.
# Funding
None.
# Declarations
Ethics approval and consent to participate Not applicable.
# Consent for publication
Not applicable.
# Competing interests
The authors declare that they have no competing interests. | None | None |
5959169d81fb8b1694465ef022d2f851b7d3693a | cma | None | The SOGC would like to thank the SOGC Genetics Committee for its input on the statement.# Introduction
The COVID-19 pandemic has already had a profound impact on both pregnant women and professionals involved in pregnancy care. Here we propose to discuss briefly how the prenatal screening strategies in Canada could be adapted to this unprecedented situation, in order to minimize time exposure of patients and health care providers and limit the number of screening tests / visits while maintaining an excellent level of screening for fetal aneuploidy and other anomalies. This document does not intend to replace or update the existing guidelines, 6 but should be seen as a statement on the potential adaptations of prenatal screening policies in Canada in the particular context of the Covid-19 pandemic.
# First trimester ultrasound
First trimester ultrasound is the cornerstone of early screening for a large number of fetal anomalies including aneuploidy. Where available with adequate expertise, the first trimester ultrasound (11 to 14 weeks' gestation) offers many advantages beyond the value of nuchal translucency for aneuploidy screening, including accurate dating of pregnancy, determination of twin chorionicity, and early detection of major structural abnormalities ( anencephaly, limb reductions, omphalocele, megacystis, cystic hygroma, etc.). 7,8 The SOGC guidelines recommend that "every effort should be made in order to provide high-quality first trimester ultrasound to all pregnant women in Canada". 6 In the context of the COVID-19 pandemic, the practice of prenatal ultrasound requires careful attention in order to minimize risks for patients and healthcare providers, as described in a recent ISUOG consensus statement. 9 Provided that adequate preventative measures and infection screening policies are in place, we suggest that the provision of first trimester ultrasound should be maintained and even expanded in the pandemic context. While some providers may have questioned the benefit of maintaining the same standard of ultrasound in order to minimize exposures, we strongly believe that the balance of benefits and risks is still in favor of universal first trimester comprehensive ultrasound performed optimally between 11-14 week's gestation. In order to provide screening ultrasound services with a high clinical value, earlier "dating" scans should be avoided if the 11-14 weeks ultrasound is regionally available, in the absence of a clinical indication such as bleeding or a previous ectopic pregnancy. 10 The only situation where the provision of the first trimester ultrasound should be questioned in the current context is a suspected or confirmed Covid-19 infection. In such a case, we endorse the ISUOG (International Integrated screening can be offered with NT ultrasound (full IPS) or without (Serum IPS, or SIPS). NT ultrasound is not mandatory but greatly improves the performance of serum-based screens, in addition to offering advantages beyond screening for common aneuploidies. 12 Full IPS has the advantage over FTS of decreasing the screen-positive from about 4-5% to 1-2%, but it has the disadvantages of delaying results and requiring additional visits. Furthermore, if NIPT (see below) is offered as a second-tier test after a positive FTS, the false positive rate of this "contingent" screening process becomes very low.
Aneuploidy screening based on cell-free circulating placental DNA (cfDNA / non-invasive prenatal testing (NIPT)), has high detection with low false positive rates for the common aneuploidies. Over the past five years, NIPT has become a major player in the field of prenatal screening and can be offered as a second-tier test, after a positive conventional screening result, or as a first-tier test for those who meet certain criteria or are willing to pay. During this pandemic, all patients should be made aware of the availability of cell free DNA testing for common aneuploidies as an alternative with improved positive predictive value. The major limitations of NIPT are the test cost, its cost-covered availability in the public healthcare system, and important technical pitfalls including low DNA fetal fraction, maternal or placental mosaicism, vanishing twin pregnancy or maternal malignancy leading to complex or 'no result' reports in 2-3% of screened patients. It is important to emphasize that the use of NIPT for genomic screening beyond the common aneuploidies (trisomy 21/18/13) is not currently recommended. It is also important to emphasize that NIPT detects only common aneuploidies, which represents only a fraction of clinically relevant fetal anomalies that can otherwise be detected by ultrasound and/or invasive genetic testing.
# Conclusion
In the pandemic context, strategies requiring multiple screening steps or visits are obviously not ideal. Each regional prenatal screening program needs to minimize patient-health care provider contacts. For this reason, we would recommend FTS, or NIPT where available and funded, be the first choice of screening for all pregnant women with available NT ultrasound. These tests should be performed after the 11-14 weeks scan in order to minimize unnecessary blood tests (nonviable pregnancies or gross anomalies requiring diagnostic tests rather than screening tests).
QUAD screening may be offered to women presenting after 14 weeks (due to late booking and/or quarantine), or in areas without the first-trimester screening availability or funded NIPT. NT: nuchal translucency ultrasound; NIPT: non-invasive prenatal testing; QUAD: quadruple second trimester serum screening.
# First trimester pregnancy
No suspicion of Covid Offer first trimester ultrasound with NT if available or dating ultrasound First trimester combined screening or orther accepted aneuplody screening process (regional standard)
NIPT if available/funded (regional standard)
# Suspected or confirmed Covid
Wait 2 weeks and reschedule
# <14 weeks
Combined test or NT+NIPT (regional standard) >=14 weeks QUAD or NIPT (regional standard) | The SOGC would like to thank the SOGC Genetics Committee for its input on the statement.# Introduction
The COVID-19 pandemic has already had a profound impact on both pregnant women and professionals involved in pregnancy care. [1][2][3][4][5] Here we propose to discuss briefly how the prenatal screening strategies in Canada could be adapted to this unprecedented situation, in order to minimize time exposure of patients and health care providers and limit the number of screening tests / visits while maintaining an excellent level of screening for fetal aneuploidy and other anomalies. This document does not intend to replace or update the existing guidelines, 6 but should be seen as a statement on the potential adaptations of prenatal screening policies in Canada in the particular context of the Covid-19 pandemic.
# First trimester ultrasound
First trimester ultrasound is the cornerstone of early screening for a large number of fetal anomalies including aneuploidy. Where available with adequate expertise, the first trimester ultrasound (11 to 14 weeks' gestation) offers many advantages beyond the value of nuchal translucency for aneuploidy screening, including accurate dating of pregnancy, determination of twin chorionicity, and early detection of major structural abnormalities ( anencephaly, limb reductions, omphalocele, megacystis, cystic hygroma, etc.). 7,8 The SOGC guidelines recommend that "every effort should be made in order to provide high-quality first trimester ultrasound to all pregnant women in Canada". 6 In the context of the COVID-19 pandemic, the practice of prenatal ultrasound requires careful attention in order to minimize risks for patients and healthcare providers, as described in a recent ISUOG consensus statement. 9 Provided that adequate preventative measures and infection screening policies are in place, we suggest that the provision of first trimester ultrasound should be maintained and even expanded in the pandemic context. While some providers may have questioned the benefit of maintaining the same standard of ultrasound in order to minimize exposures, we strongly believe that the balance of benefits and risks is still in favor of universal first trimester comprehensive ultrasound performed optimally between 11-14 week's gestation. In order to provide screening ultrasound services with a high clinical value, earlier "dating" scans should be avoided if the 11-14 weeks ultrasound is regionally available, in the absence of a clinical indication such as bleeding or a previous ectopic pregnancy. 10 The only situation where the provision of the first trimester ultrasound should be questioned in the current context is a suspected or confirmed Covid-19 infection. In such a case, we endorse the ISUOG (International Integrated screening can be offered with NT ultrasound (full IPS) or without (Serum IPS, or SIPS). NT ultrasound is not mandatory but greatly improves the performance of serum-based screens, in addition to offering advantages beyond screening for common aneuploidies. 12 Full IPS has the advantage over FTS of decreasing the screen-positive from about 4-5% to 1-2%, but it has the disadvantages of delaying results and requiring additional visits. Furthermore, if NIPT (see below) is offered as a second-tier test after a positive FTS, the false positive rate of this "contingent" screening process becomes very low.
Aneuploidy screening based on cell-free circulating placental DNA (cfDNA / non-invasive prenatal testing (NIPT)), has high detection with low false positive rates for the common aneuploidies. Over the past five years, NIPT has become a major player in the field of prenatal screening and can be offered as a second-tier test, after a positive conventional screening result, or as a first-tier test for those who meet certain criteria or are willing to pay. During this pandemic, all patients should be made aware of the availability of cell free DNA testing for common aneuploidies as an alternative with improved positive predictive value. The major limitations of NIPT are the test cost, its cost-covered availability in the public healthcare system, and important technical pitfalls including low DNA fetal fraction, maternal or placental mosaicism, vanishing twin pregnancy or maternal malignancy leading to complex or 'no result' reports in 2-3% of screened patients. It is important to emphasize that the use of NIPT for genomic screening beyond the common aneuploidies (trisomy 21/18/13) is not currently recommended. It is also important to emphasize that NIPT detects only common aneuploidies, which represents only a fraction of clinically relevant fetal anomalies that can otherwise be detected by ultrasound and/or invasive genetic testing.
# Conclusion
In the pandemic context, strategies requiring multiple screening steps or visits are obviously not ideal. Each regional prenatal screening program needs to minimize patient-health care provider contacts. For this reason, we would recommend FTS, or NIPT where available and funded, be the first choice of screening for all pregnant women with available NT ultrasound. These tests should be performed after the 11-14 weeks scan in order to minimize unnecessary blood tests (nonviable pregnancies or gross anomalies requiring diagnostic tests rather than screening tests).
QUAD screening may be offered to women presenting after 14 weeks (due to late booking and/or quarantine), or in areas without the first-trimester screening availability or funded NIPT. NT: nuchal translucency ultrasound; NIPT: non-invasive prenatal testing; QUAD: quadruple second trimester serum screening.
# First trimester pregnancy
No suspicion of Covid Offer first trimester ultrasound with NT if available or dating ultrasound First trimester combined screening or orther accepted aneuplody screening process (regional standard)
NIPT if available/funded (regional standard)
# Suspected or confirmed Covid
Wait 2 weeks and reschedule
# <14 weeks
Combined test or NT+NIPT (regional standard) >=14 weeks QUAD or NIPT (regional standard) | None | None |
d03f786cf09d0d168fa3bcf85206cd8401f577f5 | cma | None | # Background
Prostate cancer is the most common cancer among Canadian men, and is the 3rd leading cause of cancer related death in men in Canada. In 2022, it is estimated that 24,600 men will be diagnosed with prostate cancer in Canada and 4600 men will die from their disease. 1 Many patients with advanced prostate cancers are diagnosed after localized treatment, with disseminated disease being identified by rising PSA post-definitive treatment. However, some men present with de novo metastatic disease.
Guideline Questions 1. How should advanced/ metastatic prostate cancer be staged? 2. How should advanced/ metastatic prostate cancer be treated? 3. How should advanced/ metastatic prostate cancer patients be followed after treatment?
# Search Strategy
For the 2022 guideline update, selected phase III trials were reviewed by the Alberta GU Tumour group (summarized in Appendix A).
For the 2016 guideline, select literature was reviewed by a working group at the Alberta GU Tumour Team meeting. No formal systematic literature review was performed.
For the 2015 update, no formal literature review was conducted.
For the 2014 update of this guideline, the Pubmed database was searched using the search terms Locally Advanced Prostate Cancer and Metastatic Prostate Cancer from 2010 to 2014. Only phase III trials were evaluated for inclusion.
For the 2012 update of this guideline, Ovid Medline was searched using the term Prostatic neoplasms (MeSH term, subheadings drug therapy, surgery, therapy and radiotherapy), limited to clinical trials involving humans published in English, between August 2011 and August 2012. Articles were excluded if they were not phase II-IV trials, did not include survival or recurrence outcomes, was retrospective. Cochrane Database of Systematic Reviews was searched using the term "prostate cancer", published 2011-2012.
Medline & Embase were further searched using the term prostate cancer (keyword), limited to clinical trials related to "therapy (best balance of sensitivity and specificity) involving male humans published in English between August 2011-2012.
Ovid MEDLINE and EMBASE (1965 to August 2011) and clinical practice guideline databases, including the Cochrane Library and the National Guidelines Clearinghouse, were searched in order to obtain evidence relevant to this topic. are viable options. Lower rates of fracture, peripheral arterial disease, and cardiac-related complications have been reported in surgical castration patients when compared to medical castration patients in a large retrospective cohort study. 4 Castrate level serum testosterone (<1.7 nmol/L) can cause a number of undesirable side effects. For this reason intermittent ADT has theoretical advantages. However, in patients with metastatic prostate cancer continuous ADT is recommended unless survival is considered secondary to quality of life. The phase III intergroup trial reported that intermittent ADT cannot be considered non-inferior compared to continuous ADT in terms of overall survival. 5,6 Medical castration: Treatment with an LHRH agonist/GnRH antagonist: - When first introduced, a non-steroidal antiandrogen (e.g. bicalutamide 50 mg daily, flutamide 250 mg three times a day or nilutamide 300mg daily) should be given concurrently with the first administration of leuprolide, goserelin, or buserelin for 2 weeks to 1 month in order to block the potential initial testosterone flare. - The non-steroidal antiandrogen should be administered concurrently with the first LHRH analogue injection and continue for a minimum of 14 days afterward. - Medical and surgical castration is equally effective and the risks, benefits, and economic implications should be discussed with the patient. - Patients who are intolerant to Leuprolide or unable to achieve castrate testosterone should have a trial of Buserelin. - The GnRH antagonist Degarelix is as effective at suppressing testosterone and may achieve testosterone suppression faster 7 than GnRH Agonists. Treatment with a GnRH antagonist (Degarelix) avoids the risk of testosterone 'flare" that occurs with GnRH agonists. 7,8 A non steroidal antiandrogen is not required to be given concurrently with the first dose of GnRH antagonist. 3. Nilutamide 300 mg orally once a day for one month, then decrease to 150 mg daily.
Patients undergoing androgen deprivation therapy for prostate cancer have an improved quality of life if they continue to be physically active. Patients should be counseled on the role of maintaining physical fitness and activity while on hormonal therapy. 9 Ongoing total androgen blockade (e.g. castration with LHRH agonist/antagonist plus a nonsteroidal antiandrogen) is not recommended for patients in this setting. 11 demonstrated a significant overall survival benefit of 14 months in all patients (low and high volume) with metastatic CSPC. o Patients receiving chemotherapy for this indication should be offered 6 cycles of docetaxel chemotherapy at a starting dose of 75 mg/m 2 every 3 weeks (given with or without prednisone). Androgen deprivation therapy as above is continued throughout and after docetaxel completion.
# Abiraterone Acetate:
- Patients should be considered per the LATITUDE trial criteria to qualify for this treatment. The LATITUDE inclusion criteria are 12 : o Adenocarcinoma of the prostate without neuroendocrine differentiation or small cell histology. o Distant metastatic disease documented by positive bone scan or metastatic lesions on CT or MRI. o At least 2 of the following high-risk prognostic factors: Gleason score ≥8; presence of 3 or more lesions on bone scan; presence of measurable visceral (excluding lymph node disease) metastasis on CT or MRI.
- Docetaxel plus abiraterone acetate with prednisone 5 mg twice a day may be considered for patients, who are chemotherapy candidates with de novo high volume metastatic disease (defined as the presence of visceral metastases or >4 bony lesions with 1 beyond the vertebral bodies and pelvis), as per the PEACE-1 trial. 13 4. Enzalutamide (All risks/volumes). 14,15 5. Apalutamide (All risks/volumes) 16 There is insufficient evidence to recommend one single agent ARAT strategy over another. Clinical decision making should be based on patient factors and access.
# Radiation therapy:
Referral to RO for consideration of radiation therapy to the prostate for patients with de novo low volume metastatic disease (see Management of Oligometastatic Disease below), as per STAMPEDE. 17
# Follow-up Frequency
If on either docetaxel chemotherapy or ARAT (eg: abiraterone acetate, enzalutamide, apalutamide), patients should be evaluated as per standard protocol.
If on ADT alone: q3-6 months following the initiation of therapy to evaluate and then as clinically indicated.
Patients should be treated until development of castrate resistant disease, which is defined as either clinical, biochemical, or radiographic disease progression in the presence of castrate level (<1.7nmol/L) testosterone levels.
# IV. Non-Metastatic Castration Resistant Disease (Stage M0, M+)
Castrate resistant disease is defined as either clinical, biochemical, or radiographic disease progression in the presence of castrate level (<1.7nmol/L) testosterone levels.
# Staging
- Bone scan.
- CT scan of chest, abdomen, and pelvis. 3. Serum PSA, serum testosterone (to ensure that testosterone is in the castrate range). 4. Other imaging may be required as clinically indicated.
# Management of M0 CRPC Disease
Monitoring:
- Baseline ECG recommended. PSA, testosterone, and TSH should be monitored q3-6monthly.
- Systemic therapy may be considered in patients with high-risk disease, where a PSA doubling time is < 10 months and no measurable disease on conventional imaging (bone scan and CT chest, abdomen, and pelvis). A PSA doubling time calculator is recommended for calculation (e.g. MSKCC). 23 1. First line options: a. Abiraterone acetate 1000 mg oral daily in combination with prednisone 5 mg oral twice daily (COUGAR 302) can be used prior to docetaxel. 24,25 b. Docetaxel 75mg/m 2 IV every 3 weeks in combination with prednisone at a dose of 5 mg twice daily. c. Enzalutamide 160mg oral daily can be used prior to docetaxel (PREVAIL). 26
# Second line options:
a. Post progression on docetaxel chemotherapy: i. Cabazitaxel IV every 3 weeks in combination with prednisone 10 mg oral daily.20 mg or 25 mg can be considered, as the PROSELICA trial. 27 demonstrated that 20 mg dose was non-inferior to the 25 mg dose and was associated with decreased toxicity. Per the CARD trial, cabazitaxel is shown to improve overall survival, in contrast to another ARAT. 28 ii. Abiraterone acetate 29 or enzalutamide. 30 iii. Radium 223 is not funded or available in Alberta. Radium 223 can be given to patients with symptomatic bony metastatic CRPC without visceral metastases (ALSYMPCA). 31,32 Ra 223 is administered upon referral to nuclear medicine and given at a dose of 50 kBq (1.35 microcurie) per kg body weight at 4 week intervals for a total of 6 injections. b. Post progression on abiraterone, apalutamide, darolutamide or enzalutamide: i. Docetaxel chemotherapy.
ii. Olaparib -for patients with BRCA1/2 or ATM alterations. 33 ATM mutations may require strong consideration of chemotherapy prior to PARP inhibitors. Hence, medical oncology should be involved in the care of these patients prior to initiation of PARP inhibitor. Other DNA damage repair alterations do not qualify for Olaparib therapy. iii. Platinum-based chemotherapy options should be considered for patients with DNA damage repair mutations (e.g. BRCA1/2, ATM, etc.), and discussion at multidisciplinary tumour board rounds is encouraged. 23 3. Subsequent lines: a. Sequencing with another agent listed above not previously used. Optimal sequencing of these agents is unknown. b. If a patient has already received docetaxel and one ARAT, the CARD trial would suggest that cabazitaxel would be the preferred subsequent agent provided the patient is medically fit for therapy.
# Management of Oligometastatic Disease
# Radiotherapy to the prostate:
- The STAMPEDE trial 17 failed to demonstrate improvement in overall survival after radiotherapy in newly diagnosed metastatic prostate cancer. However, pre-specified subgroup analysis of patients with low metastatic burden (by CHAARTED clinical trial criteria) demonstrated an improvement in overall survival with radiotherapy to the prostate compared to standard of care (81% vs. 73% OS at 3 years; HR:0.68, 95%CI: 0.52-0.90). Discussion in multidisciplinary tumour group meetings is advised if radiotherapy is being considered.
- SBRT is an investigational option and may be considered for some patients.
- PSMA PET/CT is an investigational option and is not currently standard of care. Patient results of PSMA PET/CT should be reviewed at multidisciplinary tumour board rounds to determine best course of action in patient management.
# Follow-up:
- Patients on docetaxel, abiraterone, enzalutamide, apalutamide, darolutamide, or cabazitaxel should be monitored as per standard protocols.
- Once therapy with one of these agents has been discontinued, patients should be assessed for further therapy.
# Appendix A: Clinical Trial Summaries
# Development and Revision History
This guideline was developed by a multidisciplinary working group comprised of members from the Alberta Provincial GU Tumour Team, external participants identified by the Working Group Lead, and a methodologist from the Guideline Resource Unit. The draft guideline was externally reviewed and endorsed by members of the Alberta Provincial GU Tumour Team who were not involved in the guideline's development, including urologists, radiation oncologists, medical oncologists, nurses, pathologists, and pharmacists. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook.
This guideline was originally developed in 2019.
# Maintenance
A formal review of the guideline will be conducted in 2023. If critical new evidence is brought forward before that time, however, the guideline working group members will revise and update the document accordingly.
# Abbreviations
ADT Androgen deprivation therapy, ALT Alanine transamine, AST Aspartate transaminase, BUN Blood urea nitrogen, CBC Complete blood count, CT Computed tomography, EBRT External beam radiotherapy, GnRH Gonadotropin-releasing hormone agonist, LHRH Luteinizing hormone-releasing hormone, PSA Prostate-specific antigen | # Background
Prostate cancer is the most common cancer among Canadian men, and is the 3rd leading cause of cancer related death in men in Canada. In 2022, it is estimated that 24,600 men will be diagnosed with prostate cancer in Canada and 4600 men will die from their disease. 1 Many patients with advanced prostate cancers are diagnosed after localized treatment, with disseminated disease being identified by rising PSA post-definitive treatment. However, some men present with de novo metastatic disease.
Guideline Questions 1. How should advanced/ metastatic prostate cancer be staged? 2. How should advanced/ metastatic prostate cancer be treated? 3. How should advanced/ metastatic prostate cancer patients be followed after treatment?
# Search Strategy
For the 2022 guideline update, selected phase III trials were reviewed by the Alberta GU Tumour group (summarized in Appendix A).
For the 2016 guideline, select literature was reviewed by a working group at the Alberta GU Tumour Team meeting. No formal systematic literature review was performed.
For the 2015 update, no formal literature review was conducted.
For the 2014 update of this guideline, the Pubmed database was searched using the search terms Locally Advanced Prostate Cancer and Metastatic Prostate Cancer from 2010 to 2014. Only phase III trials were evaluated for inclusion.
For the 2012 update of this guideline, Ovid Medline was searched using the term Prostatic neoplasms (MeSH term, subheadings drug therapy, surgery, therapy and radiotherapy), limited to clinical trials involving humans published in English, between August 2011 and August 2012. Articles were excluded if they were not phase II-IV trials, did not include survival or recurrence outcomes, was retrospective. Cochrane Database of Systematic Reviews was searched using the term "prostate cancer", published 2011-2012.
Medline & Embase were further searched using the term prostate cancer (keyword), limited to clinical trials related to "therapy (best balance of sensitivity and specificity) involving male humans published in English between August 2011-2012.
Ovid MEDLINE and EMBASE (1965 to August 2011) and clinical practice guideline databases, including the Cochrane Library and the National Guidelines Clearinghouse, were searched in order to obtain evidence relevant to this topic. are viable options. Lower rates of fracture, peripheral arterial disease, and cardiac-related complications have been reported in surgical castration patients when compared to medical castration patients in a large retrospective cohort study. 4 Castrate level serum testosterone (<1.7 nmol/L) can cause a number of undesirable side effects. For this reason intermittent ADT has theoretical advantages. However, in patients with metastatic prostate cancer continuous ADT is recommended unless survival is considered secondary to quality of life. The phase III intergroup trial reported that intermittent ADT cannot be considered non-inferior compared to continuous ADT in terms of overall survival. 5,6 Medical castration: Treatment with an LHRH agonist/GnRH antagonist: • When first introduced, a non-steroidal antiandrogen (e.g. bicalutamide 50 mg daily, flutamide 250 mg three times a day or nilutamide 300mg daily) should be given concurrently with the first administration of leuprolide, goserelin, or buserelin for 2 weeks to 1 month in order to block the potential initial testosterone flare. • The non-steroidal antiandrogen should be administered concurrently with the first LHRH analogue injection and continue for a minimum of 14 days afterward. • Medical and surgical castration is equally effective and the risks, benefits, and economic implications should be discussed with the patient. • Patients who are intolerant to Leuprolide or unable to achieve castrate testosterone should have a trial of Buserelin. • The GnRH antagonist Degarelix is as effective at suppressing testosterone and may achieve testosterone suppression faster 7 than GnRH Agonists. Treatment with a GnRH antagonist (Degarelix) avoids the risk of testosterone 'flare" that occurs with GnRH agonists. 7,8 A non steroidal antiandrogen is not required to be given concurrently with the first dose of GnRH antagonist. 3. Nilutamide 300 mg orally once a day for one month, then decrease to 150 mg daily.
•
Patients undergoing androgen deprivation therapy for prostate cancer have an improved quality of life if they continue to be physically active. Patients should be counseled on the role of maintaining physical fitness and activity while on hormonal therapy. 9 Ongoing total androgen blockade (e.g. castration with LHRH agonist/antagonist plus a nonsteroidal antiandrogen) is not recommended for patients in this setting. 11 demonstrated a significant overall survival benefit of 14 months in all patients (low and high volume) with metastatic CSPC. o Patients receiving chemotherapy for this indication should be offered 6 cycles of docetaxel chemotherapy at a starting dose of 75 mg/m 2 every 3 weeks (given with or without prednisone). Androgen deprivation therapy as above is continued throughout and after docetaxel completion.
# Abiraterone Acetate:
o Patients should be considered per the LATITUDE trial criteria to qualify for this treatment. The LATITUDE inclusion criteria are 12 : o Adenocarcinoma of the prostate without neuroendocrine differentiation or small cell histology. o Distant metastatic disease documented by positive bone scan or metastatic lesions on CT or MRI. o At least 2 of the following high-risk prognostic factors: Gleason score ≥8; presence of 3 or more lesions on bone scan; presence of measurable visceral (excluding lymph node disease) metastasis on CT or MRI.
3. Docetaxel plus abiraterone acetate with prednisone 5 mg twice a day may be considered for patients, who are chemotherapy candidates with de novo high volume metastatic disease (defined as the presence of visceral metastases or >4 bony lesions with 1 beyond the vertebral bodies and pelvis), as per the PEACE-1 trial. 13 4. Enzalutamide (All risks/volumes). 14,15 5. Apalutamide (All risks/volumes) 16 There is insufficient evidence to recommend one single agent ARAT strategy over another. Clinical decision making should be based on patient factors and access.
# Radiation therapy:
Referral to RO for consideration of radiation therapy to the prostate for patients with de novo low volume metastatic disease (see Management of Oligometastatic Disease below), as per STAMPEDE. 17
# Follow-up Frequency
If on either docetaxel chemotherapy or ARAT (eg: abiraterone acetate, enzalutamide, apalutamide), patients should be evaluated as per standard protocol.
If on ADT alone: q3-6 months following the initiation of therapy to evaluate and then as clinically indicated.
Patients should be treated until development of castrate resistant disease, which is defined as either clinical, biochemical, or radiographic disease progression in the presence of castrate level (<1.7nmol/L) testosterone levels.
# IV. Non-Metastatic Castration Resistant Disease (Stage M0, M+)
Castrate resistant disease is defined as either clinical, biochemical, or radiographic disease progression in the presence of castrate level (<1.7nmol/L) testosterone levels.
# Staging
1. Bone scan.
2. CT scan of chest, abdomen, and pelvis. 3. Serum PSA, serum testosterone (to ensure that testosterone is in the castrate range). 4. Other imaging may be required as clinically indicated.
# Management of M0 CRPC Disease
Monitoring:
• Baseline ECG recommended. PSA, testosterone, and TSH should be monitored q3-6monthly.
• Systemic therapy may be considered in patients with high-risk disease, where a PSA doubling time is < 10 months and no measurable disease on conventional imaging (bone scan and CT chest, abdomen, and pelvis). A PSA doubling time calculator is recommended for calculation (e.g. MSKCC). 23 1. First line options: a. Abiraterone acetate 1000 mg oral daily in combination with prednisone 5 mg oral twice daily (COUGAR 302) can be used prior to docetaxel. 24,25 b. Docetaxel 75mg/m 2 IV every 3 weeks in combination with prednisone at a dose of 5 mg twice daily. c. Enzalutamide 160mg oral daily can be used prior to docetaxel (PREVAIL). 26
# Second line options:
a. Post progression on docetaxel chemotherapy: i. Cabazitaxel IV every 3 weeks in combination with prednisone 10 mg oral daily.20 mg or 25 mg can be considered, as the PROSELICA trial. 27 demonstrated that 20 mg dose was non-inferior to the 25 mg dose and was associated with decreased toxicity. Per the CARD trial, cabazitaxel is shown to improve overall survival, in contrast to another ARAT. 28 ii. Abiraterone acetate 29 or enzalutamide. 30 iii. Radium 223 is not funded or available in Alberta. Radium 223 can be given to patients with symptomatic bony metastatic CRPC without visceral metastases (ALSYMPCA). 31,32 Ra 223 is administered upon referral to nuclear medicine and given at a dose of 50 kBq (1.35 microcurie) per kg body weight at 4 week intervals for a total of 6 injections. b. Post progression on abiraterone, apalutamide, darolutamide or enzalutamide: i. Docetaxel chemotherapy.
ii. Olaparib -for patients with BRCA1/2 or ATM alterations. 33 ATM mutations may require strong consideration of chemotherapy prior to PARP inhibitors. Hence, medical oncology should be involved in the care of these patients prior to initiation of PARP inhibitor. Other DNA damage repair alterations do not qualify for Olaparib therapy. iii. Platinum-based chemotherapy options should be considered for patients with DNA damage repair mutations (e.g. BRCA1/2, ATM, etc.), and discussion at multidisciplinary tumour board rounds is encouraged. 23 3. Subsequent lines: a. Sequencing with another agent listed above not previously used. Optimal sequencing of these agents is unknown. b. If a patient has already received docetaxel and one ARAT, the CARD trial would suggest that cabazitaxel would be the preferred subsequent agent provided the patient is medically fit for therapy.
# Management of Oligometastatic Disease
# Radiotherapy to the prostate:
• The STAMPEDE trial 17 failed to demonstrate improvement in overall survival after radiotherapy in newly diagnosed metastatic prostate cancer. However, pre-specified subgroup analysis of patients with low metastatic burden (by CHAARTED clinical trial criteria) demonstrated an improvement in overall survival with radiotherapy to the prostate compared to standard of care (81% vs. 73% OS at 3 years; HR:0.68, 95%CI: 0.52-0.90). Discussion in multidisciplinary tumour group meetings is advised if radiotherapy is being considered.
• SBRT is an investigational option and may be considered for some patients.
• PSMA PET/CT is an investigational option and is not currently standard of care. Patient results of PSMA PET/CT should be reviewed at multidisciplinary tumour board rounds to determine best course of action in patient management.
# Follow-up:
• Patients on docetaxel, abiraterone, enzalutamide, apalutamide, darolutamide, or cabazitaxel should be monitored as per standard protocols.
• Once therapy with one of these agents has been discontinued, patients should be assessed for further therapy.
# Appendix A: Clinical Trial Summaries
# Development and Revision History
This guideline was developed by a multidisciplinary working group comprised of members from the Alberta Provincial GU Tumour Team, external participants identified by the Working Group Lead, and a methodologist from the Guideline Resource Unit. The draft guideline was externally reviewed and endorsed by members of the Alberta Provincial GU Tumour Team who were not involved in the guideline's development, including urologists, radiation oncologists, medical oncologists, nurses, pathologists, and pharmacists. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook.
This guideline was originally developed in 2019.
# Maintenance
A formal review of the guideline will be conducted in 2023. If critical new evidence is brought forward before that time, however, the guideline working group members will revise and update the document accordingly.
# Abbreviations
ADT Androgen deprivation therapy, ALT Alanine transamine, AST Aspartate transaminase, BUN Blood urea nitrogen, CBC Complete blood count, CT Computed tomography, EBRT External beam radiotherapy, GnRH Gonadotropin-releasing hormone agonist, LHRH Luteinizing hormone-releasing hormone, PSA Prostate-specific antigen
# Disclaimer
The recommendations contained in this guideline are a consensus of the Alberta Provincial GU Tumour Team and are a synthesis of currently accepted approaches to management, derived from a review of relevant scientific literature. Clinicians applying these guidelines should, in consultation with the patient, use independent medical judgment in the context of individual clinical circumstances to direct care.
# Copyright © (2023) Alberta Health Services
This copyright work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivative 4.0 International license. You are free to copy and distribute the work including in other media and formats for non-commercial purposes, as long as you attribute the work to Alberta Health Services, do not adapt the work, and abide by the other license terms. To view a copy of this license, see https://creativecommons.org/licenses/by-nc-nd/4.0/. The license does not apply to AHS trademarks, logos or content for which Alberta Health Services is not the copyright owner.
# Funding Source
Financial support for the development of Cancer Care Alberta's evidence-based clinical practice guidelines and supporting materials comes from the Cancer Care Alberta operating budget; no outside commercial funding was received to support the development of this document.
All cancer drugs described in the guidelines are funded in accordance with the Outpatient Cancer Drug Benefit Program, at no charge, to eligible residents of Alberta, unless otherwise explicitly stated. For a complete list of funded drugs, specific indications, and approved prescribers, please refer to the Outpatient Cancer Drug Benefit Program Master List.
# Conflict of Interest Statements
Dr. Nimira Alimohamed reports receiving grants from Astellas, AstraZeneca, Janssen, Merck, and Pfizer.
Dr. Naveen Basappa reports receiving grants from Pfizer, Merck, Janssen, AstraZeneca, Astellas, BMS, Bayer, Ipsen, Eisai and EMD Serono.
Dr. Brita Danielson reports receiving honoraria from Amgen, Bayer, BMS, Ferring and Janssen.
Derek Tilley has nothing to disclose. | None | None |
e1bf8ec4de66b0f3ca36685b11261421bee7e5bb | cma | None | This document has been updated to refer to human monkeypox disease as mpox and monkeypox virus as MPXV. This is consistent with other jurisdictions and scientific publications.# Introduction
The information in this document (adapted from a Question and Answer document created by the Office of the Chief Medical Officer of Health, Mary Choi, dated June 25, 2022) was developed based on best available evidence as of the date of publication. There are limitations to the evidence that is currently available. Clinicians must determine whether adopting the suggested information is clinically appropriate for individual patients. It is intended for use by clinicians in practice to provide the best possible evidence-based care and information to patients with known or suspected mpox.
Mpox disease (formerly known as monkeypox) is caused by an infection with the monkeypox virus (MPXV), which belongs to the Orthopoxvirus genus. It is related to the variola virus, which causes smallpox. Mpox is most commonly transmitted from person to person through direct contact with infectious rash, bodily fluids, and/or scabs, including through close, physical interactions, including hugging, kissing, and sexual activity.
Mpox can also be transmitted via contact with respiratory secretions during prolonged face-to-face contact, fomites (e.g., clothing or bedding contaminated by infectious rash/bodily fluids), and rarely, vertical transmission. Currently, it is unknown if mpox can spread via semen or vaginal fluids (U.S. Department of Health and Human Services 2022).
In Ontario, reported risk factors include engaging in sexual or intimate contact with new and/or multiple partners. Although most cases have been identified among men who report sexual or intimate contact with other men, anyone can get mpox.
# Clinical Presentation of Mpox
Mpox is usually a mild and self-limiting disease and most people who are infected recover within 2 to 4 weeks. However, severe illness can occur in some individuals.
Initial prodromal symptoms of mpox may include fever, chills, fatigue/weakness, headaches, myalgia, pharyngitis, coryza, cough, and lymphadenopathy that can last for 1 to 3 days prior to onset of a rash.
The rash usually begins on the face and then spreads to elsewhere in the body. It can affect the mucous membranes in the mouth, tongue, and genitalia, as well as the palms of hands and soles of the feet. The rash can last for 2 to 4 weeks and progresses through the following stages: macules, papules, vesicles, pustules, and scabs.
In some recently recorded cases, the onset of symptoms started with genital, perianal, or oral rash/lesion(s)-before onset of prodromal symptoms-which did not spread to other parts of the body. This fact sheet compares the presentation of mpox, chickenpox, and hand-foot-and-mouth disease. These two resources may also be helpful to clinicians:
- Monkeypox cases confirmed in England -latest updates Currently, children with rash consistent with an enterovirus illness (e.g., hand-foot-and-mouth disease) without epidemiological risk factors (e.g., contact with a confirmed case) do not require MPXV testing.
# Infection Prevention and Control Precautions
In addition to routine precautions, the following measures are recommended for health care workers when interacting with individuals with suspected, probable, or confirmed MPXV infection:
- Place the individual with suspect, probable, or confirmed MPXV infection in a single-patient room, with the door closed. Inpatients should be placed in a single-person room with a dedicated bathroom - Perform hand hygiene as per the four moments of hand hygiene - Use recommended personal protective equipment (PPE) such as gloves, gown, eye protection (e.g., face shields, safety glasses or goggles), and a fit-tested and seal-checked N-95 respirator (or equivalent); perform seal check after donning N95 respirator - Ensure patients wear a well-fitting medical mask - Perform routine environmental cleaning and disinfection and ensure all horizontal surfaces that may be touched by the patient and equipment that may have been used by or shared between patients are cleaned and disinfected after every use. Special and/or additional environmental cleaning and disinfection measures are not required.
# How to Test for MPXV in Primary Care
All specimens must be submitted with a Public Health Ontario general test requisition.
Skin specimens are preferred, as they have a much higher sensitivity (85%-90%) than nasopharyngeal/throat (60%-70%) and blood (40%-50%) specimens. Patients with 2 to 3 skin lesions that can be swabbed generally do not require blood or respiratory specimens collected for MPXV testing. Specimens can be packaged and placed in the fridge for up to 3 days.
In patients suspected to have MPXV infection who do not have a skin rash (e.g., an individual who is a close contact of a confirmed case, with a febrile illness but no rash) or those who have a skin rash that cannot be reliably swabbed (e.g., macular and/or papular rash only), clinicians should submit a nasopharyngeal or throat swab in addition to a blood sample.
For more detailed information on all aspects of laboratory testing for MPXV, refer to Public Health Ontario's laboratory services monkeypox virus test information sheet. Instructions for transporting samples for testing are listed in Box 1. Please note that improperly packaged/labeled specimens may result in delays. Clinicians can consult with Public Health Ontario with any questions regarding testing indications, specimen collection, or transportation via the PHOL Customer Service Centre at 1-416-235-6556/1-877-604-4567 or via the after-hours duty officer at 1-416-605-3113.
The same laboratory courier systems that currently pick up specimens from primary care clinician practice locations for microbiology testing can be used for transporting MPXV specimens.
Mpox is a reportable disease of public health significance in Ontario. All confirmed, probable, or suspected cases, as well as any persons under investigation, should be reported your local public health units.
Community laboratories will receive samples submitted for testing by primary care clinicians for transportation to the Ontario public health lab but are not themselves offering diagnostic testing for mpox, nor are they offering collection services for diagnosing mpox (e.g., lesion, throat, or nasopharyngeal swabs).
# Management of MPXV Infections
Treatment is primarily symptomatic and supportive (alleviation of fever and pruritus, hydration), including prevention and treatment of secondary bacterial infections. In severe cases, antiviral medications are available on a limited, case-by-case basis.
Patients with confirmed or probable cases of mpox should self-isolate at home until the end of the period of communicability-i.e., until lesion scabs have fallen off and new intact skin has formed below, a process which varies by individual but typically takes 2 to 4 weeks.
Other advice should include:
- Stay in a separate room/area away from other household members if possible and use a separate bathroom if available/feasible
- Avoid contact with those at higher risk of severe mpox illness, including immunosuppressed people, pregnant people, and children younger than 12 years of age - Avoid leaving the home unless necessary (e.g., to seek essential medical care) - Avoid non-essential household visitors - Wear a mask for source control (medical mask preferred), especially if respiratory symptoms are present - Cover skin lesions as much as possible (e.g., long sleeves, long pants) - Avoid contact with animals, including household pets. If possible, ask someone else in the home who is not sick and who has not been exposed to care for the pet. This is especially important for rodents, rabbits, and non-human primates. Otherwise, take precautions, such as wearing a medical mask and performing good hand hygiene
Public health units will also follow up with cases to provide further guidance and to initiate contact tracing.
# Antiviral Medications
Antiviral medications are available for the treatment of mpox for those who are severely ill/disabled due to MPXV infection.
Tecovirimat (TPoxx) is an an antiviral medication that inhibits the production of an orthopoxviral envelope protein required for cell-to-cell viral dissemination. Based on limited clinical testing in humans, it is authorized in Canada for the treatment of human smallpox disease in adults and pediatric patients weighing at least 13 kg. - Persons with MPXV infections with lesions that are leading to significant disability (e.g., proctitis, keratitis or other ocular involvement, pharyngitis/epiglottitis or other breathing/swallowing compromise) - Persons with one or more mpox complications (e.g., secondary bacterial skin infection; gastroenteritis with severe nausea/vomiting, diarrhea, or dehydration; bronchopneumonia; concurrent disease or other comorbidities)
# Vaccination
Vaccines are available for both pre-exposure (for individuals at high risk of infection before they are exposed to the virus) and post-exposure prophylaxis (after recent high risk exposure to a known case). Please contact your local public health unit for more information about eligibility and clinic information.
# Appendix 1: Transportation Label for Suspected MPXV Specimens | This document has been updated to refer to human monkeypox disease as mpox and monkeypox virus as MPXV. This is consistent with other jurisdictions and scientific publications.# Introduction
The information in this document (adapted from a Question and Answer document created by the Office of the Chief Medical Officer of Health, Mary Choi, dated June 25, 2022) was developed based on best available evidence as of the date of publication. There are limitations to the evidence that is currently available. Clinicians must determine whether adopting the suggested information is clinically appropriate for individual patients. It is intended for use by clinicians in practice to provide the best possible evidence-based care and information to patients with known or suspected mpox.
Mpox disease (formerly known as monkeypox) is caused by an infection with the monkeypox virus (MPXV), which belongs to the Orthopoxvirus genus. It is related to the variola virus, which causes smallpox. Mpox is most commonly transmitted from person to person through direct contact with infectious rash, bodily fluids, and/or scabs, including through close, physical interactions, including hugging, kissing, and sexual activity.
Mpox can also be transmitted via contact with respiratory secretions during prolonged face-to-face contact, fomites (e.g., clothing or bedding contaminated by infectious rash/bodily fluids), and rarely, vertical transmission. Currently, it is unknown if mpox can spread via semen or vaginal fluids (U.S. Department of Health and Human Services 2022).
In Ontario, reported risk factors include engaging in sexual or intimate contact with new and/or multiple partners. Although most cases have been identified among men who report sexual or intimate contact with other men, anyone can get mpox.
# Clinical Presentation of Mpox
Mpox is usually a mild and self-limiting disease and most people who are infected recover within 2 to 4 weeks. However, severe illness can occur in some individuals.
Initial prodromal symptoms of mpox may include fever, chills, fatigue/weakness, headaches, myalgia, pharyngitis, coryza, cough, and lymphadenopathy that can last for 1 to 3 days prior to onset of a rash.
The rash usually begins on the face and then spreads to elsewhere in the body. It can affect the mucous membranes in the mouth, tongue, and genitalia, as well as the palms of hands and soles of the feet. The rash can last for 2 to 4 weeks and progresses through the following stages: macules, papules, vesicles, pustules, and scabs.
In some recently recorded cases, the onset of symptoms started with genital, perianal, or oral rash/lesion(s)-before onset of prodromal symptoms-which did not spread to other parts of the body. This fact sheet compares the presentation of mpox, chickenpox, and hand-foot-and-mouth disease. These two resources may also be helpful to clinicians:
• Monkeypox cases confirmed in England -latest updates Currently, children with rash consistent with an enterovirus illness (e.g., hand-foot-and-mouth disease) without epidemiological risk factors (e.g., contact with a confirmed case) do not require MPXV testing.
# Infection Prevention and Control Precautions
In addition to routine precautions, the following measures are recommended for health care workers when interacting with individuals with suspected, probable, or confirmed MPXV infection:
• Place the individual with suspect, probable, or confirmed MPXV infection in a single-patient room, with the door closed. Inpatients should be placed in a single-person room with a dedicated bathroom • Perform hand hygiene as per the four moments of hand hygiene • Use recommended personal protective equipment (PPE) such as gloves, gown, eye protection (e.g., face shields, safety glasses or goggles), and a fit-tested and seal-checked N-95 respirator (or equivalent); perform seal check after donning N95 respirator • Ensure patients wear a well-fitting medical mask • Perform routine environmental cleaning and disinfection and ensure all horizontal surfaces that may be touched by the patient and equipment that may have been used by or shared between patients are cleaned and disinfected after every use. Special and/or additional environmental cleaning and disinfection measures are not required.
# How to Test for MPXV in Primary Care
All specimens must be submitted with a Public Health Ontario general test requisition.
Skin specimens are preferred, as they have a much higher sensitivity (85%-90%) than nasopharyngeal/throat (60%-70%) and blood (40%-50%) specimens. Patients with 2 to 3 skin lesions that can be swabbed generally do not require blood or respiratory specimens collected for MPXV testing. Specimens can be packaged and placed in the fridge for up to 3 days.
In patients suspected to have MPXV infection who do not have a skin rash (e.g., an individual who is a close contact of a confirmed case, with a febrile illness but no rash) or those who have a skin rash that cannot be reliably swabbed (e.g., macular and/or papular rash only), clinicians should submit a nasopharyngeal or throat swab in addition to a blood sample.
For more detailed information on all aspects of laboratory testing for MPXV, refer to Public Health Ontario's laboratory services monkeypox virus test information sheet. Instructions for transporting samples for testing are listed in Box 1. Please note that improperly packaged/labeled specimens may result in delays. Clinicians can consult with Public Health Ontario with any questions regarding testing indications, specimen collection, or transportation via the PHOL Customer Service Centre at 1-416-235-6556/1-877-604-4567 or via the after-hours duty officer at 1-416-605-3113.
The same laboratory courier systems that currently pick up specimens from primary care clinician practice locations for microbiology testing can be used for transporting MPXV specimens.
Mpox is a reportable disease of public health significance in Ontario. All confirmed, probable, or suspected cases, as well as any persons under investigation, should be reported your local public health units.
Community laboratories will receive samples submitted for testing by primary care clinicians for transportation to the Ontario public health lab but are not themselves offering diagnostic testing for mpox, nor are they offering collection services for diagnosing mpox (e.g., lesion, throat, or nasopharyngeal swabs).
# Management of MPXV Infections
Treatment is primarily symptomatic and supportive (alleviation of fever and pruritus, hydration), including prevention and treatment of secondary bacterial infections. In severe cases, antiviral medications are available on a limited, case-by-case basis.
Patients with confirmed or probable cases of mpox should self-isolate at home until the end of the period of communicability-i.e., until lesion scabs have fallen off and new intact skin has formed below, a process which varies by individual but typically takes 2 to 4 weeks.
Other advice should include:
• Stay in a separate room/area away from other household members if possible and use a separate bathroom if available/feasible
• Avoid contact with those at higher risk of severe mpox illness, including immunosuppressed people, pregnant people, and children younger than 12 years of age • Avoid leaving the home unless necessary (e.g., to seek essential medical care) • Avoid non-essential household visitors • Wear a mask for source control (medical mask preferred), especially if respiratory symptoms are present • Cover skin lesions as much as possible (e.g., long sleeves, long pants) • Avoid contact with animals, including household pets. If possible, ask someone else in the home who is not sick and who has not been exposed to care for the pet. This is especially important for rodents, rabbits, and non-human primates. Otherwise, take precautions, such as wearing a medical mask and performing good hand hygiene
Public health units will also follow up with cases to provide further guidance and to initiate contact tracing.
# Antiviral Medications
Antiviral medications are available for the treatment of mpox for those who are severely ill/disabled due to MPXV infection.
Tecovirimat (TPoxx) is an an antiviral medication that inhibits the production of an orthopoxviral envelope protein required for cell-to-cell viral dissemination. Based on limited clinical testing in humans, it is authorized in Canada for the treatment of human smallpox disease in adults and pediatric patients weighing at least 13 kg. • Persons with MPXV infections with lesions that are leading to significant disability (e.g., proctitis, keratitis or other ocular involvement, pharyngitis/epiglottitis or other breathing/swallowing compromise) • Persons with one or more mpox complications (e.g., secondary bacterial skin infection; gastroenteritis with severe nausea/vomiting, diarrhea, or dehydration; bronchopneumonia; concurrent disease or other comorbidities)
# Vaccination
Vaccines are available for both pre-exposure (for individuals at high risk of infection before they are exposed to the virus) and post-exposure prophylaxis (after recent high risk exposure to a known case). Please contact your local public health unit for more information about eligibility and clinic information.
# Appendix 1: Transportation Label for Suspected MPXV Specimens
| None | None |
dc792656b5f049e46d432973293e887c8c94ec4c | cma | None | This guidance is intended for health-care providers and is based on known evidence as of April 18, 2023. Patients with neuromuscular conditions with significant respiratory muscle weakness are at increased risk of hospitalization and mortality from This includes individuals with significant diseases of the neurologic system including the brain, spinal cord, motor nerves and muscles who, because of their condition require respiratory support in the form of home ventilation or bilevel positive airway pressure in order to function in daily life. 2,3 This includes individuals requiring respiratory support with the following conditions: - Motor neuron disease - Muscular dystrophy - Peripheral neuropathy including Guillain Barre Syndrome, Charcot-Marie Tooth disease, critical illness neuropathy - Myopathies including congenital myopathies, myofibrillar myopathies, metabolic myopathies, critical illness myopathy - Other neuromuscular conditions where breathing muscles are severely impacted due to their conditions - While people with spinal cord injury are not considered to be at increased risk of getting infected with the COVID-19 virus, 4 those with a spinal cord injury requiring ventilatory support have the same risk factors as other conditions requiring respiratory support mentioned above, thus the clinical judgment is that their risks are similarly high. Is COVID-19 immunization recommended for patients with neuromuscular conditions who require respiratory support? COVID-19 immunization should be encouraged for patients with neuromuscular conditions requiring respiratory support and is not contraindicated, including those who have had COVID-19 infection. This recommendation is based on the following factors: o Patients with neuromuscular conditions who require respiratory support at baseline are at extremely high risk for morbidity and mortality if they are infected with COVID-19; many would not be able to be extubated if intubation was required.#
- Weakness of respiratory muscles in individuals with neuromuscular disorders may result in impaired ability to take a deep breath, impaired cough reflex, and ineffective airway clearance of secretions predisposing to atelectasis and lung infection. 2 Acute respiratory failure may rapidly evolve in patients with chronic respiratory failure secondary to neuromuscular weakness. Risks include prolonged invasive ventilation, deterioration of respiratory or skeletal muscle function or death. 1 While data specific to the safety and efficacy of COVID-19 vaccines for people with neuromuscular disorders is currently limited, there are data to suggest that the currently available COVID-19 vaccines have efficacy. 5 The authors of this guidance agree that the benefits of vaccine-induced immunity against COVID-19 for this population outweigh any theoretical risks of immunization.
Is COVID-19 immunization efficacious and safe for patients with neuromuscular conditions who require respiratory support?
Patients with neuromuscular disease requiring respiratory support were not specifically included in the COVID-19 vaccine trials; therefore, efficacy in this population is unknown. However, there is no reason to believe the vaccine will be less efficacious in patients with neuromuscular disease requiring respiratory support than in the population studied in the clinical trials. Patients with chronic pulmonary disease comprised 7.8% of patients in the Pfizer-BioNTech vaccine trial and patients with hemiplegia and paraplegia comprised 0.1% of patients in the trial. 12 The Food and Drug Administration (FDA) have issued a for the Janssen COVID-19 vaccine about the increased risk of developing Guillain-Barré syndrome (GBS) in the 42 days after vaccination. 13 The GBS/CIDP Foundation recommends that patients who have developed their disease within 6 weeks of receiving a COVID-19 vaccination, they should make an informed consent after discussing the risks versus benefits with their healthcare professional about receiving a second dose of vaccine that is of a different type, preferably mRNA, as per the NACI guidance. 14 Patients with Duchenne's Muscular Dystrophy (DMD) who require respiratory support and who are receiving deflazacort or prednisone will require additional counseling on efficacy and timing of their vaccine with their treatment, as deflazacort and prednisone are immunosuppressing/immunomodulating. There is limited evidence about the efficacy of the Pfizer BioNTech and Moderna vaccines in people who are immunocompromised due to treatment, as immunocompromised patients were not included in the trials. It is unknown if the currently available COVID-19 vaccines are efficacious in those who take immunosuppressants compared to those who are not considered immunosuppressed.
- It is possible that, because of their immunosuppression from treatment, these patients will have a blunted immune response to the vaccine. Because of their increased risk to COVID-19, the vaccine is recommended for patients with neuromuscular conditions who are immunocompromised, but these patients should be informed that they may have a diminished immune response to any of the authorized COVID-19 vaccines. 12,15 As per NACI, safety data in immunocompromised individuals, including those receiving immunosuppressive therapy, were available from observational studies in people who were taking immunosuppressive therapies. The frequency and severity of adverse events following vaccination with an mRNA COVID-19 vaccine were comparable to that COVID-19 Vaccines for People with Neuromuscular Conditions Requiring Respiratory Support Updated: April 18, 2023 of non-immunocompromised individuals in these studies and what was reported in clinical trials. Safety data in these populations following vaccination with a viral vector vaccine is not available. - Health-care providers caring for DMD patients being treated with deflazacort or prednisone can refer to the clinical guidance for patients with neuromuscular receiving immunosuppressing/immunomodulating therapy.
Are there any specific contraindications or exceptions for patients with neuromuscular conditions who require respiratory support?
Individuals who have had a severe allergic reaction to an ingredient of one type of COVID-19 vaccine are still able to receive future doses of the other type of vaccine. 16 BCCDC has a list of the individual components and their purpose in the vaccines. For a complete list of components in the vaccine, consult the vaccine monographs found at: www.bccdc.ca/health-info/diseases-conditions/covid-19/covid-19-vaccine/vaccines-for-covid-19.
For individuals with a history of anaphylactic reaction to a previous dose of an mRNA COVID-19 vaccine, re-vaccination (i.e., administration of a subsequent dose in the series when indicated) may be offered with the same vaccine or the same mRNA platform if a risk assessment deems that the benefits outweigh the potential risks for the individual and if informed consent is provided. Prior to revaccination, consultation with an allergist or another appropriate physician (e.g., Medical Health Officer) is advised. If re-vaccination is going ahead, vaccine administration should be done in a controlled setting with expertise and equipment to manage anaphylaxis, with an extended period of observation of at least 30 minutes after re-vaccination.
Health Canada continues to monitor any adverse events following immunization through their post-authorization surveillance process.
COVID-19 vaccines can be given concomitantly with, or any time before or after any other live or inactivated vaccine. Are there specific recommendations or considerations for safe and/or most effective vaccine administration?
Individuals with muscle disease may not have adequate deltoid muscle mass, in which case the anterolateral thigh can be used to administer the vaccine. 21 Otherwise, there are no other specific recommendations that pertain to this population unless they have comorbidities requiring special care, such as being treated with immunosuppressive or immunomodulating therapy, in which case health-care providers can refer to clinical guidance for people with autoimmune neuromuscular disorders receiving immunosuppressive/immunomodulating therapy.
COVID-19 Vaccines for People with Neuromuscular Conditions Requiring Respiratory Support Updated: | This guidance is intended for health-care providers and is based on known evidence as of April 18, 2023. Patients with neuromuscular conditions with significant respiratory muscle weakness are at increased risk of hospitalization and mortality from This includes individuals with significant diseases of the neurologic system including the brain, spinal cord, motor nerves and muscles who, because of their condition require respiratory support in the form of home ventilation or bilevel positive airway pressure in order to function in daily life. 2,3 This includes individuals requiring respiratory support with the following conditions: • Motor neuron disease • Muscular dystrophy • Peripheral neuropathy including Guillain Barre Syndrome, Charcot-Marie Tooth disease, critical illness neuropathy • Myopathies including congenital myopathies, myofibrillar myopathies, metabolic myopathies, critical illness myopathy • Other neuromuscular conditions where breathing muscles are severely impacted due to their conditions • While people with spinal cord injury are not considered to be at increased risk of getting infected with the COVID-19 virus, 4 those with a spinal cord injury requiring ventilatory support have the same risk factors as other conditions requiring respiratory support mentioned above, thus the clinical judgment is that their risks are similarly high. Is COVID-19 immunization recommended for patients with neuromuscular conditions who require respiratory support? COVID-19 immunization should be encouraged for patients with neuromuscular conditions requiring respiratory support and is not contraindicated, including those who have had COVID-19 infection. This recommendation is based on the following factors: o Patients with neuromuscular conditions who require respiratory support at baseline are at extremely high risk for morbidity and mortality if they are infected with COVID-19; many would not be able to be extubated if intubation was required.#
o Weakness of respiratory muscles in individuals with neuromuscular disorders may result in impaired ability to take a deep breath, impaired cough reflex, and ineffective airway clearance of secretions predisposing to atelectasis and lung infection. 2 Acute respiratory failure may rapidly evolve in patients with chronic respiratory failure secondary to neuromuscular weakness. Risks include prolonged invasive ventilation, deterioration of respiratory or skeletal muscle function or death. 1 While data specific to the safety and efficacy of COVID-19 vaccines for people with neuromuscular disorders is currently limited, there are data to suggest that the currently available COVID-19 vaccines have efficacy. 5 The authors of this guidance agree that the benefits of vaccine-induced immunity against COVID-19 for this population outweigh any theoretical risks of immunization.
Is COVID-19 immunization efficacious and safe for patients with neuromuscular conditions who require respiratory support?
Patients with neuromuscular disease requiring respiratory support were not specifically included in the COVID-19 vaccine trials; therefore, efficacy in this population is unknown. [6][7][8][9][10][11] However, there is no reason to believe the vaccine will be less efficacious in patients with neuromuscular disease requiring respiratory support than in the population studied in the clinical trials. Patients with chronic pulmonary disease comprised 7.8% of patients in the Pfizer-BioNTech vaccine trial and patients with hemiplegia and paraplegia comprised 0.1% of patients in the trial. 12 The Food and Drug Administration (FDA) have issued a for the Janssen COVID-19 vaccine about the increased risk of developing Guillain-Barré syndrome (GBS) in the 42 days after vaccination. 13 The GBS/CIDP Foundation recommends that patients who have developed their disease within 6 weeks of receiving a COVID-19 vaccination, they should make an informed consent after discussing the risks versus benefits with their healthcare professional about receiving a second dose of vaccine that is of a different type, preferably mRNA, as per the NACI guidance. 14 Patients with Duchenne's Muscular Dystrophy (DMD) who require respiratory support and who are receiving deflazacort or prednisone will require additional counseling on efficacy and timing of their vaccine with their treatment, as deflazacort and prednisone are immunosuppressing/immunomodulating. There is limited evidence about the efficacy of the Pfizer BioNTech and Moderna vaccines in people who are immunocompromised due to treatment, as immunocompromised patients were not included in the trials. It is unknown if the currently available COVID-19 vaccines are efficacious in those who take immunosuppressants compared to those who are not considered immunosuppressed.
• It is possible that, because of their immunosuppression from treatment, these patients will have a blunted immune response to the vaccine. Because of their increased risk to COVID-19, the vaccine is recommended for patients with neuromuscular conditions who are immunocompromised, but these patients should be informed that they may have a diminished immune response to any of the authorized COVID-19 vaccines. 12,15 As per NACI, safety data in immunocompromised individuals, including those receiving immunosuppressive therapy, were available from observational studies in people who were taking immunosuppressive therapies. The frequency and severity of adverse events following vaccination with an mRNA COVID-19 vaccine were comparable to that COVID-19 Vaccines for People with Neuromuscular Conditions Requiring Respiratory Support Updated: April 18, 2023 of non-immunocompromised individuals in these studies and what was reported in clinical trials. Safety data in these populations following vaccination with a viral vector vaccine is not available. • Health-care providers caring for DMD patients being treated with deflazacort or prednisone can refer to the clinical guidance for patients with neuromuscular receiving immunosuppressing/immunomodulating therapy.
Are there any specific contraindications or exceptions for patients with neuromuscular conditions who require respiratory support?
Individuals who have had a severe allergic reaction to an ingredient of one type of COVID-19 vaccine are still able to receive future doses of the other type of vaccine. 16 BCCDC has a list of the individual components and their purpose in the vaccines. For a complete list of components in the vaccine, consult the vaccine monographs found at: www.bccdc.ca/health-info/diseases-conditions/covid-19/covid-19-vaccine/vaccines-for-covid-19.
For individuals with a history of anaphylactic reaction to a previous dose of an mRNA COVID-19 vaccine, re-vaccination (i.e., administration of a subsequent dose in the series when indicated) may be offered with the same vaccine or the same mRNA platform if a risk assessment deems that the benefits outweigh the potential risks for the individual and if informed consent is provided. Prior to revaccination, consultation with an allergist or another appropriate physician (e.g., Medical Health Officer) is advised. If re-vaccination is going ahead, vaccine administration should be done in a controlled setting with expertise and equipment to manage anaphylaxis, with an extended period of observation of at least 30 minutes after re-vaccination.
Health Canada continues to monitor any adverse events following immunization through their post-authorization surveillance process.
COVID-19 vaccines can be given concomitantly with, or any time before or after any other live or inactivated vaccine. [17][18][19][20] Are there specific recommendations or considerations for safe and/or most effective vaccine administration?
Individuals with muscle disease may not have adequate deltoid muscle mass, in which case the anterolateral thigh can be used to administer the vaccine. 21 Otherwise, there are no other specific recommendations that pertain to this population unless they have comorbidities requiring special care, such as being treated with immunosuppressive or immunomodulating therapy, in which case health-care providers can refer to clinical guidance for people with autoimmune neuromuscular disorders receiving immunosuppressive/immunomodulating therapy.
COVID-19 Vaccines for People with Neuromuscular Conditions Requiring Respiratory Support Updated: | None | None |
ec9f31e1366815d1c89692a739b59b08cfab017f | cma | None | Alcohol use disorder (AUD) is an increasingly common, under-recognized, and under-treated health concern in older adults. Its prevalence is expected to reach unprecedented levels as the Canadian population ages. In response, Health Canada commissioned the Canadian Coalition of Seniors' Mental Health to create guidelines for the prevention, screening, assessment, and treatment of AUD in older adults.A systematic review of English language literature from 2008-2018 regarding AUD in adults was conducted. Previously published guidelines were evaluated using AGREE II, and key guidelines updated using ADAPTE method by drawing on current literature. Recommendations were created and assessed using the GRADE method.Twenty-two recommendations were created. Prevention recommendations: Best advice for older adults who choose to drink is to limit intake to well below the national Low-Risk Alcohol Drinking Guidelines. Screening recommendations: Alcohol consumption should be reviewed and discussed on an annual basis by primary care providers. This type of discussion needs to be normalized and approached in a simple, neutral, straight-forward manner. Assessment recommendations: Positive screens for AUD should be followed by a comprehensive assessment. Once more details are obtained an individualized treatment plan can be recommended, negotiated, and implemented. Treatment recommendations: AUD falls on a spectrum of mild, moderate, and severe. It can also be complicated by concurrent mental health, physical, or social issues, especially in older adults. Naltrexone and Acamprosate pharmacotherapies can be used for the treatment of AUD in older adults, as individually indicated. Psychosocial treatment and support should be offered as part of a comprehensive treatment plan.These guidelines provide practical and timely clinical recommendations on the prevention, assessment, and treatment of AUD in older adults within the Canadian context.# INTRODUCTION
Despite increasing rates of illicit and prescription drug misuse among adults aged 65 years and older, alcohol remains the most commonly used and misused substance in this age group. (1) Alcohol use disorder (AUD) and risky alcohol consumption are common among older adults, with reported problem drinking rates ranging from 1-22%. (2) Older women may be at particular risk for alcohol-related problems. (3) A recent study found that a greater proportion of older adults (aged 55-70 years) drank heavily in comparison to younger adults, although AUD, as defined by the DSM-5, was less prevalent among older adults. (1) It can be difficult to identify AUD in older adults, as some of the signs and symptoms of problematic use are similar to age-related health conditions such as poor mobility, cognitive problems, and high rates of multiple comorbidities with falls and fractures, which may occur as a result of alcohol use. (4,5,6) The progression of other chronic illnesses in older adults may also mask AUD. Increased rigor with respect to screening is required, along with a broader interpretation of DSM-5 diagnostic criteria, to identify older adults living with AUD. Special attention should be paid to criteria related to failure in social roles and/or reduced or problematic social interactions, as these may not be as apparent in retired or isolated older adults.
Drinking more than 100g per week of alcohol is known to be associated with a higher risk for all-cause mortality, as well as other adverse health events such as stroke, heart failure, coronary artery disease (excluding myocardial infraction), fatal hypertensive disease, and fatal aortic aneurysm. (7) Excessive alcohol consumption among older adults may increase the risk of several health conditions including hypertension, hemorrhagic stroke, diabetes mellitus, infections, alcoholic liver disease, and gastrointestinal conditions including gastritis, gastric ulcers, and gastric bleeding. (8,9,10,11) There is clear evidence of a dose-dependent pattern of alcohol use increasing the risk of cancer in many organs, including the oropharynx, larynx, esophagus, liver, colon and rectum, and breast. (12) Excessive alcohol consumption in older adults may also be associated with an increased risk of cognitive decline and dementia. (13) AUD is a risk factor for suicide in older adults as concomitant AUD may increase the likelihood for isolation, poor health, and depression. (14,15) Older adults are often on multiple medications to manage chronic diseases. Alcohol use introduces the risk for harmful interactions between alcohol and drugs, and may reduce medication efficacy. Furthermore, older adults generally metabolize alcohol at a slower rate than younger adults (13,16,17,18,) leading to a risk of heightened effects from alcohol among older adults even at relatively low levels of consumption.
# METHODS
The CCSMH Alcohol Guideline Development Working Group was created to lead the process. Peter R. Butt and Marilyn White-Campbell were appointed as co-leads of the group. Group membership was based on willingness to commit to the project and either possessing the required professional expertise or having a lived experience perspective. Ensuring diversity in disciplinary background and geographic distribution across Canada of members guided the final composition of the Guideline Development Working Group.
Members volunteered to focus on either the prevention or management of alcohol use disorder. Within these broad areas, they assumed leadership roles in assessing and drafting recommendations to deal with specific topics. This process was guided by systematic searches of databases to identify relevant literature that was then reviewed by Guideline Development Working Group members. Bi-weekly videoconferences were held to maintain progress, discuss emerging issues, refine recommendations, ensure consistency, and identify gaps. A modified version of the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology was utilized first to assess (and score) the quality of the available evidence for each recommendation (based on consideration of study design and quality of available studies, applicability to the question being addressed, and confidence in the estimate of the effect); and then to assess its overall strength, which took into account additional factors such as the balance between benefit and harm, patient values and preferences, and whether this would be a wise use of the required resources for implementation (see Box 1). (19) A separate category was created for recommendations that were not primarily based on empirical evidence but represented best clinical practice. These were categorized as consensus recommendations.
Members of the Guideline Working Group voted on all recommendations. For adoption, a recommendation had to achieve consensus approval (75%+ affirmative vote). We were actually able to discuss until we reached 100% member consensus on each recommendation. Further details on the methodology used are available at the following-https:// ccsmh.ca/substance-use-addiction/intro/ The funder had no role in the creation or approval of the recommendations made for alcohol use disorder among older adults. Working Group members submitted annual declarations of potential conflicts of interest, all of which are available upon request.
# RESULTS/RECOMMENDATIONS Recommendation #1
For women 65 years of age or older, no more than 1 standard drink per day, with no more than 5 alcoholic drinks per week, is recommended; for men 65 years of age or older, no more than 1-2 standard drinks per day, with no more than 7 per week in total, is recommended. Non-drinking days are recommended every week. a. Depending upon health (i.e., dementia; Parkinson's disease; hemorrhagic stroke; epilepsy; cardiac dysrhythmias; hypertension; sleep apnea; COPD; liver disease; pancreatitis; GI and breast cancers; compromised balance or mobility), frailty, and medication use (i.e., benzodiazepines, opioids, Gabapentinoids, sedating antidepressants), some adults should adhere to these recommended lower levels of alcohol consumption before they reach the age of 65.
b. As the older adult ages, especially those with comorbidities (as above), alcohol should be further reduced to 1 drink or less per day, consumed on fewer occasions, and consideration should be given to abstaining from alcohol.
c. It is recommended that older adults do not drink when operating any kind of vehicle, tools or machinery; using medications or other drugs that interact with alcohol; engaging in sports or potentially dangerous physical activity; preparing for bed or having to arise at night; making important decisions; while responsible for the care of others; if living with serious physical or mental illness or a substance use disorder.
# DISCUSSION
There is a plethora of clinical guidance in the management of Alcohol Use Disorder but a paucity of evidence attributable to the unique and highly diverse older adult population. These guidelines represent a systematic approach to the literature, with particular attention to the evidence, context, and expertise. The guideline group provided multidisciplinary insight, critical analysis, clinical acumen, and lived experience. These 22 guideline recommendations for AUD in older adults cover prevention, screening, assessment, and treatment. Although good evidence exists for the treatment of AUD in adults, there is a dearth directly applicable to the older adult population. The literature varied in its definition of older adults and grappled with the diversity of this population with regard to comorbidities, living circumstances and supports, sex and gender, cultural influences, and treatment outcomes in the context of generally declining health.
Studies focused on older adults, inclusive of sub-populations, are needed to create evidence for the effectiveness of psychosocial and pharmacological treatments. The inconsistency around thiamine dosages and routes in detox need to be addressed for all patients. Somewhat related is the determination of the efficacy of oral thiamine supplementation to prevent Wernicke-Korsakoff's syndrome in ongoing chronic, heavy drinkers. Also, in need of further study is the recommendation for managed alcohol tapering in a controlled environment for those transitioning in their level of care. Finally, the use of toxicology screens in the context of falls would greatly assist in identifying the role of substance use in this common, yet highly problematic, occurrence in the older adult population.
In order to facilitate implementation of these recommendations the clinician needs to remain engaged through screening, assessment and treatment, to support both harm reduction and the potential transition into recovery. This is often described as a journey in which the patient is learning how to live without chemical coping, to address their many issues, and reconnect with life. Awareness of these transitions and the provision of appropriate support, without enabling, is an important part of the clinical role and relationship. Appropriate treatment and longitudinal, comprehensive care can be as successful with substance use disorders, as with any other chronic disease.
Care would be greatly assisted by expanded treatment resources, both pharmacologic and non-pharmacologic, for older adults with AUD. Prevention, through beverage alcohol labelling, social marketing of the low-risk drinking guidelines, and education of clinicians, is also important to reduce the human, health, and economic burden of alcohol misuse.
# CONCLUSION
Older adults are more sensitive to the effects of alcohol, and their bodies process alcohol slower than younger bodies do. Many older adults drink alcohol without problems. When problems do develop, they may begin at a young age or later in life. As the population of Canada ages, there is a growing need for resources regarding alcohol use in older adults. The recommendations found in our Clinical Guidelines are intended to provide health-care workers and policy-makers with evidence-informed, clinically relevant direction and advice on the prevention, screening, assessment, and treatment of AUD in older adults. We hope practitioners will find them both a practical and useful clinical aide, and that community members will find them a helpful educational resource. The expanded version of these guidelines can be accessed electronically (www.ccsmh.ca).
-r approval of the recommendations. Authors received an honorarium for their work. A rigorous process was undertaken to ensure that members of the working group did not have any significant conflict of interest. | Alcohol use disorder (AUD) is an increasingly common, under-recognized, and under-treated health concern in older adults. Its prevalence is expected to reach unprecedented levels as the Canadian population ages. In response, Health Canada commissioned the Canadian Coalition of Seniors' Mental Health to create guidelines for the prevention, screening, assessment, and treatment of AUD in older adults.A systematic review of English language literature from 2008-2018 regarding AUD in adults was conducted. Previously published guidelines were evaluated using AGREE II, and key guidelines updated using ADAPTE method by drawing on current literature. Recommendations were created and assessed using the GRADE method.Twenty-two recommendations were created. Prevention recommendations: Best advice for older adults who choose to drink is to limit intake to well below the national Low-Risk Alcohol Drinking Guidelines. Screening recommendations: Alcohol consumption should be reviewed and discussed on an annual basis by primary care providers. This type of discussion needs to be normalized and approached in a simple, neutral, straight-forward manner. Assessment recommendations: Positive screens for AUD should be followed by a comprehensive assessment. Once more details are obtained an individualized treatment plan can be recommended, negotiated, and implemented. Treatment recommendations: AUD falls on a spectrum of mild, moderate, and severe. It can also be complicated by concurrent mental health, physical, or social issues, especially in older adults. Naltrexone and Acamprosate pharmacotherapies can be used for the treatment of AUD in older adults, as individually indicated. Psychosocial treatment and support should be offered as part of a comprehensive treatment plan.These guidelines provide practical and timely clinical recommendations on the prevention, assessment, and treatment of AUD in older adults within the Canadian context.# INTRODUCTION
Despite increasing rates of illicit and prescription drug misuse among adults aged 65 years and older, alcohol remains the most commonly used and misused substance in this age group. (1) Alcohol use disorder (AUD) and risky alcohol consumption are common among older adults, with reported problem drinking rates ranging from 1-22%. (2) Older women may be at particular risk for alcohol-related problems. (3) A recent study found that a greater proportion of older adults (aged 55-70 years) drank heavily in comparison to younger adults, although AUD, as defined by the DSM-5, was less prevalent among older adults. (1) It can be difficult to identify AUD in older adults, as some of the signs and symptoms of problematic use are similar to age-related health conditions such as poor mobility, cognitive problems, and high rates of multiple comorbidities with falls and fractures, which may occur as a result of alcohol use. (4,5,6) The progression of other chronic illnesses in older adults may also mask AUD. Increased rigor with respect to screening is required, along with a broader interpretation of DSM-5 diagnostic criteria, to identify older adults living with AUD. Special attention should be paid to criteria related to failure in social roles and/or reduced or problematic social interactions, as these may not be as apparent in retired or isolated older adults.
Drinking more than 100g per week of alcohol is known to be associated with a higher risk for all-cause mortality, as well as other adverse health events such as stroke, heart failure, coronary artery disease (excluding myocardial infraction), fatal hypertensive disease, and fatal aortic aneurysm. (7) Excessive alcohol consumption among older adults may increase the risk of several health conditions including hypertension, hemorrhagic stroke, diabetes mellitus, infections, alcoholic liver disease, and gastrointestinal conditions including gastritis, gastric ulcers, and gastric bleeding. (8,9,10,11) There is clear evidence of a dose-dependent pattern of alcohol use increasing the risk of cancer in many organs, including the oropharynx, larynx, esophagus, liver, colon and rectum, and breast. (12) Excessive alcohol consumption in older adults may also be associated with an increased risk of cognitive decline and dementia. (13) AUD is a risk factor for suicide in older adults as concomitant AUD may increase the likelihood for isolation, poor health, and depression. (14,15) Older adults are often on multiple medications to manage chronic diseases. Alcohol use introduces the risk for harmful interactions between alcohol and drugs, and may reduce medication efficacy. Furthermore, older adults generally metabolize alcohol at a slower rate than younger adults (13,16,17,18,) leading to a risk of heightened effects from alcohol among older adults even at relatively low levels of consumption.
# METHODS
The CCSMH Alcohol Guideline Development Working Group was created to lead the process. Peter R. Butt and Marilyn White-Campbell were appointed as co-leads of the group. Group membership was based on willingness to commit to the project and either possessing the required professional expertise or having a lived experience perspective. Ensuring diversity in disciplinary background and geographic distribution across Canada of members guided the final composition of the Guideline Development Working Group.
Members volunteered to focus on either the prevention or management of alcohol use disorder. Within these broad areas, they assumed leadership roles in assessing and drafting recommendations to deal with specific topics. This process was guided by systematic searches of databases to identify relevant literature that was then reviewed by Guideline Development Working Group members. Bi-weekly videoconferences were held to maintain progress, discuss emerging issues, refine recommendations, ensure consistency, and identify gaps. A modified version of the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology was utilized first to assess (and score) the quality of the available evidence for each recommendation (based on consideration of study design and quality of available studies, applicability to the question being addressed, and confidence in the estimate of the effect); and then to assess its overall strength, which took into account additional factors such as the balance between benefit and harm, patient values and preferences, and whether this would be a wise use of the required resources for implementation (see Box 1). (19) A separate category was created for recommendations that were not primarily based on empirical evidence but represented best clinical practice. These were categorized as consensus recommendations.
Members of the Guideline Working Group voted on all recommendations. For adoption, a recommendation had to achieve consensus approval (75%+ affirmative vote). We were actually able to discuss until we reached 100% member consensus on each recommendation. Further details on the methodology used are available at the following-https:// ccsmh.ca/substance-use-addiction/intro/ The funder had no role in the creation or approval of the recommendations made for alcohol use disorder among older adults. Working Group members submitted annual declarations of potential conflicts of interest, all of which are available upon request.
# RESULTS/RECOMMENDATIONS Recommendation #1
For women 65 years of age or older, no more than 1 standard drink per day, with no more than 5 alcoholic drinks per week, is recommended; for men 65 years of age or older, no more than 1-2 standard drinks per day, with no more than 7 per week in total, is recommended. Non-drinking days are recommended every week. [GRADE: Evidence: Moderate; Strength: Strong] a. Depending upon health (i.e., dementia; Parkinson's disease; hemorrhagic stroke; epilepsy; cardiac dysrhythmias; hypertension; sleep apnea; COPD; liver disease; pancreatitis; GI and breast cancers; compromised balance or mobility), frailty, and medication use (i.e., benzodiazepines, opioids, Gabapentinoids, sedating antidepressants), some adults should adhere to these recommended lower levels of alcohol consumption before they reach the age of 65.
[GRADE: Evidence: High; Strength: Strong] b. As the older adult ages, especially those with comorbidities (as above), alcohol should be further reduced to 1 drink or less per day, consumed on fewer occasions, and consideration should be given to abstaining from alcohol.
[GRADE: Evidence: Low; Strength: Strong] c. It is recommended that older adults do not drink when operating any kind of vehicle, tools or machinery; using medications or other drugs that interact with alcohol; engaging in sports or potentially dangerous physical activity; preparing for bed or having to arise at night; making important decisions; while responsible for the care of others; if living with serious physical or mental illness or a substance use disorder.
# DISCUSSION
There is a plethora of clinical guidance in the management of Alcohol Use Disorder but a paucity of evidence attributable to the unique and highly diverse older adult population. These guidelines represent a systematic approach to the literature, with particular attention to the evidence, context, and expertise. The guideline group provided multidisciplinary insight, critical analysis, clinical acumen, and lived experience. These 22 guideline recommendations for AUD in older adults cover prevention, screening, assessment, and treatment. Although good evidence exists for the treatment of AUD in adults, there is a dearth directly applicable to the older adult population. The literature varied in its definition of older adults and grappled with the diversity of this population with regard to comorbidities, living circumstances and supports, sex and gender, cultural influences, and treatment outcomes in the context of generally declining health.
Studies focused on older adults, inclusive of sub-populations, are needed to create evidence for the effectiveness of psychosocial and pharmacological treatments. The inconsistency around thiamine dosages and routes in detox need to be addressed for all patients. Somewhat related is the determination of the efficacy of oral thiamine supplementation to prevent Wernicke-Korsakoff's syndrome in ongoing chronic, heavy drinkers. Also, in need of further study is the recommendation for managed alcohol tapering in a controlled environment for those transitioning in their level of care. Finally, the use of toxicology screens in the context of falls would greatly assist in identifying the role of substance use in this common, yet highly problematic, occurrence in the older adult population.
In order to facilitate implementation of these recommendations the clinician needs to remain engaged through screening, assessment and treatment, to support both harm reduction and the potential transition into recovery. This is often described as a journey in which the patient is learning how to live without chemical coping, to address their many issues, and reconnect with life. Awareness of these transitions and the provision of appropriate support, without enabling, is an important part of the clinical role and relationship. Appropriate treatment and longitudinal, comprehensive care can be as successful with substance use disorders, as with any other chronic disease.
Care would be greatly assisted by expanded treatment resources, both pharmacologic and non-pharmacologic, for older adults with AUD. Prevention, through beverage alcohol labelling, social marketing of the low-risk drinking guidelines, and education of clinicians, is also important to reduce the human, health, and economic burden of alcohol misuse.
# CONCLUSION
Older adults are more sensitive to the effects of alcohol, and their bodies process alcohol slower than younger bodies do. Many older adults drink alcohol without problems. When problems do develop, they may begin at a young age or later in life. As the population of Canada ages, there is a growing need for resources regarding alcohol use in older adults. The recommendations found in our Clinical Guidelines are intended to provide health-care workers and policy-makers with evidence-informed, clinically relevant direction and advice on the prevention, screening, assessment, and treatment of AUD in older adults. We hope practitioners will find them both a practical and useful clinical aide, and that community members will find them a helpful educational resource. The expanded version of these guidelines can be accessed electronically (www.ccsmh.ca).
or approval of the recommendations. Authors received an honorarium for their work. A rigorous process was undertaken to ensure that members of the working group did not have any significant conflict of interest.
# ACKNOWLEDGEMENTS
Funding for the CCSMH Substance Use Disorder Guidelines was provided by Health Canada, Substance Use and Addictions Program. The CCSMH gratefully acknowledges Health Canada for its ongoing support and continued commitment to the area of seniors' mental health. We would also like to thank Dr. Meldon Kahan, Dr. Harold Kalant, William McDonnell, Dr. Rosemary Meier, Dr. Samir Sinha, and Craig Vickers for their support in reviewing and providing their perspectives on this document. We would like to thank the Canadian Centre on Substance Use and Addiction and the Behavioural Supports Ontario Substance Use Collaborative for their support and contributions throughout the development of the Guidelines, and Tonya Mahar (Manager, Library Services, Baycrest) for her assistance with literature searches. Finally, the CCSMH would like to acknowledge the continued dedication of its Steering Committee members and the outstanding contributions of our Director, Claire Checkland and Project Coordinators Indira Fernando, Natasha Kachan, and Marc-André LeBlanc.
# DISCLAIMER
This publication is intended for information purposes only, and is not intended to be interpreted or used as a standard of medical practice. Best efforts were used to ensure that the information in this publication is accurate; however, the publisher and every person involved in the creation of this publication disclaim any warranty as to the accuracy, completeness or currency of the contents of this publication. This publication is distributed with the understanding that neither the publisher nor any person involved in the creation of this publication is rendering professional advice. Physicians and other readers must determine the appropriate clinical care for each individual patient on the basis of all the clinical data available for the individual case. The publisher and every person involved in the creation of this publication disclaim any liability arising from contract, negligence, or any other cause of action, to any party, for the publication contents or any consequences arising from its use. The views expressed herein do not necessarily represent the views of Health Canada.
# CONFLICT OF INTEREST DISCLOSURES
The project was funded by Health Canada (Substance Use and Addictions Program). The funder had no role in the creation | None | None |
fd61a335ce8e0f44f5b7eacfa6e117d406d788c3 | cma | None | with the help of our Scientific Advisory Board comprised of leading hematologists /oncologists from across Canada, created a brief report addressing important questions from patients related to COVID-19 and the vaccine, to provide guidance from the clinician and policy levels.#
In August 2021, provinces began to approve the administration of a third COVID-19 vaccine to individuals with two prior vaccinations. Provinces differ in their roll-out plan and eligibility criteria. For best guidance, please speak with your clinician to determine your eligibility and review your provinces roll-out plan for details on how to access the vaccine.
# Why might immunocompromised individuals need a third dose of the COVID-19 vaccine?
Immunocompromised individuals have a weakened immune system due to disease or treatment. Some immunocompromised individuals have a lower immune response to the COVID-19 vaccines compared to the general population .
Recent studies show that some individuals who are moderately to severely immunocompromised who did not respond to or who had a reduced immune response after two doses of an mRNA vaccine may have an increased immune response after a third dose of an mRNA vaccine . However, at this time research has not been published on the safety and efficacy of a third vaccine dose in lymphoma patients.
# How do I know if I am eligible to receive the third COVID-19 booster vaccine?
The National Advisory Committee on Immunization (NACI) released a guidance report regarding the additional dose of a COVID-19 vaccine in certain immunocompromised individuals following a 1-or 2-dose primary series. Based on research published on immunocompromised patients' response to the one or two vaccine doses and the third vaccine dose , NACI recommends the following:
- For those who have not yet been immunized, moderately to severely immunocompromised- individuals in the authorized age groups should be immunized with a primary series of three doses of an authorized mRNA vaccine. V1 (21-Sept-2021) Lymphoma Canada Telephone: 905-858-5967 Toll-free: 1-866-659-5556 [email protected] 2. For those moderately to severely immunocompromised- individuals in the authorized age groups who have previously received a 1-or 2-dose complete primary series, including those who received a mixed vaccine schedule, should be offered an additional dose of an authorized mRNA COVID-19 vaccine.
- An additional dose of a viral vector vaccine should only be considered when other authorized COVID-19 vaccines are contraindicated or inaccessible. Informed consent for an additional dose of a viral vector vaccine should include discussion about the lack of evidence on the use of an additional dose of viral vector COVID-19 vaccine in this population.
Moderately to severely immunocompromised includes individuals with the following conditions:
- Active treatment for solid tumour or hematologic malignancies - Receipt of solid-organ transplant and taking immunosuppressive therapy - Receipt of chimeric antigen receptor (CAR)-T-cell therapy or hematopoietic stem cell transplant (within 2 years of transplantation or taking immunosuppression therapy) - Moderate to severe primary immunodeficiency (e.g., DiGeorge syndrome, Wiskott-Aldrich syndrome) - Stage 3 or advanced untreated HIV infection and those with acquired immunodeficiency syndrome - Active treatment with the following categories of immunosuppressive therapies: anti-B cell therapies (monoclonal antibodies targeting CD19, CD20 and CD22), high-dose systemic corticosteroids, alkylating agents, antimetabolites, or tumor-necrosis factor (TNF) inhibitors and other biologic agents that are significantly immunosuppressive.
Many provinces are adopting these recommendations, with specific eligibility criteria available through the province's phased or non-phased roll-out plan. There may be some differences between this list above and the criteria listed by the province. Please review your provinces recommendation and eligibility criteria related to the third vaccine dose through the links below:
# Nunavut
No public statement released yet on the 3 rd COVID-19 vaccine dose.
# Is the third COVID-19 vaccine right for me?
Lymphoma Canada recommends speaking with your doctor to determine if the third COVID-19 vaccine is best for you. This can depend on where you are with your treatment schedule as well as other health conditions. There are no specific criteria at this time based on lymphoma subtype, and as per eligibility criteria patients with a hematologic malignancy (which includes lymphoma) may be eligible to receive the third COVID-19 vaccine depending on your treatment.
# How do I book my third COVID-19 vaccine?
To book your third COVID-19 vaccine, please go to your province's website where there may be the option to either book your third dose online or through a hotline. You may be required to provide a letter of support from your clinician depending on the province. If your clinician has not sent you this letter directly, please contact your doctor to discuss your eligibility to receive the vaccine and receive a support letter. Bring this letter with you to your vaccine appointment, along with personal identification. Further details on what may be required for your vaccine appointment can be found through your province's website.
# Should patients receive an antibody test to assess their immune response to the previous vaccines before considering a third COVID-19 vaccine dose?
No. It is not possible to interpret from a SARS-CoV-2 spike serology test whether a patient is fully protected against COVID-19, as the immune response can be variable after both infection and vaccination. The antibody measurement may not necessarily be the best indicator of immunity. The Canadian Immunity Task Force also does not consider SARS-CoV-2 serology an appropriate test to determine vaccine effectiveness and thus does not indicate or recommend it. Therefore, we do not recommend basing the decision to take the third COVID-19 dose off the results of a SARS-CoV-2 spike serology test. | with the help of our Scientific Advisory Board comprised of leading hematologists /oncologists from across Canada, created a brief report addressing important questions from patients related to COVID-19 and the vaccine, to provide guidance from the clinician and policy levels.#
In August 2021, provinces began to approve the administration of a third COVID-19 vaccine to individuals with two prior vaccinations. Provinces differ in their roll-out plan and eligibility criteria. For best guidance, please speak with your clinician to determine your eligibility and review your provinces roll-out plan for details on how to access the vaccine.
# Why might immunocompromised individuals need a third dose of the COVID-19 vaccine?
Immunocompromised individuals have a weakened immune system due to disease or treatment. Some immunocompromised individuals have a lower immune response to the COVID-19 vaccines compared to the general population [1][2][3][4][5][6][7][8][9][10] .
Recent studies show that some individuals who are moderately to severely immunocompromised who did not respond to or who had a reduced immune response after two doses of an mRNA vaccine may have an increased immune response after a third dose of an mRNA vaccine [11][12][13] . However, at this time research has not been published on the safety and efficacy of a third vaccine dose in lymphoma patients.
# How do I know if I am eligible to receive the third COVID-19 booster vaccine?
The National Advisory Committee on Immunization (NACI) released a guidance report regarding the additional dose of a COVID-19 vaccine in certain immunocompromised individuals following a 1-or 2-dose primary series. Based on research published on immunocompromised patients' response to the one or two vaccine doses [1][2][3][4][5][6][7][8][9][10] and the third vaccine dose [11][12][13] , NACI recommends the following:
1. For those who have not yet been immunized, moderately to severely immunocompromised* individuals in the authorized age groups should be immunized with a primary series of three doses of an authorized mRNA vaccine. V1 (21-Sept-2021) Lymphoma Canada Telephone: 905-858-5967 Toll-free: 1-866-659-5556 [email protected] 2. For those moderately to severely immunocompromised* individuals in the authorized age groups who have previously received a 1-or 2-dose complete primary series, including those who received a mixed vaccine schedule, should be offered an additional dose of an authorized mRNA COVID-19 vaccine.
• An additional dose of a viral vector vaccine should only be considered when other authorized COVID-19 vaccines are contraindicated or inaccessible. Informed consent for an additional dose of a viral vector vaccine should include discussion about the lack of evidence on the use of an additional dose of viral vector COVID-19 vaccine in this population.
Moderately to severely immunocompromised includes individuals with the following conditions:
• Active treatment for solid tumour or hematologic malignancies • Receipt of solid-organ transplant and taking immunosuppressive therapy • Receipt of chimeric antigen receptor (CAR)-T-cell therapy or hematopoietic stem cell transplant (within 2 years of transplantation or taking immunosuppression therapy) • Moderate to severe primary immunodeficiency (e.g., DiGeorge syndrome, Wiskott-Aldrich syndrome) • Stage 3 or advanced untreated HIV infection and those with acquired immunodeficiency syndrome • Active treatment with the following categories of immunosuppressive therapies: anti-B cell therapies (monoclonal antibodies targeting CD19, CD20 and CD22), high-dose systemic corticosteroids, alkylating agents, antimetabolites, or tumor-necrosis factor (TNF) inhibitors and other biologic agents that are significantly immunosuppressive.
Many provinces are adopting these recommendations, with specific eligibility criteria available through the province's phased or non-phased roll-out plan. There may be some differences between this list above and the criteria listed by the province. Please review your provinces recommendation and eligibility criteria related to the third vaccine dose through the links below:
# Nunavut
No public statement released yet on the 3 rd COVID-19 vaccine dose.
# Is the third COVID-19 vaccine right for me?
Lymphoma Canada recommends speaking with your doctor to determine if the third COVID-19 vaccine is best for you. This can depend on where you are with your treatment schedule as well as other health conditions. There are no specific criteria at this time based on lymphoma subtype, and as per eligibility criteria patients with a hematologic malignancy (which includes lymphoma) may be eligible to receive the third COVID-19 vaccine depending on your treatment.
# How do I book my third COVID-19 vaccine?
To book your third COVID-19 vaccine, please go to your province's website where there may be the option to either book your third dose online or through a hotline. You may be required to provide a letter of support from your clinician depending on the province. If your clinician has not sent you this letter directly, please contact your doctor to discuss your eligibility to receive the vaccine and receive a support letter. Bring this letter with you to your vaccine appointment, along with personal identification. Further details on what may be required for your vaccine appointment can be found through your province's website.
# Should patients receive an antibody test to assess their immune response to the previous vaccines before considering a third COVID-19 vaccine dose?
No. It is not possible to interpret from a SARS-CoV-2 spike serology test whether a patient is fully protected against COVID-19, as the immune response can be variable after both infection and vaccination. The antibody measurement may not necessarily be the best indicator of immunity. The Canadian Immunity Task Force also does not consider SARS-CoV-2 serology an appropriate test to determine vaccine effectiveness and thus does not indicate or recommend it. Therefore, we do not recommend basing the decision to take the third COVID-19 dose off the results of a SARS-CoV-2 spike serology test. | None | None |
0692072410d799cee28d239260528f6be45d6b27 | cma | None | A. Assessment and risk stratification 1. Is AF/AFL with rapid ventricular response a primary arrhythmia or secondary to medical causes? A. Rapid rate secondary to medical causes (usually in patients with pre-existing/permanent AF) e.g., sepsis, bleeding, PE, heart failure, ACS, etc.: - Investigate and treat underlying causes aggressively - Cardioversion may be harmful - Avoid aggressive rate control B. Primary arrhythmia, e.g., sudden onset of AF/AFL# Is the patient unstable?
- Instability due to acute primary AF/AFL is uncommon, except for AF with rapid ventricular pre-excitation (WPW):
- Hypotension: SBP 2 mm) on ECG despite therapy - Pulmonary edema: significant dyspnea, crackles, and hypoxia
- Treat unstable patient:
- Urgent electrical CV if onset 48 h
# Is it safe to cardiovert this patient with primary AF/AFL?
- When it is safe, rhythm control is usually preferable to rate control: patient quality of life, shorter length of stay, fewer hospital resources - It is safe to cardiovert if: A. The patient has been adequately anticoagulated for a minimum of 3 weeks, OR B. The patient is not adequately anticoagulated for > 3 weeks, has no history of stroke or TIA, AND does not have valvular heart disease, AND:
# Background and methods
The 2021 CAEP Acute Atrial Fibrillation/Flutter Best Practices Checklist has been updated from the original version published in 2018 . These checklists have been created to assist emergency physicians in Canada and elsewhere manage patients who present to the emergency department (ED) with acute/recent-onset atrial fibrillation (AF) or flutter (AFL). The checklist focuses on symptomatic patients with acute AF or AFL, i.e. those with recent-onset episodes (either first detected, recurrent paroxysmal or recurrent persistent episodes) where the onset is generally less than 48 h but may be as much as seven days. These are the most common acute arrhythmia cases requiring care in the ED. Canadian emergency physicians are known for publishing widely on this topic and for managing these patients quickly and efficiently in the ED . The 2018 Checklist project was funded by a research grant from the Cardiac Arrhythmia Network and the resultant guidelines were formally endorsed by the Canadian Association of Emergency Physicians (CAEP). We chose to adapt, for use by emergency physicians, existing high-quality clinical practice guidelines (CPG) previously developed by the Canadian Cardiovascular Society (CCS) . These CPGs were developed and revised using a rigorous process that is based on the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system of evaluation . With the assistance of our PhD methodologist (IG), we used the recently developed Canadian CAN-IMPLEMENT© process adapted from the ADAPTE Collaboration . We created an Advisory Committee consisting of ten academic emergency physicians (one also expert in thrombosis medicine), four community emergency physicians, three cardiologists, one PhD methodologist, and two patients. Our focus was four key elements of ED care: assessment and risk stratification, rhythm and rate control, short-term and longterm stroke prevention, and disposition and follow-up. The advisory committee communicated by face-to-face meetings, teleconferences, and email. The checklist was prepared and revised through a process of feedback and discussion on all issues by all panel members. These revisions went through ten iterations until consensus was achieved. We then circulated the draft checklist for comment to approximately 300 emergency medicine and cardiology colleagues. Finally, the CAEP Standards Committee posted the Checklist online for all CAEP members to provide feedback (Fig. 1).
Early in 2021 the same Checklist Advisory Committee reconvened (with one additional academic cardiologist) to discuss updates based upon new evidence , the 2018 and 2020 CCS guidelines , and several commentaries that had expressed the concern of the Canadian ED community . The Advisory Committee met twice virtually and reached consensus on updates through repeated email exchanges. The panelists then sought further feedback from their own colleagues in emergency medicine and cardiology. Finally, the 2021 Checklist was posted by CAEP for further member feedback prior to final approval. The panel continues to believe that, overall, a strategy of ED cardioversion and discharge home from the ED is preferable from both the patient and the healthcare system perspective, for most patients. Many notable revisions were incorporated, including:
- The safety of urgent cardioversion for acute AF/AFL depends upon anticoagulation status, prior stroke, valvular heart disease, time since onset, and CHADS criteria. Patients presenting between 12 and 48 h may only be cardioverted if they have 0 or 1 of the CHADS-65 crite-ria. We found that the CCS reference to CHADS 2 Scale problematic as most ED physicians no longer use that scale. 2. Anticoagulation for CHADS-65 positive patients should be initiated in the ED unless there are contradictions as per the "McMaster Checklist" created by Dr. de Wit. 3. We disagree with the CCS suggestion of 4 weeks of anticoagulation for patients who are CHADS-65 negative as this was a weak recommendation per the GRADE system, based upon low quality evidence. We suggest that oral anticoagulation might be considered for a 4-week period after careful consideration of risks and benefits and a shared decision-making process with the patient.
Our hope is that the 2021 CAEP Acute Atrial Fibrillation/Flutter Best Practices Checklist will standardize and improve care of AF and AFL in large and small EDs alike. We believe that these patients can be managed rapidly and safely, with early ED discharge and return to normal activities. from Boehringer Ingelheim, Bayer, Pfizer, and Servier. Dr. Tebbenham has received honoraria from Cardiome Pharma Corp. We thank the hundreds of Canadian emergency physicians and cardiologists who reviewed the draft guidelines and who provided very helpful feedback.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. | A. Assessment and risk stratification 1. Is AF/AFL with rapid ventricular response a primary arrhythmia or secondary to medical causes? A. Rapid rate secondary to medical causes (usually in patients with pre-existing/permanent AF) e.g., sepsis, bleeding, PE, heart failure, ACS, etc.: • Investigate and treat underlying causes aggressively • Cardioversion may be harmful • Avoid aggressive rate control B. Primary arrhythmia, e.g., sudden onset of AF/AFL# Is the patient unstable?
• Instability due to acute primary AF/AFL is uncommon, except for AF with rapid ventricular pre-excitation (WPW):
• Hypotension: SBP < 90 mmHg, or signs of shock (e.g., altered mental status) • Cardiac ischemia: ongoing severe chest pain or marked ST depression (> 2 mm) on ECG despite therapy • Pulmonary edema: significant dyspnea, crackles, and hypoxia
• Treat unstable patient:
• Urgent electrical CV if onset < 48 h or WPW • Consider trial of rate control if onset > 48 h
# Is it safe to cardiovert this patient with primary AF/AFL?
• When it is safe, rhythm control is usually preferable to rate control: patient quality of life, shorter length of stay, fewer hospital resources • It is safe to cardiovert if: A. The patient has been adequately anticoagulated for a minimum of 3 weeks, OR B. The patient is not adequately anticoagulated for > 3 weeks, has no history of stroke or TIA, AND does not have valvular heart disease, AND:
# Background and methods
The 2021 CAEP Acute Atrial Fibrillation/Flutter Best Practices Checklist has been updated from the original version published in 2018 [1]. These checklists have been created to assist emergency physicians in Canada and elsewhere manage patients who present to the emergency department (ED) with acute/recent-onset atrial fibrillation (AF) or flutter (AFL). The checklist focuses on symptomatic patients with acute AF or AFL, i.e. those with recent-onset episodes (either first detected, recurrent paroxysmal or recurrent persistent episodes) where the onset is generally less than 48 h but may be as much as seven days. These are the most common acute arrhythmia cases requiring care in the ED. Canadian emergency physicians are known for publishing widely on this topic and for managing these patients quickly and efficiently in the ED [2,3,4]. The 2018 Checklist project was funded by a research grant from the Cardiac Arrhythmia Network and the resultant guidelines were formally endorsed by the Canadian Association of Emergency Physicians (CAEP). We chose to adapt, for use by emergency physicians, existing high-quality clinical practice guidelines (CPG) previously developed by the Canadian Cardiovascular Society (CCS) [5][6][7]. These CPGs were developed and revised using a rigorous process that is based on the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system of evaluation [8]. With the assistance of our PhD methodologist (IG), we used the recently developed Canadian CAN-IMPLEMENT© process adapted from the ADAPTE Collaboration [9,10]. We created an Advisory Committee consisting of ten academic emergency physicians (one also expert in thrombosis medicine), four community emergency physicians, three cardiologists, one PhD methodologist, and two patients. Our focus was four key elements of ED care: assessment and risk stratification, rhythm and rate control, short-term and longterm stroke prevention, and disposition and follow-up. The advisory committee communicated by face-to-face meetings, teleconferences, and email. The checklist was prepared and revised through a process of feedback and discussion on all issues by all panel members. These revisions went through ten iterations until consensus was achieved. We then circulated the draft checklist for comment to approximately 300 emergency medicine and cardiology colleagues. Finally, the CAEP Standards Committee posted the Checklist online for all CAEP members to provide feedback (Fig. 1).
Early in 2021 the same Checklist Advisory Committee reconvened (with one additional academic cardiologist) to discuss updates based upon new evidence [3,4,11], the 2018 and 2020 CCS guidelines [12,13], and several commentaries that had expressed the concern of the Canadian ED community [14,15]. The Advisory Committee met twice virtually and reached consensus on updates through repeated email exchanges. The panelists then sought further feedback from their own colleagues in emergency medicine and cardiology. Finally, the 2021 Checklist was posted by CAEP for further member feedback prior to final approval. The panel continues to believe that, overall, a strategy of ED cardioversion and discharge home from the ED is preferable from both the patient and the healthcare system perspective, for most patients. Many notable revisions were incorporated, including:
1. The safety of urgent cardioversion for acute AF/AFL depends upon anticoagulation status, prior stroke, valvular heart disease, time since onset, and CHADS criteria. Patients presenting between 12 and 48 h may only be cardioverted if they have 0 or 1 of the CHADS-65 crite-ria. We found that the CCS reference to CHADS 2 Scale problematic as most ED physicians no longer use that scale. 2. Anticoagulation for CHADS-65 positive patients should be initiated in the ED unless there are contradictions as per the "McMaster Checklist" created by Dr. de Wit. 3. We disagree with the CCS suggestion of 4 weeks of anticoagulation for patients who are CHADS-65 negative as this was a weak recommendation per the GRADE system, based upon low quality evidence. We suggest that oral anticoagulation might be considered for a 4-week period after careful consideration of risks and benefits and a shared decision-making process with the patient.
Our hope is that the 2021 CAEP Acute Atrial Fibrillation/Flutter Best Practices Checklist will standardize and improve care of AF and AFL in large and small EDs alike. We believe that these patients can be managed rapidly and safely, with early ED discharge and return to normal activities. from Boehringer Ingelheim, Bayer, Pfizer, and Servier. Dr. Tebbenham has received honoraria from Cardiome Pharma Corp. We thank the hundreds of Canadian emergency physicians and cardiologists who reviewed the draft guidelines and who provided very helpful feedback.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/.
#
Acknowledgements Funding for this guideline was supported by the Cardiac Arrhythmia Network of Canada (CANet) as part of the Networks of Centres of Excellence (NCE). Dr. Stiell has received unrestricted research support from InCarda Therapeutics and Cipher Pharmaceuticals. Dr. Angaran has received research funding and/ or honoraria from BMS-Pfizer Alliance and Servier, Dr. DeWit has received research funding from Bayer. Dr. Deyell has received honoraria and research funding from Biosense Webster, Bayer, Bristol-Myers-Squibb, Abbott, and Servier. Dr. Skanes has received honoraria | None | None |
62bcca65ad15a7ba204468942500bc2e1b4924e2 | cma | None | In 2019, the GINA committee asserted what is arguably one of the most profound changes in the management of asthma in the last 30 years: treatment of asthma with short acting beta agonists (SABA) alone, taken as needed, is no longer recommended for adults and adolescents.
The present document aims to present the context of this change and discuss its potential applicability in the Canadian landscape in a question and answer format. A systematic review of the evidence is currently being undertaken by a CTS Asthma Guideline Panel and new CTS recommendations will be presented after completing a formal review.
The new GINA recommendations are summarized in the following boxes.
Adolescents (>12 years old) and adults:
- Treatment of asthma with SABA alone is not recommended 2. Patients with symptoms less than twice a month and no exacerbation risk factors (GINA Step 1): the preferred therapy is low-dose inhaled corticosteroid (ICS)-formoterol taken on a PRN basis for symptom relief. Other controller options include taking a low dose ICS inhaler whenever a SABA inhaler is taken (using separate or combination inhalers). 3. Patients with symptoms twice a month or more, or with risk factors for exacerbation (GINA Step 2): the recommended therapy is either daily low-dose ICS with as-needed SABA or low dose ICS-formoterol as needed. Other controller options include leukotriene receptor antagonists, or taking low dose ICS whenever a SABA inhaler is taken.
Children 6 to 11 years old:
- Patients with symptoms less than twice a month and no exacerbation risk factors (GINA Step 1): the recommended therapy is asneeded SABA. Other options to provide controller treatment are taking low-dose ICS inhaler whenever a SABA is taken, or daily low dose ICS with as-needed SABA 2. Children with symptoms twice a month or more, or with risk factors for exacerbations (GINA Step 2): the recommended therapy is daily low dose ICS with as-needed SABA. Other controller options are leukotriene receptor antagonist, or taking low dose ICS inhaler whenever a SABA inhaler is taken.
# Dr. Helen Reddel
Professor Reddel is a respiratory physician and research leader at the Woolcock Institute of Medical Research, University of Sydney, Australia. She is Chair of the Science Committee for Global Initiative for Asthma (GINA), Clinical Adviser to the Australian Center for Airways disease Monitoring (ACAM), and international co-chair of the large observational NOVELTY study. Dr. Reddel's current research interests focus on characterizing the clinical trajectories and the underlying mechanisms of airways disease, practical strategies to improve asthma management, and qualitative research about the experience of living with mild or severe asthma. She has a strong focus on improving communication between patients and health professionals, and on making guidelines not only evidence-based, but also practical and practice-centered.
# Questions and answers
The evidence base Q1: Dr. Reddel, could you summarize the context and evidence base that led to these major changes in the GINA 2019 Global Strategy?
A: SABAs have been first-line treatment for asthma since the 1950s, when asthma was considered a disease of bronchoconstriction. Its inflammatory nature was confirmed in the 1970s, and the risks of SABA-only treatment and of SABA overuse were documented in the 1980s-2000s following epidemics of asthma deaths. Low dose ICS improved symptom control and reduced the risk of severe exacerbations, even in patients with mild asthma; and in moderatesevere asthma, risk was further reduced by ICS-formoterol maintenance and reliever therapy. However, clinical guidelines continued to recommend that patients with infrequent, mild or short-lived asthma symptoms should be treated with SABA alone, and furthermore, adherence with ICS was known to be poor. It therefore seemed logical to GINA to investigate as-needed low dose ICS-formoterol alone for mild asthma, to reduce the risk of severe exacerbations without the need for daily treatment. In 2007, GINA members began applying for funding for such studies, submitting multiple protocols over subsequent years to manufacturers of ICSformoterol and other funding bodies, with approval finally obtained in 2014 for two large regulatory studies, SYGMA 1 and 2, that were published in 2018. 1,2 The evidence base for the GINA 2019 recommendations, published in April 2019, included extensive evidence about the risks of SABA-only treatment and SABA over-use, the SYGMA studies, 1,2 studies of as-needed low dose budesonide-formoterol for exercise-induced bronchoconstriction 3 and high dose budesonide-formoterol for acute severe asthma, 4,5 and three studies of ICS taken whenever SABA was taken. Further publications since then include two open-label studies of asneeded budesonide-formoterol 9,10 and an additional study of ICS whenever SABA is taken. 11 Q2: Recent publications, SYGMA 1 and 2, and Novel START, studied the use of budesonide-formoterol prn in mild asthma. However, it appears that GINA has recommended the use of budesonide-formoterol as a reliever across the entire spectrum of asthma severity. Can you clarify if this is what GINA has recommended, and discuss the rationale and evidence to support this?
A: We have become aware of a misunderstanding around this issue, and welcome the opportunity for clarification. Although GINA recommends as-needed ICS-formoterol as a preferred reliever across the whole spectrum of asthma severity, this does not apply to all patients in Steps 3-5. There, as stated in the GINA treatment figure and text since 2014, low dose ICS-formoterol is the reliever only for adult and adolescent patients prescribed maintenance and reliever therapy with low dose budesonideformoterol or beclometasone-formoterol. For patients prescribed other ICS-LABA combinations in Steps 3-5, their reliever is still SABA (as before), as there would be safety concerns about combining different LABAs. However, for such patients, clinicians should be alert to the potential for poor adherence, as this would leave the patient exposed to the risks of SABA-only treatment.
Q3: In the SYGMA trials, asthma control was better in patients on daily budesonide þ PRN terbutaline versus those on PRN budesonide/formoterol. Given these results and the safety of daily low dose ICS, why didn't GINA recommend daily ICS as the preferred controller option in those with persistent asthma (Step 2) and have PRN budesonide/formoterol as an "other controller option" in those with poor adherence to daily medication?
A: In recommending as-needed low dose ICS-formoterol as one of the two preferred controller options for Step 2, GINA placed high importance on the evidence from the two SYGMA studies ($8000 patients) that this strategy reduced the risk of severe exacerbations to a similar extent as maintenance ICS, without the need for daily treatment. 1,2 A lower importance was placed on the small, non-cumulative differences in standard measures of asthma symptom control (e.g. Asthma Control Questionnaire (ACQ-5) difference of $0.15 compared with the minimal clinically important difference of 0.5); and in pre-bronchodilator FEV 1 (difference $30mL). 1,2 The primary outcome measure in SYGMA 1 that had been agreed between the study Sponsor and the regulator, i.e. electronically-recorded well-controlled asthma weeks, was based on older concepts of asthma control, 12 had never been calculated from electronically recorded data, and is not feasible for use in clinical practice.
Q4: In the TREXA trial, which included children 6 to 18 years old, time to exacerbation was longer with daily beclomethasone þ PRN SABA in comparison to beclomethasone þ SABA PRN. In addition, there was no added benefit of ICS þ SABA PRN compared to SABA PRN as a reliever in those on daily ICS. Given the limited number of children 12-18 included in adult trials, do you feel that the evidence base supports the new GINA recommendations in children 12-18?
A: During the GINA discussions about mild asthma, no specific concerns were raised about children aged 12À <18 years. With maintenance and reliever therapy, the reduction in severe exacerbations among 1847 adolescents had been the same as for adult participants. 13 The SYGMA studies included 889 children aged 12À <18 years; data for this sub-population were presented at ATS 2019. The TREXA study 7 was much smaller, with 288 children aged 5-18 years randomized to four treatment arms. The outcomes in TREXA with as-needed ICS þ SABA cannot be assumed to be the same as with as-needed ICS-formoterol, because as-needed formoterol itself reduces the risk of severe exacerbations compared with as-needed SABA. 14 Q5: We acknowledge that the GINA report is not a guideline but rather an "integrated evidence-based strategy focusing on translation into clinical practice." Recommendations are framed, not as answers to isolated guideline questions, but as part of an integrated strategy to target GINA's goals of preventing asthma deaths and exacerbations, improving symptom control, its current understanding of underlying disease processes, human behavior, and implementation in clinical practice. Do you think that the GINA mandate gives the GINA committee greater latitude than a guideline panel to extend therapeutic recommendations to areas where the evidence base is not as strong?
A: We do not consider that GINA has greater latitude than a guideline panel to make recommendations that are not well supported by evidence. Three points should be considered here. First, national guidelines bodies themselves may be limited in the recommendations that they can make, because of lack of access to medications such as combination ICS-formoterol and/ or local restrictions on making off-label recommendations. Each country and jurisdiction should determine at a local level the options best suited to their resources, needs and context.
Second, the primary recommendation by GINA was that, for safety, SABA-only treatment of asthma in adolescents and adults was no longer recommended. 15 Potential therapeutic strategies for avoiding SABA-only treatment were then considered, and those with the highest quality evidence, and the strongest values and preferences, were recommended for "Preferred controller." However, GINA was aware that some countries or jurisdictions did not have access to low-dose ICS-formoterol, so we listed alternative strategies for avoiding SABA-only treatment (e.g. asneeded ICS þ SABA) for which there was some evidence, albeit less substantial and/or lower in quality. These options were labeled as "Other controller options." The categories "Preferred controller" and "Other controller options," respectively, correspond to GRADE's "recommended" and "suggested" therapies. 16 Third, for Step 1 options, i.e. for patients with symptoms less than twice a month and no risk factors for exacerbations, GINA placed a lower value on the fact that all evidence was indirect (from studies in patients eligible for Step 2 studies), and placed a high value on the fact that patients with such infrequent symptoms could have serious exacerbations but would be unlikely to take regular ICS if prescribed. A high value was also placed on the priority to avoid conflicting messages about SABAs for patients and clinicians between Step 1 and Step 2. 15 Implementation challenges Q6: GINA cites poor adherence to daily low-dose ICS as a rationale for recommending ICS-formoterol as needed as an equivalent option to daily low dose ICS in mild asthma. One concern with the ICS-formoterol as needed recommendation is that it reinforces the patient belief that asthma medication is needed only when you have symptoms which may be contrary to the provider perspective that a patient with minimal symptoms but at high risk for exacerbations, or with poor pulmonary function should take daily medication. How would you address this practitioner concern?
A: This issue is currently a major problem for guidelines that start treatment with SABA alone. There, the initial conversation is about symptom relief, for which patients quickly find SABA to be very satisfactory. However, later on, the message has to be switched to tell patients that they need to take regular daily treatment even when they have no symptoms, and the rationale that is given is to reduce their use of (the familiar and effective) SABA and to reduce their risk of exacerbations. Instead, with asneeded ICS-formoterol in mild asthma, the message to patients from the start of treatment is that this therapy will both relieve their symptoms and reduce their risk of severe exacerbations.
# Q7:
In Canada, there is only one combination therapy that has been approved by Health Canada as a controller and reliever: budesonide-formoterol. The other available combination therapy containing a fast acting LABA is the combination of mometasone and formoterol which has not been approved for use as a reliever. Do you think the use of mometasone/formoterol could be an alternative to the use of budesonide/formoterol as a reliever?
A: The dosage of mometasone-formoterol in the Product Information is 2 inhalations on each occasion (total 10mcg formoterol), so the formoterol dose would escalate rapidly with as-needed use. This is presumably why mometasone-formoterol has not been studied for maintenance and reliever therapy, although I understand that it is prescribed by some Canadian physicians with 1 inhalation per as-needed dose. A case could be made in Canada for a pragmatic study of as-needed mometasone-formoterol in mild asthma, one inhalation at a time, in order to have a second option for mild asthma. However, the pathway to a regulatory indication would be challenging.
# Q8:
In patients who are already taking another type of combination therapy, for example, fluticasone/salmeterol as a daily controller medication with SABA as needed, does GINA recommend that patients: a. continue fluticasone/salmeterol as a daily controller medication with SABA as needed if they are achieving symptom and exacerbation control; or b. continue to use fluticasone/salmeterol as a daily controller medication but change to ICS-formoterol as needed; or c. switch to an ICS-formoterol combination as a controller and reliever?
A: This question relates to patients currently prescribed Step 3-5 treatment with maintenance ICS-LABA plus as-needed SABA. As described above in Q2, option (b) is definitely NOT recommended, as there would be concerns about the safety of using two different LABAs. Options (a) and (c) can be presented for shared decision-making with the patient, based on the patient's clinical context (including exacerbations in the previous 12 months, which would favor (c)), risk factors including environmental exposures, comorbidities, ability to use the inhalers, cost, and patient preference.
Health policy and planning Q9: The recommendation to use ICS-formoterol as a reliever without a daily controller medication is currently off label for all of the available medications in Canada. This will create prescription and reimbursement challenges. What is the GINA perspective on making a recommendation for medication to be used in a way that has not yet been approved by national health authorities such as Health Canada?
(NOTE: budesonide/formoterol received approval in Canada as an anti-inflammatory reliever therapy on September 25, 2019 after this question was proposed to Dr. Reddel.)
A: The GINA Science Committee and Board held extensive discussions before deciding to make recommendations for mild asthma, knowing that some would, at least initially, be off-label in countries that had a regulatory framework for pharmacotherapy. A similar situation had been encountered in 2018 with long-term macrolides for moderate-severe asthma.
Then, GINA had decided that, if a new indication for an existing treatment was supported by good quality evidence, and if there were no new safety concerns, we would be prepared to make an off-label recommendation. For mild asthma, the driving factor was that GINA was no longer prepared to actively recommend a treatment (SABA-alone) that was associated globally with significant risk of mortality and morbidity, now that evidence was available for efficacious alternatives. Further considerations were that regulators looked to guidelines bodies for a clinical perspective on new treatment options (so each may be waiting for the other), and that a GINA recommendation might encourage manufacturers to make a regulatory submission. Q10: Given that there is only one ICS-formoterol drug approved for use in Canada as a reliever, this may create an impression of commercial bias. Can you address this concern for Canadian providers? A: As above in Q7, this situation already exists in Canada for maintenance and reliever therapy. For mild asthma, resources that may be useful to counter this perception include an editorial published in Eur Respir J 15 describing the multiple agencies that were approached, and the length of time that it took, before GINA members were successful in having the clinical trials funded; and the detailed description on the GINA website of how issues of potential conflict of interest are handled (available from /). Q11: Budesonide-formoterol as needed is almost 4 times the price of a SABA. Is there data to suggest that the switch to asneeded low-dose ICS-formoterol as the preferred reliever is cost-effective?
A: In each country, the cost to the health system and to patients (including the direct and indirect cost of exacerbations) will be important factors for consideration, depending on the price points agreed by payers. Cost-effectiveness analyses were incorporated into three of the four RCTs of as-needed budesonide-formoterol, and some of these results will be available soon.
# Safety
Q12: Are there concerns for potential risks or side effects, such as linear growth impairment or adrenal suppression with the use of an ICS each time a reliever is given, particularly for patients who are already on a daily high dose of ICS?
A: With maintenance and reliever therapy, risk of corticosteroid side-effects appears lower than with conventional maintenance therapy plus as-needed SABA, because the risk of exacerbations requiring OCS is the same or lower, and this outcome is achieved at the same or lower dose of ICS. 17 In the one maintenance and reliever study that included children, this regimen was associated with less adrenal suppression and greater linear growth compared with maintenance low dose ICS. 18 In the TREXA study, linear growth was greater in children 5-18 years randomized to asneeded ICS þ SABA or to SABA alone than to either of the maintenance low dose ICS regimens. 7 In the SYGMA 1 and SYGMA 2 studies in mild asthma, the median daily ICS dose with as-needed budesonide-formoterol was 57 mcg and 66 mcg/ day, respectively, 1,2 suggesting that the risk of adverse effects of corticosteroids would be extremely low.
Where you can find more information?
The GINA report and updated PowerPoint slide deck can be downloaded from / An editorial in European Respiratory Journal, explains the history and rationale for the key 2019 changes in mild asthma. This article is available on open access as follows:
Reddel New CTS recommendations will be posted on / as soon as they are available.
# ORCID
Dhenuka Radhakrishnan | #
In 2019, the GINA committee asserted what is arguably one of the most profound changes in the management of asthma in the last 30 years: treatment of asthma with short acting beta agonists (SABA) alone, taken as needed, is no longer recommended for adults and adolescents.
The present document aims to present the context of this change and discuss its potential applicability in the Canadian landscape in a question and answer format. A systematic review of the evidence is currently being undertaken by a CTS Asthma Guideline Panel and new CTS recommendations will be presented after completing a formal review.
The new GINA recommendations are summarized in the following boxes.
Adolescents (>12 years old) and adults:
1. Treatment of asthma with SABA alone is not recommended 2. Patients with symptoms less than twice a month and no exacerbation risk factors (GINA Step 1): the preferred therapy is low-dose inhaled corticosteroid (ICS)-formoterol taken on a PRN basis for symptom relief. Other controller options include taking a low dose ICS inhaler whenever a SABA inhaler is taken (using separate or combination inhalers). 3. Patients with symptoms twice a month or more, or with risk factors for exacerbation (GINA Step 2): the recommended therapy is either daily low-dose ICS with as-needed SABA or low dose ICS-formoterol as needed. Other controller options include leukotriene receptor antagonists, or taking low dose ICS whenever a SABA inhaler is taken.
Children 6 to 11 years old:
1. Patients with symptoms less than twice a month and no exacerbation risk factors (GINA Step 1): the recommended therapy is asneeded SABA. Other options to provide controller treatment are taking low-dose ICS inhaler whenever a SABA is taken, or daily low dose ICS with as-needed SABA 2. Children with symptoms twice a month or more, or with risk factors for exacerbations (GINA Step 2): the recommended therapy is daily low dose ICS with as-needed SABA. Other controller options are leukotriene receptor antagonist, or taking low dose ICS inhaler whenever a SABA inhaler is taken.
# Dr. Helen Reddel
Professor Reddel is a respiratory physician and research leader at the Woolcock Institute of Medical Research, University of Sydney, Australia. She is Chair of the Science Committee for Global Initiative for Asthma (GINA), Clinical Adviser to the Australian Center for Airways disease Monitoring (ACAM), and international co-chair of the large observational NOVELTY study. Dr. Reddel's current research interests focus on characterizing the clinical trajectories and the underlying mechanisms of airways disease, practical strategies to improve asthma management, and qualitative research about the experience of living with mild or severe asthma. She has a strong focus on improving communication between patients and health professionals, and on making guidelines not only evidence-based, but also practical and practice-centered.
# Questions and answers
The evidence base Q1: Dr. Reddel, could you summarize the context and evidence base that led to these major changes in the GINA 2019 Global Strategy?
A: SABAs have been first-line treatment for asthma since the 1950s, when asthma was considered a disease of bronchoconstriction. Its inflammatory nature was confirmed in the 1970s, and the risks of SABA-only treatment and of SABA overuse were documented in the 1980s-2000s following epidemics of asthma deaths. Low dose ICS improved symptom control and reduced the risk of severe exacerbations, even in patients with mild asthma; and in moderatesevere asthma, risk was further reduced by ICS-formoterol maintenance and reliever therapy. However, clinical guidelines continued to recommend that patients with infrequent, mild or short-lived asthma symptoms should be treated with SABA alone, and furthermore, adherence with ICS was known to be poor. It therefore seemed logical to GINA to investigate as-needed low dose ICS-formoterol alone for mild asthma, to reduce the risk of severe exacerbations without the need for daily treatment. In 2007, GINA members began applying for funding for such studies, submitting multiple protocols over subsequent years to manufacturers of ICSformoterol and other funding bodies, with approval finally obtained in 2014 for two large regulatory studies, SYGMA 1 and 2, that were published in 2018. 1,2 The evidence base for the GINA 2019 recommendations, published in April 2019, included extensive evidence about the risks of SABA-only treatment and SABA over-use, the SYGMA studies, 1,2 studies of as-needed low dose budesonide-formoterol for exercise-induced bronchoconstriction 3 and high dose budesonide-formoterol for acute severe asthma, 4,5 and three studies of ICS taken whenever SABA was taken. [6][7][8] Further publications since then include two open-label studies of asneeded budesonide-formoterol 9,10 and an additional study of ICS whenever SABA is taken. 11 Q2: Recent publications, SYGMA 1 and 2, and Novel START, studied the use of budesonide-formoterol prn in mild asthma. However, it appears that GINA has recommended the use of budesonide-formoterol as a reliever across the entire spectrum of asthma severity. Can you clarify if this is what GINA has recommended, and discuss the rationale and evidence to support this?
A: We have become aware of a misunderstanding around this issue, and welcome the opportunity for clarification. Although GINA recommends as-needed ICS-formoterol as a preferred reliever across the whole spectrum of asthma severity, this does not apply to all patients in Steps 3-5. There, as stated in the GINA treatment figure and text since 2014, low dose ICS-formoterol is the reliever only for adult and adolescent patients prescribed maintenance and reliever therapy with low dose budesonideformoterol or beclometasone-formoterol. For patients prescribed other ICS-LABA combinations in Steps 3-5, their reliever is still SABA (as before), as there would be safety concerns about combining different LABAs. However, for such patients, clinicians should be alert to the potential for poor adherence, as this would leave the patient exposed to the risks of SABA-only treatment.
Q3: In the SYGMA trials, asthma control was better in patients on daily budesonide þ PRN terbutaline versus those on PRN budesonide/formoterol. Given these results and the safety of daily low dose ICS, why didn't GINA recommend daily ICS as the preferred controller option in those with persistent asthma (Step 2) and have PRN budesonide/formoterol as an "other controller option" in those with poor adherence to daily medication?
A: In recommending as-needed low dose ICS-formoterol as one of the two preferred controller options for Step 2, GINA placed high importance on the evidence from the two SYGMA studies ($8000 patients) that this strategy reduced the risk of severe exacerbations to a similar extent as maintenance ICS, without the need for daily treatment. 1,2 A lower importance was placed on the small, non-cumulative differences in standard measures of asthma symptom control (e.g. Asthma Control Questionnaire (ACQ-5) difference of $0.15 compared with the minimal clinically important difference of 0.5); and in pre-bronchodilator FEV 1 (difference $30mL). 1,2 The primary outcome measure in SYGMA 1 that had been agreed between the study Sponsor and the regulator, i.e. electronically-recorded well-controlled asthma weeks, was based on older concepts of asthma control, 12 had never been calculated from electronically recorded data, and is not feasible for use in clinical practice.
Q4: In the TREXA trial, which included children 6 to 18 years old, time to exacerbation was longer with daily beclomethasone þ PRN SABA in comparison to beclomethasone þ SABA PRN. In addition, there was no added benefit of ICS þ SABA PRN compared to SABA PRN as a reliever in those on daily ICS. Given the limited number of children 12-18 included in adult trials, do you feel that the evidence base supports the new GINA recommendations in children 12-18?
A: During the GINA discussions about mild asthma, no specific concerns were raised about children aged 12À <18 years. With maintenance and reliever therapy, the reduction in severe exacerbations among 1847 adolescents had been the same as for adult participants. 13 The SYGMA studies included 889 children aged 12À <18 years; data for this sub-population were presented at ATS 2019. The TREXA study 7 was much smaller, with 288 children aged 5-18 years randomized to four treatment arms. The outcomes in TREXA with as-needed ICS þ SABA cannot be assumed to be the same as with as-needed ICS-formoterol, because as-needed formoterol itself reduces the risk of severe exacerbations compared with as-needed SABA. 14 Q5: We acknowledge that the GINA report is not a guideline but rather an "integrated evidence-based strategy focusing on translation into clinical practice." Recommendations are framed, not as answers to isolated guideline questions, but as part of an integrated strategy to target GINA's goals of preventing asthma deaths and exacerbations, improving symptom control, its current understanding of underlying disease processes, human behavior, and implementation in clinical practice. Do you think that the GINA mandate gives the GINA committee greater latitude than a guideline panel to extend therapeutic recommendations to areas where the evidence base is not as strong?
A: We do not consider that GINA has greater latitude than a guideline panel to make recommendations that are not well supported by evidence. Three points should be considered here. First, national guidelines bodies themselves may be limited in the recommendations that they can make, because of lack of access to medications such as combination ICS-formoterol and/ or local restrictions on making off-label recommendations. Each country and jurisdiction should determine at a local level the options best suited to their resources, needs and context.
Second, the primary recommendation by GINA was that, for safety, SABA-only treatment of asthma in adolescents and adults was no longer recommended. 15 Potential therapeutic strategies for avoiding SABA-only treatment were then considered, and those with the highest quality evidence, and the strongest values and preferences, were recommended for "Preferred controller." However, GINA was aware that some countries or jurisdictions did not have access to low-dose ICS-formoterol, so we listed alternative strategies for avoiding SABA-only treatment (e.g. asneeded ICS þ SABA) for which there was some evidence, albeit less substantial and/or lower in quality. These options were labeled as "Other [i.e. non-preferred] controller options." The categories "Preferred controller" and "Other controller options," respectively, correspond to GRADE's "recommended" and "suggested" therapies. 16 Third, for Step 1 options, i.e. for patients with symptoms less than twice a month and no risk factors for exacerbations, GINA placed a lower value on the fact that all evidence was indirect (from studies in patients eligible for Step 2 studies), and placed a high value on the fact that patients with such infrequent symptoms could have serious exacerbations but would be unlikely to take regular ICS if prescribed. A high value was also placed on the priority to avoid conflicting messages about SABAs for patients and clinicians between Step 1 and Step 2. 15 Implementation challenges Q6: GINA cites poor adherence to daily low-dose ICS as a rationale for recommending ICS-formoterol as needed as an equivalent option to daily low dose ICS in mild asthma. One concern with the ICS-formoterol as needed recommendation is that it reinforces the patient belief that asthma medication is needed only when you have symptoms which may be contrary to the provider perspective that a patient with minimal symptoms but at high risk for exacerbations, or with poor pulmonary function should take daily medication. How would you address this practitioner concern?
A: This issue is currently a major problem for guidelines that start treatment with SABA alone. There, the initial conversation is about symptom relief, for which patients quickly find SABA to be very satisfactory. However, later on, the message has to be switched to tell patients that they need to take regular daily treatment even when they have no symptoms, and the rationale that is given is to reduce their use of (the familiar and effective) SABA and to reduce their risk of exacerbations. Instead, with asneeded ICS-formoterol in mild asthma, the message to patients from the start of treatment is that this therapy will both relieve their symptoms and reduce their risk of severe exacerbations.
# Q7:
In Canada, there is only one combination therapy that has been approved by Health Canada as a controller and reliever: budesonide-formoterol. The other available combination therapy containing a fast acting LABA is the combination of mometasone and formoterol which has not been approved for use as a reliever. Do you think the use of mometasone/formoterol could be an alternative to the use of budesonide/formoterol as a reliever?
A: The dosage of mometasone-formoterol in the Product Information is 2 inhalations on each occasion (total 10mcg formoterol), so the formoterol dose would escalate rapidly with as-needed use. This is presumably why mometasone-formoterol has not been studied for maintenance and reliever therapy, although I understand that it is prescribed by some Canadian physicians with 1 inhalation per as-needed dose. A case could be made in Canada for a pragmatic study of as-needed mometasone-formoterol in mild asthma, one inhalation at a time, in order to have a second option for mild asthma. However, the pathway to a regulatory indication would be challenging.
# Q8:
In patients who are already taking another type of combination therapy, for example, fluticasone/salmeterol as a daily controller medication with SABA as needed, does GINA recommend that patients: a. continue fluticasone/salmeterol as a daily controller medication with SABA as needed if they are achieving symptom and exacerbation control; or b. continue to use fluticasone/salmeterol as a daily controller medication but change to ICS-formoterol as needed; or c. switch to an ICS-formoterol combination as a controller and reliever?
A: This question relates to patients currently prescribed Step 3-5 treatment with maintenance ICS-LABA plus as-needed SABA. As described above in Q2, option (b) is definitely NOT recommended, as there would be concerns about the safety of using two different LABAs. Options (a) and (c) can be presented for shared decision-making with the patient, based on the patient's clinical context (including exacerbations in the previous 12 months, which would favor (c)), risk factors including environmental exposures, comorbidities, ability to use the inhalers, cost, and patient preference.
Health policy and planning Q9: The recommendation to use ICS-formoterol as a reliever without a daily controller medication is currently off label for all of the available medications in Canada. This will create prescription and reimbursement challenges. What is the GINA perspective on making a recommendation for medication to be used in a way that has not yet been approved by national health authorities such as Health Canada?
(NOTE: budesonide/formoterol received approval in Canada as an anti-inflammatory reliever therapy on September 25, 2019 after this question was proposed to Dr. Reddel.)
A: The GINA Science Committee and Board held extensive discussions before deciding to make recommendations for mild asthma, knowing that some would, at least initially, be off-label in countries that had a regulatory framework for pharmacotherapy. A similar situation had been encountered in 2018 with long-term macrolides for moderate-severe asthma.
Then, GINA had decided that, if a new indication for an existing treatment was supported by good quality evidence, and if there were no new safety concerns, we would be prepared to make an off-label recommendation. For mild asthma, the driving factor was that GINA was no longer prepared to actively recommend a treatment (SABA-alone) that was associated globally with significant risk of mortality and morbidity, now that evidence was available for efficacious alternatives. Further considerations were that regulators looked to guidelines bodies for a clinical perspective on new treatment options (so each may be waiting for the other), and that a GINA recommendation might encourage manufacturers to make a regulatory submission. Q10: Given that there is only one ICS-formoterol drug approved for use in Canada as a reliever, this may create an impression of commercial bias. Can you address this concern for Canadian providers? A: As above in Q7, this situation already exists in Canada for maintenance and reliever therapy. For mild asthma, resources that may be useful to counter this perception include an editorial published in Eur Respir J 15 describing the multiple agencies that were approached, and the length of time that it took, before GINA members were successful in having the clinical trials funded; and the detailed description on the GINA website of how issues of potential conflict of interest are handled (available from https://ginasthma.org/about-us/methodology/). Q11: Budesonide-formoterol as needed is almost 4 times the price of a SABA. Is there data to suggest that the switch to asneeded low-dose ICS-formoterol as the preferred reliever is cost-effective?
A: In each country, the cost to the health system and to patients (including the direct and indirect cost of exacerbations) will be important factors for consideration, depending on the price points agreed by payers. Cost-effectiveness analyses were incorporated into three of the four RCTs of as-needed budesonide-formoterol, and some of these results will be available soon.
# Safety
Q12: Are there concerns for potential risks or side effects, such as linear growth impairment or adrenal suppression with the use of an ICS each time a reliever is given, particularly for patients who are already on a daily high dose of ICS?
A: With maintenance and reliever therapy, risk of corticosteroid side-effects appears lower than with conventional maintenance therapy plus as-needed SABA, because the risk of exacerbations requiring OCS is the same or lower, and this outcome is achieved at the same or lower dose of ICS. 17 In the one maintenance and reliever study that included children, this regimen was associated with less adrenal suppression and greater linear growth compared with maintenance low dose ICS. 18 In the TREXA study, linear growth was greater in children 5-18 years randomized to asneeded ICS þ SABA or to SABA alone than to either of the maintenance low dose ICS regimens. 7 In the SYGMA 1 and SYGMA 2 studies in mild asthma, the median daily ICS dose with as-needed budesonide-formoterol was 57 mcg and 66 mcg/ day, respectively, 1,2 suggesting that the risk of adverse effects of corticosteroids would be extremely low.
Where you can find more information?
The GINA report and updated PowerPoint slide deck can be downloaded from https://ginasthma.org/reports/ An editorial in European Respiratory Journal, explains the history and rationale for the key 2019 changes in mild asthma. This article is available on open access as follows:
Reddel New CTS recommendations will be posted on https://ctssct.ca/ as soon as they are available.
# ORCID
Dhenuka Radhakrishnan http://orcid.org/0000-0002-8637-1480 | None | None |
fc4c777ef2d84d1c3fc3c4d5924908fc45de35dd | cma | None | v. Biopsy is an option as part of active observation or prior to ablative therapy vi. Optional Tests: a. CT chest if T2 or T3 b. Bone scan if T2 or T3 or alkaline phosphatase is elevated c. FDG PET/CT imaging is not currently recommended or indicated as part of staging for RCC. B. Therapeutic Options i. Active Surveillance is an appropriate option for the small renal mass (less than 4 cm) in all patients: a. Active surveillance is the preferred option for elderly, frail, and/or highly comorbid patients with a small renal mass that is 4cm or smaller b. Active surveillance is the preferred option for a small renal mass that is 2cm or smaller c. Biopsy is an option if it would alter management. d. Repeat imaging every 6 months. e. Intervention is indicated if there is progression. ii. Surgical Intervention 1, 2 a. Partial nephrectomy should be considered in all cases where surgery is being considered especially small renal masses less than 4cm. This can be done either as an open, laparoscopic, or robotic-assisted laparoscopic procedure, although a minimally invasive partial nephrectomy should be favored when safe, technically feasible and oncologically sound. b. If partial nephrectomy is not feasible, consider minimally-invasive radical nephrectomy. c. If a minimally-invasive surgical procedure cannot be performed due to patient or tumor characteristics, then an open nephrectomy should be done. d. The adrenal gland should not be removed unless involved on imaging. iii. Percutaneous ablation a. Both radiofrequency ablation (RFA) and cryoablation are possible treatments for the small renal mass . However, this treatment decision should only be made after consultation with a urologist and discussed at multidisciplinary rounds. C. Adjuvant Therapy i. Adjuvant therapy using checkpoint inhibitors has demonstrated some discrepant results with only 1 of 4 trials being positive for the primary endpoint of DFS although OS results are immature. While adjuvant therapy has Health Canada approval, a comprehensive discussion is strongly suggested with each patient before recommending this treatment. a. Adjuvant pembrolizumab can be considered for patients with completely resected clear cell renal cell carcinoma and any of the following features: i. stage pT2 and grade 4 or sarcomatoid features ii. stage pT3-4 N0 iii. Any T-stage with N+ disease iv. M1 NED (i.e. complete metastasectomy within one year of nephrectomy)# Background
In 2022, it is estimated that 8100 Canadians (5400 men and 2700 women) were diagnosed with kidney and renal pelvis cancer, and that 1300 Canadians will died from kidney and renal pelvis cancer .
Renal cell carcinoma (RCC) is the main focus of this guideline. The most common subtype of renal cell carcinoma is clear cell RCC, followed by papillary and chromophobe tumours. Staging of renal cell carcinoma is currently based on the 8th edition (2017) of the American Joint Committee on Cancer's AJCC Cancer Staging Manual (see Appendix).
Guideline Questions 1. What are the appropriate diagnostic tests for renal cell carcinoma? 2. How should renal cell carcinoma be managed (i.e., surgically)? 3. What is the role of systemic therapy and radiotherapy in the management of renal cell carcinoma? 4. Are there other therapies that have shown benefit for patients with renal cell carcinoma? 5. What are the appropriate follow up strategies for renal cell carcinoma?
# Search Strategy
Phase III trials involving 'renal cell carcinoma' that had been published since the last iteration of the guideline were identified and reviewed using the pubmed database. The results of the literature review are available upon request ([email protected]).
# Target Population
Adult patients (≥18 years of age) with a diagnosis, or suspected diagnosis of renal cell carcinoma.
# Recommendations
Stage T1-3, N+/-M0, Indications include imaging suspicious for primary renal malignancy localized to the kidney or immediate surrounding structures. ii. Adjuvant therapy using anti-angiogenic therapies is currently not recommended post definitive management of renal cell carcinoma .
# D. Follow-up
Follow up is based on the recommendations of the Canadian Urological Association (CUA) as published on the CUA website (/) and the CUA Journal (CUAJ) in 2018 10 , and is stage dependent:
(pT1) Hx & PE X X X X X Blood Test X X X X X CXR X X X X X CT or U/S abdomen X X Intermediate Risk (pT2) Hx & PE X X X X X X X X Blood Test X X X X X X X X CXR X X X X X X X X CT or U/S abdomen X X X X High Risk (pT3-4)- Hx & PE X X X X X X X X Blood Test X X X X X X X X CXR X X X X X X X X CT abdomen X X X X X X Very High Risk (pTxN+)- Hx & PE X X X X X X X X X Blood Test X X X X X X X X X CXR X X X X X X X X X CT abdomen X X X X X X X X X
*For High-and Very High-risk patients, consider an extended individualized follow up beyond 60 months.
Stage T4N0M0, cTxN1Mx, TxNxM+ 11 Indications for systemic therapy include locally advanced, unresectable cancer or metastatic disease. The International mRCC Database Consortium (IMDC) risk factors (hypercalcemia, neutrophilia, thrombocytosis, anemia, Karnofsky performance status <80%, and time from diagnosis to treatment <1 year) are used to stratify patients into 3 risk groups. Patients with 0 factors vs. 1-2 factors vs. 3 or more factors are deemed favorable, intermediate, and poor-risk, respectively. 12 An online calculator is available at /.
# Management 13
A. Staging i. CT scan of head, chest, abdomen, pelvis with contrast (or MRI) ii. CBC, creatinine, urea, calcium, albumin, AST, ALT, ALP, bilirubin and TSH.
iii. If an IO is being considered additional targeted bloodwork can be requested at baseline if concerns regarding anticipated auto-immune toxicity from checkpoint inhibitors (eg: a.m. cortisol, lipase, T3, T4, creatine kinase, glucose etc). iv. Other additional imaging modalities can be considered as clinically indicated (bone scan, MRI) v. FDG-PET/CT is not recommended in this setting
# First-line Therapies
Favorable-Risk:
A. Pembrolizumab/Axitinib (Pembro/Axi) 14 i. Indication: a. First-line therapy for advanced RCC based on phase III data.
ii. Dose and Schedule: a. Pembrolizumab at 2mg/kg (capped at 200mg) intravenously once every 3 weeks plus axitinib 5mg orally twice daily. b. Pembrolizumab is given for a maximum of 35 consecutive cycles (~ 2 years). There is no recommended dose adjustment for pembrolizumab. c. Axitinib should be dose adjusted to maximum treatment tolerance by titrating dose higher or lower (maximum 10 mg po twice daily and minimum 1 mg po twice daily). d. Treatment is generally given until disease progression, intolerance or patient decision provided the caveats regarding number of total cycles of pembrolizumab.
iii. Toxicity: a. Physicians must be aware of the toxicity profile of pembrolizumab and axitinib and the potential overlapping toxicities. As a general rule, axitinib-induced toxicity would be expected to improve quickly with cessation of therapy, whereas an immune mediated adverse event (irAE) would not improve after stopping axitinib. b. It is important to have early recognition of irAEs that require prompt intervention with immunosuppressing agents (eg: high dose steroids). Colitis (diarrhea), pneumonitis, endocrinopathies (hypophysitis, hypothyroidism, adrenal insufficiency), hepatitis and rash are some examples. Patients should be educated about these toxicities and followed every cycle to look for these adverse events. c. Lenvatinib should be dose adjusted to maximum treatment tolerance by titrating dose higher or lower (maximum 10 mg po twice daily and minimum 1 mg po twice daily). d. Treatment is generally given until disease progression, intolerance or patient decision provided the caveats regarding number of total cycles of pembrolizumab.
iii. Toxicity: a. Physicians must be aware of the toxicity profile of pembrolizumab and lenvatinib and the potential overlapping toxicities. As a general rule, lenvatinib-induced toxicity would be expected to improve quickly with cessation of therapy, whereas an immune mediated adverse event (irAE) would not improve after stopping lenvatinib. ii. Dose and Schedule: a. A starting dose at 50 mg/day orally for 4 weeks followed by a 2-week rest period for a 6-week treatment cycle is indicated in the product monograph. However, an individualized schedule optimizing the therapeutic ratio with anywhere from 1-4 weeks on therapy followed by a 1-week break as determined by treatment tolerance is recommended b. Treatment is given until disease progression, intolerance or patient decision.
iii. Toxicity: a. Physicians must be aware of the toxicity profile of sunitinib and follow patients accordingly with experienced nursing support. Patients should be assessed regularly for treatment tolerance. b. Sunitinib should be dosed to maximum treatment tolerance as there is evidence that higher AUC leads to higher response rates. c. Cardiotoxicity has become an issue and in patients with pre-existing compromised cardiac function. Monitoring of ejection fraction should be considered in high risk or symptomatic patients but routine monitoring in all patients is not indicated. ii. Dose and schedule a. A starting dose 800 mg/day orally taken on a continuous basis is indicated in the product monograph. However, an individualized schedule optimizing the therapeutic ratio with anywhere from 1-4 weeks on therapy followed by a 1-week break as determined by treatment tolerance is recommended. b. Treatment is given until disease progression, intolerance or patient decision.
iii. Toxicity: a. Physicians must be aware of the toxicity profile of pazopanib and follow patients accordingly with experienced nursing support. Patients should be assessed regularly for treatment tolerance. b. Pazopanib should be dosed to maximum treatment tolerance as there is evidence that higher AUC leads to higher response rates. c. Liver enzymes and bilirubin should be frequently measured (at least once every two weeks initially) as they are elevated with this drug more frequently than with other VEGFR-TKIs. d. The COMPARZ and PISCES trial reported safety and quality-of-life profiles may favor pazopanib when compared to sunitinib. ii. Dose and Schedule a. Nivolumab at 3 mg/kg (capped at 240 mg) and Ipilimumab at 1 mg/kg both given intravenously every three weeks for four cycles. This is followed by nivolumab only as maintenance therapy at 3mg/kg (capped at 240mg) every 2 weeks or 6 mg/kg (capped at 480 mg) intravenously every 4 weeks. The maintenance schedule is determined at discretion of the physician and patient. Maintenance treatment can begin anywhere from 4-6 weeks after last dose of ipi/nivo assuming patient is benefiting from treatment. b. Treatment is given until disease progression, intolerance or patient decision.
iii. Toxicity a. It is important to have early recognition of immune mediated adverse events that require prompt intervention with high dose steroids. Colitis (diarrhea), pneumonitis, endocrinopathies (hypophysitis, hypothyroidism, adrenal insufficiency), hepatitis and rash are some examples.
Patients should be educated about these toxicities and followed every cycle to look for these adverse events.
# Discussion
# Early Stage Disease
For patients with early stage node negative disease, options for first-line therapy include partial nephrectomy, active surveillance or minimally invasive therapy with cryoablation or radiofrequency ablation. Active surveillance is best suited for individuals with small renal masses, who are elderly or medically compromised. In these patients, a biopsy is recommended initially, followed by repeat imaging every six months with intervention upon progression. Cryoablation and radiofrequency ablation can also be considered for patients with T1a disease after consultation with a urologist. Both are excellent treatment options for early stage disease, with long-term disease free survival rates ranging from 92 to 98%. A retrospective study among patients with renal cell carcinoma who underwent percutaneous CT-guided radiofrequency ablation (n=41) or cryoablation (n=70) demonstrated equivalent imaging (e.g. MRI) recurrence rates (11% vs. 7%, respectively; p=.60). In medically fit patients, including those that are elderly, partial nephrectomy is an excellent option. In an analysis of the SEER database, among patients with T1aN0M0 renal cell carcinoma (n=7,280), cancer-specific mortality for partial-and radical-nephrectomy were 1.8% and 2.5%, respectively (p=.5) for all patients and 1.0% and 3.4% (p=0.7), respectively, for patients aged 70 years and over 1 If surgery is planned, partial nephrectomy should be offered when technically feasible, especially for clinical T1a renal masses. For large renal masses and/or when partial nephrectomy would be technically challenging, radical nephrectomy can be considered. If radical nephrectomy is performed, a laparoscopic approach should be offered when possible.
# Advanced Stage Disease
# Systemic Therapy:
For patients with advanced, unresectable or metastatic disease, systemic therapy is indicated.
# First-line Therapy:
The combination of ipilimumab and nivolumab (ipi/nivo) compared to sunitinib alone was studied in the CHECKMATE 214 study 29 The JAVELIN Renal 101 trial compared the combination of avelumab + axitinib (ave/axi) to sunitinib alone 54 . As per the updated efficacy results based on minimum follow-up period of 13 months 55 , ave/axi significantly improved median PFS compared with sunitinib alone at 13.3 months vs 8.0 months (HR 0.69 p < 0.0001). The overall survival data showed no difference between the two arms however this data is immature. This combination is not Health Canada approved at the time of writing this guideline.
The CheckMate 9ER trial compared the combination of nivolumab + cabozantinib (nivo/cabo) 56 to sunitinib alone. At a median follow-up of 23.5 months 57 , nivo/cabo was superior to sunitinib in terms of PFS (17.0 months vs. 8.3 months, HR 0.52 p 40 mg of prednisone daily or equivalent). Health-related quality of life was superior in combination arm compared to sunitinib. 58 This combination is Health Canada approved but not funded at the time of writing this document.
The CLEAR study compared the combination of lenvatinib + pembrolizumab (len/pembro) or lenvatinib + everolimus (len/eve) to sunitinib alone. 15 ) with a 16.1% CR rate in the len/pembro arm compared to 9.8% and 4.2% in the len/eve and sunitinib arms respectively. Grade 3 or higher AEs occurred in 82.4%, 83.1% and 71.8% of patient in the len/pembro, len/eve, and sunitinib arms respectively. Grade 3 or higher adverse events that occurred in 10% or more of patients in any treatment group included diarrhea, hypertension, an elevated lipase level, and hypertriglyceridemia. The len/pembro combination has been Health Canada approved at the time of writing this guideline although provincial funding has yet to be finalized. The len/eve combination is not Health Canada approved.
Sunitinib and pazopanib may be treatment options first line, but the above mentioned options have demonstrated superiority to sunitinib. Only in patients in whom checkpoint inhibitors are contraindicated or in patients who refuse checkpoint inhibitor therapy should sunitinb or pazopanib be considered in the first line setting.
# After First-line Therapy:
The CheckMate 025 trial demonstrated an overall survival benefit of nivolumab compared to everolimus with fewer grade 3 or 4 adverse events in patients previously treated either 1 or 2 VEGFR-TKIs 35,59 . Median OS was 25.0 months in the nivolumab arm vs. 19.6 months in the everolimus arm (N=821). Median PFS was 4.6 months with nivolumab and 4.4 months with everolimus. Grade 3/4 treatment-related adverse events occurred in 19% of nivolumab patients and 37% of everolimus patients 35 .
Axitinib is a selective second-generation inhibitor of VEGF receptors. It has shown positive results in a phase III trial compared with sorafenib. The 723 patients included in the study had confirmed RCC that progressed despite first-line therapy containing sunitinib, bevacizumab plus interferon-alfa, temsirolimus, or cytokines. Median PFS was 6.7 months for axitinib versus 4.7 months in patients receiving sorafenib, with non-significant differences regarding toxicity 44 . Axitinib demonstrated activity in patients previously treated with checkpoint inhibitor in a non-randomized phase 2 trial (n = 40), with a median PFS of 8.8 months. 60 Retrospective analyses have also shown benefits of axitinib in the second and third-line setting, including those who have had previous exposure to checkpoint inhibitor. As of the time of writing this document, axitinib is funded as a treatment after 1 prior VEGFR-TKI but it is not funded as the next immediate option for patients who progressed on first-line checkpoint inhibitor-based regimens. 40,41 Cabozantinib is multi-targeted TKI that uniquely not only target VEGFR but also MET and AXL. Resistance to PD-1/PD-L1 inhibition has been associated with increased expression of VEGFR, MET and AXL. 61 The METEOR trial has reported PFS benefit and an OS benefit for cabozantinib when compared to everolimus in patients that progressed after VEGFR-targeted therapy. 37 Median PFS was 7.4 months with cabozantinib and 3.8 months with everolimus (p<0.001) and the ORR was higher with cabozantinib (21% vs 5% with everolimus; p<0.001). Overall survival was longer with cabozantinib when compared to everolimus (HR 0.66 . 37 Adverse events were managed with dose reduction; dose reduction occurred in 60% of patients who received cabozantinib (vs. 25% in those on everolimus), and discontinuation of treatment due to adverse events occurred in 9% of patients who received cabozantinib vs. 10% in those on everolimus.
In the METEOR trial, a minority of patients had also received immunotherapy in addition to one or two lines of TKI prior to start of cabozantinib. Furthermore, retrospective series from real-world setting have demonstrated the effectiveness of cabozantinib after failure of first-line immunotherapy, as well as those who have been heavily-pretreated, 62,63 with median time-to-treatment failure (TTF) of 8.0 months. In the absence of prospective data, cabozantinib should be a valid treatment option for those who progress on first-line immunotherapy regimen. Currently, it can be accessed through Director's Privilege as a second-line option for patients who progress on first-line pembro/axi. However, it is not funded as a second-line option for those who progress on first-line ipi/nivo.
There is also evidence from retrospective analyses supporting the use of sunitinib or pazopanib postprogression on first-line checkpoint inhibitor, with median PFS reported in the range of 6 to 13 months. 42,64,65 Both treatments are currently funded as a second-line option following ipi/nivo in intermediate or poor risk patients. However, they are not funded as a second-line option following pembro/axi.
A small, randomized, three-arm, phase 2 trial of oral multi-targeted TKI lenvatinib, everolimus, and the combination of both was conducted in patients who progressed after one previous VEGFR TKI. This study demonstrated improved PFS for the combination arm over everolimus alone (median 14.6 months vs. 5.5 months; HR 0.40 [95% CI 0.24 -0.68; p = 0.0005). 59 The combination numerically prolonged PFS compared with lenvatinib alone although this was not statistically significant (median 14.6 months vs. Historically, everolimus monotherapy was considered a reasonable treatment option post progression on a VEGFR-TKI but this is now superseded by the above. There may be rare instances where a VEGFR-TKI is not recommended or tolerated such that everolimus can be considered.
The appropriate sequencing of these agents after first-line therapy is unknown. The current recommended treatment options in Alberta are shown in figure 2.
# Local Therapy:
Prior to 2018, there is little data to guide clinical practice in relation to cytoreductive nephrectomy (CN) in the era of targeted therapy and decisions are made based on clinical indications. In phase III trials, the majority of patients had undergone a nephrectomy prior to systemic therapy 16,66,67 . Nephrectomy has proven overall survival benefit when used in conjunction with interferon 68,69 . Among patients treated with interferon alfa-2a (n=159), univariate and multivariate statistical analyses showed that prior nephrectomy was a significant prognostic factor for survival 69 . A prospective trial also showed that among patients with metastatic renal-cell cancer who were acceptable candidates for nephrectomy (n=120), the addition of interferon alfa-2b resulted in prolonged median survival (11.1 vs. 8.1 months, interferon alone; p=.05) 68,69 . Patients who appear to benefit most from nephrectomy are those with most of the tumor burden within the kidney, good performance status, and no central nervous system or liver involvement (with rare exceptions) 68,69 . Other considerations include surgical resectability, including possible morbidity to proximal vital structures, encasement of the renal hilum and other complicating factors 46,51 . Laparoscopic nephrectomy is the emerging standard surgical procedure and should be considered whenever technically feasible 70,71 .
The phase III CARMENA 49 trial was published in 2018 and it randomized patients to cytoreductive nephrectomy with sunitinib versus sunitinib alone. It demonstrated that sunitinib alone is non-inferior to the cytoreductive nephrectomy arm. It should be noted that over 40% of patients enrolled had poor-risk disease so the typical CN patient may not have been included in this trial. Thus, there remain patients that should still be considered for CN including patients with limited metastatic disease with large primary tumors and those with symptomatic primary tumors. A retrospective series of 198 patients presented at GU ASCO 2020 72 showed that cytoreductive nephrectomy was associated with improved survival for patients with metastatic renal cell carcinoma treated with immunotherapy. However, there is no prospective data on CN with first line checkpoint inhibitor combinations. Currently, upfront CN should be considered in the following clinical scenario 73 Deferred cytoreductive nephrectomy should be considered in patients with strong responses to systemic therapy. CN should rarely be performed in patients with poor-risk disease or patients with rapidly progressive disease or high disease burden who need systemic therapy.
Lastly, Nephrectomy or renal embolization (when nephrectomy is not possible) can also be offered as palliative procedures at any time when clinically indicated.
# Adjuvant Therapy:
Currently, there is no role for adjuvant therapy using anti-angiogenic therapies in localized, resected renal cell carcinoma. The adjuvant ASSURE trial 74 randomized patients between sunitinib, sorafenib and placebo and did not demonstrate any benefit. The S-TRAC trial 75 randomized higher risk clear cell patients to one year of sunitinib versus placebo. There was a difference in disease free survival however the overall survival data were immature and there was no difference. Additionally, the PROTECT clinical trial of adjuvant pazopanib vs placebo was negative for the primary endpoint. The phase III ATLAS trial evaluating axitinib (Inlyta) as adjuvant therapy for patients at high risk of recurrent RCC after nephrectomy was halted after interim analysis due to futility 76 .
The use of immunotherapy in the adjuvant setting has been tested as per the Keynote 564 study. 77,78 Here, patients with high risk of recurrence after nephrectomy were randomized to pembrolizumab or placebo for 17 cycles (approximately 1 year). After a median of 30 months follow up post randomization, the primary endpoint of disease-free survival (DFS) was met with disease-free survival at 30 months at 752% (95% CI 708-791) in the pembrolizumab group and 655% (609-697) in the placebo group. The HR for DFS was HR 063 (95% CI 050-080] and met statistical. OS data are trending toward significance but still immature. Grade 3 or higher adverse events of any cause occurred in 32% of the patients who received pembrolizumab and in 18% of those who received placebo. No deaths related to pembrolizumab therapy have occurred. Pembrolizumab has recently received Health Canada approval but is awaiting provincial funding.
There have been three other studies looking at treatment with checkpoint inhibitors in the periooperative/adjuvant setting -IMmotion01089 79 , CheckMate 914 80 , and PROSPER 81 . All three were presented at ESMO 2022 and all three did not show any benefit with DFS. It is not clear why these three trials were negative for their primary endpoint of DFS while KEYNOTE564 was positive and further investigation/analysis is pending to explain this discrepancy. Overall survival endpoints have also not been met in any of these above studies, therefore, a comprehensive discussion with each individual patient is suggested prior to recommending adjuvant checkpoint inhibitor therapy.
# Appendix
# Development and Revision History
This guideline was developed by a multidisciplinary working group comprised of members from the Alberta Provincial GU Tumour Team, external participants identified by the Working Group Lead, and a methodologist from the Guideline Resource Unit. The draft guideline was externally reviewed and endorsed by members of the Alberta Provincial GU Tumour Team who were not involved in the guideline's development, including urologists, radiation oncologists, medical oncologists, nurses, pathologists, and pharmacists. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook.
This guideline was originally developed in 2005.
# Maintenance
A formal review of the guideline will be conducted in 2024. If critical new evidence is brought forward before that time, however, the guideline working group members will revise and update the document accordingly.
# Abbreviations | v. Biopsy is an option as part of active observation or prior to ablative therapy vi. Optional Tests: a. CT chest if T2 or T3 b. Bone scan if T2 or T3 or alkaline phosphatase is elevated c. FDG PET/CT imaging is not currently recommended or indicated as part of staging for RCC. B. Therapeutic Options i. Active Surveillance is an appropriate option for the small renal mass (less than 4 cm) in all patients: a. Active surveillance is the preferred option for elderly, frail, and/or highly comorbid patients with a small renal mass that is 4cm or smaller b. Active surveillance is the preferred option for a small renal mass that is 2cm or smaller c. Biopsy is an option if it would alter management. d. Repeat imaging every 6 months. e. Intervention is indicated if there is progression. ii. Surgical Intervention 1, 2 a. Partial nephrectomy should be considered in all cases where surgery is being considered especially small renal masses less than 4cm. This can be done either as an open, laparoscopic, or robotic-assisted laparoscopic procedure, although a minimally invasive partial nephrectomy should be favored when safe, technically feasible and oncologically sound. b. If partial nephrectomy is not feasible, consider minimally-invasive radical nephrectomy. c. If a minimally-invasive surgical procedure cannot be performed due to patient or tumor characteristics, then an open nephrectomy should be done. d. The adrenal gland should not be removed unless involved on imaging. iii. Percutaneous ablation a. Both radiofrequency ablation (RFA) and cryoablation are possible treatments for the small renal mass [3][4][5][6][7][8][9] . However, this treatment decision should only be made after consultation with a urologist and discussed at multidisciplinary rounds. C. Adjuvant Therapy i. Adjuvant therapy using checkpoint inhibitors has demonstrated some discrepant results with only 1 of 4 trials being positive for the primary endpoint of DFS although OS results are immature. While adjuvant therapy has Health Canada approval, a comprehensive discussion is strongly suggested with each patient before recommending this treatment. a. Adjuvant pembrolizumab can be considered for patients with completely resected clear cell renal cell carcinoma and any of the following features: i. stage pT2 and grade 4 or sarcomatoid features ii. stage pT3-4 N0 iii. Any T-stage with N+ disease iv. M1 NED (i.e. complete metastasectomy within one year of nephrectomy)# Background
In 2022, it is estimated that 8100 Canadians (5400 men and 2700 women) were diagnosed with kidney and renal pelvis cancer, and that 1300 Canadians will died from kidney and renal pelvis cancer [link].
Renal cell carcinoma (RCC) is the main focus of this guideline. The most common subtype of renal cell carcinoma is clear cell RCC, followed by papillary and chromophobe tumours. Staging of renal cell carcinoma is currently based on the 8th edition (2017) of the American Joint Committee on Cancer's AJCC Cancer Staging Manual (see Appendix).
Guideline Questions 1. What are the appropriate diagnostic tests for renal cell carcinoma? 2. How should renal cell carcinoma be managed (i.e., surgically)? 3. What is the role of systemic therapy and radiotherapy in the management of renal cell carcinoma? 4. Are there other therapies that have shown benefit for patients with renal cell carcinoma? 5. What are the appropriate follow up strategies for renal cell carcinoma?
# Search Strategy
Phase III trials involving 'renal cell carcinoma' that had been published since the last iteration of the guideline were identified and reviewed using the pubmed database. The results of the literature review are available upon request ([email protected]).
# Target Population
Adult patients (≥18 years of age) with a diagnosis, or suspected diagnosis of renal cell carcinoma.
# Recommendations
Stage T1-3, N+/-M0, Indications include imaging suspicious for primary renal malignancy localized to the kidney or immediate surrounding structures. ii. Adjuvant therapy using anti-angiogenic therapies is currently not recommended post definitive management of renal cell carcinoma .
# D. Follow-up
Follow up is based on the recommendations of the Canadian Urological Association (CUA) as published on the CUA website (http://www.cua.org/) and the CUA Journal (CUAJ) in 2018 10 , and is stage dependent:
(pT1) Hx & PE X X X X X Blood Test X X X X X CXR X X X X X CT or U/S abdomen X X Intermediate Risk (pT2) Hx & PE X X X X X X X X Blood Test X X X X X X X X CXR X X X X X X X X CT or U/S abdomen X X X X High Risk (pT3-4)* Hx & PE X X X X X X X X Blood Test X X X X X X X X CXR X X X X X X X X CT abdomen X X X X X X Very High Risk (pTxN+)* Hx & PE X X X X X X X X X Blood Test X X X X X X X X X CXR X X X X X X X X X CT abdomen X X X X X X X X X
*For High-and Very High-risk patients, consider an extended individualized follow up beyond 60 months.
Stage T4N0M0, cTxN1Mx, TxNxM+ 11 Indications for systemic therapy include locally advanced, unresectable cancer or metastatic disease. The International mRCC Database Consortium (IMDC) risk factors (hypercalcemia, neutrophilia, thrombocytosis, anemia, Karnofsky performance status <80%, and time from diagnosis to treatment <1 year) are used to stratify patients into 3 risk groups. Patients with 0 factors vs. 1-2 factors vs. 3 or more factors are deemed favorable, intermediate, and poor-risk, respectively. 12 An online calculator is available at https://www.imdconline.com/.
# Management 13
A. Staging i. CT scan of head, chest, abdomen, pelvis with contrast (or MRI) ii. CBC, creatinine, urea, calcium, albumin, AST, ALT, ALP, bilirubin and TSH.
iii. If an IO is being considered additional targeted bloodwork can be requested at baseline if concerns regarding anticipated auto-immune toxicity from checkpoint inhibitors (eg: a.m. cortisol, lipase, T3, T4, creatine kinase, glucose etc). iv. Other additional imaging modalities can be considered as clinically indicated (bone scan, MRI) v. FDG-PET/CT is not recommended in this setting
# First-line Therapies
Favorable-Risk:
A. Pembrolizumab/Axitinib (Pembro/Axi) 14 i. Indication: a. First-line therapy for advanced RCC based on phase III data.
ii. Dose and Schedule: a. Pembrolizumab at 2mg/kg (capped at 200mg) intravenously once every 3 weeks plus axitinib 5mg orally twice daily. b. Pembrolizumab is given for a maximum of 35 consecutive cycles (~ 2 years). There is no recommended dose adjustment for pembrolizumab. c. Axitinib should be dose adjusted to maximum treatment tolerance by titrating dose higher or lower (maximum 10 mg po twice daily and minimum 1 mg po twice daily). d. Treatment is generally given until disease progression, intolerance or patient decision provided the caveats regarding number of total cycles of pembrolizumab.
iii. Toxicity: a. Physicians must be aware of the toxicity profile of pembrolizumab and axitinib and the potential overlapping toxicities. As a general rule, axitinib-induced toxicity would be expected to improve quickly with cessation of therapy, whereas an immune mediated adverse event (irAE) would not improve after stopping axitinib. b. It is important to have early recognition of irAEs that require prompt intervention with immunosuppressing agents (eg: high dose steroids). Colitis (diarrhea), pneumonitis, endocrinopathies (hypophysitis, hypothyroidism, adrenal insufficiency), hepatitis and rash are some examples. Patients should be educated about these toxicities and followed every cycle to look for these adverse events. c. Lenvatinib should be dose adjusted to maximum treatment tolerance by titrating dose higher or lower (maximum 10 mg po twice daily and minimum 1 mg po twice daily). d. Treatment is generally given until disease progression, intolerance or patient decision provided the caveats regarding number of total cycles of pembrolizumab.
iii. Toxicity: a. Physicians must be aware of the toxicity profile of pembrolizumab and lenvatinib and the potential overlapping toxicities. As a general rule, lenvatinib-induced toxicity would be expected to improve quickly with cessation of therapy, whereas an immune mediated adverse event (irAE) would not improve after stopping lenvatinib. ii. Dose and Schedule: a. A starting dose at 50 mg/day orally for 4 weeks followed by a 2-week rest period for a 6-week treatment cycle is indicated in the product monograph. However, an individualized schedule optimizing the therapeutic ratio with anywhere from 1-4 weeks on therapy followed by a 1-week break as determined by treatment tolerance is recommended b. Treatment is given until disease progression, intolerance or patient decision.
iii. Toxicity: a. Physicians must be aware of the toxicity profile of sunitinib and follow patients accordingly with experienced nursing support. Patients should be assessed regularly for treatment tolerance. b. Sunitinib should be dosed to maximum treatment tolerance as there is evidence that higher AUC leads to higher response rates. c. Cardiotoxicity has become an issue and in patients with pre-existing compromised cardiac function. Monitoring of ejection fraction should be considered in high risk or symptomatic patients but routine monitoring in all patients is not indicated. ii. Dose and schedule a. A starting dose 800 mg/day orally taken on a continuous basis is indicated in the product monograph. However, an individualized schedule optimizing the therapeutic ratio with anywhere from 1-4 weeks on therapy followed by a 1-week break as determined by treatment tolerance is recommended. b. Treatment is given until disease progression, intolerance or patient decision.
iii. Toxicity: a. Physicians must be aware of the toxicity profile of pazopanib and follow patients accordingly with experienced nursing support. Patients should be assessed regularly for treatment tolerance. b. Pazopanib should be dosed to maximum treatment tolerance as there is evidence that higher AUC leads to higher response rates. c. Liver enzymes and bilirubin should be frequently measured (at least once every two weeks initially) as they are elevated with this drug more frequently than with other VEGFR-TKIs. d. The COMPARZ and PISCES trial reported safety and quality-of-life profiles may favor pazopanib when compared to sunitinib. ii. Dose and Schedule a. Nivolumab at 3 mg/kg (capped at 240 mg) and Ipilimumab at 1 mg/kg both given intravenously every three weeks for four cycles. This is followed by nivolumab only as maintenance therapy at 3mg/kg (capped at 240mg) every 2 weeks or 6 mg/kg (capped at 480 mg) intravenously every 4 weeks. The maintenance schedule is determined at discretion of the physician and patient. Maintenance treatment can begin anywhere from 4-6 weeks after last dose of ipi/nivo assuming patient is benefiting from treatment. b. Treatment is given until disease progression, intolerance or patient decision.
iii. Toxicity a. It is important to have early recognition of immune mediated adverse events that require prompt intervention with high dose steroids. Colitis (diarrhea), pneumonitis, endocrinopathies (hypophysitis, hypothyroidism, adrenal insufficiency), hepatitis and rash are some examples.
Patients should be educated about these toxicities and followed every cycle to look for these adverse events.
# Discussion
# Early Stage Disease
For patients with early stage node negative disease, options for first-line therapy include partial nephrectomy, active surveillance or minimally invasive therapy with cryoablation or radiofrequency ablation. Active surveillance is best suited for individuals with small renal masses, who are elderly or medically compromised. In these patients, a biopsy is recommended initially, followed by repeat imaging every six months with intervention upon progression. Cryoablation and radiofrequency ablation can also be considered for patients with T1a disease after consultation with a urologist. Both are excellent treatment options for early stage disease, with long-term disease free survival rates ranging from 92 to 98%. A retrospective study among patients with renal cell carcinoma who underwent percutaneous CT-guided radiofrequency ablation (n=41) or cryoablation (n=70) demonstrated equivalent imaging (e.g. MRI) recurrence rates (11% vs. 7%, respectively; p=.60). [3][4][5][6][7][8][9] In medically fit patients, including those that are elderly, partial nephrectomy is an excellent option. In an analysis of the SEER database, among patients with T1aN0M0 renal cell carcinoma (n=7,280), cancer-specific mortality for partial-and radical-nephrectomy were 1.8% and 2.5%, respectively (p=.5) for all patients and 1.0% and 3.4% (p=0.7), respectively, for patients aged 70 years and over 1 If surgery is planned, partial nephrectomy should be offered when technically feasible, especially for clinical T1a renal masses. For large renal masses and/or when partial nephrectomy would be technically challenging, radical nephrectomy can be considered. If radical nephrectomy is performed, a laparoscopic approach should be offered when possible.
# Advanced Stage Disease
# Systemic Therapy:
For patients with advanced, unresectable or metastatic disease, systemic therapy is indicated.
# First-line Therapy:
The combination of ipilimumab and nivolumab (ipi/nivo) compared to sunitinib alone was studied in the CHECKMATE 214 study 29 The JAVELIN Renal 101 trial compared the combination of avelumab + axitinib (ave/axi) to sunitinib alone 54 . As per the updated efficacy results based on minimum follow-up period of 13 months 55 , ave/axi significantly improved median PFS compared with sunitinib alone at 13.3 months vs 8.0 months (HR 0.69 [95% CI 0.574-0.825] p < 0.0001). The overall survival data showed no difference between the two arms however this data is immature. This combination is not Health Canada approved at the time of writing this guideline.
The CheckMate 9ER trial compared the combination of nivolumab + cabozantinib (nivo/cabo) 56 to sunitinib alone. At a median follow-up of 23.5 months 57 , nivo/cabo was superior to sunitinib in terms of PFS (17.0 months vs. 8.3 months, HR 0.52 [95% CI 0.43-0.64] p<0.0001), meeting its' primary endpoint. The secondary endpoint of OS was superior in the nivo/cabo compared to sunitinib arm (NR vs. 29.5 months, HR 0.66 [95% CI 0.50 -0.87] p = 0.0034). The combination was also better than sunitinib in terms of ORR of 54.8% vs. 28.4%. The CR rate was more than doubled with 9.3% vs. 4.3%. Grade 3 or higher AEs occurred in 75% of patients in nivo/cabo arm and in 71% of patients in sunitinib arm. Overall, 19% of patients treated with nivo/cabo received corticosteroids (> 40 mg of prednisone daily or equivalent). Health-related quality of life was superior in combination arm compared to sunitinib. 58 This combination is Health Canada approved but not funded at the time of writing this document.
The CLEAR study compared the combination of lenvatinib + pembrolizumab (len/pembro) or lenvatinib + everolimus (len/eve) to sunitinib alone. 15 ) with a 16.1% CR rate in the len/pembro arm compared to 9.8% and 4.2% in the len/eve and sunitinib arms respectively. Grade 3 or higher AEs occurred in 82.4%, 83.1% and 71.8% of patient in the len/pembro, len/eve, and sunitinib arms respectively. Grade 3 or higher adverse events that occurred in 10% or more of patients in any treatment group included diarrhea, hypertension, an elevated lipase level, and hypertriglyceridemia. The len/pembro combination has been Health Canada approved at the time of writing this guideline although provincial funding has yet to be finalized. The len/eve combination is not Health Canada approved.
Sunitinib and pazopanib may be treatment options first line, but the above mentioned options have demonstrated superiority to sunitinib. Only in patients in whom checkpoint inhibitors are contraindicated or in patients who refuse checkpoint inhibitor therapy should sunitinb or pazopanib be considered in the first line setting.
# After First-line Therapy:
The CheckMate 025 trial demonstrated an overall survival benefit of nivolumab compared to everolimus with fewer grade 3 or 4 adverse events in patients previously treated either 1 or 2 VEGFR-TKIs 35,59 . Median OS was 25.0 months in the nivolumab arm vs. 19.6 months in the everolimus arm (N=821). Median PFS was 4.6 months with nivolumab and 4.4 months with everolimus. Grade 3/4 treatment-related adverse events occurred in 19% of nivolumab patients and 37% of everolimus patients 35 .
Axitinib is a selective second-generation inhibitor of VEGF receptors. It has shown positive results in a phase III trial compared with sorafenib. The 723 patients included in the study had confirmed RCC that progressed despite first-line therapy containing sunitinib, bevacizumab plus interferon-alfa, temsirolimus, or cytokines. Median PFS was 6.7 months for axitinib versus 4.7 months in patients receiving sorafenib, with non-significant differences regarding toxicity 44 . Axitinib demonstrated activity in patients previously treated with checkpoint inhibitor in a non-randomized phase 2 trial (n = 40), with a median PFS of 8.8 months. 60 Retrospective analyses have also shown benefits of axitinib in the second and third-line setting, including those who have had previous exposure to checkpoint inhibitor. As of the time of writing this document, axitinib is funded as a treatment after 1 prior VEGFR-TKI but it is not funded as the next immediate option for patients who progressed on first-line checkpoint inhibitor-based regimens. 40,41 Cabozantinib is multi-targeted TKI that uniquely not only target VEGFR but also MET and AXL. Resistance to PD-1/PD-L1 inhibition has been associated with increased expression of VEGFR, MET and AXL. 61 The METEOR trial has reported PFS benefit and an OS benefit for cabozantinib when compared to everolimus in patients that progressed after VEGFR-targeted therapy. 37 Median PFS was 7.4 months with cabozantinib and 3.8 months with everolimus (p<0.001) and the ORR was higher with cabozantinib (21% vs 5% with everolimus; p<0.001). Overall survival was longer with cabozantinib when compared to everolimus (HR 0.66 [95%CI: 0.53-0.83]. 37 Adverse events were managed with dose reduction; dose reduction occurred in 60% of patients who received cabozantinib (vs. 25% in those on everolimus), and discontinuation of treatment due to adverse events occurred in 9% of patients who received cabozantinib vs. 10% in those on everolimus.
In the METEOR trial, a minority of patients had also received immunotherapy in addition to one or two lines of TKI prior to start of cabozantinib. Furthermore, retrospective series from real-world setting have demonstrated the effectiveness of cabozantinib after failure of first-line immunotherapy, as well as those who have been heavily-pretreated, 62,63 with median time-to-treatment failure (TTF) of 8.0 months. In the absence of prospective data, cabozantinib should be a valid treatment option for those who progress on first-line immunotherapy regimen. Currently, it can be accessed through Director's Privilege as a second-line option for patients who progress on first-line pembro/axi. However, it is not funded as a second-line option for those who progress on first-line ipi/nivo.
There is also evidence from retrospective analyses supporting the use of sunitinib or pazopanib postprogression on first-line checkpoint inhibitor, with median PFS reported in the range of 6 to 13 months. 42,64,65 Both treatments are currently funded as a second-line option following ipi/nivo in intermediate or poor risk patients. However, they are not funded as a second-line option following pembro/axi.
A small, randomized, three-arm, phase 2 trial of oral multi-targeted TKI lenvatinib, everolimus, and the combination of both was conducted in patients who progressed after one previous VEGFR TKI. This study demonstrated improved PFS for the combination arm over everolimus alone (median 14.6 months vs. 5.5 months; HR 0.40 [95% CI 0.24 -0.68; p = 0.0005). 59 The combination numerically prolonged PFS compared with lenvatinib alone although this was not statistically significant (median 14.6 months vs. Historically, everolimus monotherapy was considered a reasonable treatment option post progression on a VEGFR-TKI but this is now superseded by the above. There may be rare instances where a VEGFR-TKI is not recommended or tolerated such that everolimus can be considered.
The appropriate sequencing of these agents after first-line therapy is unknown. The current recommended treatment options in Alberta are shown in figure 2.
# Local Therapy:
Prior to 2018, there is little data to guide clinical practice in relation to cytoreductive nephrectomy (CN) in the era of targeted therapy and decisions are made based on clinical indications. In phase III trials, the majority of patients had undergone a nephrectomy prior to systemic therapy 16,66,67 . Nephrectomy has proven overall survival benefit when used in conjunction with interferon 68,69 . Among patients treated with interferon alfa-2a (n=159), univariate and multivariate statistical analyses showed that prior nephrectomy was a significant prognostic factor for survival 69 . A prospective trial also showed that among patients with metastatic renal-cell cancer who were acceptable candidates for nephrectomy (n=120), the addition of interferon alfa-2b resulted in prolonged median survival (11.1 vs. 8.1 months, interferon alone; p=.05) 68,69 . Patients who appear to benefit most from nephrectomy are those with most of the tumor burden within the kidney, good performance status, and no central nervous system or liver involvement (with rare exceptions) 68,69 . Other considerations include surgical resectability, including possible morbidity to proximal vital structures, encasement of the renal hilum and other complicating factors 46,51 . Laparoscopic nephrectomy is the emerging standard surgical procedure and should be considered whenever technically feasible 70,71 .
The phase III CARMENA 49 trial was published in 2018 and it randomized patients to cytoreductive nephrectomy with sunitinib versus sunitinib alone. It demonstrated that sunitinib alone is non-inferior to the cytoreductive nephrectomy arm. It should be noted that over 40% of patients enrolled had poor-risk disease so the typical CN patient may not have been included in this trial. Thus, there remain patients that should still be considered for CN including patients with limited metastatic disease with large primary tumors and those with symptomatic primary tumors. A retrospective series of 198 patients presented at GU ASCO 2020 72 showed that cytoreductive nephrectomy was associated with improved survival for patients with metastatic renal cell carcinoma treated with immunotherapy. However, there is no prospective data on CN with first line checkpoint inhibitor combinations. Currently, upfront CN should be considered in the following clinical scenario 73 Deferred cytoreductive nephrectomy should be considered in patients with strong responses to systemic therapy. CN should rarely be performed in patients with poor-risk disease or patients with rapidly progressive disease or high disease burden who need systemic therapy.
Lastly, Nephrectomy or renal embolization (when nephrectomy is not possible) can also be offered as palliative procedures at any time when clinically indicated.
# Adjuvant Therapy:
Currently, there is no role for adjuvant therapy using anti-angiogenic therapies in localized, resected renal cell carcinoma. The adjuvant ASSURE trial 74 randomized patients between sunitinib, sorafenib and placebo and did not demonstrate any benefit. The S-TRAC trial 75 randomized higher risk clear cell patients to one year of sunitinib versus placebo. There was a difference in disease free survival however the overall survival data were immature and there was no difference. Additionally, the PROTECT clinical trial of adjuvant pazopanib vs placebo was negative for the primary endpoint. The phase III ATLAS trial evaluating axitinib (Inlyta) as adjuvant therapy for patients at high risk of recurrent RCC after nephrectomy was halted after interim analysis due to futility 76 .
The use of immunotherapy in the adjuvant setting has been tested as per the Keynote 564 study. 77,78 Here, patients with high risk of recurrence after nephrectomy were randomized to pembrolizumab or placebo for 17 cycles (approximately 1 year). After a median of 30 months follow up post randomization, the primary endpoint of disease-free survival (DFS) was met with disease-free survival at 30 months at 75•2% (95% CI 70•8-79•1) in the pembrolizumab group and 65•5% (60•9-69•7) in the placebo group. The HR for DFS was HR 0•63 (95% CI 0•50-0•80] and met statistical. OS data are trending toward significance but still immature. Grade 3 or higher adverse events of any cause occurred in 32% of the patients who received pembrolizumab and in 18% of those who received placebo. No deaths related to pembrolizumab therapy have occurred. Pembrolizumab has recently received Health Canada approval but is awaiting provincial funding.
There have been three other studies looking at treatment with checkpoint inhibitors in the periooperative/adjuvant setting -IMmotion01089 79 , CheckMate 914 80 , and PROSPER 81 . All three were presented at ESMO 2022 and all three did not show any benefit with DFS. It is not clear why these three trials were negative for their primary endpoint of DFS while KEYNOTE564 was positive and further investigation/analysis is pending to explain this discrepancy. Overall survival endpoints have also not been met in any of these above studies, therefore, a comprehensive discussion with each individual patient is suggested prior to recommending adjuvant checkpoint inhibitor therapy.
# Appendix
# Development and Revision History
This guideline was developed by a multidisciplinary working group comprised of members from the Alberta Provincial GU Tumour Team, external participants identified by the Working Group Lead, and a methodologist from the Guideline Resource Unit. The draft guideline was externally reviewed and endorsed by members of the Alberta Provincial GU Tumour Team who were not involved in the guideline's development, including urologists, radiation oncologists, medical oncologists, nurses, pathologists, and pharmacists. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook.
This guideline was originally developed in 2005.
# Maintenance
A formal review of the guideline will be conducted in 2024. If critical new evidence is brought forward before that time, however, the guideline working group members will revise and update the document accordingly.
# Abbreviations
| None | None |
83dee16fc8eadf4e9a170733bbe25a55c6696f3d | cma | None | # COVID-19
March 24, 2020 3
Case Definition (1)
# Person Under Investigation (PUI)
- A person with fever and/or cough who meets the exposure criteria and for whom a laboratory test for COVID-19 1 has been or is expected to be requested.
Note: There is limited evidence on the likelihood of COVID-19 presenting as a co-infection with other pathogens. At this time, the identification of one causative agent should not exclude where the index of suspicion 2 may be high.
# Confirmed Case
A person with laboratory confirmation of infection with the virus that causes COVID-19 is performed at a reference laboratory (NML or a provincial public health laboratory), and consists of positive nucleic acid amplification tests 3 (NAAT) on at least two specific genome targets or a single positive target with nucleic acid sequencing.
Positive laboratory tests at a non-reference laboratory require additional testing at a reference laboratory for confirmation.
# Probable Case
A person:
- with fever (over 38.0 degrees Celsius) and/or new onset of (or exacerbation of chronic) cough AND - who meets the COVID-19 exposure criteria AND - in whom laboratory diagnosis of COVID-19 is o inconclusive 4 , o negative (if specimen quality or timing is suspect), or o positive but not confirmed by the National Microbiology Laboratory (NML) or provincial public health laboratory by nucleic acid amplification tests (NAAT)
# Prince Edward Island Exposure Criteria
In the 14 days 5 before onset of illness, a person who:
- Traveled outside Prince Edward Island (PEI) OR Had close contact 6 with a confirmed or probable case of COVID-19 within 14 days before their illness onset OR Had close contact with a person with acute respiratory illness who has travelled outside of PEI within 14 days prior to their illness onset OR Laboratory exposure to biological material (e.g. primary clinical specimens, virus culture isolates) known to contain COVID-19.
Factors that raise the index of suspicion 7 should also be considered. (1-800-545-7661) or through the single window email: [email protected].
# Etiology (4)
Coronaviruses are a large family of viruses that are common in many different species of animals, including camels, cattle, cats, and bats. Rarely, animal coronaviruses can infect people and then spread between people such as with Middle East Respiratory Syndrome (MERS), Severe Acute Respiratory Syndrome (SARS), and now with COVID-19.
Cases were initially linked to exposure to live animals at a seafood market in Wuhan City but the substantial increase in cases thereafter is due to human-to-human transmission of the virus.
The COVID-19 is an emerging respiratory pathogen with uncertain key epidemiological, clinical and virological characteristics.
# Clinical Presentation
The clinical spectrum of 2019 novel coronavirus (COVID-19) infection is still being defined. Illnesses associated with the COVID-19, are similar to several respiratory illnesses and include fever, dry cough, sore throat and headache. Most cases are considered mild to moderate with a subset experiencing more severe illness with shortness of breath and difficulty breathing. Deaths have been reported among approximately two to four per cent of detected cases in China although it is likely that the actual risk of such severe outcomes is lower given milder cases are less likely to be detected.
The complete clinical picture with regard to COVID-19 is not fully understood. Reported illnesses have ranged from infected people with little to no symptoms to severe illness and death.
# Diagnosis
Diagnosis is made by isolation of the COVID-19 in a nasopharyngeal swab and throat swab for PCR and sent a provincial lab for presumptive result and confirmed by the National Microbiology Laboratory (refer to Appendix A).
# Epidemiology
# Reservoir
Early on, many of the patients in the outbreak of respiratory illness caused by COVID-19 in Wuhan, China had some link to a large seafood and live animal market, suggesting animal-toperson spread. Later, a growing number of patients reportedly did not have exposure to animal markets, indicating person-to-person spread.
# Transmission
Transmission occurs person to person in symptomatic individuals via droplet.
# Incubation Period
Current estimates of the incubation period range from 1 to 12.5 days with median estimates of 5-6 days.
# Period of Communicability
Unknown.
# Host Susceptibility
Host susceptibility remains somewhat unknown. Information indicates that risk factors for disease include host factors (chronic disease, age) and exposure factors.
# Canada
Updated numbers of COVID-19 in Canada are available on the Public Health Agency of Canada website.
# Prince Edward Island
There have been three cases of COVID-19 reported in PEI.
# Control (Appendix B) Person Under Investigation (PUI)
A person under investigation is defined as a person with a fever or acute respiratory illness, or pneumonia, who meets the exposure criteria and for whom a laboratory test for COVID-19 has been or is expected to be requested.
# Management of a Case/PUI
- Follow up is only done if the case/contact meets the case definition and is being investigated. - Droplet/contact precautions are to be put in place in health care facilities until the test is confirmed and/or the case is no longer symptomatic. - Any aerosol-generating medical procedures should be avoided in the home environment.
- Complete the Interim National COVID-19 Case Report Form (Appendix C).
- Precautions can be discontinued for a case 14 days after symptoms began, as long as the case feels well. If the case is a health care worker 2 negative swabs 24 hours apart will be required before resuming work.
# Treatment of a Case
There is no specific treatment for disease caused by a COVID-19. However, many of the symptoms can be treated and therefore treatment is based on the individual's clinical condition.
# Management of Contacts
Contact tracing and counselling are to be completed 8 for all reported cases. A close contact is defined as;
- Those who provided care for the case, including healthcare workers, family members or other caregivers, or who had other similar close physical contact without consistent and appropriate use of personal protective equipment, OR those who lived with or otherwise had close prolonged contact (within 2 metres) with a probable or confirmed case while the case was ill, OR those who have had direct contact with infectious body fluids of a probable or confirmed case (e.g., was coughed or sneezed on) while not wearing recommended personal protective equipment.
Those who are identified as a contact of a case will be instructed to self-isolate and monitor for symptoms for 14 days. Public Health Nursing (PHN) will be following up with the close contacts daily. If symptoms occur, testing will be arranged.
# Self-Isolating in the Home Setting
All people that have travelled outside Prince Edward Island are asked to self-isolate for 14 days upon their return regardless of symptoms. If symptomatic, a case or person under investigation (PUI) should call 811 to be screened for testing and isolate themselves in the home setting until advised by the Chief Public Health Office (CPHO) that isolation can be discontinued. Staying at home means:
- Not going out unless directed to do so (i.e. to seek medical care) Not going to school, work, or other public areas Not using public transportation (e.g. buses, taxis, etc) Taking short walk outside, close to home, and only if a 6 ft distance from others can be maintained.
NOTE: Exceptions will be made for individuals who are considered essential workers (e.g. health care workers, truck drivers, airline crews, essential frontline workers in the public or private sector, workers in critical sectors). Upon their return from domestic travel, essential workers will be: screened upon entry to the province asked to self-monitor daily for symptoms of COVID-19 if feeling well asked to self-isolate if experiencing symptoms of COVID-19.
# Preventative Measures
- Public education and communication about COVID-19. All travelers who have returned from outside Prince Edward Island are being asked to selfisolate for 14 days and monitor themselves and their children closely, and to call 811 if they develop any symptoms (fever, cough, or difficulty breathing).
# Testing
Testing will be arranged through 811.
The following criteria are being used to screen for testing from March 23-March 30:
# Infection Prevention and Control in the Community
Follow these routine prevention measures to stay healthy:
- Wash your hands frequently with soap and water or use alcohol-based hand rub when hands are not visibly soiled.
- Cough and sneeze into your elbow or a tissue. If using a tissue, immediately place it in a waste disposal and wash your hands.
- If possible, stay home when ill with acute respiratory symptoms; if this is not possible, limit close contact with others.
- Limit touching your eyes, nose, and mouth.
- Don't share items that may have saliva on them such as drinking glasses and water bottles.
- Frequently clean surfaces like taps, doorknobs, and countertops.
- Use of masks by the general public for respiratory illnesses such as influenza and novel coronavirus have not been shown to be effective in preventing virus spread and are not recommended for prevention.
# Infection Prevention and Control in the Healthcare Facility
In the absence of effective drugs or vaccines, infection prevention and control (IPC) strategies to prevent or limit transmission of COVID-19 in healthcare facilities include: masks, tissues and alcohol-based hand rubs (ABHR) should be available at entrances signage should be posted to instruct symptomatic patients to alert healthcare workers, thus prompting completion of a patient screening questionnaire IF a person presents with symptoms of influenza-like illness:
- and within 14 days before the onset of illness, has travelled to an area outside of PEI and/or been in close contact with a probable or confirmed case of COVID-19 THEN the following actions should be taken:
- Place the patient in a designated separate waiting area or space.
- Encourage the patient with signs and symptoms of an acute respiratory infection to perform respiratory hygiene/cough etiquette, and provide tissues, ABHR and a waste receptacle. 3. Limit visitors. 4. Do not cohort with other patients (unless necessary, in which case cohort only with patients confirmed to have COVID-19 infection).
# Application of Routine Practices and Additional Precautions
The application of routine practices and additional precautions (RPAP) is based on a point-of-care risk assessment (PCRA). Health care workers (HCWs) should use a risk assessment approach before and during each patient interaction to evaluate the likelihood of exposure.
In addition to the consistent application of routine practices, follow contact and droplet precautions. This includes the appropriate selection and use of all the following personal protective equipment (PPE):
- gloves a long-sleeved gown facial protection, such as surgical/procedural mask and eye protection, face shield, or surgical/procedural mask with visor attachment an N95 respirator (plus eye protection) should be used when performing aerosol-generating medical procedures 9 (AGMPs) on a person under investigation (PUI) for COVID-19 infection.
- Hand hygiene should be performed whenever indicated, paying particular attention to during and after removal of PPE, and after leaving the patient care environment.
# Infection Prevention and Control Guidelines
# COVID-19
March 24, 2020
# Appendix A: Novel Coronavirus (COVID-19) Testing
All people with travel and symptoms for testing will be screened through 811. Screening will take place at clinics set up in Charlottetown and Summerside. All patients admitted to the hospital for respiratory illness will be tested for COVID-19. | # COVID-19
March 24, 2020 3
Case Definition (1)
# Person Under Investigation (PUI)
• A person with fever and/or cough who meets the exposure criteria and for whom a laboratory test for COVID-19 1 has been or is expected to be requested.
Note: There is limited evidence on the likelihood of COVID-19 presenting as a co-infection with other pathogens. At this time, the identification of one causative agent should not exclude where the index of suspicion 2 may be high.
# Confirmed Case
A person with laboratory confirmation of infection with the virus that causes COVID-19 is performed at a reference laboratory (NML or a provincial public health laboratory), and consists of positive nucleic acid amplification tests 3 (NAAT) on at least two specific genome targets or a single positive target with nucleic acid sequencing.
Positive laboratory tests at a non-reference laboratory require additional testing at a reference laboratory for confirmation.
# Probable Case
A person:
• with fever (over 38.0 degrees Celsius) and/or new onset of (or exacerbation of chronic) cough AND • who meets the COVID-19 exposure criteria AND • in whom laboratory diagnosis of COVID-19 is o inconclusive 4 , o negative (if specimen quality or timing is suspect), or o positive but not confirmed by the National Microbiology Laboratory (NML) or provincial public health laboratory by nucleic acid amplification tests (NAAT)
# Prince Edward Island Exposure Criteria
In the 14 days 5 before onset of illness, a person who:
Traveled outside Prince Edward Island (PEI) OR Had close contact 6 with a confirmed or probable case of COVID-19 within 14 days before their illness onset OR Had close contact with a person with acute respiratory illness who has travelled outside of PEI within 14 days prior to their illness onset OR Laboratory exposure to biological material (e.g. primary clinical specimens, virus culture isolates) known to contain COVID-19.
Factors that raise the index of suspicion 7 should also be considered. (1-800-545-7661) or through the single window email: [email protected].
# Etiology (4)
Coronaviruses are a large family of viruses that are common in many different species of animals, including camels, cattle, cats, and bats. Rarely, animal coronaviruses can infect people and then spread between people such as with Middle East Respiratory Syndrome (MERS), Severe Acute Respiratory Syndrome (SARS), and now with COVID-19.
Cases were initially linked to exposure to live animals at a seafood market in Wuhan City but the substantial increase in cases thereafter is due to human-to-human transmission of the virus.
The COVID-19 is an emerging respiratory pathogen with uncertain key epidemiological, clinical and virological characteristics.
# Clinical Presentation
The clinical spectrum of 2019 novel coronavirus (COVID-19) infection is still being defined. Illnesses associated with the COVID-19, are similar to several respiratory illnesses and include fever, dry cough, sore throat and headache. Most cases are considered mild to moderate with a subset experiencing more severe illness with shortness of breath and difficulty breathing. Deaths have been reported among approximately two to four per cent of detected cases in China although it is likely that the actual risk of such severe outcomes is lower given milder cases are less likely to be detected.
The complete clinical picture with regard to COVID-19 is not fully understood. Reported illnesses have ranged from infected people with little to no symptoms to severe illness and death.
# Diagnosis
Diagnosis is made by isolation of the COVID-19 in a nasopharyngeal swab and throat swab for PCR and sent a provincial lab for presumptive result and confirmed by the National Microbiology Laboratory (refer to Appendix A).
# Epidemiology
# Reservoir
Early on, many of the patients in the outbreak of respiratory illness caused by COVID-19 in Wuhan, China had some link to a large seafood and live animal market, suggesting animal-toperson spread. Later, a growing number of patients reportedly did not have exposure to animal markets, indicating person-to-person spread.
# Transmission
Transmission occurs person to person in symptomatic individuals via droplet.
# Incubation Period
Current estimates of the incubation period range from 1 to 12.5 days with median estimates of 5-6 days.
# Period of Communicability
Unknown.
# Host Susceptibility
Host susceptibility remains somewhat unknown. Information indicates that risk factors for disease include host factors (chronic disease, age) and exposure factors.
# Canada
Updated numbers of COVID-19 in Canada are available on the Public Health Agency of Canada website.
# Prince Edward Island
There have been three cases of COVID-19 reported in PEI.
# Control (Appendix B) Person Under Investigation (PUI)
A person under investigation is defined as a person with a fever or acute respiratory illness, or pneumonia, who meets the exposure criteria and for whom a laboratory test for COVID-19 has been or is expected to be requested.
# Management of a Case/PUI
• Follow up is only done if the case/contact meets the case definition and is being investigated. • Droplet/contact precautions are to be put in place in health care facilities until the test is confirmed and/or the case is no longer symptomatic. • Any aerosol-generating medical procedures should be avoided in the home environment.
• Complete the Interim National COVID-19 Case Report Form (Appendix C).
• Precautions can be discontinued for a case 14 days after symptoms began, as long as the case feels well. If the case is a health care worker 2 negative swabs 24 hours apart will be required before resuming work.
# Treatment of a Case
There is no specific treatment for disease caused by a COVID-19. However, many of the symptoms can be treated and therefore treatment is based on the individual's clinical condition.
# Management of Contacts
Contact tracing and counselling are to be completed 8 for all reported cases. A close contact is defined as;
Those who provided care for the case, including healthcare workers, family members or other caregivers, or who had other similar close physical contact without consistent and appropriate use of personal protective equipment, OR those who lived with or otherwise had close prolonged contact (within 2 metres) with a probable or confirmed case while the case was ill, OR those who have had direct contact with infectious body fluids of a probable or confirmed case (e.g., was coughed or sneezed on) while not wearing recommended personal protective equipment.
Those who are identified as a contact of a case will be instructed to self-isolate and monitor for symptoms for 14 days. Public Health Nursing (PHN) will be following up with the close contacts daily. If symptoms occur, testing will be arranged.
# Self-Isolating in the Home Setting
All people that have travelled outside Prince Edward Island are asked to self-isolate for 14 days upon their return regardless of symptoms. If symptomatic, a case or person under investigation (PUI) should call 811 to be screened for testing and isolate themselves in the home setting until advised by the Chief Public Health Office (CPHO) that isolation can be discontinued. Staying at home means:
Not going out unless directed to do so (i.e. to seek medical care) Not going to school, work, or other public areas Not using public transportation (e.g. buses, taxis, etc) Taking short walk outside, close to home, and only if a 6 ft distance from others can be maintained.
NOTE: Exceptions will be made for individuals who are considered essential workers (e.g. health care workers, truck drivers, airline crews, essential frontline workers in the public or private sector, workers in critical sectors). Upon their return from domestic travel, essential workers will be: screened upon entry to the province asked to self-monitor daily for symptoms of COVID-19 if feeling well asked to self-isolate if experiencing symptoms of COVID-19.
# Preventative Measures
Public education and communication about COVID-19. All travelers who have returned from outside Prince Edward Island are being asked to selfisolate for 14 days and monitor themselves and their children closely, and to call 811 if they develop any symptoms (fever, cough, or difficulty breathing).
# Testing
Testing will be arranged through 811.
The following criteria are being used to screen for testing from March 23-March 30:
# Infection Prevention and Control in the Community
Follow these routine prevention measures to stay healthy:
• Wash your hands frequently with soap and water or use alcohol-based hand rub when hands are not visibly soiled.
• Cough and sneeze into your elbow or a tissue. If using a tissue, immediately place it in a waste disposal and wash your hands.
• If possible, stay home when ill with acute respiratory symptoms; if this is not possible, limit close contact with others.
• Limit touching your eyes, nose, and mouth.
• Don't share items that may have saliva on them such as drinking glasses and water bottles.
• Frequently clean surfaces like taps, doorknobs, and countertops.
• Use of masks by the general public for respiratory illnesses such as influenza and novel coronavirus have not been shown to be effective in preventing virus spread and are not recommended for prevention.
# Infection Prevention and Control in the Healthcare Facility
In the absence of effective drugs or vaccines, infection prevention and control (IPC) strategies to prevent or limit transmission of COVID-19 in healthcare facilities include: masks, tissues and alcohol-based hand rubs (ABHR) should be available at entrances signage should be posted to instruct symptomatic patients to alert healthcare workers, thus prompting completion of a patient screening questionnaire IF a person presents with symptoms of influenza-like illness:
and within 14 days before the onset of illness, has travelled to an area outside of PEI and/or been in close contact with a probable or confirmed case of COVID-19 THEN the following actions should be taken:
1. Place the patient in a designated separate waiting area or space.
2. Encourage the patient with signs and symptoms of an acute respiratory infection to perform respiratory hygiene/cough etiquette, and provide tissues, ABHR and a waste receptacle. 3. Limit visitors. 4. Do not cohort with other patients (unless necessary, in which case cohort only with patients confirmed to have COVID-19 infection).
# Application of Routine Practices and Additional Precautions
The application of routine practices and additional precautions (RPAP) is based on a point-of-care risk assessment (PCRA). Health care workers (HCWs) should use a risk assessment approach before and during each patient interaction to evaluate the likelihood of exposure.
In addition to the consistent application of routine practices, follow contact and droplet precautions. This includes the appropriate selection and use of all the following personal protective equipment (PPE):
gloves a long-sleeved gown facial protection, such as surgical/procedural mask and eye protection, face shield, or surgical/procedural mask with visor attachment an N95 respirator (plus eye protection) should be used when performing aerosol-generating medical procedures 9 (AGMPs) on a person under investigation (PUI) for COVID-19 infection.
Hand hygiene should be performed whenever indicated, paying particular attention to during and after removal of PPE, and after leaving the patient care environment.
# Infection Prevention and Control Guidelines
# COVID-19
March 24, 2020
# Appendix A: Novel Coronavirus (COVID-19) Testing
All people with travel and symptoms for testing will be screened through 811. Screening will take place at clinics set up in Charlottetown and Summerside. All patients admitted to the hospital for respiratory illness will be tested for COVID-19. | None | None |
d94acfa216cc78f353b67453659b651883dc8bd7 | cma | None | # Introduction
# Methodology
A comprehensive review of studies examining radiationinduced hemorrhagic cystitis was performed using PubMed, Medline, and the Cochrane Library database. The bibliographies of relevant articles were searched to avoid exclusion of meaningful articles. Where available, focus was given to systematic reviews and comparative studies; however, due to a lack of high-quality evidence, case series were included and made up the majority of articles included. All articles were reviewed using the evidence-based medicine levels, with a modified Oxford grading system for recommendations.
# Objective
This Best Practice Report (BPR) seeks to inform and educate readers on radiation-induced hemorrhagic cystitis (RHC), as well as a survey of commonly used treatment options available and the evidence available to support a given therapeutic choice. The primary outcome of interest was resolution of hematuria; where available, the effects of treatment on urinary symptoms are shared. A relative absence of comparative data has prevented previous reviews from providing firm guidelines in the management of RHC and this report relies heavily on retrospective case series with methodological limitations to form recommendations. Individual patient factors, available resources, and new research will continue to shape clinical decision-making.
# Background
Hemorrhagic cystitis refers to a collection of symptoms and signs defined by hematuria, lower urinary tract symptoms (LUTS), and cystoscopic findings indicative of underlying urothelial damage. It can have a number underlying causative factors: treatment with chemotherapeutic agents (such as cyclophosphamide and concurrent therapies); post-transplant patients; infection-mediated; treatment with radiation therapy. RHC is often an adverse event in patients with previous radiation to the pelvis for urological or gynecological malignancy and will be the focus of this BPR.
RHC is generally considered a separate pathologial process from acute radiation effects, with early signs of urothelial effects occurring at three months and pathological changes occurring 6-12 months after radiation. 1 New-onset symptoms have been recorded up to 20 years after radiation treatment. 2 The estimates for prevalence of RHC after radiation treatment varies widely depending on the diagnostic definitions used, but different studies have quoted them as 9-21% following treatment of prostate cancer, 3-6.7% for cervical cancer, and 2-47% for bladder cancer. 3 The use of modern treatment techniques, such as intensity-modulated radiation therapy and volumetric modulated arc therapy, have reduced the radiation dose to the bladder. Randomized studies have shown that the use of higher doses in the management of prostate cancer have resulted improved prostatespecific antigen (PSA) control using these modern treatment techniques, but with the same incidence of late complications. There has also been a trend to using hypofractionation radiotherapy regimens (higher dose per fraction given over a shorter timeframe). To minimize late bladder effects, emphasis needs to be paid to ensuring doses received by radiovulnerable structures, such as bowel and bladder, are kept within acceptable limits.
The exact mechanism by which radiation causes damage to the bladder is not entirely understood, but believed to be multifactorial. While direct damage to DNA is believed to be Goucher et al rare, it is hypothesized that indirect damage occurs through the creation of free radicals. 4 Histological studies have demonstrated increased proliferation of the urothelium in the months following radiation. Damage to tight cellular junctions and the loss of the normal polysaccharide layer allow for increased permeability of urine bacteria and metabolites causing increased damage to the underlying tissue. 1 This altered permeability of the urothelial cell layer has been demonstrated to be involved in late-stage radiation changes in rat models 5 and is hypothesized to play a large role in the development of post-radiation urinary symptoms. 6 Diffuse mucosal edema is noted in biopsies taken immediately post-radiation. This is followed by development of vascular telangiectasia, submucosal hemorrhage, and interstitial fibrosis. Subendothelial proliferation, edema, and medial thickening may progressively deplete the blood supply to urothelium, resulting in endarteritis obliterans causing acute and chronic ischemia. 3 These ischemic and necrotic changes are proposed to give rise to subsequent development of revascularization with superficial, fragile vessels that are responsible for bleeding in radiation cystitis. 4 Hospitalizations for RHC can be lengthy and costly. A recent retrospective study assessing 1111 patients admitted for RHC in 2013 showed the median cost associated with each admission to be $7157 USD. This number rose to $11 100 for those with hematuria severe enough to merit endoscopic evaluation/treatment. 7 Multiple studies have demonstrated the significant effect its protracted and recurrent nature can have on patient-rated quality of life scales. 8 There exists little consensus of how to best treat RHC, and previous surveys of practicing urologist have shown a lack of awareness of treatment options available. 9
# Classifications
The European Organization for Research and Treatment of Cancer/Radiation Therapy Oncology Group (EORTC/RTOG) classification of late radiation effects is a commonly used classification system for grading of RHC (Table 1). 10 It describes a combination of clinical and cystoscopic criteria for reporting late radiation effects. The Late Effects of Normal Tissues (LEBT)/SOMA scale has also been developed and uses a more complex combination of subjective, objective, management, and analytical factors into radiation effect classification. 11 A more recent move to replace these systems with a common terminology has led to the development of the Common Terminology Criteria for Adverse Events as a uniform lexicon for description of cancer-related adverse effects. 12
# Initial management
# Diagnosis and early assessment
In patients presenting with hematuria post-radiation, a thorough assessment is needed to rule out secondary causes before a diagnosis of RHC can be made. In a study exploring cystoscopic evaluation of 185 men treated with brachytherapy for prostate cancer who presented with either macroscopic hematuria, microscopic hematuria, or persistent lower urinary tract, 9.6% were found to have a new bladder tumour compared to 7% who were found to have radiation cystitis. 13 While the majority of these symptomatic post-brachytherapy patients had cystoscopies reported as normal (63.8%), a clinically significant number did have an observable etiology. Assessment should begin with a detailed history characterizing the symptoms and confirming the history and treatment plan of a patient's radiation therapy. Physical exams, including an abdominal and pelvic exam to assess for alternative causes of bleeding, should be included. Laboratory tests, including a complete blood count, coagulation studies, serum creatinine, urinalyses, urine culture and cytology, should be initiated. As with any patient presenting with hematuria and a high risk of malignancy, all patients should undergo axial imaging, preferably a computed tomography (CT)-urogram to assess for upper tract sources of bleeding, and should also undergo cystoscopic evaluation and biopsies of lesions concerning for malignancy. Mild symptoms may resolve with continuous bladder irrigation with saline solution and this should be tried first in all patients with hematuria associated with clotting or retention.
Recommendation: Assessment of a patient complaining of hematuria post-radiation therapy should identify or exclude other pathological factors that may explain or contribute to the patient's symptoms (Grade 4C).
# Cystoscopic evaluation
Cystoscopy in patients with new-onset or suspected RHC can be both diagnostic and therapeutic. The appearance of BPR: Radiation-induced hemorrhagic cystitis diffuse erythema, telangiectasia with or without ulcerations can help confirm the diagnosis of RHC. At the time of cystoscopy, fulguration of suspected vascular lesions may provide control of hematuria. In a case series assessing the effectiveness of cystoscopy and fulguration for hematuria control in patients with either radiation-or chemotherapy-induced symptoms, 61% (20/33) of patients achieved resolution of symptoms after initial endoscopic treatment. 14 Only 36% (4/11) of patients who had refractory symptoms responded to a second cystoscopy and fulguration.
Multiple small case series have assessed alternatives to fulguration with Greenlight laser, KTP laser treatment, and argon beam coagulator. All series report laser therapy being well-tolerated and having a beneficial effect. In the future, they may play a larger role in the treatment of RHC; however, until larger studies can confirm their safety and effectiveness, they remain experimental in nature. Additional studies have investigated intravesical hemostatic gelatin matrix (Floseal) in six patients and was noted to be beneficial. Fibrin glue has been trialed in the treatment of post-hematological stem cell transplant patients and found to reduce hematuria, 18 but it has yet to be investigated in the RHC population beyond individual case studies. 19 Recommendation: All patients with hematuria should undergo at least one initial cystoscopy with or without fulguration of suspect lesions and biopsy of any lesions concerning for malignancy for diagnostic and therapeutic purposes (Grade 3C). Laser therapy and endoscopic use of hemostatic agents may play a role in early management of RHC, but insufficient data exists to evaluate their efficacy and safety; long-term followup is needed prior to any recommendations being made (Grade 3D).
# Persistent or recurrent clinically significant hematuria
# Intravesical agents
# Alum irrigation
Intravesical aluminous salts act as an astringent agent and exert their effect through protein precipitation causing decreased capillary permeability, contraction of intercellular space, vasoconstriction, and hardening of the capillary endothelium. 20 It is typically administered as a 1% concentration of alum mixed with sterile water, irrigated through the bladder at 250-300 ml per hour, at a duration up to the discretion of the observing clinician. Ideally, the bladder should be irrigated free of clots prior to initiation of therapy. Historical case series have demonstrated the efficacy and tolerability of intravesical alum for a wide range of etiologies and presentations of intractable bladder hemorrhages. 21,22 The common side effects are bladder spasms, suprapubic discomfort, and clotting of the catheter due to precipitant formation. Individual case studies have reported a risk of aluminum toxicity in individuals in renal failure. 23 The most recent, and largest case series reported the use of alum irrigation in 40 patients (38 of whom had previous radiation treatment) with symptoms of hemorrhagic cystitis; 24 60% of these patients demonstrated an improvement in their symptoms and required no further treatment prior to discharge. The treatment was well-tolerated and 90% of patients were able to receive their treatment as prescribed. Two patients discontinued due to inability to tolerate bladder spasms and two for altered level of consciousness. Overall, 35% of patients experienced bladder spasms. Asymptomatic elevation in serum aluminum was detected in one patient that resolved on discontinuation of the treatment. At a median followup of 16.5 months, only 32% of patients required no further treatment, bringing the durability of this treatment into question.
Recommendation: Irrigation with alum is a practical and easily applied treatment for RHC with a comparatively acute onset of action that is generally well-tolerated. Special caution should be used in patients with poor renal function (Grade 3C).
# Hyaluronic acid
Hyaluronic acid (HA) is a mucopolysaccharide whose therapeutic benefit is believed to be mediated by the repair of the normal glycoaminoglycan layer of the bladder when applied as intravesical installations. It has been shown that radiation leads to defects in this protective layer, leading to chronic inflammatory changes and delayed or prevented healing of urothelial cells. 25 Its use as an intravesical agent is well-studied in the treatment of interstitial cystitis and painful bladder syndrome, where it was recently recommended as a treatment option in the Canadian Urological Association guideline. 26 One of the few randomized trials comparing treatment modalities for RHC randomized 36 patients to either intravesical therapy with HA or treatment with hyperbaric oxygen therapy (HBOT). 27 In the HA group, patients received intravesical therapy once weekly for one month and then monthly for two months. Patients in the HBOT group received daily treatments for 30 treatments. Followup assessment of symptoms were done at six, 12, and 18 months following therapy. Complete resolution of hematuria was noted in 88%, 75%, and 50% of HA patients at those intervals and in 75%, 50%, and 45% of patients in the HBOT group. The difference was not statistically significant at any interval and the author concluded the HA therapy was at least as effective as HBOT in the treatment of hematuria.
A prospective, observational study of 20 patients undergoing treatment with intravesical HA compared grading of radiation cystitis, including hematuria, as per EORTC/ROTG classification (scale 1-5) before treatment and again three months Goucher et al after the completion of six scheduled treatments. 28 The mean radiocystitis scores before and after HA treatment were 2.70 and 1.45, respectively (p<0.01), with only minor side effects described. It is notable that no patients with grade 4 or 5 toxicity, considered severe symptoms, were included in this study. Beyond hematuria, recent prospectively collected data suggests that intravesical treatment with HA in combination with chondroitin sulfate (another glycosamniglycan) produces a clinically significant improvement in post-radiation LUTS and bother. In a study published by Gacci et al, 29 80 patients with previous radiation therapy and new-onset or worsening LUTS symptoms were shown to have a statistically significant reduction in urgency, frequency, nocturia, and bladder pain, as measured by patient-reported outcomes after intravesical treatment with HA and chondroitin sulfate.
Recommendation: Intravesical therapy with HA may improve symptoms of RHC and may provide further benefit in those with significant LUTS. Its slow onset of action and lack of research in severe hematuria may limit its usefulness in the acute or inpatient setting (Grade 3C).
# Other intravesical agents
Intravesical instillation of the antifibrinolytic agent epsilon aminocaproic acid (EACA) was shown to improve hematuria in 34 patients in case series of 37 patients with intractable bladder hemorrhage, most of whom had either radiation-or cyclophosphamide-induced cystitis; however this has not been repeated in contemporary studies since its publication in 1992. 30 Intravesical instillations of prostaglandins have been demonstrated in several smaller case series to be effective in treating hemorrhagic cystitis secondary to treatment with cyclophosphamide, but there are no large studies to suggest their effectiveness in RHC. 31 Silver nitrate instillations have been tried and were found to be ineffective in limiting RHC. 32 Recommendation: Several intravesical options have been trialed in limited case series, but require replication, etiology-specific assessment, or comparative data before they can be formally included as recommendations (Grade 3D).
# Systemic agents
# Hyperbaric oxygen therapy (HBOT)
Radiation to the bladder causes obliterative endarteritis of blood vessels creating cellular hypoxia, bladder ischemia, and fibrosis. This may lead to superficial fragile blood vessels prone to recurrent bleeding. 3 Patients who undergo HBOT inhale 100% O 2 at pressures of 1.4-3.0 ATM, allowing for hyperoxygenation of tissue. Hyperoxia induces primary neovascularization, secondary growth of healthy granulation tissue, and induces short-term vasoconstriction that may help control active bleeding. 33 HBOT is the most studied treatment option for RHC. A scoping review and meta-analyses evaluating this treatment on resolution of hematuria was recently published. It included one small, randomized control trial, two prospective trials, and 11 retrospective case series. 34 This meta-analysis represents 602 patients followed for at least one year. Partial or complete response was noted in 84% of patients (confidence interval 76-91) in the pooled analysis. The most common complications were barotrauma, frequent barotraumatic otitis in 6% of participants. Visual field disturbances were noted in 1% of participants.
Select case series offer followup data available for up to a decade after treatment and seem to suggest that successful treatment with HBOT may offer a durable response for patients. One study followed 32 of its participants for an average of 11.6 years and found the resolution rate of macroscopic hematuria to be 81%. 35 A smaller case series supported this data, as 12 of 13 participants remained free of hematuria at 10 years. 36 Recently, authors have sought to describe their experience using HBOT as a primary therapy in cases of severe RHC. In one study, 38 patients presenting with grade IV EORTC hematuria requiring transfusions received HBOT therapy as first-line monotherapy. 37 After an average of 33 treatments, 87% of patients had complete resolution of hematuria. Long-term data were not available to assess the durability to of treatment.
# Recommendation: Multiple studies have demonstrated that HBOT is safe and effective and should be considered an early treatment option for RHC in patients who have failed cystoscopy and fulguration. Due to significant resource and expertise requirements, its use may be limited based on access and availability (Grade 3C).
# Sodium pentosan polysulfate
Sodium pentosan polysulfate (SPP) is a semisynthetic polyscaccharide formulated as an oral medication that serves as a synthetic glycosaminoglycan. It adheres to the bladder mucosa, where it supplements the bladder's own glycosaminoglycan layer in a similar fashion as intravesical treatment with HA. It has been previously shown to be effective in the treatment of interstitial cystitis. 38 The largest study to assess its effectiveness in hematuria secondary to radiation followed 60 consecutively enrolled patients who were treated with 100 mg orally of SPP three times daily. 39 In 10 patients, hematuria was noted to have resolved completely, and there was partial resolution in 21 patients. However, the applicability of this study was limited by the large number of participants not available for followup or who passed away during the study from causes unrelated to hematuria. Two other small case series have also demonstrated the benefits of oral SPP. 40,41 Its usefulness was noted primarily by its safety, tolerability, and ease of administration; however, the onset of action was found to be 1-8 weeks, limiting its use in the acute setting. A recent case series has suggested a risk of pigmentary maculopathy associated with long-term chronic use of SPP (median duration of 186 months). 42 BPR: Radiation-induced hemorrhagic cystitis Recommendation: Several case series have shown a potential reduction of hematuria with treatment with SPP in patients with RHC. It is safe and generally well-tolerated, however, the slow onset of action may limit its usefulness in treatment of acute or severe RHC (Grade 3C).
# Experimental options
WF10, an intravenously administered macrophage regulator, has shown promising results for treatment and decreased recurrence of RCH in two studies published at a single centre, 43,44 but is not commercially available in Canada.
Two small case studies explored the use of estrogen in treatment of hemorrhagic cystitis of multiple etiologies. 45,46 While both showed reduction in hematuria, larger studies are needed before recommendations regarding effectiveness or safety can be made.
There is conflicting evidence that may point to a role for cranberry juice in preventing acute urinary symptoms in patients undergoing pelvic radiation; however, there is no data to suggest it has a role in management of late-effect RHC. There is a growing body of evidence exploring the use of tranexamic acid in the control of hemorrhage of multiple etiologies. Its use has previously been suggested in the management of RHC. 50 A randomized control trial recently assessed the use of intravenous tranexamic acid in controlling of hematuria of multiple etiologies in the acute setting. It found a decreased time on CBI until resolution of hematuria; however, no significant difference in blood loss or transfusions rates were noticed in the treatment group. 51 While further studies may demonstrate a benefit in treatment of patients with RHC with tranexamic acid, at this time there is insufficient published data to support this.
Recommendation: Multiple systemic agents have been used in small experimental situations for treatment of RHC. Until further studies are completed, no formal recommendations can be made regarding their use (Grade 3D).
# Refractory and life-threatening hematuria
# Transarterial embolization
Advances in interventional radiology have allowed for accurate selective and super-selective transarterial embolizations (TAE) that provide clinicians with management alternatives to more radical surgical procedures in patients with persistent or life-threatening hematuria. The benefit of TAE is its safety and tolerability in comparison to more aggressive surgical procedures in the frail and elderly patients, who make up a significant proportion of patients with RHC. However, these procedures are not without their own risks and side effects.
Unfortunately, many of the studies on TAE for hematuria include urological bleeding of multiple etiologies and do not discriminate between blood loss from bladder or prostatic origins. In a case series of 44 patients looking at the role of TAE in the management of intractable hematuria hemorrhage of oncological origin, Liguori et al found that the majority of patients (82%) experienced an initial resolution of hematuria. 52 The ability to perform selective and superselective TAE has reduced the risk of ischemic-related side effects. Historical studies have demonstrated ischemic-mediated side effects in as high as 65% in patients undergoing internal iliac artery embolization. 53 Although most of these are transient post-embolization syndrome, they also include more serious complications, such as bladder necrosis and, in rare cases, Brown-Sequard syndrome. Comparable modern series published in the last decade quote minor and selfresolving complication rates from 9-31%, with a technical success rate of 88-100%. 54,55 Recommendation: TAE is a viable option for control of RHC in those for whom less invasive methods have been unsuccessful. Preference should be given to selective or super-selective embolization when available to lessen possible side effects (Grade 3C).
# Formalin
Intravesical formalin was first described in the treatment of bladder hemorrhage in the late 1960s, and was soon assessed in a RHC cohort. The proposed mechanism involved capillary occlusion and protein fixation at the urothelium level. 56 Due to pain with administration, it must administered in an operating room setting with either a general or spinal anesthetic. While its rapid onset of action is appealing, its use is somewhat controversial because of its high morbidity, which appears to be proportional to the concentration of formalin used. 3 The largest review of the efficacy of formalin instillation to treat hemorrhagic cystitis of multiple etiologies was a systematic review of retrospective case series published in 1989. 57 The article included 235 patients stratified into three groups by the concentration of formalin instilled (10% vs. 3-6% vs. 1-2%). The complete response rates were 88%, 78%, and 71%, respectively. One benefit of formalin instillations was that complete response was typically achieved within 48 hours of a single instillation. Major complications were typically associated with refluxing into the upper urinary tract and consisted of ureteric stricture function, ureteropelvic junction and uretrovesical junction obstruction requiring urinary diversion, decreased bladder capacity, and vesicular fistulas. The mortality rates for 10% and 4-6% formalin instillation were recorded at 5.7% and 2.2%, respectively. No mortalities occurred in the 21 patients treated with 1-2% concentration.
Several other studies were completed that found formalin to be associated with a high treatment efficacy, but with Goucher et al potentially severe complications. In a study of 35 patient with RHC post-cervical radiation, 89% were found to have complete response after a single instillations; however, 31% had major complications. 58 One contemporary study investigated eight patients treated with formalin instillations after less invasive treatments had failed. In this study, each patient had a preoperative cystogram to assess for perforation or vesicoureteral reflux, and if any reflux was suspected, Fogarty catheters were used to obstruct the ureter. 56 Formalin concentration ranged from 1-4% and contact time was kept to 10-15 minutes. The complete resolution rate was 75% and only one patient had major complications necessitating intensive care unit admission. A detailed description of the procedure can be found within this article for clinicians unfamiliar with this treatment option.
Procedural variations for decreasing the morbidity associated with formalin instillations have been proposed, from decreasing formalin concentration to alternative methods of formalin delivery. A small, prospective study compared intravesical instillation of 4% formalin in 11 patients to endoscopic placement of formalin soaked pledgets. 59 Success rate was similar (82% and 75%, respectively), however the intravesicle instillation group suffered from four major complications, whereas the pledget group suffered only minor side effects. The differences were not statistically significant and while a comparable method was described in two individual case studies, 60,61 followup with further larger or prospective studies is lacking.
Recommendation: Due to significant morbidity associated with the procedure, formalin instillations should only be used in those who have failed less invasive treatments. If treatment is necessary, all attempts should be made to prevent reflux into the upper tracts, and the patient needs careful monitoring for potential side effects (Grade 3C).
# Cystectomy and urinary diversion
Unfortunately, a small percentage of patients will present with life-threatening hemorrhagic cystitis that is refractory to conservative and non-operative measures. These patients can be successfully treated with urinary diversion and cystectomy, however, the associated morbidity with this procedure is high. Several case series have examined the use of cystectomy in patients who had previously failed less invasive therapies. One series identified 21 patients with hemorrhagic cystitis, 17 from radiation therapy, who underwent cystectomy. 62 In this series, 42% of patients experienced severe complications (defined as Clavien grade III-V) and the 90-day mortality rate was 16%. This study echoes the findings of a larger case series looking at surgical outcomes from men undergoing urinary diversion via cystectomy for multiple adverse effects of radiation, including hematuria. 63 In this series, 36% of patients experienced Clavian III or greater complications, including 15% who required a second operation, and death in 4.5% of patients within the first 90 days. These rates of complications outpace the comparable rates in patients undergoing radical cystectomy for bladder cancer. Both authors attributed this to baseline fragility and comorbidities in this patient population exacerbated with the challenge of operating in a previously radiated field.
Small case studies have evaluated the use of urinary diversion alone in those who may not tolerate a cystectomy, either through cutaneous ureterostomy 64 or bilateral nephrostomy tubes. 65 Although both studies were quite small, they showed improvement in hematuria using urinary diversion alone; this may be a beneficial surgical alternative in patients for whom cystectomy is not a viable option. Caution should be advised, as long-term followup in urinary diversion without cystectomy for benign conditions has shown a high rate of complications in the remaining bladder. 66 Recommendation: Urinary diversion with or without cystectomy for RHC should be reserved only for those who have failed previously available therapy, and clinicians and patients should be aware of the high morbidity and mortality of the procedure before proceeding with surgery (Grade 3C).
# Discussion
# Treatment sequencing
There is a lack of consensus or comparative evidence to suggest superiority of one treatment of RHC over another. The lack of high-quality evidence has limited the ability for previous authors to conclusively state the order that treatment should be provided in the cases of refractory therapy. There have been several previous attempts to make recommendations for treatment algorithms, with the general consensus that treatments should be offered initially using the least invasive approaches and progressing to more invasive approaches as a general principle. This report seeks to provide a logical and stepwise approach to the management of radiation cystitis. Given the wide variety of clinical states that a patient with RHC may present, a linear treatment algorithm would be insufficient to provide treatment suggestions appropriate for different patients depending on the acuity and severity of the symptoms. Instead we have divided our treatments into three groups based on severity of clinical presentation and associated morbidity with treatment options (Fig. 1). The first box represents initial management and provides suggestions for investigations and supportive therapy. It is focused on upfront investigations to rule out other causes that may explain or exacerbate hemorrhagic cystitis. Underlying cor-BPR: Radiation-induced hemorrhagic cystitis rectable factors, such as infection, malignancy, or coagulopathies, should be treated if clinically possible.
The second group, patients with persistent or recurrent clinically significant hematuria, may apply to those who have required continuous bladder irrigation, irrigation, and clot evacuation as an inpatient and continue to have hematuria, but also acknowledges that there are many patients who have recurrent hematuria that is clinically significant who may benefit from treatment as an outpatient. The definition of "clinically significant" here may be broadly applied to any gross hematuria that is causing a marked burden on patients or negatively impacting their day-to-day living. Treatments recommended for patients in this group have been shown to be effective, safe, and well-tolerated by most patients. The four recommended treatment options here were chosen because they have evidence replicated from multiple centres, are clinically available in Canada, and have been approved and proven in comparable pathologies. As more research continues to be done on radiation cystitis, we may be able to add further therapies to this group. HBOT is offered here as initial therapy to reflect the growing amount of evidence that suggest it is an effective and safe treatment for RHC, including in those presenting with high-grade toxicities. Within this group, a clinician may consider onset of action as a deciding factor between therapies, as only alum irrigation has been shown to provide improvement within days of being started. HA and SPP both treat urinary symptoms associated with hemorrhagic cystitis in addition to hematuria.
The third category, "Refractory and life-threatening hematuria," includes patients who have previously been trialed and failed with treatment options from groups 1 and 2, and continue to have symptomatic hematuria that poses a threat to their safety and well-being. In these patients, treatment options typically have a rapid onset of action and have been proven to be effective, but may be associated with significant morbidity to the patient. Less invasive procedures, such as embolization or formalin instillation, should be attempted prior to surgical therapy. Once a mainstay of treatment, and commonly recommended in many former treatment algorithms, we recommend caution with the usage of formalin instillations, with special care to limit contact time, use the least concentrated formulation necessary, and to prevent systemic uptake or refluxing into the upper tracts. Clinicians and patients need to be aware of the high risk associated with cystectomy in post-radiation patients before proceeding to surgical intervention. In patients whom a cystectomy would not be appropriate, or with a limited life span, temporary diversion with either percutaneous nephrostomy tubes or cutaneous ureterostomies may be considered as an alternative.
# Conclusion
RHC remains a challenging medical condition that often presents in a frail and vulnerable population. In this report, we have presented a general approach and suggestions for management, as well as an overview of key research supporting specific therapies. These guidelines should always be used in the context of an individual patient's presentation, and may continue to evolve, as more evidence becomes available on the subject.
Competing interests: Dr. Saad reports personal fees and research grants from Amgen Inc, Astellas, Bayer, Janssen, and Sanofi. Dr. Lukka is a speaker for Astellas; has received grants and/or honoraria from Abbvie, Actavis, Amgen, Astellas, Bayer, Ferring, Janssen, Sanofi, and Tersera; owns stock and options in Vertex Pharmaceutical; and has participated in clinical trials supported by Bayer and Janssen. Dr. Kapoor has been an advisor for and has participated in clinical trials supported by Amgen, Astellas, GSK, Janssen, Novartis, Pfizer, and Sanofi. The remaining authors report no competing personal or financial interest related to this work. This paper has been peer-reviewed. | # Introduction
# Methodology
A comprehensive review of studies examining radiationinduced hemorrhagic cystitis was performed using PubMed, Medline, and the Cochrane Library database. The bibliographies of relevant articles were searched to avoid exclusion of meaningful articles. Where available, focus was given to systematic reviews and comparative studies; however, due to a lack of high-quality evidence, case series were included and made up the majority of articles included. All articles were reviewed using the evidence-based medicine levels, with a modified Oxford grading system for recommendations.
# Objective
This Best Practice Report (BPR) seeks to inform and educate readers on radiation-induced hemorrhagic cystitis (RHC), as well as a survey of commonly used treatment options available and the evidence available to support a given therapeutic choice. The primary outcome of interest was resolution of hematuria; where available, the effects of treatment on urinary symptoms are shared. A relative absence of comparative data has prevented previous reviews from providing firm guidelines in the management of RHC and this report relies heavily on retrospective case series with methodological limitations to form recommendations. Individual patient factors, available resources, and new research will continue to shape clinical decision-making.
# Background
Hemorrhagic cystitis refers to a collection of symptoms and signs defined by hematuria, lower urinary tract symptoms (LUTS), and cystoscopic findings indicative of underlying urothelial damage. It can have a number underlying causative factors: treatment with chemotherapeutic agents (such as cyclophosphamide and concurrent therapies); post-transplant patients; infection-mediated; treatment with radiation therapy. RHC is often an adverse event in patients with previous radiation to the pelvis for urological or gynecological malignancy and will be the focus of this BPR.
RHC is generally considered a separate pathologial process from acute radiation effects, with early signs of urothelial effects occurring at three months and pathological changes occurring 6-12 months after radiation. 1 New-onset symptoms have been recorded up to 20 years after radiation treatment. 2 The estimates for prevalence of RHC after radiation treatment varies widely depending on the diagnostic definitions used, but different studies have quoted them as 9-21% following treatment of prostate cancer, 3-6.7% for cervical cancer, and 2-47% for bladder cancer. 3 The use of modern treatment techniques, such as intensity-modulated radiation therapy and volumetric modulated arc therapy, have reduced the radiation dose to the bladder. Randomized studies have shown that the use of higher doses in the management of prostate cancer have resulted improved prostatespecific antigen (PSA) control using these modern treatment techniques, but with the same incidence of late complications. There has also been a trend to using hypofractionation radiotherapy regimens (higher dose per fraction given over a shorter timeframe). To minimize late bladder effects, emphasis needs to be paid to ensuring doses received by radiovulnerable structures, such as bowel and bladder, are kept within acceptable limits.
The exact mechanism by which radiation causes damage to the bladder is not entirely understood, but believed to be multifactorial. While direct damage to DNA is believed to be Goucher et al rare, it is hypothesized that indirect damage occurs through the creation of free radicals. 4 Histological studies have demonstrated increased proliferation of the urothelium in the months following radiation. Damage to tight cellular junctions and the loss of the normal polysaccharide layer allow for increased permeability of urine bacteria and metabolites causing increased damage to the underlying tissue. 1 This altered permeability of the urothelial cell layer has been demonstrated to be involved in late-stage radiation changes in rat models 5 and is hypothesized to play a large role in the development of post-radiation urinary symptoms. 6 Diffuse mucosal edema is noted in biopsies taken immediately post-radiation. This is followed by development of vascular telangiectasia, submucosal hemorrhage, and interstitial fibrosis. Subendothelial proliferation, edema, and medial thickening may progressively deplete the blood supply to urothelium, resulting in endarteritis obliterans causing acute and chronic ischemia. 3 These ischemic and necrotic changes are proposed to give rise to subsequent development of revascularization with superficial, fragile vessels that are responsible for bleeding in radiation cystitis. 4 Hospitalizations for RHC can be lengthy and costly. A recent retrospective study assessing 1111 patients admitted for RHC in 2013 showed the median cost associated with each admission to be $7157 USD. This number rose to $11 100 for those with hematuria severe enough to merit endoscopic evaluation/treatment. 7 Multiple studies have demonstrated the significant effect its protracted and recurrent nature can have on patient-rated quality of life scales. 8 There exists little consensus of how to best treat RHC, and previous surveys of practicing urologist have shown a lack of awareness of treatment options available. 9
# Classifications
The European Organization for Research and Treatment of Cancer/Radiation Therapy Oncology Group (EORTC/RTOG) classification of late radiation effects is a commonly used classification system for grading of RHC (Table 1). 10 It describes a combination of clinical and cystoscopic criteria for reporting late radiation effects. The Late Effects of Normal Tissues (LEBT)/SOMA scale has also been developed and uses a more complex combination of subjective, objective, management, and analytical factors into radiation effect classification. 11 A more recent move to replace these systems with a common terminology has led to the development of the Common Terminology Criteria for Adverse Events as a uniform lexicon for description of cancer-related adverse effects. 12
# Initial management
# Diagnosis and early assessment
In patients presenting with hematuria post-radiation, a thorough assessment is needed to rule out secondary causes before a diagnosis of RHC can be made. In a study exploring cystoscopic evaluation of 185 men treated with brachytherapy for prostate cancer who presented with either macroscopic hematuria, microscopic hematuria, or persistent lower urinary tract, 9.6% were found to have a new bladder tumour compared to 7% who were found to have radiation cystitis. 13 While the majority of these symptomatic post-brachytherapy patients had cystoscopies reported as normal (63.8%), a clinically significant number did have an observable etiology. Assessment should begin with a detailed history characterizing the symptoms and confirming the history and treatment plan of a patient's radiation therapy. Physical exams, including an abdominal and pelvic exam to assess for alternative causes of bleeding, should be included. Laboratory tests, including a complete blood count, coagulation studies, serum creatinine, urinalyses, urine culture and cytology, should be initiated. As with any patient presenting with hematuria and a high risk of malignancy, all patients should undergo axial imaging, preferably a computed tomography (CT)-urogram to assess for upper tract sources of bleeding, and should also undergo cystoscopic evaluation and biopsies of lesions concerning for malignancy. Mild symptoms may resolve with continuous bladder irrigation with saline solution and this should be tried first in all patients with hematuria associated with clotting or retention.
Recommendation: Assessment of a patient complaining of hematuria post-radiation therapy should identify or exclude other pathological factors that may explain or contribute to the patient's symptoms (Grade 4C).
# Cystoscopic evaluation
Cystoscopy in patients with new-onset or suspected RHC can be both diagnostic and therapeutic. The appearance of BPR: Radiation-induced hemorrhagic cystitis diffuse erythema, telangiectasia with or without ulcerations can help confirm the diagnosis of RHC. At the time of cystoscopy, fulguration of suspected vascular lesions may provide control of hematuria. In a case series assessing the effectiveness of cystoscopy and fulguration for hematuria control in patients with either radiation-or chemotherapy-induced symptoms, 61% (20/33) of patients achieved resolution of symptoms after initial endoscopic treatment. 14 Only 36% (4/11) of patients who had refractory symptoms responded to a second cystoscopy and fulguration.
Multiple small case series have assessed alternatives to fulguration with Greenlight laser, KTP laser treatment, and argon beam coagulator. [15][16][17] All series report laser therapy being well-tolerated and having a beneficial effect. In the future, they may play a larger role in the treatment of RHC; however, until larger studies can confirm their safety and effectiveness, they remain experimental in nature. Additional studies have investigated intravesical hemostatic gelatin matrix (Floseal) in six patients and was noted to be beneficial. [15][16][17] Fibrin glue has been trialed in the treatment of post-hematological stem cell transplant patients and found to reduce hematuria, 18 but it has yet to be investigated in the RHC population beyond individual case studies. 19 Recommendation: All patients with hematuria should undergo at least one initial cystoscopy with or without fulguration of suspect lesions and biopsy of any lesions concerning for malignancy for diagnostic and therapeutic purposes (Grade 3C). Laser therapy and endoscopic use of hemostatic agents may play a role in early management of RHC, but insufficient data exists to evaluate their efficacy and safety; long-term followup is needed prior to any recommendations being made (Grade 3D).
# Persistent or recurrent clinically significant hematuria
# Intravesical agents
# Alum irrigation
Intravesical aluminous salts act as an astringent agent and exert their effect through protein precipitation causing decreased capillary permeability, contraction of intercellular space, vasoconstriction, and hardening of the capillary endothelium. 20 It is typically administered as a 1% concentration of alum mixed with sterile water, irrigated through the bladder at 250-300 ml per hour, at a duration up to the discretion of the observing clinician. Ideally, the bladder should be irrigated free of clots prior to initiation of therapy. Historical case series have demonstrated the efficacy and tolerability of intravesical alum for a wide range of etiologies and presentations of intractable bladder hemorrhages. 21,22 The common side effects are bladder spasms, suprapubic discomfort, and clotting of the catheter due to precipitant formation. Individual case studies have reported a risk of aluminum toxicity in individuals in renal failure. 23 The most recent, and largest case series reported the use of alum irrigation in 40 patients (38 of whom had previous radiation treatment) with symptoms of hemorrhagic cystitis; 24 60% of these patients demonstrated an improvement in their symptoms and required no further treatment prior to discharge. The treatment was well-tolerated and 90% of patients were able to receive their treatment as prescribed. Two patients discontinued due to inability to tolerate bladder spasms and two for altered level of consciousness. Overall, 35% of patients experienced bladder spasms. Asymptomatic elevation in serum aluminum was detected in one patient that resolved on discontinuation of the treatment. At a median followup of 16.5 months, only 32% of patients required no further treatment, bringing the durability of this treatment into question.
Recommendation: Irrigation with alum is a practical and easily applied treatment for RHC with a comparatively acute onset of action that is generally well-tolerated. Special caution should be used in patients with poor renal function (Grade 3C).
# Hyaluronic acid
Hyaluronic acid (HA) is a mucopolysaccharide whose therapeutic benefit is believed to be mediated by the repair of the normal glycoaminoglycan layer of the bladder when applied as intravesical installations. It has been shown that radiation leads to defects in this protective layer, leading to chronic inflammatory changes and delayed or prevented healing of urothelial cells. 25 Its use as an intravesical agent is well-studied in the treatment of interstitial cystitis and painful bladder syndrome, where it was recently recommended as a treatment option in the Canadian Urological Association guideline. 26 One of the few randomized trials comparing treatment modalities for RHC randomized 36 patients to either intravesical therapy with HA or treatment with hyperbaric oxygen therapy (HBOT). 27 In the HA group, patients received intravesical therapy once weekly for one month and then monthly for two months. Patients in the HBOT group received daily treatments for 30 treatments. Followup assessment of symptoms were done at six, 12, and 18 months following therapy. Complete resolution of hematuria was noted in 88%, 75%, and 50% of HA patients at those intervals and in 75%, 50%, and 45% of patients in the HBOT group. The difference was not statistically significant at any interval and the author concluded the HA therapy was at least as effective as HBOT in the treatment of hematuria.
A prospective, observational study of 20 patients undergoing treatment with intravesical HA compared grading of radiation cystitis, including hematuria, as per EORTC/ROTG classification (scale 1-5) before treatment and again three months Goucher et al after the completion of six scheduled treatments. 28 The mean radiocystitis scores before and after HA treatment were 2.70 and 1.45, respectively (p<0.01), with only minor side effects described. It is notable that no patients with grade 4 or 5 toxicity, considered severe symptoms, were included in this study. Beyond hematuria, recent prospectively collected data suggests that intravesical treatment with HA in combination with chondroitin sulfate (another glycosamniglycan) produces a clinically significant improvement in post-radiation LUTS and bother. In a study published by Gacci et al, 29 80 patients with previous radiation therapy and new-onset or worsening LUTS symptoms were shown to have a statistically significant reduction in urgency, frequency, nocturia, and bladder pain, as measured by patient-reported outcomes after intravesical treatment with HA and chondroitin sulfate.
Recommendation: Intravesical therapy with HA may improve symptoms of RHC and may provide further benefit in those with significant LUTS. Its slow onset of action and lack of research in severe hematuria may limit its usefulness in the acute or inpatient setting (Grade 3C).
# Other intravesical agents
Intravesical instillation of the antifibrinolytic agent epsilon aminocaproic acid (EACA) was shown to improve hematuria in 34 patients in case series of 37 patients with intractable bladder hemorrhage, most of whom had either radiation-or cyclophosphamide-induced cystitis; however this has not been repeated in contemporary studies since its publication in 1992. 30 Intravesical instillations of prostaglandins have been demonstrated in several smaller case series to be effective in treating hemorrhagic cystitis secondary to treatment with cyclophosphamide, but there are no large studies to suggest their effectiveness in RHC. 31 Silver nitrate instillations have been tried and were found to be ineffective in limiting RHC. 32 Recommendation: Several intravesical options have been trialed in limited case series, but require replication, etiology-specific assessment, or comparative data before they can be formally included as recommendations (Grade 3D).
# Systemic agents
# Hyperbaric oxygen therapy (HBOT)
Radiation to the bladder causes obliterative endarteritis of blood vessels creating cellular hypoxia, bladder ischemia, and fibrosis. This may lead to superficial fragile blood vessels prone to recurrent bleeding. 3 Patients who undergo HBOT inhale 100% O 2 at pressures of 1.4-3.0 ATM, allowing for hyperoxygenation of tissue. Hyperoxia induces primary neovascularization, secondary growth of healthy granulation tissue, and induces short-term vasoconstriction that may help control active bleeding. 33 HBOT is the most studied treatment option for RHC. A scoping review and meta-analyses evaluating this treatment on resolution of hematuria was recently published. It included one small, randomized control trial, two prospective trials, and 11 retrospective case series. 34 This meta-analysis represents 602 patients followed for at least one year. Partial or complete response was noted in 84% of patients (confidence interval [CI] 76-91) in the pooled analysis. The most common complications were barotrauma, frequent barotraumatic otitis in 6% of participants. Visual field disturbances were noted in 1% of participants.
Select case series offer followup data available for up to a decade after treatment and seem to suggest that successful treatment with HBOT may offer a durable response for patients. One study followed 32 of its participants for an average of 11.6 years and found the resolution rate of macroscopic hematuria to be 81%. 35 A smaller case series supported this data, as 12 of 13 participants remained free of hematuria at 10 years. 36 Recently, authors have sought to describe their experience using HBOT as a primary therapy in cases of severe RHC. In one study, 38 patients presenting with grade IV EORTC hematuria requiring transfusions received HBOT therapy as first-line monotherapy. 37 After an average of 33 treatments, 87% of patients had complete resolution of hematuria. Long-term data were not available to assess the durability to of treatment.
# Recommendation: Multiple studies have demonstrated that HBOT is safe and effective and should be considered an early treatment option for RHC in patients who have failed cystoscopy and fulguration. Due to significant resource and expertise requirements, its use may be limited based on access and availability (Grade 3C).
# Sodium pentosan polysulfate
Sodium pentosan polysulfate (SPP) is a semisynthetic polyscaccharide formulated as an oral medication that serves as a synthetic glycosaminoglycan. It adheres to the bladder mucosa, where it supplements the bladder's own glycosaminoglycan layer in a similar fashion as intravesical treatment with HA. It has been previously shown to be effective in the treatment of interstitial cystitis. 38 The largest study to assess its effectiveness in hematuria secondary to radiation followed 60 consecutively enrolled patients who were treated with 100 mg orally of SPP three times daily. 39 In 10 patients, hematuria was noted to have resolved completely, and there was partial resolution in 21 patients. However, the applicability of this study was limited by the large number of participants not available for followup or who passed away during the study from causes unrelated to hematuria. Two other small case series have also demonstrated the benefits of oral SPP. 40,41 Its usefulness was noted primarily by its safety, tolerability, and ease of administration; however, the onset of action was found to be 1-8 weeks, limiting its use in the acute setting. A recent case series has suggested a risk of pigmentary maculopathy associated with long-term chronic use of SPP (median duration of 186 months). 42 BPR: Radiation-induced hemorrhagic cystitis Recommendation: Several case series have shown a potential reduction of hematuria with treatment with SPP in patients with RHC. It is safe and generally well-tolerated, however, the slow onset of action may limit its usefulness in treatment of acute or severe RHC (Grade 3C).
# Experimental options
WF10, an intravenously administered macrophage regulator, has shown promising results for treatment and decreased recurrence of RCH in two studies published at a single centre, 43,44 but is not commercially available in Canada.
Two small case studies explored the use of estrogen in treatment of hemorrhagic cystitis of multiple etiologies. 45,46 While both showed reduction in hematuria, larger studies are needed before recommendations regarding effectiveness or safety can be made.
There is conflicting evidence that may point to a role for cranberry juice in preventing acute urinary symptoms in patients undergoing pelvic radiation; however, there is no data to suggest it has a role in management of late-effect RHC. [47][48][49] There is a growing body of evidence exploring the use of tranexamic acid in the control of hemorrhage of multiple etiologies. Its use has previously been suggested in the management of RHC. 50 A randomized control trial recently assessed the use of intravenous tranexamic acid in controlling of hematuria of multiple etiologies in the acute setting. It found a decreased time on CBI until resolution of hematuria; however, no significant difference in blood loss or transfusions rates were noticed in the treatment group. 51 While further studies may demonstrate a benefit in treatment of patients with RHC with tranexamic acid, at this time there is insufficient published data to support this.
Recommendation: Multiple systemic agents have been used in small experimental situations for treatment of RHC. Until further studies are completed, no formal recommendations can be made regarding their use (Grade 3D).
# Refractory and life-threatening hematuria
# Transarterial embolization
Advances in interventional radiology have allowed for accurate selective and super-selective transarterial embolizations (TAE) that provide clinicians with management alternatives to more radical surgical procedures in patients with persistent or life-threatening hematuria. The benefit of TAE is its safety and tolerability in comparison to more aggressive surgical procedures in the frail and elderly patients, who make up a significant proportion of patients with RHC. However, these procedures are not without their own risks and side effects.
Unfortunately, many of the studies on TAE for hematuria include urological bleeding of multiple etiologies and do not discriminate between blood loss from bladder or prostatic origins. In a case series of 44 patients looking at the role of TAE in the management of intractable hematuria hemorrhage of oncological origin, Liguori et al found that the majority of patients (82%) experienced an initial resolution of hematuria. 52 The ability to perform selective and superselective TAE has reduced the risk of ischemic-related side effects. Historical studies have demonstrated ischemic-mediated side effects in as high as 65% in patients undergoing internal iliac artery embolization. 53 Although most of these are transient post-embolization syndrome, they also include more serious complications, such as bladder necrosis and, in rare cases, Brown-Sequard syndrome. Comparable modern series published in the last decade quote minor and selfresolving complication rates from 9-31%, with a technical success rate of 88-100%. 54,55 Recommendation: TAE is a viable option for control of RHC in those for whom less invasive methods have been unsuccessful. Preference should be given to selective or super-selective embolization when available to lessen possible side effects (Grade 3C).
# Formalin
Intravesical formalin was first described in the treatment of bladder hemorrhage in the late 1960s, and was soon assessed in a RHC cohort. The proposed mechanism involved capillary occlusion and protein fixation at the urothelium level. 56 Due to pain with administration, it must administered in an operating room setting with either a general or spinal anesthetic. While its rapid onset of action is appealing, its use is somewhat controversial because of its high morbidity, which appears to be proportional to the concentration of formalin used. 3 The largest review of the efficacy of formalin instillation to treat hemorrhagic cystitis of multiple etiologies was a systematic review of retrospective case series published in 1989. 57 The article included 235 patients stratified into three groups by the concentration of formalin instilled (10% vs. 3-6% vs. 1-2%). The complete response rates were 88%, 78%, and 71%, respectively. One benefit of formalin instillations was that complete response was typically achieved within 48 hours of a single instillation. Major complications were typically associated with refluxing into the upper urinary tract and consisted of ureteric stricture function, ureteropelvic junction and uretrovesical junction obstruction requiring urinary diversion, decreased bladder capacity, and vesicular fistulas. The mortality rates for 10% and 4-6% formalin instillation were recorded at 5.7% and 2.2%, respectively. No mortalities occurred in the 21 patients treated with 1-2% concentration.
Several other studies were completed that found formalin to be associated with a high treatment efficacy, but with Goucher et al potentially severe complications. In a study of 35 patient with RHC post-cervical radiation, 89% were found to have complete response after a single instillations; however, 31% had major complications. 58 One contemporary study investigated eight patients treated with formalin instillations after less invasive treatments had failed. In this study, each patient had a preoperative cystogram to assess for perforation or vesicoureteral reflux, and if any reflux was suspected, Fogarty catheters were used to obstruct the ureter. 56 Formalin concentration ranged from 1-4% and contact time was kept to 10-15 minutes. The complete resolution rate was 75% and only one patient had major complications necessitating intensive care unit admission. A detailed description of the procedure can be found within this article for clinicians unfamiliar with this treatment option.
Procedural variations for decreasing the morbidity associated with formalin instillations have been proposed, from decreasing formalin concentration to alternative methods of formalin delivery. A small, prospective study compared intravesical instillation of 4% formalin in 11 patients to endoscopic placement of formalin soaked pledgets. 59 Success rate was similar (82% and 75%, respectively), however the intravesicle instillation group suffered from four major complications, whereas the pledget group suffered only minor side effects. The differences were not statistically significant and while a comparable method was described in two individual case studies, 60,61 followup with further larger or prospective studies is lacking.
Recommendation: Due to significant morbidity associated with the procedure, formalin instillations should only be used in those who have failed less invasive treatments. If treatment is necessary, all attempts should be made to prevent reflux into the upper tracts, and the patient needs careful monitoring for potential side effects (Grade 3C).
# Cystectomy and urinary diversion
Unfortunately, a small percentage of patients will present with life-threatening hemorrhagic cystitis that is refractory to conservative and non-operative measures. These patients can be successfully treated with urinary diversion and cystectomy, however, the associated morbidity with this procedure is high. Several case series have examined the use of cystectomy in patients who had previously failed less invasive therapies. One series identified 21 patients with hemorrhagic cystitis, 17 from radiation therapy, who underwent cystectomy. 62 In this series, 42% of patients experienced severe complications (defined as Clavien grade III-V) and the 90-day mortality rate was 16%. This study echoes the findings of a larger case series looking at surgical outcomes from men undergoing urinary diversion via cystectomy for multiple adverse effects of radiation, including hematuria. 63 In this series, 36% of patients experienced Clavian III or greater complications, including 15% who required a second operation, and death in 4.5% of patients within the first 90 days. These rates of complications outpace the comparable rates in patients undergoing radical cystectomy for bladder cancer. Both authors attributed this to baseline fragility and comorbidities in this patient population exacerbated with the challenge of operating in a previously radiated field.
Small case studies have evaluated the use of urinary diversion alone in those who may not tolerate a cystectomy, either through cutaneous ureterostomy 64 or bilateral nephrostomy tubes. 65 Although both studies were quite small, they showed improvement in hematuria using urinary diversion alone; this may be a beneficial surgical alternative in patients for whom cystectomy is not a viable option. Caution should be advised, as long-term followup in urinary diversion without cystectomy for benign conditions has shown a high rate of complications in the remaining bladder. 66 Recommendation: Urinary diversion with or without cystectomy for RHC should be reserved only for those who have failed previously available therapy, and clinicians and patients should be aware of the high morbidity and mortality of the procedure before proceeding with surgery (Grade 3C).
# Discussion
# Treatment sequencing
There is a lack of consensus or comparative evidence to suggest superiority of one treatment of RHC over another. The lack of high-quality evidence has limited the ability for previous authors to conclusively state the order that treatment should be provided in the cases of refractory therapy. There have been several previous attempts to make recommendations for treatment algorithms, with the general consensus that treatments should be offered initially using the least invasive approaches and progressing to more invasive approaches as a general principle. [67][68][69][70][71] This report seeks to provide a logical and stepwise approach to the management of radiation cystitis. Given the wide variety of clinical states that a patient with RHC may present, a linear treatment algorithm would be insufficient to provide treatment suggestions appropriate for different patients depending on the acuity and severity of the symptoms. Instead we have divided our treatments into three groups based on severity of clinical presentation and associated morbidity with treatment options (Fig. 1). The first box represents initial management and provides suggestions for investigations and supportive therapy. It is focused on upfront investigations to rule out other causes that may explain or exacerbate hemorrhagic cystitis. Underlying cor-BPR: Radiation-induced hemorrhagic cystitis rectable factors, such as infection, malignancy, or coagulopathies, should be treated if clinically possible.
The second group, patients with persistent or recurrent clinically significant hematuria, may apply to those who have required continuous bladder irrigation, irrigation, and clot evacuation as an inpatient and continue to have hematuria, but also acknowledges that there are many patients who have recurrent hematuria that is clinically significant who may benefit from treatment as an outpatient. The definition of "clinically significant" here may be broadly applied to any gross hematuria that is causing a marked burden on patients or negatively impacting their day-to-day living. Treatments recommended for patients in this group have been shown to be effective, safe, and well-tolerated by most patients. The four recommended treatment options here were chosen because they have evidence replicated from multiple centres, are clinically available in Canada, and have been approved and proven in comparable pathologies. As more research continues to be done on radiation cystitis, we may be able to add further therapies to this group. HBOT is offered here as initial therapy to reflect the growing amount of evidence that suggest it is an effective and safe treatment for RHC, including in those presenting with high-grade toxicities. Within this group, a clinician may consider onset of action as a deciding factor between therapies, as only alum irrigation has been shown to provide improvement within days of being started. HA and SPP both treat urinary symptoms associated with hemorrhagic cystitis in addition to hematuria.
The third category, "Refractory and life-threatening hematuria," includes patients who have previously been trialed and failed with treatment options from groups 1 and 2, and continue to have symptomatic hematuria that poses a threat to their safety and well-being. In these patients, treatment options typically have a rapid onset of action and have been proven to be effective, but may be associated with significant morbidity to the patient. Less invasive procedures, such as embolization or formalin instillation, should be attempted prior to surgical therapy. Once a mainstay of treatment, and commonly recommended in many former treatment algorithms, we recommend caution with the usage of formalin instillations, with special care to limit contact time, use the least concentrated formulation necessary, and to prevent systemic uptake or refluxing into the upper tracts. Clinicians and patients need to be aware of the high risk associated with cystectomy in post-radiation patients before proceeding to surgical intervention. In patients whom a cystectomy would not be appropriate, or with a limited life span, temporary diversion with either percutaneous nephrostomy tubes or cutaneous ureterostomies may be considered as an alternative.
# Conclusion
RHC remains a challenging medical condition that often presents in a frail and vulnerable population. In this report, we have presented a general approach and suggestions for management, as well as an overview of key research supporting specific therapies. These guidelines should always be used in the context of an individual patient's presentation, and may continue to evolve, as more evidence becomes available on the subject.
#
Competing interests: Dr. Saad reports personal fees and research grants from Amgen Inc, Astellas, Bayer, Janssen, and Sanofi. Dr. Lukka is a speaker for Astellas; has received grants and/or honoraria from Abbvie, Actavis, Amgen, Astellas, Bayer, Ferring, Janssen, Sanofi, and Tersera; owns stock and options in Vertex Pharmaceutical; and has participated in clinical trials supported by Bayer and Janssen. Dr. Kapoor has been an advisor for and has participated in clinical trials supported by Amgen, Astellas, GSK, Janssen, Novartis, Pfizer, and Sanofi. The remaining authors report no competing personal or financial interest related to this work. This paper has been peer-reviewed. | None | None |
a46536061e02e7b323c068cea7741448c8139bc0 | cma | None | - The document entitled Guidance for Surgery After COVID-19 Infection: Timing of Surgery Following Recovery from COVID-19 to Reduce Risk of Postoperative Mortality has been rescinded.
- This guidance document was developed in January 2022.
- It was based on pre-Omicron variant COVID-19 data. There is now more information available about how the Omicron sub-variants affect patients peri-operatively. - In addition, the patient population is generally more immune due to COVID-19 infection or vaccine or both.
- Clinicians should follow the American Society of Anesthesiologists (ASA) and Anesthesia Patient Safety Foundation (APSF) Joint Statement on Elective Surgery and Anesthesia for Patients after COVID-19 Infection when determining timing of surgery following recovery from COVID-19 infection in a shared decision-making model with the patient.
- It is hoped that there will be an update to this guidance that takes into account the effect of COVID-19 immunization status on patient surgical outcomes. - COVID-19 immunization status is one component of the risk assessment that should be done pre-operatively. This information may not always be available. - Therefore, it is up to the clinical team to use best judgement based on the available information. - However, procedures should not be delayed or cancelled based on COVID-19 immunization status alone.
Please contact:
- [email protected] for general questions about this provincial guidance.
- Site Surgery and/or Anesthesia leads for patient-or site-specific questions. | #
1. The document entitled Guidance for Surgery After COVID-19 Infection: Timing of Surgery Following Recovery from COVID-19 to Reduce Risk of Postoperative Mortality has been rescinded.
• This guidance document was developed in January 2022.
• It was based on pre-Omicron variant COVID-19 data. There is now more information available about how the Omicron sub-variants affect patients peri-operatively. • In addition, the patient population is generally more immune due to COVID-19 infection or vaccine or both.
2. Clinicians should follow the American Society of Anesthesiologists (ASA) and Anesthesia Patient Safety Foundation (APSF) Joint Statement on Elective Surgery and Anesthesia for Patients after COVID-19 Infection when determining timing of surgery following recovery from COVID-19 infection in a shared decision-making model with the patient.
• It is hoped that there will be an update to this guidance that takes into account the effect of COVID-19 immunization status on patient surgical outcomes. • COVID-19 immunization status is one component of the risk assessment that should be done pre-operatively. This information may not always be available. • Therefore, it is up to the clinical team to use best judgement based on the available information. • However, procedures should not be delayed or cancelled based on COVID-19 immunization status alone.
Please contact:
• [email protected] for general questions about this provincial guidance.
• Site Surgery and/or Anesthesia leads for patient-or site-specific questions. | None | None |
d0e9e09a7346636b37235e3b1ab982f7da6d0b5b | cma | None | CT-confirmed Grade 1-2 splenic injuries without evidence of active haemorrhage or pseudoaneurysm, anticoagulated patient, associated major injury, age ≥65 or limited physiologic reserve. - CT-confirmed Grade 1-2 splenic injuries without evidence of active haemorrhage or pseudoaneurysm, anticoagulated patient, associated major injury, age ≥65 or limited physiologic reserve.# TABLE OF CONTENTS
# PURPOSE
The purpose of this clinical practice guideline (CPG) is to review best evidence and generate expert consensus on recommendations for the management of isolated blunt splenic trauma in adult patients ( 5. With regard to selective versus non-selective angioembolization, what is the preferred approach to angioembolization in splenic injuries?
# III. TRANSFER TO HIGHER LEVEL OF CARE
- What are the indications for transfer of patients with blunt splenic injuries to a higher-level trauma center?
IV. ACUTE HOSPITAL CARE 7. What type and duration of monitoring are necessary for patients with blunt splenic injuries? 8. When is supplementary imaging required in the hospitalized patient?
- What activity restrictions should be imposed on patients with blunt splenic injuries, in hospital and post-discharge?
# V. VENOUS THROMBOEMBOLISM (VTE) PROPHYLAXIS
- What is the optimal timing for initiating deep vein thrombosis (DVT) prophylaxis in patients with blunt splenic injuries? The injury grade can be estimated from the radiology report. The radiologist should report: i. the presence/absence of hilar involvement, ii.
the percentage of splenic parenchymal injury/hematoma (50%), iii.
the presence of active bleeding, and iv.
presence of a pseudoaneurysm.
Generally, Grade 1 and 2 injuries are considered low grade injuries while Grade 3-5 are considered high grade injuries.
# ALGORITHM
# SUMMARY OF RECOMMENDATIONS
All recommendations are newly drafted by the Thoraco-Abdominal SAG, unless indicated otherwise.
# I. INITIAL ASSESSMENT AND MANAGEMENT
A. Initial resuscitation and management of the patient with blunt abdominal trauma should follow the Advanced Trauma Life Support® (ATLS®) principles.
B. In centres with surgical capability, the on-call general surgeon should be consulted promptly when a splenic injury is suspected or proven.
# II. OPERATIVE MANAGEMENT
A. In centres with general surgical capability, urgent splenectomy should be performed for a hemodynamically unstable patient with a splenic injury who is not responding to appropriate resuscitation.
B. Grade or severity of splenic injury is not, in and of itself, an indication for surgical management of the injured spleen. The decision to proceed to splenectomy should be based on the clinical presentation of the patient and situational context, which includes the capabilities of the site, resources available, presence of other injuries, transport availability, and transfer related issues.
C. A general surgeon should be involved early in decision-making for suspected or proven splenic injury. Tele-conferencing through Patient Transfer Network (PTN) to discuss optimal management (transport vs. splenectomy) should be performed. The conference call should include the sending physician, the receiving general surgeon and the receiving Trauma Team Leader (TTL) at the higher level of care (HLOC) trauma referral centre.
# III. NON-OPERATIVE MANAGEMENT
A. A trial of non-operative management (NOM) for splenic injury is indicated in patients with proven splenic injury who are hemodynamically stable after appropriate resuscitation. There are no absolute contraindications to a trial of NOM of known splenic injury in the hemodynamically stable or stabilized patient.
B. Hemodynamically stable patients with negligible risk- of ongoing or delayed hemorrhage may be safely managed, without higher level of care (HLOC) transfer, in a rural/remote facility provided at least 2 units of packed red blood cells are available. This management plan should be reviewed with a general surgeon and Trauma Team Leader (TTL) on call at the HLOC trauma referral centre in sites without surgical capabilities.
C. NOM of Grade 3-5 splenic injuries should only be considered in a hospital that has capabilities for physiologic monitoring and serial clinical evaluations by a general surgeon are possible. The hospital also needs 4 or more units of blood available, CT imaging, and 24-7 operating room access. Access to 24-7 interventional radiology for angiography/angioembolization is preferred but not essential. For transfer indications, see IV. TRANSFER TO HIGHER LEVEL OF CARE below.
# IV. ANGIOGRAPHY/ANGIOEMBOLIZATION
A. Emergent angiography/angioembolization is indicated in hemodynamically unstable patients with immediate access to interventional radiology who have responded to appropriate resuscitation and demonstrate active vascular extravasation on contrast CT. The higher level of care transfer of splenic injury patients that are or have been unstable for the purposes of urgent angioembolization is not recommended if the patient is in a centre with general surgical capability and can perform splenectomy.
B. Emergent angiography/angioembolization is indicated in hemodynamically stable patients with major free extravasation not likely to abate.
C. Angioembolization within 72 hours is indicated in hemodynamically stable or stabilized patients with pseudoaneurysm or arterio-venous fistula identified on CT or ultrasound imaging.
D. Patients with splenic injury demonstrating contrast blush on CT are at an elevated risk for failing non-operative management (NOM). The consulting surgeon and interventional radiologist should communicate once initial imaging is completed and collaborate on a management plan in the event of failure of NOM.
E. In centres without interventional radiology capability, if follow-up imaging demonstrates an indication for angioembolization, patients should be transferred under the care of a general surgeon to a higher level of care (HLOC) trauma referral centre for this procedure within 48 hours.
F. In the presence of a single vascular abnormality (contrast blush, pseudo-aneurysms, and arteriovenous fistula) in minor and moderate injuries, the currently available literature is inconclusive regarding whether proximal or distal embolization should be used. In general, selective angioembolization is preferred, where safe and feasible.
# V. TRANSFER TO HIGHER LEVEL OF CARE (HLOC)
Immediate Transfer (< 24 hours):
A. Patients who are hemodynamically stable with associated major injuries requiring urgent higher level of care (e.g. traumatic brain injury) should be transferred promptly to a Level 1 or 2 trauma centre.
B. Hemodynamically stable patients with negligible risk- of ongoing or delayed hemorrhage may be safely managed, without higher level of care (HLOC) transfer, in a rural/remote facility provided at least 2 units of packed red blood cells are available. This management plan should be reviewed with a general surgeon and Trauma Team Leader (TTL) on call at the HLOC trauma referral centre in sites without surgical capabilities.
C. Patients with Grade 3-5 splenic injuries or associated major injury should be transferred to an appropriate trauma referral centre. Centres receiving these patients should have IR capability to facilitate angioembolization if needed. A general surgeon must be actively involved in the transfer process and the ongoing care of transferred patients.
D. The HLOC transfer of splenic injury patients that are or have been unstable for the purposes of urgent angioembolization is not recommended if the patient is in a centre with general surgical capability and can perform splenectomy.
E. For patients undergoing emergent splenectomy prior to HLOC transfer, arrangements for transfer through Patient Transfer Network (PTN) should be made as early as possible, preferably pre-operatively or intraoperatively to avoid delay.
Delayed Transfer (> 24 hours):
F. In centres without interventional radiology capability, if follow-up imaging demonstrates an indication for angioembolization, patients should be transferred under the care of a general surgeon to a HLOC trauma referral centre for this procedure within 48 hours.
# VI. ACUTE HOSPITAL CARE
A. Patients with Grade 1-2 splenic injuries can be monitored in a general surgery ward. The patient should have good IV access and assessed frequently for vital signs.
B. Patients with Grade 3-5 splenic injuries undergoing non-operative management (NOM) should be observed initially in a monitored intermediate care unit or intensive care unit (ICU). Appropriate initial monitoring includes the capacity to provide hourly vital signs as well as cardiac, oxygen saturation and urine output monitoring. Serial examination by a general surgeon is essential.
C. Hemoglobin should be monitored at regular intervals until stabilized.
D. It is recommended that therapeutic anticoagulation be reversed promptly in patients with high risk splenic injury, unless the risk of reversal is considered higher than the risk of splenic hemorrhage.
E. Repeat CT imaging in hemodynamically stable patients should be obtained within 72 hours postinjury for Grade 3-5 splenic injuries. Any changes in clinical status should prompt urgent reassessment, including laboratory investigations and/or CT as appropriate.
F. There is no need to restrict mobilization in patients with splenic injury and early mobilization is encouraged. Patients with high risk injuries- should remain supervised until assessed as safe to ambulate independently off unit.
*CT-confirmed Grade 3-5 splenic injuries, particularly with evidence of active haemorrhage or pseudoaneurysm, anticoagulated patient, associated major injury, age ≥65 or limited physiologic reserve.
G. Post-discharge, patients with Grade 3-5 splenic injuries should avoid contact sports or vigorous activities for at least 8 weeks. Patients with Grade 3-5 splenic injuries should be re-imaged prior to resuming high-risk activities.
# VII. VENOUS THROMBOEMBOLISM (VTE) PROPHYLAXIS
A. Pharmacologic prophylaxis to prevent venous thromboembolism (VTE) can be used for patients with isolated blunt splenic injuries without increasing the failure rate of non-operative management. Although the optimal timing of safe initiation has not been determined, deep vein thrombosis (DVT) prophylaxis may be started as soon as possible after trauma and within 12 hours for every Grade of splenic injury (e.g. 36 hours for Grade 3 injury) or sooner if hemoglobin is stable. B. Mechanical prophylaxis should be used in all patients with absolute contraindication to pharmacologic prophylaxis, except in patients with lower extremity trauma in which case mechanical prophylaxis is not efficacious.
# SCIENTIFIC DISCUSSION
All recommendations are newly drafted by the Thoraco-Abdominal SAG, unless indicated otherwise.
# I. INITIAL ASSESSMENT AND MANAGEMENT
# II. OPERATIVE MANAGEMENT
# KMQ-2. What are the indications for operative management (OM) of blunt splenic injuries? RECOMMENDATIONS
A. In centres with general surgical capability, urgent splenectomy should be performed for a hemodynamically unstable patient with a splenic injury who is not responding to appropriate resuscitation.
B. Grade or severity of splenic injury is not, in and of itself, an indication for surgical management of the injured spleen. The decision to proceed to splenectomy should be based on the clinical presentation of the patient and situational context, which includes the capabilities of the site, resources available, presence of other injuries, transport availability, and transfer related issues.
C. A general surgeon should be involved early in decision-making for suspected or proven splenic injury. Tele-conferencing through Patient Transfer Network (PTN) to discuss optimal management (transport vs. splenectomy) should be performed. The conference call should include the sending physician, the receiving general surgeon and the receiving Trauma Team Leader (TTL) at the higher level of care (HLOC) trauma referral centre.
# KNOWLEDGE SYNTHESIS
# Additional Literature Support
# What is the success rate of non-operative management of blunt splenic injuries?
Overall reported success rate of observational management (without angiography) is 92-96 %. 3,4,5,6 Recent success rate of non-operative management (NOM) (i.e. observational management only + NOM with angioembolization) has been reported in the range of 93-100 %. 6,8
# Success rate of observational management of blunt splenic injury by injury grade
# What are the complications of non-operative management of blunt splenic injury?
Complications in NOM in blunt splenic injury include progression to splenectomy, hemodynamic instability and/or evidence of ongoing bleeding, and delayed laparotomy for missed associated injury, resulting in re-admission or emergency laparotomy.
Overall reported failure rate of NOM is 4-15 % (according to a 2017 review of studies published 2000 onwards 9 ), with higher rates reported for high grade injuries:
# What is the risk (probability) of delayed hemorrhage following non-operative management of splenic injuries?
Probability of delayed hemorrhage after NOM ranges from 0-15 % 6,16,17, with a higher probability in higher Grade injuries. 2 It is difficult to distinguish between delayed hemorrhage and hemorrhage that was missed on the initial CT. This is particularly the case with older studies that used older CT technology. For this reason, more recent studies that clearly indicate delayed hemorrhage have been consulted.
# What is the rate of spontaneous resolution of active hemorrhage detected as contrast blush on initial CT scan?
Probability of blush detected on CT leading to absence of extravasation on angiography ranges from 2.3-47 % 18,19,20 One retrospective study showed 100% (3/3) patients with contrast blush on initial CT had no blush on post-transfer repeat CT. 19 Conservatively estimated, NOM of splenic injury results in a success rate of >98% for Grade 1-2 injuries, >90% for Grade 3 injuries, and >75% for Grade 4-5 injuries. Angiography is variably used to achieve these rates.
# IV. ANGIOGRAPHY / ANGIOEMBOLIZATION
# Additional Literature Support
# What is the success rate of angiography/angioembolizations in blunt splenic injuries?
Success rate of AG/AE range from 73-100%. 21 In severe injuries (Grades 4-5), difference in success rate between NOM with and without angioembolization can be as great as 78.4 %. 6 Failure rate of NOM without AG/AE can be as high as 26% in these injuries. 22 Conflicting evidence exists for the benefits of angioembolization in preventing splenectomy. 23,24 What are the complications of angiography/angioembolizations in blunt splenic injuries?
Major complications of AE include: delayed bleeding, total or subtotal splenic infarction, splenic abscesses, acute renal insufficiency, pseudocysts, and puncture-related complications. Rate of major complications range from 3.7-28.5 %. 1,2 Minor complications include fever, pleural effusion, coil migration, and partial splenic infarction. Rate of minor complications range from 23-61 %. 1,2 No randomized control trials exist comparing morbidity related to AG/AE and NOM without AG/AE.
A large prospective study found AG/AE-related morbidity of 47% compared to morbidity of 10% in NOM without AG/AE. 6 A large study of post-discharge complications in patients who received NOM found higher rate of thirty-day readmission among patients who received NOM with AE than patients who did not receive AE (12.8% vs. 7.4%, p=0.002). 25 KMQ-5. With regard to selective versus non-selective angioembolization, what is the preferred approach to angioembolization in splenic injuries?
# RECOMMENDATIONS
F. In the presence of a single vascular abnormality (contrast blush, pseudo-aneurysms, and arteriovenous fistula) in minor and moderate injuries, the currently available literature is inconclusive regarding whether proximal or distal embolization should be used. In general, selective angioembolization is preferred, where safe and feasible.
# KNOWLEDGE SYNTHESIS
External Recommendations SAG's Rationale In the presence of a single vascular abnormality (contrast blush, pseudo-aneurysms, and artero-venous fistula) in minor and moderate injuries, the currently available literature is inconclusive regarding whether proximal or distal embolization should be used. In the presence of multiple splenic vascular abnormalities or in the presence of a severe lesion, proximal or combined AG/AE should be used, after confirming the presence of a permissive pancreatic vascular anatomy. Adopted first sentence. Replaced second sentence with preference for selective (i.e. proximal) angioembolization due to fewer minor complications reported in retrospective cohort studies (see below).
# Additional Literature Support
# What is the effectiveness of selective versus non-selective angioembolization? What are the complications?
No prospective studies or randomized controlled trials available on the subject.
No significant difference observed in overall failure rate between distal and proximal embolization.
No significant difference has been observed between proximal and distal embolization for incidence of major infarctions, infections or re-bleeding.
Higher rate of minor complications has been reported in distal than in proximal embolization (see C. Patients with Grade 3-5 splenic injuries or associated major injury should be transferred to an appropriate trauma referral centre. Centres receiving these patients should have IR capability to facilitate angioembolization if needed. A general surgeon must be actively involved in the transfer process and the ongoing care of transferred patients.
D. The HLOC transfer of splenic injury patients that are or have been unstable for the purposes of urgent angioembolization is not recommended if the patient is in a centre with general surgical capability and can perform splenectomy.
E. For patients undergoing emergent splenectomy prior to HLOC transfer, arrangements for transfer through Patient Transfer Network (PTN) should be made as early as possible, preferably pre-operatively or intraoperatively to avoid delay.
Delayed Transfer (> 24 hours):
F. In centres without interventional radiology capability, if follow-up imaging demonstrates an indication for angioembolization, patients should be transferred under the care of a general surgeon to a HLOC trauma referral centre for this procedure within 48 hours.
# KNOWLEDGE SYNTHESIS External Recommendations SAG's Rationale
None Recommendations regarding transfer to higher level of care were drafted, based on provincial realities and the expert opinion of the SAG. C. Hemoglobin should be monitored at regular intervals until stabilized.
# VI. ACUTE HOSPITAL CARE
D. It is recommended that therapeutic anticoagulation be reversed promptly in patients with high risk splenic injury, unless the risk of reversal is considered higher than the risk of splenic hemorrhage.
# KNOWLEDGE SYNTHESIS
# Additional Literature Support
# What is the incidence of delayed splenic pseudoaneurysm formation by injury grade? Timing of formation?
Overall rate of incidence of delayed splenic pseudoaneurysm formation ranges from 3.0-15.4 % 17,28,29,30,31,32 to as high as 74 %. 33 A retrospective multicenter study 30 found incidence of delayed splenic pseudoaneurysm formation in 17.7 % of patients treated with initial observation and 11.9 % of patients treated with early angioembolization. D. Regarding infection prophylaxis in asplenic and hyposplenic adult patients: immunization against seasonal flu is recommended; malaria prophylaxis is strongly recommended for travellers; antibiotic therapy should be strongly considered in the event of any sudden onset of unexplained fever, malaise, chills or other constitutional symptoms, especially when medical review is not readily accessible; and primary care providers should be aware of the splenectomy/angioembolization. Adopted and combined the two statements into one recommendation.
# VIII. OVERWHELMING POST-SPLENECTOMY INFECTION PROPHYLAXIS
# Other vaccination indications
Adopted and combined the four statements into one recommendation for easier reading.
# KNOWLEDGE SYNTHESIS External Recommendations SAG's Rationale
None available With lack of scientific evidence or external clinical guidance on the management of delayed splenic pseudoaneurysms, a new recommendation was developed based on the SAG's expert opinion.
# RECOMMENDATIONS
F. There is no need to restrict mobilization in patients with splenic injury and early mobilization is encouraged. Patients with high risk injuries- should remain supervised until assessed as safe to ambulate independently off unit.
*CT-confirmed Grade 3-5 splenic injuries, particularly with evidence of active haemorrhage or pseudoaneurysm, anticoagulated patient, associated major injury, age ≥65 or limited physiologic reserve.
G. Post-discharge, patients with Grade 3-5 splenic injuries should avoid contact sports or vigorous activities for at least 8 weeks. Patients with Grade 3-5 splenic injuries should be re-imaged prior to resuming high-risk activities.
# KNOWLEDGE SYNTHESIS External Recommendations SAG's Rationale
- Activity restriction may be suggested for 4-6 weeks in minor injuries and up to 2-4 months in moderate and severe injuries.
New recommendation has been created, based on recent evidence (see below) and expert opinion of the SAG.
# Additional Literature Support
# What is the risk of delayed hemorrhage in blunt splenic patients without activity restrictions?
Several recent studies have shown no association between early mobilization with minimal bed rest and delayed splenic hemorrhage both in adult 16,36,37,38 and pediatric 39,40,41 patients with blunt splenic injuries managed via NOM.
# Additional Literature Support
# What is the risk of developing thrombosis VTE prophylaxis after blunt splenic injuries?
A prospective study (n=147) found 5 % risk of developing VTE after trauma-related splenectomy. 42 A large retrospective study (n=6,162) found 1.97 times greater risk of VTE in splenic injury than in control, with a rate of 10.08 per 10,000 person-years (8.46 no splenectomy, 11.81 splenectomy). 43 A large prospective study (n=675) found increased risk for VTE with splenectomy (AOR 2.6, 95% CI 1.2 to 5.9). 44
# What is the incidence of hemorrhage in splenic patients with/without VTE prophylaxis?
Several retrospective studies indicate low-molecular weight heparin (LMWH) administration does not increase the failure rate of NOM 45,46 or increase the risk of bleeding events. 47
# External Recommendations SAG's Rationale
- Regarding infections prophylaxis in asplenic and hyposplenic adult and pediatric patients, immunization against seasonal flu is recommended for patients over 6 months of age. Regarding infections prophylaxis in asplenic and hyposplenic adult and pediatric patients, Malaria prophylaxis is strongly recommended for travelers. Regarding infections prophylaxis in asplenic and hyposplenic adult and pediatric patients, antibiotic therapy should be strongly considered in the event of any sudden onset of unexplained fever, malaise, chills or other constitutional symptoms, especially when medical review is not readily accessible. Regarding infections prophylaxis in asplenic and hyposplenic adult and pediatric patients, primary care providers should be aware of the splenectomy/ angioembolization.
# Additional Literature Support
# What is the risk of overwhelming post-splenectomy infection (OPSI) with splenectomy or splenic embolization after splenic injury?
Risk of overwhelming post-splenectomy infection (OPSI) with splenectomy or splenic embolization ranges from 0.05-23 %, 2,48 with the majority of infections occurring more than 2 years following the procedure. 49 A large retrospective study (n= 4,360) of blunt splenic trauma patients in California reported short-and long-term infectious complications by procedure 50 :
# What is the optimal timing of vaccination?
All vaccines are best administered 2 weeks after surgery. If the patient is discharged earlier and there is concern that they might not return for follow-up, vaccines should be administered prior to discharge. 51
# What is the effectiveness of vaccination? What is the effectiveness of repeat vaccination? Effectiveness and administration schedule of vaccination in asplenic/hyposplenic adults
# Additional Literature Support
For risk of delayed hemorrhage after non-operative management of blunt splenic injury, see page 17.
For the risk and timing of pseudoaneurysm formation after non-operative management of blunt splenic injury, see p. 24.
# KMQ-13.
What is the preferred management of delayed pseudoaneurysm?
# RECOMMENDATIONS
C. If a new pseudoaneurysm is noted on follow-up imaging, discussion with general surgery is recommended to determine best management, e.g. serial imaging vs. embolization. | CT-confirmed Grade 1-2 splenic injuries without evidence of active haemorrhage or pseudoaneurysm, anticoagulated patient, associated major injury, age ≥65 or limited physiologic reserve. * CT-confirmed Grade 1-2 splenic injuries without evidence of active haemorrhage or pseudoaneurysm, anticoagulated patient, associated major injury, age ≥65 or limited physiologic reserve.# TABLE OF CONTENTS
# PURPOSE
The purpose of this clinical practice guideline (CPG) is to review best evidence and generate expert consensus on recommendations for the management of isolated blunt splenic trauma in adult patients ( 5. With regard to selective versus non-selective angioembolization, what is the preferred approach to angioembolization in splenic injuries?
# III. TRANSFER TO HIGHER LEVEL OF CARE
6. What are the indications for transfer of patients with blunt splenic injuries to a higher-level trauma center?
IV. ACUTE HOSPITAL CARE 7. What type and duration of monitoring are necessary for patients with blunt splenic injuries? 8. When is supplementary imaging required in the hospitalized patient?
9. What activity restrictions should be imposed on patients with blunt splenic injuries, in hospital and post-discharge?
# V. VENOUS THROMBOEMBOLISM (VTE) PROPHYLAXIS
10. What is the optimal timing for initiating deep vein thrombosis (DVT) prophylaxis in patients with blunt splenic injuries? The injury grade can be estimated from the radiology report. The radiologist should report: i. the presence/absence of hilar involvement, ii.
the percentage of splenic parenchymal injury/hematoma (<25%, 25-50%, >50%), iii.
the presence of active bleeding, and iv.
presence of a pseudoaneurysm.
Generally, Grade 1 and 2 injuries are considered low grade injuries while Grade 3-5 are considered high grade injuries.
# 8
# ALGORITHM
# 9
# SUMMARY OF RECOMMENDATIONS
All recommendations are newly drafted by the Thoraco-Abdominal SAG, unless indicated otherwise.
# I. INITIAL ASSESSMENT AND MANAGEMENT
A. Initial resuscitation and management of the patient with blunt abdominal trauma should follow the Advanced Trauma Life Support® (ATLS®) principles.
B. In centres with surgical capability, the on-call general surgeon should be consulted promptly when a splenic injury is suspected or proven.
# II. OPERATIVE MANAGEMENT
A. In centres with general surgical capability, urgent splenectomy should be performed for a hemodynamically unstable patient with a splenic injury who is not responding to appropriate resuscitation.
B. Grade or severity of splenic injury is not, in and of itself, an indication for surgical management of the injured spleen. The decision to proceed to splenectomy should be based on the clinical presentation of the patient and situational context, which includes the capabilities of the site, resources available, presence of other injuries, transport availability, and transfer related issues.
C. A general surgeon should be involved early in decision-making for suspected or proven splenic injury. Tele-conferencing through Patient Transfer Network (PTN) to discuss optimal management (transport vs. splenectomy) should be performed. The conference call should include the sending physician, the receiving general surgeon and the receiving Trauma Team Leader (TTL) at the higher level of care (HLOC) trauma referral centre.
# III. NON-OPERATIVE MANAGEMENT
A. A trial of non-operative management (NOM) for splenic injury is indicated in patients with proven splenic injury who are hemodynamically stable after appropriate resuscitation. There are no absolute contraindications to a trial of NOM of known splenic injury in the hemodynamically stable or stabilized patient.
B. Hemodynamically stable patients with negligible risk* of ongoing or delayed hemorrhage may be safely managed, without higher level of care (HLOC) transfer, in a rural/remote facility provided at least 2 units of packed red blood cells are available. This management plan should be reviewed with a general surgeon and Trauma Team Leader (TTL) on call at the HLOC trauma referral centre in sites without surgical capabilities.
C. NOM of Grade 3-5 splenic injuries should only be considered in a hospital that has capabilities for physiologic monitoring and serial clinical evaluations by a general surgeon are possible. The hospital also needs 4 or more units of blood available, CT imaging, and 24-7 operating room access. Access to 24-7 interventional radiology for angiography/angioembolization is preferred but not essential. For transfer indications, see IV. TRANSFER TO HIGHER LEVEL OF CARE below.
# IV. ANGIOGRAPHY/ANGIOEMBOLIZATION
A. Emergent angiography/angioembolization is indicated in hemodynamically unstable patients with immediate access to interventional radiology who have responded to appropriate resuscitation and demonstrate active vascular extravasation on contrast CT. The higher level of care transfer of splenic injury patients that are or have been unstable for the purposes of urgent angioembolization is not recommended if the patient is in a centre with general surgical capability and can perform splenectomy.
B. Emergent angiography/angioembolization is indicated in hemodynamically stable patients with major free extravasation not likely to abate.
C. Angioembolization within 72 hours is indicated in hemodynamically stable or stabilized patients with pseudoaneurysm or arterio-venous fistula identified on CT or ultrasound imaging.
D. Patients with splenic injury demonstrating contrast blush on CT are at an elevated risk for failing non-operative management (NOM). The consulting surgeon and interventional radiologist should communicate once initial imaging is completed and collaborate on a management plan in the event of failure of NOM.
E. In centres without interventional radiology capability, if follow-up imaging demonstrates an indication for angioembolization, patients should be transferred under the care of a general surgeon to a higher level of care (HLOC) trauma referral centre for this procedure within 48 hours.
F. In the presence of a single vascular abnormality (contrast blush, pseudo-aneurysms, and arteriovenous fistula) in minor and moderate injuries, the currently available literature is inconclusive regarding whether proximal or distal embolization should be used. In general, selective angioembolization is preferred, where safe and feasible. [Adopted from WSES with modification]
# V. TRANSFER TO HIGHER LEVEL OF CARE (HLOC)
Immediate Transfer (< 24 hours):
A. Patients who are hemodynamically stable with associated major injuries requiring urgent higher level of care (e.g. traumatic brain injury) should be transferred promptly to a Level 1 or 2 trauma centre.
B. Hemodynamically stable patients with negligible risk* of ongoing or delayed hemorrhage may be safely managed, without higher level of care (HLOC) transfer, in a rural/remote facility provided at least 2 units of packed red blood cells are available. This management plan should be reviewed with a general surgeon and Trauma Team Leader (TTL) on call at the HLOC trauma referral centre in sites without surgical capabilities.
C. Patients with Grade 3-5 splenic injuries or associated major injury should be transferred to an appropriate trauma referral centre. Centres receiving these patients should have IR capability to facilitate angioembolization if needed. A general surgeon must be actively involved in the transfer process and the ongoing care of transferred patients.
D. The HLOC transfer of splenic injury patients that are or have been unstable for the purposes of urgent angioembolization is not recommended if the patient is in a centre with general surgical capability and can perform splenectomy.
E. For patients undergoing emergent splenectomy prior to HLOC transfer, arrangements for transfer through Patient Transfer Network (PTN) should be made as early as possible, preferably pre-operatively or intraoperatively to avoid delay.
Delayed Transfer (> 24 hours):
F. In centres without interventional radiology capability, if follow-up imaging demonstrates an indication for angioembolization, patients should be transferred under the care of a general surgeon to a HLOC trauma referral centre for this procedure within 48 hours.
# VI. ACUTE HOSPITAL CARE
A. Patients with Grade 1-2 splenic injuries can be monitored in a general surgery ward. The patient should have good IV access and assessed frequently for vital signs.
B. Patients with Grade 3-5 splenic injuries undergoing non-operative management (NOM) should be observed initially in a monitored intermediate care unit or intensive care unit (ICU). Appropriate initial monitoring includes the capacity to provide hourly vital signs as well as cardiac, oxygen saturation and urine output monitoring. Serial examination by a general surgeon is essential.
C. Hemoglobin should be monitored at regular intervals until stabilized.
D. It is recommended that therapeutic anticoagulation be reversed promptly in patients with high risk splenic injury, unless the risk of reversal is considered higher than the risk of splenic hemorrhage.
E. Repeat CT imaging in hemodynamically stable patients should be obtained within 72 hours postinjury for Grade 3-5 splenic injuries. Any changes in clinical status should prompt urgent reassessment, including laboratory investigations and/or CT as appropriate.
F. There is no need to restrict mobilization in patients with splenic injury and early mobilization is encouraged. Patients with high risk injuries* should remain supervised until assessed as safe to ambulate independently off unit.
*CT-confirmed Grade 3-5 splenic injuries, particularly with evidence of active haemorrhage or pseudoaneurysm, anticoagulated patient, associated major injury, age ≥65 or limited physiologic reserve.
G. Post-discharge, patients with Grade 3-5 splenic injuries should avoid contact sports or vigorous activities for at least 8 weeks. Patients with Grade 3-5 splenic injuries should be re-imaged prior to resuming high-risk activities.
# VII. VENOUS THROMBOEMBOLISM (VTE) PROPHYLAXIS
A. Pharmacologic prophylaxis to prevent venous thromboembolism (VTE) can be used for patients with isolated blunt splenic injuries without increasing the failure rate of non-operative management. Although the optimal timing of safe initiation has not been determined, deep vein thrombosis (DVT) prophylaxis may be started as soon as possible after trauma and within 12 hours for every Grade of splenic injury (e.g. 36 hours for Grade 3 injury) or sooner if hemoglobin is stable. [Adopted from EAST and WSES with modification] B. Mechanical prophylaxis should be used in all patients with absolute contraindication to pharmacologic prophylaxis, except in patients with lower extremity trauma in which case mechanical prophylaxis is not efficacious.
# SCIENTIFIC DISCUSSION
All recommendations are newly drafted by the Thoraco-Abdominal SAG, unless indicated otherwise.
# I. INITIAL ASSESSMENT AND MANAGEMENT
# II. OPERATIVE MANAGEMENT
# KMQ-2. What are the indications for operative management (OM) of blunt splenic injuries? RECOMMENDATIONS
A. In centres with general surgical capability, urgent splenectomy should be performed for a hemodynamically unstable patient with a splenic injury who is not responding to appropriate resuscitation.
B. Grade or severity of splenic injury is not, in and of itself, an indication for surgical management of the injured spleen. The decision to proceed to splenectomy should be based on the clinical presentation of the patient and situational context, which includes the capabilities of the site, resources available, presence of other injuries, transport availability, and transfer related issues.
C. A general surgeon should be involved early in decision-making for suspected or proven splenic injury. Tele-conferencing through Patient Transfer Network (PTN) to discuss optimal management (transport vs. splenectomy) should be performed. The conference call should include the sending physician, the receiving general surgeon and the receiving Trauma Team Leader (TTL) at the higher level of care (HLOC) trauma referral centre.
# KNOWLEDGE SYNTHESIS
# Additional Literature Support
# What is the success rate of non-operative management of blunt splenic injuries?
Overall reported success rate of observational management (without angiography) is 92-96 %. 3,4,5,6 Recent success rate of non-operative management (NOM) (i.e. observational management only + NOM with angioembolization) has been reported in the range of 93-100 %. 6,8
# Success rate of observational management of blunt splenic injury by injury grade
# What are the complications of non-operative management of blunt splenic injury?
Complications in NOM in blunt splenic injury include progression to splenectomy, hemodynamic instability and/or evidence of ongoing bleeding, and delayed laparotomy for missed associated injury, resulting in re-admission or emergency laparotomy.
Overall reported failure rate of NOM is 4-15 % (according to a 2017 review of studies published 2000 onwards 9 ), with higher rates reported for high grade injuries:
# What is the risk (probability) of delayed hemorrhage following non-operative management of splenic injuries?
Probability of delayed hemorrhage after NOM ranges from 0-15 % 6,16,17, with a higher probability in higher Grade injuries. 2 It is difficult to distinguish between delayed hemorrhage and hemorrhage that was missed on the initial CT. This is particularly the case with older studies that used older CT technology. For this reason, more recent studies that clearly indicate delayed hemorrhage have been consulted.
# What is the rate of spontaneous resolution of active hemorrhage detected as contrast blush on initial CT scan?
Probability of blush detected on CT leading to absence of extravasation on angiography ranges from 2.3-47 % 18,19,20 One retrospective study showed 100% (3/3) patients with contrast blush on initial CT had no blush on post-transfer repeat CT. 19 Conservatively estimated, NOM of splenic injury results in a success rate of >98% for Grade 1-2 injuries, >90% for Grade 3 injuries, and >75% for Grade 4-5 injuries. Angiography is variably used to achieve these rates.
# IV. ANGIOGRAPHY / ANGIOEMBOLIZATION
# Additional Literature Support
# What is the success rate of angiography/angioembolizations in blunt splenic injuries?
Success rate of AG/AE range from 73-100%. 21 In severe injuries (Grades 4-5), difference in success rate between NOM with and without angioembolization can be as great as 78.4 %. 6 Failure rate of NOM without AG/AE can be as high as 26% in these injuries. 22 Conflicting evidence exists for the benefits of angioembolization in preventing splenectomy. 23,24 What are the complications of angiography/angioembolizations in blunt splenic injuries?
Major complications of AE include: delayed bleeding, total or subtotal splenic infarction, splenic abscesses, acute renal insufficiency, pseudocysts, and puncture-related complications. Rate of major complications range from 3.7-28.5 %. 1,2 Minor complications include fever, pleural effusion, coil migration, and partial splenic infarction. Rate of minor complications range from 23-61 %. 1,2 No randomized control trials exist comparing morbidity related to AG/AE and NOM without AG/AE.
A large prospective study found AG/AE-related morbidity of 47% compared to morbidity of 10% in NOM without AG/AE. 6 A large study of post-discharge complications in patients who received NOM found higher rate of thirty-day readmission among patients who received NOM with AE than patients who did not receive AE (12.8% vs. 7.4%, p=0.002). 25 KMQ-5. With regard to selective versus non-selective angioembolization, what is the preferred approach to angioembolization in splenic injuries?
# RECOMMENDATIONS
F. In the presence of a single vascular abnormality (contrast blush, pseudo-aneurysms, and arteriovenous fistula) in minor and moderate injuries, the currently available literature is inconclusive regarding whether proximal or distal embolization should be used. In general, selective angioembolization is preferred, where safe and feasible. [Adopted from WSES with modification]
# KNOWLEDGE SYNTHESIS
External Recommendations SAG's Rationale In the presence of a single vascular abnormality (contrast blush, pseudo-aneurysms, and artero-venous fistula) in minor and moderate injuries, the currently available literature is inconclusive regarding whether proximal or distal embolization should be used. In the presence of multiple splenic vascular abnormalities or in the presence of a severe lesion, proximal or combined AG/AE should be used, after confirming the presence of a permissive pancreatic vascular anatomy. [WSES: 1C] Adopted first sentence. Replaced second sentence with preference for selective (i.e. proximal) angioembolization due to fewer minor complications reported in retrospective cohort studies (see below).
# Additional Literature Support
# What is the effectiveness of selective versus non-selective angioembolization? What are the complications?
No prospective studies or randomized controlled trials available on the subject.
No significant difference observed in overall failure rate between distal and proximal embolization.
No significant difference has been observed between proximal and distal embolization for incidence of major infarctions, infections or re-bleeding.
Higher rate of minor complications has been reported in distal than in proximal embolization (see C. Patients with Grade 3-5 splenic injuries or associated major injury should be transferred to an appropriate trauma referral centre. Centres receiving these patients should have IR capability to facilitate angioembolization if needed. A general surgeon must be actively involved in the transfer process and the ongoing care of transferred patients.
D. The HLOC transfer of splenic injury patients that are or have been unstable for the purposes of urgent angioembolization is not recommended if the patient is in a centre with general surgical capability and can perform splenectomy.
E. For patients undergoing emergent splenectomy prior to HLOC transfer, arrangements for transfer through Patient Transfer Network (PTN) should be made as early as possible, preferably pre-operatively or intraoperatively to avoid delay.
Delayed Transfer (> 24 hours):
F. In centres without interventional radiology capability, if follow-up imaging demonstrates an indication for angioembolization, patients should be transferred under the care of a general surgeon to a HLOC trauma referral centre for this procedure within 48 hours.
# KNOWLEDGE SYNTHESIS External Recommendations SAG's Rationale
None Recommendations regarding transfer to higher level of care were drafted, based on provincial realities and the expert opinion of the SAG. C. Hemoglobin should be monitored at regular intervals until stabilized.
# VI. ACUTE HOSPITAL CARE
D. It is recommended that therapeutic anticoagulation be reversed promptly in patients with high risk splenic injury, unless the risk of reversal is considered higher than the risk of splenic hemorrhage.
# KNOWLEDGE SYNTHESIS
# Additional Literature Support
# What is the incidence of delayed splenic pseudoaneurysm formation by injury grade? Timing of formation?
Overall rate of incidence of delayed splenic pseudoaneurysm formation ranges from 3.0-15.4 % 17,28,29,30,31,32 to as high as 74 %. 33 A retrospective multicenter study 30 found incidence of delayed splenic pseudoaneurysm formation in 17.7 % of patients treated with initial observation and 11.9 % of patients treated with early angioembolization. D. Regarding infection prophylaxis in asplenic and hyposplenic adult patients: immunization against seasonal flu is recommended; malaria prophylaxis is strongly recommended for travellers; antibiotic therapy should be strongly considered in the event of any sudden onset of unexplained fever, malaise, chills or other constitutional symptoms, especially when medical review is not readily accessible; and primary care providers should be aware of the splenectomy/angioembolization. Adopted and combined the two statements into one recommendation.
# VIII. OVERWHELMING POST-SPLENECTOMY INFECTION PROPHYLAXIS
# Other vaccination indications
Adopted and combined the four statements into one recommendation for easier reading.
# KNOWLEDGE SYNTHESIS External Recommendations SAG's Rationale
None available With lack of scientific evidence or external clinical guidance on the management of delayed splenic pseudoaneurysms, a new recommendation was developed based on the SAG's expert opinion.
# RECOMMENDATIONS
F. There is no need to restrict mobilization in patients with splenic injury and early mobilization is encouraged. Patients with high risk injuries* should remain supervised until assessed as safe to ambulate independently off unit.
*CT-confirmed Grade 3-5 splenic injuries, particularly with evidence of active haemorrhage or pseudoaneurysm, anticoagulated patient, associated major injury, age ≥65 or limited physiologic reserve.
G. Post-discharge, patients with Grade 3-5 splenic injuries should avoid contact sports or vigorous activities for at least 8 weeks. Patients with Grade 3-5 splenic injuries should be re-imaged prior to resuming high-risk activities.
# KNOWLEDGE SYNTHESIS External Recommendations SAG's Rationale
Activity restriction may be suggested for 4-6 weeks in minor injuries and up to 2-4 months in moderate and severe injuries.
[WSES: 2C] New recommendation has been created, based on recent evidence (see below) and expert opinion of the SAG.
# Additional Literature Support
# What is the risk of delayed hemorrhage in blunt splenic patients without activity restrictions?
Several recent studies have shown no association between early mobilization with minimal bed rest and delayed splenic hemorrhage both in adult 16,36,37,38 and pediatric 39,40,41 patients with blunt splenic injuries managed via NOM.
# Additional Literature Support
# What is the risk of developing thrombosis VTE prophylaxis after blunt splenic injuries?
A prospective study (n=147) found 5 % risk of developing VTE after trauma-related splenectomy. 42 A large retrospective study (n=6,162) found 1.97 times greater risk of VTE in splenic injury than in control, with a rate of 10.08 per 10,000 person-years (8.46 no splenectomy, 11.81 splenectomy). 43 A large prospective study (n=675) found increased risk for VTE with splenectomy (AOR 2.6, 95% CI 1.2 to 5.9). 44
# What is the incidence of hemorrhage in splenic patients with/without VTE prophylaxis?
Several retrospective studies indicate low-molecular weight heparin (LMWH) administration does not increase the failure rate of NOM 45,46 or increase the risk of bleeding events. 47
# External Recommendations SAG's Rationale
Regarding infections prophylaxis in asplenic and hyposplenic adult and pediatric patients, immunization against seasonal flu is recommended for patients over 6 months of age. [WSES: 1C] Regarding infections prophylaxis in asplenic and hyposplenic adult and pediatric patients, Malaria prophylaxis is strongly recommended for travelers. [WSES: 2C] Regarding infections prophylaxis in asplenic and hyposplenic adult and pediatric patients, antibiotic therapy should be strongly considered in the event of any sudden onset of unexplained fever, malaise, chills or other constitutional symptoms, especially when medical review is not readily accessible. [WSES: 2A] Regarding infections prophylaxis in asplenic and hyposplenic adult and pediatric patients, primary care providers should be aware of the splenectomy/ angioembolization. [WSES: 2C]
# Additional Literature Support
# What is the risk of overwhelming post-splenectomy infection (OPSI) with splenectomy or splenic embolization after splenic injury?
Risk of overwhelming post-splenectomy infection (OPSI) with splenectomy or splenic embolization ranges from 0.05-23 %, 2,48 with the majority of infections occurring more than 2 years following the procedure. 49 A large retrospective study (n= 4,360) of blunt splenic trauma patients in California reported short-and long-term infectious complications by procedure 50 :
# What is the optimal timing of vaccination?
All vaccines are best administered 2 weeks after surgery. If the patient is discharged earlier and there is concern that they might not return for follow-up, vaccines should be administered prior to discharge. 51
# What is the effectiveness of vaccination? What is the effectiveness of repeat vaccination? Effectiveness and administration schedule of vaccination in asplenic/hyposplenic adults
# Additional Literature Support
For risk of delayed hemorrhage after non-operative management of blunt splenic injury, see page 17.
For the risk and timing of pseudoaneurysm formation after non-operative management of blunt splenic injury, see p. 24.
# KMQ-13.
What is the preferred management of delayed pseudoaneurysm?
# RECOMMENDATIONS
C. If a new pseudoaneurysm is noted on follow-up imaging, discussion with general surgery is recommended to determine best management, e.g. serial imaging vs. embolization. | None | None |
f630013e97657eb2cf3fbadb05be4086591c05c3 | cma | None | Background Little evidence has been generated for how best to manage patients with non-small-cell lung cancer (nsclc) presenting with rarer clinical scenarios, including oligometastases, oligoprogression, and pseudoprogression. In each of those scenarios, oncologists have to consider how best to balance efficacy with quality of life, while maximizing the duration of each line of therapy and ensuring that patients are still eligible for later options, including clinical trial enrolment. Methods An expert panel was convened to define the clinical questions. Using case-based presentations, consensus practice recommendations for each clinical scenario were generated through focused, evidencebased discussions.Treatment strategies and best-practice or consensus recommendations are presented, with areas of consensus and areas of uncertainty identified.In each situation, treatment has to be tailored to suit the individual patient, but with the intent of extending and maximizing the use of each line of treatment, while keeping treatment options in reserve for later lines of therapy. Patient participation in clinical trials examining these issues should be encouraged.# BACKGROUND
Little evidence has been generated for how best to treat patients with non-small-cell lung cancer (nsclc) presenting with rarer clinical scenarios, including oligometastases, oligoprogression, and pseudoprogression. In each of those scenarios, oncologists have to consider how best to balance efficacy with quality of life, while maximizing the duration of each line of therapy and ensuring that patients are still eligible for later options, including clinical trial enrolment.
# METHODS
An invited expert panel of thoracic oncology specialists in medical and radiation oncology and anatomic and molecular pathology was convened. Panellists were tasked to perform an evidence-based overview of specific topics related to oligometastatic and oligoprogressive nsclc and to pseudoprogression on immuno-oncology agents. Case presentations were used to illustrate typical examples of those rare clinical situations, and after an overview of the evidence by all attendees, evidence-informed recommendations for practice were developed. The guideline presented here was drafted by the first author with the assistance of a medical writer, and all authors provided feedback. The final guideline was approved by all authors and submitted for publication.
# RESULTS
# Non-Central Nervous System Oligometastatic and Oligopersistent Wild-Type NSCLC
# Case Description
An incidental left upper lobe mass found in a 59-year-old male ex-smoker during a coronary angiogram was followed by serial computed tomography (ct) imaging until slight growth prompted investigations. Combined positronemission tomography and ct imaging in March 2016 identified a 2.3 cm left upper lobe mass (standardized uptake value 13.6), and biopsy showed an adenocarcinoma, which was EGFR-and ALK-negative (Figure 1, left panel). A positronemission tomography-positive 1.8 cm mass was also noted in the left adrenal gland (Figure 1, right panel), and although an adrenal biopsy in April 2016 showed only rare atypical cells, there was some concern that this location might represent a single site of metastatic disease.
In June 2016, the patient had a left upper lobe lobectomy to remove a 2.3 cm node-negative invasive adenocarcinoma. Because the adrenal biopsy was non-diagnostic, benefit of the doubt led to planning for an adrenalectomy. However, before that surgery occurred, the patient developed a rapidly growing malignant right supraclavicular lymph node, and repeat imaging confirmed significant progression of his adrenal metastasis.
Carboplatin-gemcitabine chemotherapy was initiated, but by the 3rd cycle, the supraclavicular node had progressed, although the adrenal metastasis had shrunk to 6×5 cm from 8×7 cm. Because the patient was PD-L1 positive , he received 4 cycles of pembrolizumab. Initially, there appeared to be no clinical response, but after the 4th cycle, the patient experienced a rapid and excellent response such that the node in his neck was no longer palpable, and the adrenal metastasis had shrunk further to 2.9×1.5 cm by July 2017 (Figure 2). The patient continues on treatment and is doing well.
# Panelist Presenters
Drs. J. Laskin and P. Cheung
# Clinical Questions
n What is oligometastatic nsclc, and proportionally, how many patients present in this fashion? n Is oligometastatic nsclc a distinct clinical entity? n Which patients warrant aggressive, localized ablative therapy of all sites of metastatic disease, either as initial therapy or after induction chemotherapy?
Oligometastasis, a term first formally defined in 1995 1 , refers to a minimal metastatic state in which patients have a low burden of metastatic disease with only a small number of metastatic sites at initial presentation of their illness. Given that metastatic burden is a continuum, some authors question the existence of the oligometastatic state 2 . However, many believe that it represents a distinct group of patients who might have a more favourable outcome and in whom more aggressive therapy might be warranted. There are data to suggest that, compared with patients having more diffuse disease, those with fewer sites of metastases might experience longer survival . The recognition that different sites and numbers of metastases are associated with different prognoses has been integrated into the 8th edition of the staging system for nsclc, in which malignant effusions or isolated contralateral lung metastases are considered M1a, a single site of extrathoracic metastatic disease is considered M1b, and more extensive extrathoracic metastatic disease is considered M1c 6 . "Oligopersistent disease" is a closely related concept referring to an oligometastatic state that, after systemic therapy, either persists or is induced from a more widely metastatic state.
It is known that patients with a solitary site of metastatic disease (most commonly brain or adrenal gland) who undergo surgical resection of both their primary and the metastasis can occasionally experience long-term survival or cure, and that dual resection is a generally accepted treatment strategy for such patients . Whether patients with wild-type nsclc and more than a solitary site of distant metastatic spread should be considered for more aggressive localized therapy was the topic for discussion. The development of increasingly sophisticated radiotherapy techniques allows for the delivery of radical doses of radiation safely in a very short treatment time to almost any body site 10 , thus making the local control option feasible for some patients with metastatic nsclc.
The rationale for the treatment of oligometastatic and oligopersistent disease arises from the fact that, rather than develop metastases at new sites, many patients with advanced nsclc treated with systemic therapy relapse at a site of pre-existing disease . Hypothetically, those sites will harbour chemotherapy-resistant clones and can serve to seed other sites with metastases. There are data to suggest that the larger the tumour deposit, the greater the likelihood of residual resistant clones, and thus the greater the likelihood of benefit from local control of that lesion 14 . Thus, it might be possible to delay the onset of treatment resistance and the development of new sites of metastases by aggressive ablative local therapy to the oligometastatic sites.
The absolute number of metastatic sites that constitutes the upper limit of the oligometastatic state remains a subject of debate, ranging from 3 or fewer 7 or 5 or fewer 15,16 to 6 active extracranial lesions (3 each in liver and lung parenchyma) 17 . Estimates of its occurrence fall into the 26% -55% range 3,15,18,19 , with the variation likely representing definition differences. An individual patient metaanalysis of 757 patients having 1-5 either synchronous or metachronous nsclc metastases found that most oligometastases were either in brain (35.5%) or lung (33.6%), followed by adrenal gland (13.0%), bone (8.5%), other (7.8%), liver (2.4%), and lymph node (2.4%) 16 . The meta-analysis revealed that, in patients treated with ablation to all sites of disease, including the primary, median overall survival was 26 months, and survival at 1, 2, 5, and 8 years was 70.2%, 51.1%, 29.4%, and 23.4% respectively. The longest survival times were observed in patients with metachronous metastases and an absence of nodal disease, but the 5-year overall survival rate was still 13.8% in patients with synchronous metastases and N1-2 disease.
Data about whether the treatment of oligometastatic or oligopersistent disease alters the natural history of advanced nsclc are limited, given that most of the published literature consists of retrospective case series or single-arm phase ii trials and are thus subject to selection bias. Data suggest that, for treated patients, progression-free survival (pfs) or even overall survival might be prolonged in comparisons with historical controls 17,20 . The optimal sequencing of systemic therapy and local ablative therapy (lat) remains unclear. Initial ablative treatment to all disease might delay the need for initiation of systemic therapy in selected patients. It might also be a useful strategy for those not felt to be suitable for systemic therapy because of poor performance status or comorbidities, or for patients who want to avoid the toxicities of systemic therapy. However, somewhat more data about the use of local ablative therapies as consolidation treatment after the use of systemic therapy are available.
In a small randomized phase ii study, 49 patients with oligometastatic nsclc (≤3 sites of metastatic disease) who had received at least 4 cycles of chemotherapy or 3 months of an appropriate targeted therapy and who had not progressed were randomized to maintenance systemic therapy or to sbrt to all sites of disease, followed by maintenance therapy 7 . Most patients (88%) had wild-type EGFR. The trial was halted early because a significant improvement in pfs in favour of sbrt was observed (11.9 months vs. 3.9 months; hazard ratio: 0.35; p = 0.0054), with no significant toxicities.
Since the consensus meeting, a second small (29 patients) single-centre randomized phase ii study, enrolling only patients with wild-type EGFR and up to 5 sites of metastatic disease in addition to the primary lesion, has been published. It also revealed increased pfs (9.7 months vs. 3.5 months, p = 0.01) with no significant increase in toxic effects 21 . In that study (NCT02045446 at . gov/), patients who experienced stable disease or a partial response after 4-6 cycles of first-line platinum-based chemotherapy were randomized to sabr plus maintenance chemotherapy or to maintenance chemotherapy alone. The results satisfied the hypothesis that using sabr prevented local failure at the original disease sites-the most likely sites of first recurrence. Based on the findings of that study, the use of radiation therapy after chemotherapy is being evaluated in a phase iii setting for patients with limited metastatic nsclc.
# Consensus Statement
Overall, the current level of evidence does not support the routine use of lat as the initial treatment in oligometastatic disease, for which systemic therapy remains the standard of care. Local treatment approaches could be considered for patients not suitable for, or who refuse or want to delay, systemic therapy. Some available data suggest that the use of consolidative local ablative radiotherapy (sbrt) to all sites of disease in patients without progression after first-line systemic therapy might lead to longer pfs without undue toxicity. Those data were obtained mostly in patients with EGFR wild-type nsclc. We encourage the enrolment of such patients into ongoing clinical trials that are examining this issue. Outside a clinical trial, such an approach could be considered in selected patients.
# Non-Central Nervous System Oligoprogressive Oncogene-Driven NSCLC
# Case Description-Oligoprogressive Oncogene-Driven NSCLC, ALK Rearrangement
A previously well 42-year-old male never-smoker first presented in 2009 with extensive pulmonary infiltrates, biopsy-proven to be adenocarcinoma. During the subsequent year, he received multiple therapies, including a platinum doublet, pemetrexed, and erlotinib.
By mid-2010, the patient was very symptomatic with progressive disease, and results of fluorescence in situ hybridization testing revealed that he had an ALK rearrangement. He started treatment with crizotinib in October 2010 and experienced a dramatic response [Figure 3(A-C
# Clinical Questions
n What is oligoprogression, and how often does it occur? n When might treatment past progression with a tyrosine kinase inhibitor (tki) be considered for patients with extracranial progressive disease?
Compared with standard platinum-based chemotherapy, targeted therapy for oncogene-driven (EGFR-mutated and ALK-translocated) nsclc is associated with significantly improved outcomes . Most patients treated with an appropriate targeted therapy will experience some degree of tumour shrinkage. However, treatment resistance remains an inevitable occurrence, and at some point, all patients on targeted therapy will progress. Acquired resistance to firstline tkis typically develops after 9-12 months on erlotinib, gefitinib, or afatinib 22,24,25,28 and after approximately 11 months on crizotinib 31 .
Acquired resistance can be attributed to a number of different mechanisms (concisely described elsewhere 34 ) that can either already exist at low frequency in subclones at diagnosis or that can develop under the selective pressure of drug exposure 34,35 . Three different patterns of resistance can be observed with tki therapy: isolated central nervous system (cns) progression without extra-cns progression (discussed in a later subsection), generalized disease progression requiring a change in therapy (extra-cns with or without cns progression), and oligoprogression 36 .
Oligoprogressive disease describes a situation in which a patient develops disease progression in one or a limited number of sites after a targeted therapy has resulted in either a period of stable disease or a partial or complete response 34,37 . Some definitions describe a specific numbers of lesions, such as "≤4 discrete lesions amenable to invasive/non-invasive ablation" 38 . The frequency of oligoprogression during tki treatment varies depending on the definition used and whether isolated cns progression is included; however, estimates range from 15% to 47% 11,37,38 . Oligoprogression is felt to arise as a consequence of tumour heterogeneity, and the development of an isolated resistant subclone at only 1 or a few metastatic sites 39 .
An increasingly common method for treating oligoprogression in nsclc patients with driver mutations is to continue the tki that is controlling the greater proportion of the disease, while using lat to eradicate the resistant clones in the area or areas of progression. Given its relatively few fractions and short treatment time, sbrt might be preferred to more extended radiation schedules or invasive surgery, both of which can be associated with longer interruptions of the tki. Retrospective studies suggest that aggressive local treatment can eradicate tki-resistant oligometastases and could have several theoretical benefits, including prevention or treatment of local symptoms and complications from a growing tumour; prevention of secondary seeding by the tki-resistant clone or clones; and potential for ongoing maintenance with the current tki, which might be providing overall clinical benefit despite oligoprogression. Retrospective data suggest that sbrt can permit continuation of the tki and delay the time to a change in therapy. For example, in a review of 18 patients with EGFR mutation-positive disease treated with lat, the median time to another progression event was 10 months, and the median time to a change in therapy was 22 months 40 . In another cohort of 46 patients, the median time to another progression event was 7 months 41 . Similar results were observed in a cohort of 33 patients with ALK-positive lung cancer who experienced progression while on crizotinib. In 14 patients with oligoprogression who were suitable for lat, the median total duration of crizotinib was 28 months, compared with 10 months in those who progressed and were not suitable for lat 42 . Data suggest that higher radiation doses might lead to better local control of the oligoprogressive sites, although it is unclear whether doses as used for curative intent are required in this setting 34 .
Retrospective studies such as the foregoing are inherently susceptible to selection bias, and the lack of a control arm precludes definitive conclusions about the true value of lat in this setting. However, based on limited data, guidelines from the U.S. National Comprehensive Cancer Network currently recommend this strategy 9 . Ongoing clinical trials conducted specifically in oligoprogressive oncogene-driven nsclc (summarized in Kim et al. 43 ) will help to provide prospective evidence for the use of this strategy in this situation, and participation in such trials should be encouraged. Likewise, as in the case of EGFR wild-type nsclc, there is also a desire to evaluate the role of lat in oligopersistent disease after a period of time on a tki in oncogene-driven disease. Sites of residual tumour could be more likely to harbour resistant subclones that could lead to treatment failure. Ongoing trials are studying this strategy (see NCT02759835, NCT01941654, and NCT01573702 at /).
# Consensus Statement
Canadian oncologists believe that certain selected patients with limited extra-cns oligoprogression, who are otherwise experiencing clinical benefit and good tolerance of their targeted therapy, could be considered for an approach that combines lat with continuation of their current targeted therapy. Generally, to avoid prolonged interruption of the targeted therapy, and because it is safe and effective, sbrt or sabr is, when possible, preferred to more protracted radiation courses or surgery. Careful and close follow-up of treated patients is required, because additional progression events are expected.
# Case Description-Baseline CNS Oligometastatic Disease, Both Wild-Type and Oncogene-Driven
In October 2014, an otherwise healthy 49-year-old male architect presented with an 18-month history of progressive fatigue; intermittent left chest pain; and retrosternal, back, and eye pain.
Staging investigations revealed a dominant left upper lobe mass, with widespread metastases to mediastinal lymph nodes, lung, pleura, and brain. Biopsy of the lung lesions confirmed adenocarcinoma. Molecular testing of the biopsy sample revealed the presence of the EGFR exon 21 L858R mutation.
In November 2014, the patient received whole-brain radiotherapy (wbrt). He then started gefitinib. In December 2014, after 6 weeks of gefitinib, the patient demonstrated a slight interval decrease in the left upper lobe mass, stable small pulmonary nodules, and stable or improved brain metastases (Figure 4). The patient continued with gefitinib and continued to show a decrease in enhancing brain lesions and stable disease in the chest.
In January 2016, after 14 months taking gefitinib, the patient began to experience some headaches, and magnetic resonance imaging of the brain showed an interval increase in a cerebellar lesion. The remainder of his disease burden was stable, and so the cerebellar lesion was treated with stereotactic radiosurgery (srs), and the patient was continued on gefitinib.
In May 2016, after 18 months on gefitinib, the patient was still clinically well, but chest ct imaging suggested early progression, with slightly more prominent pulmonary nodules, suggestive of possible lymphangitic carcinomatosis. The patient continued gefitinib with closer monitoring.
By the following month, June 2016, brain magnetic resonance imaging revealed that 6 enhancing lesions in the brain were starting to enlarge (Figure 5). The patient received further srs to all lesions and continued taking gefitinib.
In August 2016, the patient started to experience mild hemoptysis. Imaging by ct showed an increase in the size of the dominant left upper lobe mass, a bilateral increase in pulmonary nodules, appearance of new nodules, and worsening lymphangitic carcinomatosis . The molecular analysis of a biopsy sample from the left upper lobe mass revealed that the patient had an EGFR T790M resistance mutation. The gefitinib was therefore stopped after 21 months, and treatment with osimertinib was started.
By September 2016, brain magnetic resonance imaging showed 2 enlarging brain metastases, which were treated by srs. The patient continued on osimertinib, and by December 2016, after 3 months on the drug, his best response was stable disease. Chest ct imaging showed a slight decrease in the size of the left upper lobe mass, with the remainder of his disease being stable .
By March 2017, he had been treated with osimertinib for 7 months. A routine restaging ct showed that his pulmonary disease was completely stable, but a new paraaortic lymph node (1.8×2.2 cm) was visible. The nodule was irradiated (25 Gy in 5 fractions), and osimertinib treatment is ongoing. Patients who present with symptomatic brain metastases require appropriate treatment with corticosteroids and consultations with radiation oncology or neurosurgery (or both). There has been a shift away from the use of wbrt, because it has become clear that this therapy is associated with short-term effects of asthenia and longer-term neurocognitive toxicity. Many authors advocate that its use be avoided or postponed whenever possible 38 . Thus, if radiation is felt to be required (either as definitive treatment or after resection), patients, whenever suitable, should be considered for srs. For patients with 1-4 metastases, srs is replacing wbrt, because srs is associated with improved cognitive outcomes .
Multiple randomized trials have compared wbrt and srs with srs alone or wbrt alone . In general, those studies have shown that overall survival is as good with srs alone as with strategies that use wbrt. At the time points studied, neurocognitive functioning has been better preserved with srs alone; however, cns recurrences are more common with srs alone than when wbrt is used. Strategies to decrease the neurocognitive effects of wbrt include the use of memantine, an N-methyl-d-aspartate receptor antagonist used in the treatment of dementia 52 , and the concept of hippocampal avoidance, which is being studied in randomized trials.
For patients with surgically resected metastases, adjuvant srs, compared with wbrt, provides inferior intracranial control at 12 months 46 . Although the randomized trial did not show that the use of local srs, compared with whole-brain treatment, is associated with an increased risk of leptomeningeal relapse, multiple published retrospective experiences show that such relapse can be an important pattern after srs alone 53 . Careful surveillance is a crucial component of any strategy, especially when wbrt is withheld, and the issues of neurocognitive impact and increased intracranial recurrence have to be discussed with patients.
In patients presenting with asymptomatic brain metastases that do not require corticosteroids and for whom urgent local therapy is not felt to be required, consideration could be given to initiating systemic therapy-particularly for patients with an oncogenic driver, in whom targeted agents have a high likelihood of controlling cns disease. Studies of gefitinib, erlotinib, and afatinib have revealed intracranial disease control rates of up to 89% in patients with nsclc showing common EGFR mutations 54,55 . In patients with measurable cns disease, response rates of up to 40% have been reported 54,56,57 . Similarly, in ALKtranslocated nsclc, crizotinib leads to intracranial disease control in 56% of patients with previously untreated brain metastases and in 62% of patients with previously treated brain metastases, with an objective response rate in the range of 18% -33% depending on whether the patient has received prior treatment 58 . Control of cns disease appears to be even higher with newer alk inhibitors. In the phase iii ascend-4 trial comparing ceritinib with chemotherapy as first-line therapy 32 , ceritinib was associated with an intracranial response rate of 73% in patients with measurable disease, and at 24 weeks, a 70% rate of disease control in all 54 patients with brain metastasis (both measurable and non-measurable). In the more recently reported phase iii alex trial 59 , which compared crizotinib with alectinib as first-line treatment, analysis of patients with measurable disease found that alectinib was associated with longer pfs overall and with an 81% intracranial response rate (38% complete response rate) compared with crizotinib's 50% intracranial response rate (5% complete response rate), with a median duration of intracranial response of 17.3 months compared with 5.5 months. Furthermore, the risk of cns progression was markedly reduced with alectinib, even in patients with baseline cns metastases.
Standard platinum doublet chemotherapy has also been shown to have intracranial activity in ALK-positive nsclc. For example, in profile 1014, disease control rates with chemotherapy, while less than those with crizotinib, were approximately 40% at 12 weeks and 20% at 24 weeks in patients with previously treated brain metastases 60 . Similar results were seen for the chemotherapy arm of ascend-4, with an intracranial disease control rate of 55% at 24 weeks 32 . Fewer data about the value of chemotherapy in the treatment of EGFR mutation-positive brain metastases are available. In a pooled analysis of patients enrolled to lux-Lung 3 and 6, rates of cns progression with chemotherapy were similar to rates seen with afatinib in patients both with and without brain metastases at baseline 55 . Newer tkis might result in even better outcomes for patients with brain metastases. Initial results of the phase iii aura3 trial showed a longer duration of pfs for osimertinib compared with platinum therapy plus pemetrexed in the subgroup of patients with cns metastases 61 . Independent radiologic assessment of all intracranial metastases for that trial is ongoing, and so intracranial response and disease control rates are not yet available. Preliminary data from the flaura trial comparing osimertinib with erlotinib or gefitinib as first-line therapy in nsclc patients with common EGFR mutations were recently presented 62 , demonstrating that osimertinib shows durable cns control. Similarly, lorlatinib and brigatinib, next-generation ALK/ROS1 inhibitors, demonstrated substantial intracranial efficacy in phase ii trials 63,64 .
Although data are limited, response rates to chemotherapy in previously untreated brain metastases from EGFR wild-type lung cancer appear to approach response rates in extracranial disease 65 -although response rates appear to be lower than those observed with targeted therapies in mutation-positive disease and could be lower than those observed with platinum-doublet chemotherapy in ALK-positive nsclc, given data suggesting that ALKpositive cancers might be more susceptible to pemetrexed 66,67 . Thus, any patient with wild-type nsclc for whom local brain-directed therapy is delayed in favour of a trial of systemic therapy will have to be monitored very closely for cns progression.
# Oligoprogression in the CNS in Patients Without Baseline CNS Metastases and With Oncogene-Driven NSCLC:
In some patients, the cns will be the sole site of progression, while extracranial disease remains completely or mostly controlled; in others, cns progression will be just one component of more generalized disease progression. In nsclc, cns metastases are a frequent occurrence, affecting 21%-64% of patients 12,68 , with one third of patients presenting with brain metastasis at baseline 58 . The rates of cns progression with first-line tki are 20%-46% for nsclc patients with ALK-positive translocations 38,58 and 22%-52% for nsclc patients with EGFR mutations 11,38,40,69 . Treatment decisions will depend on the degree of progression both intracranially and extracranially, and on the systemic treatment options remaining for the patient. Regardless, patients with symptomatic cns metastases require the approach described earlier: corticosteroids and a referral to radiation oncology or neurosurgery (or both).
In patients with oncogene-driven asymptomatic cns progression in the setting of more widespread progression, a change of systemic therapy is usually warranted. If another targeted agent with cns activity is available, treatment with that agent and careful cns surveillance can be considered. In patients with cns oligoprogression alone, consideration could be given to local brain treatment and continuation of the current targeted therapy that is controlling the extra-cns disease. Alternatively, if another targeted agent is available that has cns activity, withholding local therapy and switching to the other targeted agent, with careful brain surveillance, could also be considered.
In pat ients w it h A LK-posit ive nsclc i n w hom oligoprogressive cns disease develops during crizotinib treatment, some data suggest that both ceritinib and alectinib (both available in Canada) can lead to an intracranial response, at rates of 45% and 52% -67% respectively . Osimertinib has been approved by Health Canada for patients with an acquired EGFR T790M resistance mutation after first-or second-generation tkis. A subset analysis of the aura 3 trial demonstrated that patients with 1 or more measurable or non-measurable cns metastases on baseline brain imaging experienced a significantly longer median pfs with osimertinib than with chemotherapy: 11.7 months compared with 5.6 months (p = 0.004). The cns objective response rate was 70% with osimertinib and 31% with chemotherapy for those with evaluable disease in the brain 73 .
# Asymptomatic Oligoprogression in the CNS in Wild-Type NSCLC Without Baseline CNS Metastases:
In this situation, greater consideration should be given to local therapy (srs, if feasible), given that data about the role of systemic therapies, either further cytotoxic chemotherapy or immunotherapy, are limited. Responses in the cns with immunotherapy have been reported 74,75 , but the relevant data are too preliminary to routinely support the use of immunotherapy specifically for the treatment of cns metastases. If a local therapy is deferred in this situation, very careful cns monitoring is recommended.
# Consensus Statement
If clinically appropriate and possible, wbrt should be deferred in favour of srs. With small-volume asymptomatic brain metastases, consideration might be given to starting with systemic therapy, particularly if the patient has an oncogenic driver. Careful brain surveillance is vital to ensure disease control in the cns.
# Pseudoprogression with Immuno-oncology Agents in NSCLC
# Case Description
In February 2016, a fit 80-year-old woman with EGFR-and ALK-negative adenocarcinoma of the lung was started on therapy with a PD-1 inhibitor. Originally diagnosed with metastatic nsclc in 2013, her previous treatments had included carboplatin doublet chemotherapy and single-agent pemetrexed in addition to stereotactic radiation to liver and brain.
At restaging in June 2016 after several months of a PD-1 inhibitor, the patient's liver lesions had grown in size, as had her paratracheal lymph node . Because she remained fit, with an Eastern Cooperative Oncology Group performance status of 0 and good tolerance to treatment save for a mild rash and hypothyroidism, the patient was continued on the PD-1 inhibitor. After 4 more doses, she was restaged, with clear evidence of improvement , thus demonstrating that the original imaging was indicative of pseudoprogression. The patient was therefore continued on therapy. By February 2017, she was experiencing clinical deterioration, with increased pain and worsening performance status. At that point, imaging confirmed significant disease progression and immunotherapy was discontinued. Immunotherapy can be effective in nsclc: approximately 20% of patients with advanced disease experience durable responses with immune checkpoint inhibitor therapy 76 . Multiple anti-PD-1 and -PD-L1 antibodies have become standard therapies in the first-or second-line treatment of patients with advanced nsclc 74, , and still others are in various phases of clinical development. In contrast to cytotoxic chemotherapy and targeted agents, immunotherapy is associated with a number of response patterns, including delayed response to therapy, disease regression that continues even after therapy is discontinued, and pseudoprogression. Pseudoprogression has to be differentiated from hyperprogression-very rapid disease progression associated with clinical deterioration that has been described with immuno-oncology agents 81 and which is not discussed here.
Definitions of pseudoprogression vary, but generally describe apparent tumour growth arising from a treatment effect rather than true disease progression. Distinguishing between pseudo and true disease progression is crucial to avoid prematurely discontinuing an effective therapy, while at the same time not continuing an ineffective, costly, and potentially toxic treatment and losing an opportunity to move on to another therapy if the patient deteriorates clinically from true disease progression.
In the initial clinical trials of immuno-oncology agents, it was clear that patients were occasionally manifesting radiologic disease progression that met recist 1.1 criteria for progressive disease, but were felt to be clinically benefiting from treatment. Those patients were continued on study therapy, and some subsequently went on to experience either a radiologic response or more prolonged stabilization of disease after the initial progression. After this "atypical" or "unconventional" response pattern was recognized, attempts were made to standardize its measurement using either international consensus (for example, immune-related response criteria 82 ) or agent-and protocol-specific criteria (for example, in clinical trials of nivolumab 74,78 ). More recently, the immunotherapy recist (irecist) criteria, based on recist 1.1 83 , have been published 84 . The irecist framework standardizes tumour response evaluation in clinical trials of immunotherapy agents, but it requires further validation and is not meant for decision-making in routine clinical practice. However, aspects of irecist are helpful in defining pseudoprogression.
Pseudoprogression might manifest as temporary tumour growth or development of new lesions (or both) on imaging, subsequently followed by disease stabilization or a disease response 85 . The cause of the apparent tumour growth is unclear, but might possibly be related to infiltration of the tumour with immune effector cells and inflammation.
Table i summarizes differences between disease progression and pseudoprogression. Although changes in tumour size over time as measured on serial radiologic imaging will eventually distinguish the two, the patient's clinical status at any given time is crucial. With true disease progression, the patient is more likely to experience a deterioration in performance status and worsening of disease-related symptoms. With pseudoprogression, the patient's performance status usually remains stable or improves, systemic symptoms might or might not improve, and symptoms of tumour enlargement might or might not be present.
In clinical trials, some cancer patients treated beyond recist disease progression with immuno-oncology agents appear to do well 86 . However, in nsclc, pseudoprogression is uncommon; data from clinical trials in nsclc reveal that such "unconventional" responses occur much less than 10% of the time (Table ii). Thus, although many patients have been treated past response in the clinical trials of immune agents, many received only a few additional cycles of therapy, suggesting that the greatest proportion of those patients were experiencing true disease progression (Table iii). Those observations highlight the rarity of pseudoprogression and the rarity of long-term benefit resulting from treating past progression. Given current uncertainty about the role of PD-L1 status in selecting patients for immuno-oncology therapy, no data of which we are aware correlate baseline PD-L1 status and the likelihood of experiencing pseudoprogression. Given that genuine pseudoprogression is uncommon, the panel recommends close follow-up imaging in patients who continue treatment beyond progression to ascertain whether ongoing benefit is being achieved.
# Consensus Statement
Canadian oncologists emphasize that pseudoprogression is uncommon in patients with nsclc treated with PD-1/ PD-L1 inhibitors. In patients showing clinical evidence of deterioration at radiologic progression, therapy should be discontinued, and the patient should be switched to another line of therapy, if appropriate. When selecting patients to continue on immunotherapy past recist progression, oncologists should use clinical judgment and take the patient's clinical characteristics and burden of illness into consideration. Patients who continue immunotherapy must be in stable clinical condition, have no signs of rapid disease progression, and be tolerating the treatment. Patients who continue immunotherapy have to be continually monitored and re-imaged by ct at 4-8 weeks to ensure that they are not on a trajectory of true disease progression. No biomarkers are currently available to delineate between pseudo and true disease progression. | Background Little evidence has been generated for how best to manage patients with non-small-cell lung cancer (nsclc) presenting with rarer clinical scenarios, including oligometastases, oligoprogression, and pseudoprogression. In each of those scenarios, oncologists have to consider how best to balance efficacy with quality of life, while maximizing the duration of each line of therapy and ensuring that patients are still eligible for later options, including clinical trial enrolment. Methods An expert panel was convened to define the clinical questions. Using case-based presentations, consensus practice recommendations for each clinical scenario were generated through focused, evidencebased discussions.Treatment strategies and best-practice or consensus recommendations are presented, with areas of consensus and areas of uncertainty identified.In each situation, treatment has to be tailored to suit the individual patient, but with the intent of extending and maximizing the use of each line of treatment, while keeping treatment options in reserve for later lines of therapy. Patient participation in clinical trials examining these issues should be encouraged.# BACKGROUND
Little evidence has been generated for how best to treat patients with non-small-cell lung cancer (nsclc) presenting with rarer clinical scenarios, including oligometastases, oligoprogression, and pseudoprogression. In each of those scenarios, oncologists have to consider how best to balance efficacy with quality of life, while maximizing the duration of each line of therapy and ensuring that patients are still eligible for later options, including clinical trial enrolment.
# METHODS
An invited expert panel of thoracic oncology specialists in medical and radiation oncology and anatomic and molecular pathology was convened. Panellists were tasked to perform an evidence-based overview of specific topics related to oligometastatic and oligoprogressive nsclc and to pseudoprogression on immuno-oncology agents. Case presentations were used to illustrate typical examples of those rare clinical situations, and after an overview of the evidence by all attendees, evidence-informed recommendations for practice were developed. The guideline presented here was drafted by the first author with the assistance of a medical writer, and all authors provided feedback. The final guideline was approved by all authors and submitted for publication.
# RESULTS
# Non-Central Nervous System Oligometastatic and Oligopersistent Wild-Type NSCLC
# Case Description
An incidental left upper lobe mass found in a 59-year-old male ex-smoker during a coronary angiogram was followed by serial computed tomography (ct) imaging until slight growth prompted investigations. Combined positronemission tomography and ct imaging in March 2016 identified a 2.3 cm left upper lobe mass (standardized uptake value 13.6), and biopsy showed an adenocarcinoma, which was EGFR-and ALK-negative (Figure 1, left panel). A positronemission tomography-positive 1.8 cm mass was also noted in the left adrenal gland (Figure 1, right panel), and although an adrenal biopsy in April 2016 showed only rare atypical cells, there was some concern that this location might represent a single site of metastatic disease.
In June 2016, the patient had a left upper lobe lobectomy to remove a 2.3 cm node-negative invasive adenocarcinoma. Because the adrenal biopsy was non-diagnostic, benefit of the doubt led to planning for an adrenalectomy. However, before that surgery occurred, the patient developed a rapidly growing malignant right supraclavicular lymph node, and repeat imaging confirmed significant progression of his adrenal metastasis.
Carboplatin-gemcitabine chemotherapy was initiated, but by the 3rd cycle, the supraclavicular node had progressed, although the adrenal metastasis had shrunk to 6×5 cm from 8×7 cm. Because the patient was PD-L1 positive [≥50% tumour progression score by the Dako 28-8 pharmDx PD-L1 immunohistochemistry assay (Dako Corporation, Glostrup, Denmark)], he received 4 cycles of pembrolizumab. Initially, there appeared to be no clinical response, but after the 4th cycle, the patient experienced a rapid and excellent response such that the node in his neck was no longer palpable, and the adrenal metastasis had shrunk further to 2.9×1.5 cm by July 2017 (Figure 2). The patient continues on treatment and is doing well.
# Panelist Presenters
Drs. J. Laskin and P. Cheung
# Clinical Questions
n What is oligometastatic nsclc, and proportionally, how many patients present in this fashion? n Is oligometastatic nsclc a distinct clinical entity? n Which patients warrant aggressive, localized ablative therapy of all sites of metastatic disease, either as initial therapy or after induction chemotherapy?
Oligometastasis, a term first formally defined in 1995 1 , refers to a minimal metastatic state in which patients have a low burden of metastatic disease with only a small number of metastatic sites at initial presentation of their illness. Given that metastatic burden is a continuum, some authors question the existence of the oligometastatic state 2 . However, many believe that it represents a distinct group of patients who might have a more favourable outcome and in whom more aggressive therapy might be warranted. There are data to suggest that, compared with patients having more diffuse disease, those with fewer sites of metastases might experience longer survival [3][4][5] . The recognition that different sites and numbers of metastases are associated with different prognoses has been integrated into the 8th edition of the staging system for nsclc, in which malignant effusions or isolated contralateral lung metastases are considered M1a, a single site of extrathoracic metastatic disease is considered M1b, and more extensive extrathoracic metastatic disease is considered M1c 6 . "Oligopersistent disease" is a closely related concept referring to an oligometastatic state that, after systemic therapy, either persists or is induced from a more widely metastatic state.
It is known that patients with a solitary site of metastatic disease (most commonly brain or adrenal gland) who undergo surgical resection of both their primary and the metastasis can occasionally experience long-term survival or cure, and that dual resection is a generally accepted treatment strategy for such patients [7][8][9] . Whether patients with wild-type nsclc and more than a solitary site of distant metastatic spread should be considered for more aggressive localized therapy was the topic for discussion. The development of increasingly sophisticated radiotherapy techniques [stereotactic body radiation (sbrt), also called stereotactic ablative radiation (sabr)] allows for the delivery of radical doses of radiation safely in a very short treatment time to almost any body site 10 , thus making the local control option feasible for some patients with metastatic nsclc.
The rationale for the treatment of oligometastatic and oligopersistent disease arises from the fact that, rather than develop metastases at new sites, many patients with advanced nsclc treated with systemic therapy relapse at a site of pre-existing disease [11][12][13] . Hypothetically, those sites will harbour chemotherapy-resistant clones and can serve to seed other sites with metastases. There are data to suggest that the larger the tumour deposit, the greater the likelihood of residual resistant clones, and thus the greater the likelihood of benefit from local control of that lesion 14 . Thus, it might be possible to delay the onset of treatment resistance and the development of new sites of metastases by aggressive ablative local therapy to the oligometastatic sites.
The absolute number of metastatic sites that constitutes the upper limit of the oligometastatic state remains a subject of debate, ranging from 3 or fewer 7 or 5 or fewer 15,16 to 6 active extracranial lesions (3 each in liver and lung parenchyma) 17 . Estimates of its occurrence fall into the 26% -55% range 3,15,18,19 , with the variation likely representing definition differences. An individual patient metaanalysis of 757 patients having 1-5 either synchronous or metachronous nsclc metastases found that most oligometastases were either in brain (35.5%) or lung (33.6%), followed by adrenal gland (13.0%), bone (8.5%), other (7.8%), liver (2.4%), and lymph node (2.4%) 16 . The meta-analysis revealed that, in patients treated with ablation to all sites of disease, including the primary, median overall survival was 26 months, and survival at 1, 2, 5, and 8 years was 70.2%, 51.1%, 29.4%, and 23.4% respectively. The longest survival times were observed in patients with metachronous metastases and an absence of nodal disease, but the 5-year overall survival rate was still 13.8% in patients with synchronous metastases and N1-2 disease.
Data about whether the treatment of oligometastatic or oligopersistent disease alters the natural history of advanced nsclc are limited, given that most of the published literature consists of retrospective case series or single-arm phase ii trials and are thus subject to selection bias. Data suggest that, for treated patients, progression-free survival (pfs) or even overall survival might be prolonged in comparisons with historical controls 17,20 . The optimal sequencing of systemic therapy and local ablative therapy (lat) remains unclear. Initial ablative treatment to all disease might delay the need for initiation of systemic therapy in selected patients. It might also be a useful strategy for those not felt to be suitable for systemic therapy because of poor performance status or comorbidities, or for patients who want to avoid the toxicities of systemic therapy. However, somewhat more data about the use of local ablative therapies as consolidation treatment after the use of systemic therapy are available.
In a small randomized phase ii study, 49 patients with oligometastatic nsclc (≤3 sites of metastatic disease) who had received at least 4 cycles of chemotherapy or 3 months of an appropriate targeted therapy and who had not progressed were randomized to maintenance systemic therapy or to sbrt to all sites of disease, followed by maintenance therapy 7 . Most patients (88%) had wild-type EGFR. The trial was halted early because a significant improvement in pfs in favour of sbrt was observed (11.9 months vs. 3.9 months; hazard ratio: 0.35; p = 0.0054), with no significant toxicities.
Since the consensus meeting, a second small (29 patients) single-centre randomized phase ii study, enrolling only patients with wild-type EGFR and up to 5 sites of metastatic disease in addition to the primary lesion, has been published. It also revealed increased pfs (9.7 months vs. 3.5 months, p = 0.01) with no significant increase in toxic effects 21 . In that study (NCT02045446 at http://ClinicalTrials. gov/), patients who experienced stable disease or a partial response [by the Response Evaluation Criteria in Solid Tumors (recist)] after 4-6 cycles of first-line platinum-based chemotherapy were randomized to sabr plus maintenance chemotherapy or to maintenance chemotherapy alone. The results satisfied the hypothesis that using sabr prevented local failure at the original disease sites-the most likely sites of first recurrence. Based on the findings of that study, the use of radiation therapy after chemotherapy is being evaluated in a phase iii setting for patients with limited metastatic nsclc.
# Consensus Statement
Overall, the current level of evidence does not support the routine use of lat as the initial treatment in oligometastatic disease, for which systemic therapy remains the standard of care. Local treatment approaches could be considered for patients not suitable for, or who refuse or want to delay, systemic therapy. Some available data suggest that the use of consolidative local ablative radiotherapy (sbrt) to all sites of disease in patients without progression after first-line systemic therapy might lead to longer pfs without undue toxicity. Those data were obtained mostly in patients with EGFR wild-type nsclc. We encourage the enrolment of such patients into ongoing clinical trials [such as nrg-lu002 (NCT03137771 at http://ClinicalTrials.gov/)] that are examining this issue. Outside a clinical trial, such an approach could be considered in selected patients.
# Non-Central Nervous System Oligoprogressive Oncogene-Driven NSCLC
# Case Description-Oligoprogressive Oncogene-Driven NSCLC, ALK Rearrangement
A previously well 42-year-old male never-smoker first presented in 2009 with extensive pulmonary infiltrates, biopsy-proven to be adenocarcinoma. During the subsequent year, he received multiple therapies, including a platinum doublet, pemetrexed, and erlotinib.
By mid-2010, the patient was very symptomatic with progressive disease, and results of fluorescence in situ hybridization testing revealed that he had an ALK rearrangement. He started treatment with crizotinib in October 2010 and experienced a dramatic response [Figure 3(A-C
# Clinical Questions
n What is oligoprogression, and how often does it occur? n When might treatment past progression with a tyrosine kinase inhibitor (tki) be considered for patients with extracranial progressive disease?
Compared with standard platinum-based chemotherapy, targeted therapy for oncogene-driven (EGFR-mutated and ALK-translocated) nsclc is associated with significantly improved outcomes [22][23][24][25][26][27][28][29][30][31][32][33] . Most patients treated with an appropriate targeted therapy will experience some degree of tumour shrinkage. However, treatment resistance remains an inevitable occurrence, and at some point, all patients on targeted therapy will progress. Acquired resistance to firstline tkis typically develops after 9-12 months on erlotinib, gefitinib, or afatinib 22,24,25,28 and after approximately 11 months on crizotinib 31 .
Acquired resistance can be attributed to a number of different mechanisms (concisely described elsewhere 34 ) that can either already exist at low frequency in subclones at diagnosis or that can develop under the selective pressure of drug exposure 34,35 . Three different patterns of resistance can be observed with tki therapy: isolated central nervous system (cns) progression without extra-cns progression (discussed in a later subsection), generalized disease progression requiring a change in therapy (extra-cns with or without cns progression), and oligoprogression 36 .
Oligoprogressive disease describes a situation in which a patient develops disease progression in one or a limited number of sites after a targeted therapy has resulted in either a period of stable disease or a partial or complete response 34,37 . Some definitions describe a specific numbers of lesions, such as "≤4 discrete lesions amenable to invasive/non-invasive ablation" 38 . The frequency of oligoprogression during tki treatment varies depending on the definition used and whether isolated cns progression is included; however, estimates range from 15% to 47% 11,37,38 . Oligoprogression is felt to arise as a consequence of tumour heterogeneity, and the development of an isolated resistant subclone at only 1 or a few metastatic sites 39 .
An increasingly common method for treating oligoprogression in nsclc patients with driver mutations is to continue the tki that is controlling the greater proportion of the disease, while using lat to eradicate the resistant clones in the area or areas of progression. Given its relatively few fractions and short treatment time, sbrt might be preferred to more extended radiation schedules or invasive surgery, both of which can be associated with longer interruptions of the tki. Retrospective studies suggest that aggressive local treatment can eradicate tki-resistant oligometastases and could have several theoretical benefits, including prevention or treatment of local symptoms and complications from a growing tumour; prevention of secondary seeding by the tki-resistant clone or clones; and potential for ongoing maintenance with the current tki, which might be providing overall clinical benefit despite oligoprogression. Retrospective data suggest that sbrt can permit continuation of the tki and delay the time to a change in therapy. For example, in a review of 18 patients with EGFR mutation-positive disease treated with lat, the median time to another progression event was 10 months, and the median time to a change in therapy was 22 months 40 . In another cohort of 46 patients, the median time to another progression event was 7 months 41 . Similar results were observed in a cohort of 33 patients with ALK-positive lung cancer who experienced progression while on crizotinib. In 14 patients with oligoprogression who were suitable for lat, the median total duration of crizotinib was 28 months, compared with 10 months in those who progressed and were not suitable for lat 42 . Data suggest that higher radiation doses might lead to better local control of the oligoprogressive sites, although it is unclear whether doses as used for curative intent are required in this setting 34 .
Retrospective studies such as the foregoing are inherently susceptible to selection bias, and the lack of a control arm precludes definitive conclusions about the true value of lat in this setting. However, based on limited data, guidelines from the U.S. National Comprehensive Cancer Network currently recommend this strategy 9 . Ongoing clinical trials conducted specifically in oligoprogressive oncogene-driven nsclc (summarized in Kim et al. 43 ) will help to provide prospective evidence for the use of this strategy in this situation, and participation in such trials should be encouraged. Likewise, as in the case of EGFR wild-type nsclc, there is also a desire to evaluate the role of lat in oligopersistent disease after a period of time on a tki in oncogene-driven disease. Sites of residual tumour could be more likely to harbour resistant subclones that could lead to treatment failure. Ongoing trials are studying this strategy (see NCT02759835, NCT01941654, and NCT01573702 at http://ClinicalTrials.gov/).
# Consensus Statement
Canadian oncologists believe that certain selected patients with limited extra-cns oligoprogression, who are otherwise experiencing clinical benefit and good tolerance of their targeted therapy, could be considered for an approach that combines lat with continuation of their current targeted therapy. Generally, to avoid prolonged interruption of the targeted therapy, and because it is safe and effective, sbrt or sabr is, when possible, preferred to more protracted radiation courses or surgery. Careful and close follow-up of treated patients is required, because additional progression events are expected.
# Case Description-Baseline CNS Oligometastatic Disease, Both Wild-Type and Oncogene-Driven
In October 2014, an otherwise healthy 49-year-old male architect presented with an 18-month history of progressive fatigue; intermittent left chest pain; and retrosternal, back, and eye pain.
Staging investigations revealed a dominant left upper lobe mass, with widespread metastases to mediastinal lymph nodes, lung, pleura, and brain. Biopsy of the lung lesions confirmed adenocarcinoma. Molecular testing of the biopsy sample revealed the presence of the EGFR exon 21 L858R mutation.
In November 2014, the patient received whole-brain radiotherapy (wbrt). He then started gefitinib. In December 2014, after 6 weeks of gefitinib, the patient demonstrated a slight interval decrease in the left upper lobe mass, stable small pulmonary nodules, and stable or improved brain metastases (Figure 4). The patient continued with gefitinib and continued to show a decrease in enhancing brain lesions and stable disease in the chest.
In January 2016, after 14 months taking gefitinib, the patient began to experience some headaches, and magnetic resonance imaging of the brain showed an interval increase in a cerebellar lesion. The remainder of his disease burden was stable, and so the cerebellar lesion was treated with stereotactic radiosurgery (srs), and the patient was continued on gefitinib.
In May 2016, after 18 months on gefitinib, the patient was still clinically well, but chest ct imaging suggested early progression, with slightly more prominent pulmonary nodules, suggestive of possible lymphangitic carcinomatosis. The patient continued gefitinib with closer monitoring.
By the following month, June 2016, brain magnetic resonance imaging revealed that 6 enhancing lesions in the brain were starting to enlarge (Figure 5). The patient received further srs to all lesions and continued taking gefitinib.
In August 2016, the patient started to experience mild hemoptysis. Imaging by ct showed an increase in the size of the dominant left upper lobe mass, a bilateral increase in pulmonary nodules, appearance of new nodules, and worsening lymphangitic carcinomatosis [Figure 6(A,B)]. The molecular analysis of a biopsy sample from the left upper lobe mass revealed that the patient had an EGFR T790M resistance mutation. The gefitinib was therefore stopped after 21 months, and treatment with osimertinib was started.
By September 2016, brain magnetic resonance imaging showed 2 enlarging brain metastases, which were treated by srs. The patient continued on osimertinib, and by December 2016, after 3 months on the drug, his best response was stable disease. Chest ct imaging showed a slight decrease in the size of the left upper lobe mass, with the remainder of his disease being stable [Figure 6(C)].
By March 2017, he had been treated with osimertinib for 7 months. A routine restaging ct showed that his pulmonary disease was completely stable, but a new paraaortic lymph node (1.8×2.2 cm) was visible. The nodule was irradiated (25 Gy in 5 fractions), and osimertinib treatment is ongoing. Patients who present with symptomatic brain metastases require appropriate treatment with corticosteroids and consultations with radiation oncology or neurosurgery (or both). There has been a shift away from the use of wbrt, because it has become clear that this therapy is associated with short-term effects of asthenia and longer-term neurocognitive toxicity. Many authors advocate that its use be avoided or postponed whenever possible 38 . Thus, if radiation is felt to be required (either as definitive treatment or after resection), patients, whenever suitable, should be considered for srs. For patients with 1-4 metastases, srs is replacing wbrt, because srs is associated with improved cognitive outcomes [44][45][46] .
Multiple randomized trials have compared wbrt and srs with srs alone or wbrt alone [44][45][46][47][48][49][50][51] . In general, those studies have shown that overall survival is as good with srs alone as with strategies that use wbrt. At the time points studied, neurocognitive functioning has been better preserved with srs alone; however, cns recurrences are more common with srs alone than when wbrt is used. Strategies to decrease the neurocognitive effects of wbrt include the use of memantine, an N-methyl-d-aspartate receptor antagonist used in the treatment of dementia 52 , and the concept of hippocampal avoidance, which is being studied in randomized trials.
For patients with surgically resected metastases, adjuvant srs, compared with wbrt, provides inferior intracranial control at 12 months [40.7% (95% confidence interval: 25.9% to 64.2%) vs. 81.5% (95% confidence interval: 68.1% to 97.5%)] 46 . Although the randomized trial did not show that the use of local srs, compared with whole-brain treatment, is associated with an increased risk of leptomeningeal relapse, multiple published retrospective experiences show that such relapse can be an important pattern after srs alone 53 . Careful surveillance is a crucial component of any strategy, especially when wbrt is withheld, and the issues of neurocognitive impact and increased intracranial recurrence have to be discussed with patients.
In patients presenting with asymptomatic brain metastases that do not require corticosteroids and for whom urgent local therapy is not felt to be required, consideration could be given to initiating systemic therapy-particularly for patients with an oncogenic driver, in whom targeted agents have a high likelihood of controlling cns disease. Studies of gefitinib, erlotinib, and afatinib have revealed intracranial disease control rates of up to 89% in patients with nsclc showing common EGFR mutations 54,55 . In patients with measurable cns disease, response rates of up to 40% have been reported 54,56,57 . Similarly, in ALKtranslocated nsclc, crizotinib leads to intracranial disease control in 56% of patients with previously untreated brain metastases and in 62% of patients with previously treated brain metastases, with an objective response rate in the range of 18% -33% depending on whether the patient has received prior treatment 58 . Control of cns disease appears to be even higher with newer alk inhibitors. In the phase iii ascend-4 trial comparing ceritinib with chemotherapy as first-line therapy 32 , ceritinib was associated with an intracranial response rate of 73% in patients with measurable disease, and at 24 weeks, a 70% rate of disease control in all 54 patients with brain metastasis (both measurable and non-measurable). In the more recently reported phase iii alex trial 59 , which compared crizotinib with alectinib as first-line treatment, analysis of patients with measurable disease found that alectinib was associated with longer pfs overall and with an 81% intracranial response rate (38% complete response rate) compared with crizotinib's 50% intracranial response rate (5% complete response rate), with a median duration of intracranial response of 17.3 months compared with 5.5 months. Furthermore, the risk of cns progression was markedly reduced with alectinib, even in patients with baseline cns metastases.
Standard platinum doublet chemotherapy has also been shown to have intracranial activity in ALK-positive nsclc. For example, in profile 1014, disease control rates with chemotherapy, while less than those with crizotinib, were approximately 40% at 12 weeks and 20% at 24 weeks in patients with previously treated brain metastases 60 . Similar results were seen for the chemotherapy arm of ascend-4, with an intracranial disease control rate of 55% at 24 weeks 32 . Fewer data about the value of chemotherapy in the treatment of EGFR mutation-positive brain metastases are available. In a pooled analysis of patients enrolled to lux-Lung 3 and 6, rates of cns progression with chemotherapy were similar to rates seen with afatinib in patients both with and without brain metastases at baseline 55 . Newer tkis might result in even better outcomes for patients with brain metastases. Initial results of the phase iii aura3 trial showed a longer duration of pfs for osimertinib compared with platinum therapy plus pemetrexed in the subgroup of patients with cns metastases 61 . Independent radiologic assessment of all intracranial metastases for that trial is ongoing, and so intracranial response and disease control rates are not yet available. Preliminary data from the flaura trial comparing osimertinib with erlotinib or gefitinib as first-line therapy in nsclc patients with common EGFR mutations were recently presented 62 , demonstrating that osimertinib shows durable cns control. Similarly, lorlatinib and brigatinib, next-generation ALK/ROS1 inhibitors, demonstrated substantial intracranial efficacy in phase ii trials 63,64 .
Although data are limited, response rates to chemotherapy in previously untreated brain metastases from EGFR wild-type lung cancer appear to approach response rates in extracranial disease 65 -although response rates appear to be lower than those observed with targeted therapies in mutation-positive disease and could be lower than those observed with platinum-doublet chemotherapy in ALK-positive nsclc, given data suggesting that ALKpositive cancers might be more susceptible to pemetrexed 66,67 . Thus, any patient with wild-type nsclc for whom local brain-directed therapy is delayed in favour of a trial of systemic therapy will have to be monitored very closely for cns progression.
# Oligoprogression in the CNS in Patients Without Baseline CNS Metastases and With Oncogene-Driven NSCLC:
In some patients, the cns will be the sole site of progression, while extracranial disease remains completely or mostly controlled; in others, cns progression will be just one component of more generalized disease progression. In nsclc, cns metastases are a frequent occurrence, affecting 21%-64% of patients 12,68 , with one third of patients presenting with brain metastasis at baseline 58 . The rates of cns progression with first-line tki are 20%-46% for nsclc patients with ALK-positive translocations 38,58 and 22%-52% for nsclc patients with EGFR mutations 11,38,40,69 . Treatment decisions will depend on the degree of progression both intracranially and extracranially, and on the systemic treatment options remaining for the patient. Regardless, patients with symptomatic cns metastases require the approach described earlier: corticosteroids and a referral to radiation oncology or neurosurgery (or both).
In patients with oncogene-driven asymptomatic cns progression in the setting of more widespread progression, a change of systemic therapy is usually warranted. If another targeted agent with cns activity is available, treatment with that agent and careful cns surveillance can be considered. In patients with cns oligoprogression alone, consideration could be given to local brain treatment and continuation of the current targeted therapy that is controlling the extra-cns disease. Alternatively, if another targeted agent is available that has cns activity, withholding local therapy and switching to the other targeted agent, with careful brain surveillance, could also be considered.
In pat ients w it h A LK-posit ive nsclc i n w hom oligoprogressive cns disease develops during crizotinib treatment, some data suggest that both ceritinib and alectinib (both available in Canada) can lead to an intracranial response, at rates of 45% and 52% -67% respectively [70][71][72] . Osimertinib has been approved by Health Canada for patients with an acquired EGFR T790M resistance mutation after first-or second-generation tkis. A subset analysis of the aura 3 trial demonstrated that patients with 1 or more measurable or non-measurable cns metastases on baseline brain imaging experienced a significantly longer median pfs with osimertinib than with chemotherapy: 11.7 months compared with 5.6 months (p = 0.004). The cns objective response rate was 70% with osimertinib and 31% with chemotherapy for those with evaluable disease in the brain 73 .
# Asymptomatic Oligoprogression in the CNS in Wild-Type NSCLC Without Baseline CNS Metastases:
In this situation, greater consideration should be given to local therapy (srs, if feasible), given that data about the role of systemic therapies, either further cytotoxic chemotherapy or immunotherapy, are limited. Responses in the cns with immunotherapy have been reported 74,75 , but the relevant data are too preliminary to routinely support the use of immunotherapy specifically for the treatment of cns metastases. If a local therapy is deferred in this situation, very careful cns monitoring is recommended.
# Consensus Statement
If clinically appropriate and possible, wbrt should be deferred in favour of srs. With small-volume asymptomatic brain metastases, consideration might be given to starting with systemic therapy, particularly if the patient has an oncogenic driver. Careful brain surveillance is vital to ensure disease control in the cns.
# Pseudoprogression with Immuno-oncology Agents in NSCLC
# Case Description
In February 2016, a fit 80-year-old woman with EGFR-and ALK-negative adenocarcinoma of the lung was started on therapy with a PD-1 inhibitor. Originally diagnosed with metastatic nsclc in 2013, her previous treatments had included carboplatin doublet chemotherapy and single-agent pemetrexed in addition to stereotactic radiation to liver and brain.
At restaging in June 2016 after several months of a PD-1 inhibitor, the patient's liver lesions had grown in size, as had her paratracheal lymph node [Figure 7(A)]. Because she remained fit, with an Eastern Cooperative Oncology Group performance status of 0 and good tolerance to treatment save for a mild rash and hypothyroidism, the patient was continued on the PD-1 inhibitor. After 4 more doses, she was restaged, with clear evidence of improvement [Figure 7(B)], thus demonstrating that the original imaging was indicative of pseudoprogression. The patient was therefore continued on therapy. By February 2017, she was experiencing clinical deterioration, with increased pain and worsening performance status. At that point, imaging confirmed significant disease progression [Figure 7(C)] and immunotherapy was discontinued. Immunotherapy can be effective in nsclc: approximately 20% of patients with advanced disease experience durable responses with immune checkpoint inhibitor therapy 76 . Multiple anti-PD-1 and -PD-L1 antibodies have become standard therapies in the first-or second-line treatment of patients with advanced nsclc 74,[77][78][79][80] , and still others are in various phases of clinical development. In contrast to cytotoxic chemotherapy and targeted agents, immunotherapy is associated with a number of response patterns, including delayed response to therapy, disease regression that continues even after therapy is discontinued, and pseudoprogression. Pseudoprogression has to be differentiated from hyperprogression-very rapid disease progression associated with clinical deterioration that has been described with immuno-oncology agents 81 and which is not discussed here.
Definitions of pseudoprogression vary, but generally describe apparent tumour growth arising from a treatment effect rather than true disease progression. Distinguishing between pseudo and true disease progression is crucial to avoid prematurely discontinuing an effective therapy, while at the same time not continuing an ineffective, costly, and potentially toxic treatment and losing an opportunity to move on to another therapy if the patient deteriorates clinically from true disease progression.
In the initial clinical trials of immuno-oncology agents, it was clear that patients were occasionally manifesting radiologic disease progression that met recist 1.1 criteria for progressive disease, but were felt to be clinically benefiting from treatment. Those patients were continued on study therapy, and some subsequently went on to experience either a radiologic response or more prolonged stabilization of disease after the initial progression. After this "atypical" or "unconventional" response pattern was recognized, attempts were made to standardize its measurement using either international consensus (for example, immune-related response criteria 82 ) or agent-and protocol-specific criteria (for example, in clinical trials of nivolumab 74,78 ). More recently, the immunotherapy recist (irecist) criteria, based on recist 1.1 83 , have been published 84 . The irecist framework standardizes tumour response evaluation in clinical trials of immunotherapy agents, but it requires further validation and is not meant for decision-making in routine clinical practice. However, aspects of irecist are helpful in defining pseudoprogression.
Pseudoprogression might manifest as temporary tumour growth or development of new lesions (or both) on imaging, subsequently followed by disease stabilization or a disease response 85 . The cause of the apparent tumour growth is unclear, but might possibly be related to infiltration of the tumour with immune effector cells and inflammation.
Table i summarizes differences between disease progression and pseudoprogression. Although changes in tumour size over time as measured on serial radiologic imaging will eventually distinguish the two, the patient's clinical status at any given time is crucial. With true disease progression, the patient is more likely to experience a deterioration in performance status and worsening of disease-related symptoms. With pseudoprogression, the patient's performance status usually remains stable or improves, systemic symptoms might or might not improve, and symptoms of tumour enlargement might or might not be present.
In clinical trials, some cancer patients treated beyond recist disease progression with immuno-oncology agents appear to do well 86 . However, in nsclc, pseudoprogression is uncommon; data from clinical trials in nsclc reveal that such "unconventional" responses occur much less than 10% of the time (Table ii). Thus, although many patients have been treated past response in the clinical trials of immune agents, many received only a few additional cycles of therapy, suggesting that the greatest proportion of those patients were experiencing true disease progression (Table iii). Those observations highlight the rarity of pseudoprogression and the rarity of long-term benefit resulting from treating past progression. Given current uncertainty about the role of PD-L1 status in selecting patients for immuno-oncology therapy, no data of which we are aware correlate baseline PD-L1 status and the likelihood of experiencing pseudoprogression. Given that genuine pseudoprogression is uncommon, the panel recommends close follow-up imaging in patients who continue treatment beyond progression to ascertain whether ongoing benefit is being achieved.
# Consensus Statement
Canadian oncologists emphasize that pseudoprogression is uncommon in patients with nsclc treated with PD-1/ PD-L1 inhibitors. In patients showing clinical evidence of deterioration at radiologic progression, therapy should be discontinued, and the patient should be switched to another line of therapy, if appropriate. When selecting patients to continue on immunotherapy past recist progression, oncologists should use clinical judgment and take the patient's clinical characteristics and burden of illness into consideration. Patients who continue immunotherapy must be in stable clinical condition, have no signs of rapid disease progression, and be tolerating the treatment. Patients who continue immunotherapy have to be continually monitored and re-imaged by ct at 4-8 weeks to ensure that they are not on a trajectory of true disease progression. No biomarkers are currently available to delineate between pseudo and true disease progression.
# ACKNOWLEDGMENTS
This initiative was funded by an unrestricted educational grant from Pfizer Canada. Pfizer did not have representation at meetings, did not provide input into the content at any point, and did not review the consensus document before submission.
The authors thank Chrystal Palaty phd, from Metaphase Health Research Consulting Inc., for assistance with manuscript writing and submission.
# CONFLICT OF INTEREST DISCLOSURES
We have read and understood Current Oncology's policy on disclosing conflicts of interest, and we declare the following interests: SAL has received honoraria from Pfizer, AstraZeneca, Boehringer Ingelheim, and Novartis; SB has served on advisory boards for As-traZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Novartis, Pfizer, and Roche, and has received research funding from AstraZeneca and Merck; NB has served on advisory boards for Amgen, AstraZeneca, Merck, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Novartis, Pfizer, Sanofi, and Roche; SB has received honoraria from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eisai, and Merck; PKC has served as an advisor for AstraZeneca, Boehringer Ingelheim, Hoffmann-La Roche, Pfizer, Novartis, Takeda, Eli Lilly, and Bristol-Myers Squibb, and has received research funding from Boehringer Ingelheim and Hoffmann-La Roche; PC has received grants for investigator-initiated research projects from AbbVie, | None | None |
132464a37a33a592a63b7c557a498e225fa6fc46 | cma | None | on behalf of the Infectious Disease Committee of the Society of Obstetricians and Gynaecologists of Canada. Original: May 2020 *The information contained in this document has been reaffirmed for scientific validity. While this document is no longer identified to be clinically useful for the Canadian health care provider, it may be relevant to providers abroad.# Introduction
In December 2019, a novel coronavirus (severe acute respiratory syndrome coronavirus 2, or COVID- 19) was identified in Wuhan, China. 1 In a few short months, COVID-19 has become an unprecedented global pandemic. While every effort is being made to flatten the curve, additional infections in pregnancy are inevitable. One of the many challenges faced by clinicians caring for critically ill pregnant women and their fetuses will be management of preterm pregnancy. More specifically, questions may arise regarding the routine administration of antenatal steroids for fetal lung maturation as the impact of corticosteroid use in COVID-19 patients is currently unclear.
# Steroid use in non-pregnant COVID-19 patients
The role of corticosteroids in the treatment of severe respiratory manifestations of COVID-19, is currently unclear. While recent metanalyses on the use of steroids in viral pneumonia (influenza, coronavirus and others) 10,11 have suggested an association between steroid use and increased mortality, our ability to extrapolate this data is limited because included studies were not controlled trials, had significant heterogeneity, and were susceptible to confounding by indication (sicker patients more likely to be given steroids). Moreover, doses administered were typically higher and/or more prolonged than that required in one course of antenatal lung maturation (12mg of Betamethasone = 75mg of prednisone; doses typically used in adult critical care are ~50mg of prednisone for 5-10 days). Research during Middle East Respiratory Syndrome (MERS) coronavirus outbreak, found that routine treatment with corticosteroids was not beneficial and was associated with decreased viral clearance, but had no impact on 90 day mortality. 12 In contrast, in a retrospective cohort study of 201 patients with COVID-19, almost 50% of those with ARDS (N=84) received corticosteroids, and these patients had a lower risk of mortality than those who did not receive corticosteroids (HR 0.38, 95%CI 0.20-0.72). 13 A published (non-peer reviewed) report of 26 patients with severe COVID-19 suggested the use of methylprednisone (1-2mg/kg/day x5-7 days) was associated with decreased duration of supplemental oxygen use (8.2d vs 13.5d p<0.001) and improvement in radiographic findings. 14 These findings are again limited by concerns around sample size and confounding and as such, strong conclusions cannot be drawn. This sentiment is also reflected in current guidelines where limited recommendations around the use of corticosteroids in COVID-19 patients have been made. 15 A randomized control trial investigating the effectiveness of corticosteroids in COVID-19 patients is currently underway. 16
# What we know about the impact of antenatal corticosteroids on neonates
Antenatal corticosteroids are a cornerstone of obstetric management. Overall, administration of antenatal corticosteroids reduces the risk of respiratory distress syndrome from 18% to 12% (RR 0.66, 95% CI 0.56 to 0.77), reduces the risk of intraventricular hemorrhage from 5% to 3% (RR 0.55, 95% CI 0.40 to 0.76), and reduces the risk of perinatal death from 10% to 7% (RR 0.72, 95% CI 0.58 to 0.89). 17 However, the absolute benefits of antenatal corticosteroids change as 2 gestational age advances and baseline risks of neonatal morbidity decrease. For example, among births <32 weeks' gestation, antenatal corticosteroids reduce the absolute risk of RDS by 20% (from to 46% to 26%, RR 0.56, 95% CI 0.45, 0.71), 18 while among those born between 34-36 weeks' this treatment reduces the absolute risk of severe RDS by 0.9% (from 2.3% to 1.4%, RR 0.60, 95% CI 0.33 to 0.94). 19 These differences by gestational age may be helpful to keep in mind when weighing the benefits of antenatal corticosteroids against any potential or unknown maternal risks.
# Summary
As our experience with this pandemic evolves, so will the evidence to support optimal care. With the evidence we have so far, a decision about the use of corticosteroids for antenatal lung maturation must be weighed between the uncertainty of effect on the mother versus the known benefit for the neonate by gestational age at birth. This assessment should, whenever possible, also take into consideration the preferences and values of the mother.
Based on the current evidence, and because definite harm to maternal health has not been demonstrated, we recommend continuing with routine administration of antenatal corticosteroids up to 34+6 weeks of gestation. If new evidence arises regarding the impact of steroids on COVID-19 patients, or in the situation of a critically unwell COVID-19 positive preterm mother, interdisciplinary collaboration and shared decision making will become even more imperative. | on behalf of the Infectious Disease Committee of the Society of Obstetricians and Gynaecologists of Canada. Original: May 2020 *The information contained in this document has been reaffirmed for scientific validity. While this document is no longer identified to be clinically useful for the Canadian health care provider, it may be relevant to providers abroad.# Introduction
In December 2019, a novel coronavirus (severe acute respiratory syndrome coronavirus 2, or COVID- 19) was identified in Wuhan, China. 1 In a few short months, COVID-19 has become an unprecedented global pandemic. While every effort is being made to flatten the curve, additional infections in pregnancy are inevitable. One of the many challenges faced by clinicians caring for critically ill pregnant women and their fetuses will be management of preterm pregnancy. More specifically, questions may arise regarding the routine administration of antenatal steroids for fetal lung maturation as the impact of corticosteroid use in COVID-19 patients is currently unclear.
# Steroid use in non-pregnant COVID-19 patients
The role of corticosteroids in the treatment of severe respiratory manifestations of COVID-19, is currently unclear. While recent metanalyses on the use of steroids in viral pneumonia (influenza, coronavirus and others) 10,11 have suggested an association between steroid use and increased mortality, our ability to extrapolate this data is limited because included studies were not controlled trials, had significant heterogeneity, and were susceptible to confounding by indication (sicker patients more likely to be given steroids). Moreover, doses administered were typically higher and/or more prolonged than that required in one course of antenatal lung maturation (12mg of Betamethasone = 75mg of prednisone; doses typically used in adult critical care are ~50mg of prednisone for 5-10 days). Research during Middle East Respiratory Syndrome (MERS) coronavirus outbreak, found that routine treatment with corticosteroids was not beneficial and was associated with decreased viral clearance, but had no impact on 90 day mortality. 12 In contrast, in a retrospective cohort study of 201 patients with COVID-19, almost 50% of those with ARDS (N=84) received corticosteroids, and these patients had a lower risk of mortality than those who did not receive corticosteroids (HR 0.38, 95%CI 0.20-0.72). 13 A published (non-peer reviewed) report of 26 patients with severe COVID-19 suggested the use of methylprednisone (1-2mg/kg/day x5-7 days) was associated with decreased duration of supplemental oxygen use (8.2d vs 13.5d p<0.001) and improvement in radiographic findings. 14 These findings are again limited by concerns around sample size and confounding and as such, strong conclusions cannot be drawn. This sentiment is also reflected in current guidelines where limited recommendations around the use of corticosteroids in COVID-19 patients have been made. 15 A randomized control trial investigating the effectiveness of corticosteroids in COVID-19 patients is currently underway. 16
# What we know about the impact of antenatal corticosteroids on neonates
Antenatal corticosteroids are a cornerstone of obstetric management. Overall, administration of antenatal corticosteroids reduces the risk of respiratory distress syndrome from 18% to 12% (RR 0.66, 95% CI 0.56 to 0.77), reduces the risk of intraventricular hemorrhage from 5% to 3% (RR 0.55, 95% CI 0.40 to 0.76), and reduces the risk of perinatal death from 10% to 7% (RR 0.72, 95% CI 0.58 to 0.89). 17 However, the absolute benefits of antenatal corticosteroids change as 2 gestational age advances and baseline risks of neonatal morbidity decrease. For example, among births <32 weeks' gestation, antenatal corticosteroids reduce the absolute risk of RDS by 20% (from to 46% to 26%, RR 0.56, 95% CI 0.45, 0.71), 18 while among those born between 34-36 weeks' this treatment reduces the absolute risk of severe RDS by 0.9% (from 2.3% to 1.4%, RR 0.60, 95% CI 0.33 to 0.94). 19 These differences by gestational age may be helpful to keep in mind when weighing the benefits of antenatal corticosteroids against any potential or unknown maternal risks.
# Summary
As our experience with this pandemic evolves, so will the evidence to support optimal care. With the evidence we have so far, a decision about the use of corticosteroids for antenatal lung maturation must be weighed between the uncertainty of effect on the mother versus the known benefit for the neonate by gestational age at birth. This assessment should, whenever possible, also take into consideration the preferences and values of the mother.
Based on the current evidence, and because definite harm to maternal health has not been demonstrated, we recommend continuing with routine administration of antenatal corticosteroids up to 34+6 weeks of gestation. If new evidence arises regarding the impact of steroids on COVID-19 patients, or in the situation of a critically unwell COVID-19 positive preterm mother, interdisciplinary collaboration and shared decision making will become even more imperative. | None | None |
1c35f133000bb0e354b38644d85c6cb7e1d873ce | cma | None | This report is copyrighted by Cancer Care Ontario; the report and the illustrations herein may not be reproduced without the express written permission of Cancer Care Ontario. Cancer Care Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization. Disclaimer Care has been taken in the preparation of the information contained in this report. Nonetheless, any person seeking to apply or consult the report is expected to use independent medical judgment in the context of individual clinical circumstances or seek out the supervision of a qualified clinician. Cancer Care Ontario makes no representation or guarantees of any kind whatsoever regarding the report content or use or application and disclaims any responsibility for its application or use in any way.# Table of Contents
# Biodegradable Rectal Spacers for Prostate Cancer Radiotherapy Section 1: Recommendations and Key Evidence
# OBJECTIVES
The objective of this guideline is to provide clinical practice recommendations for the use of biodegradable spacers for prostate cancer treatment.
# TARGET POPULATION
Patients undergoing radiation treatment for localized prostate cancer.
# INTENDED USERS
Radiation oncologists and genitourinary oncologists involved in the management of prostate cancer.
# RECOMMENDATIONS, KEY EVIDENCE, AND INTERPRETATION OF EVIDENCE Recommendation 1
Biodegradable spacer insertion is a technology that may be used to decrease toxicity and maintain quality of life (QOL) in appropriately selected prostate cancer patients receiving radiotherapy (RT).
# Qualifying Statements for Recommendation 1
Spacer insertion should be performed by individuals trained in the use of transperineal interventional procedures and where there is institutional support.
Selection of appropriate patients remains to be fully defined but may include: those in whom standard rectal dose-volume criteria are not met; those treated with ultrahypofractionated RT; and those at higher baseline risk of rectal toxicity.
# Key Evidence for Recommendation 1
In a multicentre randomized controlled trial (RCT), 222 patients receiving the rectal spacer experienced significantly lower incidence and lower severity of long-term (greater than 3 months) rectal complications compared with patients not receiving spacers. There were significantly fewer patients experiencing grade 2 or greater longterm rectal toxicity (3 to 15 months) in the spacer (2%) group, compared with the nonspacer group (7%) (p=0.044). However, there were no significant differences observed in the rates of early rectal toxicity. Overall safety of the spacer was excellent, with no device-related adverse events, and no rectal infections or rectal complications . - A follow-up report for this RCT involved 63% of the original sample at a median followup of 37 months. . Grade ≥1 rectal toxicity at three years of follow-up was decreased by 75% in relative terms in the spacer group (hazard ratio , 0.24; 95% confidence interval , 0.06 to 0.97; p0.5) or grade ≥2 urinary toxicity . - There were no statistically significant differences in QOL measures for the one RCT examined in this report .
- In a cohort study of 167 patients, mean bowel function scores did not change for patients with a spacer in contrast to patients without a spacer more than one year after RT in comparison to baseline, with 0% versus 12% reporting a new moderate/big problem with passing stools (p<0.01) .
The RCT discussed in this recommendation report received an overall judgment of "unclear' as to risk of bias, mainly due to uncertainty regarding missing data, the potential for selective reporting, and the study being funded by Augmenix Incorporated, makers of the biodegradable rectal spacer (SpaceOAR®) and two of the authors were stakeholders in the company.
Evidence in the three non-randomized studies presented in Section 3 showed small magnitude of benefit for relatively mild symptoms and were considered to be at "high risk of bias" mainly due to inadequate study design.
# Interpretation of Evidence for Recommendation 1
The evidence is adequate to support the use of biodegradable rectal spacers for RT in patients with localized prostate cancer. However, given the low rates of toxicity observed overall in both arms of the RCT, there may be limited benefit to routine application of this technology. Further evidence to direct the appropriate selection of patients and to evaluate the efficacy of this technology beyond conventionally fractionated RT is warranted.
# IMPLEMENTATION CONSIDERATIONS
Biodegradable rectal spacers are approved for use by Health Canada and thus implementation is left to the discretion of individual cancer centres. It is envisaged that each individual cancer centre may consider their local operational environment in facilitating the adoption of this technology. For example, centres with brachytherapy services may choose to adapt their system to allow for the transperineal insertion of the rectal spacer within the RT department, whereas those without brachytherapy services may choose to engage their local (interventional) radiology or urology departments. The associated costs, such as disposables, related to the transperineal procedure and the costs of the technology itself may need to be taken into account depending on the model of implementation.
# FUTURE RESEARCH
More phase II/III randomized trials to further evaluate the efficacy of this technology are warranted. Additional research is also needed to identify the clinical and dosimetric risk factors that can determine those at greatest risk of rectal toxicity and who might benefit most from the use of this technology. As conventional fractionation was used exclusively in the completed RCT, evaluation of rectal spacer technology in the setting of hypofractionated RT is also warranted.
# Biodegradable Rectal Spacers for Prostate Cancer Radiotherapy Section 2: Recommendation Report Methods Overview
This section summarizes the methods used to create the guideline. For the systematic review, see Section 3.
# THE PROGRAM IN EVIDENCE-BASED CARE
The Program in Evidence-Based Care (PEBC) is an initiative of the Ontario provincial cancer system, Cancer Care Ontario (CCO). The PEBC mandate is to improve the lives of Ontarians affected by cancer through the development, dissemination, and evaluation of evidence-based products designed to facilitate clinical, planning, and policy decisions about cancer control.
The PEBC is a provincial initiative of CCO supported by the Ontario Ministry of Health and Long-Term Care (OMHLTC). All work produced by the PEBC is editorially independent from the OMHLTC.
# BACKGROUND FOR RECOMMENDATION REPORT
The PEBC was asked to develop recommendations for the use of biodegradable rectal spacer insertion for prostate cancer treatment. The PEBC identified an 'interventional procedural guidance (IPG)' document developed by the National Institute for health and Care Excellence (NICE) in the United Kingdom and a Cochrane systematic review assessing hydrogel spacers as a subsection of a document on interventions to reduce acute and late adverse gastrointestinal effects of pelvic RT as relevant to this report. A recent report on the use of hydrogel spacer insertion prepared for the Health Technology Assessment Unit of the McGill University Health Centre (MUHC) was also deemed relevant . Since the abovementioned documents differed in their conclusions as to the efficacy of biodegradable spacers, the relevant primary literature was assessed directly by the PEBC methodologist.
# RECOMMENDATION REPORT DEVELOPERS
This recommendation report was developed by a Working Group consisting of four radiation oncologists (see Appendix 1) at the request of the biodegradable spacer insertion during radiotherapy for prostate cancer recommendation report group (hereby known as the SPACER RRG).
The Working Group was responsible for reviewing the evidence base, drafting the recommendations, and responding to comments received during the document review process. Conflict of interest declarations for all authors are summarized in Appendix 1, and were managed in accordance with the PEBC Conflict of Interest Policy.
# RECOMMENDATION REPORT DEVELOPMENT METHODS
The PEBC produces evidence-based and evidence-informed guidance documents using the methods of the Practice Guidelines Development Cycle . For Recommendation Reports this process includes a systematic review, interpretation of the evidence by the Working Group and draft recommendations, internal review by a methodology experts, and final approval by the Sponsoring Committee.
The PEBC uses the AGREE II framework as a methodological strategy for guideline development. AGREE II is a 23-item validated tool that is designed to assess the methodological rigour and transparency of guideline development.
The currency of each document is ensured through periodic review and evaluation of the scientific literature and, where appropriate, the addition of newer literature to the original evidence-base. This is described in the PEBC Document Assessment and Review Protocol. PEBC guideline recommendations were based on clinical evidence, along with consideration of implementation issues with magnetic resonance imaging. A list of implementation considerations such as costs, human resources, and unique requirements for special or disadvantaged populations is provided along with the recommendations for information purposes. PEBC guideline development methods are described in more detail in the PEBC Handbook and the PEBC Methods Handbook.
# Search for Existing Guidelines
A search for existing guidelines is generally undertaken prior to searching for existing systematic reviews or primary literature. This is done with the goal of identifying existing guidelines for adaptation, using the ADAPTE framework , or endorsement in order to avoid the duplication of guideline development efforts across jurisdictions. For this project, the following sources were searched for existing guidelines that addressed the research questions:
# RECOMMENDATION REPORT REVIEW AND APPROVAL
# Internal Review
The recommendation report was reviewed by the PEBC Report Approval Panel (RAP). The Working Group was responsible for ensuring the necessary changes were made. If those changes could be made without substantially altering the recommendations, the altered draft would not need to be resubmitted for approval again. Table 2-1 shows the Working Group's responses to the RAP review. While the majority of the evidentiary base concerned hydrogel spacers, we considered spacers of all types in our literature search and therefore have decided to leave the title unchanged. Of note, one trial that employed hyaluronic acid spacers (Prada et al.) was included and discussed in the report. Well written -Magnitude of absolute benefit is small (2% vs. 7%) -Could highlight this This has been pointed out in the recommendation section and in the discussion.
# Report Approval by SPACER RRG
After internal review, the SPACER RRG reviewed the document on November 29 th , 2018 and formally approved the document. Of the eight SPACER RRG members approached, one abstained and one did not submit a conflict of interest statement. All of the remaining six eligible members approved (100%) the document. Table 2-2 shows comments addressed by the Working Group.
# Table 2-2. Working Group Responses to Recommendation Report Group SPACER RRG member
Working Group Response I do have some concern that the main piece of evidence is a small phase 2 RCT that was sponsored by the company, conducted by some investigators with COIs and with short follow-up (< 60 mo). Margins used in the trial were hugely variable considering all patients got gold-seed IGRT (5 -10mm CTV-PTV margin). There's no documentation of what the median (IQR) margins were in each group.
I would have liked to see 4-5mm margins in both groups but alas that was the way the study was designed.
Having said that, I think the conclusion is reasonably cautious given the above. It would be interesting to see a cost effectiveness analysis in the Canadian setting -SpaceOAR at $2700 (not including MD fees, disposibles or other personnel costs) doubles the cost of 60 Gy in 20fx and triples the cost of SBRT (40 Gy / 5fx).
Yes, we agree and the wording of the recommendation reflects that the evidence is only adequate to support the use of biodegradable rectal spacers for RT in patients with localized prostate cancer. We also state that since both arms of the RCT experienced low toxicity, there may be limited benefit to routine application of this technology.
Is there any data about when all hydrogel is either absorbed or congealed after instillation in humans/animals? Is it worthwhile to either allude to that data if available or to add a one liner indicating the absence of such data. One presumes this is going to be not at all like silicone implants.
We do not have evidence of rate of absorption but in addition to the estimates, in the RCT of 149 patients only 3 (2%) had any visible remnant of the get which consisted of water density cyst on MRI, as patients had MRI performed at 12 months after hydrogel insertion. This will be added to the findings sections of this report. | This report is copyrighted by Cancer Care Ontario; the report and the illustrations herein may not be reproduced without the express written permission of Cancer Care Ontario. Cancer Care Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization. Disclaimer Care has been taken in the preparation of the information contained in this report. Nonetheless, any person seeking to apply or consult the report is expected to use independent medical judgment in the context of individual clinical circumstances or seek out the supervision of a qualified clinician. Cancer Care Ontario makes no representation or guarantees of any kind whatsoever regarding the report content or use or application and disclaims any responsibility for its application or use in any way.# Table of Contents
# Biodegradable Rectal Spacers for Prostate Cancer Radiotherapy Section 1: Recommendations and Key Evidence
# OBJECTIVES
The objective of this guideline is to provide clinical practice recommendations for the use of biodegradable spacers for prostate cancer treatment.
# TARGET POPULATION
Patients undergoing radiation treatment for localized prostate cancer.
# INTENDED USERS
Radiation oncologists and genitourinary oncologists involved in the management of prostate cancer.
# RECOMMENDATIONS, KEY EVIDENCE, AND INTERPRETATION OF EVIDENCE Recommendation 1
Biodegradable spacer insertion is a technology that may be used to decrease toxicity and maintain quality of life (QOL) in appropriately selected prostate cancer patients receiving radiotherapy (RT).
# Qualifying Statements for Recommendation 1 •
Spacer insertion should be performed by individuals trained in the use of transperineal interventional procedures and where there is institutional support.
# •
Selection of appropriate patients remains to be fully defined but may include: those in whom standard rectal dose-volume criteria are not met; those treated with ultrahypofractionated RT; and those at higher baseline risk of rectal toxicity.
# Key Evidence for Recommendation 1 •
In a multicentre randomized controlled trial (RCT), 222 patients receiving the rectal spacer experienced significantly lower incidence and lower severity of long-term (greater than 3 months) rectal complications compared with patients not receiving spacers. There were significantly fewer patients experiencing grade 2 or greater longterm rectal toxicity (3 to 15 months) in the spacer (2%) group, compared with the nonspacer group (7%) (p=0.044). However, there were no significant differences observed in the rates of early rectal toxicity. Overall safety of the spacer was excellent, with no device-related adverse events, and no rectal infections or rectal complications [1]. • A follow-up report for this RCT involved 63% of the original sample at a median followup of 37 months. [2]. Grade ≥1 rectal toxicity at three years of follow-up was decreased by 75% in relative terms in the spacer group (hazard ratio [HR], 0.24; 95% confidence interval [CI], 0.06 to 0.97; p<0.03). No grade ≥2 rectal toxicity was observed in the spacer group (3-year rate: spacer 0%, non-spacer 6%, 95% CI, 2% to 17%; p<0.015) and one case of grade 3 rectal toxicity developed in the non-spacer group. A reduction was also seen in cumulative grade ≥1 urinary incontinence at three years (p=0.046), with no difference in other grade ≥1 urinary toxicities (p>0.5) or grade ≥2 urinary toxicity [2]. • There were no statistically significant differences in QOL measures for the one RCT examined in this report [1].
• In a cohort study of 167 patients, mean bowel function scores did not change for patients with a spacer in contrast to patients without a spacer more than one year after RT in comparison to baseline, with 0% versus 12% reporting a new moderate/big problem with passing stools (p<0.01) [3].
# •
The RCT discussed in this recommendation report received an overall judgment of "unclear' as to risk of bias, mainly due to uncertainty regarding missing data, the potential for selective reporting, and the study being funded by Augmenix Incorporated, makers of the biodegradable rectal spacer (SpaceOAR®) and two of the authors were stakeholders in the company.
# •
Evidence in the three non-randomized studies presented in Section 3 [3][4][5] showed small magnitude of benefit for relatively mild symptoms and were considered to be at "high risk of bias" mainly due to inadequate study design.
# Interpretation of Evidence for Recommendation 1
The evidence is adequate to support the use of biodegradable rectal spacers for RT in patients with localized prostate cancer. However, given the low rates of toxicity observed overall in both arms of the RCT, there may be limited benefit to routine application of this technology. Further evidence to direct the appropriate selection of patients and to evaluate the efficacy of this technology beyond conventionally fractionated RT is warranted.
# IMPLEMENTATION CONSIDERATIONS
Biodegradable rectal spacers are approved for use by Health Canada and thus implementation is left to the discretion of individual cancer centres. It is envisaged that each individual cancer centre may consider their local operational environment in facilitating the adoption of this technology. For example, centres with brachytherapy services may choose to adapt their system to allow for the transperineal insertion of the rectal spacer within the RT department, whereas those without brachytherapy services may choose to engage their local (interventional) radiology or urology departments. The associated costs, such as disposables, related to the transperineal procedure and the costs of the technology itself may need to be taken into account depending on the model of implementation.
# FUTURE RESEARCH
More phase II/III randomized trials to further evaluate the efficacy of this technology are warranted. Additional research is also needed to identify the clinical and dosimetric risk factors that can determine those at greatest risk of rectal toxicity and who might benefit most from the use of this technology. As conventional fractionation was used exclusively in the completed RCT, evaluation of rectal spacer technology in the setting of hypofractionated RT is also warranted.
# Biodegradable Rectal Spacers for Prostate Cancer Radiotherapy Section 2: Recommendation Report Methods Overview
This section summarizes the methods used to create the guideline. For the systematic review, see Section 3.
# THE PROGRAM IN EVIDENCE-BASED CARE
The Program in Evidence-Based Care (PEBC) is an initiative of the Ontario provincial cancer system, Cancer Care Ontario (CCO). The PEBC mandate is to improve the lives of Ontarians affected by cancer through the development, dissemination, and evaluation of evidence-based products designed to facilitate clinical, planning, and policy decisions about cancer control.
The PEBC is a provincial initiative of CCO supported by the Ontario Ministry of Health and Long-Term Care (OMHLTC). All work produced by the PEBC is editorially independent from the OMHLTC.
# BACKGROUND FOR RECOMMENDATION REPORT
The PEBC was asked to develop recommendations for the use of biodegradable rectal spacer insertion for prostate cancer treatment. The PEBC identified an 'interventional procedural guidance (IPG)' document developed by the National Institute for health and Care Excellence (NICE) in the United Kingdom [6] and a Cochrane systematic review [7] assessing hydrogel spacers as a subsection of a document on interventions to reduce acute and late adverse gastrointestinal effects of pelvic RT as relevant to this report. A recent report on the use of hydrogel spacer insertion prepared for the Health Technology Assessment Unit of the McGill University Health Centre (MUHC) was also deemed relevant [8]. Since the abovementioned documents differed in their conclusions as to the efficacy of biodegradable spacers, the relevant primary literature was assessed directly by the PEBC methodologist.
# RECOMMENDATION REPORT DEVELOPERS
This recommendation report was developed by a Working Group consisting of four radiation oncologists (see Appendix 1) at the request of the biodegradable spacer insertion during radiotherapy for prostate cancer recommendation report group (hereby known as the SPACER RRG).
The Working Group was responsible for reviewing the evidence base, drafting the recommendations, and responding to comments received during the document review process. Conflict of interest declarations for all authors are summarized in Appendix 1, and were managed in accordance with the PEBC Conflict of Interest Policy.
# RECOMMENDATION REPORT DEVELOPMENT METHODS
The PEBC produces evidence-based and evidence-informed guidance documents using the methods of the Practice Guidelines Development Cycle [9,10]. For Recommendation Reports this process includes a systematic review, interpretation of the evidence by the Working Group and draft recommendations, internal review by a methodology experts, and final approval by the Sponsoring Committee.
The PEBC uses the AGREE II framework [11] as a methodological strategy for guideline development. AGREE II is a 23-item validated tool that is designed to assess the methodological rigour and transparency of guideline development.
The currency of each document is ensured through periodic review and evaluation of the scientific literature and, where appropriate, the addition of newer literature to the original evidence-base. This is described in the PEBC Document Assessment and Review Protocol. PEBC guideline recommendations were based on clinical evidence, along with consideration of implementation issues with magnetic resonance imaging. A list of implementation considerations such as costs, human resources, and unique requirements for special or disadvantaged populations is provided along with the recommendations for information purposes. PEBC guideline development methods are described in more detail in the PEBC Handbook and the PEBC Methods Handbook.
# Search for Existing Guidelines
A search for existing guidelines is generally undertaken prior to searching for existing systematic reviews or primary literature. This is done with the goal of identifying existing guidelines for adaptation, using the ADAPTE framework [12], or endorsement in order to avoid the duplication of guideline development efforts across jurisdictions. For this project, the following sources were searched for existing guidelines that addressed the research questions:
•
# RECOMMENDATION REPORT REVIEW AND APPROVAL
# Internal Review
The recommendation report was reviewed by the PEBC Report Approval Panel (RAP). The Working Group was responsible for ensuring the necessary changes were made. If those changes could be made without substantially altering the recommendations, the altered draft would not need to be resubmitted for approval again. Table 2-1 shows the Working Group's responses to the RAP review. While the majority of the evidentiary base concerned hydrogel spacers, we considered spacers of all types in our literature search and therefore have decided to leave the title unchanged. Of note, one trial that employed hyaluronic acid spacers (Prada et al.) was included and discussed in the report. Well written -Magnitude of absolute benefit is small (2% vs. 7%) -Could highlight this This has been pointed out in the recommendation section and in the discussion.
# Report Approval by SPACER RRG
After internal review, the SPACER RRG reviewed the document on November 29 th , 2018 and formally approved the document. Of the eight SPACER RRG members approached, one abstained and one did not submit a conflict of interest statement. All of the remaining six eligible members approved (100%) the document. Table 2-2 shows comments addressed by the Working Group.
# Table 2-2. Working Group Responses to Recommendation Report Group SPACER RRG member
Working Group Response I do have some concern that the main piece of evidence is a small phase 2 RCT that was sponsored by the company, conducted by some investigators with COIs and with short follow-up (< 60 mo). Margins used in the trial were hugely variable considering all patients got gold-seed IGRT (5 -10mm CTV-PTV margin). There's no documentation of what the median (IQR) margins were in each group.
I would have liked to see 4-5mm margins in both groups but alas that was the way the study was designed.
Having said that, I think the conclusion is reasonably cautious given the above. It would be interesting to see a cost effectiveness analysis in the Canadian setting -SpaceOAR at $2700 (not including MD fees, disposibles or other personnel costs) doubles the cost of 60 Gy in 20fx and triples the cost of SBRT (40 Gy / 5fx).
Yes, we agree and the wording of the recommendation reflects that the evidence is only adequate to support the use of biodegradable rectal spacers for RT in patients with localized prostate cancer. We also state that since both arms of the RCT experienced low toxicity, there may be limited benefit to routine application of this technology.
Is there any data about when all hydrogel is either absorbed or congealed after instillation in humans/animals? Is it worthwhile to either allude to that data if available or to add a one liner indicating the absence of such data. One presumes this is going to be not at all like silicone implants.
We do not have evidence of rate of absorption but in addition to the estimates, in the RCT of 149 patients only 3 (2%) had any visible remnant of the get which consisted of water density cyst on MRI, as patients had MRI performed at 12 months after hydrogel insertion. This will be added to the findings sections of this report.
# ACKNOWLEDGEMENTS
The SPACER RRG and the Working Group would like to thank the following individuals for their assistance in developing this report:
• Sheila McNair, Jonathan Sussman, Melissa Brouwers, Emily Vella, Duvaraga Sivajohanathan, Fulvia Baldassarre, and Donna Maziak for providing feedback on draft versions. • Sarah Deshpande for conducting a data audit.
• Sara Miller for copy editing.
# Biodegradable Rectal Spacers for Prostate Cancer Radiotherapy Section 3: Systematic Review INTRODUCTION
External beam RT is a standard definitive treatment option for men with localized prostate cancer. Technical developments, including intensity modulation and image guidance, have allowed for greater precision in RT delivery to the prostate and enhanced sparing of surrounding normal tissues. However, optimal tumour control rates require escalated RT doses, and even with modern techniques, a portion of the anterior rectal wall remains exposed to considerable doses of radiation, which may result in acute and late toxicities. There is an unmet need for interventions that reduce rectal irradiation and thereby improve the therapeutic ratio of prostate RT.
The application of spacers placed between the prostate and rectum to create a 'space' is a logical solution to reduce the volume of rectal tissue receiving undesirable doses. A number of biodegradable materials have been evaluated for use as spacers, including polyethylene glycol hydrogels, hyaluronic acid, collagen, and saline-filled balloons. Early clinical studies with hydrogels have shown favourable outcomes. They are typically injected or inserted in a short procedure under transrectal ultrasound guidance using a transperineal approach. A distance of approximately 1.0 to 1.5 cm is usually achieved between the rectum and prostate, excluding the rectal wall from the high isodoses. Estimates suggest it takes approximately three months to liquefy by hydrolysis and absorb and clear the body via renal filtration [13]. A low incidence of major procedural adverse effects with hydrogel use has been reported. Hydrogel holds promise in establishing itself as an adjunct to standard of care in prostate RT and has been approved by Health Canada for this purpose.
This systematic review summarizes published reports on the effectiveness of the use of biodegradable spacers during RT for prostate cancer in reducing toxicity and maintaining QOL. The data provide the foundation for recommendations about the use of biodegradable rectal spacers during RT for prostate cancer patients in Ontario.
# OBJECTIVES AND RESEARCH QUESTIONS
The Working Group developed the following objective for this guideline in consultation with the SPACER RRG:
• To assess the evidence regarding the use of biodegradable hydrogel spacers during RT for localized prostate cancer with particular reference to rectal toxicity and QOL following treatment.
From this objective, the following research question was derived to direct the search for available evidence to inform recommendations to meet the objectives.
• Does the use of biodegradable hydrogel spacers during RT for prostate cancer decrease rectal (and other) toxicities and maintain QOL following treatment?
# METHODS
This evidence review was conducted in two planned stages, including a search for systematic reviews and guidelines followed by a search for primary literature. These stages are described in subsequent sections.
# Search for Existing Systematic Reviews and Guidelines
MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews were searched for existing systematic reviews published since 2015. Relevant articles were identified by searches of MEDLINE (2015 -October 2018 week 40), EMBASE (2015 -2018 week 40), and the Cochrane Library (2018). The reference lists of eligible articles were searched for relevant articles, and the National Guidelines Clearinghouse (http://www.guideline.gov/index.asp) was searched for existing evidence-based practice guidelines. Expert colleagues were also asked to identify any relevant unpublished or published trials not otherwise identified. The complete MEDLINE and EMBASE search strategies are detailed in Appendix 2. This search identified three documents [6][7][8] (see Section 2 and subsequent sections for details)
# Search for Primary Literature
Given that pre-2017 studies were identified in the NICE [6], Cochrane [7], and MUHC [8] documents, an updated search of the literature was conducted from June 2017 to June 2018 to supplement the existing primary literature. The subject was searched using MEDLINE (2017 through October, 2018), EMBASE (2017 through October, 2018), the Cochrane Central Register of Controlled Trials (OVID CCTR: August 2018), and the Database of Abstracts of Reviews of Effects (OVID DARE: 1st quarter 2018). In addition, the proceedings of the meetings of the ASCO (2017 to 2018), the American Society of Therapeutic Radiology and Oncology (ASTRO; 2017 to 2018), the Canadian Association of Radiation Oncology (CARO; 2009 to 2018) and the European Society for RT and Oncology (ESTRO; 2017 to 2018) were searched for relevant abstracts. Reference lists of studies deemed eligible for inclusion were scanned for additional citations. The literature search of the electronic databases combined disease-specific terms (prostate cancer, prostate carcinoma, etc.) and treatment-specific terms (RT, biodegradable spacers, etc.) (Appendix 2).
# Study Selection Criteria and Process
Articles were eligible for inclusion in the systematic review if they met the following criteria:
• They were randomized controlled trials (RCTs).
# •
They were cohort (comparative) studies with contemporaneous controls.
# •
They compared patients receiving biodegradable hydrogel spacers to those not receiving spacers.
# •
They assessed adults aged ≥18 years with localized prostate cancer undergoing RT as part of cancer treatment.
# •
They reported on acute and/or late toxicities.
Studies were excluded if they:
• Were case reports, case series, case studies, commentaries or editorials.
# •
Had a sample size of fewer than 30 per group (non-RCTs only).
# •
Reported only on the technical aspects of biodegradable spacers.
# •
Reported only on dosimetric surrogates as outcomes.
# •
Were non-English-language articles (translation issues).
# Data Extraction and Assessment of Study Quality and Potential for Bias
All relevant papers identified by the primary literature search were assessed against the above selection criteria independently by one of the authors (JB) (see Appendix 1 for a list of authors of this report). Uncertainties regarding eligibility were subsequently resolved by consensus of all the authors. The methodological quality of eligible studies was assessed using the Cochrane Collaboration's tool for assessing risk of bias in randomized trials [14] and "ROBINS-I" [15], a tool for assessing the risk of bias in non-randomized studies of interventions [16]. Data extraction was performed by one of the authors (JB), while a second reviewer (PC or SM or WK or DD) acted as an independent auditor to verify the accuracy of the data extraction.
# Synthesizing the Evidence
A quantitative analysis of the trial data was planned for the outcomes of interest if the authors deemed it appropriate (i.e., clinical homogeneity of the treatment regimens and patient populations). When data were available from two or more trials, a meta-analysis would be performed using Review Manager (RevMan 5.3.1) [16] provided by the Cochrane Collaboration. The HR is the preferred statistic for pooling time-to-event outcomes because it incorporates data from the entire Kaplan-Meier curve and allows for censoring. When available, the HR would be extracted directly from the most recently reported trial results. The variances of the HR estimates would be calculated from the reported confidence CIs or p-values using the methods described by Parmar et al. [17]. Qualitative assessment of the data, along with consideration of implementation issues with MR, also informed the recommendations.
# RESULTS
# Overview of Existing Systematic Reviews and Guidelines
As previously indicated, the following three relevant documents were identified: 1) a NICE IPG document [6], 2) a Cochrane review [7], and 3) an MUHC technology assessment report [8].
The NICE document searched databases for studies relevant to biodegradable spacer insertions to reduce rectal toxicity, covering the period up to April 2017. The report included 1074 patients from one RCT [1], one quasi-RCT [4], two cohort studies [18,19], and other noncomparative studies. The report concluded that "current evidence on the safety and efficacy of insertion of a biodegradable spacer to reduce rectal toxicity during RT for prostate cancer is adequate to support the use of this procedure provided that standard arrangements are in place for clinical governance, consent and audit" [6].
The Cochrane review was much broader in scope than the NICE document, examining a variety of prophylactic interventions to reduce adverse gastrointestinal effects among adults receiving radiotherapy to treat primary pelvic cancers (literature searched up to November 2017). For the spacer insertions component of the review, one RCT [1] and one quasi-RCT [4] reporting on approximately 300 patients were included. The review concluded that lowcertainty evidence on balloon and hydrogel spacers suggest that these interventions for prostate cancer RT may make little or no difference to genitourinary (GI) outcomes" [7].
The MUHC technology assessment report examined the efficacy, safety, and costeffectiveness of biodegradable spacers, and undertook a budget impact analysis to assess suitability for adoption into MUHC practice. They identified one RCT [1] and five comparative non-RCTs [3,5,[20][21][22] examining over 800 patients. They found that the hydrogel spacer was effective in reducing the amount of radiation to the rectum; however, they concluded that it was unclear whether the reductions translate into lower rectal toxicity and improved QOL. They concluded that "given the limited and inconclusive evidence of the clinical benefit of SpaceOAR®, and the high costs associated with its use at the MUHC routine use of SpaceOAR® in prostate cancer patients receiving RT is not approved" [8].
Since these documents differed in their conclusions as to the efficacy of biodegradable spacers, the relevant primary literature from the existing reviews was extracted and assessed directly by the PEBC methodologist. Studies that met our inclusion criteria were one RCT [1], one quasi-RCT [4], and two of the cohort studies identified above [3,5]. The Prada et al. [4] study identified as a quasi-RCT by NICE and Cochrane will be referred to as a cohort/non-RCT study in the remainder of this report, since it could not be determined if any (or what type of) quasi-randomization assignment occurred (e.g., randomized by birthdate, medical record number, time of recruitment, etc.). The remaining comparative studies listed above were excluded from this report either because they did not include an outcome of interest [19,21], the sample size in one of the groups was less than 30 [18], or because there was no comparison group of interest to the current review [22].
# Literature Search for Post-2017 Studies
The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) flow diagram summarizing this information is provided in Appendix 3.
One hundred three articles were identified and retrieved from the MEDLINE (n=81) and EMBASE (n=22) databases, and no additional records were identified through other sources. After duplicates were removed from the combined search results, 92 articles were assessed by title and abstract for possible inclusion in the evidence summary. Of these, 60 articles were rejected at the title level and the remaining 32 were assessed at the level of full text.
No new studies were identified in the updated search. Updates of four studies [1,3-5] identified previously in the reports identified above [6][7][8] were included in this recommendation report. The most recent publication was used where duplicate reports of the same outcomes existed.
# Study Design and Quality
One RCT (with two publications) [1,2] and three cohort studies [3][4][5] were identified in this review.
Appendix 4 contains the quality assessment for the four studies assessed in this review. In the RCT by Mariados et al. [1], it was "unclear" how patient sequence generation was generated and whether group allocation was concealed. Although attrition was low in the trial, only 63% of participants were included in the three-year follow-up and, thus, it was "unclear" whether incomplete data were appropriately addressed in the study [2]. As well, only percentages (and not absolute numbers) were given for some of the final results and thus it was "unclear" exactly how many individuals were in each group and whether selective reporting was a potential bias in the study. Finally, this RCT was funded by Augmenix Incorporated, makers of the SpaceOAR®, and two of the authors were shareholders; thus, it was "unclear" if these factors potentially created other unknown bias in the study. The study was rated as "low" on risk of bias for blinding of participants and outcome assessors. The study received an overall judgement of "unclear" as to risk of bias (see Appendix 4).
The three cohort studies were judged as "high risk of bias" for confounding, given their non-randomized nature. The study by Pinkawa et al. [3] was judged at "low" risk of bias for selection of participants into the study, classification of interventions, and departure from intended intervention since participants were consecutive and incident cases, and were prospectively recruited. It was "unclear" as to whether there was any bias introduced in the study due to the possibility of missing data and in selection of the reported results. Finally, potential bias in measurement of outcomes was considered "moderate" since some patient data were collected retrospectively. The study received an overall judgement of "high risk of bias" (see Appendix 4).
In the study by Prada et al. [4] it was "unclear" whether patents were selected consecutively and whether there was bias due to missing data. The study was judged to be at a "low" risk for bias on classification of intervention and bias due to departures from intended interventions. Risk of bias due to measurement of outcomes, and in selection of the reported results was considered high. The study received an overall judgement of "high risk of bias" (see Appendix 4).
In the study by Te Velde et al. [5] it was "unclear" whether patents were selected consecutively and whether there was bias due to missing data or in selection of the reported results. The study was judged to be at a "moderate" risk for bias on classification of intervention and in measurement of outcomes, due to its retrospective nature. Risk of bias due to classification in departure from intended interventions was considered low. The study received an overall judgement of "high risk of bias" (see Appendix 4).
# Study Characteristics
Table 3-1 shows the characteristics of the four studies selected for inclusion. Mariados et al. [1] randomized 222 men with low-risk or intermediate-risk prostate cancer 2:1 to spacer hydrogel (n=149) or control (n=73). The study was performed at 20 centres in the United States between 2012 and 2016 and the men were blinded to randomization. Fiducial markers were placed for image guidance during spacer placement and anesthesia was administered per investigator discretion. The men received computed tomography and magnetic resonance imaging planning scans following the procedure and underwent image-guided intensitymodulated RT (79.2 Gy in 44 fractions). Spacer safety and impact on rectal irradiation, toxicity, and QOL were assessed up to 15 months [1].
Prada et al. [4] examined 69 consecutive outpatients enrolled in a clinical trial with low-and intermediate-risk prostate cancer between January 2005 and July 2006. One group received brachytherapy with permanent seed implant of I-125 along with a hyaluronic acid spacer to protect the rectal wall; the control group received brachytherapy with permanent implant of I-125 alone. Six to eight cubic centimetres of hyaluronic acid was injected into the perirectal fat, to increase the distance between the prostate and the anterior rectal wall. The median follow-up was 18 months [4].
Pinkawa et al. [3] examined a group of 167 consecutive patients receiving treatment of the prostate plus/minus base of the seminal vesicles without pelvic lymph nodes with RT with 2 Gy fractions up to 76 Gy (without hydrogel, n=66) or 76 to 80 Gy (with hydrogel, n=101) treated in a single institution between 2010 and 2013. The injection of 10 mL hydrogel was performed under transrectal ultrasound guidance after dissecting the space between prostate and rectum with a saline/lidocaine solution under local anesthesia. Patients were interviewed prospectively before RT, at the last day of RT, and at a median of two and 17 months after RT. The numbers of recorded bowel problems during the first two years after RT were compared [3].
Te Velde et al. [5] retrospectively compared 125 patients with localized prostate cancer between 2014 and 2015; 65 patients received hydrogel spacers (inserted by five different urologists) and 60 patients, treated over the same time period, did not receive the hydrogel spacers. Patients were treated with 81 Gy in 45 fractions of intensity-modulated RT over nine weeks. Planning aims included restricting rectal doses to V40 Gy <35%, V65 Gy <17%, and V75 Gy <10%. Gel volumes for the spacers were at the urologist's discretion and generally measured between 5 and 8 mL. Acute toxicity assessments covered radiation-induced rectal toxicity including diarrhea, proctitis, fecal incontinence, and hemorrhoids and were evaluated weekly during RT and at 12 weeks [5].
# Outcomes
Mariados et al. [1] published 15 month findings regarding use of the hydrogel spacer. Patients receiving the rectal spacer experienced significantly lower incidence and severity of long-term (greater than 3 months) rectal complications compared with patients not receiving spacers. There were significantly fewer patients experiencing an absence of grade 2 or greater long-term rectal toxicity (3 to 15 months) with a 2.0% and 7.0% late rectal toxicity in the spacer and the non-spacer groups (p=0.044), respectively. However, there was no significant difference observed in the rates of early rectal toxicity. Overall safety of the spacer was excellent, with no device-related adverse events (AE), no rectal infections, rectal complications, or other AEs [1].
A follow-up involving 63% of the original sample [2] found grade ≥1 rectal toxicity at three years of follow-up was decreased by 75% in the spacer group (spacer: 2%, 95% CI, 1% to 6%; non-spacer: 9%, 95% CI, 4% to 20%; HR 0.24, 95% CI, 0.06 to 0.97; p<0.03). No grade ≥2 rectal toxicity was observed in the spacer group (3-year rate: spacer 0%, non-spacer 6%, 95% CI, 2% to 17%; p<0.015) and one case of grade 3 rectal toxicity developed in the non-spacer group. A reduction was also seen in cumulative grade ≥1 urinary incontinence at three years (spacer: 4%, 95% CI, 2% to 10%; non-spacer: 15%, 95% CI, 8% to 29%; p=0.046), with no difference in other grade ≥1 urinary toxicities (p>0.5) or grade ≥2 urinary toxicity. Of 149 patients, only 3 (2%) had any visible remnant of the gel, which consisted of water density cyst on MRI, as patients had MRI performed at 12 months after hydrogel insertion [2].
The Mariados et al. [1] study showed a moderate decline in QOL (assessed according to the function and bother score of the Expanded Prostate Cancer Index Composite [EPIC]) with 12% and 21% of spacer and control patients, respectively, experiencing 10-point declines at 15 months (p=0.09). At 36 months, 5% of men in the spacer group had a non-significant decline in bowel QOL compared with 21% in the non-spacer group (p=0.09) [2].
In the Prada study, the spacer and non-spacers groups were similar in tumour, treatment, and dosimetric characteristics. The spacer group had a significantly smaller incidence of mucosal damage at the proctoscopic examinations (5% vs. 36%, p=0.002) and no macroscopic rectal bleeding (0% vs. 12%, p=0.047) compared with the non-spacer group. No toxicity outcomes were seen from the hyaluronic acid or its injection [4].
In the Pinkawa study, baseline patient characteristics were well balanced. The spacer group needed less treatment for bowel symptoms (0 vs. 11%; p<0.01) and endoscopic examinations (3 vs. 19%; p<0.01) were performed less frequently compared with the non-spacer group. In QOL change measures after RT, in comparison to baseline, mean bowel function scores did not change for patients with a spacer in contrast to patients without a spacer (mean decrease of 5 points) >1 year after RT in comparison to baseline, with 0 vs. 12% reporting a new moderate/big problem with passing stools (p<0.01). No other QOL measures (urinary, sexual, hormonal), relative to baseline, were significant. Statistically significant improved differences for the spacer group were found for the self-reported symptoms of "loose stools" (p=0.003) "bloody stools" (p<0.001), "painful bowel movements" (p<0.001), and "frequency of bowel movements" (p=0.004) compared with the non-spacer group [3].
In the study by Te Velde et al., rectal volume parameters were all significantly lower in the spacer group, with an associated reduction in acute diarrhea (13.8% vs. 31.7%). There were no significant differences in the very low rates of acute and late fecal incontinence or proctitis [5]. Toxicity outcomes are reported in Table 3-2.
# Ongoing, Unpublished, or Incomplete Studies
There were no ongoing, unpublished or incomplete studies identified for this report.
# DISCUSSION
There was one RCT [1,2] and three non-RCTs [3][4][5] identified in this review. We concluded that biodegradable spacer insertion during RT is a technology that may be used to decrease toxicity and maintain QOL in appropriate patients with prostate cancer. Selection of appropriate patients remains to be fully defined but may include those in whom standard rectal dose-volume criteria are not met; those treated with ultrahypofractionated RT; and those at higher baseline risk of rectal toxicity. It should be noted that spacer insertion should be performed by individuals trained in the use of transperineal interventional procedures.
Although there was only one RCT examining a biodegradable rectal spacer, it was concluded this was adequate evidence to support its use, provided institutional procedures are in place. In the multicentred RCT patients experienced significantly lower incidence and severity of long-term (greater than 3 months) rectal complications compared with patients not receiving spacers and there were significantly fewer patients experiencing an absence of grade 2 or greater long-term rectal toxicity (3 to 15 months) [1]. A follow-up to this RCT involving 63% of the original sample found grade ≥1 rectal toxicity at three years of follow-up decreased by 75% and no grade ≥2 rectal toxicity in the spacer group. A significant reduction was also seen in cumulative grade ≥1 urinary incontinence at three years in the spacer group compared with the non-spacer group [2]. However, the overall rates of late rectal toxicity in both arms of the RCT were low and absolute rates of grade ≥2 were 0% (no-spacer) versus 5.7% (spacer).
There is lack of data as to the most appropriate patients that would be likely to benefit from the use of such technology as the magnitude of benefit in this population is likely to be modest if it were routinely applied. This technology has not been tested in RCTs beyond conventional fractionation and should be the subject of further studies as well as examination of factors that may help to select those individuals that are at higher risk of toxicity. Until such data are available, in our expert opinion, it may be prudent to use this technology in selected patients that might include the following: those in whom standard rectal dose-volume criteria are not met; those treated with ultrahypofractionated RT; and those at higher baseline risk of rectal toxicity.
Our findings are consistent with that of the NICE document, which states that "current evidence on the safety and efficacy of insertion of a biodegradable spacer to reduce rectal toxicity during RT for prostate cancer is adequate to support the use of this procedure provided that standard arrangements are in place for clinical governance, consent and audit" [6]. In contrast, the Cochrane review concluded that "low-certainty evidence on balloon and hydrogel spacers suggest that these interventions for prostate cancer RT may make little or no difference to GI outcomes" [7]. However, in contrast to the NICE document and the current review, the Cochrane review had a much broader remit and examined a large number of differing technologies, concentrating mainly on different RT techniques and doses in patients undergoing RT for pelvic malignancies.
The MUHC technology assessment concluded that "given the limited and inconclusive evidence of the clinical benefit of SpaceOAR®, and the high costs associated with its use at the MUHC routine use of SpaceOAR® in prostate cancer patients receiving RT is not approved" [8]. The MUHC report was examining their specific situation based on their cost/funding institution's model and made the assumption that the only reduction in toxicity that was of concern was grade 2 or more rectal toxicity. Furthermore the report used data from the preliminary RCT publication and rates of grade ≥2 toxicity increased particularly in the non-spacer patients with further follow-up, as was reported in the final results of the RCT. The MUHC document reported on the associated costs for their institution in Quebec. Economic analyses fall outside the mandate and expertise of the PEBC, and are out of scope for this document.
# CONCLUSIONS
Biodegradable spacer is a technology that may be used to decrease toxicity and maintain QOL in appropriately selected patients with prostate cancer who are receiving RT. As conventional fractionation was used exclusively in the completed RCT, evaluation of rectal spacer technology in the setting of hypofractionated RT is also warranted. Additional research is also needed to identify the clinical and dosimetric risk factors that may determine those at greatest risk of rectal toxicity and might benefit most from the use of this technology.
#
Te Velde, 2017 [5] Retrospective study Australia
# SpaceOAR vs. non-SpacOAR
During RT -diarrhea Grade1 86.2% vs. 68.3%, p=0.02 Grade2 13.8% vs. 31.7%, p=0.02 Grade3 0% vs. 0%, p=1 12 wks. after RT -diarrhea Grade1 95.4% vs. 95.0%, p=1 Grade2 4.6% vs. 5.0%, p=1 Grade3 0% vs. 0%, p=1 During RT -fecal incontinence Grade1 96.9% vs. 96.7%, p=1 Grade2 3.1% vs. 3.3%, p=1 Grade3 0% vs. 0%, p=1 12 wks. after RT -fecal incontinence Grade1 100% vs. 98.3%, p=0.5 Grade2 0% vs. 1.7%, p=0.5 Grade3 0% vs. 0%, p=1 During RT -proctitis Grade1 86.2% vs. 85.0%, p=1 Grade2 9.2% vs. 13 | None | None |
a7babb163c634fff40d7ff0e4a6a54e4e158093c | cma | None | - Updated to include ChAdOx1 (AstraZeneca Oxford; Serum Institute of India) and Ad26.COV2.S (Johnson & Johnson) vaccines, in addition to BNT 162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna). The Canadian Rheumatology Association guideline panel suggests using COVID-19 vaccination in persons with autoimmune rheumatic disease. (Conditional recommendation, low certainty of the evidence about effects for BNT 162b2 (Pfizer-BioNTech), mRNA-1273 (Moderna) and Ad26.COV2.S (Johnson & Johnson); very low certainty for ChAdOx1 (AstraZeneca)) Remarks: This recommendation is based on evidence for currently approved COVID-19 vaccines: BNT 162b2 (Pfizer-BioNTech), mRNA-1273 (Moderna), Ad26.COV2.S (Johnson & Johnson), and ChAdOx1 (AstraZeneca). The recommendation needs to be viewed in the context of any restrictions to vaccine use for the general public set by national or provincial bodies, that may change over time.The panel was unanimous that for the majority of patients the potential benefits outweigh the potential harms in people with ARDs. The recommendation was graded as conditional because of uncertainty about the effects in the population of interest. Primary implementation consideration for policy makers and providers: Persons with autoimmune rheumatic diseases who meet local eligibility criteria for COVID-19 vaccination should not be denied access to vaccination and should not be required to take additional steps compared to people without autoimmune rheumatic diseases to obtain their vaccination. View the Evidence Profile and Evidence-to-Decision Framework for the question: should mRNA COVID vaccine vs. placebo be used for preventing COVID? View the Evidence Profile and Evidence-to-Decision Framework for the question: should ChAdOx1 SD/SD vs. MenACWY/saline be used for preventing COVID? View the Evidence Profile and Evidence-to-Decision Framework for the question: should Ad26.COV2.S COVID vaccine (J&J) vs. placebo be used for preventing COVID?The CRA panel suggests using COVID-19 vaccination due to moderate certainty of large anticipated desirable effects, low/very low certainty of trivial anticipated undesirable effects, increased health equity, and probable acceptability and feasibility.# Detailed justification
The CRA panel decided on a conditional recommendation for COVID-19 vaccination. The panel balanced the moderate certainty in the vaccine benefits (prevention of symptomatic and severe/critical COVID-19 infection) against the low/very low certainty of evidence for harms. Although the magnitude of the best estimate of harms was judged to be trivial, the uncertainty in the evidence led to a conditional recommendation. This is a living recommendation and will be reassessed when important new evidence becomes available.
# Subgroup considerations
- People taking rituximab: Based on serological studies from other vaccines, rituximab is expected to decrease immunogenicity . Prior guidelines for other vaccines in patients with ARDs have recommended that immunization be deferred to ⩾4-5 months after the last dose and at least 4 weeks prior to the subsequent dose of rituximab . - People taking other DMARDs: Some other DMARDs may reduce protection from the vaccine.
Given the large magnitude of benefit of the COVID-19 vaccines, it is likely that the benefits of the vaccine will still be large for most ARD patients. Continuing medications will often be the safest option to prevent disease flares until more evidence is available. This is in line with guidance from the British Society of Rheumatology . Recent guidance from the American College of Rheumatology recommended holding some medications (methotrexate, JAK inhibitors, abatacept) around the time of COVID-19 vaccination, but the full guideline had not been published and the evidence supporting this was unclear . The CRA COVID-19 guideline panel did not feel that this guidance could be endorsed at this point but will review new evidence as it emerges. Any decision to hold medications should be discussed between a patient and their rheumatologist or healthcare team.
- Additional considerations apply for pregnant and breastfeeding women. These were not covered in the scope of this guideline.
# Implementation considerations
- As vaccine access is determined by provincial health authorities, it will be essential to ensure people with ARDs do not face unnecessary additional barriers to vaccine access. For instance, people with ARDs should not be required to obtain a physician's letter as proof of an informed decision discussion. A decision tool, co-developed by the Canadian Rheumatology Association and the Canadian Arthritis Patient Alliance to support decision-making for the COVID-19 vaccine in people with ARDs is available at: / . - People with ARDs may have mobility limitations and appropriate access to vaccine clinics should be ensured. - The available data is for on-label dosing (doses separated by 1-month for mRNA and AZ vaccines). Given that people with ARDs may have reduced vaccine-induced immunity, the benefits of off-label dosing may be lower compared to people without AIRDs. As such, the CRA has recently advocated for on-label dosing for immunosuppressed patients .
# Monitoring and evaluation
- Monitoring of vaccine uptake should occur in people with ARDs, including populations at risk of inequity. Low uptake may point to barriers to access or hesitancy. - The frequency of serious adverse events, disease flares, and COVID-19 infection/serious outcomes should be followed in patients with ARDs who do and do not receive the vaccine. - People with ARDs should be encouraged to track their immunization history using an online Canadian vaccination tracker, developed with funding support from the Public Health Agency of Canada ().
# Research priorities
The following research areas were considered a high priority:
- Observational evidence on the frequency of harms (in particular serious adverse events/serious disease flares) in people with AIRDs: If very infrequent, may lower the importance of these outcomes. - Evidence comparing the frequency of serious adverse events and autoimmune adverse events in people with ARDs: if not different with sufficient certainty, the panel may decide not to rate the quality of evidence for harms down for indirectness. - Evidence on the benefits (both clinical outcomes and serological studies) in people with ARDs on different medications, including the impact of off-label dosing in effectiveness: may help identify subpopulations of patients with lower benefits and inform decisions regarding whether to hold medications around the time of vaccination. - Evidence on patient values preferences for the benefits and harms across different patient populations.
- Understanding vaccine hesitancy and barriers to vaccine access faced by persons with ARDs.
- Understanding vaccine benefits and harms in populations at risk for inequities. We additionally encourage the collection of data that documents vaccine access difficulties for patients facing barriers to accessing vaccination, to support advocacy for improved prioritization protocols and vaccine delivery. | • Updated to include ChAdOx1 (AstraZeneca Oxford; Serum Institute of India) and Ad26.COV2.S (Johnson & Johnson) vaccines, in addition to BNT 162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna). The Canadian Rheumatology Association guideline panel suggests using COVID-19 vaccination in persons with autoimmune rheumatic disease. (Conditional recommendation, low certainty of the evidence about effects for BNT 162b2 (Pfizer-BioNTech), mRNA-1273 (Moderna) and Ad26.COV2.S (Johnson & Johnson); very low certainty for ChAdOx1 (AstraZeneca)) Remarks: This recommendation is based on evidence for currently approved COVID-19 vaccines: BNT 162b2 (Pfizer-BioNTech), mRNA-1273 (Moderna), Ad26.COV2.S (Johnson & Johnson), and ChAdOx1 (AstraZeneca). The recommendation needs to be viewed in the context of any restrictions to vaccine use for the general public set by national or provincial bodies, that may change over time.The panel was unanimous that for the majority of patients the potential benefits outweigh the potential harms in people with ARDs. The recommendation was graded as conditional because of uncertainty about the effects in the population of interest. Primary implementation consideration for policy makers and providers: Persons with autoimmune rheumatic diseases who meet local eligibility criteria for COVID-19 vaccination should not be denied access to vaccination and should not be required to take additional steps compared to people without autoimmune rheumatic diseases to obtain their vaccination. View the Evidence Profile and Evidence-to-Decision Framework for the question: should mRNA COVID vaccine vs. placebo be used for preventing COVID? View the Evidence Profile and Evidence-to-Decision Framework for the question: should ChAdOx1 SD/SD vs. MenACWY/saline be used for preventing COVID? View the Evidence Profile and Evidence-to-Decision Framework for the question: should Ad26.COV2.S COVID vaccine (J&J) vs. placebo be used for preventing COVID?The CRA panel suggests using COVID-19 vaccination due to moderate certainty of large anticipated desirable effects, low/very low certainty of trivial anticipated undesirable effects, increased health equity, and probable acceptability and feasibility.# Detailed justification
The CRA panel decided on a conditional recommendation for COVID-19 vaccination. The panel balanced the moderate certainty in the vaccine benefits (prevention of symptomatic and severe/critical COVID-19 infection) against the low/very low certainty of evidence for harms. Although the magnitude of the best estimate of harms was judged to be trivial, the uncertainty in the evidence led to a conditional recommendation. This is a living recommendation and will be reassessed when important new evidence becomes available.
# Subgroup considerations
• People taking rituximab: Based on serological studies from other vaccines, rituximab is expected to decrease immunogenicity [2]. Prior guidelines for other vaccines in patients with ARDs have recommended that immunization be deferred to ⩾4-5 months after the last dose and at least 4 weeks prior to the subsequent dose of rituximab [2]. • People taking other DMARDs: Some other DMARDs may reduce protection from the vaccine.
Given the large magnitude of benefit of the COVID-19 vaccines, it is likely that the benefits of the vaccine will still be large for most ARD patients. Continuing medications will often be the safest option to prevent disease flares until more evidence is available. This is in line with guidance from the British Society of Rheumatology [14]. Recent guidance from the American College of Rheumatology recommended holding some medications (methotrexate, JAK inhibitors, abatacept) around the time of COVID-19 vaccination, but the full guideline had not been published and the evidence supporting this was unclear [12]. The CRA COVID-19 guideline panel did not feel that this guidance could be endorsed at this point but will review new evidence as it emerges. Any decision to hold medications should be discussed between a patient and their rheumatologist or healthcare team.
• Additional considerations apply for pregnant and breastfeeding women. These were not covered in the scope of this guideline.
# Implementation considerations
• As vaccine access is determined by provincial health authorities, it will be essential to ensure people with ARDs do not face unnecessary additional barriers to vaccine access. For instance, people with ARDs should not be required to obtain a physician's letter as proof of an informed decision discussion. A decision tool, co-developed by the Canadian Rheumatology Association and the Canadian Arthritis Patient Alliance to support decision-making for the COVID-19 vaccine in people with ARDs is available at: https://rheum.ca/decision-aid/ [13]. • People with ARDs may have mobility limitations and appropriate access to vaccine clinics should be ensured. • The available data is for on-label dosing (doses separated by 1-month for mRNA and AZ vaccines). Given that people with ARDs may have reduced vaccine-induced immunity, the benefits of off-label dosing may be lower compared to people without AIRDs. As such, the CRA has recently advocated for on-label dosing for immunosuppressed patients [13].
# Monitoring and evaluation
• Monitoring of vaccine uptake should occur in people with ARDs, including populations at risk of inequity. Low uptake may point to barriers to access or hesitancy. • The frequency of serious adverse events, disease flares, and COVID-19 infection/serious outcomes should be followed in patients with ARDs who do and do not receive the vaccine. • People with ARDs should be encouraged to track their immunization history using an online Canadian vaccination tracker, developed with funding support from the Public Health Agency of Canada (https://www.canimmunize.ca/en/home).
# Research priorities
The following research areas were considered a high priority:
• Observational evidence on the frequency of harms (in particular serious adverse events/serious disease flares) in people with AIRDs: If very infrequent, may lower the importance of these outcomes. • Evidence comparing the frequency of serious adverse events and autoimmune adverse events in people with ARDs: if not different with sufficient certainty, the panel may decide not to rate the quality of evidence for harms down for indirectness. • Evidence on the benefits (both clinical outcomes and serological studies) in people with ARDs on different medications, including the impact of off-label dosing in effectiveness: may help identify subpopulations of patients with lower benefits and inform decisions regarding whether to hold medications around the time of vaccination. • Evidence on patient values preferences for the benefits and harms across different patient populations.
• Understanding vaccine hesitancy and barriers to vaccine access faced by persons with ARDs.
• Understanding vaccine benefits and harms in populations at risk for inequities. We additionally encourage the collection of data that documents vaccine access difficulties for patients facing barriers to accessing vaccination, to support advocacy for improved prioritization protocols and vaccine delivery. | None | None |
ba07e83728082d4f714c85c30686c74ab35a8730 | cma | None | reconstruction to be performed on the same day the cancer is removed further optimizing the patient's care, convenience and surgical outcome. Guideline Questions (1) What are the indications for MMS? (2) Are there any cases where the use of MMS is inappropriate?# Background
# Nonmelanoma skin cancer (NMSC)
Nonmelanoma skin cancer (NMSC) is the most commonly diagnosed cancer among Canadians. 1 The most prevalent form of NMSC is basal cell carcinoma (BCC), followed by squamous cell carcinoma (SCC). Together they account for approximately 95% of all cases of NMSC in Canada. 2 From 1988 to 2007, there were 66,192 BCCs, 19,959 invasive SCCs, and 12,494 SCCs in situ in Alberta. 3 Sunlight exposure is the most significant risk factor in the etiology of NMSC. Fair complexion, lighter hair and eye colour, and a positive personal or family history are also risk factors for developing BCC or SCC. 4,5 There are many approaches to the treatment of NMSC. Generally, the primary goal of treatment is complete tumour eradication with maximal preservation of function and cosmesis. Current guidelines for the management of BCC and SCC consider surgery (including standard excision, Mohs micrographic surgery, or curettage and electrodessication) as the most effective treatment option for most cases of NMSC. Other treatment options include cryotherapy, radiation, photodynamic therapy, and topical therapy. This guideline focuses on the indications for Mohs micrographic surgery (MMS) in NMSC.
# Mohs micrographic surgery (MMS)
Mohs micrographic surgery (MMS) is a specialized technique, originally developed by Dr. Frederick E. Mohs, which has been refined to allow the precise microscopically controlled removal of skin tumors. The technique involves excising a skin tumor with a minimum margin, and processing the tissue in a very specific way using a fresh frozen preparation technique to create pathology slides. This ultimately allows the surgeon to examine the entire margin of the excised skin cancer. MMS is suitable for the surgical extraction of tumors that have a contiguous pattern of growth occurring on sensitive body sites such as the face, hands feet and genitals where the sparing of healthy surrounding tissue is considered essential. In certain cases, the skin cancer may be debulked or curetted prior to removing a layer of tissue. This debulking is not considered as taking a layer of skin.
The Mohs procedure begins with the precise marking of clinically tumor free margins immediately adjacent to the skin tumor (and any associated scar) to be removed. Typically utilizing local anesthesia, these margins are incised in a beveled fashion and a precise layer of tissue is removed surgically. This tissue layer is color inked in a manner devised to map its orientation relative to the patient's surgical wound. The beveled margins of the layer are then flattened to facilitate frozen section processing. The resultant tissue sections are subsequently stained so microscopic slides can be produced that demonstrate 100% of the tissue margins for examination.
The performance of Mohs technique includes the capability to provide reliable pathologic analysis of these slides. If tumor is noted to persist at the margin, its location is related back to the original tissue map and another layer is incised while again sparing tissue not involved by tumor. A correlating map of this layer is generated again being sure to include color inked margins to preserve it precise orientation. This process is repeated until all margins are clear of tumor microscopically. This insures that the Mohs technique attains some of the highest success rates in the treatment of non-melanoma skin cancer -up to 99%.
Finally, MMS involves the knowledge and skill to offer management of the resulting surgical wound including complex reconstructive surgical flap repair as necessary. The combination of this expertise allows 5. Yes *Area H: "mask areas" of face (central face, eyelids, eyebrows, periorbital, nose, lips , chin, mandible, preauricular and postauricular skin/sulci, temple, ear), genitalia, hands, and feet. Area M: cheeks, forehead, scalp, neck, and pretibia. Area L: trunk and extremities (excluding pretibial, hands, feet, nail units, and ankles). Location independent of size may constitute high risk. *High-risk histologic subtypes: acantholytic (adenoid), adenosquamous (showing mucin production), desmoplastic, or metaplastic (carcinosarcomatous) subtypes. Clark level defines depth of invasion, with level I being confined to the epidermis as a carcinoma in situ and with all other levels being invasive tumours that extend into the dermis. Clark level V tumours extend all the way through the dermis and have entered the subcutaneous fat layer.
(Recurrent disease: Level of Evidence: III 63 and IV 61 Results: 2
# Inclusion Criteria:
Randomized controlled trials, controlled clinical trials, or multicenter studies conducted on humans that were published between 1997 and 2018 in English. Study topic had to be on basal cell or squamous cell carcinoma where treatment included Moh's micrographic surgery. Studies needed to report on at least one of the following: treatment outcomes, tumour reoccurrence rates, or quality of life. Reference sections from all included articles were screened for additional literature.
# Exclusion Criteria:
Reasons for excluding abstracts (571 articles reviewed) -Single centre retrospective review with surgical outcomes only (ie. Factors predictive of more surgical stages) -Assessment of surgical rates -Access to care studies/cost analysis/ looking at differences between centres to assess access to care -Proposed deficit vs mohs deficit -Surgical outcomes slow mohs -Earlier version of article -Incidence epidemiological studies Predictors of satisfaction with Mohs (no comparisons to other treatments)
# Search for Existing Guidelines:
The National Guidelines Clearinghouse and individual guideline organizations were searched for practice guidelines relevant to this topic. A total of fifteen clinical practice guidelines with at least one recommendation directly related to MMS were identified from the following organizations or groups: American Academy of Dermatology, National Comprehensive Cancer Network, UptoDate, and American Society for Dermatologic Surgery, British Association of Dermatologists, London Cancer Alliance, Scottish Intercollegiate Guidelines Network, Cancer Council Australia, and the UK National Multidisciplinary Guidelines committee.
# Literature Search Outcomes:
In total 1098 primary articles were identified from the Medline/ Pubmed/ Embase/ Cochrane literature searches of which 571 articles were unique. 492 articles were excluded based on an abstract screen, and a further 35 were excluded after a full-text screen, leaving 44 articles. 7 articles were added after a review of the reference sections from the included articles.
In total, 51 primary articles were identified and included in the literature search (below). 22 articles were focused on both BCC and SCC (Appendix A Table 1), 18 focused exclusively on BCC (Appendix A Table 2), and 11 focused exclusively on SCC (Appendix A Table 3).
Additionally, 13 relevant guidelines were identified and reviewed by the guideline working group (Appendix A Table 4). (77) Key Findings: 1) MMS is recommended as a first-line option for high-risk primary or recurrent basal cell carcinoma or squamous cell carcinoma 2) MMS may be considered as one of the options for squamous cell carcinoma, especially where tissue preservation or margin controls are challenging, or when the tumor is at a critical anatomical site 3) In squamous cell carcinoma in situ (Bowden's disease), MMS may be indicated for digital and penile tumour, or in recurrent or incompletely excised lesions. 4) MMS may be considered for melanoma in situ (lentigo maligna) and Merkel cell carcinoma, especially when the tumor is in a sensitive area and there are concerns of functional impairment from an excision that is too radical. 5) Although the size of the lesion should be analyzed together with its location and histological pattern, MMS could be a better treatment option for tumors larger than 2 cm which present higher chance of incomplete removal with conventional surgery. 6) MMS leads to a smaller recurrence rate than conventional surgery for dermatofibrosarcoma protuberans. 7) The majority of the recommendations on the use of MMS for skin cancers were based on evidence of limited quality and need to be interpreted with caution. More high-quality trials are required to elucidate the role of MMS on skin cancers. Cancer Care Ontario: Patient Indications for Mohs Micrographic Surgery, 2018 (13) Recommendations: 1. Surgery (with postoperative or intraoperative marginal assessment), or radiation for those who are ineligible for surgery, should remain the standard of care for patients with skin cancer given the lack of high-quality, comparative evidence. 2. MMS is recommended for those with histologically confirmed recurrent basal cell carcinoma (BCC) of the face, and is appropriate for primary BCCs of the face that are >1 cm, have aggressive histology, or are located on the H zone of the face (Figure 1-1). 3. MMS should be performed by physicians who have completed a degree in medicine or equivalent, including a Royal College of Physicians and Surgeons of Canada Specialist Certificate or equivalent, and have received advanced training in MMS. 4. Surgery (with postoperative or intraoperative marginal assessment), or radiation for those who are ineligible for surgery, should remain the standard of care for patients with skin cancer given the lack of high-quality, comparative evidence. 5. MMS is recommended for those with histologically confirmed recurrent basal cell carcinoma (BCC) of the face, and is appropriate for primary BCCs of the face that are >1 cm, have aggressive histology, or are located on the H zone of the face (Figure 2-1). 6. MMS should be performed by physicians who have completed a degree in medicine or equivalent, including a Royal College of Physicians and Surgeons of Canada (RCPSC) Specialist Certificate or equivalent, and have received advanced training in MMS. Guidelines of care for the management of cutaneous squamous cell carcinoma JAAD, 2018 (7) Recommendations: 1. Stratification of localized SCCs using the NCCN guideline framework is recommended for clinical practice. Clinicians should refer to the BWH tumor classification system to obtain the most accurate prognostication of patients with localized cSCC. 2. The recommended biopsy techniques for cSCC are punch biopsy, shave biopsy, and excisional biopsy. The biopsy technique used will depend on the characteristics of the suspected malignancy (morphology, location, etc) and the judgment of the physician. The biopsy size and depth should be adequate to provide the recommended clinical information and pathology report elements to permit accurate diagnosis and guide therapy.
# Guideline Developer
Recommendations 3. A treatment plan that considers recurrence rate, preservation of function, patient expectations, and potential adverse effects is recommended. C&E may be considered for low-risk, primary cSCC in none terminal hairebearing locations. For low-risk primary cSCC, standard excision with a 4-to 6-mm margin to a depth of the mid-subcutaneous adipose tissue with histologic margin assessment is recommended. Standard excision may be considered for select high-risk tumors. However, strong caution is advised when selecting a treatment modality for high-risk tumors without a complete margin assessment. MMS is recommended for high-risk cSCC.t biopsy may be considered if the initial biopsy specimen is inadequate for accurate diagnosis. 4. If surgical therapy is not feasible or preferred, radiation therapy (eg, superficial radiation therapy, brachytherapy, external electron beam therapy, and other traditional radiotherapy forms) can be considered when tumors are low risk, with the understanding that the cure rate may be lower. Cryosurgery may be considered for low-risk cSCC when more effective therapies are contraindicated or impractical. Topical therapies (imiquimod or 5-FU) and PDT are not recommended for the treatment of cSCC on the basis of available data. There is insufficient evidence available to make a recommendation on the use laser therapies or electronic surface brachytherapy in the treatment of cSCC. 5. Surgical resection, with or without adjuvant radiation therapy and possible systemic therapy are recommended for regional lymph node metastases. Combination chemoradiation therapy should be considered for inoperable disease. Epidermal growth factor inhibitors and cisplatin, as a single agent or in combination therapy, may be considered, as they have demonstrated efficacy for metastatic disease, albeit on the basis of limited data. Multidisciplinary consultation and management, particularly in immunosuppressed individuals, is recommended for patients with locoregional or distant metastases. In some cases, such consultation may be appropriate for patients with locally advanced disease without known metastases. Patients with advanced disease should be provided with or referred for best supportive and palliative care to optimize symptom management and maximize quality of life. 6. After diagnosis of a first SCC, screening for new keratinocyte cancers (BCC or cSCC) and for melanoma should be performed on at least an annual basis. Patients with a history of cSCC should be counseled on skin self-examination and sun protection. Topical and oral retinoids (eg, tretinoin, retinol, acitretin, and isotretinoin) should not be prescribed to reduce the incidence of keratinocyte cancers in those with a history of cSCC, unless they are SOTRs. In the situation of SOTRs, only acitretin may be beneficial. Dietary supplementation of selenium and b-carotene is not recommended to reduce the incidence of future keratinocyte cancers in those with a history of cSCC. There is insufficient evidence to make a recommendation on the use of oral nicotinamide, DFMO, or celecoxib in the chemoprevention of cSCC. Guidelines of care for the management of basal cell carcinoma JAAD, 2018 (6) Recommendations: 1. Stratification of localized BCC using the NCCN guideline framework is recommended for clinical practice. 2. The recommended biopsy techniques for BCC are punch biopsy, shave biopsy, and excisional biopsy. The biopsy technique used will depend on the characteristics of the suspected malignancy (morphology, location, etc) and the judgment of the physician. The biopsy size and depth should be adequate to provide the recommended clinical information and pathology report elements to permit accurate diagnosis and guide therapy. Repeat biopsy may be considered if initial biopsy specimen is inadequate for accurate diagnosis. 3. A treatment plan that considers recurrence rate, preservation of function, patient expectations, and potential adverse effects is recommended. C&E may be considered for low-risk tumors in none terminal hairebearing locations. For lowrisk primary BCC, surgical excision with 4-mm clinical margins and histologic margin assessment is recommended. Standard excision may be considered for select high-risk tumors. However, strong caution is advised when selecting a treatment modality without complete margin assessment for high-risk tumors. Mohs micrographic surgery is recommended for high-risk BCC. 4. Cryosurgery may be considered for low-risk BCC when more effective therapies are contraindicated or impractical. If surgical therapy is not feasible or preferred, topical therapy (eg, imiquimod or 5-FU), MAL-or ALA-PDT, and radiation therapy (eg, superficial radiation therapy, brachytherapy, external electron beam, and other traditional radiotherapy forms for BCC) can be considered when tumors are low risk, with the understanding that the cure rate may be lower. Adjustment of topical therapy dosing regimen on the basis of side effect tolerance is recommended. There is insufficient evidence to recommend the routine use of laser or electronic surface brachytherapy in the treatment of BCC. 5. Multidisciplinary consultation and smoothened inhibitors are recommended for patients with metastatic BCC. If treatment of metastatic BCC with smoothened inhibitors is not feasible, platinum-based chemotherapy or best supportive care is recommended. If surgery and radiation therapy are contraindicated or inappropriate for the treatment of locally advanced BCC, or if residual tumor persists following surgery and/or radiation therapy and further surgery and radiation therapy are contraindicated or inappropriate, systemic therapy with a smoothened inhibitor should be considered. Patients with advanced disease should be provided with or referred for best supportive and palliative care, to optimize symptom management and maximize quality of life.
BCC: Mohs micrographic surgery may be considered as a first-line option for high-risk primary BCC, incompletely excised high-risk BCC, and most recurrent BCCs amenable to surgery.
High-risk primary or recurrent SCC: Mohs micrographic surgery should always be considered for lesions with poorly defined borders, particularly if such lesions occur on cosmetically sensitive areas, such as face, hands, and feet. For reasons of cosmesis and function, SCCs on certain sites (eyebrows, eyelids, nose, hands, and feet) should also be treated as high risk, with preferential use of Mohs micrographic surgery to spare as much as possible of the surrounding healthy tissue. American Society for Dermatologic Surgery, 2015 (5) BCC: Mohs surgery is the treatment of choice for high-risk BCCs and recurrent BCCs because of its high cure rate and tissue-sparing benefit. Because the most effective treatment for any BCC is Mohs surgery, it also remains the best treatment option for tumors at high risk of recurrence after other treatment modalities.
# British Association of Dermatologists, 2014 (71)
SCC: Mohs micrographic surgery may be indicated for digital SCC in situ (around the nail in particular) and for some cases of genital (especially penile) SCC in situ for its tissue-sparing benefits. There may also be a role for Mohs in recurrent or incompletely excised lesions.
London Cancer Alliance, 2014 (72) BCC: poorly defined borders, high-risk site (i.e. H-zone), aggressive histology such as morphoeic or infiltrative or micronodular, perineural invasion, lymphovascular invasion, recurrent tumors (or incompletely excised), large tumors (>2cm), immune-compromised patient SCC: poorly defined borders, high-risk site (i.e. H-zone), perineural invasion, lymphovascular invasion, recurrent tumors (or incompletely excised), large tumors (>2cm), immune-compromised patient, persistent Bowen's disease at awkward site (i.e. genitals, eyelid, scalp, nails)
# Scottish Intercollegiate Guidelines Network (SIGN), 2014 (73)
Mohs micrographic surgery should be considered at the MDT meeting, for selected patients with high-risk tumours where tissue preservation or margin control is challenging, and on an individual case basis for patients with any tumour at a critical anatomical site. This guideline was originally developed in August 2019.
# Maintenance
A formal review of the guideline will be conducted in 2020. If critical new evidence is brought forward before that time, however, the guideline working group members will revise and update the document accordingly.
# Abbreviations | reconstruction to be performed on the same day the cancer is removed further optimizing the patient's care, convenience and surgical outcome. Guideline Questions (1) What are the indications for MMS? (2) Are there any cases where the use of MMS is inappropriate?# Background
# Nonmelanoma skin cancer (NMSC)
Nonmelanoma skin cancer (NMSC) is the most commonly diagnosed cancer among Canadians. 1 The most prevalent form of NMSC is basal cell carcinoma (BCC), followed by squamous cell carcinoma (SCC). Together they account for approximately 95% of all cases of NMSC in Canada. 2 From 1988 to 2007, there were 66,192 BCCs, 19,959 invasive SCCs, and 12,494 SCCs in situ in Alberta. 3 Sunlight exposure is the most significant risk factor in the etiology of NMSC. Fair complexion, lighter hair and eye colour, and a positive personal or family history are also risk factors for developing BCC or SCC. 4,5 There are many approaches to the treatment of NMSC. Generally, the primary goal of treatment is complete tumour eradication with maximal preservation of function and cosmesis. Current guidelines for the management of BCC and SCC consider surgery (including standard excision, Mohs micrographic surgery, or curettage and electrodessication) as the most effective treatment option for most cases of NMSC. [4][5][6][7][8][9][10][11][12][13] Other treatment options include cryotherapy, radiation, photodynamic therapy, and topical therapy. This guideline focuses on the indications for Mohs micrographic surgery (MMS) in NMSC.
# Mohs micrographic surgery (MMS)
Mohs micrographic surgery (MMS) is a specialized technique, originally developed by Dr. Frederick E. Mohs, which has been refined to allow the precise microscopically controlled removal of skin tumors. The technique involves excising a skin tumor with a minimum margin, and processing the tissue in a very specific way using a fresh frozen preparation technique to create pathology slides. This ultimately allows the surgeon to examine the entire margin of the excised skin cancer. MMS is suitable for the surgical extraction of tumors that have a contiguous pattern of growth occurring on sensitive body sites such as the face, hands feet and genitals where the sparing of healthy surrounding tissue is considered essential. In certain cases, the skin cancer may be debulked or curetted prior to removing a layer of tissue. This debulking is not considered as taking a layer of skin.
The Mohs procedure begins with the precise marking of clinically tumor free margins immediately adjacent to the skin tumor (and any associated scar) to be removed. Typically utilizing local anesthesia, these margins are incised in a beveled fashion and a precise layer of tissue is removed surgically. This tissue layer is color inked in a manner devised to map its orientation relative to the patient's surgical wound. The beveled margins of the layer are then flattened to facilitate frozen section processing. The resultant tissue sections are subsequently stained so microscopic slides can be produced that demonstrate 100% of the tissue margins for examination.
The performance of Mohs technique includes the capability to provide reliable pathologic analysis of these slides. If tumor is noted to persist at the margin, its location is related back to the original tissue map and another layer is incised while again sparing tissue not involved by tumor. A correlating map of this layer is generated again being sure to include color inked margins to preserve it precise orientation. This process is repeated until all margins are clear of tumor microscopically. This insures that the Mohs technique attains some of the highest success rates in the treatment of non-melanoma skin cancer -up to 99%.
Finally, MMS involves the knowledge and skill to offer management of the resulting surgical wound including complex reconstructive surgical flap repair as necessary. The combination of this expertise allows 5. Yes *Area H: "mask areas" of face (central face, eyelids, eyebrows, periorbital, nose, lips [cutaneous and vermilion], chin, mandible, preauricular and postauricular skin/sulci, temple, ear), genitalia, hands, and feet. Area M: cheeks, forehead, scalp, neck, and pretibia. Area L: trunk and extremities (excluding pretibial, hands, feet, nail units, and ankles). **Location independent of size may constitute high risk. ***High-risk histologic subtypes: acantholytic (adenoid), adenosquamous (showing mucin production), desmoplastic, or metaplastic (carcinosarcomatous) subtypes. **** Clark level defines depth of invasion, with level I being confined to the epidermis as a carcinoma in situ and with all other levels being invasive tumours that extend into the dermis. Clark level V tumours extend all the way through the dermis and have entered the subcutaneous fat layer.
(Recurrent disease: Level of Evidence: III 63 and IV 61 Results: 2
# Inclusion Criteria:
Randomized controlled trials, controlled clinical trials, or multicenter studies conducted on humans that were published between 1997 and 2018 in English. Study topic had to be on basal cell or squamous cell carcinoma where treatment included Moh's micrographic surgery. Studies needed to report on at least one of the following: treatment outcomes, tumour reoccurrence rates, or quality of life. Reference sections from all included articles were screened for additional literature.
# Exclusion Criteria:
Reasons for excluding abstracts (571 articles reviewed) -Single centre retrospective review with surgical outcomes only (ie. Factors predictive of more surgical stages) -Assessment of surgical rates -Access to care studies/cost analysis/ looking at differences between centres to assess access to care -Proposed deficit vs mohs deficit -Surgical outcomes slow mohs -Earlier version of article -Incidence epidemiological studies Predictors of satisfaction with Mohs (no comparisons to other treatments)
# Search for Existing Guidelines:
The National Guidelines Clearinghouse and individual guideline organizations were searched for practice guidelines relevant to this topic. A total of fifteen clinical practice guidelines with at least one recommendation directly related to MMS were identified from the following organizations or groups: American Academy of Dermatology, National Comprehensive Cancer Network, UptoDate, and American Society for Dermatologic Surgery, British Association of Dermatologists, London Cancer Alliance, Scottish Intercollegiate Guidelines Network, Cancer Council Australia, and the UK National Multidisciplinary Guidelines committee.
# Literature Search Outcomes:
In total 1098 primary articles were identified from the Medline/ Pubmed/ Embase/ Cochrane literature searches of which 571 articles were unique. 492 articles were excluded based on an abstract screen, and a further 35 were excluded after a full-text screen, leaving 44 articles. 7 articles were added after a review of the reference sections from the included articles.
In total, 51 primary articles were identified and included in the literature search (below). 22 articles were focused on both BCC and SCC (Appendix A Table 1), 18 focused exclusively on BCC (Appendix A Table 2), and 11 focused exclusively on SCC (Appendix A Table 3).
Additionally, 13 relevant guidelines were identified and reviewed by the guideline working group (Appendix A Table 4). (77) Key Findings: 1) MMS is recommended as a first-line option for high-risk primary or recurrent basal cell carcinoma or squamous cell carcinoma 2) MMS may be considered as one of the options for squamous cell carcinoma, especially where tissue preservation or margin controls are challenging, or when the tumor is at a critical anatomical site 3) In squamous cell carcinoma in situ (Bowden's disease), MMS may be indicated for digital and penile tumour, or in recurrent or incompletely excised lesions. 4) MMS may be considered for melanoma in situ (lentigo maligna) and Merkel cell carcinoma, especially when the tumor is in a sensitive area and there are concerns of functional impairment from an excision that is too radical. 5) Although the size of the lesion should be analyzed together with its location and histological pattern, MMS could be a better treatment option for tumors larger than 2 cm which present higher chance of incomplete removal with conventional surgery. 6) MMS leads to a smaller recurrence rate than conventional surgery for dermatofibrosarcoma protuberans. 7) The majority of the recommendations on the use of MMS for skin cancers were based on evidence of limited quality and need to be interpreted with caution. More high-quality trials are required to elucidate the role of MMS on skin cancers. Cancer Care Ontario: Patient Indications for Mohs Micrographic Surgery, 2018 (13) Recommendations: 1. Surgery (with postoperative or intraoperative marginal assessment), or radiation for those who are ineligible for surgery, should remain the standard of care for patients with skin cancer given the lack of high-quality, comparative evidence. 2. MMS is recommended for those with histologically confirmed recurrent basal cell carcinoma (BCC) of the face, and is appropriate for primary BCCs of the face that are >1 cm, have aggressive histology, or are located on the H zone of the face (Figure 1-1). 3. MMS should be performed by physicians who have completed a degree in medicine or equivalent, including a Royal College of Physicians and Surgeons of Canada Specialist Certificate or equivalent, and have received advanced training in MMS. 4. Surgery (with postoperative or intraoperative marginal assessment), or radiation for those who are ineligible for surgery, should remain the standard of care for patients with skin cancer given the lack of high-quality, comparative evidence. 5. MMS is recommended for those with histologically confirmed recurrent basal cell carcinoma (BCC) of the face, and is appropriate for primary BCCs of the face that are >1 cm, have aggressive histology, or are located on the H zone of the face (Figure 2-1). 6. MMS should be performed by physicians who have completed a degree in medicine or equivalent, including a Royal College of Physicians and Surgeons of Canada (RCPSC) Specialist Certificate or equivalent, and have received advanced training in MMS. Guidelines of care for the management of cutaneous squamous cell carcinoma JAAD, 2018 (7) Recommendations: 1. Stratification of localized SCCs using the NCCN guideline framework is recommended for clinical practice. Clinicians should refer to the BWH tumor classification system to obtain the most accurate prognostication of patients with localized cSCC. 2. The recommended biopsy techniques for cSCC are punch biopsy, shave biopsy, and excisional biopsy. The biopsy technique used will depend on the characteristics of the suspected malignancy (morphology, location, etc) and the judgment of the physician. The biopsy size and depth should be adequate to provide the recommended clinical information and pathology report elements to permit accurate diagnosis and guide therapy.
# Guideline Developer
Recommendations 3. A treatment plan that considers recurrence rate, preservation of function, patient expectations, and potential adverse effects is recommended. C&E may be considered for low-risk, primary cSCC in none terminal hairebearing locations. For low-risk primary cSCC, standard excision with a 4-to 6-mm margin to a depth of the mid-subcutaneous adipose tissue with histologic margin assessment is recommended. Standard excision may be considered for select high-risk tumors. However, strong caution is advised when selecting a treatment modality for high-risk tumors without a complete margin assessment. MMS is recommended for high-risk cSCC.t biopsy may be considered if the initial biopsy specimen is inadequate for accurate diagnosis. 4. If surgical therapy is not feasible or preferred, radiation therapy (eg, superficial radiation therapy, brachytherapy, external electron beam therapy, and other traditional radiotherapy forms) can be considered when tumors are low risk, with the understanding that the cure rate may be lower. Cryosurgery may be considered for low-risk cSCC when more effective therapies are contraindicated or impractical. Topical therapies (imiquimod or 5-FU) and PDT are not recommended for the treatment of cSCC on the basis of available data. There is insufficient evidence available to make a recommendation on the use laser therapies or electronic surface brachytherapy in the treatment of cSCC. 5. Surgical resection, with or without adjuvant radiation therapy and possible systemic therapy are recommended for regional lymph node metastases. Combination chemoradiation therapy should be considered for inoperable disease. Epidermal growth factor inhibitors and cisplatin, as a single agent or in combination therapy, may be considered, as they have demonstrated efficacy for metastatic disease, albeit on the basis of limited data. Multidisciplinary consultation and management, particularly in immunosuppressed individuals, is recommended for patients with locoregional or distant metastases. In some cases, such consultation may be appropriate for patients with locally advanced disease without known metastases. Patients with advanced disease should be provided with or referred for best supportive and palliative care to optimize symptom management and maximize quality of life. 6. After diagnosis of a first SCC, screening for new keratinocyte cancers (BCC or cSCC) and for melanoma should be performed on at least an annual basis. Patients with a history of cSCC should be counseled on skin self-examination and sun protection. Topical and oral retinoids (eg, tretinoin, retinol, acitretin, and isotretinoin) should not be prescribed to reduce the incidence of keratinocyte cancers in those with a history of cSCC, unless they are SOTRs. In the situation of SOTRs, only acitretin may be beneficial. Dietary supplementation of selenium and b-carotene is not recommended to reduce the incidence of future keratinocyte cancers in those with a history of cSCC. There is insufficient evidence to make a recommendation on the use of oral nicotinamide, DFMO, or celecoxib in the chemoprevention of cSCC. Guidelines of care for the management of basal cell carcinoma JAAD, 2018 (6) Recommendations: 1. Stratification of localized BCC using the NCCN guideline framework is recommended for clinical practice. 2. The recommended biopsy techniques for BCC are punch biopsy, shave biopsy, and excisional biopsy. The biopsy technique used will depend on the characteristics of the suspected malignancy (morphology, location, etc) and the judgment of the physician. The biopsy size and depth should be adequate to provide the recommended clinical information and pathology report elements to permit accurate diagnosis and guide therapy. Repeat biopsy may be considered if initial biopsy specimen is inadequate for accurate diagnosis. 3. A treatment plan that considers recurrence rate, preservation of function, patient expectations, and potential adverse effects is recommended. C&E may be considered for low-risk tumors in none terminal hairebearing locations. For lowrisk primary BCC, surgical excision with 4-mm clinical margins and histologic margin assessment is recommended. Standard excision may be considered for select high-risk tumors. However, strong caution is advised when selecting a treatment modality without complete margin assessment for high-risk tumors. Mohs micrographic surgery is recommended for high-risk BCC. 4. Cryosurgery may be considered for low-risk BCC when more effective therapies are contraindicated or impractical. If surgical therapy is not feasible or preferred, topical therapy (eg, imiquimod or 5-FU), MAL-or ALA-PDT, and radiation therapy (eg, superficial radiation therapy, brachytherapy, external electron beam, and other traditional radiotherapy forms for BCC) can be considered when tumors are low risk, with the understanding that the cure rate may be lower. Adjustment of topical therapy dosing regimen on the basis of side effect tolerance is recommended. There is insufficient evidence to recommend the routine use of laser or electronic surface brachytherapy in the treatment of BCC. 5. Multidisciplinary consultation and smoothened inhibitors are recommended for patients with metastatic BCC. If treatment of metastatic BCC with smoothened inhibitors is not feasible, platinum-based chemotherapy or best supportive care is recommended. If surgery and radiation therapy are contraindicated or inappropriate for the treatment of locally advanced BCC, or if residual tumor persists following surgery and/or radiation therapy and further surgery and radiation therapy are contraindicated or inappropriate, systemic therapy with a smoothened inhibitor should be considered. Patients with advanced disease should be provided with or referred for best supportive and palliative care, to optimize symptom management and maximize quality of life.
#
(8,12,)
BCC: Mohs micrographic surgery may be considered as a first-line option for high-risk primary BCC, incompletely excised high-risk BCC, and most recurrent BCCs amenable to surgery.
High-risk primary or recurrent SCC: Mohs micrographic surgery should always be considered for lesions with poorly defined borders, particularly if such lesions occur on cosmetically sensitive areas, such as face, hands, and feet. For reasons of cosmesis and function, SCCs on certain sites (eyebrows, eyelids, nose, hands, and feet) should also be treated as high risk, with preferential use of Mohs micrographic surgery to spare as much as possible of the surrounding healthy tissue. American Society for Dermatologic Surgery, 2015 (5) BCC: Mohs surgery is the treatment of choice for high-risk BCCs and recurrent BCCs because of its high cure rate and tissue-sparing benefit. Because the most effective treatment for any BCC is Mohs surgery, it also remains the best treatment option for tumors at high risk of recurrence after other treatment modalities.
# British Association of Dermatologists, 2014 (71)
SCC: Mohs micrographic surgery may be indicated for digital SCC in situ (around the nail in particular) and for some cases of genital (especially penile) SCC in situ for its tissue-sparing benefits. There may also be a role for Mohs in recurrent or incompletely excised lesions.
London Cancer Alliance, 2014 (72) BCC: poorly defined borders, high-risk site (i.e. H-zone), aggressive histology such as morphoeic or infiltrative or micronodular, perineural invasion, lymphovascular invasion, recurrent tumors (or incompletely excised), large tumors (>2cm), immune-compromised patient SCC: poorly defined borders, high-risk site (i.e. H-zone), perineural invasion, lymphovascular invasion, recurrent tumors (or incompletely excised), large tumors (>2cm), immune-compromised patient, persistent Bowen's disease at awkward site (i.e. genitals, eyelid, scalp, nails)
# Scottish Intercollegiate Guidelines Network (SIGN), 2014 (73)
Mohs micrographic surgery should be considered at the MDT meeting, for selected patients with high-risk tumours where tissue preservation or margin control is challenging, and on an individual case basis for patients with any tumour at a critical anatomical site. This guideline was originally developed in August 2019.
# Maintenance
A formal review of the guideline will be conducted in 2020. If critical new evidence is brought forward before that time, however, the guideline working group members will revise and update the document accordingly.
# Abbreviations
| None | None |
372ed8e8ca8884e6ead1a0cbb78a917f0644d6c3 | cma | None | Guidance for healthcare providers May 2023 Recently, various novel agents have become available in BC for the treatment of COVID-19 in mild-moderately ill patients. These therapies include a direct-acting oral combination antiviral nirmatrelvir/ritonavir (Paxlovid), an IV antiviral remdesivir (Veklury) and an anti-spike protein monoclonal antibody (mAb) sotrovimab (Xevudy) Please see the full guide developed by the B.C. COVID Therapeutics Committee for more information: Clinical Practice Guide for the Use of Therapeutics in Mild-Moderate COVID-19 Who is the treatment currently being considered for? Refer to: Practice Tool #1-Assessment Steps and Practice Tool #2-CEV Definitions Patients who test positive for COVID-19 via a Polymerase Chain Reaction (PCR) or Rapid Antigen Test (RAT) test AND have been identified as being at increased risk for needing to go to the hospital for COVID-19: o Individuals who are immunocompromised or have high-risk conditions identified as Clinically Extremely Vulnerable (CEV) regardless of vaccine status or previous infection (Not all children ages 12-17 who are CEV will benefit from treatment. Those with multiple co-morbidities would have the highest potential benefit)#
- Individuals with TWO of the following three risk factors: o ≥70 years (≥60 years if they are Indigenous) o Are unvaccinated or under-vaccinated as per Strong Recommendations by NACI^ o Have at least one serious chronic medical condition- ^ National Advisory Committee on Immunization: i.e., lack of a primary two-dose series PLUS a "Fall Booster" (or a booster in the last year), which may be delayed up to 6 months post COVID-19 infection *Serious chronic medical conditions may include stroke, heart failure, heart disease, diabetes, kidney or liver disease, chronic lung disease like COPD or interstitial lung disease, neurological conditions. Some discretion can be used
# Therapy recommendations:
Patients offered treatment should be appreciably symptomatic from COVID 19. Nirmatrelvir/ritonavir is also contraindicated with drugs that are potent CYP3A inducers where significantly reduced nirmatrelvir or ritonavir plasma concentrations may be associated with the potential for loss of virologic response and possible resistance.
# Significant drug-drug interactions:
(See Practice Tool 3: Drug Interactions and Contraindications for more details).
- Most common contraindications include amiodarone, DOACs, some antipsychotics, statins, midazolam and triazolam, fentanyl and antiepileptics Some drug-drug interactions can be managed
The most comprehensive drug-drug interaction checker with nirmatrelvir/ritonavir was developed by the University of Liverpool and is found here: . This tool should be consulted when considering modifying therapy due to drug-drug interactions. Use multiple resources (e.g. LexiComp) as some information may be conflicting or incomplete.
# THERAPY: remdesivir (Veklury)direct acting antiviral administered by intravenous injection
When to start: IV x 3 daily doses is recommended within 7 days of symptom onset as an alternative to nirmatrelvir/ritonavir in cases where IV administration is feasible. Patients with a risk of hospitalization of ≥ 5% are currently being prioritized and offered treatment with remdesivir.
Remdesivir infusions are currently being delivered through Health Authority based clinics.
# Contraindications and Cautions
Drug-to-Drug Interactions Hypersensitivity reactions and infusion reactions are rare. ALT > 5X ULN Patients with an eGFR of < 30ml/min require dose adjustments and monitoring.
Possesses no significant drug-drug interactions.
# THERAPY: sotrovimab (Xevudy)monoclonal antibody administered by intravenous injection
When to start: IV x 1 dose within 7 days of symptom onset in extenuating circumstances when remdesivir cannot be given. Sotrovimab has demonstrated reduced neutralization against the BA.2 variant although it may retain some activity. If sotrovimab is used as a last line agent where potential of benefit outweighs the risk, disclosure to patients of risks and benefits in consideration of individual circumstances (clinical status, patient values, logistics) is necessary. Sotrovimab should not be chosen solely for convenience reasons.
Sotrovimab infusions are currently being delivered through Health Authority based clinics.
# Contraindications and Cautions Drug-to-Drug Interactions
Hypersensitivity reactions and infusion reactions are rare. If reactions develop during the 1-hour infusion, the infusion should be stopped.
Possesses no significant drug-drug interactions. | Guidance for healthcare providers May 2023 Recently, various novel agents have become available in BC for the treatment of COVID-19 in mild-moderately ill patients. These therapies include a direct-acting oral combination antiviral nirmatrelvir/ritonavir (Paxlovid), an IV antiviral remdesivir (Veklury) and an anti-spike protein monoclonal antibody (mAb) sotrovimab (Xevudy) Please see the full guide developed by the B.C. COVID Therapeutics Committee for more information: Clinical Practice Guide for the Use of Therapeutics in Mild-Moderate COVID-19 Who is the treatment currently being considered for? Refer to: Practice Tool #1-Assessment Steps and Practice Tool #2-CEV Definitions Patients who test positive for COVID-19 via a Polymerase Chain Reaction (PCR) or Rapid Antigen Test (RAT) test AND have been identified as being at increased risk for needing to go to the hospital for COVID-19: o Individuals who are immunocompromised or have high-risk conditions identified as Clinically Extremely Vulnerable (CEV) regardless of vaccine status or previous infection (Not all children ages 12-17 who are CEV will benefit from treatment. Those with multiple co-morbidities would have the highest potential benefit)#
o Individuals with TWO of the following three risk factors: o ≥70 years (≥60 years if they are Indigenous) o Are unvaccinated or under-vaccinated as per Strong Recommendations by NACI^ o Have at least one serious chronic medical condition* ^ National Advisory Committee on Immunization: i.e., lack of a primary two-dose series PLUS a "Fall Booster" (or a booster in the last year), which may be delayed up to 6 months post COVID-19 infection *Serious chronic medical conditions may include stroke, heart failure, heart disease, diabetes, kidney or liver disease, chronic lung disease like COPD or interstitial lung disease, neurological conditions. Some discretion can be used
# Therapy recommendations:
Patients offered treatment should be appreciably symptomatic from COVID 19. Nirmatrelvir/ritonavir is also contraindicated with drugs that are potent CYP3A inducers where significantly reduced nirmatrelvir or ritonavir plasma concentrations may be associated with the potential for loss of virologic response and possible resistance.
# Significant drug-drug interactions:
(See Practice Tool 3: Drug Interactions and Contraindications for more details).
Most common contraindications include amiodarone, DOACs, some antipsychotics, statins, midazolam and triazolam, fentanyl and antiepileptics Some drug-drug interactions can be managed
#
The most comprehensive drug-drug interaction checker with nirmatrelvir/ritonavir was developed by the University of Liverpool and is found here: https://www.covid19druginteractions.org/checker. This tool should be consulted when considering modifying therapy due to drug-drug interactions. Use multiple resources (e.g. LexiComp) as some information may be conflicting or incomplete.
# THERAPY: remdesivir (Veklury)direct acting antiviral administered by intravenous injection
When to start: IV x 3 daily doses is recommended within 7 days of symptom onset as an alternative to nirmatrelvir/ritonavir in cases where IV administration is feasible. Patients with a risk of hospitalization of ≥ 5% are currently being prioritized and offered treatment with remdesivir.
Remdesivir infusions are currently being delivered through Health Authority based clinics.
# Contraindications and Cautions
Drug-to-Drug Interactions Hypersensitivity reactions and infusion reactions are rare. ALT > 5X ULN Patients with an eGFR of < 30ml/min require dose adjustments and monitoring.
Possesses no significant drug-drug interactions.
# THERAPY: sotrovimab (Xevudy)monoclonal antibody administered by intravenous injection
When to start: IV x 1 dose within 7 days of symptom onset in extenuating circumstances when remdesivir cannot be given. Sotrovimab has demonstrated reduced neutralization against the BA.2 variant although it may retain some activity. If sotrovimab is used as a last line agent where potential of benefit outweighs the risk, disclosure to patients of risks and benefits in consideration of individual circumstances (clinical status, patient values, logistics) is necessary. Sotrovimab should not be chosen solely for convenience reasons.
Sotrovimab infusions are currently being delivered through Health Authority based clinics.
# Contraindications and Cautions Drug-to-Drug Interactions
Hypersensitivity reactions and infusion reactions are rare. If reactions develop during the 1-hour infusion, the infusion should be stopped.
Possesses no significant drug-drug interactions. | None | None |
2f88376e94490f2db2ed77f29d158a21557ae4d0 | cma | None | Background For patients who are diagnosed with early-stage cutaneous melanoma, the principal therapy is wide surgical excision of the primary tumour and assessment of lymph nodes. The purpose of the present guideline was to update the 2010 Cancer Care Ontario guideline on wide local excision margins and sentinel lymph node biopsy (slnb), including treatment of the positive sentinel node, for melanomas of the trunk, extremities, and head and neck. Methods Using Ovid, the medline and embase electronic databases were systematically searched for systematic reviews and primary literature evaluating narrow compared with wide excision margins and the use of slnb for melanoma of the truck and extremities and of the head and neck. Search timelines ran from 2010 through week 25 of 2017. Results Four systematic reviews were chosen for inclusion in the evidence base. Where systematic reviews were available, the search of the primary literature was conducted starting from the end date of the search in the reviews. Where systematic reviews were absent, the search for primary literature ran from 2010 forward. Of 1213 primary studies identified, 8 met the inclusion criteria. Two randomized controlled trials were used to inform the recommendation on completion lymph node dissection. Key updated recommendations include: Wide local excision margins should be 2 cm for melanomas of the trunk, extremities, and head and neck that exceed 2 mm in depth. slnb should be offered to patients with melanomas of the trunk, extremities, and head and neck that exceed 0.8 mm in depth. Patients with sentinel node metastasis should be considered for nodal observation with ultrasonography rather than for completion lymph node dissection.Recommendations for primary excision margins, sentinel lymph node biopsy, and completion lymph node dissection in patients with cutaneous melanoma have been updated based on the current literature.# INTRODUCTION
The incidence of melanoma is increasing both worldwide and in Canada. In Canada between 2001 and 2010, the incidence rates of melanoma increased by 2.3% per year in men and by 2.9% per year in women 1 . Melanoma is the 7th most common cancer in Canada, and in 2017, 7300 new cases were diagnosed and more than 1250 deaths were recorded 1 . For patients who are diagnosed with early-stage cutaneous melanoma , the principal therapy is wide surgical excision of the primary tumour and assessment of lymph nodes.
In the past, standard therapy included wide radial excision margins of up to 5 cm; however, that practice is associated with significant morbidity and disfigurement. A series of randomized controlled trials (rcts) demonstrated that narrower margins have not been associated with higher local recurrence rates or worse overall survival (os) . However, uncertainty about optimal excision margins for the primary tumour-especially those deeper than 2 mm-remains 8 .
Standard surgical treatment for patients who are clinically node-negative also includes assessment of the regional lymph nodes. The risk for nodal involvement rises with increasing tumour thickness; however, 90% of patients with stage i and ii cutaneous melanomas have no clinical evidence of lymphadenopathy at initial presentation, and yet approximately 16% are found to have microscopic involvement upon further examination 9 .
Sentinel lymph node biopsy (slnb) is a surgical procedure that identifies the sentinel node, the first lymph node or nodes that drain the primary melanoma site. The slnb is identified by lymphatic mapping with a blue dye (isosulfan or patent blue) and a radioactive tracer (Tc-99). The process allows for the status of a clinically nodenegative regional basin to be determined without a complete lymph node dissection. The nodes are serially sectioned and carefully examined pathologically for the presence of melanoma meta stases (hematoxylin and eosin stain and immunohistochemistry for hmb-45, S-100, and mart-1). The technique is predicated on the empiric observation that melanoma metastasizes through lymphatics sequentially, preferentially to the sentinel lymph node (sln) and then to other regional lymph nodes. The Multi-site Lymphadenectomy Trial I (mslt-i) demonstrated a survival benefit of slnb at 5 years for patients with an intermediate-thickness melanoma when completion lymphadenectomy was performed after melanoma metastases in the slns were identified 9 . However, uncertainty remains about the optimal indications for slnb, especially for melanomas that are thin (4 mm) or that occur on the head and neck.
After the publication of mslt-i, two key studies assessed the survival benefit of completion lymphadenectomy (clnd) after identification of a positive slnb by comparing clnd with ultrasound monitoring of the lymph node basin: decog-slt and mslt-ii 10,11 .
In the present guideline, we also synthesize the literature about whether clnd after identification of a positive sln improves outcomes. The purpose of the guideline was to update the 2010 Cancer Care Ontario guideline about wide local excision margins and slnb, including the positive sln for trunk, extremities, and head and neck, in the context of recent literature.
# METHODS
This practice guideline was developed by the Melanoma Disease Site Group (dsg) of Cancer Care Ontario's Program in Evidence-Based Care (pebc) using the methods of the practice guidelines development cycle 12 . For this guideline, the core method used to develop the evidentiary base was an update of a systematic review from a previous version of the guideline, together with the addition of a systematic review evaluating excision margins and the use of slnb in patients with head-and-neck melanoma. Evidence was selected and reviewed by 2 members of the Melanoma dsg and 1 research methodologist.
This practice guideline is an up-to-date source of the best available evidence about optimal primary resection margins and the use of slnb in patients with cutaneous melanoma located on the trunk, extremities, or head and neck. It was developed by systematic review, data synthesis, internal review by a clinician and a methodologist, and external review by clinical experts and Ontario practitioners. The systematic review evidence forms the basis of the recommendations developed by the Melanoma dsg. This practice guideline is intended to promote evidence-based practice in Ontario. The pebc is supported by the Ontario Ministry of Health and Long-Term Care through Cancer Care Ontario. All work produced by the pebc is editorially independent from its funding source.
# Questions
The Melanoma dsg determined that these questions would guide the literature review: In patients with nonmetastatic cutaneous melanoma with clinically node-negative or node-positive disease of the trunk or extremities, what are the optimal primary clinical margins of excision? In patients with a diagnosis of melanoma of the trunk or extremities and concurrent distant metastases at presentation, what are the optimal primary clinical margins of excision for the cutaneous disease? Which patients with clinically node-negative cutaneous melanoma of the trunk and extremities should undergo slnb? In patients with nonmetastatic cutaneous melanoma with clinically node-negative or node-positive disease of the head and neck, what are the optimal primary margins of excision? In patients with a diagnosis of melanoma of the head and neck and concurrent distant metastases at presentation, what are the optimal primary margins of excision for the cutaneous disease? Which patients with clinically node-negative cutaneous melanoma of the head and neck should undergo slnb? What is the optimal surgical management of patients with positive slns from cutaneous melanoma of the trunk or extremities with respect to clnd compared with observation at the time of sln positivity.
It should be noted that, for all research questions (with the exception of clnd), these categories of melanoma thickness were addressed: in situ, less than 1 mm, 1.01-2 mm, 2.01-4 mm, and 4.01 mm or more.
# Target Population
The guideline recommendations apply to adults (>18 years of age) diagnosed with truncal, extremity, or head-andneck cutaneous melanoma.
# Systematic Review
A search for existing guidelines was undertaken to determine whether an existing guideline could be adapted or endorsed. To that end, these sources were searched for existing guidelines addressing the research questions: Using Ovid, the medline and embase electronic databases were systematically searched for systematic reviews and primary literature evaluating narrow compared with wide excision margins and the use of slnb. For melanoma of the trunk and extremities, the Ovid search ran from 2010 to week 25 of 2017, and for melanoma of the head and neck, the Ovid search ran from 2002 to week 25 of 2017. For both searches, these keywords were used: "melanoma," "head and neck" (for the head-and-neck search only), "excision margin," "slnb," and "sentinel node." In addition, Web sites and databases of specific guideline developers that used systematic reviews as their evidentiary base and of producers of systematic reviews were also searched, using the same keywords and the same time periods.
Using Ovid, the medline and embase electronic databases were systematically searched for primary studies evaluating optimal excision margins and use of slnb in adults diagnosed with melanoma. The search ran from 2002 for head-and-neck populations, and from 2010 for trunk and extremity populations, through week 25 of 2017. The literature search strategy included keywords for identification of excision margins, slnb, head-and-neck melanoma populations, and trunk and extremity melanoma populations. In addition to the medline and embase database searches, reference lists of included systematic reviews and primary literature were scanned for potentially useful studies.
The titles and abstracts that resulted from the search were reviewed by one reviewer (LHS) and verified by a second (FCW). For items that warranted full-text review, 1 reviewer determined whether the inclusion and exclusion criteria were met. The list of proposed studies was verified by the Melanoma dsg.
# Development of Recommendations
The pebc produces evidence-based and evidence-informed guidance documents using the methods of the practice guidelines development cycle 12,13 . That process includes a systematic review; interpretation of the evidence by a Working Group, with production of draft recommendations; an internal review by content and methodology experts; and external reviews by Ontario clinicians and other stakeholders.
The pebc uses the agree ii framework 14 as its methodologic strategy for guideline development. The 23-item validated agree ii tool is designed to assess the methodologic rigour and transparency of guideline development.
# RESULTS
# Literature Search Results
The search for existing systematic reviews identified 126 possible reviews on optimal resection margins and use of slnb in melanoma patients. Four systematic reviews were chosen for inclusion in the evidence base. One review evaluated narrow compared with wide excision margins in patients with melanoma of the trunk and extremities 18 ; the remaining three reviews assessed the use of slnb in melanoma of the trunk and extremities 15,16 and in melanoma of the head and neck 17 .
The systematic review of the primar y literature addressed outcomes of interest not covered by the four systematic reviews included in the evidence base. Where one or more systematic reviews were available, the search of the primary literature started from the end date of the search in the review or reviews. Of 1213 studies identified, 8 studies met the inclusion criteria. Table i summarizes the number of studies identified per research question, the melanoma location, and the Breslow thickness.
Details about the methodologic characteristics and clinical outcomes of the included trials can be found in the full guideline report at the Cancer Care Ontario Web site 26 .
It should be noted that the present guideline focuses on patients with clinically node-negative disease. The reason for that decision was that no data were available concerning the extent of wide local excision in patients who were node-positive or who had metastatic disease. The current standard of practice for patients with node-positive disease is a standard wide local excision. No data were found for patients with metastatic disease, and the extent of wide local excision should be discussed in a multidisciplinary team cancer conference on a case-by-case basis.
# Recommendation 1-Surgical Margins for Melanoma Located on the Trunk and Extremities
After initial excision or biopsy for melanoma located on the trunk and extremities, the radial excision margins, measured clinically from the edge of the melanoma or biopsy scar, should accord with the recommendations in
# Topic
# Melanoma location Breslow thickness Studies
# Primary excision margins Trunk and extremities
In situ None identified ≤1 mm 1 SR with meta-analysis 18,a 1 Case-control study 19 1.01-2 mm 1 SR with meta-analysis 18,a 2.01-4 mm 1 SR with meta-analysis 18,a 1 Randomized controlled trial 20,b ≥4.01 mm 1 SR with meta-analysis 18,a 1 Randomized controlled trial 20,b Head and neck In situ 1 Retrospective cohort 21,c ≤1 mm 2 Retrospective cohorts 21,22,c 1.01-2 mm 2 Retrospective cohorts 21,22,c 2.01-4 mm 2 Retrospective cohorts 21,22,c ≥4.01 mm 3 Retrospective cohorts 21,22,23,c Sentinal lymph node biopsy Trunk and extremities
# In situ
No studies identified ≤1 mm 2 SRs with meta-analyses 15,16 1 Randomized controlled trial 9,d 1.01-2 mm 1 SR with meta-analysis 15 2 Randomized controlled trials 9,24,d,e
2.01-4 mm 1 SR with meta-analysis 15 1 Randomized controlled trial 9,d ≥4.01 mm 1 SR with meta-analysis 15 1 Randomized controlled trial 9,d
# Qualifying Statements
The total wide local excision margin can be a composite margin from the biopsy and from the wide local excision.
For melanoma in situ, no rcts have evaluated appropriate surgical margins. In a single prospective study of pathologic margins for melanoma in situ, 86% of patients had clear pathologic margins with a 6 mm wide excision margin, and 98.9% of melanomas in situ were completely excised with a 9 mm surgical margin 27 . Consequently, some patients might require wider surgical margins of 1 cm to achieve clear pathologic margins; however, a 5 mm margin is suggested as the initial wider margin, especially in areas in which obtaining wider margins is challenging or in which wider margins would have an unacceptable effect on form or function.
Where possible, it might be desirable to take a wider margin (2 cm) for pT2 lesions, depending on tumour site and surgeon or patient preference, because the evidence concerning optimal excision margins in those cases (1 cm vs. 2 cm) is unclear.
# Key Evidence and Interpretation
A 2016 systematic review with meta-analysis that pooled six rcts compared narrow (1-2 cm) with wide (3-5 cm) excision margins for thin (≤2 mm) and thick (>2 mm) melanomas 18 . That meta-analysis by Wheatley et al. found that, for all patients (≤2 mm and >2 mm alike), os and recurrence-free survival (rfs) were not different when narrow compared with wide margins were used; however, melanoma-specific survival (mss) was improved with wide margins (3-5 cm) compared with narrow margins (1-2 cm) 18 . Subgroup analysis for thin and thick melanomas found no difference in os, mss, rfs, or locoregional recurrence when the melanoma depths (≤2 mm and >2 mm) were separately assessed 18 . Furthermore, the nodal status of the patients was unknown in most studies, thus potentially affecting mss results.
A new rct that was not included in the Wheatley et al. meta-analysis and that enrolled patients with thick melanomas (≥2 mm), found no difference in os when comparing 1 cm with 3 cm margins; however, a trend toward a reduction in mss was seen that did not reach statistical significance 20 . The nodal status of the patients in this new study was unknown, thus potentially affecting the results.
The Working Group considered both the Wheatley metaanalysis, previous margin studies, and the potential morbidity associated with a 3-5 cm margin for all melanomas when making its recommendations. In particular, for the meta-analysis data 18 , several factors were considered: patient numbers within each depth range; the fact that this analysis was the first to suggest that narrow margins were associated with worse mss; and the morbidity of larger margins, with the likelihood of more complex closures using skin grafts and flaps. The Working Group believes that more confirmatory data are needed before such a significant practice change (a >3 cm excision margin for all melanomas) can be recommended.
An additional case-control study that enrolled patients with thin melanomas (≤1 mm) who had experienced local recurrence found that median time to recurrence was significantly shorter for patients with margins less than 1 cm, but was not different when margins greater than 2 cm were compared with margins less than 2 cm 19 .
# Recommendation 2-Surgical Margins for Cutaneous Melanoma Located on the Head and Neck
After initial excision or biopsy for cutaneous melanoma located on the head and neck, the radial excision margins, measured clinically from the edge of the melanoma or biopsy scar, should accord with the recommendations in Table iii.
# Qualifying Statements
For pT2 melanomas, it could be desirable, where possible, to take a wider surgical margin (2 cm) depending on tumour site and surgeon or patient preference, because evidence concerning optimal excision margins is unclear.
The total wide local excision margin can be a composite margin from the biopsy and the wide local excision.
It is recognized, however, that wide margins might not always be possible, based on the location of the melanoma in relation to facial structures. When possible, wide margins should be used; however, they could be difficult to achieve when the melanoma is located on the eyelid, nose, lip, or ear.
For melanoma in situ, margin-controlled excision might provide tissue-sparing and improved tumour clearance in challenging locations such as near the eye, nose, lips, and ears.
# Key Evidence and Interpretation
Three low-quality retrospective cohort studies were identified to directly inform this recommendation for invasive (pT1-pT4) melanoma. All three reviewed the medical records of patients diagnosed with melanoma located on the head and neck and found no difference in survival rates or recurrence rates 22,23 when margins of different sizes were compared.
No rcts were identified to inform a recommendation for melanoma in situ in the head and neck. The Working Group applied knowledge from the Mohs micrographic surgery literature, which indicates that margins of 9-10 mm might be needed to achieve a complete clearance rate in some patients with melanoma in situ, but that a 5 mm margin is suggested as the initial surgical margin 27,28 .
# Recommendation 3-SLNB for Melanoma Located on the Trunk and Extremities
Patients with a clinically node-negative stage i or ii melanoma 0.8 mm in thickness and located on the trunk or extremities should be given the opportunity to discuss slnb to provide staging and prognostic information (Table iv).
# Qualifying Statements
Sentinel lymph node biopsy should be performed only after a discussion of the options with the patient, when access to appropriate surgical, nuclear medicine, and pathology services is available.
The false-negative rate of slnb is lowest when more than 50 cases have been performed at the institution 29 .
A double dye technique with Tc-99 and blue dye (isosulfan or patent blue) increases the identification rate of the slns 30 .
It should be noted that, in mslt-i 29 , the subgroup for intermediate-thickness melanoma was 1.2-3.5 mm. We applied the mslt-i data to all intermediate-thickness melanomas 1-4 mm.
For patients with intermediate-thickness melanomas diagnosed with nodal metastases on pathology of the sentinel node or nodes, a 10-year mss benefit for slnb was reported on a planned subset analysis; however, os was not reported.
Sentinel lymph node biopsy should be discussed with patients to identify those eligible for adjuvant therapy and for enrolment into clinical trials.
Ideally, for best accuracy, slnb is performed at the same time as the wide local excision of the primary melanoma. Sentinel lymph node biopsy is less reliable or might fail when performed as a separate operation for a patient already having had wide local excision and repair with any flap (with the exception of an advancement flap) or skin graft.
# Key Evidence and Interpretation
The 10-year follow-up of mslt-i 9 was published after the 2010 guideline. That rct enrolled patients with thin (3.5 mm) melanomas, but the 10-year follow-up publication reported only on the patients with intermediate and thick melanomas. Patients were randomized to a wide excision (2-3 cm) alone (observation group) or wide excision (2-3 cm) plus slnb (biopsy group) 9 . Patients in the biopsy group with a positive slnb underwent immediate lymphadenectomy; patients in the observation group received nodal observation and lymphadenectomy only if they later presented with nodal relapse 9 . The mslt-i update reported on disease-free survival (dfs) and mss, but not os. The 10-year dfs was significantly higher in the slnb group than in the observation group whether patients had intermediate or thick melanomas (p = 0.01 and p = 0.03 respectively) 9 . Overall, the 10-year mss was not different between the groups with either intermediate or thick melanomas 9 . However, for patients with nodal metastases, the 10-year mss on a planned subset analysis was significantly higher for patients with intermediate-thickness melanomas in the slnb group than for those in the observation group (62.1% ± 4.8% vs. 41.5% ± 5.6%) 9 ; the same case did not hold for the patients with thick melanomas.
Other studies reviewed for recommendation 3 included a meta-analysis that considered studies of multiple Breslow thicknesses, but because of missing data, could pool data only for thick melanomas (>4.01 mm), finding that os was reduced in patients having positive slns compared with patients having negative slns 15 . A second meta-analysis included only studies involving patients diagnosed with thin melanomas (≤1 mm), finding that, overall, 4.5% of those patients had positive slns 16 . Melanoma thickness of 0.75 mm or greater, Clark level 4 or 5, high mitotic rate (≥1 mitosis/ mm 2 ), ulceration, and microsatellites were predictors of sln metastases, with the rates of sln positivity being 8.8%, 7.3%, 8.8%, 5.8%, and 26.6% for each predictor respectively 16 . Lastly, based on the systematic review with metaanalysis from Cordeiro et al. 16 in patients with thin melanomas, any or some combination of a melanoma thickness of 0.75 mm or greater, Clark level 4 or 5, a high mitotic rate, ulceration, or microsatellites indicated a higher chance for sln positivity, and physicians should therefore discuss slnb with affected patients. For guideline recommendation 3, the 8th edition of the American Joint Committee on Cancer staging manual for melanoma was used 31 .
# Recommendation 4-SLNB for Cutaneous Melanoma Located on the Head and Neck
Patients with a clinically node-negative stage i or ii cutaneous melanoma more than 0.8 mm in thickness and located on the head and neck should be given the opportunity to discuss slnb to provide staging and prognostic information (Table v).
# Qualifying Statements
Sentinel lymph node biopsy should be performed only after a discussion of the options with the patient, when access to appropriate surgical, nuclear medicine, and pathology services is available.
The false-negative rate of slnb is lowest when more than 50 cases have been performed at an institution 29 .
A double dye technique with Tc-99 and blue dye (isosulfan or patent blue) increases the identification rate of the slns 30 .
Sentinel lymph node biopsy should be discussed with patients to identify those eligible for adjuvant therapy and for enrolment into clinical trials.
Ideally, for greatest accuracy, slnb should be performed at the same time as the wide local excision of the primary melanoma. Sentinel lymph node biopsy is less reliable or might fail when performed as a separate operation for a patient already having had a wide local excision and repair with any flap (with the exception of an advancement flap) or skin graft 32,33 .
# Key Evidence and Interpretation
One systematic review 17 and one diagnostic cohort study 25 assessed the diagnostic performance of slnb for melanoma located on the head and neck and reported high false-negative rates: 20.4% and 4.8% respectively.
It is now known that mslt-i 9 included 334 patients with primary melanomas located on the head and neck (Faries M. Personal communication. 2 June 2016). Although headand-neck patients were not separately analyzed, 10-year dfs for all enrolled patients was significantly higher in the slnb group than in the observation group for patients with intermediate or thick melanomas 9 . Additionally, in patients with intermediate-thickness melanomas and nodal metastases, a planned subset analysis found that 10-year mss was significantly higher in the slnb group than in the observation group 9 . However, mss was not improved for patients with thick melanomas.
# Recommendation 5-CLND Compared with Observation at the Time of SLN Positivity
Patients with sln metastasis should be considered for nodal observation with ultrasonography rather than for clnd. Monitoring of the affected nodal basin with ultrasonography and clinical exam will be required, at a minimum, every 4-6 months for the first 2 years and every 6 months from year 3 to year 5. Suspicion of a nodal recurrence in a lymph node basin includes any 2 of these observations: lymph node length-to-depth ratio less than 2; hypoechoic centre; and failure to identify a nodal hilar vessel or focal rounded area of low-level echoes with increased vascularity in that area, or both. Suspicion of a nodal recurrence by ultrasonography should be confirmed with a biopsy of the suspicious lymph node. If the biopsy shows melanoma, the patient should be re-staged before any further surgery. For certain patients with a positive sln, a clnd rather than ultrasound monitoring might still be the best option for local control, but the choice should be discussed by a multidisciplinary team.
# Qualifying Statements
In mslt-ii 11 , one third of the patients had melanoma meta stases greater than 1 mm in diameter, and 72% of ≤1.0 mm If melanoma is ≥0.8 mm in thickness, is Clark level 4 or 5, has a high mitotic rate (≥1 mitosis/mm 2 ), ulceration, or microsatellites, the physician should discuss SLNB with the patient. Biopsy might provide a melanomaspecific survival benefit if the sentinel node contains melanoma metastases. Such patients might also benefit from adjuvant therapy or entry into adjuvant clinical trials (or both).
pT2 and pT3
1.01-2.0 mm 2.01-4. 0mm
For these patients, SLNB is recommended to provide locoregional control and to identify individuals who might benefit from adjuvant therapy or entry into adjuvant clinical trials (or both). Biopsy might provide a melanomaspecific survival benefit if the sentinel node contains melanoma metastases. pT4 ≥4.01 mm Physicians should discuss SLNB with these patients. Biopsy will provide prognostic information. If the sentinel node contains melanoma metastases, removal might provide locoregional control, but not a melanoma-specific survival benefit. These patients might also benefit from adjuvant therapy or entry into adjuvant clinical trials (or both). the patients had 1 sentinel node with metastases. A subgroup evaluation of patients with a greater disease burden (maximal tumour diameter > 1 mm) did not indicate that a benefit from clnd was more likely in high-risk groups (>1 mm) than in low-risk groups (≤1 mm) 11 . Patients for whom clnd might be a better option than nodal observation with ultrasonography are those with extensive snl metastasis in which clnd would provide regional control. those unlikely to comply with an intensive surveillance protocol. those treated at centres in which radiologists are not comfortable performing serial surveillance ultrasonography examinations.
Although guideline 5 is specific to the trunk and extremities, the same recommendation can be applied to melanomas of the head and neck and their respective drainage basins.
# Key Evidence and Interpretation
Two randomized trials, mslt-ii 11 and decog-slt 10 , evaluated the utility of clnd compared with observation through frequent nodal ultrasonography, with dissection only in melanoma patients with progression of nodal disease. In mslt-ii 11 , patients with melanoma metastases in a sln were randomized to either nodal observation (every 4 months for 3 years and then every 6 months for 2 years for a total of 5 years of nodal observation) or to immediate clnd. Patients with biopsy-proven isolated nodal recurrence underwent a therapeutic lymph node dissection. Median follow-up was 43 months. In a planned subset analysis, no patients were found to benefit from immediate clnd. Most patients had low-volume nodal tumour burden (1 positive sln; mean diameter of nodal metastasis: 1.1 mm). The 3-year mss was 86% ± 1.3% in the clnd group and 86% ± 1.2% the observation group (p = 0.42). The 3-year dfs rate was slightly higher in the clnd group (p = 0.05), but the investigators suggested caution about the significance of that result based on the lack of significance of the mss, which was the primary outcome. Overall, some regional control and prognostic value can be derived from clnd, but at the expense of increased adverse events-in particular, lymphedema and a potential delay to adjuvant therapy. The nonsignificant difference in mss and the increase in adverse events in the clnd group indicate that clnd is not recommended for low-volume nodal tumour burden and does not offer a survival benefit. Whether a clnd should or should not be recommended with larger-volume disease in the slns is unclear; however, on subset analysis, no patients (including those with a higher volume of melanoma metastases) benefited from clnd, which led to recommendation 5. Similarly, the decog-slt trial 10 found no difference in distant metastasis-free survival, os, or rfs when patients with positive slns who received clnd were compared with patients who were observed with nodal ultrasonography and computed tomography imaging of the affected basin. Median follow-up for the trial was 35 months 10 .
# DISCUSSION
In this systematic review, we summarize the last 8 years of surgical melanoma trials for patients with head-andneck, truncal, and extremity primaries. In particular, we focus on the extent of wide local excision for the primary melanoma, which patients should be offered a slnb, and which patients with melanoma metastases in their sln should undergo clnd.
One of the most discussed papers identified during this update was the Wheatley et al. systematic review and metaanalysis 18 . The findings from that study could substantially change practice with respect to wide local excision margins for patients with melanoma. The Working Group members interpreted those data with extreme caution. The meta-analysis found that, for all patients with melanoma, os, locoregional recurrence, and rfs were not different when narrow margins (1-2 cm) were compared with wide margins (3-5 cm), but that mss was improved with wide margins 18 . Using Bayesian likelihood plots, the systematic review reported a high probability that narrow margins were worse than wide margins for os, mss, rfs, and locoregional recurrence 18 , providing the first-ever published data indicating that narrow margins are not safe and refuting clinical practice guidelines from worldwide organizations. When making its recommendations, the Working Group considered the Wheatley meta-analysis, prior margin studies, and the potential morbidity associated with a 3-5 cm margin for all melanomas. In particular, for the meta-analysis data 18 , we considered patient numbers within each depth range; the fact that the Wheatley analysis is the first to suggest that mss is worse with narrow margins; and the morbidity of larger margins, with the likelihood of more complex closures requiring skin grafts and flaps. The Working Group believes that more confirmatory data are needed before such a significant practice change (a >3 cm excision margin for all melanomas) can be recommended. The main change that was made to the original guideline was to increase the margin recommendation for melanomas of 2.0-4.0 mm thickness to 2 cm from 1-2 cm. The Working Group strongly supports a rct comparing margins of 1 cm, 2 cm, and 3 cm.
The Working Group also made changes to the margin recommendations for melanoma in situ. The original recommendation of a 5 mm margin was adopted from the Australia-New Zealand guideline developers 34 . Two factors led to a change in the recommendation: a recent prospective study of pathologic margins for melanoma in situ, which found that 86% of patients had clear pathologic margins with a 6 mm wide excision margin and that 98.9% of melanomas in situ were completely excised with a 9 mm surgical margin 27 ; and the clinical experience of the group. The Working Group now suggests a 5 mm to 1 cm margin for melanoma in situ, although a 5 mm margin is recommended for the initial excision, and a 1 cm margin is recommended only if the margins are positive after the initial excision.
With respect to the recommendations for slnb, the Working Group recommends that all patients with a melanoma greater than 0.8 mm in thickness and with no clinical evidence of nodal metastasis should be given the opportunity to discuss slnb. Sentinel lymph node biopsy is performed to provide information for staging and prognosis, and to identify patients who could benefit from adjuvant therapy or clinical trials. Although the mslt-i trial did not report on os at 10 years, it reported a mss benefit for patients with intermediate-thickness melanomas and nodal metastases, and in a planned subset analysis, improved locoregional control for patients with melanomas of 1.2 mm to more than 3.5 mm thickness on the trunk and extremities or head and neck. Some controversy attends that result because, overall, the trial was negative and no os was reported. For patients with a melanoma thicker than 4.0 mm, slnb provides locoregional control, and patients should still be given the opportunity to discuss the role of slnb for prognostic information, locoregional control, and consideration of adjuvant therapy .
Lastly, based on the Cordeiro systematic review with meta-analysis 16 , patients with thin melanomas that are Clark level 4 or 5 or have high mitotic rates, ulceration, or microsatellites have a higher chance of sln positivity, and thus, physicians should discuss slnb with them. When discussing melanoma located on the head and neck alone, the available data indicate a higher chance for a false negative from the slnb 17,25 . To help minimize the number of false negatives, the Working Group suggests performing the slnb in a high-volume centre (>50 cases) 29 ; using a dual tracer technique with Tc-99 and blue dye to improve the sln detection rate 30 ; and using integrated single-photon emission computed tomography-computed tomography, which might improve the localization of slns in head and neck areas 38 .
Until the publication of the mslt-ii trial, the value of clnd in patients with sln metastasis had been inconclusive and controversial. The mslt-ii trial provided sufficient data to determine that, in patients with sln metastasis, clnd, compared with nodal observation, provided no statistically significant survival benefit 11 . The Working Group acknowledges that most patients enrolled in the trial had a low-volume nodal tumour burden; however, a subgroup analysis of patients with a greater disease burden (maximal tumour diameter > 1 mm) did not indicate that a benefit of clnd was more likely to accrue in high-risk groups than in low-risk groups 11 . Although clnd provided some regional control and improved staging, the Working Group weighed those data against the increased potential for adverse events-in particular, lymphedema and a possible delay to adjuvant therapy-and determined that the regional control and improvements in staging did not outweigh the increased possibility of complications and morbidity associated with clnd. The Working Group consequently recommends that all patients with melanoma metastasis in their slns be considered for nodal observation. Those guidelines are similar to the 2017 recommendations from the American Society of Clinical Oncology concerning slns and the management of regional lymph nodes in melanoma 39,40 .
# INTERNAL AND EXTERNAL REVIEW OF THE PRACTICE GUIDELINE
The pebc Report Approval Panel reviewed the draft systematic review and practice guideline and provided feedback.
The draft systematic review and practice guideline were distributed to health care providers in the province of Ontario. The results of those two sources of feedback can be found in the full guideline report at the Cancer Care Ontario Web site 26 .
# REVIEW AND UPDATE
Practice guidelines developed by the pebc are reviewed and updated regularly. Please visit the Cancer Care Ontario Web site (/ en) for the full evidence-based series report 26 and any subsequent updates. | Background For patients who are diagnosed with early-stage cutaneous melanoma, the principal therapy is wide surgical excision of the primary tumour and assessment of lymph nodes. The purpose of the present guideline was to update the 2010 Cancer Care Ontario guideline on wide local excision margins and sentinel lymph node biopsy (slnb), including treatment of the positive sentinel node, for melanomas of the trunk, extremities, and head and neck. Methods Using Ovid, the medline and embase electronic databases were systematically searched for systematic reviews and primary literature evaluating narrow compared with wide excision margins and the use of slnb for melanoma of the truck and extremities and of the head and neck. Search timelines ran from 2010 through week 25 of 2017. Results Four systematic reviews were chosen for inclusion in the evidence base. Where systematic reviews were available, the search of the primary literature was conducted starting from the end date of the search in the reviews. Where systematic reviews were absent, the search for primary literature ran from 2010 forward. Of 1213 primary studies identified, 8 met the inclusion criteria. Two randomized controlled trials were used to inform the recommendation on completion lymph node dissection. Key updated recommendations include: ■ Wide local excision margins should be 2 cm for melanomas of the trunk, extremities, and head and neck that exceed 2 mm in depth. ■ slnb should be offered to patients with melanomas of the trunk, extremities, and head and neck that exceed 0.8 mm in depth. ■ Patients with sentinel node metastasis should be considered for nodal observation with ultrasonography rather than for completion lymph node dissection.Recommendations for primary excision margins, sentinel lymph node biopsy, and completion lymph node dissection in patients with cutaneous melanoma have been updated based on the current literature.# INTRODUCTION
The incidence of melanoma is increasing both worldwide and in Canada. In Canada between 2001 and 2010, the incidence rates of melanoma increased by 2.3% per year in men and by 2.9% per year in women 1 . Melanoma is the 7th most common cancer in Canada, and in 2017, 7300 new cases were diagnosed and more than 1250 deaths were recorded 1 . For patients who are diagnosed with early-stage cutaneous melanoma [clinically node-negative and <4 mm thickness (pT1-pT3)], the principal therapy is wide surgical excision of the primary tumour and assessment of lymph nodes.
In the past, standard therapy included wide radial excision margins of up to 5 cm; however, that practice is associated with significant morbidity and disfigurement. A series of randomized controlled trials (rcts) demonstrated that narrower margins have not been associated with higher local recurrence rates or worse overall survival (os) [2][3][4][5][6][7] . However, uncertainty about optimal excision margins for the primary tumour-especially those deeper than 2 mm-remains 8 .
Standard surgical treatment for patients who are clinically node-negative also includes assessment of the regional lymph nodes. The risk for nodal involvement rises with increasing tumour thickness; however, 90% of patients with stage i and ii cutaneous melanomas have no clinical evidence of lymphadenopathy at initial presentation, and yet approximately 16% are found to have microscopic involvement upon further examination 9 .
Sentinel lymph node biopsy (slnb) is a surgical procedure that identifies the sentinel node, the first lymph node or nodes that drain the primary melanoma site. The slnb is identified by lymphatic mapping with a blue dye (isosulfan or patent blue) and a radioactive tracer (Tc-99). The process allows for the status of a clinically nodenegative regional basin to be determined without a complete lymph node dissection. The nodes are serially sectioned and carefully examined pathologically for the presence of melanoma meta stases (hematoxylin and eosin stain and immunohistochemistry for hmb-45, S-100, and mart-1). The technique is predicated on the empiric observation that melanoma metastasizes through lymphatics sequentially, preferentially to the sentinel lymph node (sln) and then to other regional lymph nodes. The Multi-site Lymphadenectomy Trial I (mslt-i) demonstrated a survival benefit of slnb at 5 years for patients with an intermediate-thickness melanoma when completion lymphadenectomy was performed after melanoma metastases in the slns were identified 9 . However, uncertainty remains about the optimal indications for slnb, especially for melanomas that are thin (<1 mm) or thick (>4 mm) or that occur on the head and neck.
After the publication of mslt-i, two key studies assessed the survival benefit of completion lymphadenectomy (clnd) after identification of a positive slnb by comparing clnd with ultrasound monitoring of the lymph node basin: decog-slt and mslt-ii 10,11 .
In the present guideline, we also synthesize the literature about whether clnd after identification of a positive sln improves outcomes. The purpose of the guideline was to update the 2010 Cancer Care Ontario guideline about wide local excision margins and slnb, including the positive sln for trunk, extremities, and head and neck, in the context of recent literature.
# METHODS
This practice guideline was developed by the Melanoma Disease Site Group (dsg) of Cancer Care Ontario's Program in Evidence-Based Care (pebc) using the methods of the practice guidelines development cycle 12 . For this guideline, the core method used to develop the evidentiary base was an update of a systematic review from a previous version of the guideline, together with the addition of a systematic review evaluating excision margins and the use of slnb in patients with head-and-neck melanoma. Evidence was selected and reviewed by 2 members of the Melanoma dsg and 1 research methodologist.
This practice guideline is an up-to-date source of the best available evidence about optimal primary resection margins and the use of slnb in patients with cutaneous melanoma located on the trunk, extremities, or head and neck. It was developed by systematic review, data synthesis, internal review by a clinician and a methodologist, and external review by clinical experts and Ontario practitioners. The systematic review evidence forms the basis of the recommendations developed by the Melanoma dsg. This practice guideline is intended to promote evidence-based practice in Ontario. The pebc is supported by the Ontario Ministry of Health and Long-Term Care through Cancer Care Ontario. All work produced by the pebc is editorially independent from its funding source.
# Questions
The Melanoma dsg determined that these questions would guide the literature review: ■ In patients with nonmetastatic cutaneous melanoma with clinically node-negative or node-positive disease of the trunk or extremities, what are the optimal primary clinical margins of excision? ■ In patients with a diagnosis of melanoma of the trunk or extremities and concurrent distant metastases at presentation, what are the optimal primary clinical margins of excision for the cutaneous disease? ■ Which patients with clinically node-negative cutaneous melanoma of the trunk and extremities should undergo slnb? ■ In patients with nonmetastatic cutaneous melanoma with clinically node-negative or node-positive disease of the head and neck, what are the optimal primary margins of excision? ■ In patients with a diagnosis of melanoma of the head and neck and concurrent distant metastases at presentation, what are the optimal primary margins of excision for the cutaneous disease? ■ Which patients with clinically node-negative cutaneous melanoma of the head and neck should undergo slnb? ■ What is the optimal surgical management of patients with positive slns from cutaneous melanoma of the trunk or extremities with respect to clnd compared with observation at the time of sln positivity.
It should be noted that, for all research questions (with the exception of clnd), these categories of melanoma thickness were addressed: in situ, less than 1 mm, 1.01-2 mm, 2.01-4 mm, and 4.01 mm or more.
# Target Population
The guideline recommendations apply to adults (>18 years of age) diagnosed with truncal, extremity, or head-andneck cutaneous melanoma.
# Systematic Review
A search for existing guidelines was undertaken to determine whether an existing guideline could be adapted or endorsed. To that end, these sources were searched for existing guidelines addressing the research questions: Using Ovid, the medline and embase electronic databases were systematically searched for systematic reviews and primary literature evaluating narrow compared with wide excision margins and the use of slnb. For melanoma of the trunk and extremities, the Ovid search ran from 2010 to week 25 of 2017, and for melanoma of the head and neck, the Ovid search ran from 2002 to week 25 of 2017. For both searches, these keywords were used: "melanoma," "head and neck" (for the head-and-neck search only), "excision margin," "slnb," and "sentinel node." In addition, Web sites and databases of specific guideline developers that used systematic reviews as their evidentiary base and of producers of systematic reviews were also searched, using the same keywords and the same time periods.
■
Using Ovid, the medline and embase electronic databases were systematically searched for primary studies evaluating optimal excision margins and use of slnb in adults diagnosed with melanoma. The search ran from 2002 for head-and-neck populations, and from 2010 for trunk and extremity populations, through week 25 of 2017. The literature search strategy included keywords for identification of excision margins, slnb, head-and-neck melanoma populations, and trunk and extremity melanoma populations. In addition to the medline and embase database searches, reference lists of included systematic reviews and primary literature were scanned for potentially useful studies.
The titles and abstracts that resulted from the search were reviewed by one reviewer (LHS) and verified by a second (FCW). For items that warranted full-text review, 1 reviewer determined whether the inclusion and exclusion criteria were met. The list of proposed studies was verified by the Melanoma dsg.
# Development of Recommendations
The pebc produces evidence-based and evidence-informed guidance documents using the methods of the practice guidelines development cycle 12,13 . That process includes a systematic review; interpretation of the evidence by a Working Group, with production of draft recommendations; an internal review by content and methodology experts; and external reviews by Ontario clinicians and other stakeholders.
The pebc uses the agree ii framework 14 as its methodologic strategy for guideline development. The 23-item validated agree ii tool is designed to assess the methodologic rigour and transparency of guideline development.
# RESULTS
# Literature Search Results
The search for existing systematic reviews identified 126 possible reviews on optimal resection margins and use of slnb in melanoma patients. Four systematic reviews [15][16][17][18] were chosen for inclusion in the evidence base. One review evaluated narrow compared with wide excision margins in patients with melanoma of the trunk and extremities 18 ; the remaining three reviews assessed the use of slnb in melanoma of the trunk and extremities 15,16 and in melanoma of the head and neck 17 .
The systematic review of the primar y literature addressed outcomes of interest not covered by the four systematic reviews included in the evidence base. Where one or more systematic reviews were available, the search of the primary literature started from the end date of the search in the review or reviews. Of 1213 studies identified, 8 studies met the inclusion criteria. Table i summarizes the number of studies identified per research question, the melanoma location, and the Breslow thickness.
Details about the methodologic characteristics and clinical outcomes of the included trials can be found in the full guideline report at the Cancer Care Ontario Web site 26 .
It should be noted that the present guideline focuses on patients with clinically node-negative disease. The reason for that decision was that no data were available concerning the extent of wide local excision in patients who were node-positive or who had metastatic disease. The current standard of practice for patients with node-positive disease is a standard wide local excision. No data were found for patients with metastatic disease, and the extent of wide local excision should be discussed in a multidisciplinary team cancer conference on a case-by-case basis.
# Recommendation 1-Surgical Margins for Melanoma Located on the Trunk and Extremities
After initial excision or biopsy for melanoma located on the trunk and extremities, the radial excision margins, measured clinically from the edge of the melanoma or biopsy scar, should accord with the recommendations in
# Topic
# Melanoma location Breslow thickness Studies
# Primary excision margins Trunk and extremities
In situ None identified ≤1 mm 1 SR with meta-analysis 18,a 1 Case-control study 19 1.01-2 mm 1 SR with meta-analysis 18,a 2.01-4 mm 1 SR with meta-analysis 18,a 1 Randomized controlled trial 20,b ≥4.01 mm 1 SR with meta-analysis 18,a 1 Randomized controlled trial 20,b Head and neck In situ 1 Retrospective cohort 21,c ≤1 mm 2 Retrospective cohorts 21,22,c 1.01-2 mm 2 Retrospective cohorts 21,22,c 2.01-4 mm 2 Retrospective cohorts 21,22,c ≥4.01 mm 3 Retrospective cohorts 21,22,23,c Sentinal lymph node biopsy Trunk and extremities
# In situ
No studies identified ≤1 mm 2 SRs with meta-analyses 15,16 1 Randomized controlled trial 9,d 1.01-2 mm 1 SR with meta-analysis 15 2 Randomized controlled trials 9,24,d,e
2.01-4 mm 1 SR with meta-analysis 15 1 Randomized controlled trial 9,d ≥4.01 mm 1 SR with meta-analysis 15 1 Randomized controlled trial 9,d
# Qualifying Statements
The total wide local excision margin can be a composite margin from the biopsy and from the wide local excision.
For melanoma in situ, no rcts have evaluated appropriate surgical margins. In a single prospective study of pathologic margins for melanoma in situ, 86% of patients had clear pathologic margins with a 6 mm wide excision margin, and 98.9% of melanomas in situ were completely excised with a 9 mm surgical margin 27 . Consequently, some patients might require wider surgical margins of 1 cm to achieve clear pathologic margins; however, a 5 mm margin is suggested as the initial wider margin, especially in areas in which obtaining wider margins is challenging or in which wider margins would have an unacceptable effect on form or function.
Where possible, it might be desirable to take a wider margin (2 cm) for pT2 lesions, depending on tumour site and surgeon or patient preference, because the evidence concerning optimal excision margins in those cases (1 cm vs. 2 cm) is unclear.
# Key Evidence and Interpretation
A 2016 systematic review with meta-analysis that pooled six rcts compared narrow (1-2 cm) with wide (3-5 cm) excision margins for thin (≤2 mm) and thick (>2 mm) melanomas 18 . That meta-analysis by Wheatley et al. found that, for all patients (≤2 mm and >2 mm alike), os and recurrence-free survival (rfs) were not different when narrow compared with wide margins were used; however, melanoma-specific survival (mss) was improved with wide margins (3-5 cm) compared with narrow margins (1-2 cm) 18 . Subgroup analysis for thin and thick melanomas found no difference in os, mss, rfs, or locoregional recurrence when the melanoma depths (≤2 mm and >2 mm) were separately assessed 18 . Furthermore, the nodal status of the patients was unknown in most studies, thus potentially affecting mss results.
A new rct that was not included in the Wheatley et al. meta-analysis and that enrolled patients with thick melanomas (≥2 mm), found no difference in os when comparing 1 cm with 3 cm margins; however, a trend toward a reduction in mss was seen that did not reach statistical significance 20 . The nodal status of the patients in this new study was unknown, thus potentially affecting the results.
The Working Group considered both the Wheatley metaanalysis, previous margin studies, and the potential morbidity associated with a 3-5 cm margin for all melanomas when making its recommendations. In particular, for the meta-analysis data 18 , several factors were considered: patient numbers within each depth range; the fact that this analysis was the first to suggest that narrow margins were associated with worse mss; and the morbidity of larger margins, with the likelihood of more complex closures using skin grafts and flaps. The Working Group believes that more confirmatory data are needed before such a significant practice change (a >3 cm excision margin for all melanomas) can be recommended.
An additional case-control study that enrolled patients with thin melanomas (≤1 mm) who had experienced local recurrence found that median time to recurrence was significantly shorter for patients with margins less than 1 cm, but was not different when margins greater than 2 cm were compared with margins less than 2 cm 19 .
# Recommendation 2-Surgical Margins for Cutaneous Melanoma Located on the Head and Neck
After initial excision or biopsy for cutaneous melanoma located on the head and neck, the radial excision margins, measured clinically from the edge of the melanoma or biopsy scar, should accord with the recommendations in Table iii.
# Qualifying Statements
For pT2 melanomas, it could be desirable, where possible, to take a wider surgical margin (2 cm) depending on tumour site and surgeon or patient preference, because evidence concerning optimal excision margins is unclear.
The total wide local excision margin can be a composite margin from the biopsy and the wide local excision.
It is recognized, however, that wide margins might not always be possible, based on the location of the melanoma in relation to facial structures. When possible, wide margins should be used; however, they could be difficult to achieve when the melanoma is located on the eyelid, nose, lip, or ear.
For melanoma in situ, margin-controlled excision might provide tissue-sparing and improved tumour clearance in challenging locations such as near the eye, nose, lips, and ears.
# Key Evidence and Interpretation
Three low-quality retrospective cohort studies were identified to directly inform this recommendation for invasive (pT1-pT4) melanoma. All three reviewed the medical records of patients diagnosed with melanoma located on the head and neck and found no difference in survival rates [21][22][23] or recurrence rates 22,23 when margins of different sizes were compared.
No rcts were identified to inform a recommendation for melanoma in situ in the head and neck. The Working Group applied knowledge from the Mohs micrographic surgery literature, which indicates that margins of 9-10 mm might be needed to achieve a complete clearance rate in some patients with melanoma in situ, but that a 5 mm margin is suggested as the initial surgical margin 27,28 .
# Recommendation 3-SLNB for Melanoma Located on the Trunk and Extremities
Patients with a clinically node-negative stage i or ii melanoma 0.8 mm in thickness and located on the trunk or extremities should be given the opportunity to discuss slnb to provide staging and prognostic information (Table iv).
# Qualifying Statements
Sentinel lymph node biopsy should be performed only after a discussion of the options with the patient, when access to appropriate surgical, nuclear medicine, and pathology services is available.
The false-negative rate of slnb is lowest when more than 50 cases have been performed at the institution 29 .
A double dye technique with Tc-99 and blue dye (isosulfan or patent blue) increases the identification rate of the slns 30 .
It should be noted that, in mslt-i 29 , the subgroup for intermediate-thickness melanoma was 1.2-3.5 mm. We applied the mslt-i data to all intermediate-thickness melanomas 1-4 mm.
For patients with intermediate-thickness melanomas diagnosed with nodal metastases on pathology of the sentinel node or nodes, a 10-year mss benefit for slnb was reported on a planned subset analysis; however, os was not reported.
Sentinel lymph node biopsy should be discussed with patients to identify those eligible for adjuvant therapy and for enrolment into clinical trials.
Ideally, for best accuracy, slnb is performed at the same time as the wide local excision of the primary melanoma. Sentinel lymph node biopsy is less reliable or might fail when performed as a separate operation for a patient already having had wide local excision and repair with any flap (with the exception of an advancement flap) or skin graft.
# Key Evidence and Interpretation
The 10-year follow-up of mslt-i 9 was published after the 2010 guideline. That rct enrolled patients with thin (<1.2 mm), intermediate (1.2-3.5 mm), and thick (>3.5 mm) melanomas, but the 10-year follow-up publication reported only on the patients with intermediate and thick melanomas. Patients were randomized to a wide excision (2-3 cm) alone (observation group) or wide excision (2-3 cm) plus slnb (biopsy group) 9 . Patients in the biopsy group with a positive slnb underwent immediate lymphadenectomy; patients in the observation group received nodal observation and lymphadenectomy only if they later presented with nodal relapse 9 . The mslt-i update reported on disease-free survival (dfs) and mss, but not os. The 10-year dfs was significantly higher in the slnb group than in the observation group whether patients had intermediate or thick melanomas (p = 0.01 and p = 0.03 respectively) 9 . Overall, the 10-year mss was not different between the groups with either intermediate or thick melanomas 9 . However, for patients with nodal metastases, the 10-year mss on a planned subset analysis was significantly higher for patients with intermediate-thickness melanomas in the slnb group than for those in the observation group (62.1% ± 4.8% vs. 41.5% ± 5.6%) 9 ; the same case did not hold for the patients with thick melanomas.
Other studies reviewed for recommendation 3 included a meta-analysis that considered studies of multiple Breslow thicknesses, but because of missing data, could pool data only for thick melanomas (>4.01 mm), finding that os was reduced in patients having positive slns compared with patients having negative slns 15 . A second meta-analysis included only studies involving patients diagnosed with thin melanomas (≤1 mm), finding that, overall, 4.5% of those patients had positive slns 16 . Melanoma thickness of 0.75 mm or greater, Clark level 4 or 5, high mitotic rate (≥1 mitosis/ mm 2 ), ulceration, and microsatellites were predictors of sln metastases, with the rates of sln positivity being 8.8%, 7.3%, 8.8%, 5.8%, and 26.6% for each predictor respectively 16 . Lastly, based on the systematic review with metaanalysis from Cordeiro et al. 16 in patients with thin melanomas, any or some combination of a melanoma thickness of 0.75 mm or greater, Clark level 4 or 5, a high mitotic rate, ulceration, or microsatellites indicated a higher chance for sln positivity, and physicians should therefore discuss slnb with affected patients. For guideline recommendation 3, the 8th edition of the American Joint Committee on Cancer staging manual for melanoma was used 31 .
# Recommendation 4-SLNB for Cutaneous Melanoma Located on the Head and Neck
Patients with a clinically node-negative stage i or ii cutaneous melanoma more than 0.8 mm in thickness and located on the head and neck should be given the opportunity to discuss slnb to provide staging and prognostic information (Table v).
# Qualifying Statements
Sentinel lymph node biopsy should be performed only after a discussion of the options with the patient, when access to appropriate surgical, nuclear medicine, and pathology services is available.
The false-negative rate of slnb is lowest when more than 50 cases have been performed at an institution 29 .
A double dye technique with Tc-99 and blue dye (isosulfan or patent blue) increases the identification rate of the slns 30 .
Sentinel lymph node biopsy should be discussed with patients to identify those eligible for adjuvant therapy and for enrolment into clinical trials.
Ideally, for greatest accuracy, slnb should be performed at the same time as the wide local excision of the primary melanoma. Sentinel lymph node biopsy is less reliable or might fail when performed as a separate operation for a patient already having had a wide local excision and repair with any flap (with the exception of an advancement flap) or skin graft 32,33 .
# Key Evidence and Interpretation
One systematic review 17 and one diagnostic cohort study 25 assessed the diagnostic performance of slnb for melanoma located on the head and neck and reported high false-negative rates: 20.4% and 4.8% respectively.
It is now known that mslt-i 9 included 334 patients with primary melanomas located on the head and neck (Faries M. Personal communication. 2 June 2016). Although headand-neck patients were not separately analyzed, 10-year dfs for all enrolled patients was significantly higher in the slnb group than in the observation group for patients with intermediate or thick melanomas 9 . Additionally, in patients with intermediate-thickness melanomas and nodal metastases, a planned subset analysis found that 10-year mss was significantly higher in the slnb group than in the observation group 9 . However, mss was not improved for patients with thick melanomas.
# Recommendation 5-CLND Compared with Observation at the Time of SLN Positivity
Patients with sln metastasis should be considered for nodal observation with ultrasonography rather than for clnd. Monitoring of the affected nodal basin with ultrasonography and clinical exam will be required, at a minimum, every 4-6 months for the first 2 years and every 6 months from year 3 to year 5. Suspicion of a nodal recurrence in a lymph node basin includes any 2 of these observations: lymph node length-to-depth ratio less than 2; hypoechoic centre; and failure to identify a nodal hilar vessel or focal rounded area of low-level echoes with increased vascularity in that area, or both. Suspicion of a nodal recurrence by ultrasonography should be confirmed with a biopsy of the suspicious lymph node. If the biopsy shows melanoma, the patient should be re-staged before any further surgery. For certain patients with a positive sln, a clnd rather than ultrasound monitoring might still be the best option for local control, but the choice should be discussed by a multidisciplinary team.
# Qualifying Statements
In mslt-ii 11 , one third of the patients had melanoma meta stases greater than 1 mm in diameter, and 72% of ≤1.0 mm If melanoma is ≥0.8 mm in thickness, is Clark level 4 or 5, has a high mitotic rate (≥1 mitosis/mm 2 ), ulceration, or microsatellites, the physician should discuss SLNB with the patient. Biopsy might provide a melanomaspecific survival benefit if the sentinel node contains melanoma metastases. Such patients might also benefit from adjuvant therapy or entry into adjuvant clinical trials (or both).
pT2 and pT3
1.01-2.0 mm 2.01-4. 0mm
For these patients, SLNB is recommended to provide locoregional control and to identify individuals who might benefit from adjuvant therapy or entry into adjuvant clinical trials (or both). Biopsy might provide a melanomaspecific survival benefit if the sentinel node contains melanoma metastases. pT4 ≥4.01 mm Physicians should discuss SLNB with these patients. Biopsy will provide prognostic information. If the sentinel node contains melanoma metastases, removal might provide locoregional control, but not a melanoma-specific survival benefit. These patients might also benefit from adjuvant therapy or entry into adjuvant clinical trials (or both). the patients had 1 sentinel node with metastases. A subgroup evaluation of patients with a greater disease burden (maximal tumour diameter > 1 mm) did not indicate that a benefit from clnd was more likely in high-risk groups (>1 mm) than in low-risk groups (≤1 mm) 11 . Patients for whom clnd might be a better option than nodal observation with ultrasonography are ■ those with extensive snl metastasis in which clnd would provide regional control. ■ those unlikely to comply with an intensive surveillance protocol. ■ those treated at centres in which radiologists are not comfortable performing serial surveillance ultrasonography examinations.
Although guideline 5 is specific to the trunk and extremities, the same recommendation can be applied to melanomas of the head and neck and their respective drainage basins.
# Key Evidence and Interpretation
Two randomized trials, mslt-ii 11 and decog-slt 10 , evaluated the utility of clnd compared with observation through frequent nodal ultrasonography, with dissection only in melanoma patients with progression of nodal disease. In mslt-ii 11 , patients with melanoma metastases in a sln were randomized to either nodal observation (every 4 months for 3 years and then every 6 months for 2 years for a total of 5 years of nodal observation) or to immediate clnd. Patients with biopsy-proven isolated nodal recurrence underwent a therapeutic lymph node dissection. Median follow-up was 43 months. In a planned subset analysis, no patients were found to benefit from immediate clnd. Most patients had low-volume nodal tumour burden (1 positive sln; mean diameter of nodal metastasis: 1.1 mm). The 3-year mss was 86% ± 1.3% in the clnd group and 86% ± 1.2% the observation group (p = 0.42). The 3-year dfs rate was slightly higher in the clnd group (p = 0.05), but the investigators suggested caution about the significance of that result based on the lack of significance of the mss, which was the primary outcome. Overall, some regional control and prognostic value can be derived from clnd, but at the expense of increased adverse events-in particular, lymphedema and a potential delay to adjuvant therapy. The nonsignificant difference in mss and the increase in adverse events in the clnd group indicate that clnd is not recommended for low-volume nodal tumour burden and does not offer a survival benefit. Whether a clnd should or should not be recommended with larger-volume disease in the slns is unclear; however, on subset analysis, no patients (including those with a higher volume of melanoma metastases) benefited from clnd, which led to recommendation 5. Similarly, the decog-slt trial 10 found no difference in distant metastasis-free survival, os, or rfs when patients with positive slns who received clnd were compared with patients who were observed with nodal ultrasonography and computed tomography imaging of the affected basin. Median follow-up for the trial was 35 months 10 .
# DISCUSSION
In this systematic review, we summarize the last 8 years of surgical melanoma trials for patients with head-andneck, truncal, and extremity primaries. In particular, we focus on the extent of wide local excision for the primary melanoma, which patients should be offered a slnb, and which patients with melanoma metastases in their sln should undergo clnd.
One of the most discussed papers identified during this update was the Wheatley et al. systematic review and metaanalysis 18 . The findings from that study could substantially change practice with respect to wide local excision margins for patients with melanoma. The Working Group members interpreted those data with extreme caution. The meta-analysis found that, for all patients with melanoma, os, locoregional recurrence, and rfs were not different when narrow margins (1-2 cm) were compared with wide margins (3-5 cm), but that mss was improved with wide margins 18 . Using Bayesian likelihood plots, the systematic review reported a high probability that narrow margins were worse than wide margins for os, mss, rfs, and locoregional recurrence 18 , providing the first-ever published data indicating that narrow margins are not safe and refuting clinical practice guidelines from worldwide organizations. When making its recommendations, the Working Group considered the Wheatley meta-analysis, prior margin studies, and the potential morbidity associated with a 3-5 cm margin for all melanomas. In particular, for the meta-analysis data 18 , we considered patient numbers within each depth range; the fact that the Wheatley analysis is the first to suggest that mss is worse with narrow margins; and the morbidity of larger margins, with the likelihood of more complex closures requiring skin grafts and flaps. The Working Group believes that more confirmatory data are needed before such a significant practice change (a >3 cm excision margin for all melanomas) can be recommended. The main change that was made to the original guideline was to increase the margin recommendation for melanomas of 2.0-4.0 mm thickness to 2 cm from 1-2 cm. The Working Group strongly supports a rct comparing margins of 1 cm, 2 cm, and 3 cm.
The Working Group also made changes to the margin recommendations for melanoma in situ. The original recommendation of a 5 mm margin was adopted from the Australia-New Zealand guideline developers 34 . Two factors led to a change in the recommendation: a recent prospective study of pathologic margins for melanoma in situ, which found that 86% of patients had clear pathologic margins with a 6 mm wide excision margin and that 98.9% of melanomas in situ were completely excised with a 9 mm surgical margin 27 ; and the clinical experience of the group. The Working Group now suggests a 5 mm to 1 cm margin for melanoma in situ, although a 5 mm margin is recommended for the initial excision, and a 1 cm margin is recommended only if the margins are positive after the initial excision.
With respect to the recommendations for slnb, the Working Group recommends that all patients with a melanoma greater than 0.8 mm in thickness and with no clinical evidence of nodal metastasis should be given the opportunity to discuss slnb. Sentinel lymph node biopsy is performed to provide information for staging and prognosis, and to identify patients who could benefit from adjuvant therapy or clinical trials. Although the mslt-i trial did not report on os at 10 years, it reported a mss benefit for patients with intermediate-thickness melanomas and nodal metastases, and in a planned subset analysis, improved locoregional control for patients with melanomas of 1.2 mm to more than 3.5 mm thickness on the trunk and extremities or head and neck. Some controversy attends that result because, overall, the trial was negative and no os was reported. For patients with a melanoma thicker than 4.0 mm, slnb provides locoregional control, and patients should still be given the opportunity to discuss the role of slnb for prognostic information, locoregional control, and consideration of adjuvant therapy [35][36][37] .
Lastly, based on the Cordeiro systematic review with meta-analysis 16 , patients with thin melanomas [≥0.75 mm (now 0.8 mm with the new American Joint Committee on Cancer staging)] that are Clark level 4 or 5 or have high mitotic rates, ulceration, or microsatellites have a higher chance of sln positivity, and thus, physicians should discuss slnb with them. When discussing melanoma located on the head and neck alone, the available data indicate a higher chance for a false negative from the slnb 17,25 . To help minimize the number of false negatives, the Working Group suggests performing the slnb in a high-volume centre (>50 cases) 29 ; using a dual tracer technique with Tc-99 and blue dye to improve the sln detection rate 30 ; and using integrated single-photon emission computed tomography-computed tomography, which might improve the localization of slns in head and neck areas 38 .
Until the publication of the mslt-ii trial, the value of clnd in patients with sln metastasis had been inconclusive and controversial. The mslt-ii trial provided sufficient data to determine that, in patients with sln metastasis, clnd, compared with nodal observation, provided no statistically significant survival benefit 11 . The Working Group acknowledges that most patients enrolled in the trial had a low-volume nodal tumour burden; however, a subgroup analysis of patients with a greater disease burden (maximal tumour diameter > 1 mm) did not indicate that a benefit of clnd was more likely to accrue in high-risk groups than in low-risk groups 11 . Although clnd provided some regional control and improved staging, the Working Group weighed those data against the increased potential for adverse events-in particular, lymphedema and a possible delay to adjuvant therapy-and determined that the regional control and improvements in staging did not outweigh the increased possibility of complications and morbidity associated with clnd. The Working Group consequently recommends that all patients with melanoma metastasis in their slns be considered for nodal observation. Those guidelines are similar to the 2017 recommendations from the American Society of Clinical Oncology concerning slns and the management of regional lymph nodes in melanoma 39,40 .
# INTERNAL AND EXTERNAL REVIEW OF THE PRACTICE GUIDELINE
The pebc Report Approval Panel reviewed the draft systematic review and practice guideline and provided feedback.
The draft systematic review and practice guideline were distributed to health care providers in the province of Ontario. The results of those two sources of feedback can be found in the full guideline report at the Cancer Care Ontario Web site 26 .
# REVIEW AND UPDATE
Practice guidelines developed by the pebc are reviewed and updated regularly. Please visit the Cancer Care Ontario Web site (https://www.cancercareontario.ca/ en) for the full evidence-based series report 26 and any subsequent updates.
# ACKNOWLEDGMENTS
The authors thank the members of the Melanoma dsg for their contributions to the development of this practice guideline. DM provided guidance on slnb as a standard of care.
# CONFLICT OF INTEREST DISCLOSURES
We have read and understood Current Oncology's policy on disclosing conflicts of interest, and we declare that we have none.
# AUTHOR AFFILIATIONS
| None | None |
4bbbdc6c6db4c1256b35275269381103b22cc445 | cma | None | This guidance is intended for healthcare providers. It is based on known evidence as of April 18, 2023. Adults and children with inflammatory bowel disease (IBD) may require immune modulating therapies for disease control. Being on immune therapies for IBD may increase the risk for some infections, but the currently available information does not show an increased risk of infection or development of COVID-19 in individuals with IBD or those who are on the standard therapies. 1 Active IBD and high-dose steroids (>20 mg/day) are two of the biggest risk factors for infection and effective treatment of IBD with medical therapy has been shown to lower infectious risk. 2,3 Because of limited data, it is unknown whether there are any significant differences in COVID-19 vaccine effectiveness or safety in the diverse group of people with IBD on immunosuppressant therapies compared to those included in vaccine trials. The degree of response to the vaccine may be affected by the degree of immunosuppression which will depend on the individual patient's underlying disease progression (and co-morbidities) and the immunosuppressive therapies required to control their disease and/or symptoms. As patients wait for their vaccine administration, it would be important to counsel patients not to hold or stop their chronic immunosuppressant therapy without direct consultation with their prescriber.# Is COVID-19 immunization recommended for people with inflammatory bowel disease?
COVID-19 vaccines should be encouraged for patients with inflammatory bowel disease and are not contraindicated, including those who have had COVID-19 infection. This recommendation is based on the following review:
- Canadian Association of Gastroenterology highlights evidence that people with IBD who have COVID- 19 (including those on long-term biologics or non-steroid immunomodulatory therapies) may not have an increased risk of severe outcomes (hospitalization or death) compared to COVID-19 patients without IBD. However, recent corticosteroid use may be associated with a higher risk of severe COVID-19 outcomes. 4 - Although the majority of people with IBD who are immunosuppressed were excluded from clinical trials of the COVID-19 vaccines, the American College of Gastroenterology 1 , Canadian Association of Gastroenterology 4 and British Society of Gastroenterology 5 have all released position statements strongly supporting the use of COVID-19 vaccination in this population.
- Experts agree that the potential benefits and anticipated desirable effects of COVID-19 vaccination outweigh the potential harms in persons with IBD who take immunosuppressing/immunomodulating therapy. 1,4,5 Clinical Guidance on COVID-19 Vaccines for Persons with Inflammatory Bowel Disease Updated: April 18, 2023 While data specific to the safety and efficacy of COVID-19 vaccines in people who take immunosuppressant or immunomodulating therapies is currently limited, there are data to suggest that the currently available COVID-19 vaccines have efficacy. 6 The authors of this guidance agree that the benefits of COVID-19 immunization with these vaccines outweigh any theoretical risks of immunization.
Is COVID-19 immunization efficacious and safe for patients with inflammatory bowel disease?
Individuals who are treated with immunosuppressant and immunomodulating therapies were excluded from the clinical trials of all of the COVID-19 vaccines. Post-vaccine studies have shown attenuated immunogenicity and lower antibody concentrations for patients with IBD taking infliximab, but seroconversion rates were higher after a second dose of the vaccine. 12 There is one study that suggests that a third dose of COVID-19 vaccine in immunocompromised patients can increase antibody levels. 12 Small studies on third doses of the mRNA COVID-19 vaccines have shown that immunogenicity (immunity measured in the blood) may increase with a third dose. 13 Safety data for people with inflammatory diseases taking immunosuppressive medications are available in observational studies. The frequency and severity of adverse events following vaccination with an mRNA COVID-19 vaccine were comparable to that of non-immunosuppressed individuals in these studies and what was reported in clinical trials. Safety data in these populations following vaccination with a viral vector vaccine is not available. The safety of a third mRNA dose is unknown at this time, but in these small studies reactions were found to be similar to that of prior doses.
Informed consent should include discussion about the possibility that individuals who are immunosuppressed may have a diminished immune response to any of the COVID-19 vaccines. If the patient has an autoimmune disease as well, informed consent should include discussion about the emerging evidence of the safety of mRNA COVID-19 vaccines in these populations. However, they should also be reassured that expert consensus is that benefits of immunization outweigh the risks. 1,4, Safety and efficacy considerations for inflammatory bowel disease patients treated with immune modulating therapies are as follows:
- In IBD patients taking immunosuppressive drugs, including biologics and small molecule inhibitors, the key concerns are related to the theoretical risk of suboptimal vaccine responses rather than vaccine side effects. 1 - Canadian Association of Gastroenterology suggests that patients with inflammatory bowel disease (IBD) may have a lower immune response to certain vaccines. However, inactivated (or non-live) vaccines are safe with no serious adverse events in people with IBD regardless of whether or not they are on immunosuppressive therapy. 15 - There are currently no known factors that would predispose these patients with inflammatory bowel disease to adverse events associated with the vaccines beyond those experienced by the general population. At the time of Health Canada's authorization, there were no known serious warning signals or precautions associated with these vaccines specifically in patients on immunosuppressants, apart from considerations about potential reduced efficacy. - As immune response to COVID-19 immunization is unknown for those taking immunosuppressant or immunomodulating therapy, patients who take these therapies and who receive the COVID-19 vaccine should continue to closely follow public health recommendations including social distancing, regular hand washing and cleaning/disinfection.
# Are there any specific contraindications or exceptions for patients with inflammatory bowel disease?
Individuals who have had a severe allergic reaction to an ingredient of one type of COVID-19 vaccine are still able to receive future doses of the other type of vaccine. 17 BCCDC has a list of the individual components and their purpose in the vaccines. For a complete list of components in the vaccine, consult the vaccine monographs found at: www.bccdc.ca/health-info/diseases-conditions/covid-19/covid-19-vaccine/vaccines-for-covid-19.
For individuals with a history of anaphylactic reaction to a previous dose of an mRNA COVID-19 vaccine, re-vaccination (i.e., administration of a subsequent dose in the series when indicated) may be offered with the same vaccine or the same mRNA platform if a risk assessment deems that the benefits outweigh the potential risks for the individual and if informed consent is provided. Prior to revaccination, consultation with an allergist or another appropriate physician (e.g., Medical Health Officer) is advised. If re-vaccination is going ahead, vaccine administration should be done in a controlled setting with expertise and equipment to manage anaphylaxis, with an extended period of observation of at least 30 minutes after re-vaccination.
Health Canada continues to monitor any adverse events following immunization through their post-authorization surveillance process.
Other than allergy, there are no specific contradictions or exceptions for people with IBD apart from the efficacy and safety considerations outlined above.
Currently, it is recommended that COVID-19 vaccines can be given concomitantly with, or any time before or after any other indicated vaccine including the seasonal influenza vaccine. Are there specific recommendations or considerations for safe and/or most effective administration?
One of the general principles for immunization of immunocompromised patients is to vaccinate when maximum immune response can be anticipated. 22 For patients who are stabilized on their immunosuppressant therapy, finding the optimal timing relative to the COVID-19 dosing schedule is challenging. Delaying some therapies may risk destabilizing disease control. Medication timing recommendations are as follows: o For patients on rituximab or ocrelizumab, COVID-19 immunization should ideally be timed four to five months after their last infusion and two to four weeks prior to their next infusion, when possible, in order to optimize vaccine response. However, in patients who require immediate infusion or who are unable to optimize timing of infusion product and vaccine, it is likely more important to have the COVID vaccine as soon as possible than it is to delay based on timing of B-cell therapy.
- For patients on prednisone 20mg/day or higher or equivalents, consider waiting until the prednisone dose is tapered to below 20mg/d to receive both vaccine doses, providing that tapering makes clinical sense for the patient at that time and providing that the time needed to taper down is limited. It is likely more important to have the COVID vaccine as soon as possible than it is to delay based on timing of steroid therapy. Pediatric patients on high-dose steroids should consult with their pediatric rheumatologist to decide on the best time to receive the vaccine. 26
# Authors | This guidance is intended for healthcare providers. It is based on known evidence as of April 18, 2023. Adults and children with inflammatory bowel disease (IBD) may require immune modulating therapies for disease control. Being on immune therapies for IBD may increase the risk for some infections, but the currently available information does not show an increased risk of infection or development of COVID-19 in individuals with IBD or those who are on the standard therapies. 1 Active IBD and high-dose steroids (>20 mg/day) are two of the biggest risk factors for infection and effective treatment of IBD with medical therapy has been shown to lower infectious risk. 2,3 Because of limited data, it is unknown whether there are any significant differences in COVID-19 vaccine effectiveness or safety in the diverse group of people with IBD on immunosuppressant therapies compared to those included in vaccine trials. The degree of response to the vaccine may be affected by the degree of immunosuppression which will depend on the individual patient's underlying disease progression (and co-morbidities) and the immunosuppressive therapies required to control their disease and/or symptoms. As patients wait for their vaccine administration, it would be important to counsel patients not to hold or stop their chronic immunosuppressant therapy without direct consultation with their prescriber.# Is COVID-19 immunization recommended for people with inflammatory bowel disease?
COVID-19 vaccines should be encouraged for patients with inflammatory bowel disease and are not contraindicated, including those who have had COVID-19 infection. This recommendation is based on the following review:
• Canadian Association of Gastroenterology highlights evidence that people with IBD who have COVID- 19 (including those on long-term biologics or non-steroid immunomodulatory therapies) may not have an increased risk of severe outcomes (hospitalization or death) compared to COVID-19 patients without IBD. However, recent corticosteroid use may be associated with a higher risk of severe COVID-19 outcomes. 4 • Although the majority of people with IBD who are immunosuppressed were excluded from clinical trials of the COVID-19 vaccines, the American College of Gastroenterology 1 , Canadian Association of Gastroenterology 4 and British Society of Gastroenterology 5 have all released position statements strongly supporting the use of COVID-19 vaccination in this population.
• Experts agree that the potential benefits and anticipated desirable effects of COVID-19 vaccination outweigh the potential harms in persons with IBD who take immunosuppressing/immunomodulating therapy. 1,4,5 Clinical Guidance on COVID-19 Vaccines for Persons with Inflammatory Bowel Disease Updated: April 18, 2023 While data specific to the safety and efficacy of COVID-19 vaccines in people who take immunosuppressant or immunomodulating therapies is currently limited, there are data to suggest that the currently available COVID-19 vaccines have efficacy. 6 The authors of this guidance agree that the benefits of COVID-19 immunization with these vaccines outweigh any theoretical risks of immunization.
Is COVID-19 immunization efficacious and safe for patients with inflammatory bowel disease?
Individuals who are treated with immunosuppressant and immunomodulating therapies were excluded from the clinical trials of all of the COVID-19 vaccines. [7][8][9][10][11] Post-vaccine studies have shown attenuated immunogenicity and lower antibody concentrations for patients with IBD taking infliximab, but seroconversion rates were higher after a second dose of the vaccine. 12 There is one study that suggests that a third dose of COVID-19 vaccine in immunocompromised patients can increase antibody levels. 12 Small studies on third doses of the mRNA COVID-19 vaccines have shown that immunogenicity (immunity measured in the blood) may increase with a third dose. 13 Safety data for people with inflammatory diseases taking immunosuppressive medications are available in observational studies. The frequency and severity of adverse events following vaccination with an mRNA COVID-19 vaccine were comparable to that of non-immunosuppressed individuals in these studies and what was reported in clinical trials. Safety data in these populations following vaccination with a viral vector vaccine is not available. The safety of a third mRNA dose is unknown at this time, but in these small studies reactions were found to be similar to that of prior doses.
Informed consent should include discussion about the possibility that individuals who are immunosuppressed may have a diminished immune response to any of the COVID-19 vaccines. If the patient has an autoimmune disease as well, informed consent should include discussion about the emerging evidence of the safety of mRNA COVID-19 vaccines in these populations. However, they should also be reassured that expert consensus is that benefits of immunization outweigh the risks. 1,4,[14][15][16] Safety and efficacy considerations for inflammatory bowel disease patients treated with immune modulating therapies are as follows:
• In IBD patients taking immunosuppressive drugs, including biologics and small molecule inhibitors, the key concerns are related to the theoretical risk of suboptimal vaccine responses rather than vaccine side effects. 1 • Canadian Association of Gastroenterology suggests that patients with inflammatory bowel disease (IBD) may have a lower immune response to certain vaccines. However, inactivated (or non-live) vaccines are safe with no serious adverse events in people with IBD regardless of whether or not they are on immunosuppressive therapy. 15 • There are currently no known factors that would predispose these patients with inflammatory bowel disease to adverse events associated with the vaccines beyond those experienced by the general population. [7][8][9][10][11] At the time of Health Canada's authorization, there were no known serious warning signals or precautions associated with these vaccines specifically in patients on immunosuppressants, apart from considerations about potential reduced efficacy. [7][8][9][10][11] • As immune response to COVID-19 immunization is unknown for those taking immunosuppressant or immunomodulating therapy, patients who take these therapies and who receive the COVID-19 vaccine should continue to closely follow public health recommendations including social distancing, regular hand washing and cleaning/disinfection.
# Are there any specific contraindications or exceptions for patients with inflammatory bowel disease?
Individuals who have had a severe allergic reaction to an ingredient of one type of COVID-19 vaccine are still able to receive future doses of the other type of vaccine. 17 BCCDC has a list of the individual components and their purpose in the vaccines. For a complete list of components in the vaccine, consult the vaccine monographs found at: www.bccdc.ca/health-info/diseases-conditions/covid-19/covid-19-vaccine/vaccines-for-covid-19.
For individuals with a history of anaphylactic reaction to a previous dose of an mRNA COVID-19 vaccine, re-vaccination (i.e., administration of a subsequent dose in the series when indicated) may be offered with the same vaccine or the same mRNA platform if a risk assessment deems that the benefits outweigh the potential risks for the individual and if informed consent is provided. Prior to revaccination, consultation with an allergist or another appropriate physician (e.g., Medical Health Officer) is advised. If re-vaccination is going ahead, vaccine administration should be done in a controlled setting with expertise and equipment to manage anaphylaxis, with an extended period of observation of at least 30 minutes after re-vaccination.
Health Canada continues to monitor any adverse events following immunization through their post-authorization surveillance process.
Other than allergy, there are no specific contradictions or exceptions for people with IBD apart from the efficacy and safety considerations outlined above.
Currently, it is recommended that COVID-19 vaccines can be given concomitantly with, or any time before or after any other indicated vaccine including the seasonal influenza vaccine. [18][19][20][21] Are there specific recommendations or considerations for safe and/or most effective administration?
One of the general principles for immunization of immunocompromised patients is to vaccinate when maximum immune response can be anticipated. 22 For patients who are stabilized on their immunosuppressant therapy, finding the optimal timing relative to the COVID-19 dosing schedule is challenging. Delaying some therapies may risk destabilizing disease control. [23][24][25] Medication timing recommendations are as follows: o For patients on rituximab or ocrelizumab, COVID-19 immunization should ideally be timed four to five months after their last infusion and two to four weeks prior to their next infusion, when possible, in order to optimize vaccine response. However, in patients who require immediate infusion or who are unable to optimize timing of infusion product and vaccine, it is likely more important to have the COVID vaccine as soon as possible than it is to delay based on timing of B-cell therapy.
o For patients on prednisone 20mg/day or higher or equivalents, consider waiting until the prednisone dose is tapered to below 20mg/d to receive both vaccine doses, providing that tapering makes clinical sense for the patient at that time and providing that the time needed to taper down is limited. It is likely more important to have the COVID vaccine as soon as possible than it is to delay based on timing of steroid therapy. Pediatric patients on high-dose steroids should consult with their pediatric rheumatologist to decide on the best time to receive the vaccine. 26
# Authors
| None | None |
085e87e2ba5a26de742e7ae00a0bf182eec30120 | cma | None | Minimize serious illness and overall deaths while preserving health system capacity; Reduce transmission to protect high risk populations. Refer to NACI's methods for further information on NACI's recommendation development process.To operationalize guidance for this population, NACI has reviewed several sources to identify which pediatric populations who are immunocompromised would likely benefit most from an additional dose of COVID-19 vaccine at this time. These sources have included evidence available in published and grey literature, the CIG chapter on Immunization of Immunocompromised Persons, and eligibility criteria for additional doses of COVID-19 vaccine in pediatric populations who are immunocompromised currently being used by other jurisdictions. In addition, the clinical expertise of committee members informed the definition of pediatric populations who are immunocompromised for the recommendations outlined in this statement.Canada is currently facing an Omicron wave of the pandemic, and this variant is partially evasive to previous immunity conferred by COVID-19 vaccine or a previous SARS-CoV-2 infection. Numerous reports have shown that mRNA COVID-19 vaccines offer reduced protection against infection with the Omicron variant, and modeling estimates anticipate a fast trajectory to the peak of the Omicron wave, with substantial breakthrough cases in individuals who have received 2 or 3 doses of mRNA and other COVID-19 vaccines (1) . Canadian children 5 to 11 years of age are facing record-high incidence rates of COVID-19 (1) . While additional data are required to fully determine the disease severity caused by the Omicron variant in specific populations including unvaccinated individuals, young children (<5 years of age) and the elderly, several reports and emerging studies are reporting reduced frequencies of severe outcomes from COVID-19 for the Omicron variant compared to the Delta variant (2)(3)(4) . For the most up to date information on the epidemiology of COVID-19 in Canada, please refer to the COVID-19 daily epidemiology update.Consistent with previous SARS-CoV-2 variants of concern (VOC), children 5 to 11 years of age remain at low risk of severe outcomes from the Omicron variant. While COVID-19 associated hospitalizations among children 5 to 11 years of age have increased, which is consistent with all# PREAMBLE
The National Advisory Committee on Immunization (NACI) is an External Advisory Body that provides the Public Health Agency of Canada (PHAC) with independent, ongoing and timely medical, scientific, and public health advice in response to questions from PHAC relating to immunization.
In addition to burden of disease and vaccine characteristics, PHAC has expanded the mandate of NACI to include the systematic consideration of programmatic factors in developing evidence based recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels.
The additional factors to be systematically considered by NACI include: economics, ethics, equity, feasibility, and acceptability. Not all NACI Statements will require in-depth analyses of all programmatic factors. While systematic consideration of programmatic factors will be conducted using evidence-informed tools to identify distinct issues that could impact decision-making for recommendation development, only distinct issues identified as being specific to the vaccine or vaccine-preventable disease will be included.
This statement contains NACI's independent advice and recommendations, which are based upon the best current available scientific knowledge. This document is being disseminated for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph. Recommendations for use and other information set out herein may differ from that set out in the product monographs of the Canadian manufacturers of the vaccines. Manufacturer(s) have sought approval of the vaccines and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of PHAC's Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.
# INTRODUCTION
On December 3, 2021, NACI published updated guidance on booster COVID-19 vaccine doses in Canada and reaffirmed previous NACI guidance on the recommended use of COVID-19 vaccines in children 5 to 11 years of age. Since this guidance:
- Additional evidence on the transmissibility and disease severity of the Omicron variant has emerged; Additional safety surveillance data on the 2-dose primary series of Pfizer-BioNTech Comirnaty (10 mcg) in children 5 to 11 years of age has been released, providing preliminary estimates on the risk of myocarditis/pericarditis in children 5 to 11 years of age; Many children aged 5 to 11 years who are moderately to severely immunocompromised will have completed their 2-dose series and will be seeking guidance on whether additional doses are required.
The Pfizer-BioNTech Comirnaty mRNA COVID-19 vaccine is currently the only COVID-19 vaccine authorized in Canada for use in pediatric populations under 12 years of age. Pfizer-BioNTech was approved for children 5 to 11 years of age on November 19, 2021 as a two-dose primary series. The Pfizer-BioNTech Comirnaty COVID-19 vaccine previously has been authorized by Health Canada for individuals 12 years of age and older, using a 30 mcg dose (December 9, 2020, individuals 16 years of age and older; May 18 2021, individuals 12 to 15 years of age).
The Pfizer-BioNTech Comirnaty COVID-19 vaccine in Canada is approved for use as a 3-dose primary series in individuals who are immunocompromised. As per the product monograph (for both 10 mcg and 30 mcg doses), persons who are immunocompromised, including individuals receiving immunosuppressant therapy, may have a diminished immune response to the vaccine and in these individuals, a third dose may be considered as part of the primary series.
NACI has reviewed the evolving situation and evidence and has updated evidence-informed recommendations on the use of COVID-19 vaccines in pediatric populations.
# METHODS
On January 11, 2022, NACI reviewed the recent evidence on COVID-19 vaccines for pediatric populations including real-world safety surveillance data from the United States (US) and Canada on the Pfizer-BioNTech Comirnaty (10 mcg) vaccine in children 5 to 11 years of age. NACI approved their updated recommendations on the use of COVID-19 vaccines in pediatric populations 5 to 11 years of age on January 19, 2022.
For further information on NACI's recommendations on the use of COVID-19 vaccines, please refer to the COVID-19 vaccine chapter in the Canadian Immunization Guide (CIG).
NACI's recommendations are aligned with the goals of the Canadian COVID-19 Immunization Program, updated in October 2021: To enable as many Canadians as possible to be immunized as quickly as possible against COVID-19, while ensuring that high risk populations be prioritized; other age groups in Canada during the Omicron wave (1) , the proportion of COVID-19 cases among children 5 to 11 years of age that have been hospitalized or admitted to ICU remains low (5) . Indirect evidence from adolescent populations in the US suggests risk of severe outcomes may be further decreased by COVID-19 vaccination. In a recent study from the CDC conducted before the arrival of the Omicron variant, among hospitalized patients 12 to 18 years of age, two doses of the Pfizer-BioNTech Comirnaty COVID-19 vaccine (30 mcg) were highly effective at preventing COVID-19-related hospitalization and ICU admission or the need for life support (6) .
There is limited evidence on clinical risk factors for severe COVID-19 disease in pediatric populations (7) . Children 5 to 11 years of age at increased risk for severe outcomes may include children who are obese, children who are medically fragile/have medical complexities, children with more than one comorbidity (8) , children with neurological disorders (9,10) , and children with immune dysregulation associated with Down Syndrome (8) and other immunocompromising conditions.
For additional information, please refer to the Recommendation on the use of Pfizer-BioNTech COVID-19 vaccine (10 mcg) in children 5 to 11 years of age.
# MIS-C, post-COVID condition and myocarditis following COVID-19
Children and adolescents infected with SARS-CoV-2 are at risk of multiple inflammatory syndrome in children (MIS-C), a rare but serious condition that can occur in the weeks following infection (11) . Recent surveillance data from the US has reported high vaccine effectiveness (VE) against MIS-C (91%; 95% CI 78 to 97%) (12) for the Pfizer-BioNTech COVID-19 vaccine (30 mcg, 2-dose series) in adolescents 12 to 18 years of age.
While evidence is limited in children 5 to 11 years of age, SARS-CoV-2 infection may lead to post-COVID condition/post acute COVID syndrome (i.e., long COVID or post acute COVID-19 syndrome) (13) . Current evidence suggests the risk is lower in children compared to older age groups (14,15) .
Myocarditis can also occur as a complication of SARS-CoV-2 infection, including, very rarely, in children (16) .
Overall evidence is limited on the long-term consequences of Omicron infection in children 5 to 11 years of age.
Additional information on MIS-C, post-COVID condition and myocarditis following COVID-19 in children 5 to 11 years of age can be found in NACI's Recommendation on the use of Pfizer-BioNTech COVID-19 vaccine (10 mcg) in children 5 to 11 years of age.
# Additional harms to children during the pandemic
Children and adolescents are also at risk of collateral harms of the COVID-19 pandemic. Prolonged schooling disruptions, social isolation, and reduced access to academic and extra- curricular resources have profoundly impacted the mental and physical well-being of children and their families (17)(18)(19)(20)(21)(22) .
# COVID-19 Burden of Disease in Pediatric Populations Who Are Immunocompromised
Currently, evidence is limited with respect to the relationship between immunocompromising conditions and COVID-19 disease severity in pediatric populations, given the relatively low frequency of severe outcomes from COVID-19 in children overall. In Canadian jurisdictions nationally reporting age and presence or absence of underlying comorbidity (AB, YT, and PEI), children 5 to 11 years of age with confirmed COVID-19 are more frequently hospitalized if malignancy or immunodeficiency is listed as an underlying condition than children 5 to 11 years of age with COVID-19 who do not identify malignancy or primary immunodeficiency (4.4% vs <0.5%; data as of January 5, 2022 (23) ). Precautionary admission due to comorbidity may contribute to the increased frequency; however, it is unclear to what extent. Regardless of comorbidity, frequency of ICU admission remained low (<0.1%) (23) in children 5 to 11 years of age.
To assess the current evidence on the risk of severe outcomes of COVID-19 in pediatric populations who are immunocompromised, all relevant studies published before December 8, 2021, which investigated the severity of SARS-CoV-2 infection in children under the age of 18 with immunocompromising conditions compared to children without immunocompromising conditions in the same age group were systematically identified (n=21 observational studies) (9,10,(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42) . These observational studies included approximately 380,000 children from 32 different countries. Seven of the included studies reported on the association between immunocompromising conditions and hospitalization due to COVID-19 (24,27,28,32,33,36,38) , five of which provided a statistical estimate of the relationship between immunocompromising conditions and COVID-19 associated hospitalization (24,28,33,36,38) . Additionally, 11 studies reported on risk of ICU admission due to COVID-19 (25, 28-31, 36-40, 42) , 8 studies reported on risk of severe disease from COVID-19 (9,10,24,26,32,34,39,41) , and 7 studies reported on risk of death from COVID-19 (25,26,30,34,35,39,41) . Four out of five studies reporting on risk of hospitalization indicated that children with an immunocompromising condition may be at an increased risk of hospitalization due to COVID-19, compared to children without immunocompromising conditions (24,28,33,36,38) . Interpretation of this outcome is limited by wide confidence intervals for some of the estimates of risk and the potential for risk of bias in study design and conduct that led to uncertainty in the confidence of those estimates. In particular, the higher likelihood of precautionary hospital admission triggered by the presence of an immunocompromising condition may contribute to the elevated hospitalization rates. The majority of studies reporting on risk of ICU admission indicated that children with an immunocompromising condition may not be at increased risk of ICU admission due to COVID-19, compared to children without immunocompromising conditions (25, 28-31, 36-40, 42) ; however, these findings were limited in interpretation by wide confidence intervals for some of the risk estimates. Overall, current evidence is insufficient to inform on whether children who are considered moderately to severely immunocompromised are at higher risk of severe outcomes from COVID-19.
# Summary of Evidence on a 2-Dose Pfizer-BioNTech Comirnaty Series in Pediatric Populations Who Are Immunocompromised
# Effectiveness of a 2-dose COVID-19 vaccine series in pediatric populations who are immunocompromised
Evidence on the effectiveness of a 2-dose COVID-19 vaccine series in persons who are immunocompromised is currently limited to adult populations, where observational studies show a reduction in VE against SARS-CoV-2 infection and COVID-19 disease in adults who are immunocompromised when compared to adults who are not immunocompromised (based on use of the vaccines as per the manufacturers' schedules). The criteria for being considered immunocompromised were not consistent across the included studies, and these analyses do not provide sufficient data to determine VE for specific immunocompromising conditions or treatments.
For further information, please refer to the NACI rapid response: Additional dose of COVID-19 vaccine in immunocompromised individuals following 1-or 2-dose primary series.
# Immunogenicity and safety of a 2-dose COVID-19 vaccine series in pediatric populations who are immunocompromised
A rapid review of the evidence was undertaken to study the effectiveness, immunogenicity and safety of a two-or three-dose primary series of a COVID-19 mRNA vaccine in pediatric populations who are moderately to severely immunocompromised (≤18 years of age). This review identified five observational studies from four countries (Canada, France, United Kingdom, US ) (43)(44)(45)(46)(47) . A total of 179 persons who were moderately to severely immunocompromised were included (solid tumor , solid organ transplant , inflammatory bowel disease (IBD) patients receiving anti-TNF , heart transplant , and children with severe neurodisabilities ). There were no children under the age of 12 years included in any of the identified studies. All studies used the Pfizer-BioNTech mRNA COVID-19 vaccine; however, none of the studies reported VE.
Immunogenicity: Four studies (n=105 persons) reported on the immunogenicity after the 2 nd dose in pediatric populations (43,(45)(46)(47) who were immunocompromised. Overall, the seroconversion rate after the second dose of the Pfizer-BioNTech vaccine was moderately reduced compared to pediatric populations who were not immunocompromised. Specific adolescent populations had reduced seroconversion rates (patients with solid tumours, solid organ transplant recipients (45)(46)(47) ) and these conditions were also associated with a lower risk of seroconversion in an analogous review in the adult population (48) . Safety: Only two studies (n=38 persons) reported safety outcomes (44,46) . The safety profile was similar to that observed in adult populations (48) who were immunocompromised; overall the vaccine was well tolerated. There were no cases of myocarditis observed in any study, although sample sizes were small. Overall, the current evidence is insufficient to inform on the safety and/or effectiveness of COVID-19 vaccines in children 5 to 11 years of age who are moderately to severely immunocompromised. However, limited data from adolescent populations who are immunocompromised indicates a similar seroconversion rate after a second dose to adult populations who are immunocompromised, as well as a similar safety profile, although data are very limited.
For further information, please refer to NACI rapid response: Additional dose of COVID-19 vaccine in immunocompromised individuals following 1-or 2-dose primary series.
# Summary of evidence on an additional dose of COVID-19 vaccines following a 2-dose series in populations who are immunocompromised
There are currently no data on the safety, immunogenicity, or efficacy of an additional dose of a COVID-19 vaccine following a 2-dose series in children or adolescents who are immunocompromised. Current data in adults demonstrates that a third dose of an mRNA COVID-19 vaccine leads to a modest increase in antibody levels in adults who are moderately to severely immunocompromised and a modest increase in the overall proportion of adults who seroconvert/respond to vaccination. Preliminary post-market data from Israel presented at the Advisory Committee on Immunization Practices (ACIP) meeting on January 5, 2022 indicate that a third dose of Pfizer-BioNTech 30mcg vaccine is well tolerated among individuals aged 12 to 15 years (49) . Among 41,610 booster doses administered to individuals aged 12 to 15 years, 2 cases of myocarditis have been reported (a 13 year-old male with a history of pericarditis in 2019 and myocarditis 3 days after the COVID-19 booster dose and a 15 year-old male with myocarditis 4 days after the COVID-19 booster dose). Both cases were discharged from hospital in good condition.
Real World Safety Surveillance Data on Pfizer-BioNTech Comirnaty in Children 5 to 11 Years of Age As of January 7, 2022, preliminary Canadian passive surveillance data show that among over 1,400,000 Pfizer-BioNTech COVID-19 vaccine doses administered in individuals aged 5 to 11 years (including the Pfizer 30 mcg doses administered to 11-year-old individuals before the 10 mcg pediatric dose was authorized), a total of 116 adverse events (AEs) (56 males, 50 females and 10 with unidentified sex) were reported. Vaccine safety monitoring is ongoing.
In the US, about 8.7 million doses of the Pfizer-BioNTech COVID-19 vaccine (10 mcg) have been administered to individuals aged 5 to 11 years as of December 19, 2021; the US uses the manufacturer's recommended 21-day interval between doses. Reactogenicity data from the v- (50) . The cases of myocarditis among the 5 to 11 yearold population appear to have similar characteristics to those reported in older age groups (onset usually within a week after vaccination, more often after dose 2, more often in males than females, and the majority of individuals tend to recover quickly). However, after dose 2, the reported rate of myocarditis in males aged 5 to 11 years (4.3 cases per million doses administered) is substantially lower than in males aged 12 to 15 years (45.7 cases per million doses administered) and males aged 16 to 17 years (70.2 cases per million doses administered).
While the preliminary safety data available to date are reassuring, more information will assist in further assessment of the risk of myocarditis/pericarditis among individuals aged 5 to 11 years. At this time, the risk of myocarditis/pericarditis after dose 2 when using an extended interval (at least 8 weeks) among children ages 5 to 11 years and the safety of a third dose of COVID-19 vaccine in individuals aged 5 to 11 years are unknown. NACI continues to review the evidence as it emerges and will update its recommendations as needed.
# Additional Information and Considerations
# Ethics and equity considerations
Evidence has shown that some individuals who are immunocompromised have a reduced immune response to the use of the COVID-19 vaccines as per the manufacturers' schedules.
Although some reduction in VE has been identified in adults who are immunocompromised when compared to the general population, the extent of the loss is unclear due to the limited evidence in this population and heterogeneous nature of immunocompromising conditions and treatments.
Vaccination strategies aimed at protecting these populations have also varied across studies and jurisdictions. While VE data for children who are immunocompromised are limited, and waiting for more evidence would increase the certainty of this recommendation, it is still possible to extrapolate based on adolescent data. Available evidence on immunogenicity and safety in adolescent populations supports offering an additional vaccine dose to children 5 to 11 years of age who are moderately to severely immunocompromised, to optimize direct protection conferred by vaccine. The additional dose provides an opportunity to obtain protective immunity against COVID-19.
# Timing of the additional dose and considerations for vaccine providers
There are currently limited data to determine the optimal interval between doses for individuals who are immunocompromised. Dosing intervals between the second and third doses in adults who are immunocompromised varied across studies, ranging from 28 days to 127 days, with most studies having assessed an interval of 2 to 3 months between doses (48) . A longer interval between doses in this three-dose series is likely to result in better immune responses. However, delaying the interval between doses increases the period during which the individual who is immunocompromised may be sub-optimally protected and could leave the individual who is immunocompromised susceptible to SARS-CoV-2 infection while waiting to be vaccinated with the additional dose. In general, NACI recommends that individuals who are immunocompromised be immunized at the time when maximum immune response can be anticipated; if possible, weighing the risk of exposure and severe disease while waiting for vaccination: Complete a vaccine series at least 2 weeks before initiation of immunosuppressive therapies where possible.
- Delay immunization if the immunodeficiency is transient (consider if this can be done safely because exposure is unlikely in the individual's setting and circumstance (51) ).
- Stop or reduce immunosuppression to permit better vaccine response, if appropriate. For more details on the timing of vaccination in relation to immunosuppressive therapy, please consult the chapter on Immunization of Immunocompromised Persons in the Canadian Immunization Guide.
In individuals who are immunocompromised, providers should aim to provide each dose of the 3dose series with an interval of 4 to 8 weeks between doses. An interval longer than 4 weeks between each dose is likely to result in a better immune response and duration of protection. However, if a longer interval is being considered, then risk factors for exposure (including local epidemiology and circulation of VOC) and risk of severe disease (including pre-existing medical conditions, social factors, and varying access to health care services) should also be considered. Some individuals who are immunocompromised may still be susceptible after 2 doses with the Pfizer-BioNTech COVID-19 vaccine, so their period of susceptibility until receipt of the additional dose will also increase if the interval between doses is increased. Some individuals who are immunocompromised will also remain susceptible after a third dose of Pfizer-BioNTech COVID-19 vaccine.
# RECOMMENDATIONS
Please see Table 1 for an explanation of strong versus discretionary NACI recommendations.
# Recommendations on the use of COVID-19 vaccines in children 5 to 11 years of age:
In careful consideration of additional safety data that has emerged since NACI first issued guidance on the use of COVID-19 vaccines in children 5 to 11 years of age, and considering benefits of vaccination in adolescents to prevent severe outcomes including MIS-C, NACI has now strengthened its previous discretionary recommendation:
# NACI recommends that a complete series with the Pfizer-BioNTech COVID-19 vaccine (10 mcg) should be offered to children 5 to 11 years of age who do not have contraindications to the vaccine, with a dosing interval of at least 8 weeks between first and second dose. (Strong NACI Recommendation)
It is essential that children aged 5 to 11 years and their parents are supported and respected in their decisions regarding COVID-19 vaccinations for their children, whatever decisions they make, and are not stigmatised for accepting, or not accepting, the vaccination offer.
NACI continues to recommend a longer dosing interval for most children despite the Omicron variant wave that is currently dominant in Canada. It is important that children are given the opportunity to establish optimal long-term immunity against COVID-19 that will persist while the Omicron variant circulates and beyond. Longer intervals between vaccine doses allow for more robust strength and breadth of immune responses, which may be important to establish durable protection against new or resurgent VOC that may be more severe. Based on current epidemiological data, the risk of severe outcomes from the Omicron variant in children 5 to 11 years of age is expected to remain low during the interval between vaccine doses. Furthermore, based on vaccine safety monitoring in adolescents and adults, it is expected that longer intervals between doses of the Pfizer-BioNTech Comirnaty vaccine will further reduce the very rare risk of myocarditis or pericarditis following vaccination in children.
# Additional considerations and rationale:
- Real-world safety data from the US (v-safe) suggests the Pfizer-BioNTech COVID-19 vaccine (10 mcg) is well tolerated in children 5 to 11 years of age, where the majority of AEs reported are non-severe, and AEs are less frequently reported than in adolescents 12 to 15 years of age.
- Currently, there are limited data on the risk of myocarditis/pericarditis in children following immunization with the 10 mcg dose of the Pfizer-BioNTech vaccine. Safety surveillance data from the US suggests that the risk of myocarditis/pericarditis may be lower in children aged 5 to 11 years following Pfizer-BioNTech (10 mcg) vaccination compared to adolescents and young adults (who receive a 30 mcg Pfizer-BioNTech dose). Among children 5 to 11 years of age, very rare cases were most often reported following dose 2 and among males. Children considered moderately to severely immunocompromised- should receive a 3dose primary series where the interval between each dose is between 4 and 8 weeks. A longer interval between doses is likely to result in a better immune response and duration of protection. However, if a longer interval is being considered, then risk factors for exposure (including local epidemiology and circulation of VOC) and risk of severe disease should also be taken into account. Some children who are immunocompromised may still be susceptible after 2 doses with Pfizer-BioNTech Comirnaty, so their period of susceptibility until receipt of the additional dose will also increase if the interval between doses is increased.
# Summary of evidence, additional considerations and rationale:
- Children 5 to 11 years of age who are immunocompromised may be at increased risk of severe outcomes from COVID-19 compared to children who are not immunocompromised, and data from older populations suggests individuals who are moderately to severely immunocompromised may have a reduced immunological response to a 2-dose mRNA COVID-19 vaccine primary series.
- In general, NACI recommends immunization of individuals who are immunocompromised at a time when the immune response can be maximized. However, delaying COVID-19 vaccinations to optimize the response (including delaying offering an additional dose) needs to be weighed against the increased period of susceptibility and risk of infection and subsequent serious complications.
- Several studies in adults who are immunocompromised have reported a third dose of an mRNA COVID-19 vaccine led to a modest increase in antibody levels compared to the response following dose 2. However, not all vaccine recipients who are immunocompromised may respond to the third dose. Therefore, individuals who are immunocompromised should continue to follow recommended public health measures for prevention and control of SARS-CoV-2 infection and transmission. It is also important that household members, healthcare workers providing care, and other close contacts of individuals who are immunocompromised be vaccinated to provide indirect protection for these individuals.
- For guidance on the timing of vaccination for transplant recipients and those requiring immunosuppressive therapies, refer to Immunization of Immunocompromised Persons chapter in the Canadian Immunization Guide, Part 3 -Vaccination of Specific Populations for a more fulsome list of conditions leading to primary immunodeficiency, and for further information on immunosuppressive therapies.
Other considerations informing NACI recommendations on the use of COVID-19 vaccines for children 5 to 11 years of age Due to high transmissibility and partial immune evasion in vaccinated individuals, children, and older populations alike, continue to be at risk of infection with the Omicron variant regardless of vaccination status, although risk of severe disease is lowered with 2 or 3 dose of a COVID-19 vaccine. It is anticipated that many children will be infected with SARS-CoV-2 during the Omicron wave of the pandemic.
- Children 5 to 11 years of age are at low risk of severe outcomes of COVID-19. Emerging evidence suggests that children are also at low risk of severe illness with the Omicron variant. While hospitalizations may be increasing, this is likely due to the magnitude of the increase in infection incidence.
- Overall evidence is limited on the long-term consequences of Omicron infection in children 5 to 11 years of age.
- Program planning should ensure equitable access to vaccination information and services and minimize inequities in vaccine acceptance and uptake based on socioeconomic status.
NACI is continuing to monitor the evidence and will update guidance as required.
Refer to the chapter on COVID-19 vaccine in the Canadian Immunization Guide for further information on COVID-19 vaccines.
# RESEARCH PRIORITIES
- NACI recommends continuous monitoring of data on the safety, immunogenicity, efficacy, and effectiveness of the Pfizer-BioNTech COVID-19 vaccine in children through clinical trials and studies in real-world settings, including clinical implications of previous history of SARS-CoV-2 infection, MIS-C, myocarditis, or pericarditis, on the safety, efficacy, and effectiveness of COVID-19 vaccines in pediatric populations and in children considered moderately to severely immunocompromised. NACI recommends continuous monitoring of vaccine uptake, particularly according to the socioeconomic status of families with children 5 to 11 years of age. NACI recommends vigilant reporting across Canadian jurisdictions for timely assessment of myocarditis and pericarditis cases as well as other potential rare or very rare AEs in pediatric populations following COVID-19 vaccination. In addition, efforts should be made to facilitate investigation of previous SARS-CoV-2 infection in cases of suspected adverse events following immunization (AEFI). Global collaboration should be prioritized to enable data sharing so decision makers around the world can weigh benefits and risks of COVID-19 vaccination for their own specific pediatric populations. NACI recommends that further evaluations of dosage intervals and the impact of the interval on effectiveness and safety in children 5 to 11 years of age should be undertaken. NACI recommends that further evaluations of the optimal interval between previous infection and vaccination be undertaken (for both COVID-19 vaccine primary series and
# Implication
A strong recommendation applies to most populations/individuals and should be followed unless a clear and compelling rationale for an alternative approach is present.
A discretionary recommendation may be offered for some populations/individuals in some circumstances. Alternative approaches may be reasonable. | Minimize serious illness and overall deaths while preserving health system capacity; Reduce transmission to protect high risk populations. Refer to NACI's methods for further information on NACI's recommendation development process.To operationalize guidance for this population, NACI has reviewed several sources to identify which pediatric populations who are immunocompromised would likely benefit most from an additional dose of COVID-19 vaccine at this time. These sources have included evidence available in published and grey literature, the CIG chapter on Immunization of Immunocompromised Persons, and eligibility criteria for additional doses of COVID-19 vaccine in pediatric populations who are immunocompromised currently being used by other jurisdictions. In addition, the clinical expertise of committee members informed the definition of pediatric populations who are immunocompromised for the recommendations outlined in this statement.Canada is currently facing an Omicron wave of the pandemic, and this variant is partially evasive to previous immunity conferred by COVID-19 vaccine or a previous SARS-CoV-2 infection. Numerous reports have shown that mRNA COVID-19 vaccines offer reduced protection against infection with the Omicron variant, and modeling estimates anticipate a fast trajectory to the peak of the Omicron wave, with substantial breakthrough cases in individuals who have received 2 or 3 doses of mRNA and other COVID-19 vaccines (1) . Canadian children 5 to 11 years of age are facing record-high incidence rates of COVID-19 (1) . While additional data are required to fully determine the disease severity caused by the Omicron variant in specific populations including unvaccinated individuals, young children (<5 years of age) and the elderly, several reports and emerging studies are reporting reduced frequencies of severe outcomes from COVID-19 for the Omicron variant compared to the Delta variant (2)(3)(4) . For the most up to date information on the epidemiology of COVID-19 in Canada, please refer to the COVID-19 daily epidemiology update.Consistent with previous SARS-CoV-2 variants of concern (VOC), children 5 to 11 years of age remain at low risk of severe outcomes from the Omicron variant. While COVID-19 associated hospitalizations among children 5 to 11 years of age have increased, which is consistent with all# PREAMBLE
The National Advisory Committee on Immunization (NACI) is an External Advisory Body that provides the Public Health Agency of Canada (PHAC) with independent, ongoing and timely medical, scientific, and public health advice in response to questions from PHAC relating to immunization.
In addition to burden of disease and vaccine characteristics, PHAC has expanded the mandate of NACI to include the systematic consideration of programmatic factors in developing evidence based recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels.
The additional factors to be systematically considered by NACI include: economics, ethics, equity, feasibility, and acceptability. Not all NACI Statements will require in-depth analyses of all programmatic factors. While systematic consideration of programmatic factors will be conducted using evidence-informed tools to identify distinct issues that could impact decision-making for recommendation development, only distinct issues identified as being specific to the vaccine or vaccine-preventable disease will be included.
This statement contains NACI's independent advice and recommendations, which are based upon the best current available scientific knowledge. This document is being disseminated for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph. Recommendations for use and other information set out herein may differ from that set out in the product monographs of the Canadian manufacturers of the vaccines. Manufacturer(s) have sought approval of the vaccines and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of PHAC's Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.
# INTRODUCTION
On December 3, 2021, NACI published updated guidance on booster COVID-19 vaccine doses in Canada and reaffirmed previous NACI guidance on the recommended use of COVID-19 vaccines in children 5 to 11 years of age. Since this guidance:
Additional evidence on the transmissibility and disease severity of the Omicron variant has emerged; Additional safety surveillance data on the 2-dose primary series of Pfizer-BioNTech Comirnaty (10 mcg) in children 5 to 11 years of age has been released, providing preliminary estimates on the risk of myocarditis/pericarditis in children 5 to 11 years of age; Many children aged 5 to 11 years who are moderately to severely immunocompromised will have completed their 2-dose series and will be seeking guidance on whether additional doses are required.
The Pfizer-BioNTech Comirnaty mRNA COVID-19 vaccine is currently the only COVID-19 vaccine authorized in Canada for use in pediatric populations under 12 years of age. Pfizer-BioNTech [10 microgram (mcg) dose] was approved for children 5 to 11 years of age on November 19, 2021 as a two-dose primary series. The Pfizer-BioNTech Comirnaty COVID-19 vaccine previously has been authorized by Health Canada for individuals 12 years of age and older, using a 30 mcg dose (December 9, 2020, individuals 16 years of age and older; May 18 2021, individuals 12 to 15 years of age).
The Pfizer-BioNTech Comirnaty COVID-19 vaccine in Canada is approved for use as a 3-dose primary series in individuals who are immunocompromised. As per the product monograph (for both 10 mcg and 30 mcg doses), persons who are immunocompromised, including individuals receiving immunosuppressant therapy, may have a diminished immune response to the vaccine and in these individuals, a third dose may be considered as part of the primary series.
NACI has reviewed the evolving situation and evidence and has updated evidence-informed recommendations on the use of COVID-19 vaccines in pediatric populations.
# METHODS
On January 11, 2022, NACI reviewed the recent evidence on COVID-19 vaccines for pediatric populations including real-world safety surveillance data from the United States (US) and Canada on the Pfizer-BioNTech Comirnaty (10 mcg) vaccine in children 5 to 11 years of age. NACI approved their updated recommendations on the use of COVID-19 vaccines in pediatric populations 5 to 11 years of age on January 19, 2022.
For further information on NACI's recommendations on the use of COVID-19 vaccines, please refer to the COVID-19 vaccine chapter in the Canadian Immunization Guide (CIG).
NACI's recommendations are aligned with the goals of the Canadian COVID-19 Immunization Program, updated in October 2021: To enable as many Canadians as possible to be immunized as quickly as possible against COVID-19, while ensuring that high risk populations be prioritized; other age groups in Canada during the Omicron wave (1) , the proportion of COVID-19 cases among children 5 to 11 years of age that have been hospitalized or admitted to ICU remains low (5) . Indirect evidence from adolescent populations in the US suggests risk of severe outcomes may be further decreased by COVID-19 vaccination. In a recent study from the CDC conducted before the arrival of the Omicron variant, among hospitalized patients 12 to 18 years of age, two doses of the Pfizer-BioNTech Comirnaty COVID-19 vaccine (30 mcg) were highly effective at preventing COVID-19-related hospitalization and ICU admission or the need for life support (6) .
There is limited evidence on clinical risk factors for severe COVID-19 disease in pediatric populations (7) . Children 5 to 11 years of age at increased risk for severe outcomes may include children who are obese, children who are medically fragile/have medical complexities, children with more than one comorbidity (8) , children with neurological disorders (9,10) , and children with immune dysregulation associated with Down Syndrome (8) and other immunocompromising conditions.
For additional information, please refer to the Recommendation on the use of Pfizer-BioNTech COVID-19 vaccine (10 mcg) in children 5 to 11 years of age.
# MIS-C, post-COVID condition and myocarditis following COVID-19
Children and adolescents infected with SARS-CoV-2 are at risk of multiple inflammatory syndrome in children (MIS-C), a rare but serious condition that can occur in the weeks following infection (11) . Recent surveillance data from the US has reported high vaccine effectiveness (VE) against MIS-C (91%; 95% CI 78 to 97%) (12) for the Pfizer-BioNTech COVID-19 vaccine (30 mcg, 2-dose series) in adolescents 12 to 18 years of age.
While evidence is limited in children 5 to 11 years of age, SARS-CoV-2 infection may lead to post-COVID condition/post acute COVID syndrome (i.e., long COVID or post acute COVID-19 syndrome) (13) . Current evidence suggests the risk is lower in children compared to older age groups (14,15) .
Myocarditis can also occur as a complication of SARS-CoV-2 infection, including, very rarely, in children (16) .
Overall evidence is limited on the long-term consequences of Omicron infection in children 5 to 11 years of age.
Additional information on MIS-C, post-COVID condition and myocarditis following COVID-19 in children 5 to 11 years of age can be found in NACI's Recommendation on the use of Pfizer-BioNTech COVID-19 vaccine (10 mcg) in children 5 to 11 years of age.
# Additional harms to children during the pandemic
Children and adolescents are also at risk of collateral harms of the COVID-19 pandemic. Prolonged schooling disruptions, social isolation, and reduced access to academic and extra- curricular resources have profoundly impacted the mental and physical well-being of children and their families (17)(18)(19)(20)(21)(22) .
# COVID-19 Burden of Disease in Pediatric Populations Who Are Immunocompromised
Currently, evidence is limited with respect to the relationship between immunocompromising conditions and COVID-19 disease severity in pediatric populations, given the relatively low frequency of severe outcomes from COVID-19 in children overall. In Canadian jurisdictions nationally reporting age and presence or absence of underlying comorbidity (AB, YT, and PEI), children 5 to 11 years of age with confirmed COVID-19 are more frequently hospitalized if malignancy or immunodeficiency is listed as an underlying condition than children 5 to 11 years of age with COVID-19 who do not identify malignancy or primary immunodeficiency (4.4% vs <0.5%; data as of January 5, 2022 (23) ). Precautionary admission due to comorbidity may contribute to the increased frequency; however, it is unclear to what extent. Regardless of comorbidity, frequency of ICU admission remained low (<0.1%) (23) in children 5 to 11 years of age.
To assess the current evidence on the risk of severe outcomes of COVID-19 in pediatric populations who are immunocompromised, all relevant studies published before December 8, 2021, which investigated the severity of SARS-CoV-2 infection in children under the age of 18 with immunocompromising conditions compared to children without immunocompromising conditions in the same age group were systematically identified (n=21 observational studies) (9,10,(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42) . These observational studies included approximately 380,000 children from 32 different countries. Seven of the included studies reported on the association between immunocompromising conditions and hospitalization due to COVID-19 (24,27,28,32,33,36,38) , five of which provided a statistical estimate of the relationship between immunocompromising conditions and COVID-19 associated hospitalization (24,28,33,36,38) . Additionally, 11 studies reported on risk of ICU admission due to COVID-19 (25, 28-31, 36-40, 42) , 8 studies reported on risk of severe disease from COVID-19 (9,10,24,26,32,34,39,41) , and 7 studies reported on risk of death from COVID-19 (25,26,30,34,35,39,41) . Four out of five studies reporting on risk of hospitalization indicated that children with an immunocompromising condition may be at an increased risk of hospitalization due to COVID-19, compared to children without immunocompromising conditions (24,28,33,36,38) . Interpretation of this outcome is limited by wide confidence intervals for some of the estimates of risk and the potential for risk of bias in study design and conduct that led to uncertainty in the confidence of those estimates. In particular, the higher likelihood of precautionary hospital admission triggered by the presence of an immunocompromising condition may contribute to the elevated hospitalization rates. The majority of studies reporting on risk of ICU admission indicated that children with an immunocompromising condition may not be at increased risk of ICU admission due to COVID-19, compared to children without immunocompromising conditions (25, 28-31, 36-40, 42) ; however, these findings were limited in interpretation by wide confidence intervals for some of the risk estimates. Overall, current evidence is insufficient to inform on whether children who are considered moderately to severely immunocompromised are at higher risk of severe outcomes from COVID-19.
# Summary of Evidence on a 2-Dose Pfizer-BioNTech Comirnaty Series in Pediatric Populations Who Are Immunocompromised
# Effectiveness of a 2-dose COVID-19 vaccine series in pediatric populations who are immunocompromised
Evidence on the effectiveness of a 2-dose COVID-19 vaccine series in persons who are immunocompromised is currently limited to adult populations, where observational studies show a reduction in VE against SARS-CoV-2 infection and COVID-19 disease in adults who are immunocompromised when compared to adults who are not immunocompromised (based on use of the vaccines as per the manufacturers' schedules). The criteria for being considered immunocompromised were not consistent across the included studies, and these analyses do not provide sufficient data to determine VE for specific immunocompromising conditions or treatments.
For further information, please refer to the NACI rapid response: Additional dose of COVID-19 vaccine in immunocompromised individuals following 1-or 2-dose primary series.
# Immunogenicity and safety of a 2-dose COVID-19 vaccine series in pediatric populations who are immunocompromised
A rapid review of the evidence was undertaken to study the effectiveness, immunogenicity and safety of a two-or three-dose primary series of a COVID-19 mRNA vaccine in pediatric populations who are moderately to severely immunocompromised (≤18 years of age). This review identified five observational studies from four countries (Canada, France, United Kingdom, US [n=2]) (43)(44)(45)(46)(47) . A total of 179 persons who were moderately to severely immunocompromised were included (solid tumor [n=13], solid organ transplant [n=45], inflammatory bowel disease (IBD) patients receiving anti-TNF [n=68], heart transplant [n=26], and children with severe neurodisabilities [n=27]). There were no children under the age of 12 years included in any of the identified studies. All studies used the Pfizer-BioNTech mRNA COVID-19 vaccine; however, none of the studies reported VE.
Immunogenicity: Four studies (n=105 persons) reported on the immunogenicity after the 2 nd dose in pediatric populations (43,(45)(46)(47) who were immunocompromised. Overall, the seroconversion rate after the second dose of the Pfizer-BioNTech vaccine was moderately reduced compared to pediatric populations who were not immunocompromised. Specific adolescent populations had reduced seroconversion rates (patients with solid tumours, solid organ transplant recipients (45)(46)(47) ) and these conditions were also associated with a lower risk of seroconversion in an analogous review in the adult population (48) . Safety: Only two studies (n=38 persons) reported safety outcomes (44,46) . The safety profile was similar to that observed in adult populations (48) who were immunocompromised; overall the vaccine was well tolerated. There were no cases of myocarditis observed in any study, although sample sizes were small. Overall, the current evidence is insufficient to inform on the safety and/or effectiveness of COVID-19 vaccines in children 5 to 11 years of age who are moderately to severely immunocompromised. However, limited data from adolescent populations who are immunocompromised indicates a similar seroconversion rate after a second dose to adult populations who are immunocompromised, as well as a similar safety profile, although data are very limited.
For further information, please refer to NACI rapid response: Additional dose of COVID-19 vaccine in immunocompromised individuals following 1-or 2-dose primary series.
# Summary of evidence on an additional dose of COVID-19 vaccines following a 2-dose series in populations who are immunocompromised
There are currently no data on the safety, immunogenicity, or efficacy of an additional dose of a COVID-19 vaccine following a 2-dose series in children or adolescents who are immunocompromised. Current data in adults demonstrates that a third dose of an mRNA COVID-19 vaccine leads to a modest increase in antibody levels in adults who are moderately to severely immunocompromised and a modest increase in the overall proportion of adults who seroconvert/respond to vaccination. Preliminary post-market data from Israel presented at the Advisory Committee on Immunization Practices (ACIP) meeting on January 5, 2022 indicate that a third dose of Pfizer-BioNTech 30mcg vaccine is well tolerated among individuals aged 12 to 15 years (49) . Among 41,610 booster doses administered to individuals aged 12 to 15 years, 2 cases of myocarditis have been reported (a 13 year-old male with a history of pericarditis in 2019 and myocarditis 3 days after the COVID-19 booster dose and a 15 year-old male with myocarditis 4 days after the COVID-19 booster dose). Both cases were discharged from hospital in good condition.
Real World Safety Surveillance Data on Pfizer-BioNTech Comirnaty in Children 5 to 11 Years of Age As of January 7, 2022, preliminary Canadian passive surveillance data show that among over 1,400,000 Pfizer-BioNTech COVID-19 vaccine doses administered in individuals aged 5 to 11 years (including the Pfizer 30 mcg doses administered to 11-year-old individuals before the 10 mcg pediatric dose was authorized), a total of 116 adverse events (AEs) (56 males, 50 females and 10 with unidentified sex) were reported. Vaccine safety monitoring is ongoing.
In the US, about 8.7 million doses of the Pfizer-BioNTech COVID-19 vaccine (10 mcg) have been administered to individuals aged 5 to 11 years as of December 19, 2021; the US uses the manufacturer's recommended 21-day interval between doses. Reactogenicity data from the v- (50) . The cases of myocarditis among the 5 to 11 yearold population appear to have similar characteristics to those reported in older age groups (onset usually within a week after vaccination, more often after dose 2, more often in males than females, and the majority of individuals tend to recover quickly). However, after dose 2, the reported rate of myocarditis in males aged 5 to 11 years (4.3 cases per million doses administered) is substantially lower than in males aged 12 to 15 years (45.7 cases per million doses administered) and males aged 16 to 17 years (70.2 cases per million doses administered).
While the preliminary safety data available to date are reassuring, more information will assist in further assessment of the risk of myocarditis/pericarditis among individuals aged 5 to 11 years. At this time, the risk of myocarditis/pericarditis after dose 2 when using an extended interval (at least 8 weeks) among children ages 5 to 11 years and the safety of a third dose of COVID-19 vaccine in individuals aged 5 to 11 years are unknown. NACI continues to review the evidence as it emerges and will update its recommendations as needed.
# Additional Information and Considerations
# Ethics and equity considerations
Evidence has shown that some individuals who are immunocompromised have a reduced immune response to the use of the COVID-19 vaccines as per the manufacturers' schedules.
Although some reduction in VE has been identified in adults who are immunocompromised when compared to the general population, the extent of the loss is unclear due to the limited evidence in this population and heterogeneous nature of immunocompromising conditions and treatments.
Vaccination strategies aimed at protecting these populations have also varied across studies and jurisdictions. While VE data for children who are immunocompromised are limited, and waiting for more evidence would increase the certainty of this recommendation, it is still possible to extrapolate based on adolescent data. Available evidence on immunogenicity and safety in adolescent populations supports offering an additional vaccine dose to children 5 to 11 years of age who are moderately to severely immunocompromised, to optimize direct protection conferred by vaccine. The additional dose provides an opportunity to obtain protective immunity against COVID-19.
# Timing of the additional dose and considerations for vaccine providers
There are currently limited data to determine the optimal interval between doses for individuals who are immunocompromised. Dosing intervals between the second and third doses in adults who are immunocompromised varied across studies, ranging from 28 days to 127 days, with most studies having assessed an interval of 2 to 3 months between doses (48) . A longer interval between doses in this three-dose series is likely to result in better immune responses. However, delaying the interval between doses increases the period during which the individual who is immunocompromised may be sub-optimally protected and could leave the individual who is immunocompromised susceptible to SARS-CoV-2 infection while waiting to be vaccinated with the additional dose. In general, NACI recommends that individuals who are immunocompromised be immunized at the time when maximum immune response can be anticipated; if possible, weighing the risk of exposure and severe disease while waiting for vaccination: Complete a vaccine series at least 2 weeks before initiation of immunosuppressive therapies where possible.
Delay immunization if the immunodeficiency is transient (consider if this can be done safely because exposure is unlikely in the individual's setting and circumstance (51) ).
Stop or reduce immunosuppression to permit better vaccine response, if appropriate. For more details on the timing of vaccination in relation to immunosuppressive therapy, please consult the chapter on Immunization of Immunocompromised Persons in the Canadian Immunization Guide.
In individuals who are immunocompromised, providers should aim to provide each dose of the 3dose series with an interval of 4 to 8 weeks between doses. An interval longer than 4 weeks between each dose is likely to result in a better immune response and duration of protection. However, if a longer interval is being considered, then risk factors for exposure (including local epidemiology and circulation of VOC) and risk of severe disease (including pre-existing medical conditions, social factors, and varying access to health care services) should also be considered. Some individuals who are immunocompromised may still be susceptible after 2 doses with the Pfizer-BioNTech COVID-19 vaccine, so their period of susceptibility until receipt of the additional dose will also increase if the interval between doses is increased. Some individuals who are immunocompromised will also remain susceptible after a third dose of Pfizer-BioNTech COVID-19 vaccine.
# RECOMMENDATIONS
Please see Table 1 for an explanation of strong versus discretionary NACI recommendations.
# Recommendations on the use of COVID-19 vaccines in children 5 to 11 years of age:
In careful consideration of additional safety data that has emerged since NACI first issued guidance on the use of COVID-19 vaccines in children 5 to 11 years of age, and considering benefits of vaccination in adolescents to prevent severe outcomes including MIS-C, NACI has now strengthened its previous discretionary recommendation:
# NACI recommends that a complete series with the Pfizer-BioNTech COVID-19 vaccine (10 mcg) should be offered to children 5 to 11 years of age who do not have contraindications to the vaccine, with a dosing interval of at least 8 weeks between first and second dose. (Strong NACI Recommendation)
It is essential that children aged 5 to 11 years and their parents are supported and respected in their decisions regarding COVID-19 vaccinations for their children, whatever decisions they make, and are not stigmatised for accepting, or not accepting, the vaccination offer.
NACI continues to recommend a longer dosing interval for most children despite the Omicron variant wave that is currently dominant in Canada. It is important that children are given the opportunity to establish optimal long-term immunity against COVID-19 that will persist while the Omicron variant circulates and beyond. Longer intervals between vaccine doses allow for more robust strength and breadth of immune responses, which may be important to establish durable protection against new or resurgent VOC that may be more severe. Based on current epidemiological data, the risk of severe outcomes from the Omicron variant in children 5 to 11 years of age is expected to remain low during the interval between vaccine doses. Furthermore, based on vaccine safety monitoring in adolescents and adults, it is expected that longer intervals between doses of the Pfizer-BioNTech Comirnaty vaccine will further reduce the very rare risk of myocarditis or pericarditis following vaccination in children.
# Additional considerations and rationale:
Real-world safety data from the US (v-safe) suggests the Pfizer-BioNTech COVID-19 vaccine (10 mcg) is well tolerated in children 5 to 11 years of age, where the majority of AEs reported are non-severe, and AEs are less frequently reported than in adolescents 12 to 15 years of age.
Currently, there are limited data on the risk of myocarditis/pericarditis in children following immunization with the 10 mcg dose of the Pfizer-BioNTech vaccine. Safety surveillance data from the US suggests that the risk of myocarditis/pericarditis may be lower in children aged 5 to 11 years following Pfizer-BioNTech (10 mcg) vaccination compared to adolescents and young adults (who receive a 30 mcg Pfizer-BioNTech dose). Among children 5 to 11 years of age, very rare cases were most often reported following dose 2 and among males. Children considered moderately to severely immunocompromised* should receive a 3dose primary series where the interval between each dose is between 4 and 8 weeks. A longer interval between doses is likely to result in a better immune response and duration of protection. However, if a longer interval is being considered, then risk factors for exposure (including local epidemiology and circulation of VOC) and risk of severe disease should also be taken into account. Some children who are immunocompromised may still be susceptible after 2 doses with Pfizer-BioNTech Comirnaty, so their period of susceptibility until receipt of the additional dose will also increase if the interval between doses is increased.
# Summary of evidence, additional considerations and rationale:
Children 5 to 11 years of age who are immunocompromised may be at increased risk of severe outcomes from COVID-19 compared to children who are not immunocompromised, and data from older populations suggests individuals who are moderately to severely immunocompromised may have a reduced immunological response to a 2-dose mRNA COVID-19 vaccine primary series.
In general, NACI recommends immunization of individuals who are immunocompromised at a time when the immune response can be maximized. However, delaying COVID-19 vaccinations to optimize the response (including delaying offering an additional dose) needs to be weighed against the increased period of susceptibility and risk of infection and subsequent serious complications.
Several studies in adults who are immunocompromised have reported a third dose of an mRNA COVID-19 vaccine led to a modest increase in antibody levels compared to the response following dose 2. However, not all vaccine recipients who are immunocompromised may respond to the third dose. Therefore, individuals who are immunocompromised should continue to follow recommended public health measures for prevention and control of SARS-CoV-2 infection and transmission. It is also important that household members, healthcare workers providing care, and other close contacts of individuals who are immunocompromised be vaccinated to provide indirect protection for these individuals.
For guidance on the timing of vaccination for transplant recipients and those requiring immunosuppressive therapies, refer to Immunization of Immunocompromised Persons chapter in the Canadian Immunization Guide, Part 3 -Vaccination of Specific Populations for a more fulsome list of conditions leading to primary immunodeficiency, and for further information on immunosuppressive therapies.
Other considerations informing NACI recommendations on the use of COVID-19 vaccines for children 5 to 11 years of age Due to high transmissibility and partial immune evasion in vaccinated individuals, children, and older populations alike, continue to be at risk of infection with the Omicron variant regardless of vaccination status, although risk of severe disease is lowered with 2 or 3 dose of a COVID-19 vaccine. It is anticipated that many children will be infected with SARS-CoV-2 during the Omicron wave of the pandemic.
Children 5 to 11 years of age are at low risk of severe outcomes of COVID-19. Emerging evidence suggests that children are also at low risk of severe illness with the Omicron variant. While hospitalizations may be increasing, this is likely due to the magnitude of the increase in infection incidence.
Overall evidence is limited on the long-term consequences of Omicron infection in children 5 to 11 years of age.
Program planning should ensure equitable access to vaccination information and services and minimize inequities in vaccine acceptance and uptake based on socioeconomic status.
NACI is continuing to monitor the evidence and will update guidance as required.
Refer to the chapter on COVID-19 vaccine in the Canadian Immunization Guide for further information on COVID-19 vaccines.
# RESEARCH PRIORITIES
NACI recommends continuous monitoring of data on the safety, immunogenicity, efficacy, and effectiveness of the Pfizer-BioNTech COVID-19 vaccine in children through clinical trials and studies in real-world settings, including clinical implications of previous history of SARS-CoV-2 infection, MIS-C, myocarditis, or pericarditis, on the safety, efficacy, and effectiveness of COVID-19 vaccines in pediatric populations and in children considered moderately to severely immunocompromised. NACI recommends continuous monitoring of vaccine uptake, particularly according to the socioeconomic status of families with children 5 to 11 years of age. NACI recommends vigilant reporting across Canadian jurisdictions for timely assessment of myocarditis and pericarditis cases as well as other potential rare or very rare AEs in pediatric populations following COVID-19 vaccination. In addition, efforts should be made to facilitate investigation of previous SARS-CoV-2 infection in cases of suspected adverse events following immunization (AEFI). Global collaboration should be prioritized to enable data sharing so decision makers around the world can weigh benefits and risks of COVID-19 vaccination for their own specific pediatric populations. NACI recommends that further evaluations of dosage intervals and the impact of the interval on effectiveness and safety in children 5 to 11 years of age should be undertaken. NACI recommends that further evaluations of the optimal interval between previous infection and vaccination be undertaken (for both COVID-19 vaccine primary series and
# Implication
A strong recommendation applies to most populations/individuals and should be followed unless a clear and compelling rationale for an alternative approach is present.
A discretionary recommendation may be offered for some populations/individuals in some circumstances. Alternative approaches may be reasonable.
# ACKNOWLEDGMENTS
| None | None |
fe06c5f0f663b919dec5874857383bc3e30ee60b | cma | None | This guideline summarizes suggested wait times for common indications where Computed Tomography (CT) is the recommended first imaging test. The purpose is to inform primary care practitioners of how referrals are prioritized by Radiologists and Radiology departments across the province. This guideline is an adaptation of the British Columbia Radiological Society (BCRS) CT Prioritization Guidelines (2013). 1 Management of the listed clinical problems is beyond the scope of this guideline. However, in some cases, notes and alternative tests are provided for additional clinical context. Primary care practitioners are encouraged to consult a Radiologist if they have any concerns or questions regarding which appropriate imaging test to choose for a problem. If in doubt consult with a Radiologist and review provincial guidance materials. 2 # Background
The 2013 BCRS CT Prioritization Guidelines were developed to provide imaging departments with a consistent, provincial approach to prioritizing commonly ordered CT tests according to suggested maximum wait times. The BCRS guidelines were developed by consensus and are based on BC expert opinion with representation of Radiologists from across the province. Several considerations apply:
- These are guidelines, and as such, are designed to apply in general terms. They are not intended to replace clinical judgement or practitioner-to-practitioner discussion. - Prioritization levels were selected to match other similar guidelines for Magnetic Resonance Imaging (MRI) and Ultrasound (US) and are typically assigned by Radiologists rather than referring practitioners. - These guidelines should not be applied rigidly to each case, as varying clinical factors may shift an indication from one priority level to another. - Access to CT and the ability to respond to CT requests will depend on resources and local availability.
- Providing detailed patient information is essential to aid with the prioritization process.
- The clinical topics included in this guideline represent broad examples, and do not encompass all possible scenarios or all requirements for CT examinations.
# Priority Level Definitions
The priority levels defined below (Table 1) are in alignment with the Canadian Association of Radiologists national designation Five Point Classification System. 3
# P1
An examination immediately necessary to diagnose and/or treat life-threatening disease. Such an examination will need to be done either stat or not later than the day of the request.
Immediately to 24 hours
# P2
An examination indicated within one week of a request to resolve a clinical management imperative. Maximum 7 calendar days
# P3
An examination indicated to investigate symptoms of potential importance. Maximum 30 calendar days
# P4
An examination indicated for long-range management or for prevention. Maximum 60 calendar days
# P5
Timed follow-up exam or specified procedure date recommended by Radiologist and/or clinician.
Source: Adapted from the Canadian Association of Radiologists National Maximum Wait Time Access Targets for Medical Imaging.
# Prioritization of Potential Diagnoses
CT is widely indicated for and includes but is not limited to the following 4 The following potential diagnoses, where CT is the recommended first test, are grouped according to body system and then further subdivided into priority levels. For each system, an overview table is presented followed by a more detailed table outlining additional notes and alternative tests where CT may be less appropriate due to ionizing radiation exposure.
For CT also consider the patient risk of radiation exposure, refer to Appendix A: Radiation Exposure.
Referring practitioners should include clear, pertinent clinical history on radiology requisitions to assist the triaging/ prioritizing of examinations and interpretation of images and may consider noting the priority directly on the requisition where possible.
# Pediatric
Consider alternatives to CT, if appropriate, to reduce radiation exposure for pediatric patients. See Appendix A: Radiation Exposure, for more information. | This guideline summarizes suggested wait times for common indications where Computed Tomography (CT) is the recommended first imaging test. The purpose is to inform primary care practitioners of how referrals are prioritized by Radiologists and Radiology departments across the province. This guideline is an adaptation of the British Columbia Radiological Society (BCRS) CT Prioritization Guidelines (2013). 1 Management of the listed clinical problems is beyond the scope of this guideline. However, in some cases, notes and alternative tests are provided for additional clinical context. Primary care practitioners are encouraged to consult a Radiologist if they have any concerns or questions regarding which appropriate imaging test to choose for a problem. If in doubt consult with a Radiologist and review provincial guidance materials. 2 # Background
The 2013 BCRS CT Prioritization Guidelines were developed to provide imaging departments with a consistent, provincial approach to prioritizing commonly ordered CT tests according to suggested maximum wait times. The BCRS guidelines were developed by consensus and are based on BC expert opinion with representation of Radiologists from across the province. Several considerations apply:
• These are guidelines, and as such, are designed to apply in general terms. They are not intended to replace clinical judgement or practitioner-to-practitioner discussion. • Prioritization levels were selected to match other similar guidelines for Magnetic Resonance Imaging (MRI) and Ultrasound (US) and are typically assigned by Radiologists rather than referring practitioners. • These guidelines should not be applied rigidly to each case, as varying clinical factors may shift an indication from one priority level to another. • Access to CT and the ability to respond to CT requests will depend on resources and local availability.
• Providing detailed patient information is essential to aid with the prioritization process.
• The clinical topics included in this guideline represent broad examples, and do not encompass all possible scenarios or all requirements for CT examinations.
# Priority Level Definitions
The priority levels defined below (Table 1) are in alignment with the Canadian Association of Radiologists national designation Five Point Classification System. 3
# P1
An examination immediately necessary to diagnose and/or treat life-threatening disease. Such an examination will need to be done either stat or not later than the day of the request.
Immediately to 24 hours
# P2
An examination indicated within one week of a request to resolve a clinical management imperative. Maximum 7 calendar days
# P3
An examination indicated to investigate symptoms of potential importance. Maximum 30 calendar days
# P4
An examination indicated for long-range management or for prevention. Maximum 60 calendar days
# P5
Timed follow-up exam or specified procedure date recommended by Radiologist and/or clinician.
Source: Adapted from the Canadian Association of Radiologists National Maximum Wait Time Access Targets for Medical Imaging.
# Prioritization of Potential Diagnoses
CT is widely indicated for and includes but is not limited to the following 4 The following potential diagnoses, where CT is the recommended first test, are grouped according to body system and then further subdivided into priority levels. For each system, an overview table is presented followed by a more detailed table outlining additional notes and alternative tests where CT may be less appropriate due to ionizing radiation exposure.
For CT also consider the patient risk of radiation exposure, refer to Appendix A: Radiation Exposure.
Referring practitioners should include clear, pertinent clinical history on radiology requisitions to assist the triaging/ prioritizing of examinations and interpretation of images and may consider noting the priority directly on the requisition where possible.
# Pediatric
Consider alternatives to CT, if appropriate, to reduce radiation exposure for pediatric patients. See Appendix A: Radiation Exposure, for more information.
# Disclaimer
The Clinical Practice Guidelines (the "Guidelines") have been developed by the Guidelines and Protocols Advisory Committee on behalf of the Medical Services Commission. The Guidelines are intended to give an understanding of a clinical problem, and outline one or more preferred approaches to the investigation and management of the problem. The Guidelines are not intended as a substitute for the advice or professional judgment of a health care professional, nor are they intended to be the only approach to the management of clinical problem. We cannot respond to patients or patient advocates requesting advice on issues related to medical conditions. If you need medical advice, please contact a health care professional.
# THE GUIDELINES AND PROTOCOLS ADVISORY COMMITTEE
This guideline is based on expert BC clinical practice current as of the effective date. This guideline was developed by the Guidelines and Protocols Advisory Committee based on the British Columbia Radiological Society Computed Tomography Prioritization Guidelines (2013), and approved by the Medical Services Commission.
# Appendix A: Radiation Exposure
BCGuidelines.ca: CT Prioritization: Appendix A (2020) 1
Radiation exists in the natural environment and this natural background radiation may vary based on location. Ionizing radiation is used during a CT scan to produce the image. CT scans are about as much radiation as 200 chest x-rays. 2 Living at high altitude for a year would be the same as having four chest x-rays. 2 A ten-hour plane flight is about the same amount of radiation as one chest x-ray. 2 The risk of an adult getting cancer from a CT scan is about 1 in 1000. 2 However, large studies have found some slight increases in cancer risk due to radiation exposure that is more pronounced amongst children. 3 For this reason, children's medical imaging scans in particular try to follow the ALARA principle (As Low As Reasonably Achievable), to obtain images at the lowest dose of radiation possible. 4 Image Gently Campaign's strategies to minimize radiation risk for children: 3 • Image when there is a clear medical benefit • Use the lowest amount of radiation for adequate imaging based on the size of the child • Image only the indicated area • Avoid multiple scans • Use alternative diagnostic studies that do not use radiation (such as ultrasound or MRI) when possible.
# Sources and
| None | None |
795281a477c3bd3fbcb70c556218e8c578614dda | cma | None | The COVID-19 pandemic has had a major impact on clinical practice. Safe standards of practice are essential to protect health care workers while still allowing them to provide good care. The Canadian Society of Clinical Neurophysiologists, the Canadian Association of Electroneurophysiology Technologists, the Association of Electromyography Technologists of Canada, the Board of Registration of Electromyography Technologists of Canada, and the Canadian Board of Registration of Electroencephalograph Technologists have combined to review current published literature about safe practices for neurophysiology laboratories. Herein, we present the results of our review and provide our expert opinion regarding the safe practice of neurophysiology during the COVID-19 pandemic in Canada. RÉSUMÉ : Lignes directrices et pratiques exemplaires destinées, dans le contexte de la pandémie de COVID-19, aux laboratoires canadiens de neurophysiologie. La pandémie de COVID-19 a eu un impact majeur sur la pratique clinique. En matière de pratique, des normes sécuritaires demeurent justement essentielles afin de protéger les travailleurs de la santé tout en leur permettant de prodiguer des soins adéquats. La Société canadienne des neurophysiologistes cliniques (CSCN), l'Association canadienne des technologues en électro-neurophysiologie, l'Association canadienne des technologues en électromyographie, le Board of Registration of Electromyography Technologists of Canada et le Conseil canadien d'enregistrement des technologues en électroencéphalographe se sont ainsi associés afin de passer en revue la littérature scientifique actuelle portant sur les pratiques sécuritaires au sein des laboratoires de neurophysiologie. Nous souhaitons donc présenter ici les résultats de notre revue de littérature et proposer, dans le contexte de la COVID-19, un regard éclairé en ce qui regarde les pratiques sécuritaires en neurophysiologie au Canada.# INTRODUCTION
Given that the current COVID-19 pandemic will continue to affect Canadian health care for the foreseeable future, our organizations felt that it was appropriate to provide some guidance on safe practices during the pandemic. We begin by presenting the key points in table form in order to emphasize the practical aim of this article. The main body of the article elaborates on these points and provides the scientific rationale for their inclusion, when this exists.
# PURPOSE
To provide guidelines for safe functioning of neurophysiology laboratories during the COVID-19 pandemic, recommendations are based on expert opinion and review of relevant published guidelines. These guidelines are not intended to replace institutional, regional, or provincial protocols.
# BACKGROUND
Named "Severe Acute Respiratory Syndrome (SARS)-CoV-2" by the Coronaviridae Study Group, the coronavirus causing the current pandemic is responsible for the third outbreak of acute respiratory syndrome in the last two decades after the SARS in 2003 and the Middle East Respiratory Syndrome (MERS) in 2012. 20 The disease caused by this coronavirus is known as "COVID-19" and the full spectrum of its symptomatology and pathophysiology is yet to be defined. As its name implies, the respiratory symptoms (cough, fever, and dyspnea) are present in more than 60% of hospitalized patients and are the main cause of death. 21 It is clear that staff in the neurophysiology laboratory will be exposed to COVID-19 due to the nature of this disease. The reported neurological manifestations include a wide range of symptoms and signs such as headaches, anosmia and ageusia, impaired consciousness, toxic-metabolic encephalopathy, encephalitis, seizures and status epilepticus, strokes and vascular events, Guillain-Barré syndrome, myositis, and peripheral nerve disorders. 22 The current ongoing Canadian provincial plans to re-launch the economy are at different levels of complexity in each province. However, some have already announced the re-opening of regulated health profession services and some have scheduled nonurgent surgeries as long as they continue to follow approved guidelines set by their professional colleges. 23 These developments have led the Canadian Society of Clinical Neurophysiologists (CSCN), the Canadian Association of Electroneurophysiology Technologists, the Association of Electromyography Technologists of Canada, the Board of Registration of Electromyography Technologists of Canada, and the Canadian Board of Registration of Electroencephalograph Technologists to elaborate this guideline for safe practice in the neurophysiology laboratories of Canada.
# GENERAL INFECTION CONTROL RECOMMENDATIONS (TABLE 1)
Booking of patients for neurophysiology testing should be prudent and minimize unnecessary testing. If the test will not change clinical management, avoid an emergency department visit, or avoid morbidity and mortality it should in general be deferred. During crisis or peak periods of the pandemic, only cases that are urgent or time-sensitive should be seen, such as those posing threat to life, limb, or long-term outcome. 1,2 As the pandemic starts to come under control and laboratories gain greater experience with safely seeing patients, the threshold for selecting appropriate patients for neurophysiological testing will become progressively lower. Patient workflow should still be adjusted in order to assess high-risk cases safely. 1,3 In COVID-19-positive cases, neurodiagnostic testing should be performed only in the inpatient setting with full personal protective equipment (PPE) equipment as per local protocols, only if test results will change management (treatment and/or diagnosis), and ideally in an airborne infection isolation room (AIIR) as the virus could survive several hours to days on certain surfaces. 2,4,7 If done in AIIR, these tests should be postponed for at least 4 h if recent aerosol generating medical procedure (AGMP) had been performed (i.e., nebulizer therapy, chest physiotherapy, intubation, bronchoscopy, sputum induction, bilevel positive airway pressure , or continuous positive airway pressure use). 5,7 The outpatient setting is reserved for COVID-19-negative patients when triaging deems necessary. 8 The waiting room must be utilized in a way that will allow a 2-m gap (physical distancing) between patients, including not concomitant bookings if needed due to limited physical space. 9 Electroencephalogram (EEG) and electromyogram/ nerve conduction study (EMG/NCS) technologists must avoid remaining in the waiting room to minimize physical contact with patients. There should be sufficient time between appointments to allow for distancing arrangements and the cleaning of equipment. 2,4 If multiple clinics running simultaneously share the waiting room, staff should consider the implications of a large volume of patients in shared spaces, including corridors. 1 Table 1: General infection control recommendations - Scheduling should be guided by medical urgency, laboratory/staff limitations, and waiting room occupancy considerations (respecting 2-m physical distancing).
- All patients should undergo screening for COVID-19 exposure by questionnaire or patient transport service checklist. If local institutional versions do not exist, online versions are available.
- Clinical neurophysiological investigations require prolonged, close contact with patients. All patients and companions, doctors, and technologists should be required to wear a mask and gloves unless otherwise contraindicated.
- Testing of COVID-19-positive patients should be performed only if critical for patient diagnosis and medical management.
- In the training laboratory, the number of personnel should be minimized. One instructor and one trainee are preferable. Accompanying escorts/caregivers should be accommodated only if essential, with close adherence to distancing requirements.
- Use of PPE and precautions consistent with institutional or other conventionally accepted guidelines for known or suspected COVID-19-positive patients must be applied. Staff must complete PPE use training and use PPE consistent with institutional/provincial guidelines.
- Whenever possible, disposable equipment should be used. All exposed nondisposable neurodiagnostic equipment should be sanitized between patients with facility approved disinfectant preparations according to manufacturer's recommendations.
- Consider dedicating portable units for use in high-risk areas and/or for positive/ probable cases of COVID-19 Special attention should be paid to patients requiring escorts (i.e., pediatric or with disabilities). These patients' requisitions should be flagged in order to be identified in advance and account for the extra space needed in the waiting room. Prohibiting visitors and family members from attending the visit unless necessary is encouraged. The use of a clinical and epidemiological screening tool looking for high-risk patients prior to confirming the appointment and right before proceeding with the test (if done on a different date) is recommended. 1,3,4 Everyone, including all health care workers (HCWs), patients, and visitors, should be considered as potential carriers of COVID-19 in order to minimize risks. 10,11 Laboratory staff must be screened with a fit for work screening tool or questionnaire on a regular basis, preferable on a daily basis, to prevent institutional spreading of the infection. 1,10,11 They should adhere to all guidelines for physical distancing, isolation, or quarantine if required. Appropriate precautions, as dictated by local infection prevention and control (IPAC) leaders, should be used at all times at work. 11 Considerations for limiting technologist exposure to high-risk patients include limiting tests to only as long as absolutely necessary for a clinical decision, reducing inpatient technologist coverage hours, implementing alternate technologist shifts, identifying experienced technologists to manage challenging cases, and delaying testing until such expertise is available (although caution may be required for technologists over 60 years of age), considering mitigating factors (i.e., pregnancy, immunodeficiency, and living with elders), and providing resources for technologist counselling. 6 Laboratory leaders should reinforce that appropriate use of recommended equipment and processes will protect staff. They should also minimize personal displays of fear or anxiety that are not productive or helpful. 2 Re-triaging and prioritization of all cancelled or postponed patients is important including updates of the current status on their clinical conditions to confirm whether the test is still necessary or if an upgraded triage score is needed. Inpatients and after hours requests should be triaged by the attending neurologist on service or on-callnot a designate. Triaging of outpatient requests should be done by the laboratory director or a designate approved by the laboratory director. Patients must have appropriate notification on file and on the test requisition of confirmed or suspected COVID-19 infection to alert laboratory staff. PPE occupies a key role in preventing infection and dissemination of the disease. Three different tiers of facial masks are available including respirator masks (N95 and FFP2 variants) with higher filtering capacity particularly in aerosol-generating procedures. The second tier include the surgical masks which are classified into three levels according to their filtration efficacy. They offer protection against droplets from direct spatter although they are not as effective as the previous category for small particles. There is a variant of these masks which includes eye plastic shield increasing the protection capabilities. Finally, single-use masks may be made of a single layer and are not used in the healthcare setting as they can control mainly large volume of saliva emission. Two other elements for facial protection are available. Facial shields provide an additional physical barrier and could be utilized along with the previously mentioned masks to minimize risks. Powered air-purifying respirators are mainly used in dentistry practice. The last two options should be considered for high-risk procedures. 12,13 Surgical facial masks (preferable with plastic eye shield) and gloves should be used by the patient, escorts, technologists, physicians, and trainees at all times during the duration of the encounter. In select circumstances, N95 masks may be used if deemed appropriate (i.e., single-fiber EMG in facial muscles and confirmed COVID-19-positive patient). 2,4,9 Disposable or reusable PPE and biohazard waste management must follow well-known recommendations (i.e., Government of Canada, Center of Disease Control). Please refer to their websites for further details as it is beyond the scope of this document. 10,11 Staff should be trained in PPE use. 2 Equipment and testing rooms must be cleaned, disinfected, and sanitized at the beginning of the working day and after every patient tested. Minimal handling of equipment and testing materials is also desirable in order to minimize the possibilities of contamination. Consider the use of dedicated NCS/EMG/EEG/ evoked potential (EP) equipment for high-risk areas and/or positive/probable cases with COVID-19. 2,7 Strict cleaning procedures, that follow local IPAC guidance, should include but are not limited to :
- Cleaning all surfaces patients touch (beds, linens, chairs, doorknobs, grab bars, etc.)
- Cleaning all surfaces staff touch (keyboards, carts, cables, etc.)
- Disposable items should be used whenever cleaning is not feasible.
- If not disposable, consider covering ancillary equipment pieces in disposable single-use clear medical grade plastic, especially if equipment (e.g., jackboxes) is located close to the patient.
- Consider consulting the manufacturers of NCS/EMG/EEG/ EP units to ensure surface disinfectants used are compatible with the external hardware of the units and do not pose a risk of compromising equipment.
- The EEG equipment will usually require cleaning of the amplifier (headbox), computerkeyboard, cableswires, particularly if these are non-disposable. Extra time is needed for the disinfectant to air dry. This procedure usually takes extra 15-30 min per patient of the regular 75-90 min appointment.
- Cleaning of an EMG/NCS equipment may be quicker as most items making contact with the patient are disposable. An additional 15 min for cleaning/disinfecting should suffice.
Clinicians may want to consider providing some part of the care via virtual platforms such as initial history taking, discussion of results, and/or follow-up visits.
# EMG/NCS SPECIFIC RECOMMENDATIONS (TABLE 2)
In general, EMG/NCS in the setting of COVID-19 requires focus on the prevention of spread through contact and droplets, in addition to the usual body fluid precautions. Unless there is an AGMP in process (e.g., a patient is intubated, or on CPAP, or BiPAP,) or facial SFEMG is performed, there is no need for N95 masks and eyes protection. Although performing facial SFEMG is not considered an aerosolization maneuver, due to the proximity to involuntary sources of rapid exhalation (i.e., cough and sneeze) and the length of time exposed to the patient, a preference for using an N95 mask and facial shield or goggles seems reasonable based on individual risk assessment at the time. 2,4,8,9 Surgical masks (preferable with plastic eye shield) should be considered when performing peripheral EMG/NCS in COVID-19-negative patients; however, in COVID-19-positive patients, due to the potential aerosolization of the virus in the room, N95 mask and facial shield or goggles should be used. 9,12,13 Testing should be performed as many hours after an AGMP was performed as possible (preferable after 4 h). 6,7 Both patient and HCWs should have PPE appropriate for the prolonged, close contact. 10,11 Testing should be the minimum requirement for diagnosis and management. This will minimize in person contact. Measures should be taken to reduce the risk of patient-to-patient transmission such as doing inpatient studies on the wards instead of bringing patients to the lab. 2,4 When time-sensitive interventions or diagnostic accuracy is hinging upon EMG/NCS, these should be prioritized and performed using appropriate precautions. 8 Examples of such situations include patients who may be candidates for nerve transfers, patients with rapidly progressive deficits (e.g., suspected Guillain-Barré syndrome), patients in whom definitive diagnosis is required for treatment (e.g., generalized myasthenia gravis when the wait for serology results could be prolonged), or patients waiting for confirmation of serious conditions (e.g., suspected amyotrophic lateral sclerosis). When there is uncertainty about the urgency of a particular referral, then consideration should be given to contacting the referring physician and obtaining further information.
# EEG AND EMU SPECIFIC RECOMMENDATIONS (TABLE 3)
The decision to use collodion versus paste and tape must consider possible aerosolization risk with collodion application against the need to reapply paste and tape electrodes from poor adherence. 2,4,6 The length of the study should be short enough to address the patient management and at the same time to minimize the exposure of the technologist to a high-risk patient maintaining the minimal standards. 4,5 Hyperventilation should not be routinely performed, but if justified for high diagnostic yield (e.g., pediatric absence epilepsy), patients must wear surgical masks. Utilization of surgical mask and goggles or N95 and facial shield should be considered for inpatients when in the ward or intensive care units (ICUs), respectively. In COVID-19positive patients, the second facial protection combination is preferred. 7,9,12,13 Inpatient/continuous EEG should situate the portable video-EEG system outside the patient room using long cables if safe and necessary, particularly if COVID-19 positive or if the physical space in the epilepsy monitoring unit (EMU) room does not allow to place the EEG machine 2 m apart from the patient. 4 The number of different technologists entering each patient room should be limited. Stimulation for reactivity assessment can still be performed. Recordings should last at least 20 min, but may be delayed by at least 4 h to reduce potential airborne transmission if there has been nebulizer treatment. 2,4,6 Prior to EMU reopening, ensure adequate staffing and rescue medications, mask and COVID-19 testing availability, limiting patient breaks, available ICU beds for post-operative care and status epilepticus, and physical distance from COVID-19 areas. Rounds and surgical conferences should be virtualized, with consideration to additional operations and business meetings to review lists of previously cancelled/held admissions, new admissions, and intracranial subdural/stereo-EEG/electrocorticography logistics. 4,14 Admissions should consider whether nasal/oropharyngeal swab for rapid COVID-19 testing is deemed necessary as - For electrode application, the decision to use collodion versus paste and tape must consider possible aerosolization risk with collodion application against the need to reapply paste and tape electrodes due to poor adherence.
- The test's length should be sufficient to address patient management while maintaining minimal standards.
- Hyperventilation should not be routinely performed. If justified for high diagnostic yield (e.g., pediatric absence epilepsy), patients must wear surgical masks.
- In the inpatient setting, equipment should be outside the patient's room using a long cable if possible. Stimulation for reactivity assessment can still be performed.
- Nasal/oropharyngeal swab test for rapid COVID-19 detection could be considered at admission to EMU with the aim to mitigate contagious risks.
- EMU admissions should consider whether a single companion is allowed in the EMU when needed for safety and/or diagnostic accuracy.
- Priority indications may include but are not limited to: potential for management changes based on monitoring, pre-surgical workup (phase I, II, and ictal SPECT), high seizure burden, SUDEP risk, threat of disease worsening, and frequent emergency department visits.
- If ambulatory EEG is used as an EMU alternative it should include video, ideally with outpatient dis/connection.
- VNS/DBS insertion for epilepsy, setting revisions, or battery exchange should be considered only if seizure frequency and severity outweighs COVID-19 risk.
- Cleaning of EP equipment must use disinfectants that are compatible, and if using earbuds or inner ear electrodes for BAEP, they must be discarded after each use.
SUDEP = sudden unexpected death in epilepsy; SPECT = single-photon emission computed tomography. - Testing should be the minimum requirement for diagnosis and management including the number of conduction studies and/or the number of muscles assessed with needle EMG.
- When time-sensitive interventions or diagnostic accuracy is hinging upon EMG/ NCS, these should be prioritized and performed using appropriate precautions. 8 Examples include (but are not limited to) patients waiting for nerve transfers or those with suspected Guillain-Barré syndrome, myasthenia gravis, or amyotrophic lateral sclerosis.
- Surgical mask and facial shield or goggles are considered satisfactory for the majority of EMG procedures. Although performing facial SFEMG is not considered an aerosolization maneuver, due to the proximity to involuntary sources of rapid exhalation (i.e., cough and sneeze) and the length of time exposed to the patient, a preference for using an N95 mask and facial shield or goggles seems reasonable based on individual risk assessment at the time.
an early infection detection could prevent further contagious disease. 15 Consideration should be present for allowing family members in the EMU if needed for safety and diagnostic accuracy. Priority indications may include potential for management changes based on monitoring, pre-surgical workup (phase I, II, and ictal single-photon emission computed tomography), high seizure burden, sudden unexpected death in epilepsy risk, threat of disease worsening, and frequent emergency department visits. 14 To avoid cross-contamination between hospital populations, EMUs should be populated by persons with, or suspected to have, epilepsy. EMUs may also consider initially reopening at half capacity with physical distancing and enhanced barrier protection measures (e.g., plastic over curtains). 2,4,14 As a possible EMU alternative, ambulatory EEG should include video, ideally with outpatient dis/connection external to hospital, plastic covering for community COVID-19 settings, and allowing a "rest period" between uses for potentially difficult to disinfect ambulatory pieces (e.g., pouches and straps), while keeping in mind battery limitations. 14 NEUROSTIMULATION (TABLE 3) If stable, consider using virtual visits and deferring programmatic changes, with alternatives such as optimizing anti-seizure medications and instituting a rescue medication strategy. While vagus nerve stimulator (VNS) auto-titration and deep brain stimulation (DBS) program sets allow automated changes, decompensation may occur in remote settings, and surgical procedures may be limited even in urban centres. The need for in-person programming/evaluation should consider factors such as status epilepticus, increased seizures, seizure-related injuries, severe stimulation-related side effects, battery depletion, nonsuperficial hardware infection, and hardware malfunction on a case-by-case basis. 16
# EP SPECIFIC RECOMMENDATIONS (TABLE 3)
Consult the manufacturer of goggles and headphones to ensure surface disinfectants used are compatible with the external hardware and do not pose a risk of compromising equipment or patient care. If using earbuds or inner ear electrodes for sound generation, they must be discarded after each use. 4 When somatosensory EPs are needed in the ICU setting, assess whether the patient poses a risk of aerosol-generating procedures and ensure adequate PPE is used according to your facilities' recommendations; N95 mask may be necessary in these cases. 2,4,7 IOM SPECIFIC RECOMMENDATIONS Patients with active infectious disease, including COVID-19, or those on droplet or contact precautions are unlikely to undergo surgery requiring intraoperative monitoring, unless it is deemed medically emergent. 4,17 In these cases, consideration of aerosolgenerating procedures such as intubation or cautery should determine the appropriate PPE required and the safe distance from the patient. 2,4,17 Only sterile single-use needle and corkscrew electrodes should be used. Surface electrodes should be single-use and discarded after use. 17 Remote monitoring could reduce exposure to the neurophysiologist or technologist. 4,17
# FUTURE DIRECTIONS (TABLE 4)
The COVID-19 pandemic has created opportunities for innovation and potential improvement in delivery of diagnostic testing and care for patients with neurological disorders. The remote clinical practice is now a global reality. Clinicians may consider providing some part of their electrophysiological care via phone or virtual platforms where internet or cellphone network is accessible. This could include screening of referrals, initial history taking, discussion of results with either patients or other health care personnel, seeking second opinions, team management meetings, and/or follow-up visits. 18,19 The development or revision of local guidelines on appropriate referral criteria for neurodiagnostic studies could optimize the use of clinical neurophysiology resources, minimizing unnecessary testing and prioritizing studies that otherwise could have been delayed due to saturation of the health system. Local guidelines could also address the need for and frequency of follow-up studies in those cases where neurophysiological studies are the only objective way to measure improvement of medical or surgical interventions. 18,19 Validation of the utility and the cost-effectiveness of remote-virtual care needs further assessment. The lack of reported data on the pros and cons of virtual care in neurophysiology in comparison to in-person visits merits further assessment in the field.
These guidelines may also serve as a useful reference in the case of future pandemics. Eventual resolution of the pandemic or the development of successful therapy for COVID-19 may make these guidelines obsolete. However, in the meantime, following the above recommendations is crucial to minimize the spreading of COVID-19. Revised versions will be made available on the CSCN website.
# DISCLOSURES
Dr. Venance reports personal fees from Sanofi Genzyme, outside the submitted work. None of the other authors report any conflicts of interest.
# STATEMENT OF AUTHORSHIP
JPA and FM were equal lead authors of this work. They compiled all partial drafts, multiple feedbacks from all co-authors at different stages, wrote the first draft of the manuscript, and - Clinicians may consider providing some part of the care via virtual platforms. This could include screening of referrals, initial history taking, discussion of results with either patients or other health care personnel, and/or follow-up visits.
- Development or revision of local guidelines on appropriate referral criteria for neurodiagnostic studies could help to optimize the use of clinical neurophysiology resources.
- Local guidelines could also address the need for and frequency of follow-up studies.
- Validation of the utility and the cost-effectiveness of remote-virtual care needs further assessment.
- These guidelines may be revised if and when more evidence become available.
produced the final version of the manuscript after revisions and editing were made. SKB, KMC, TD, TH, M-LJ, MMM, SMM, MN, JN, VO, CP, LR, AS, JT-Z, MVN, and SV produced different sections of the manuscript, discussed the pertinent topic, and provided feedback of the whole work during revisions of the first draft, the manuscript at different stages, and the editing of the final document. | The COVID-19 pandemic has had a major impact on clinical practice. Safe standards of practice are essential to protect health care workers while still allowing them to provide good care. The Canadian Society of Clinical Neurophysiologists, the Canadian Association of Electroneurophysiology Technologists, the Association of Electromyography Technologists of Canada, the Board of Registration of Electromyography Technologists of Canada, and the Canadian Board of Registration of Electroencephalograph Technologists have combined to review current published literature about safe practices for neurophysiology laboratories. Herein, we present the results of our review and provide our expert opinion regarding the safe practice of neurophysiology during the COVID-19 pandemic in Canada. RÉSUMÉ : Lignes directrices et pratiques exemplaires destinées, dans le contexte de la pandémie de COVID-19, aux laboratoires canadiens de neurophysiologie. La pandémie de COVID-19 a eu un impact majeur sur la pratique clinique. En matière de pratique, des normes sécuritaires demeurent justement essentielles afin de protéger les travailleurs de la santé tout en leur permettant de prodiguer des soins adéquats. La Société canadienne des neurophysiologistes cliniques (CSCN), l'Association canadienne des technologues en électro-neurophysiologie, l'Association canadienne des technologues en électromyographie, le Board of Registration of Electromyography Technologists of Canada et le Conseil canadien d'enregistrement des technologues en électroencéphalographe se sont ainsi associés afin de passer en revue la littérature scientifique actuelle portant sur les pratiques sécuritaires au sein des laboratoires de neurophysiologie. Nous souhaitons donc présenter ici les résultats de notre revue de littérature et proposer, dans le contexte de la COVID-19, un regard éclairé en ce qui regarde les pratiques sécuritaires en neurophysiologie au Canada.# INTRODUCTION
Given that the current COVID-19 pandemic will continue to affect Canadian health care for the foreseeable future, our organizations felt that it was appropriate to provide some guidance on safe practices during the pandemic. We begin by presenting the key points in table form in order to emphasize the practical aim of this article. The main body of the article elaborates on these points and provides the scientific rationale for their inclusion, when this exists.
# PURPOSE
To provide guidelines for safe functioning of neurophysiology laboratories during the COVID-19 pandemic, recommendations are based on expert opinion and review of relevant published guidelines. These guidelines are not intended to replace institutional, regional, or provincial protocols.
# BACKGROUND
Named "Severe Acute Respiratory Syndrome (SARS)-CoV-2" by the Coronaviridae Study Group, the coronavirus causing the current pandemic is responsible for the third outbreak of acute respiratory syndrome in the last two decades after the SARS in 2003 and the Middle East Respiratory Syndrome (MERS) in 2012. 20 The disease caused by this coronavirus is known as "COVID-19" and the full spectrum of its symptomatology and pathophysiology is yet to be defined. As its name implies, the respiratory symptoms (cough, fever, and dyspnea) are present in more than 60% of hospitalized patients and are the main cause of death. 21 It is clear that staff in the neurophysiology laboratory will be exposed to COVID-19 due to the nature of this disease. The reported neurological manifestations include a wide range of symptoms and signs such as headaches, anosmia and ageusia, impaired consciousness, toxic-metabolic encephalopathy, encephalitis, seizures and status epilepticus, strokes and vascular events, Guillain-Barré syndrome, myositis, and peripheral nerve disorders. 22 The current ongoing Canadian provincial plans to re-launch the economy are at different levels of complexity in each province. However, some have already announced the re-opening of regulated health profession services and some have scheduled nonurgent surgeries as long as they continue to follow approved guidelines set by their professional colleges. 23 These developments have led the Canadian Society of Clinical Neurophysiologists (CSCN), the Canadian Association of Electroneurophysiology Technologists, the Association of Electromyography Technologists of Canada, the Board of Registration of Electromyography Technologists of Canada, and the Canadian Board of Registration of Electroencephalograph Technologists to elaborate this guideline for safe practice in the neurophysiology laboratories of Canada.
# GENERAL INFECTION CONTROL RECOMMENDATIONS (TABLE 1)
Booking of patients for neurophysiology testing should be prudent and minimize unnecessary testing. If the test will not change clinical management, avoid an emergency department visit, or avoid morbidity and mortality it should in general be deferred. During crisis or peak periods of the pandemic, only cases that are urgent or time-sensitive should be seen, such as those posing threat to life, limb, or long-term outcome. 1,2 As the pandemic starts to come under control and laboratories gain greater experience with safely seeing patients, the threshold for selecting appropriate patients for neurophysiological testing will become progressively lower. [3][4][5][6] Patient workflow should still be adjusted in order to assess high-risk cases safely. 1,3 In COVID-19-positive cases, neurodiagnostic testing should be performed only in the inpatient setting with full personal protective equipment (PPE) equipment as per local protocols, only if test results will change management (treatment and/or diagnosis), and ideally in an airborne infection isolation room (AIIR) as the virus could survive several hours to days on certain surfaces. 2,4,7 If done in AIIR, these tests should be postponed for at least 4 h if recent aerosol generating medical procedure (AGMP) had been performed (i.e., nebulizer therapy, chest physiotherapy, intubation, bronchoscopy, sputum induction, bilevel positive airway pressure [BiPAP], or continuous positive airway pressure [CPAP] use). 5,7 The outpatient setting is reserved for COVID-19-negative patients when triaging deems necessary. [3][4][5][6]8 The waiting room must be utilized in a way that will allow a 2-m gap (physical distancing) between patients, including not concomitant bookings if needed due to limited physical space. [1][2][3][4]9 Electroencephalogram (EEG) and electromyogram/ nerve conduction study (EMG/NCS) technologists must avoid remaining in the waiting room to minimize physical contact with patients. There should be sufficient time between appointments to allow for distancing arrangements and the cleaning of equipment. 2,4 If multiple clinics running simultaneously share the waiting room, staff should consider the implications of a large volume of patients in shared spaces, including corridors. 1 Table 1: General infection control recommendations [1][2][3][4][5][6][7][8][9][10][11][12][13] • Scheduling should be guided by medical urgency, laboratory/staff limitations, and waiting room occupancy considerations (respecting 2-m physical distancing).
• All patients should undergo screening for COVID-19 exposure by questionnaire or patient transport service checklist. If local institutional versions do not exist, online versions are available.
• Clinical neurophysiological investigations require prolonged, close contact with patients. All patients and companions, doctors, and technologists should be required to wear a mask and gloves unless otherwise contraindicated.
• Testing of COVID-19-positive patients should be performed only if critical for patient diagnosis and medical management.
• In the training laboratory, the number of personnel should be minimized. One instructor and one trainee are preferable. Accompanying escorts/caregivers should be accommodated only if essential, with close adherence to distancing requirements.
• Use of PPE and precautions consistent with institutional or other conventionally accepted guidelines for known or suspected COVID-19-positive patients must be applied. Staff must complete PPE use training and use PPE consistent with institutional/provincial guidelines.
• Whenever possible, disposable equipment should be used. All exposed nondisposable neurodiagnostic equipment should be sanitized between patients with facility approved disinfectant preparations according to manufacturer's recommendations.
• Consider dedicating portable units for use in high-risk areas and/or for positive/ probable cases of COVID-19 Special attention should be paid to patients requiring escorts (i.e., pediatric or with disabilities). These patients' requisitions should be flagged in order to be identified in advance and account for the extra space needed in the waiting room. Prohibiting visitors and family members from attending the visit unless necessary is encouraged. The use of a clinical and epidemiological screening tool looking for high-risk patients prior to confirming the appointment and right before proceeding with the test (if done on a different date) is recommended. 1,3,4 Everyone, including all health care workers (HCWs), patients, and visitors, should be considered as potential carriers of COVID-19 in order to minimize risks. 10,11 Laboratory staff must be screened with a fit for work screening tool or questionnaire on a regular basis, preferable on a daily basis, to prevent institutional spreading of the infection. 1,10,11 They should adhere to all guidelines for physical distancing, isolation, or quarantine if required. Appropriate precautions, as dictated by local infection prevention and control (IPAC) leaders, should be used at all times at work. 11 Considerations for limiting technologist exposure to high-risk patients include limiting tests to only as long as absolutely necessary for a clinical decision, reducing inpatient technologist coverage hours, implementing alternate technologist shifts, identifying experienced technologists to manage challenging cases, and delaying testing until such expertise is available (although caution may be required for technologists over 60 years of age), considering mitigating factors (i.e., pregnancy, immunodeficiency, and living with elders), and providing resources for technologist counselling. [1][2][3][4]6 Laboratory leaders should reinforce that appropriate use of recommended equipment and processes will protect staff. They should also minimize personal displays of fear or anxiety that are not productive or helpful. 2 Re-triaging and prioritization of all cancelled or postponed patients is important including updates of the current status on their clinical conditions to confirm whether the test is still necessary or if an upgraded triage score is needed. Inpatients and after hours requests should be triaged by the attending neurologist on service or on-callnot a designate. Triaging of outpatient requests should be done by the laboratory director or a designate approved by the laboratory director. Patients must have appropriate notification on file and on the test requisition of confirmed or suspected COVID-19 infection to alert laboratory staff. [2][3][4] PPE occupies a key role in preventing infection and dissemination of the disease. Three different tiers of facial masks are available including respirator masks (N95 and FFP2 variants) with higher filtering capacity particularly in aerosol-generating procedures. The second tier include the surgical masks which are classified into three levels according to their filtration efficacy. They offer protection against droplets from direct spatter although they are not as effective as the previous category for small particles. There is a variant of these masks which includes eye plastic shield increasing the protection capabilities. Finally, single-use masks may be made of a single layer and are not used in the healthcare setting as they can control mainly large volume of saliva emission. Two other elements for facial protection are available. Facial shields provide an additional physical barrier and could be utilized along with the previously mentioned masks to minimize risks. Powered air-purifying respirators are mainly used in dentistry practice. The last two options should be considered for high-risk procedures. 12,13 Surgical facial masks (preferable with plastic eye shield) and gloves should be used by the patient, escorts, technologists, physicians, and trainees at all times during the duration of the encounter. In select circumstances, N95 masks may be used if deemed appropriate (i.e., single-fiber EMG [SFEMG] in facial muscles and confirmed COVID-19-positive patient). 2,4,9 Disposable or reusable PPE and biohazard waste management must follow well-known recommendations (i.e., Government of Canada, Center of Disease Control). Please refer to their websites for further details as it is beyond the scope of this document. 10,11 Staff should be trained in PPE use. 2 Equipment and testing rooms must be cleaned, disinfected, and sanitized at the beginning of the working day and after every patient tested. Minimal handling of equipment and testing materials is also desirable in order to minimize the possibilities of contamination. Consider the use of dedicated NCS/EMG/EEG/ evoked potential (EP) equipment for high-risk areas and/or positive/probable cases with COVID-19. 2,7 Strict cleaning procedures, that follow local IPAC guidance, should include but are not limited to [1][2][3][4][5][6][7][8] :
• Cleaning all surfaces patients touch (beds, linens, chairs, doorknobs, grab bars, etc.)
• Cleaning all surfaces staff touch (keyboards, carts, cables, etc.)
• Disposable items should be used whenever cleaning is not feasible.
• If not disposable, consider covering ancillary equipment pieces in disposable single-use clear medical grade plastic, especially if equipment (e.g., jackboxes) is located close to the patient.
• Consider consulting the manufacturers of NCS/EMG/EEG/ EP units to ensure surface disinfectants used are compatible with the external hardware of the units and do not pose a risk of compromising equipment.
• The EEG equipment will usually require cleaning of the amplifier (headbox), computerkeyboard, cableswires, particularly if these are non-disposable. Extra time is needed for the disinfectant to air dry. This procedure usually takes extra 15-30 min per patient of the regular 75-90 min appointment.
• Cleaning of an EMG/NCS equipment may be quicker as most items making contact with the patient are disposable. An additional 15 min for cleaning/disinfecting should suffice.
Clinicians may want to consider providing some part of the care via virtual platforms such as initial history taking, discussion of results, and/or follow-up visits.
# EMG/NCS SPECIFIC RECOMMENDATIONS (TABLE 2)
In general, EMG/NCS in the setting of COVID-19 requires focus on the prevention of spread through contact and droplets, in addition to the usual body fluid precautions. Unless there is an AGMP in process (e.g., a patient is intubated, or on CPAP, or BiPAP,) or facial SFEMG is performed, there is no need for N95 masks and eyes protection. [2][3][4] Although performing facial SFEMG is not considered an aerosolization maneuver, due to the proximity to involuntary sources of rapid exhalation (i.e., cough and sneeze) and the length of time exposed to the patient, a preference for using an N95 mask and facial shield or goggles seems reasonable based on individual risk assessment at the time. 2,4,8,9 Surgical masks (preferable with plastic eye shield) should be considered when performing peripheral EMG/NCS in COVID-19-negative patients; however, in COVID-19-positive patients, due to the potential aerosolization of the virus in the room, N95 mask and facial shield or goggles should be used. 9,12,13 Testing should be performed as many hours after an AGMP was performed as possible (preferable after 4 h). 6,7 Both patient and HCWs should have PPE appropriate for the prolonged, close contact. 10,11 Testing should be the minimum requirement for diagnosis and management. This will minimize in person contact. Measures should be taken to reduce the risk of patient-to-patient transmission such as doing inpatient studies on the wards instead of bringing patients to the lab. 2,4 When time-sensitive interventions or diagnostic accuracy is hinging upon EMG/NCS, these should be prioritized and performed using appropriate precautions. 8 Examples of such situations include patients who may be candidates for nerve transfers, patients with rapidly progressive deficits (e.g., suspected Guillain-Barré syndrome), patients in whom definitive diagnosis is required for treatment (e.g., generalized myasthenia gravis when the wait for serology results could be prolonged), or patients waiting for confirmation of serious conditions (e.g., suspected amyotrophic lateral sclerosis). When there is uncertainty about the urgency of a particular referral, then consideration should be given to contacting the referring physician and obtaining further information.
# EEG AND EMU SPECIFIC RECOMMENDATIONS (TABLE 3)
The decision to use collodion versus paste and tape must consider possible aerosolization risk with collodion application against the need to reapply paste and tape electrodes from poor adherence. 2,4,6 The length of the study should be short enough to address the patient management and at the same time to minimize the exposure of the technologist to a high-risk patient maintaining the minimal standards. 4,5 Hyperventilation should not be routinely performed, but if justified for high diagnostic yield (e.g., pediatric absence epilepsy), patients must wear surgical masks. [4][5][6] Utilization of surgical mask and goggles or N95 and facial shield should be considered for inpatients when in the ward or intensive care units (ICUs), respectively. In COVID-19positive patients, the second facial protection combination is preferred. 7,9,12,13 Inpatient/continuous EEG should situate the portable video-EEG system outside the patient room using long cables if safe and necessary, particularly if COVID-19 positive or if the physical space in the epilepsy monitoring unit (EMU) room does not allow to place the EEG machine 2 m apart from the patient. 4 The number of different technologists entering each patient room should be limited. Stimulation for reactivity assessment can still be performed. Recordings should last at least 20 min, but may be delayed by at least 4 h to reduce potential airborne transmission if there has been nebulizer treatment. 2,4,6 Prior to EMU reopening, ensure adequate staffing and rescue medications, mask and COVID-19 testing availability, limiting patient breaks, available ICU beds for post-operative care and status epilepticus, and physical distance from COVID-19 areas. Rounds and surgical conferences should be virtualized, with consideration to additional operations and business meetings to review lists of previously cancelled/held admissions, new admissions, and intracranial subdural/stereo-EEG/electrocorticography logistics. 4,14 Admissions should consider whether nasal/oropharyngeal swab for rapid COVID-19 testing is deemed necessary as • For electrode application, the decision to use collodion versus paste and tape must consider possible aerosolization risk with collodion application against the need to reapply paste and tape electrodes due to poor adherence.
• The test's length should be sufficient to address patient management while maintaining minimal standards.
• Hyperventilation should not be routinely performed. If justified for high diagnostic yield (e.g., pediatric absence epilepsy), patients must wear surgical masks.
• In the inpatient setting, equipment should be outside the patient's room using a long cable if possible. Stimulation for reactivity assessment can still be performed.
• Nasal/oropharyngeal swab test for rapid COVID-19 detection could be considered at admission to EMU with the aim to mitigate contagious risks.
• EMU admissions should consider whether a single companion is allowed in the EMU when needed for safety and/or diagnostic accuracy.
• Priority indications may include but are not limited to: potential for management changes based on monitoring, pre-surgical workup (phase I, II, and ictal SPECT), high seizure burden, SUDEP risk, threat of disease worsening, and frequent emergency department visits.
• If ambulatory EEG is used as an EMU alternative it should include video, ideally with outpatient dis/connection.
• VNS/DBS insertion for epilepsy, setting revisions, or battery exchange should be considered only if seizure frequency and severity outweighs COVID-19 risk.
• Cleaning of EP equipment must use disinfectants that are compatible, and if using earbuds or inner ear electrodes for BAEP, they must be discarded after each use.
SUDEP = sudden unexpected death in epilepsy; SPECT = single-photon emission computed tomography. • Testing should be the minimum requirement for diagnosis and management including the number of conduction studies and/or the number of muscles assessed with needle EMG.
• When time-sensitive interventions or diagnostic accuracy is hinging upon EMG/ NCS, these should be prioritized and performed using appropriate precautions. 8 Examples include (but are not limited to) patients waiting for nerve transfers or those with suspected Guillain-Barré syndrome, myasthenia gravis, or amyotrophic lateral sclerosis.
• Surgical mask and facial shield or goggles are considered satisfactory for the majority of EMG procedures. Although performing facial SFEMG is not considered an aerosolization maneuver, due to the proximity to involuntary sources of rapid exhalation (i.e., cough and sneeze) and the length of time exposed to the patient, a preference for using an N95 mask and facial shield or goggles seems reasonable based on individual risk assessment at the time.
an early infection detection could prevent further contagious disease. 15 Consideration should be present for allowing family members in the EMU if needed for safety and diagnostic accuracy. Priority indications may include potential for management changes based on monitoring, pre-surgical workup (phase I, II, and ictal single-photon emission computed tomography), high seizure burden, sudden unexpected death in epilepsy risk, threat of disease worsening, and frequent emergency department visits. 14 To avoid cross-contamination between hospital populations, EMUs should be populated by persons with, or suspected to have, epilepsy. EMUs may also consider initially reopening at half capacity with physical distancing and enhanced barrier protection measures (e.g., plastic over curtains). 2,4,14 As a possible EMU alternative, ambulatory EEG should include video, ideally with outpatient dis/connection external to hospital, plastic covering for community COVID-19 settings, and allowing a "rest period" between uses for potentially difficult to disinfect ambulatory pieces (e.g., pouches and straps), while keeping in mind battery limitations. [4][5][6]14 NEUROSTIMULATION (TABLE 3) If stable, consider using virtual visits and deferring programmatic changes, with alternatives such as optimizing anti-seizure medications and instituting a rescue medication strategy. While vagus nerve stimulator (VNS) auto-titration and deep brain stimulation (DBS) program sets allow automated changes, decompensation may occur in remote settings, and surgical procedures may be limited even in urban centres. The need for in-person programming/evaluation should consider factors such as status epilepticus, increased seizures, seizure-related injuries, severe stimulation-related side effects, battery depletion, nonsuperficial hardware infection, and hardware malfunction on a case-by-case basis. 16
# EP SPECIFIC RECOMMENDATIONS (TABLE 3)
Consult the manufacturer of goggles and headphones to ensure surface disinfectants used are compatible with the external hardware and do not pose a risk of compromising equipment or patient care. If using earbuds or inner ear electrodes for sound generation, they must be discarded after each use. 4 When somatosensory EPs are needed in the ICU setting, assess whether the patient poses a risk of aerosol-generating procedures and ensure adequate PPE is used according to your facilities' recommendations; N95 mask may be necessary in these cases. 2,4,7 IOM SPECIFIC RECOMMENDATIONS Patients with active infectious disease, including COVID-19, or those on droplet or contact precautions are unlikely to undergo surgery requiring intraoperative monitoring, unless it is deemed medically emergent. 4,17 In these cases, consideration of aerosolgenerating procedures such as intubation or cautery should determine the appropriate PPE required and the safe distance from the patient. 2,4,17 Only sterile single-use needle and corkscrew electrodes should be used. Surface electrodes should be single-use and discarded after use. 17 Remote monitoring could reduce exposure to the neurophysiologist or technologist. 4,17
# FUTURE DIRECTIONS (TABLE 4)
The COVID-19 pandemic has created opportunities for innovation and potential improvement in delivery of diagnostic testing and care for patients with neurological disorders. The remote clinical practice is now a global reality. Clinicians may consider providing some part of their electrophysiological care via phone or virtual platforms where internet or cellphone network is accessible. This could include screening of referrals, initial history taking, discussion of results with either patients or other health care personnel, seeking second opinions, team management meetings, and/or follow-up visits. 18,19 The development or revision of local guidelines on appropriate referral criteria for neurodiagnostic studies could optimize the use of clinical neurophysiology resources, minimizing unnecessary testing and prioritizing studies that otherwise could have been delayed due to saturation of the health system. Local guidelines could also address the need for and frequency of follow-up studies in those cases where neurophysiological studies are the only objective way to measure improvement of medical or surgical interventions. 18,19 Validation of the utility and the cost-effectiveness of remote-virtual care needs further assessment. The lack of reported data on the pros and cons of virtual care in neurophysiology in comparison to in-person visits merits further assessment in the field.
These guidelines may also serve as a useful reference in the case of future pandemics. Eventual resolution of the pandemic or the development of successful therapy for COVID-19 may make these guidelines obsolete. However, in the meantime, following the above recommendations is crucial to minimize the spreading of COVID-19. Revised versions will be made available on the CSCN website.
# DISCLOSURES
Dr. Venance reports personal fees from Sanofi Genzyme, outside the submitted work. None of the other authors report any conflicts of interest.
# STATEMENT OF AUTHORSHIP
JPA and FM were equal lead authors of this work. They compiled all partial drafts, multiple feedbacks from all co-authors at different stages, wrote the first draft of the manuscript, and • Clinicians may consider providing some part of the care via virtual platforms. This could include screening of referrals, initial history taking, discussion of results with either patients or other health care personnel, and/or follow-up visits.
• Development or revision of local guidelines on appropriate referral criteria for neurodiagnostic studies could help to optimize the use of clinical neurophysiology resources.
• Local guidelines could also address the need for and frequency of follow-up studies.
• Validation of the utility and the cost-effectiveness of remote-virtual care needs further assessment.
• These guidelines may be revised if and when more evidence become available.
produced the final version of the manuscript after revisions and editing were made. SKB, KMC, TD, TH, M-LJ, MMM, SMM, MN, JN, VO, CP, LR, AS, JT-Z, MVN, and SV produced different sections of the manuscript, discussed the pertinent topic, and provided feedback of the whole work during revisions of the first draft, the manuscript at different stages, and the editing of the final document. | None | None |
2e3587c0b67668cfc6a82b73b0de4892a9ef9b51 | cma | None | This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY# Introduction
Breast cancer is a common disease in Canada, with approximately 25,000 new cases per year . Survival outcomes with early-stage breast cancer have significantly improved over time with advances in systemic therapy, especially adjuvant chemotherapy and endocrine therapy .
Breast cancer is a heterogenous disease classified traditionally by expression of the ER, PR and/or HER receptor. Clinical decision making regarding adjuvant systemic therapy may vary and is commonly influenced by patient, clinical and pathologic factors, including tumor size, histologic grade, lymph node status and ER, PR and HER2 expression, all of which have been shown to significantly influence the risk of disease recurrence . Given the potential side effects and toxicity of systemic therapy, several molecular gene expression profiling tests have been developed to assess the risk of recurrence. The use of these assays is meant to improve clinical decision making and optimize the use of systemic therapy for breast cancer.
Clinical decision-making regarding the use of adjuvant chemotherapy has historically been based on a variety of factors, including breast cancer stage, tumor biology and patient characteristics, all of which can be used to target patients at higher risk of disease recurrence. However, treatment decision remains challenging, especially among ER-positive, HER2-negative invasive breast cancers that are often less responsive to chemotherapy and may derive more clinical benefit from endocrine therapy alone. Previous treatment recommendations were generated from population-based or clinical trial data and were not necessarily indicative of clinical benefit at an individual patient level . This imprecision has resulted in the overuse of adjuvant chemotherapy in some breast cancer patients, with unnecessary exposure to side effects and potential toxicity . To mitigate this, several molecular profiling tests have been developed and validated that classify tumours into low-, intermediate-, or high-risk categories for risk of disease recurrence. These multigene profiling assays are generally prognostic of breast cancer outcomes. Some may also predict the potential benefit from systemic therapy in terms of distant recurrence, IDFS, and OS . Currently, several multigene profiling assays are approved by health regulatory agencies and supported for use by international breast cancer clinical guidelines. These assays are used in standard clinical practice to guide clinical decision making regarding the use of adjuvant chemotherapy for node-negative ER-positive/HER2-negative invasive breast cancer.
Ontario Health (Cancer Care Ontario)'s Program in Evidence-Based Care, together with the Molecular Oncology and Testing Advisory Committee, developed the present guideline reviewing several multigene expression assays, including Oncotype DX (Exact Sciences Corporation, Madison, WI, USA), Mammaprint (Agendia, Irvine, CA, USA), Prosigna (Veracyte, South San Francisco, CA, USA) EndoPredict (Myriad Genetics, Inc., Zurich, Switzerland), and Breast Cancer Index (Biotheranostics, Inc., San Diego, CA, USA).
Another assay, IHC4, was not included, given potential concerns regarding the reproducibility of the Ki67 measurement across pathology laboratories. IHC4 is not a commercially available test; however, it can be calculated on the basis of ER, PR, and HER2 expression and Ki67 scoring . The Working Group decided not to focus its investigation on the utility of multigene profiling assays with regard to supporting clinical decision making for neoadjuvant chemotherapy or radiation therapy, given the number of ongoing trials.
The objectives of the current review were to assess the clinical utility of Oncotype DX, MammaPrint, Prosigna, EndoPredict, and Breast Cancer Index in terms of their ability to predict response to adjuvant chemotherapy and extended adjuvant endocrine therapy. A specific aim was to investigate the evidence for the use of these molecular profiling assays in the setting of either node-negative or node-positive ER-positive/HER2-negative breast cancer patients in guiding clinical decisions to withhold or offer adjuvant chemotherapy. Additionally, important patient factors impacting the utilization of molecular profiling results, including age at diagnosis and menopausal status, were of special interest in this review.
# Methods
# The Program in Evidence-Based Care (PEBC)
The PEBC is an initiative of the Ontario provincial cancer system, Ontario Health (Cancer Care Ontario). The PEBC produces evidence-based and evidence-informed guidance documents using the methods of the Practice Guidelines Development Cycle . The process for the current guideline included a systematic review with interpretation of the evidence by the authors, who then drafted recommendations based on the evidence and expert consensus; internal review by content and methodology experts; and external review by clinicians and other stakeholders. The authors had expertise in medical oncology, pathology, medical genetics, and health research methodology.
Further details of the methods and findings of the systematic review that informed these recommendations have been published elsewhere . Briefly, MEDLINE, EMBASE and the Cochrane Library were searched for studies that reported predictive data based on assay outcome (i.e., studies considering differential treatment effect). If there were no predictive studies available for either adjuvant chemotherapy or extended adjuvant endocrine therapy, then prognostic studies examining late recurrence (i.e., 5-10 years) were included. The risk of bias was assessed for each included RCT or retrospective analyses of RCTs, where the randomization was not broken using Cochrane's Risk of Bias tool, /, accessed on 10 June 2021 (Part 2, Section 8.5). Criteria from the QUIPS tool were used to assess the risk of bias for all prognostic studies.
# Patient and Caregiver-Specific Consultation Group
Patients/survivors/caregivers participated as Consultation Group members. They reviewed copies of the project plan, drafted recommendations and provided feedback on their comprehensibility, appropriateness, and feasibility to the Working Group's Health Research Methodologist. The Health Research Methodologist relayed this feedback to the Working Group for consideration.
# Internal Review
PEBC guidelines were reviewed by a panel of content experts (Expert Panel) and a methodology panel (Report Approval Panel). For the guideline document to be approved, 75% of the content experts who comprise the Expert Panel must cast a vote indicating whether or not they approve the document or abstain from voting for a specified reason, and of those that vote, 75% must approve the document. In addition, the PEBC Report Approval Panel, a three-person panel with methodology expertise, must unanimously approve the document.
# External Review
Feedback on the approved draft guideline was obtained from content experts and the target users through two processes. Through the Targeted Peer Review, a small number of content experts were identified by the Guideline Development Group (GDG) and asked to review and provide feedback on the guideline document. Through Professional Consultation, which is intended to facilitate dissemination of the final guidelines to Ontario practitioners, relevant care providers and other potential users of the guideline were contacted and asked to provide feedback on the guideline recommendations through a brief online survey.
# Results
The full systematic review provides more details of the methodologic characteristics and clinical outcomes .
# Patient and Caregiver-Specific Consultation Group
Three patients/survivors/caregivers participated as Consultation Group members. The Consultation Group found the recommendations were clear and detailed, with ad-equate evidence to support each recommendation. It was also noted that the guideline addresses issues of concern to patients, such as treatment versus survival benefits, and takes into consideration the emotional impact of testing.
# Internal Review
Three Report Approval Panel members, including the PEBC Scientific Director and two methodology experts, reviewed and approved the draft guideline in September 2021.
Of the 10 members of the Expert Panel, 8 members cast votes for an 80% response rate in August 2021. All of those who voted approved the document (100%).
# External Review
After approval of the document at internal review, the authors circulated the draft document to external review participants for review and feedback. Four clinical experts from Ontario and British Columbia were identified by the Working Group to be targeted peer reviewers. Two agreed to be reviewers; one response was received. Table 1 summarizes the survey results. Table 1. Responses to nine items on the targeted peer reviewer questionnaire.
# Question
Reviewer Ratings (n = 1) - None were noted.
Lowest Quality Highest Quality (1)(2) (3) (4) (5)
For Professional Consultation, two hundred ninety-two individuals who practice in Ontario were contacted. Fifty-five (18.8%) responses were received. Thirty stated that they did not have interest in this area or were unavailable to review this guideline at the time. Table 2 summarizes the results of the survey responses from nine professionals.
# Recommendations and Key Evidence
The target population for this guideline is individuals diagnosed with early-stage invasive breast cancer for whom further information is needed for prognosis and treatment decision making. In this guideline, early-stage invasive breast cancer is defined as stage I to III breast cancers that are surgically operable and do not have evidence of locally recurrent or distant metastatic disease with pT1-T3 or pN0-N1a based on surgical pathologic staging. The intended users of this guideline are clinicians and policymakers involved in the diagnosis and treatment of breast cancer.
The purpose of this guideline is to determine the clinical utility of multigene profiling assays (i.e., Oncotype DX, MammaPrint, Prosigna, EndoPredict, and Breast Cancer Index), not to identify which assay is better. No prospective studies have compared these assays head-to-head. Given that the assays use different scoring systems and classification systems, please refer to Table 3 for a summary of each of the assays. Further, this guideline does not cover the utility of multigene profiling assays in helping to guide clinical treatment decisions regarding the use of either neoadjuvant chemotherapy or radiation. Figures 1-3 provide a summary of the recommendations in a decision tree.
# Recommendation 1
In patients with early-stage estrogen receptor (ER)-positive/human epidermal growth factor 2 (HER2)-negative breast cancer, clinicians should consider using multigene profiling assays (i.e., Oncotype DX, MammaPrint, Prosigna, EndoPredict, and Breast Cancer Index) to help guide the use of systemic therapy.
# Recommendation 1
In patients with early-stage estrogen receptor (ER)-positive/human epidermal growth factor 2 (HER2)-negative breast cancer, clinicians should consider using multigene profiling assays (i.e., Oncotype DX, MammaPrint, Prosigna, EndoPredict, and Breast Cancer Index) to help guide the use of systemic therapy.
# Justification for Recommendation 1
The main purpose of most multigene profiling assays is to determine whether a tumour has a high or low risk for recurrence. The five multigene profiling assays considered in this guidance evaluate the intrinsic molecular characteristics of a tumour to prognosticate behaviour, with some being able to predict treatment benefit; however, the genes used to ascertain this predicted risk differ among assays. Although the results of different assays should be similar in terms of risk category, each individual assay uses a different scoring system, and the results may not be directly comparable. The value in multigene ER-positive, HER2-negative early-stage breast cancer that is under consideration for extended adjuvant endocrine therapy (following five years of tamoxifen, an aromatase inhibitor or both)
# Justification for Recommendation 1
The main purpose of most multigene profiling assays is to determine whether a tumour has a high or low risk for recurrence. The five multigene profiling assays considered in this guidance evaluate the intrinsic molecular characteristics of a tumour to prognosticate behaviour, with some being able to predict treatment benefit; however, the genes used to ascertain this predicted risk differ among assays. Although the results of different assays should be similar in terms of risk category, each individual assay uses a different scoring system, and the results may not be directly comparable. The value in multigene profiling is more evident and potentially limited to providing support for decision-making regarding systemic therapy when such decisions remain difficult for the clinician and patient, even after considering all clinical, pathologic, and patient-related factors. Although no males were included in any of the included studies, given the similarities in the management of male and female breast cancer, multigene profiling assays may be used in all individuals with early-stage ER-positive, HER2-negative invasive breast cancer.
Although multigene profiling assays may be used to guide treatment and ultimately improve patient outcomes, it is important to note the emotional impact such testing may have on patients, especially those who receive a high score. Clinician and patient discussions should be conducted concerning the implications of results.
# Recommendation 2
In patients with early-stage node-negative ER-positive/HER2-negative disease, clinicians may use a low-risk result from Oncotype DX, MammaPrint, Prosigna, EndoPredict/EPclin, or Breast Cancer Index assays to support a decision not to use adjuvant chemotherapy. In patients with a low-grade tumour (i.e., grade 1) less than 1 cm in size, the Working Group members do not recommend a multigene assay profiling as this is unlikely to inform a treatment decision to use adjuvant chemotherapy. The Working Group would also not suggest the use of multigene profiling assays in patients who would not be willing or medically able to undergo chemotherapy.
# Key Evidence for Recommendation 2
For Oncotype DX, the evidence comes from one randomized controlled trial (RCT) and two retrospective analyses of an RCT with an overall low level of certainty as assessed using the GRADE approach.
In the TAILORx trial , patients with a recurrence score (RS) There was a statistically significant interaction between chemotherapy treatment and RS score (p = 0.038). In the analysis by Geyer et al. , excluding patients with HER2-positive tumours, there was no benefit of chemotherapy in patients with low and intermediate scores. In a multivariable analysis, the test for interaction between chemotherapy and RS was statistically significant (p = 0.023) when controlling for patient age, tumour size, ER and progesterone receptor (PR) status, and tumour grade.
Similarly, when the patients were recategorized by RS using TAILORx cut-offs, a statistically significant benefit was shown with the addition of chemotherapy for patients with an RS > 25, but there was no benefit in patients with RS < 11 and RS 11 to 25.
For MammaPrint, the evidence comes from one RCT with a low level of certainty as assessed using the GRADE approach.
In a prespecified exploratory subgroup analysis of the MINDACT trial of nodenegative, ER-positive, HER2-negative patients, there was no significant difference in distant metastasis-free survival between patients who received chemotherapy and no chemotherapy in the high clinical risk and low genomic risk group (p = NR) or in the low clinical risk and high genomic risk group (p = NR). However, after a median follow-up of 8.7 years, there was a significant difference between the two treatment groups in the high clinical risk and low genomic risk group (HR, 0.60; 95% CI, 0.38 to 0.96; p = NR), but no significant difference in the low clinical risk and high genomic risk group (p = 0.815);
In a predefined exploratory analysis of hormone receptor (HR)-positive, HER2-negative women at high clinical risk and low genomic risk, a significant chemotherapy benefit was shown (HR, 0.54; 95% CI, 0.30 to 0.98; p = NR) with an absolute difference of 5.0% in the rate of survival without distant metastases between the treatment groups in women 50 years of age or younger. No significant benefit was shown in women older than 50 years (HR, 0.82; 95% CI 0.55 to 1.24; p = NR). However, it is important to note that premenopausal patients were not mandated to receive ovarian suppression prior to treatment.
For Prosigna, the evidence comes from two predictive studies of retrospective analyses of RCTs and three prognostic studies assessing late recurrence . The prognostic studies did not maintain randomization from the original trials and, as a result, are treated as observational studies with very low certainty of the evidence as assessed using the GRADE approach.
In both exploratory retrospective analyses of patients from the NCIC CTG MA.21 and DBCG 77B trials, the categorical Risk of Relapse (ROR) score was not predictive of response to chemotherapy regimen (p = 0.232) for recurrence-free survival (RFS) or treatment (p = 0.10) for disease-free survival (DFS) , respectively;
In a retrospective analysis of the ATAC trial, Sestak et al. found that the risk of distant recurrence at 5 to 10 years was 1.4% (95% CI, 0.5 to 3.8) for low-risk patients.
In a retrospective analysis of the ABSCG-8 trial, Filipits et al. found the probability for 15-year distant RFS (DRFS) was 97.6% (95% CI, 94.7 to 98.9) for low-risk patients with a significant difference in late DRFS between patients in the high-vs. low-risk group (HR, 4.74; 95% CI, 1.89 to 11.87; p < 0.001);
In a study combining both the ATAC trial and ABCSG-8 trial together , there was a significant difference in late distant recurrence (i.e., five to 10 years) between patients in the high-vs. low-risk group (HR, 5.49; 95% CI, 2.92 to 10.35; p = NR).
For EndoPredict, the evidence comes from two retrospective analyses of RCTs assessing late recurrence. These prognostic studies did not maintain randomization from the original trials and, as a result. are treated as observational studies with very low certainty of the evidence as assessed using the GRADE approach.
In a retrospective analysis of the ATAC trial, Sestak et al. found the risk of distant recurrence for EPclin low-risk patients at 5 to 10 years was 4.3% (95% CI, 2.6 to 7.1);
In an analysis of both the ABCSG-8 and ABCSG-6 trial together , there was a significant difference in DRFR from 5 to 15 years in women who were distant recurrence-free at 5 years between those with low and high EPclin scores (HR, 4.52; 95% CI, 2.65 to 7.72; p < 0.001).
For the Breast Cancer Index, the evidence comes from three retrospective analyses of RCTs assessing late recurrence. These prognostic studies did not maintain randomization from the original trials and, as a result, are treated as observational studies with very low certainty of the evidence as assessed using the GRADE approach.
In retrospective analyses of the ATAC trial , there was a significant difference between high Breast Cancer Index scores (BCI-high) and BCI-low groups (13.3% vs. 3.5%; HR, 2.97; 95% CI, 1.23 to 7.13; p = NR). In a multivariate analysis for late recurrence, the BCI molecular grade index MGI HOXB13/IL17BR (MGI H/I) was prognostic for risk of distant late recurrence in node-negative (HR, 1.95; 95% CI, 1.22 to 3.14) and node-negative HER2-negative populations (HR, 2.12; 95% CI, 1.30 to 3.47). Sestak et al. found the risk of distant recurrence at 5 to 10 years was 2.6% (95% CI, 1.3 to 5.0) for low-risk patients and 15.9% (95% CI, 8.9 to 27.6) for high-risk patients; - Zhang et al. found there was a significant difference in late DRFS between the BCIlow, BCI-intermediate, and BCI-high-risk groups for patients in both the Stockholm cohort and the multi-institutional cohort (p = 0.0152 and p = 0.0002, respectively). In a multivariate Cox regression including clinicopathologic variables, BCI was significant for ER-positive, HER2-negative patients in both the Stockholm cohort (HR, 3.50; 95% CI, 1.09 to 11.21; p = 0.035) and the multi-institutional cohort (HR, 9.24; 95% CI, 2.85 to 30.0; p = 0.0002).
# Justification for Recommendation 2
Patients from the Consultation Group rated both recurrence risk and survival as critical outcomes, along with quality of life and adverse events. The benefits of withholding adjuvant chemotherapy would be large and acceptable to patients when there are no significant differences in survival benefits. Prognostic studies from Prosigna and EndoPredict demonstrate a low risk of late recurrence, which would make it acceptable to withhold chemotherapy given the potential side effects and toxicity associated with adjuvant chemotherapy. The Working Group notes that although the overall certainty of the evidence is low for both Oncotype DX and MammaPrint, the TAILORx and MINDACT trials provide the strongest available evidence and best trial design available for this population. Given the similarities in the management of male and female breast cancer, these data can be generalized to all individuals with early-stage ER-positive, HER2-negative invasive breast cancer.
# Recommendation 3
In patients with node-negative ER-positive/HER2-negative disease, clinicians may use a high-risk result from Oncotype DX to support a decision to offer chemotherapy. A high Oncotype DX recurrence score is capable of predicting adjuvant chemotherapy benefit.
# Qualifying Statement for Recommendation 3
MammaPrint, Prosigna, EndoPredict or EPclin and the Breast Cancer Index do not have sufficient evidence to support a predictive benefit of adjuvant chemotherapy among clinically low-risk breast cancer patients whose multigene profiling testing indicates a high-risk score.
# Key Evidence for Recommendation 3
The evidence comes from one RCT and two retrospective analyses of an RCT with an overall low level of certainty as assessed using the GRADE approach.
In the TAILORx trial , the rate of freedom from recurrence of breast cancer at a distant site for high-risk patients (RS 26-100) treated with endocrine therapy plus adjuvant chemotherapy was 93% at five years and 86.8% at nine years;
In a retrospective analysis of the NSABP B20 trial , patients with high RS (RS ≥ 31) experienced a large chemotherapy benefit (60.5% vs. 88.1%; relative risk (RR), 0.26; 95% CI, 0.13 to 0.53) and a statistically significant interaction between chemotherapy treatment and RS score (p = 0.038). In the second re-analysis by Geyer et al. , a benefit of chemotherapy remained for patients with high RS (HR 0.18; 95% CI, 0.07 to 0.47; p 25. In a multivariable analysis, the test for interaction between chemotherapy and RS was statistically significant (p = 0.014) when controlling for patient age, tumour size, ER and PR status, and tumour grade. It is important to note that the patients included in the tamoxifen-only arm were used in the initial development of the Oncotype DX assay, and as a result, these results may be confounded.
# Justification for Recommendation 3
Patients from the Consultation Group rated both recurrence rate and invasive DFS as critical outcomes along with quality of life and adverse events. The Working Group determined that the beneficial effects of lower recurrence rates and higher survival rates outweigh the adverse effects of adjuvant chemotherapy.
Given the similarities in the management of male and female breast cancer, these data can be generalized to all individuals with early-stage ER-positive, HER2-negative invasive breast cancer.
# Recommendation 4
In postmenopausal patients with ER-positive/HER2-negative tumours and one to three nodes involved (N1a disease), clinicians may withhold chemotherapy based on a low-risk Oncotype DX or MammaPrint score if the decision is supported by other clinical, pathological, or patient-related factors. For Oncotype DX, the evidence comes from one RCT , the RxPONDER trial, and a retrospective study of the SWOG 8814 trial with low certainty of the evidence as assessed using the GRADE approach.
The RxPONDER trial reported there was no significant difference in IDFS at five years between patients (RS ≤ 25) who received chemoendocrine therapy or endocrine therapy (92.2% vs. 91.0%; HR, 0.86; 95% CI, 0.72 to 1.03; p = 0.10). The interaction between chemotherapy benefit and continuous recurrence score was not statistically significant for IDFS when controlling for continuous RS, menopausal status, and treatment group (p = 0.35);
In a prespecified analysis, a significant interaction was found between the addition of adjuvant chemotherapy and menopausal status (p = 0.008), allowing for subgroup analysis by menopausal status. In postmenopausal women, there was no significant difference in IDFS between those who received chemoendocrine therapy or endocrine therapy (91.3% vs. 91.9%; HR, 1.02; 95% CI, 0.82 to 1.26; p = 0.89); In premenopausal women, a significant benefit was found in IDFS for women who received chemoendocrine therapy (93.9% vs. 89.0%; HR, 0.60; 95% CI, 0.43 to 0.83; p = 0.002). In premenopausal women who were 50 years old or older, there was no significant chemotherapy benefit (HR, 0.98; 95% CI, 0.54 to 1.78); however, in premenopausal women younger than 50 years old, a significant chemotherapy benefit was observed (HR, 0.48; 95% CI, 0.32 to 0.72; p = NR). The interaction between age and chemotherapy benefit in premenopausal women was not significant (p = 0.06);
In a retrospective analysis of the SWOG-8814 trial , there was no significant benefit for DFS or OS between patients who received either tamoxifen alone or cyclophosphamide, doxorubicin, and 5-fluorouracil (CAF) followed by tamoxifen at 10 years for those with RS < 18 (p = 0.97 and p = 0.68, respectively) or RS between 18 and 30 (p = 0.48 and p = 065, respectively). For DFS, there was no significant interaction between RS and treatment (p = 0.053); however, when assessing the first five years, a significant interaction was seen between RS and treatment for both DFS and OS (p = 0.029 and p = 0.016, respectively) but not after five years (p = 0.58 and p = 0.87, respectively).
For MammaPrint, the evidence comes from one RCT with a low level of certainty as assessed using the GRADE approach.
- In node-positive patients in the MINDACT trial, there was no significant difference between patients who received chemotherapy and no chemotherapy in the high clinical risk and low genomic risk group for distant metastasis-free survival after a median follow-up of five years (absolute benefit of 0.7% in the chemotherapy arm) ; (p = 0.724) or eight years (absolute benefit of 1.3% in the chemotherapy arm; p = NS) . The number of node-positive patients in the low clinical risk and high genomic risk was too small to be analyzed.
# Justification for Recommendation 4
Patients from the Consultation Group rated both recurrence risk and survival as critical outcomes, along with quality of life and adverse events. The benefits from withholding adjuvant chemotherapy would be large and acceptable to patients when there are no significant differences in survival benefits. Although favourable prognostic data exist for late recurrence with Prosigna, EndoPredict and the Breast Cancer Index, given the increased clinical risk in lymph node-positive patients, strong predictive data regarding the use of these assays are needed. Given the similarities in the management of male and female breast cancer, these data can be generalized to all individuals with early-stage ER-positive, HER2-negative invasive breast cancer.
# Recommendation 5
The evidence to support the use of molecular profiling to select the duration of endocrine therapy is evolving. In patients with ER-positive disease, clinicians may consider using a Breast Cancer Index (H/I) high assay result to support a decision to extend adjuvant endocrine therapy if the decision is supported by other clinical, pathological, or patient-related factors.
While a number of studies have demonstrated the clinical utility of BCI for extending adjuvant endocrine therapy, the preliminary results of the NSABP B42 trial are negative, leading to some uncertainty. Treatment decisions should be based on all available clinical and pathological information for each patient rather than depending only on multigene profiling tests;
- MammaPrint, Oncotype DX, Prosigna, and EndoPredict currently have insufficient evidence to guide the extension of adjuvant endocrine therapy; however, these molecular assays may prognosticate a very low rate of disease recurrence that might not justify an extension of endocrine therapy.
# Key Evidence for Recommendation 5
For the Breast Cancer Index, the evidence comes from four retrospective analyses of RCTs . One is currently available in abstract form, with low certainty of evidence as assessed using the GRADE approach.
In a retrospective review of the NSABP B42 trial , currently in abstract form, there was no significant difference between receiving an additional five years of letrozole or placebo for recurrence-free interval in those who were BCI (H/I)-low (HR, 0. There was a significant interaction between BCI (H/I) level and treatment in both the overall population (p = 0.045) and in the subgroup of patients who received primary adjuvant endocrine therapy with an AI (p = 0.025) after adjusting for age, tumour grade, pT stage, pN stage, prior endocrine therapy and prior chemotherapy;
In the Trans-aTTom study , consisting of node-positive patients only, those classified as BCI (H/I)-high showed a significant benefit from extended tamoxifen (HR, 0.35; 95% CI, 0.15 to 0.86; p = 0.027) with an absolute recurrence risk difference of 10.2%. There was a significant interaction between continuous BCI (H/I) and extended tamoxifen treatment (p = 0.012) after adjusting for age, tumour size, tumour grade, and ER and PR status;
In the retrospective review of the NCIC CTG MA 17 trial , for patients with high H/I, there was a significant difference in the five-year RFS of 73% (95% CI, 56.6 to 84.1) and 89.5% (95% CI, 80.3 to 94.5) for patients receiving placebo and letrozole, respectively, with an absolute risk of reduction of 16.5% (p = 0.007). In an adjusted model, high H/I was significantly associated with patient benefit from letrozole (odds ratio (OR), 0.32; 95% CI, 0.14 to 0.72; p = 0.006). The interaction between H/I and letrozole therapy was significant (p = 0.03).
# Justification for Recommendation 5
Patients from the Consultation Group rated both the recurrence risk and RFS as critical outcomes along with quality of life and adverse events. The Working Group determined the beneficial effects of lower recurrence and higher survival rates outweigh the adverse effects of extended adjuvant endocrine therapy. This recommendation can be generalized to all patients with node-negative and -positive, ER-positive breast cancer.
The Working Group acknowledges the emerging evidence for MammaPrint in this area as well as the retrospective study of the NSABP B42 trial for BCI ; however, abstracts of studies are insufficient to make recommendations. Translational studies from the IDEAL, Trans-aTTom, and NCI CCTG MA 17 clinical trials all demonstrated a clinical benefit from extended adjuvant endocrine therapy among patients with a Breast Cancer Index (H/I) high assay result; however, the results from the recent analysis of the NSABP B42 trial were negative. While the NSABP B42 trial is only presented as an abstract, this preliminary result does raise some uncertainty regarding the predictive capacity of BCI, and the Working Group has thus issued a weak recommendation for BCI (H/I) testing to guide extended adjuvant endocrine therapy.
# Conclusions
The use of multigene profiling assays for early-stage, node-negative, ER-positive, HER2-negative breast cancer is well established. A variety of assays can be used to identify low-risk patients with a favourable disease prognosis who can be safely treated with endocrine therapy alone. We have now updated our clinical practice guideline demonstrating that both Oncotype DX and MammaPrint can also be used in patients with limited lymph node-positive disease (pN1a or 1-3 positive lymph nodes) to help identify patients at low risk who do not require treatment with adjuvant chemotherapy. Caution should be used in interpreting low-risk multigene assay scores in premenopausal women where a small adjuvant chemotherapy benefit exists even among patients with low-risk scores. The role of multigene profiling assays to guide clinical decisions regarding the duration of adjuvant endocrine therapy is also emerging, and the Breast Cancer Index may be considered for use in aiding decisions regarding extending adjuvant endocrine therapy. Further research is required, and future studies will also help clarify the potential use of multigene profiling assays to guide clinical decision making regarding neoadjuvant chemotherapy and adjuvant radiation therapy. Overall, multigene profiling assays are valuable clinical tools to be discussed with patients to help guide and facilitate personalized clinical treatment decisions for adjuvant systemic therapy in patients with early-stage breast cancer. | This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY# Introduction
Breast cancer is a common disease in Canada, with approximately 25,000 new cases per year [1]. Survival outcomes with early-stage breast cancer have significantly improved over time with advances in systemic therapy, especially adjuvant chemotherapy and endocrine therapy [2].
Breast cancer is a heterogenous disease classified traditionally by expression of the ER, PR and/or HER receptor. Clinical decision making regarding adjuvant systemic therapy may vary and is commonly influenced by patient, clinical and pathologic factors, including tumor size, histologic grade, lymph node status and ER, PR and HER2 expression, all of which have been shown to significantly influence the risk of disease recurrence [3]. Given the potential side effects and toxicity of systemic therapy, several molecular gene expression profiling tests have been developed to assess the risk of recurrence. The use of these assays is meant to improve clinical decision making and optimize the use of systemic therapy for breast cancer.
Clinical decision-making regarding the use of adjuvant chemotherapy has historically been based on a variety of factors, including breast cancer stage, tumor biology and patient characteristics, all of which can be used to target patients at higher risk of disease recurrence. However, treatment decision remains challenging, especially among ER-positive, HER2-negative invasive breast cancers that are often less responsive to chemotherapy and may derive more clinical benefit from endocrine therapy alone. Previous treatment recommendations were generated from population-based or clinical trial data and were not necessarily indicative of clinical benefit at an individual patient level [4,5]. This imprecision has resulted in the overuse of adjuvant chemotherapy in some breast cancer patients, with unnecessary exposure to side effects and potential toxicity [6]. To mitigate this, several molecular profiling tests have been developed and validated that classify tumours into low-, intermediate-, or high-risk categories for risk of disease recurrence. These multigene profiling assays are generally prognostic of breast cancer outcomes. Some may also predict the potential benefit from systemic therapy in terms of distant recurrence, IDFS, and OS [7]. Currently, several multigene profiling assays are approved by health regulatory agencies and supported for use by international breast cancer clinical guidelines. These assays are used in standard clinical practice to guide clinical decision making regarding the use of adjuvant chemotherapy for node-negative ER-positive/HER2-negative invasive breast cancer.
Ontario Health (Cancer Care Ontario)'s Program in Evidence-Based Care, together with the Molecular Oncology and Testing Advisory Committee, developed the present guideline reviewing several multigene expression assays, including Oncotype DX (Exact Sciences Corporation, Madison, WI, USA), Mammaprint (Agendia, Irvine, CA, USA), Prosigna (Veracyte, South San Francisco, CA, USA) EndoPredict (Myriad Genetics, Inc., Zurich, Switzerland), and Breast Cancer Index (Biotheranostics, Inc., San Diego, CA, USA).
Another assay, IHC4, was not included, given potential concerns regarding the reproducibility of the Ki67 measurement across pathology laboratories. IHC4 is not a commercially available test; however, it can be calculated on the basis of ER, PR, and HER2 expression and Ki67 scoring [8]. The Working Group decided not to focus its investigation on the utility of multigene profiling assays with regard to supporting clinical decision making for neoadjuvant chemotherapy or radiation therapy, given the number of ongoing trials.
The objectives of the current review were to assess the clinical utility of Oncotype DX, MammaPrint, Prosigna, EndoPredict, and Breast Cancer Index in terms of their ability to predict response to adjuvant chemotherapy and extended adjuvant endocrine therapy. A specific aim was to investigate the evidence for the use of these molecular profiling assays in the setting of either node-negative or node-positive ER-positive/HER2-negative breast cancer patients in guiding clinical decisions to withhold or offer adjuvant chemotherapy. Additionally, important patient factors impacting the utilization of molecular profiling results, including age at diagnosis and menopausal status, were of special interest in this review.
# Methods
# The Program in Evidence-Based Care (PEBC)
The PEBC is an initiative of the Ontario provincial cancer system, Ontario Health (Cancer Care Ontario). The PEBC produces evidence-based and evidence-informed guidance documents using the methods of the Practice Guidelines Development Cycle [9,10]. The process for the current guideline included a systematic review with interpretation of the evidence by the authors, who then drafted recommendations based on the evidence and expert consensus; internal review by content and methodology experts; and external review by clinicians and other stakeholders. The authors had expertise in medical oncology, pathology, medical genetics, and health research methodology.
Further details of the methods and findings of the systematic review that informed these recommendations have been published elsewhere [11]. Briefly, MEDLINE, EMBASE and the Cochrane Library were searched for studies that reported predictive data based on assay outcome (i.e., studies considering differential treatment effect). If there were no predictive studies available for either adjuvant chemotherapy or extended adjuvant endocrine therapy, then prognostic studies examining late recurrence (i.e., 5-10 years) were included. The risk of bias was assessed for each included RCT or retrospective analyses of RCTs, where the randomization was not broken using Cochrane's Risk of Bias tool, http://handbook.cochrane.org/, accessed on 10 June 2021 (Part 2, Section 8.5). Criteria from the QUIPS tool were used to assess the risk of bias for all prognostic studies.
# Patient and Caregiver-Specific Consultation Group
Patients/survivors/caregivers participated as Consultation Group members. They reviewed copies of the project plan, drafted recommendations and provided feedback on their comprehensibility, appropriateness, and feasibility to the Working Group's Health Research Methodologist. The Health Research Methodologist relayed this feedback to the Working Group for consideration.
# Internal Review
PEBC guidelines were reviewed by a panel of content experts (Expert Panel) and a methodology panel (Report Approval Panel). For the guideline document to be approved, 75% of the content experts who comprise the Expert Panel must cast a vote indicating whether or not they approve the document or abstain from voting for a specified reason, and of those that vote, 75% must approve the document. In addition, the PEBC Report Approval Panel, a three-person panel with methodology expertise, must unanimously approve the document.
# External Review
Feedback on the approved draft guideline was obtained from content experts and the target users through two processes. Through the Targeted Peer Review, a small number of content experts were identified by the Guideline Development Group (GDG) and asked to review and provide feedback on the guideline document. Through Professional Consultation, which is intended to facilitate dissemination of the final guidelines to Ontario practitioners, relevant care providers and other potential users of the guideline were contacted and asked to provide feedback on the guideline recommendations through a brief online survey.
# Results
The full systematic review provides more details of the methodologic characteristics and clinical outcomes [11].
# Patient and Caregiver-Specific Consultation Group
Three patients/survivors/caregivers participated as Consultation Group members. The Consultation Group found the recommendations were clear and detailed, with ad-equate evidence to support each recommendation. It was also noted that the guideline addresses issues of concern to patients, such as treatment versus survival benefits, and takes into consideration the emotional impact of testing.
# Internal Review
Three Report Approval Panel members, including the PEBC Scientific Director and two methodology experts, reviewed and approved the draft guideline in September 2021.
Of the 10 members of the Expert Panel, 8 members cast votes for an 80% response rate in August 2021. All of those who voted approved the document (100%).
# External Review
After approval of the document at internal review, the authors circulated the draft document to external review participants for review and feedback. Four clinical experts from Ontario and British Columbia were identified by the Working Group to be targeted peer reviewers. Two agreed to be reviewers; one response was received. Table 1 summarizes the survey results. Table 1. Responses to nine items on the targeted peer reviewer questionnaire.
# Question
Reviewer Ratings (n = 1) • None were noted.
Lowest Quality Highest Quality (1)(2) (3) (4) (5)
For Professional Consultation, two hundred ninety-two individuals who practice in Ontario were contacted. Fifty-five (18.8%) responses were received. Thirty stated that they did not have interest in this area or were unavailable to review this guideline at the time. Table 2 summarizes the results of the survey responses from nine professionals.
# Recommendations and Key Evidence
The target population for this guideline is individuals diagnosed with early-stage invasive breast cancer for whom further information is needed for prognosis and treatment decision making. In this guideline, early-stage invasive breast cancer is defined as stage I to III breast cancers that are surgically operable and do not have evidence of locally recurrent or distant metastatic disease with pT1-T3 or pN0-N1a based on surgical pathologic staging. The intended users of this guideline are clinicians and policymakers involved in the diagnosis and treatment of breast cancer.
The purpose of this guideline is to determine the clinical utility of multigene profiling assays (i.e., Oncotype DX, MammaPrint, Prosigna, EndoPredict, and Breast Cancer Index), not to identify which assay is better. No prospective studies have compared these assays head-to-head. Given that the assays use different scoring systems and classification systems, please refer to Table 3 for a summary of each of the assays. Further, this guideline does not cover the utility of multigene profiling assays in helping to guide clinical treatment decisions regarding the use of either neoadjuvant chemotherapy or radiation. Figures 1-3 provide a summary of the recommendations in a decision tree.
# Recommendation 1
In patients with early-stage estrogen receptor (ER)-positive/human epidermal growth factor 2 (HER2)-negative breast cancer, clinicians should consider using multigene profiling assays (i.e., Oncotype DX, MammaPrint, Prosigna, EndoPredict, and Breast Cancer Index) to help guide the use of systemic therapy.
# Recommendation 1
In patients with early-stage estrogen receptor (ER)-positive/human epidermal growth factor 2 (HER2)-negative breast cancer, clinicians should consider using multigene profiling assays (i.e., Oncotype DX, MammaPrint, Prosigna, EndoPredict, and Breast Cancer Index) to help guide the use of systemic therapy.
# Justification for Recommendation 1
The main purpose of most multigene profiling assays is to determine whether a tumour has a high or low risk for recurrence. The five multigene profiling assays considered in this guidance evaluate the intrinsic molecular characteristics of a tumour to prognosticate behaviour, with some being able to predict treatment benefit; however, the genes used to ascertain this predicted risk differ among assays. Although the results of different assays should be similar in terms of risk category, each individual assay uses a different scoring system, and the results may not be directly comparable. The value in multigene ER-positive, HER2-negative early-stage breast cancer that is under consideration for extended adjuvant endocrine therapy (following five years of tamoxifen, an aromatase inhibitor or both)
# Justification for Recommendation 1
The main purpose of most multigene profiling assays is to determine whether a tumour has a high or low risk for recurrence. The five multigene profiling assays considered in this guidance evaluate the intrinsic molecular characteristics of a tumour to prognosticate behaviour, with some being able to predict treatment benefit; however, the genes used to ascertain this predicted risk differ among assays. Although the results of different assays should be similar in terms of risk category, each individual assay uses a different scoring system, and the results may not be directly comparable. The value in multigene profiling is more evident and potentially limited to providing support for decision-making regarding systemic therapy when such decisions remain difficult for the clinician and patient, even after considering all clinical, pathologic, and patient-related factors. Although no males were included in any of the included studies, given the similarities in the management of male and female breast cancer, multigene profiling assays may be used in all individuals with early-stage ER-positive, HER2-negative invasive breast cancer.
Although multigene profiling assays may be used to guide treatment and ultimately improve patient outcomes, it is important to note the emotional impact such testing may have on patients, especially those who receive a high score. Clinician and patient discussions should be conducted concerning the implications of results.
# Recommendation 2
In patients with early-stage node-negative ER-positive/HER2-negative disease, clinicians may use a low-risk result from Oncotype DX, MammaPrint, Prosigna, EndoPredict/EPclin, or Breast Cancer Index assays to support a decision not to use adjuvant chemotherapy. In patients with a low-grade tumour (i.e., grade 1) less than 1 cm in size, the Working Group members do not recommend a multigene assay profiling as this is unlikely to inform a treatment decision to use adjuvant chemotherapy. The Working Group would also not suggest the use of multigene profiling assays in patients who would not be willing or medically able to undergo chemotherapy.
# Key Evidence for Recommendation 2
For Oncotype DX, the evidence comes from one randomized controlled trial (RCT) [12,13] and two retrospective analyses of an RCT [14,15] with an overall low level of certainty as assessed using the GRADE approach.
# •
In the TAILORx trial [12], patients with a recurrence score (RS) There was a statistically significant interaction between chemotherapy treatment and RS score (p = 0.038). In the analysis by Geyer et al. [15], excluding patients with HER2-positive tumours, there was no benefit of chemotherapy in patients with low and intermediate scores. In a multivariable analysis, the test for interaction between chemotherapy and RS was statistically significant (p = 0.023) when controlling for patient age, tumour size, ER and progesterone receptor (PR) status, and tumour grade.
≤
Similarly, when the patients were recategorized by RS using TAILORx cut-offs, a statistically significant benefit was shown with the addition of chemotherapy for patients with an RS > 25, but there was no benefit in patients with RS < 11 and RS 11 to 25.
For MammaPrint, the evidence comes from one RCT [16,17] with a low level of certainty as assessed using the GRADE approach.
# •
In a prespecified exploratory subgroup analysis of the MINDACT trial of nodenegative, ER-positive, HER2-negative patients, there was no significant difference in distant metastasis-free survival between patients who received chemotherapy and no chemotherapy in the high clinical risk and low genomic risk group (p = NR) or in the low clinical risk and high genomic risk group (p = NR). However, after a median follow-up of 8.7 years, there was a significant difference between the two treatment groups in the high clinical risk and low genomic risk group (HR, 0.60; 95% CI, 0.38 to 0.96; p = NR), but no significant difference in the low clinical risk and high genomic risk group (p = 0.815); •
In a predefined exploratory analysis of hormone receptor (HR)-positive, HER2-negative women at high clinical risk and low genomic risk, a significant chemotherapy benefit was shown (HR, 0.54; 95% CI, 0.30 to 0.98; p = NR) with an absolute difference of 5.0% in the rate of survival without distant metastases between the treatment groups in women 50 years of age or younger. No significant benefit was shown in women older than 50 years (HR, 0.82; 95% CI 0.55 to 1.24; p = NR). However, it is important to note that premenopausal patients were not mandated to receive ovarian suppression prior to treatment.
For Prosigna, the evidence comes from two predictive studies of retrospective analyses of RCTs [18,19] and three prognostic studies assessing late recurrence [20][21][22]. The prognostic studies did not maintain randomization from the original trials and, as a result, are treated as observational studies with very low certainty of the evidence as assessed using the GRADE approach.
# •
In both exploratory retrospective analyses of patients from the NCIC CTG MA.21 and DBCG 77B trials, the categorical Risk of Relapse (ROR) score was not predictive of response to chemotherapy regimen (p = 0.232) [18] for recurrence-free survival (RFS) or treatment (p = 0.10) for disease-free survival (DFS) [19], respectively; •
In a retrospective analysis of the ATAC trial, Sestak et al. [20] found that the risk of distant recurrence at 5 to 10 years was 1.4% (95% CI, 0.5 to 3.8) for low-risk patients.
# •
In a retrospective analysis of the ABSCG-8 trial, Filipits et al. [21] found the probability for 15-year distant RFS (DRFS) was 97.6% (95% CI, 94.7 to 98.9) for low-risk patients with a significant difference in late DRFS between patients in the high-vs. low-risk group (HR, 4.74; 95% CI, 1.89 to 11.87; p < 0.001); •
In a study combining both the ATAC trial and ABCSG-8 trial together [22], there was a significant difference in late distant recurrence (i.e., five to 10 years) between patients in the high-vs. low-risk group (HR, 5.49; 95% CI, 2.92 to 10.35; p = NR).
For EndoPredict, the evidence comes from two retrospective analyses of RCTs [20,23] assessing late recurrence. These prognostic studies did not maintain randomization from the original trials and, as a result. are treated as observational studies with very low certainty of the evidence as assessed using the GRADE approach.
# •
In a retrospective analysis of the ATAC trial, Sestak et al. [20] found the risk of distant recurrence for EPclin low-risk patients at 5 to 10 years was 4.3% (95% CI, 2.6 to 7.1);
# •
In an analysis of both the ABCSG-8 and ABCSG-6 trial together [23], there was a significant difference in DRFR from 5 to 15 years in women who were distant recurrence-free at 5 years between those with low and high EPclin scores (HR, 4.52; 95% CI, 2.65 to 7.72; p < 0.001).
For the Breast Cancer Index, the evidence comes from three retrospective analyses of RCTs [20,24,25] assessing late recurrence. These prognostic studies did not maintain randomization from the original trials and, as a result, are treated as observational studies with very low certainty of the evidence as assessed using the GRADE approach.
# •
In retrospective analyses of the ATAC trial [25], there was a significant difference between high Breast Cancer Index scores (BCI-high) and BCI-low groups (13.3% vs. 3.5%; HR, 2.97; 95% CI, 1.23 to 7.13; p = NR). In a multivariate analysis for late recurrence, the BCI molecular grade index MGI HOXB13/IL17BR (MGI H/I) was prognostic for risk of distant late recurrence in node-negative (HR, 1.95; 95% CI, 1.22 to 3.14) and node-negative HER2-negative populations (HR, 2.12; 95% CI, 1.30 to 3.47). Sestak et al. [20] found the risk of distant recurrence at 5 to 10 years was 2.6% (95% CI, 1.3 to 5.0) for low-risk patients and 15.9% (95% CI, 8.9 to 27.6) for high-risk patients; • Zhang et al. [24] found there was a significant difference in late DRFS between the BCIlow, BCI-intermediate, and BCI-high-risk groups for patients in both the Stockholm cohort and the multi-institutional cohort (p = 0.0152 and p = 0.0002, respectively). In a multivariate Cox regression including clinicopathologic variables, BCI was significant for ER-positive, HER2-negative patients in both the Stockholm cohort (HR, 3.50; 95% CI, 1.09 to 11.21; p = 0.035) and the multi-institutional cohort (HR, 9.24; 95% CI, 2.85 to 30.0; p = 0.0002).
# Justification for Recommendation 2
Patients from the Consultation Group rated both recurrence risk and survival as critical outcomes, along with quality of life and adverse events. The benefits of withholding adjuvant chemotherapy would be large and acceptable to patients when there are no significant differences in survival benefits. Prognostic studies from Prosigna and EndoPredict demonstrate a low risk of late recurrence, which would make it acceptable to withhold chemotherapy given the potential side effects and toxicity associated with adjuvant chemotherapy. The Working Group notes that although the overall certainty of the evidence is low for both Oncotype DX and MammaPrint, the TAILORx and MINDACT trials provide the strongest available evidence and best trial design available for this population. Given the similarities in the management of male and female breast cancer, these data can be generalized to all individuals with early-stage ER-positive, HER2-negative invasive breast cancer.
# Recommendation 3
In patients with node-negative ER-positive/HER2-negative disease, clinicians may use a high-risk result from Oncotype DX to support a decision to offer chemotherapy. A high Oncotype DX recurrence score is capable of predicting adjuvant chemotherapy benefit.
# Qualifying Statement for Recommendation 3
MammaPrint, Prosigna, EndoPredict or EPclin and the Breast Cancer Index do not have sufficient evidence to support a predictive benefit of adjuvant chemotherapy among clinically low-risk breast cancer patients whose multigene profiling testing indicates a high-risk score.
# Key Evidence for Recommendation 3
The evidence comes from one RCT [12,13,26] and two retrospective analyses of an RCT [14,15] with an overall low level of certainty as assessed using the GRADE approach.
# •
In the TAILORx trial [26], the rate of freedom from recurrence of breast cancer at a distant site for high-risk patients (RS 26-100) treated with endocrine therapy plus adjuvant chemotherapy was 93% at five years and 86.8% at nine years; •
In a retrospective analysis of the NSABP B20 trial [14], patients with high RS (RS ≥ 31) experienced a large chemotherapy benefit (60.5% vs. 88.1%; relative risk (RR), 0.26; 95% CI, 0.13 to 0.53) and a statistically significant interaction between chemotherapy treatment and RS score (p = 0.038). In the second re-analysis by Geyer et al. [15], a benefit of chemotherapy remained for patients with high RS (HR 0.18; 95% CI, 0.07 to 0.47; p < 0.001); however, there was no benefit of chemotherapy in patients with RS < 18 and RS 18 to 30. In a multivariable analysis, the test for interaction between chemotherapy and RS was statistically significant (p = 0.023) when controlling for patient age, tumour size, ER and PR status, and tumour grade. Similarly, when the patients were recategorized by RS using TAILORx cut-offs, a statistically significant benefit was shown with the addition of chemotherapy for patients with an RS > 25. In a multivariable analysis, the test for interaction between chemotherapy and RS was statistically significant (p = 0.014) when controlling for patient age, tumour size, ER and PR status, and tumour grade. It is important to note that the patients included in the tamoxifen-only arm were used in the initial development of the Oncotype DX assay, and as a result, these results may be confounded.
# Justification for Recommendation 3
Patients from the Consultation Group rated both recurrence rate and invasive DFS as critical outcomes along with quality of life and adverse events. The Working Group determined that the beneficial effects of lower recurrence rates and higher survival rates outweigh the adverse effects of adjuvant chemotherapy.
Given the similarities in the management of male and female breast cancer, these data can be generalized to all individuals with early-stage ER-positive, HER2-negative invasive breast cancer.
# Recommendation 4
In postmenopausal patients with ER-positive/HER2-negative tumours and one to three nodes involved (N1a disease), clinicians may withhold chemotherapy based on a low-risk Oncotype DX or MammaPrint score if the decision is supported by other clinical, pathological, or patient-related factors. For Oncotype DX, the evidence comes from one RCT [27], the RxPONDER trial, and a retrospective study of the SWOG 8814 trial [28] with low certainty of the evidence as assessed using the GRADE approach.
# •
The RxPONDER trial [27] reported there was no significant difference in IDFS at five years between patients (RS ≤ 25) who received chemoendocrine therapy or endocrine therapy (92.2% vs. 91.0%; HR, 0.86; 95% CI, 0.72 to 1.03; p = 0.10). The interaction between chemotherapy benefit and continuous recurrence score was not statistically significant for IDFS when controlling for continuous RS, menopausal status, and treatment group (p = 0.35);
In a prespecified analysis, a significant interaction was found between the addition of adjuvant chemotherapy and menopausal status (p = 0.008), allowing for subgroup analysis by menopausal status. In postmenopausal women, there was no significant difference in IDFS between those who received chemoendocrine therapy or endocrine therapy (91.3% vs. 91.9%; HR, 1.02; 95% CI, 0.82 to 1.26; p = 0.89); In premenopausal women, a significant benefit was found in IDFS for women who received chemoendocrine therapy (93.9% vs. 89.0%; HR, 0.60; 95% CI, 0.43 to 0.83; p = 0.002). In premenopausal women who were 50 years old or older, there was no significant chemotherapy benefit (HR, 0.98; 95% CI, 0.54 to 1.78); however, in premenopausal women younger than 50 years old, a significant chemotherapy benefit was observed (HR, 0.48; 95% CI, 0.32 to 0.72; p = NR). The interaction between age and chemotherapy benefit in premenopausal women was not significant (p = 0.06);
•
In a retrospective analysis of the SWOG-8814 trial [28], there was no significant benefit for DFS or OS between patients who received either tamoxifen alone or cyclophosphamide, doxorubicin, and 5-fluorouracil (CAF) followed by tamoxifen at 10 years for those with RS < 18 (p = 0.97 and p = 0.68, respectively) or RS between 18 and 30 (p = 0.48 and p = 065, respectively). For DFS, there was no significant interaction between RS and treatment (p = 0.053); however, when assessing the first five years, a significant interaction was seen between RS and treatment for both DFS and OS (p = 0.029 and p = 0.016, respectively) but not after five years (p = 0.58 and p = 0.87, respectively).
For MammaPrint, the evidence comes from one RCT [16,17] with a low level of certainty as assessed using the GRADE approach.
• In node-positive patients in the MINDACT trial, there was no significant difference between patients who received chemotherapy and no chemotherapy in the high clinical risk and low genomic risk group for distant metastasis-free survival after a median follow-up of five years (absolute benefit of 0.7% in the chemotherapy arm) [16]; (p = 0.724) or eight years (absolute benefit of 1.3% in the chemotherapy arm; p = NS) [17]. The number of node-positive patients in the low clinical risk and high genomic risk was too small to be analyzed.
# Justification for Recommendation 4
Patients from the Consultation Group rated both recurrence risk and survival as critical outcomes, along with quality of life and adverse events. The benefits from withholding adjuvant chemotherapy would be large and acceptable to patients when there are no significant differences in survival benefits. Although favourable prognostic data exist for late recurrence with Prosigna, EndoPredict and the Breast Cancer Index, given the increased clinical risk in lymph node-positive patients, strong predictive data regarding the use of these assays are needed. Given the similarities in the management of male and female breast cancer, these data can be generalized to all individuals with early-stage ER-positive, HER2-negative invasive breast cancer.
# Recommendation 5
The evidence to support the use of molecular profiling to select the duration of endocrine therapy is evolving. In patients with ER-positive disease, clinicians may consider using a Breast Cancer Index (H/I) high assay result to support a decision to extend adjuvant endocrine therapy if the decision is supported by other clinical, pathological, or patient-related factors.
# •
While a number of studies have demonstrated the clinical utility of BCI for extending adjuvant endocrine therapy, the preliminary results of the NSABP B42 trial are negative, leading to some uncertainty. Treatment decisions should be based on all available clinical and pathological information for each patient rather than depending only on multigene profiling tests;
• MammaPrint, Oncotype DX, Prosigna, and EndoPredict currently have insufficient evidence to guide the extension of adjuvant endocrine therapy; however, these molecular assays may prognosticate a very low rate of disease recurrence that might not justify an extension of endocrine therapy.
# Key Evidence for Recommendation 5
For the Breast Cancer Index, the evidence comes from four retrospective analyses of RCTs [29][30][31][32]. One [32] is currently available in abstract form, with low certainty of evidence as assessed using the GRADE approach.
# •
In a retrospective review of the NSABP B42 trial [32], currently in abstract form, there was no significant difference between receiving an additional five years of letrozole or placebo for recurrence-free interval in those who were BCI (H/I)-low (HR, 0. There was a significant interaction between BCI (H/I) level and treatment in both the overall population (p = 0.045) and in the subgroup of patients who received primary adjuvant endocrine therapy with an AI (p = 0.025) after adjusting for age, tumour grade, pT stage, pN stage, prior endocrine therapy and prior chemotherapy; •
In the Trans-aTTom study [30], consisting of node-positive patients only, those classified as BCI (H/I)-high showed a significant benefit from extended tamoxifen (HR, 0.35; 95% CI, 0.15 to 0.86; p = 0.027) with an absolute recurrence risk difference of 10.2%. There was a significant interaction between continuous BCI (H/I) and extended tamoxifen treatment (p = 0.012) after adjusting for age, tumour size, tumour grade, and ER and PR status; •
In the retrospective review of the NCIC CTG MA 17 trial [29], for patients with high H/I, there was a significant difference in the five-year RFS of 73% (95% CI, 56.6 to 84.1) and 89.5% (95% CI, 80.3 to 94.5) for patients receiving placebo and letrozole, respectively, with an absolute risk of reduction of 16.5% (p = 0.007). In an adjusted model, high H/I was significantly associated with patient benefit from letrozole (odds ratio (OR), 0.32; 95% CI, 0.14 to 0.72; p = 0.006). The interaction between H/I and letrozole therapy was significant (p = 0.03).
# Justification for Recommendation 5
Patients from the Consultation Group rated both the recurrence risk and RFS as critical outcomes along with quality of life and adverse events. The Working Group determined the beneficial effects of lower recurrence and higher survival rates outweigh the adverse effects of extended adjuvant endocrine therapy. This recommendation can be generalized to all patients with node-negative and -positive, ER-positive breast cancer.
The Working Group acknowledges the emerging evidence for MammaPrint in this area [33] as well as the retrospective study of the NSABP B42 trial for BCI [32]; however, abstracts of studies are insufficient to make recommendations. Translational studies from the IDEAL, Trans-aTTom, and NCI CCTG MA 17 clinical trials all demonstrated a clinical benefit from extended adjuvant endocrine therapy among patients with a Breast Cancer Index (H/I) high assay result; however, the results from the recent analysis of the NSABP B42 trial were negative. While the NSABP B42 trial is only presented as an abstract, this preliminary result does raise some uncertainty regarding the predictive capacity of BCI, and the Working Group has thus issued a weak recommendation for BCI (H/I) testing to guide extended adjuvant endocrine therapy.
# Conclusions
The use of multigene profiling assays for early-stage, node-negative, ER-positive, HER2-negative breast cancer is well established. A variety of assays can be used to identify low-risk patients with a favourable disease prognosis who can be safely treated with endocrine therapy alone. We have now updated our clinical practice guideline demonstrating that both Oncotype DX and MammaPrint can also be used in patients with limited lymph node-positive disease (pN1a or 1-3 positive lymph nodes) to help identify patients at low risk who do not require treatment with adjuvant chemotherapy. Caution should be used in interpreting low-risk multigene assay scores in premenopausal women where a small adjuvant chemotherapy benefit exists even among patients with low-risk scores. The role of multigene profiling assays to guide clinical decisions regarding the duration of adjuvant endocrine therapy is also emerging, and the Breast Cancer Index may be considered for use in aiding decisions regarding extending adjuvant endocrine therapy. Further research is required, and future studies will also help clarify the potential use of multigene profiling assays to guide clinical decision making regarding neoadjuvant chemotherapy and adjuvant radiation therapy. Overall, multigene profiling assays are valuable clinical tools to be discussed with patients to help guide and facilitate personalized clinical treatment decisions for adjuvant systemic therapy in patients with early-stage breast cancer.
# Acknowledgments:
The Indications for Multigene Profiling Assays in Early-Stage Invasive Breast Cancer Guideline Development Group would like to thank the following individuals for their assistance in developing this report: Fulvia Baldassare, William (Bill) Evans, Karen Gelmon, Donna Maziak, Sheila McNair, Jonathan Sussman, Emily Vella, and Xiaomei Yao for providing feedback on draft versions, and Alan Chen for conducting a data audit.
#
Author Contributions: All authors contributed to the conceptualization, methodology, and the review and editing of the manuscript. D.S. and P.B. drafted the first report and developed the figures and tables. D.S. conducted the literature search. All authors have read and agreed to the published version of the manuscript. | None | None |
3185d46890aa5600d76a22c393be0906c6aaa9ad | cma | None | Community cardiologists play a pivotal role in pre-emptive care. This will limit visits to the emergency department, prevent hospital admissions, direct patients to the most appropriate specialized care and reduce the burden on family physicians. Rather than abbreviating or eliminating patient access, efforts should be focused on patients who require timely assessment, and directing triage, diagnostic testing, and important, effective therapies for the at-risk public. Guidance on the provision of accessible urgent care to at-risk patients is outlined below.# Introduction
CCS represents the entire spectrum of cardiovascular healthcare professionals. A clear, concise statement is desired for the community cardiologist/health care provider in a clinic setting who is managing cardiovascular disease during the COVID-19 pandemic. Hospitals are currently focused solely on providing care for patients with urgent and emergent cardiovascular disease. The public is instructed to avoid hospitals, unless absolutely necessary. This may mean that patients who should attend the Emergency Department for urgent and emergent conditions risk are not doing so. Consequently, optimal care for common cardiac conditions, such as acute coronary syndromes, heart failure, and atrial fibrillation may be delayed. Evidence from China and Italy suggests a marked drop in acute cardiac presentations with presumed consequences when medical attention is not sought. The unintended sequelae may be increased cardiovascular morbidity and mortality during this pandemic.
# Principles
Be a champion: Lead the people around you in advocating for best practices to reduce transmission of COVID and flatten the curve (see Figure below).
Teamwork: It is critical that hospitals focus on the sickest and highest-risk patients. In the COVID era, it is important that community cardiologists play a central role in preventing emergency department visits and hospitalizations and support early discharge of hospitalized cardiac patients. This includes urgent care, satellite, and outreach clinics to ensure access to care.
Regional planning. Coordinate with other providers and services to ensure access to urgent cardiac clinical assessment, using ambulatory facilities, particularly Emergency Departments. Sites are encouraged to increase consultant availability to increase capacity for urgent assessments, which could involve recent retirees. Patients assured of rapid access are likely to accept reassurance and comply with follow-up.
Triage. Community cardiologists have a leadership role in the triage of referrals with active clinical decision-making, regarding prioritizing referrals and determining the best course of action for investigation, care and follow-up. The CCS guidance document on ambulatory management and diagnostic testing during the COVID-19 crisis is a useful resource (www.ccs.ca).
# Diagnostic testing.
Access to selective diagnostic testing is necessary after clinical assessment that incorporates risk prioritization and maximizes telehealth and videoconferencing for initial review. Testing should focus on clinically urgent situations where tests would result in immediately actionable data, or potentially disclose high-risk or life-threatening disease. Routine tests should be deferred wherever possible.
Providing patient-focused care. Promote telemedicine (by telephone, or virtual care when technology is available and practical for patients). In some cases, an in-office visit may be necessary, with appropriate precautions. Consider faxing prescriptions or providing verbal prescriptions to pharmacies to reduce the amount of time a patient spends in public waiting in the pharmacy. Ensure adequate followup is arranged to avoid visits to the Emergency Department. Most jurisdictions support full reimbursement for virtual care, and some have introduced temporary billing codes for telephone visits/virtual care.
# Show your commitment.
Implementing these changes will involve additional effort and reduced efficiency initially but are a tangible message of our commitment to patients. We are responsible physicians who recognize that these measures are necessary for optimal patient care.
Take time to plan.
- Take inventory of personal protective equipment (PPE) and restocking.
From "When does social distancing end? Where we're headed and why". Ivan Semeniuk. The Globe and Mail, March 20, 2020.
- Office location hours may change and impact access (e.g., mall hours).
- Consider office exposure and measures to reduce contamination (see below)
- Be vigilant about physician and staff exposure risk, which will result in 14-day isolation or illness.
- Ensure a plan is in place for your call group, including back up call schedules in the event of member illness. - Protect your home from exposure if working in a high-risk area like a hospital.
# Diagnostic Testing
# In-Person Office Care
If a patient's condition requires an in-office visit, we recommend the following protocols: a) Implement a policy of mandatory screening of all patients (and caregivers who will be accompanying them) before they attend the office. Several screening tools are outlined under resources below.
b) Have staff call the patient the day before their appointment to confirm their attendance, and to complete a screening questionnaire with the patient (and accompanying caregiver). Staff and office voicemail should convey the need for screening. Once a patient has been screened, sign and date the questionnaire and place in the patient chart. A patient with a high-risk screen should be directed to 811. A borderline screen should lead to physician follow-up.
c) The office entrance should include clear signage regarding the COVID screening process that the patient and caregiver should expect. Consider the languages necessary to best serve the population, and reflect that in any signage. Keep the medical office assistant window closed except when in use with a patient. If consent for testing is obtained, consider verbal consent to minimize contact and paper.
d) Schedule appointments to ensure minimal waiting persons in the waiting room. Move chairs two meters apart to ensure social distancing. Any items that cannot be easily cleaned (e.g., pamphlets, newspapers, magazines, stuffed toys) should be removed. Offer the option of the patient (and caregiver) to wait in their vehicle and text or call them when it's time for their appointment.
e) Add additional hand sanitizer stations throughout your clinic. Ask staff to regularly check on the availability of hand sanitizer and soap.
f) Minimize clinical decisions that lead to additional diagnostic testing (such as medication adjustment with associated blood work). d) Determine your policy regarding "excused from work". A request to be off work may come from a patient for a variety of reasons, including patients in essential services such as health care workers. Weigh the risk of exposure and infection consequences in the workplace in rendering your judgment. There is no current decision framework for this difficult decision.
# Cleaning the Clinic | Community cardiologists play a pivotal role in pre-emptive care. This will limit visits to the emergency department, prevent hospital admissions, direct patients to the most appropriate specialized care and reduce the burden on family physicians. Rather than abbreviating or eliminating patient access, efforts should be focused on patients who require timely assessment, and directing triage, diagnostic testing, and important, effective therapies for the at-risk public. Guidance on the provision of accessible urgent care to at-risk patients is outlined below.# Introduction
CCS represents the entire spectrum of cardiovascular healthcare professionals. A clear, concise statement is desired for the community cardiologist/health care provider in a clinic setting who is managing cardiovascular disease during the COVID-19 pandemic. Hospitals are currently focused solely on providing care for patients with urgent and emergent cardiovascular disease. The public is instructed to avoid hospitals, unless absolutely necessary. This may mean that patients who should attend the Emergency Department for urgent and emergent conditions risk are not doing so. Consequently, optimal care for common cardiac conditions, such as acute coronary syndromes, heart failure, and atrial fibrillation may be delayed. Evidence from China and Italy suggests a marked drop in acute cardiac presentations with presumed consequences when medical attention is not sought. The unintended sequelae may be increased cardiovascular morbidity and mortality during this pandemic.
# Principles
Be a champion: Lead the people around you in advocating for best practices to reduce transmission of COVID and flatten the curve (see Figure below).
Teamwork: It is critical that hospitals focus on the sickest and highest-risk patients. In the COVID era, it is important that community cardiologists play a central role in preventing emergency department visits and hospitalizations and support early discharge of hospitalized cardiac patients. This includes urgent care, satellite, and outreach clinics to ensure access to care.
Regional planning. Coordinate with other providers and services to ensure access to urgent cardiac clinical assessment, using ambulatory facilities, particularly Emergency Departments. Sites are encouraged to increase consultant availability to increase capacity for urgent assessments, which could involve recent retirees. Patients assured of rapid access are likely to accept reassurance and comply with follow-up.
Triage. Community cardiologists have a leadership role in the triage of referrals with active clinical decision-making, regarding prioritizing referrals and determining the best course of action for investigation, care and follow-up. The CCS guidance document on ambulatory management and diagnostic testing during the COVID-19 crisis is a useful resource (www.ccs.ca).
# Diagnostic testing.
Access to selective diagnostic testing is necessary after clinical assessment that incorporates risk prioritization and maximizes telehealth and videoconferencing for initial review. Testing should focus on clinically urgent situations where tests would result in immediately actionable data, or potentially disclose high-risk or life-threatening disease. Routine tests should be deferred wherever possible.
Providing patient-focused care. Promote telemedicine (by telephone, or virtual care when technology is available and practical for patients). In some cases, an in-office visit may be necessary, with appropriate precautions. Consider faxing prescriptions or providing verbal prescriptions to pharmacies to reduce the amount of time a patient spends in public waiting in the pharmacy. Ensure adequate followup is arranged to avoid visits to the Emergency Department. Most jurisdictions support full reimbursement for virtual care, and some have introduced temporary billing codes for telephone visits/virtual care.
# Show your commitment.
Implementing these changes will involve additional effort and reduced efficiency initially but are a tangible message of our commitment to patients. We are responsible physicians who recognize that these measures are necessary for optimal patient care.
Take time to plan.
• Take inventory of personal protective equipment (PPE) and restocking.
From "When does social distancing end? Where we're headed and why". Ivan Semeniuk. The Globe and Mail, March 20, 2020.
• Office location hours may change and impact access (e.g., mall hours).
• Consider office exposure and measures to reduce contamination (see below)
• Be vigilant about physician and staff exposure risk, which will result in 14-day isolation or illness.
• Ensure a plan is in place for your call group, including back up call schedules in the event of member illness. • Protect your home from exposure if working in a high-risk area like a hospital.
# Diagnostic Testing
# In-Person Office Care
If a patient's condition requires an in-office visit, we recommend the following protocols: a) Implement a policy of mandatory screening of all patients (and caregivers who will be accompanying them) before they attend the office. Several screening tools are outlined under resources below.
b) Have staff call the patient the day before their appointment to confirm their attendance, and to complete a screening questionnaire with the patient (and accompanying caregiver). Staff and office voicemail should convey the need for screening. Once a patient has been screened, sign and date the questionnaire and place in the patient chart. A patient with a high-risk screen should be directed to 811. A borderline screen should lead to physician follow-up.
c) The office entrance should include clear signage regarding the COVID screening process that the patient and caregiver should expect. Consider the languages necessary to best serve the population, and reflect that in any signage. Keep the medical office assistant window closed except when in use with a patient. If consent for testing is obtained, consider verbal consent to minimize contact and paper.
d) Schedule appointments to ensure minimal waiting persons in the waiting room. Move chairs two meters apart to ensure social distancing. Any items that cannot be easily cleaned (e.g., pamphlets, newspapers, magazines, stuffed toys) should be removed. Offer the option of the patient (and caregiver) to wait in their vehicle and text or call them when it's time for their appointment.
e) Add additional hand sanitizer stations throughout your clinic. Ask staff to regularly check on the availability of hand sanitizer and soap.
f) Minimize clinical decisions that lead to additional diagnostic testing (such as medication adjustment with associated blood work). d) Determine your policy regarding "excused from work". A request to be off work may come from a patient for a variety of reasons, including patients in essential services such as health care workers. Weigh the risk of exposure and infection consequences in the workplace in rendering your judgment. There is no current decision framework for this difficult decision.
# Cleaning the Clinic
| None | None |
9951edfe3cb9ea797c3841d8668d833e08561c0c | cma | None | This guidance is intended for health-care providers responsible for newborn care. It is based on known evidence as of April 13, 2021.# Summary of Key Changes in This Update | This guidance is intended for health-care providers responsible for newborn care. It is based on known evidence as of April 13, 2021.# Summary of Key Changes in This Update
Disclaimer: This guidance is subject to change as new data becomes available and new developments arise with the SARS-CoV-2 virus. Furthermore, unique situations may require some discretion in adjusting these guidelines, which are meant to be supportive, not prescriptive.
# This document is intended to meet the minimum expectations for safe practice with appropriate personal protective equipment (PPE).
Definitions COVID-19 disease categories as used in this document: 1, 2 Confirmed case: A person or newborn with laboratory confirmation of a positive SARS-CoV-2 test result. Person under clinical investigation: Mother/individual or caregiver who meets the criteria for SARS-CoV-2 testing and is waiting to be tested or waiting for the results of a test. A pregnant mother/individual who presents during labour with a temperature above 38 degrees Celsius will be tested for SARS-CoV-2 even in the absence of exposure criteria and/or close contact with a person with a confirmed COVID-19 diagnosis or a person under clinical investigation for COVID-19. Newborn under clinical investigation: A newborn who is symptomatic and/or had close contact with a person with a confirmed COVID-19 diagnosis or a person under clinical investigation for COVID-19. They can be either waiting to be tested for SARS-CoV-2 or waiting for the results of a test. Close contact: A person or newborn who had close physical contact with, or who lived with a person with a confirmed COVID-19 diagnosis or a person under clinical investigation for COVID-19. Parental critical illness: Pregnant person with any of the following: 3 Is intubated. SpO2 measures < 94% in room air. Is on supplemental oxygen due to COVID-19. Is receiving end-organ support. Is significantly immunosuppressed (e.g., HIV with CD4<200). And/or is deemed collectively by members of the delivery team as critically unwell.
Newborn: Infant in the first 28 days after birth. Mother/individual-newborn dyad: Grouping of the mother/individual and the newborn in an interactional situation and the underlying philosophy of family-centered care, referred to also, as dyad. Mother/individual: The term mother/individual is used in this guideline to be inclusive of transgender individuals who gave birth to the newborn, and in cases where the caregiver of the newborn is not the birth parent (e.g., foster parent). Vertical transmission: Transmission of infection directly from mother/individual to embryo, fetus or newborn during the perinatal period through the placenta, through bodily fluid exposure during labour and delivery, or through human breast milk. Horizontal transmission: Transmission of infection from one person to another through contact with bodily fluids (respiratory droplets, sputum, blood, etc.).
# General Information
SARS-CoV-2 is a novel coronavirus that causes COVID-19 illness in adults, children, and newborns. The incubation period is two to 14 days, with a median of five days. 3 Studies continue to show that COVID-19 infection in newborns is uncommon and most newborns that may become infected are asymptomatic or present with mild to moderate disease. 4,6,7 Clinical outcomes following COVID-19 infection during pregnancy are mostly good with spontaneous and iatrogenic preterm birth the most commonly reported adverse outcomes. 4,5,6 While there is currently no reported increased risk of congenital anomaly, available data is limited and, at this time, the risk of teratogenicity cannot be excluded. 4,5 While there is no strong evidence of vertical transmission of SARS-CoV-2, the newborn is at risk for postnatal horizontal transmission. 4 -6, 8 -12 The rate of infection does not vary regardless of mode of delivery, breast/chest feeding or rooming-in with the mother/individual with a probable case of COVID-19 or confirmed diagnosis of COVID-19. 10
# Clinical Manifestation of COVID-19 in Newborns
# Neurological
Temperature instability, lethargy, irritability
# Respiratory
Grunting, nasal flaring, tachypnea, chest retractions, central cyanosis/pallor, apnea, cough, nasal congestion
# Gastrointestinal
Abdominal distension, feeding intolerance, diarrhea/watery stools, emesis Laboratory Findings Normal or leukopenia, lymphopenia, mild thrombocytopenia, elevated CK, ALP, ALT, AST and LDH
# Radiology Findings
Chest X-ray infiltrates
# Recommendations Personal Protective Equipment and Infection Control Precautions
Refer to health authority-specific guidance and the BCCDC's resources on PPE and aerosol generating medical procedures (AGMP) for the most up-to-date information. Droplet and contact precautions are recommended for all team members involved in the direct care of a newborn that is a probable or confirmed case of COVID-19.
There is no strong evidence of vertical transmission of SARS-CoV-2. Therefore, the risk of transmission during AGMPs employed during newborn resuscitation at birth remains low and additional airborne precautions are not warranted. 5 -10 Airborne precautions are only indicated in the case of AGMPs, such as bag-mask ventilation and intubation.
To limit the transmission of SARS-CoV-2, only essential staff should enter the mother/individual and newborn's room and visitors should be kept to a minimum. Consult local infection prevention and control (IPC) guidelines for site specific measures.
# Isolation Precautions
If a newborn tests positive for SARS-CoV-2, the newborn needs to isolate until: At least 10 days have passed since the onset of symptoms; AND, Symptoms (respiratory, gastrointestinal and systemic) have improved.
If a newborn tests negative for SARS-CoV-2, isolate with the mother/individual as a close contact and monitor for symptoms suggestive of COVID-19. Continue isolation with the mother/individual for 14 days to ensure the full incubation and infectious period has passed.
The mother/individual and newborn need to continue to isolate at home after discharge until the 14-day period is complete.
# Investigations for SARS-CoV-2
Routine testing for SARS-CoV-2 of newborns born to mothers/individuals who are suspect cases of COVID-19 is not recommended. Test a newborn only if the mother/individual's test result has come back as positive for SARS-CoV-2, and they are within the infectious window of testing for COVID-19 disease.
Clean a newborn's face with warm water and soap prior to nasopharyngeal swab collection. Add HOS (Hospitalized) to specimen label to prioritize testing requisition.
# General Care Principles
Newborn Bathing
Several studies have found no evidence of the presence of SARS-CoV-2 in amniotic fluid. 13,14 Another study showed no evidence of transmission of SARS-CoV-2 due to delayed bathing. 11 To prevent complications related to cold stress, delay the first bath until the newborn is stable and transition is completed. Transition is usually completed in four to six hours after birth but can take up to 24 hours. 15,16
# Rooming-In
There is no evidence to indicate that the newborn born to a mother/individual who is a confirmed or suspect case of COVID-19 should be separated from the mother/individual. Isolating a newborn from their mother/individual is not necessary unless clinically indicated by disease severity.
The decision to practice rooming-in should be a shared decision between the mother/individual and the health-care provider. Inform the mother/individual about safe rooming-in practices: Limit essential visitors. Prior to touching, caring, feeding and skin-to-skin contact, the mother/individual should: o wash their hands; and, o put on a surgical mask. When not practicing skin-to-skin contact or caring for their newborn, the mother/individual should maintain a physical distance of two metres from the newborn. 4,11,12 Human Milk Feeding
The SARS-CoV-2 virus has not been detected in human milk. 14 Direct breast/chest feeding, or expressed human milk feeding, provides higher protection against infection as it provides antibodies targeted towards the microbes to which the newborn is exposed. 17 There is no evidence of vertical transmission of COVID-19 to newborns through direct breast/chest feeding. 11,12 Consult the lactation guidelines for women/individuals who are confirmed or suspect cases of COVID-19 for additional information regarding specific infection control measures to be employed to reduce the risk of horizontal transmission.
# Discharge Considerations
Complete all routine screening, immunization and discharge teaching. For more information, see maternal and newborn acute care discharge planning and continued care in community settings during the COVID-19 pandemic.
The mother/individual-newborn dyad need to continue isolation at home if the newborn is discharged prior to the end of the isolation period.
The B.C. community liaison record -postpartum & newborn is an important tool to connect acute care, primary care, and public health services for discharge planning. A COVID-19 positive diagnosis should be indicated on this record.
# Parent Resources
Keep your Baby Safe: Your Baby and COVID-19 Is my Baby Sick with COVID-19? | None | None |
47f44a13f6d97a1cf63f1820274d0de90db14f42 | cma | None | Introduction: This clinical practice guideline is based on a systematic review to assess the use of multiparametric magnetic resonance imaging (mpMRI) in the diagnosis of clinically significant prostate cancer (csPCa) for biopsy-naive men and men with a prior negative transrectal ultrasound-guided systematic biopsy (TRUS-SB) at elevated risk. Methods: The methods of the clinical practice guideline included searches to September of 2020 of MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials. Internal and external reviews were conducted. Results: The recommendations are: Recommendation 1: For biopsy-naive patients at elevated risk of csPCa, mpMRI is recommended prior to biopsy in patients who are candidates for curative management with suspected clinically localized prostate cancer. -If the mpMRI is positive, mpMRI-targeted biopsy (TB) and TRUS-SB should be performed together to maximize detection of csPCa. -If the mpMRI is negative, consider forgoing any biopsy after discussion of the risks and benefits with the patient as part of shared decision-making and ongoing followup. Recommendation 2: In patients who had a prior negative TRUS-SB and demonstrate a high risk of having csPCa in whom curative management is being considered: -mpMRI should be performed. -If the mpMRI is positive, targeted biopsy should be performed. Concomitant TRUS-SB can be considered depending on the patient's risk profile and time since prior TRUS-SB biopsy. -If the mpMRI is negative, consider forgoing a TRUS-SB only after discussion of the risks and benefits with the patient as part of shared decision-making and ongoing followup. Recommendation 3: mpMRI should be performed and interpreted in compliance with the current Prostate Imaging Reporting & Data System (PI-RADS) guidelines.# Introduction
Prostate cancer is the most common cancer among Canadian men, excluding non-melanoma skin cancers, and is the third leading cause of death in Canadian male cancer patients. 1 In most clinical practices, the current standard for diagnosing clinically significant prostate cancer (csPCa) in biopsy-naive men at risk is transrectal ultrasound (TRUS)-guided systematic biopsy (TRUS-SB) of 10-12 cores. 2 Transperineal systematic biopsy may also performed but is less commonly applied in Canada. Because TRUS-SB systematically samples areas from the prostate and not a specific imaged target, this approach has been shown to lead to over-detection of clinically insignificant prostate cancer (cisPCa) 3 and can miss csPCa. 4 Over the past several years, there has been growing use of multiparametric magnetic resonance imaging (mpMRI) as a non-invasive tool to diagnose and localize csPCa. mpMRI followed by targeted biopsy (mpMRI-TB), particularly in men with prior negative biopsy, may be considered in the detection of csPCa, as per the Ontario provincial guidelines previ-CCO: Use of mpMRI in diagnosis of csPCa ously published. 5 However, at the time of the writing of that guideline, there was a paucity of high-quality data supporting the use of mpMRI-TB in biopsy-naive men. In addition, there have been no Canadian guidelines published that address the minimum acceptable standards in the acquisition, interpretation, and reporting of mpMRI or the minimal acceptable standards for performance of mpMRI-TB. The guidelines sought to address this latter issue primarily through expert opinion.
The Working Group (WG) guideline authors (with expertise in diagnostic imaging, radiation oncology, urology, and health research methodology), in association with the Program in Evidence-based Care (PEBC) of Ontario Health (Cancer Care Ontario) and the mpMRI in Prostate Cancer Guideline Development Group (GDG) conducted an update of a systematic review to develop a clinical practice guideline to assess the use of mpMRI in the diagnosis of csPCa for biopsy-naive men and men with a prior negative TRUS-SB at elevated risk (according to prostate-specific antigen levels and/or nomograms).
# Methods
The systematic review will be published separately. Briefly, MEDLINE (May 2013 through September 1, 2020), EMBASE (May 2013 through September 1, 2020), the Cochrane Central Register of Controlled Trials (OVID CCTR: September 2020), and the Database of Abstracts of Reviews of Effects (OVID DARE: third quarter 2020) were searched for systematic reviews, review-based guidelines, original studies, and conference abstracts.
The report was assessed and approved by the PEBC Report Approval Panel (RAP), which consisted of two oncologists with expertise in clinical and methodological issues. Nine members of the mpMRI in the Diagnosis of Clinically Significant Prostate Cancer Expert Panel (EP) (a larger group of radiologists, urologists, and surgical oncologists of which the WG were selected) also reviewed and approved this report.
Following approval by the RAP and EP, a targeted peer review was conducted to obtain direct feedback on the draft report from a small number of specified content experts, and a professional consultation took place, intended to facilitate dissemination of the final guidance report to Ontario practitioners.
# Results
# Literature search results
Of the 3754 studies identified in the literature search, 36 studies from 39 publications met the inclusion criteria. The overall risk of bias of the studies ranged from low to high.
# Internal and external review
The summary of main RAP and EP comments and the WG's responses/modifications are shown in Table 1.
Responses were received by two targeted reviewers. Results of the feedback survey are summarized in Table 2. The main comments from targeted peer-reviewers and responses form the WG are summarized in Table 3.
The response rate for professional consultation was 6% (12 respondents). The results of the survey from the 12 participants are summarized in Table 4. The main comments from the professional consultation and the WG's responses are summarized in Table 5.
# Practice guidelines
The finalized version of the report reflects feedback from the internal and external review processes, with final approval granted by the mpMRI in Prostate Cancer GDG. These guidelines apply to patients without contraindications to mpMRI (i.e., patients with MRI-incompatible medical devices).
# Recommendation 1
For biopsy-naive patients at elevated risk of csPCa, mpMRI is recommended prior to biopsy in patients who are candidates for curative management with suspected clinically localized prostate cancer.
-If the mpMRI is positive, mpMRI-TB and TRUS-SB should be performed together to maximize detection of csPCa.
-If the mpMRI is negative, consider forgoing any biopsy after discussion of the risks and benefits with the patient as part of shared decision-making and ongoing followup.
# Key evidence for recommendation 1
Twenty-three trials (all full-text publications) compared mpMRI with a reference standard (n=5, all cohort studies) or with TRUS-SB (n=18: 2 randomized controlled trials and 16 cohort studies) for biopsy-naive men. The certainty of the aggregate study evidence for each comparison showed 14 of the 21 cohort studies to be at either low 6,32,40 or moderate 7,9,11,2,14,16,18,22,25,33,44 risk of bias based on a GRADE approach. 48 One of the RCTs was assessed to be at low risks of bias 20 and the other was assessed at being at unclear risk. 30 -In the five studies where template transperineal mapping biopsy (TTMB) was the reference standard, mpMRI ranges were sensitivity 87-96%, specificity 29-45%, positive predictive values (PPVs) 46-65%, and negative predictive values (NPVs) 76-92%. 6,17,18,25,38 Of these five studies, PROMIS was a prospective, multicenter trial (MCT). 6 In this study,
Haider et al it was estimated that unnecessary biopsies could be reduced by up to 27%. mpMRI was more sensitive (88% vs. 48%, 95% confidence interval 43-54, p<0.0001) but less specific (45% vs. 99%, 95% CI 97-100, p<0.0001) than TRUS-SB in this study. 6 -Two RCTs compared CSPCa detection rates of mpMRI-TB vs. TRUS-SB. 20,30 Estimates for csPCa when combining the two RCTs showed increased detection favoring mpMRI by 18% (95% CI 5-32, p=0.009). Estimates for the two RCTs combined for
# Main comments Responses
The PRECISE data likely would not influence the recommendations, but they should be incorporated into the evidence discussion. This was a major trans-Canadian initiative, co-funded by the Ontario Institute for Cancer Research, whose goal was to influence funding for prostate MRI in Canada.
PRECISE trial results have been added in the discussion of the systematic review.
I have some serious concerns about the wording of Recommendation 2. In particular, the statement, "In patients who had a prior negative TRUS-SB and demonstrate a high or an increasing risk of having csPCa in whom curative management is being considered: mpMRI should be performed."
The problem with this strategy is the risk of overdiagnosis.
The principal role for MRI in biopsy-naive patients is complete biopsy avoidance to reduce the risk of overdiagnosis. This is the primary advantage of the strategy and produces the largest reduction in overdiagnosis. Once a decision to perform a biopsy is made because of a positive MRI, it is assumed there is also an intent to pursue curative intent therapy. mpMRI-TB combined with TRUS-SB in MRI-positive patients still allows for overall reduction in TRUS-SB in those patients who are mpMRInegative, with only a slight increase in cisPCa detection (8%) while increasing CSPCa detection by 6%.
Treatment alternatives in Recommendation 1 should be expanded beyond surgery and radiation, (i.e., to include partial gland ablation and energybased technologies). The statement implying that radiation and surgery are the only curative options is outdated. Suggest including partial gland ablation as a treatment option. (This is not to endorse partial gland ablation, but only to acknowledge they are approved options that are often offered to patients).
Removed specification of radiation therapy and surgery leaving the door open to focal therapy or other curative intent therapies in the future.
Obviously, the issue of the role of systematic biopsies in men having targeted biopsy is not black and white. If the objective is to maximize diagnosis, they are clearly required. But another objective is to minimize morbidity and reduce number of cores. In the lower-risk patient, the NPV in the regions of the gland where the MRI is negative is sufficiently high (90%) that systematic biopsies may be omitted. Therefore, I believe the concept of risk stratification as the basis for decision-making should be addressed in the document more than it is.
We have not further delved into risk stratification, as this is an extensive and complex topic and beyond the scope of this document. CCO: Use of mpMRI in diagnosis of csPCa cisPCa showed decreased detection favoring mpMRI by 9% (95% CI -17-1, p=0.03). -In total, 16 cohort studies and the two RCTs mentioned above presented detection rates comparing mpMRI-TB to TRUS-SB. 7,9,11,12,14,16,40, Estimates for csPCa showed increased detection favoring mpMRI-TB by 3% (95% CI 0-7, p=0.03).
For cisPCa, the estimate showed decreased detection favoring mpMRI by 8% (95% CI -11-5%, p<0.00001). -Of the above cohort studies examining mpMRI-TB vs.
TRUS-SB, two were prospective MCTs. 32,40 A paired diagnostic study (MRI-FIRST) enrolled 251 patients. 32 Patients received both TRUS-SB and mpMRI-TB. There were no significant differences in the detection of csPCa in mpMRI-TB vs. TRUS-SB (32% vs. 30%, p=0.225). However, mpMRI-TB detected significantly less cisPCa than TRUS-SB (6% vs. 20%, p<0.0001). Five percent of csPCa was detected by TRUS-SB that was missed by mpMRI-TB and 8% was detected by mpMRI-TB and missed by TRUS-SB. Thus, detection of csPCa was improved by combining TRUS-SB and mpMRI-TB. 32 Another prospective MCT enrolled 646 men to receive MPMRI followed by TRUS-SB and in-bore MPRI-TB. 40 This study showed similar csPCa detection rates (25% vs. 23%, p=0.392); however, cisPCa was detected in significantly fewer patients by mpMRI-TB than in TRUS-SB (14% vs. 25%, p<0.0001). mpRI-TB enabled biopsy avoidance in 49% of patients while missing only 35 cases with csPCa. Meanwhile, TRUS-SB would have overdetected cisPCa in 20% of patients. 40 Overall estimates for the studies comparing mpMRI-TB plus TRUS-SB to targeted biopsy alone showed 6% increased csPCa detection when combining the systematic and targeted biopsy (95% CI 4-8, p<0.00001) and 8% increased detection of cis-PCa (95% CI 6-10, p<0.00001). 9,11,12,14,16,39,40, Justification for recommendation 1
-The issue of how targeted biopsy alone should be interpreted in overall whole gland Gleason scoring has not been resolved in the care community. Targeted biopsy plus systematic biopsy is believed to be necessary if mpMRI is positive in biopsy-naive patients, as multifocality and positive biopsy in other regions not seen by mpMRI is important in clinical decision-making and treatment planning given the use of focal dose-escalation therapies. In addition, the risk of severe complications, such as hospital admission for urosepsis, does not increase when changing from targeted biopsy to targeted biopsy plus systematic biopsy, although the risk of less severe complications does increase.
# Recommendation 2
In patients who had a prior negative TRUS-SB and demonstrate a high risk of having csPCa in whom curative management is being considered: -mpMRI should be performed, -If the mpMRI is positive, targeted biopsy should be performed. Concomitant TRUS-SB can be considered depending on the patients risk profile and time since prior TRUS-SB biopsy. -If the mpMRI is negative, consider forgoing a TRUS-SB only after discussion of the risks and benefits with the patient as part of shared decision-making and ongoing followup.
# Key evidence for recommendation 2
Twenty-two trials (all full-text publications) compared mpMRI with a reference standard (n=7) or with TRUS-SB (n=15) for previously negative men. The certainty of the aggregate study evidence for each comparison showed 15 of the 22 studies to be at either low, 8,10,15,37 , moderate, 7,12,16,21,22,25 or unclear 17,19, risk of bias based on a GRADE approach. 48 -Seven studies reported on the diagnostic accuracy of mpMRI for previously negative patients with sensitivities of 78-100%, specificities of 30-100%, PPVs of 36-100%, and NPVs of 69-100%. 18,19,25,37 -The overall improvement in csPCa detection rate for the 15 studies comparing mpMRI-TB alone to TRUS-SB was 5% (95% CI 3-7, p<0.0001), with a reduction of cisPCa detection of 7% (95% CI 4-9, p<0.00001). -The overall improvement in csPCa detection for the five cohort studies comparing mpMRI-TB plus TRUS-SB to mpMRI-TB alone was 5% (95% CI 2-8, p=0.0005). -The overall improvement across studies in csPCa detection for mpMRI-TB plus TRUS-SB compared with TRUS-SB alone was 11% (95% CI 8-14, p<0.00001).
# Justification for recommendation 2
-All the eligible studies show mpMRI-TB detected a higher number of csPCa when compared with TRUS-SB. These points are well taken; however, specific recommendations on how risk should be assessed are difficult and beyond the scope of this guideline.
Many studies are available to estimate the number of biopsy avoidance based on a negative mpMRI result among the biopsynaive patients.
There were reviews identified that did not fully meet our study criteria and, thus, were not used (did not separate biopsy-naive and previously negative men according to our inclusion criteria).
More specific guidance on who can apply bpMRI would also be helpful; we have considered switching to bpMRI to expedite MRI exams, given our long waittimes; however, we decided not to, given our uncertainty about the tradeoffs and the experience level of our radiologists This is out of scope and will have to come from further discussions with Ministry/ CCO.
# Key evidence for recommendation 3
-This recommendation is based on expert opinion and review of the PI-RADS committee guidelines, as well as the Standard Operating Procedure of the American Urological Association (AUA) (. org/guidelines/mri-of-the-prostate-sop). -Four cores per lesion have been performed in recent MCTs evaluating mpMRI but if one combines systematic biopsy and four cores/lesion in a patient with multiple mpMRI lesions, the core count will be unreasonable. Prior single-center studies have shown small incremental and diminishing increases in target biopsy yield as core count increases . For this reason, the operator is given discretion in the choice of number of cores per target for non-index lesions or when multiple lesions are present. mpMRI diagnostic performance varies by reader experience, as does mpMRI-TB performance. 52 Justification for recommendation 3 -All the published studies demonstrating the performance of mpMRI involved diagnostic radiologists and biopsy operators with training and experience in performing mpMRI and mpMRI-TB. They all used defined five-point scoring schemes and, more recently, have used the PI-RADS v2 scoring scheme.
To ensure similar performance in clinical practice, radiologists interpreting mpMRI and practitioners performing mpMRI-TB should have experience and demonstrate consistent performance levels.
# Implementation considerations
Before mpMRI is used in clinical practice, radiologists who perform and interpret mpMRI and physicians treating PCa should be familiar with current PI-RADS prostate MRI minimum technical specifications and reporting standards. 39 The patient care pathway in Ontario and the incorporation of mpMRI will need ongoing evaluation for its impact on patient care and outcomes. The value of mpMRI cannot be realized without attention to quality assurance. Studies have demonstrated only moderate agreement in PI-RADS scoring among readers 40,41 and a wide CI for the PPVs of PI-RADS score ≥3 (35%, 95% CI 27-43%). 42 There is currently no quality assurance program in place for mpMRI in Ontario or nationally. Quality standards or development of a quality assurance program is advisable before wide scale adoption of these recommendations occurs outside of centers with established expertise. Since prostate mpMRI and mpMRI-TB involve new technologies, skills, and education, knowledge transfer to practitioners should also be considered as part of implementation. In developing a local or provincial quality assurance program, metrics to consider collecting include: target yield (defined as the number of csPCa detected per lesion biopsied), stratified by PI-RADS score, and the number of false-negative mpMRI (i.e., instances where mpMRI is reported as negative and a csPCa is diagnosed at TRUS-SB or prostatectomy). Changes may be required in biopsy collection and reporting at institutions that begin performing mpMRI-TB, where all targeted biopsy specimens are labeled and placed in a separate vial labelled with target number and location.
Although cost-effectiveness and resource allocation issues are beyond the scope of this PEBC guideline, the WG was sensitive to the fact that there are limited MRI resources in Canada. Further study into the resource implications of the implementation of these guidelines is required, especially in the biopsy-naive population addressed in Recommendation 1. The lack of ready access to computer/software-aided fusion biopsy systems may require the use of cognitive fusion biopsy in many centers, which will require additional operator training, though the former are becoming more widely available. Cost savings from biopsy deferral in selected men choosing to forego TRUS-SB with negative mpMRI through shared decision-making could be considerable. Further cost savings may be realized through judicious use of biparametric MRI (bpMRI). The use of bpMRI in Canada is an attractive option to improve access and lower cost; however, this requires rigorous quality assurance, expertise, radiology/pathology feedback, and informed use from all stakeholders, including patients and physicians treating PCa.
The use of bpMRI, meaning omitting the dynamic contrast-enhanced MRI (DCEMRI), from mpMRI remains a controversial subject. This is being considered as an alternative to mpMRI, principally due to resource issues. By omitting DCEMRI, considerable savings in contrast agent cost and MRI time can be achieved. This is highly relevant in the context of the expected increase in volume of prostate MRI, with major implications on Canadian MRI capacity, once mpMRI becomes the anticipated standard of care in biopsy-naive patients. There are both single-center studies Haider et al and meta-analyses data showing non-inferiority of bpMRI to mpMRI; however, concern remains regarding the retrospective nature of these studies and the potential increase in indeterminate (PI-RADS 3) interpretations using only bpMRI. Prospective MCT or trials comparing impact on decisionmaking and outcomes between bpMRI and mpMRI are lacking. For this reason, mpMRI is still recommended as the standard of care; however, given anticipated resource pressures, bpMRI can be performed at the discretion of the radiologist in centers that have demonstrated local bpMRI performance similar to mpMRI It is expected that additional compelling evidence on the tradeoffs in diagnostic performance between mpMRI and bpMRI -its relationship to cost, safety, decision-making, and outcomes -will alter practice in the future. As the cost implications of implementing mpMRI in Ontario for biopsynaive patients may be prohibitive, the WG recognized that bpMRI may ease the financial burdens of performing MRI in this population and is a viable alternative to mpMRI if carefully monitored.
# Updating
All PEBC documents are maintained and updated through an annual assessment review process ().
Competing interests: The authors do not report any competing personal or financial interests related to this work. | Introduction: This clinical practice guideline is based on a systematic review to assess the use of multiparametric magnetic resonance imaging (mpMRI) in the diagnosis of clinically significant prostate cancer (csPCa) for biopsy-naive men and men with a prior negative transrectal ultrasound-guided systematic biopsy (TRUS-SB) at elevated risk. Methods: The methods of the clinical practice guideline included searches to September of 2020 of MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials. Internal and external reviews were conducted. Results: The recommendations are: Recommendation 1: For biopsy-naive patients at elevated risk of csPCa, mpMRI is recommended prior to biopsy in patients who are candidates for curative management with suspected clinically localized prostate cancer. -If the mpMRI is positive, mpMRI-targeted biopsy (TB) and TRUS-SB should be performed together to maximize detection of csPCa. -If the mpMRI is negative, consider forgoing any biopsy after discussion of the risks and benefits with the patient as part of shared decision-making and ongoing followup. Recommendation 2: In patients who had a prior negative TRUS-SB and demonstrate a high risk of having csPCa in whom curative management is being considered: -mpMRI should be performed. -If the mpMRI is positive, targeted biopsy should be performed. Concomitant TRUS-SB can be considered depending on the patient's risk profile and time since prior TRUS-SB biopsy. -If the mpMRI is negative, consider forgoing a TRUS-SB only after discussion of the risks and benefits with the patient as part of shared decision-making and ongoing followup. Recommendation 3: mpMRI should be performed and interpreted in compliance with the current Prostate Imaging Reporting & Data System (PI-RADS) guidelines.# Introduction
Prostate cancer is the most common cancer among Canadian men, excluding non-melanoma skin cancers, and is the third leading cause of death in Canadian male cancer patients. 1 In most clinical practices, the current standard for diagnosing clinically significant prostate cancer (csPCa) in biopsy-naive men at risk is transrectal ultrasound (TRUS)-guided systematic biopsy (TRUS-SB) of 10-12 cores. 2 Transperineal systematic biopsy may also performed but is less commonly applied in Canada. Because TRUS-SB systematically samples areas from the prostate and not a specific imaged target, this approach has been shown to lead to over-detection of clinically insignificant prostate cancer (cisPCa) 3 and can miss csPCa. 4 Over the past several years, there has been growing use of multiparametric magnetic resonance imaging (mpMRI) as a non-invasive tool to diagnose and localize csPCa. mpMRI followed by targeted biopsy (mpMRI-TB), particularly in men with prior negative biopsy, may be considered in the detection of csPCa, as per the Ontario provincial guidelines previ-CCO: Use of mpMRI in diagnosis of csPCa ously published. 5 However, at the time of the writing of that guideline, there was a paucity of high-quality data supporting the use of mpMRI-TB in biopsy-naive men. In addition, there have been no Canadian guidelines published that address the minimum acceptable standards in the acquisition, interpretation, and reporting of mpMRI or the minimal acceptable standards for performance of mpMRI-TB. The guidelines sought to address this latter issue primarily through expert opinion.
The Working Group (WG) guideline authors (with expertise in diagnostic imaging, radiation oncology, urology, and health research methodology), in association with the Program in Evidence-based Care (PEBC) of Ontario Health (Cancer Care Ontario) and the mpMRI in Prostate Cancer Guideline Development Group (GDG) conducted an update of a systematic review to develop a clinical practice guideline to assess the use of mpMRI in the diagnosis of csPCa for biopsy-naive men and men with a prior negative TRUS-SB at elevated risk (according to prostate-specific antigen [PSA] levels and/or nomograms).
# Methods
The systematic review will be published separately. Briefly, MEDLINE (May 2013 through September 1, 2020), EMBASE (May 2013 through September 1, 2020), the Cochrane Central Register of Controlled Trials (OVID CCTR: September 2020), and the Database of Abstracts of Reviews of Effects (OVID DARE: third quarter 2020) were searched for systematic reviews, review-based guidelines, original studies, and conference abstracts.
The report was assessed and approved by the PEBC Report Approval Panel (RAP), which consisted of two oncologists with expertise in clinical and methodological issues. Nine members of the mpMRI in the Diagnosis of Clinically Significant Prostate Cancer Expert Panel (EP) (a larger group of radiologists, urologists, and surgical oncologists of which the WG were selected) also reviewed and approved this report.
Following approval by the RAP and EP, a targeted peer review was conducted to obtain direct feedback on the draft report from a small number of specified content experts, and a professional consultation took place, intended to facilitate dissemination of the final guidance report to Ontario practitioners.
# Results
# Literature search results
Of the 3754 studies identified in the literature search, 36 studies from 39 publications met the inclusion criteria. The overall risk of bias of the studies ranged from low to high. [45][46][47]
# Internal and external review
The summary of main RAP and EP comments and the WG's responses/modifications are shown in Table 1.
Responses were received by two targeted reviewers. Results of the feedback survey are summarized in Table 2. The main comments from targeted peer-reviewers and responses form the WG are summarized in Table 3.
The response rate for professional consultation was 6% (12 respondents). The results of the survey from the 12 participants are summarized in Table 4. The main comments from the professional consultation and the WG's responses are summarized in Table 5.
# Practice guidelines
The finalized version of the report reflects feedback from the internal and external review processes, with final approval granted by the mpMRI in Prostate Cancer GDG. These guidelines apply to patients without contraindications to mpMRI (i.e., patients with MRI-incompatible medical devices).
# Recommendation 1
For biopsy-naive patients at elevated risk of csPCa, mpMRI is recommended prior to biopsy in patients who are candidates for curative management with suspected clinically localized prostate cancer.
-If the mpMRI is positive, mpMRI-TB and TRUS-SB should be performed together to maximize detection of csPCa.
-If the mpMRI is negative, consider forgoing any biopsy after discussion of the risks and benefits with the patient as part of shared decision-making and ongoing followup.
# Key evidence for recommendation 1
Twenty-three trials (all full-text publications) compared mpMRI with a reference standard (n=5, all cohort studies) or with TRUS-SB (n=18: 2 randomized controlled trials [RCTs] and 16 cohort studies) for biopsy-naive men. The certainty of the aggregate study evidence for each comparison showed 14 of the 21 cohort studies to be at either low 6,32,40 or moderate 7,9,11,2,14,16,18,22,25,33,44 risk of bias based on a GRADE approach. 48 One of the RCTs was assessed to be at low risks of bias 20 and the other was assessed at being at unclear risk. 30 -In the five studies where template transperineal mapping biopsy (TTMB) was the reference standard, mpMRI ranges were sensitivity 87-96%, specificity 29-45%, positive predictive values (PPVs) 46-65%, and negative predictive values (NPVs) 76-92%. 6,17,18,25,38 Of these five studies, PROMIS was a prospective, multicenter trial (MCT). 6 In this study,
Haider et al it was estimated that unnecessary biopsies could be reduced by up to 27%. mpMRI was more sensitive (88% vs. 48%, 95% confidence interval [CI] 43-54, p<0.0001) but less specific (45% vs. 99%, 95% CI 97-100, p<0.0001) than TRUS-SB in this study. 6 -Two RCTs compared CSPCa detection rates of mpMRI-TB vs. TRUS-SB. 20,30 Estimates for csPCa when combining the two RCTs showed increased detection favoring mpMRI by 18% (95% CI 5-32, p=0.009). Estimates for the two RCTs combined for
# Main comments Responses
The PRECISE data likely would not influence the recommendations, but they should be incorporated into the evidence discussion. This was a major trans-Canadian initiative, co-funded by the Ontario Institute for Cancer Research, whose goal was to influence funding for prostate MRI in Canada.
PRECISE trial results have been added in the discussion of the systematic review.
I have some serious concerns about the wording of Recommendation 2. In particular, the statement, "In patients who had a prior negative TRUS-SB and demonstrate a high or an increasing risk of having csPCa in whom curative management is being considered: mpMRI should be performed."
The problem with this strategy is the risk of overdiagnosis.
The principal role for MRI in biopsy-naive patients is complete biopsy avoidance to reduce the risk of overdiagnosis. This is the primary advantage of the strategy and produces the largest reduction in overdiagnosis. Once a decision to perform a biopsy is made because of a positive MRI, it is assumed there is also an intent to pursue curative intent therapy. mpMRI-TB combined with TRUS-SB in MRI-positive patients still allows for overall reduction in TRUS-SB in those patients who are mpMRInegative, with only a slight increase in cisPCa detection (8%) while increasing CSPCa detection by 6%.
Treatment alternatives in Recommendation 1 should be expanded beyond surgery and radiation, (i.e., to include partial gland ablation and energybased technologies). The statement implying that radiation and surgery are the only curative options is outdated. Suggest including partial gland ablation as a treatment option. (This is not to endorse partial gland ablation, but only to acknowledge they are approved options that are often offered to patients).
Removed specification of radiation therapy and surgery leaving the door open to focal therapy or other curative intent therapies in the future.
Obviously, the issue of the role of systematic biopsies in men having targeted biopsy is not black and white. If the objective is to maximize diagnosis, they are clearly required. But another objective is to minimize morbidity and reduce number of cores. In the lower-risk patient, the NPV in the regions of the gland where the MRI is negative is sufficiently high (90%) that systematic biopsies may be omitted. Therefore, I believe the concept of risk stratification as the basis for decision-making should be addressed in the document more than it is.
We have not further delved into risk stratification, as this is an extensive and complex topic and beyond the scope of this document. CCO: Use of mpMRI in diagnosis of csPCa cisPCa showed decreased detection favoring mpMRI by 9% (95% CI -17-1, p=0.03). -In total, 16 cohort studies and the two RCTs mentioned above presented detection rates comparing mpMRI-TB to TRUS-SB. 7,9,11,12,14,16,[22][23][24][31][32][33]40,[42][43][44] Estimates for csPCa showed increased detection favoring mpMRI-TB by 3% (95% CI 0-7, p=0.03).
For cisPCa, the estimate showed decreased detection favoring mpMRI by 8% (95% CI -11-5%, p<0.00001). -Of the above cohort studies examining mpMRI-TB vs.
TRUS-SB, two were prospective MCTs. 32,40 A paired diagnostic study (MRI-FIRST) enrolled 251 patients. 32 Patients received both TRUS-SB and mpMRI-TB. There were no significant differences in the detection of csPCa in mpMRI-TB vs. TRUS-SB (32% vs. 30%, p=0.225). However, mpMRI-TB detected significantly less cisPCa than TRUS-SB (6% vs. 20%, p<0.0001). Five percent of csPCa was detected by TRUS-SB that was missed by mpMRI-TB and 8% was detected by mpMRI-TB and missed by TRUS-SB. Thus, detection of csPCa was improved by combining TRUS-SB and mpMRI-TB. 32 Another prospective MCT enrolled 646 men to receive MPMRI followed by TRUS-SB and in-bore MPRI-TB. 40 This study showed similar csPCa detection rates (25% vs. 23%, p=0.392); however, cisPCa was detected in significantly fewer patients by mpMRI-TB than in TRUS-SB (14% vs. 25%, p<0.0001). mpRI-TB enabled biopsy avoidance in 49% of patients while missing only 35 cases with csPCa. Meanwhile, TRUS-SB would have overdetected cisPCa in 20% of patients. 40 Overall estimates for the studies comparing mpMRI-TB plus TRUS-SB to targeted biopsy alone showed 6% increased csPCa detection when combining the systematic and targeted biopsy (95% CI 4-8, p<0.00001) and 8% increased detection of cis-PCa (95% CI 6-10, p<0.00001). 9,11,12,14,16,[31][32][33]39,40,[42][43][44] Justification for recommendation 1
-The issue of how targeted biopsy alone should be interpreted in overall whole gland Gleason scoring has not been resolved in the care community. Targeted biopsy plus systematic biopsy is believed to be necessary if mpMRI is positive in biopsy-naive patients, as multifocality and positive biopsy in other regions not seen by mpMRI is important in clinical decision-making and treatment planning given the use of focal dose-escalation therapies. In addition, the risk of severe complications, such as hospital admission for urosepsis, does not increase when changing from targeted biopsy to targeted biopsy plus systematic biopsy, although the risk of less severe complications does increase.
# Recommendation 2
In patients who had a prior negative TRUS-SB and demonstrate a high risk of having csPCa in whom curative management is being considered: -mpMRI should be performed, -If the mpMRI is positive, targeted biopsy should be performed. Concomitant TRUS-SB can be considered depending on the patients risk profile and time since prior TRUS-SB biopsy. -If the mpMRI is negative, consider forgoing a TRUS-SB only after discussion of the risks and benefits with the patient as part of shared decision-making and ongoing followup.
# Key evidence for recommendation 2
Twenty-two trials (all full-text publications) compared mpMRI with a reference standard (n=7) or with TRUS-SB (n=15) for previously negative men. The certainty of the aggregate study evidence for each comparison showed 15 of the 22 studies to be at either low, 8,10,15,37 , moderate, 7,12,16,21,22,25 or unclear 17,19,[27][28][29] risk of bias based on a GRADE approach. 48 -Seven studies reported on the diagnostic accuracy of mpMRI for previously negative patients with sensitivities of 78-100%, specificities of 30-100%, PPVs of 36-100%, and NPVs of 69-100%. 18,19,25,[27][28][29]37 -The overall improvement in csPCa detection rate for the 15 studies comparing mpMRI-TB alone to TRUS-SB was 5% (95% CI 3-7, p<0.0001), with a reduction of cisPCa detection of 7% (95% CI 4-9, p<0.00001). -The overall improvement in csPCa detection for the five cohort studies comparing mpMRI-TB plus TRUS-SB to mpMRI-TB alone was 5% (95% CI 2-8, p=0.0005). -The overall improvement across studies in csPCa detection for mpMRI-TB plus TRUS-SB compared with TRUS-SB alone was 11% (95% CI 8-14, p<0.00001).
# Justification for recommendation 2
-All the eligible studies show mpMRI-TB detected a higher number of csPCa when compared with TRUS-SB. These points are well taken; however, specific recommendations on how risk should be assessed are difficult and beyond the scope of this guideline.
Many studies are available to estimate the number of biopsy avoidance based on a negative mpMRI result among the biopsynaive patients.
There were reviews identified that did not fully meet our study criteria and, thus, were not used (did not separate biopsy-naive and previously negative men according to our inclusion criteria).
More specific guidance on who can apply bpMRI would also be helpful; we have considered switching to bpMRI to expedite MRI exams, given our long waittimes; however, we decided not to, given our uncertainty about the tradeoffs and the experience level of our radiologists This is out of scope and will have to come from further discussions with Ministry/ CCO.
# Key evidence for recommendation 3
-This recommendation is based on expert opinion and review of the PI-RADS committee guidelines, as well as the Standard Operating Procedure of the American Urological Association (AUA) (https://www.auanet. org/guidelines/mri-of-the-prostate-sop). -Four cores per lesion have been performed in recent MCTs evaluating mpMRI but if one combines systematic biopsy and four cores/lesion in a patient with multiple mpMRI lesions, the core count will be unreasonable. Prior single-center studies have shown small incremental and diminishing increases in target biopsy yield as core count increases . [49][50][51] For this reason, the operator is given discretion in the choice of number of cores per target for non-index lesions or when multiple lesions are present. mpMRI diagnostic performance varies by reader experience, as does mpMRI-TB performance. 52 Justification for recommendation 3 -All the published studies demonstrating the performance of mpMRI involved diagnostic radiologists and biopsy operators with training and experience in performing mpMRI and mpMRI-TB. They all used defined five-point scoring schemes and, more recently, have used the PI-RADS v2 scoring scheme.
To ensure similar performance in clinical practice, radiologists interpreting mpMRI and practitioners performing mpMRI-TB should have experience and demonstrate consistent performance levels.
# Implementation considerations
Before mpMRI is used in clinical practice, radiologists who perform and interpret mpMRI and physicians treating PCa should be familiar with current PI-RADS prostate MRI minimum technical specifications and reporting standards. 39 The patient care pathway in Ontario and the incorporation of mpMRI will need ongoing evaluation for its impact on patient care and outcomes. The value of mpMRI cannot be realized without attention to quality assurance. Studies have demonstrated only moderate agreement in PI-RADS scoring among readers 40,41 and a wide CI for the PPVs of PI-RADS score ≥3 (35%, 95% CI 27-43%). 42 There is currently no quality assurance program in place for mpMRI in Ontario or nationally. Quality standards or development of a quality assurance program is advisable before wide scale adoption of these recommendations occurs outside of centers with established expertise. Since prostate mpMRI and mpMRI-TB involve new technologies, skills, and education, knowledge transfer to practitioners should also be considered as part of implementation. In developing a local or provincial quality assurance program, metrics to consider collecting include: target yield (defined as the number of csPCa detected per lesion biopsied), stratified by PI-RADS score, and the number of false-negative mpMRI (i.e., instances where mpMRI is reported as negative and a csPCa is diagnosed at TRUS-SB or prostatectomy). Changes may be required in biopsy collection and reporting at institutions that begin performing mpMRI-TB, where all targeted biopsy specimens are labeled and placed in a separate vial labelled with target number and location.
Although cost-effectiveness and resource allocation issues are beyond the scope of this PEBC guideline, the WG was sensitive to the fact that there are limited MRI resources in Canada. Further study into the resource implications of the implementation of these guidelines is required, especially in the biopsy-naive population addressed in Recommendation 1. The lack of ready access to computer/software-aided fusion biopsy systems may require the use of cognitive fusion biopsy in many centers, which will require additional operator training, though the former are becoming more widely available. Cost savings from biopsy deferral in selected men choosing to forego TRUS-SB with negative mpMRI through shared decision-making could be considerable. Further cost savings may be realized through judicious use of biparametric MRI (bpMRI). The use of bpMRI in Canada is an attractive option to improve access and lower cost; however, this requires rigorous quality assurance, expertise, radiology/pathology feedback, and informed use from all stakeholders, including patients and physicians treating PCa.
The use of bpMRI, meaning omitting the dynamic contrast-enhanced MRI (DCEMRI), from mpMRI remains a controversial subject. This is being considered as an alternative to mpMRI, principally due to resource issues. By omitting DCEMRI, considerable savings in contrast agent cost and MRI time can be achieved. This is highly relevant in the context of the expected increase in volume of prostate MRI, with major implications on Canadian MRI capacity, once mpMRI becomes the anticipated standard of care in biopsy-naive patients. There are both single-center studies Haider et al and meta-analyses data showing non-inferiority of bpMRI to mpMRI; [46][47][48][49] however, concern remains regarding the retrospective nature of these studies and the potential increase in indeterminate (PI-RADS 3) interpretations using only bpMRI. Prospective MCT or trials comparing impact on decisionmaking and outcomes between bpMRI and mpMRI are lacking. For this reason, mpMRI is still recommended as the standard of care; however, given anticipated resource pressures, bpMRI can be performed at the discretion of the radiologist in centers that have demonstrated local bpMRI performance similar to mpMRI It is expected that additional compelling evidence on the tradeoffs in diagnostic performance between mpMRI and bpMRI -its relationship to cost, safety, decision-making, and outcomes -will alter practice in the future. As the cost implications of implementing mpMRI in Ontario for biopsynaive patients may be prohibitive, the WG recognized that bpMRI may ease the financial burdens of performing MRI in this population and is a viable alternative to mpMRI if carefully monitored.
# Updating
All PEBC documents are maintained and updated through an annual assessment review process (https://www.cancercareontario.ca/sites/ccocancercare/files/assets/CCOPEBCDARP.pdf).
Competing interests: The authors do not report any competing personal or financial interests related to this work. | None | None |
9d1abc68e0525c0e71d6efdb8e723cd33d4d7d29 | cma | None | The information in this document is intended to help Canadian health care decision-makers, health care professionals, health systems leaders, and policy-makers make well-informed decisions and thereby improve the quality of health care services. While patients and others may access this document, the document is made available for informational purposes only and no representations or warranties are made with respect to its fitness for any particular purpose. The information in this document should not be used as a substitute for professional medical advice or as a substitute for the application of clinical judgment in respect of the care of a particular patient or other professional judgment in any decision-making process. The Canadian Agency for Drugs and Technologies in Health (CADTH) does not endorse any information, drugs, therapies, treatments, products, processes, or services. While care has been taken to ensure that the information prepared by CADTH in this document is accurate, complete, and up to date as at the applicable date the material was first published by CADTH, CADTH does not make any guarantees to that effect. CADTH does not guarantee and is not responsible for the quality, currency, propriety, accuracy, or reasonableness of any statements, information, or conclusions contained in any third-party materials used in preparing this document. The views and opinions of third parties published in this document do not necessarily state or reflect those of CADTH. CADTH is not responsible for any errors, omissions, injury, loss, or damage arising from or relating to the use (or misuse) of any information, statements, or conclusions contained in or implied by the contents of this document or any of the source materials. This document may contain links to third-party websites. CADTH does not have control over the content of such sites. Use of third-party sites is governed by the third-party website owners' own terms and conditions set out for such sites. CADTH does not make any guarantee with respect to any information contained on such third-party sites and CADTH is not responsible for any injury, loss, or damage suffered as a result of using such third-party sites. CADTH has no responsibility for the collection, use, and disclosure of personal information by third-party sites. Subject to the aforementioned limitations, the views expressed herein do not necessarily reflect the views of Health Canada, Canada's provincial or territorial governments, other CADTH funders, or any third-party supplier of information. This document is prepared and intended for use in the context of the Canadian health care system. The use of this document outside of Canada is done so at the user's own risk.# List of Tables
# Key Messages
- Long-term symptoms after developing COVID-19, known as post-COVID-19 condition or colloquially as long COVID, is a new condition estimated to affect millions of people worldwide. While standard diagnostic criteria have not yet been developed, current estimates suggest that 21% to 23% of people suspected of having had COVID-19 may have symptoms 4 weeks after their COVID-19 infections and 14% may have symptoms 12 weeks post-infection. Among people with self-reported post-COVID-19, an estimated 40% may continue to experience symptoms for at least a year.
- To provide health care providers and people with post-COVID-19 condition advice regarding diagnosis and treatment, guidelines have been published by the National Institute for Health and Care Excellence (NICE) and by the Centers for Disease Control and Prevention (CDC). The CDC guidelines were published more recently and refer to newer data on post-COVID-19 condition.
- Post-COVID symptoms can affect multiple organ systems and symptoms may vary by patient characteristics such as age and sex, as well as change over time. Some people may develop more severe symptoms or have increased risk of developing other illnesses.
As there are currently no known unique symptoms and no tests available to diagnose post-COVID-19 syndrome, guidelines from NICE and the CDC recommend diagnosing based on symptoms, suspected previous COVID-19 infection, and ruling out other potential causes of symptoms.
- Current treatment recommendations focus on multidisciplinary care and personalized treatment to address the potential range of symptoms unique to each patient. Different methods of delivering treatment have been suggested and implemented around the world, including specialized post-COVID-19 clinics and integrating treatment into primary care.
- Post-COVID-19 condition can result in a reduced ability to work or attend school, and reduced independence, which can impact quality of life. These effects may have a disproportionate impact on disadvantaged groups, which will have important implications for health equity.
- Limited evidence on the clinical effectiveness and cost-effectiveness of therapies for post-COVID-19 condition was identified. However, many trials have been registered and are in progress to address this knowledge gap.
# Purpose
The purpose of this Horizon Scan is to present health care stakeholders in Canada with an overview of information related to long-term symptoms after a COVID-19 infection -often referred to as long COVID or post-COVID-19 condition. The Horizon Scan also aims to include ongoing or emerging research regarding this topic and how to treat, manage, or rehabilitate the symptoms of post-COVID-19. This report is not a systematic review and does not involve a critical appraisal or include a detailed summary of study findings. It is not intended to provide recommendations.
The content of this report was considered up to date as of September 9, 2021 and only citations retrieved before September 8, 2021 were considered for inclusion. Care has been taken to ensure that the information is accurate, but it should be noted that international scientific evidence about COVID-19 is changing and growing rapidly.
# Methods
A limited literature search was conducted by an information specialist on key resources including MEDLINE and Embase through Ovid, the Cochrane Database of Systematic Reviews, the international HTA database, the websites of Canadian and major international health technology agencies, as well as a focused internet search. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine's MeSH (Medical Subject Headings), and keywords. The main search concept was post-acute (sequelae of) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) -or long COVID -and synonyms. No filters were applied to limit the retrieval by study type. Where possible, retrieval was limited to the human population. The search was also limited to English-language documents published between January 1, 2019 and June 4, 2021.
Regular alerts updated the database literature searches until the publication of the final report.
One author screened the literature search results and reviewed the full text of all potentially relevant studies. Studies were considered for inclusion if the population was people with longterm symptoms after a confirmed or suspected COVID-19 infection. Preprint publications, conference abstracts, and grey literature were included when they provided additional information to that available in the published studies.
# Peer Review
A draft version of this bulletin was reviewed by 1 clinical expert.
# Background
The coronavirus disease 2019 has spread rapidly around the globe since it was first identified in late 2019. 1 Caused by the SARS-CoV-2 virus, it was initially characterized by WHO as a relatively short-term, acute disease. In March 2020, WHO stated that, on average, mild cases would recover 2 weeks after symptom onset, while severe cases would recover 3 to 6 weeks after symptom onset. 2 The focus was on severe cases, with mild cases expected to make a quick and full recovery. 3 However, some people were not experiencing the expected full recovery within that time frame and began to share their experiences on social media as early as March of 2020. 3 Online support groups were established and editorials were published by people experiencing these long-term symptoms. Dubbing themselves "long-haulers" experiencing "long COVID," the term "long COVID" moved from social media to print media and was formally acknowledged in name as an issue by WHO during the summer of 2020. 3 Since then, research related to this new condition is aiming to understand the long-term effects of long COVID, its prevalence and risk factors, and to determine the most effective models of treatment.
The evidence base about post-COVID-19 condition, also known as long COVID, is emerging. Its long-term effects on people and health systems are uncertain, but based on the latest estimates, hundreds of thousands of people in Canada and millions of people around the world may be affected. As the evidence base continues to evolve, the purpose of this bulletin is to provide health care decision-makers in Canada an awareness about:
- what is known about post-COVID-19 condition
- what the major emerging research questions being explored are
- what the important implications could be for health systems to consider.
What is Post-COVID-19 Condition?
Research on classifying post-COVID-19 condition is developing and at the time of this report consensus on the terminology had yet to be reached. "Acute COVID-19" is typically used to refer to the acute infection phase, defined as the period up to 4 weeks after being infected. 4 After 4 weeks, new or ongoing symptoms were initially referred to on social media as "long COVID" by people with these long-term symptoms. 3 WHO uses the term "post COVID-19 condition" but notes that multiple names have been used, including long COVID, chronic COVID syndrome, late sequelae of COVID-19, post-acute sequelae SARS-CoV-2 infection (PASC), and long haul COVID, among others. 5 Different groups may use slightly different definitions for any of these terms. 4 WHO is convening a multidisciplinary panel consisting of patients and patient advocates, clinicians, researchers, and other stakeholders to develop a clinical case definition of post-COVID-19 condition. 5,6 This report will also use "post-COVID-19 condition" to refer to symptoms beyond the acute infection phase (i.e., 4 weeks after being infected), while recognizing that some patient advocates may dislike the term post-COVID-19, as it may be interpreted as having no active disease process or suggest that they have recovered. 7 In this context, post-COVID-19 can be considered a short form of post-acute infection phase of COVID-19.
# Classifying Post-COVID-19 Condition
# By Time
A common method of describing the stages of post-COVID-19 condition has been by the amount of time a person has had symptoms or the time elapsed since contracting the SARS-CoV-2 infection. The National Institute for Health and Care Excellence (NICE), the Scottish Intercollegiate Guidelines Network, and the Royal College of General Practitioners use the following terms to characterize different stages of post-COVID-19 condition: 4,8 - ongoing symptomatic COVID-19: symptoms from 4 to 12 weeks after being infected
- post-COVID-19 syndrome: symptoms beyond 12 weeks, or continuing 3 months after infection.
However, these terms are not universally agreed upon; as previously mentioned, WHO uses "post COVID-19 condition" to refer to symptoms after 4 weeks. As another example, a research group from Spain proposed the following groupings:
- potentially infection-related symptoms (weeks 4 to 5)
- acute post-COVID-19 symptoms (weeks 5 to 12)
- long post-COVID-19 symptoms (weeks 12 to 24)
- persistent post-COVID-19 symptoms (beyond 24 weeks). 9 Generally, clinical groups are proposing that post-COVID-19 refers to new or persisting symptoms occurring after 4 to 5 weeks of the infection and lasting up to 12 weeks or longer.
# By Subtypes or Syndromes
Post-COVID-19 symptoms can vary widely across multiple organ systems, which may indicate that it consists of multiple subtypes or syndromes. It may include: 7,10 - Post-viral chronic fatigue syndrome (or myalgic encephalomyelitis/chronic fatigue syndrome ). ME/CFS can occur after a viral infection and features some symptoms similar to post-COVID-19 condition (e.g., fatigue). 11
- Post-intensive care syndrome (PICS), also sometimes referred to as post-critical-illness syndrome. PICS is caused by medical treatment in the intensive care unit (ICU). 12 Its symptoms may include chronically impaired pulmonary function, neuromuscular weakness, and long-term psychological impacts. 8
- Post-traumatic stress disorder (PTSD). Acute illness and intense treatment can be deeply stressful experiences that may lead to increased risk of developing PTSD. Approximately 9% of people hospitalized for COVID-19, or 23% of those with post-COVID-19 condition, may develop PTSD symptoms. 13,14 - Exacerbation of a pre-existing health condition or disability. For example, a casecontrolled study reported that 7 months after hospital discharge for COVID-19, 53% of people who had pre-existing musculoskeletal pain reported that their pain had worsened. 15 - A unique post-acute COVID syndrome. 7,10 Other proposed methods of classifying people with post-COVID-19 condition are based on when the symptoms appear (i.e., persistent symptoms after acute infection or new symptoms that appear after the acute phase), by pathogenesis (e.g., residual damage from acute infection versus persistent immune activation), or by multiple factors. Distinguishing between subtypes may help to provide targeted treatment options. For example, people experiencing symptoms related to prolonged mechanical ventilation in the ICU will likely require different treatment courses from people who developed symptoms caused by organ damage. However, limited published research on characterizing the different subtypes or potential syndromes with specific diagnostic criteria was identified. The ongoing initiative of WHO to develop clinical case definitions based on international consensus will help to standardize the different characterizations and identify specific subtypes that would be important for making treatment decisions. 5
# Symptoms
Symptoms of post-COVID-19 condition can vary widely due to COVID-19's ability to impact multiple organs, with some studies assessing over 200 possible post-COVID-19 symptoms with a broad range of reported prevalence estimates. 4, People seeking care for post-COVID-19 condition may present with any combination of:
- generalized symptoms (e.g., fatigue, fever, pain)
- respiratory symptoms (e.g., breathlessness, cough)
- cardiovascular symptoms (e.g., chest tightness or pain, palpitations)
- neurologic symptoms (e.g., cognitive impairment , headache, sleep disturbance, dizziness, delirium )
- gastrointestinal symptoms (e.g., abdominal pain, nausea, diarrhea, anorexia, and reduced appetite )
- musculoskeletal symptoms (e.g., joint and muscle pain)
- psychological or psychiatric symptoms (e.g., depression, anxiety)
- ear, nose, and throat symptoms (e.g., tinnitus, earache, sore throat, dizziness, loss of taste and/or smell)
- dermatological symptoms (e.g., skin rashes, hair loss).
Evidence from a preprint systematic review 23 suggests that 83% of people with confirmed COVID-19 may experience 1 or more symptoms after 4 to 12 weeks of their infections. These symptoms may include body and muscle aches, dyspnea (i.e., shortness of breath) or breathing difficulties, and weakness or fatigue, which have been reported by multiple studies. 21, After 12 weeks, the systematic review reported that 56% of people may experience 1 or more symptoms, with fatigue being 1 of the most common symptoms and experienced by nearly half of people (47%). 23 Other new or persisting symptoms after 12 weeks include breathing difficulties or shortness of breath, post-exertional malaise (worsening of symptoms after physical or mental activity), cognitive dysfunction, reduced exercise capacity, and loss of taste and/or smell. 22, The preprint systematic review noted that there is relatively little research examining the prevalence of symptoms after 12 weeks and that many studies have limited sample sizes (fewer than 200 people) and are often without comparison groups, increasing the risk of bias. 23 Without comparatives, studies are limited in attributing the reported symptoms specifically to post-COVID-19, as other pre-existing health conditions and factors may also be contributing to symptom occurrence. There may be differences by age, sex, and other factors, and symptoms may change over time, all of which warrants more in-depth and longer-term research. 21,22,30,32,35 While comparative studies are emerging, a large cohort study of adults (more than 73,000 with confirmed COVID-19) from the US found that people who had confirmed COVID-19 but were not hospitalized were more likely to develop a variety of other health conditions in the 6 months after their initial diagnosis compared to adults (matched based on age, sex, ethnicity, and other factors) who did not have a COVID-19 diagnosis and were also not hospitalized. 20 The study also found that people who had acquired COVID-19 were significantly more likely to be diagnosed with neurologic, respiratory, mental health, cardiovascular, and other health conditions over the follow-up period. 20 Evidence from 3 additional non-randomized studies comparing people who were hospitalized with COVID-19 to matched control (people who were hospitalized without COVID-19) also suggest that people who acquire COVID-19 may be more likely to develop other diseases in the long-term (defined variably), including respiratory, cardiovascular, and neurologic diseases, among other conditions and disorders. Researchers are also investigating the similarities between post-COVID-19 condition and the long-term health consequences of previous coronaviruses, particularly the SARS outbreak in 2003 and Middle East respiratory syndrome. 39 One systematic review found that 6 months after hospital discharge, people who had SARS or Middle East respiratory syndrome had similar symptoms as post-COVID-19 condition including lung abnormalities, reduced exercise capacity, and psychological impairment. 40 An estimated 40% of people who had SARS had chronic fatigue 3.5 years after being diagnosed. 40 It is possible that a similar trend could be found for post-COVID-19 condition.
Overall, the emerging evidence about the type of symptoms and long-term health effects of post-COVID-19 condition suggests that many people can experience a heterogenous range of symptoms after their initial COVID-19 infection. The diversity, length, and severity of symptoms reported vary considerably in different studies and more research is needed to characterize the factors that may be associated with symptoms. 23 The emerging comparative studies examining the health effects of people who acquire COVID-19 to those who do not suggest that there could be a rise in other health conditions. However, longer-term research understanding the mechanisms of how COVID-19 may exacerbate or contribute to other conditions is needed.
# Pediatric Population
The effects of post-COVID-19 condition on children are more uncertain, with fewer studies compared to adults. Many studies of post-COVID-19 condition follow up with people who were hospitalized, but, as children are more likely to have mild symptoms or be asymptomatic, they are less likely to be hospitalized. 41 Children may also have been less likely to be tested for COVID-19 when testing recommendations were focused on symptomatic acute illness. Detecting post-COVID-19 in children can be complicated by differences in common post-COVID-19 symptoms between children and adults, by the fact that children may have more difficulty explaining specific symptoms (e.g., brain fog), by a lack of diagnostic criteria, and because of the variations of post-COVID-19 symptoms in children. 42 Like adults, post-COVID-19 symptoms in children can range widely: the most frequently reported symptoms include pain, breathing difficulties, fatigue, cough, and headache. Other symptoms include insomnia, rash, and neuropsychiatric symptoms such as concentration difficulties. A preprint survey study of children with symptoms lasting for more than 4 weeks reported that symptoms lasted, on average, for months and that 94% of study participants reported experiencing at least 4 symptoms. 46 Post-COVID-19 condition in children may include multiple subtypes or syndromes. Based on an analysis of 570 pediatric patients, the CDC suggested that there may be 3 subtypes: multisystem inflammatory syndrome in children (MIS-C), atypical Kawasaki disease, and pediatric post-COVID-19 condition. 47 MIS-C is a post-viral hyperinflammatory condition that affects multiple organ systems. Its symptoms typically occur 2 to 6 weeks after exposure to COVID-19 and can include persistent fever, gastrointestinal symptoms, cardiovascular symptoms, abdominal pain, and rash. 47,48 It has been compared to Kawasaki disease because of similarities in clinical presentation but differs on the average age and biomarker test results (e.g., neutrophil counts), which suggests that it could be a different disease. 47
# Diagnosis
Currently, post-COVID-19 condition is primarily diagnosed based on 2 factors: having been infected with COVID-19 in the past and presenting with post-COVID-19 symptoms. The Mayo Clinic released its definition and diagnostic criteria for post-COVID-19 condition, which includes several criteria to help health care providers determine probable or possible cases. 49 Guidelines from NICE and the Mayo Clinic, as well as a UK-based clinical practice guideline, state that a positive COVID-19 test (polymerase chain reaction, antibody, or antigen) or hospitalization due to COVID-19 should not be necessary to diagnose post-COVID-19 condition. Suspected previous COVID-19 illness (e.g., having symptoms closely linked to a COVID-19 infection) is an adequate reason to suspect post-COVID-19 condition as a cause for any new or ongoing symptoms beyond 4 weeks. 4,49,50 This flexibility is important because some people may have contracted COVID-19 but did not need to be hospitalized, did not get tested (e.g., certain areas had recommended people only get tested if they were symptomatic, or community testing may not have been available or accessible), or may have received a false-negative test result. People in Canada with post-COVID-19 condition have reported frustrations over not being able to access post-COVID-19 clinics because they did not have a positive test result despite their health care provider diagnosing them with post-COVID-19 condition after ruling out other likely causes. 51 The Mayo Clinic's criteria recommends looking for symptoms affecting at least 2 of 6 major organ symptoms (general, cardiac, respiratory, gastrointestinal, musculoskeletal, and neurologic), as well as for a decrease in functional status. 49 NICE recommends that health care providers consider any ongoing or new symptoms after acute COVID-19 as potentially being caused by post-COVID-19 condition, but also that people with suspected post-COVID-19 condition undergo tests to determine if their symptoms are being caused by another condition. 4 This will help prevent misdiagnosis by attributing symptoms to post-COVID-19 condition when these same symptoms may have another cause, and allow for targeted treatment where possible.
NICE also recommends that health care providers use a screening questionnaire during the consultation to develop a clearer understanding of each person's symptoms. 4 Specific populations (e.g., children and older adults) may not show the most common symptoms of post-COVID-19 condition, which should be taken into account during diagnosis. 4 WHO have also developed a post-COVID-19 case report form to help collect standardized clinical data from people suspected of having post-COVID-19 condition. 52 In the absence of diagnostic tests, providing health care professionals with training and education about recognizing post-COVID-19 condition will be important. In surveys, people have reported being misdiagnosed by having their symptoms attributed to anxiety or being dismissed by health care professionals. 53,54 This may be because of a lack of awareness of how to diagnose post-COVID-19 condition. Developing clear diagnosis criteria may help reduce misdiagnosis and improve access to care.
# Prevalence
Estimates of the prevalence of post-COVID-19 condition vary widely across studies. One systematic review noted that estimates ranged from 5% to 80%, 55 which may be due to various factors:
- study methodology (e.g., choosing to limit to people who had a positive COVID-19 test or were hospitalized for COVID-19, health administrative data versus survey data)
- a lack of a consistent definition for post-COVID-19 condition (e.g., timing , what conditions and symptoms are considered to be caused by post-COVID-19 condition)
- local factors (e.g., COVID testing availability for different areas at different times).
# Prevalence in People With Positive COVID-19 Tests and/or People Hospitalized for COVID-19
Many studies focus on people with laboratory-confirmed COVID-19 and/or people who had been hospitalized for COVID-19. Two systematic reviews 23,29 (including 1 that has not yet been peer-reviewed 23 ) estimated that 63% to 84% of people with confirmed COVID-19 had symptoms 4 weeks after either diagnosis or hospitalization and 46% to 56% experienced symptoms after 12 weeks. Three cohort studies 32,34,56 reported that 33% to 39% of people may experience symptoms after 6 to 9 months. Two cohort studies 57,58 reported that 28% to 49% of people who had been hospitalized for COVID-19 experienced symptoms after 12 months.
Although estimates range widely, it appears that the prevalence decreases with time (i.e., fewer people report symptoms at 6 to 9 months compared to at 3 months), which may indicate that some people with post-COVID-19 condition will recover gradually over time. Studies of people who had been hospitalized during the acute phase tend to show a higher prevalence of post-COVID-19 condition compared to people who had milder acute illness and who did not require hospitalization. 7,21 Prevalence When Including Suspected COVID-19
A major limitation recognized by researchers and health care stakeholders is that there are people who may not have had access to COVID-19 testing. As emerging evidence indicates that people who were initially asymptomatic or had mild acute illness can develop post-COVID-19 condition, 21 understanding the prevalence among this subset of people is needed to better characterize the prevalence of people who have or could develop post-COVID-19 condition. Studies that include suspected cases, together with confirmed COVID-19 cases, estimate that 21% to 23% of people who had COVID-19 develop ongoing or new symptoms after 4 weeks or 30 days 21,59 and approximately 14% experience symptoms after 12 weeks. 59 Limited studies about longer-term (beyond 12 weeks) prevalence rates among this subset of people was identified. However, based on household surveys, the Office for National Statistics from the UK has estimated that among people who experience self-reported post-COVID-19 symptoms, 40% may continue to experience symptoms for at least 1 year. 60
# Prevalence in Canada
A rapid systematic review published in June 2021 estimated that 150,000 Canadians have post-COVID-19 condition, although it is unclear if this is limited to confirmed COVID-19. 61 A survey of 1,048 people in Canada with suspected or confirmed post-COVID-19 condition conducted by the COVID Long-Haulers Support Group Canada found that 80% of respondents had symptoms for more than 3 months and almost 50% had symptoms had symptoms for more than 11 months. 51
# Prevalence in Children
In cohort studies limited to children with a positive COVID-19 test, a survey study found that 4% of children aged 5 to 17 had symptoms beyond 4 weeks and 2% had symptoms beyond 8 weeks, 45 while another cohort study found that 13% of participants aged 15 or younger had symptoms after 6 months. 30 An Italian survey that included children without a confirmed COVID-19 test reported that 43% of children had symptoms for more than 60 days after infection. 43 The prevalence of MIS-C, a subtype of post-COVID-19 condition that may occur in some children, appears to be relatively low. One cohort study assessed 99 children (95 with a positive COVID-19 test) and estimated prevalence at around 2 cases per 100,000 children, 62 but the prevalence may be higher among children who had been hospitalized. 48 A survey study from Italy reported that about 2% of children who had COVID-19 developed MIS-C. 43 The variability in prevalence estimates between different studies may be due to low testing rates among children.
# Risk Factors
Understanding potential risk factors that may be associated with developing post-COVID-19 condition may help characterize the cause or causes of the condition, support the development and implementation of preventive interventions, and tailor treatment and management plans. However, a variation in how studies are defining the condition, a heterogenous and complex range of symptoms, and other factors have made it challenging to clearly determine specific risk factors. Retrospective and cross-sectional studies suggest that some potential risk factors for developing post-COVID-19 condition may include:
- severity of acute illness. People who were hospitalized may have a higher risk of developing or having a more severe post-COVID-19 condition compared to people who had milder symptoms. 7,20,21,23,55,63 Other studies have found no association. Acute illness severity may be associated with specific post-COVID-19 symptoms or with PICS. 68
- female sex and older age. Females 26,39,55,69 and older people (defined variably) 26,55,67 may be associated with higher risk of developing post-COVID-19 condition, although others have also found no correlation. 31,67,70,71 Specific symptoms may vary by age and sex, and may change over time. 21,22,30,32,33,35,72 Symptoms may peak for people between ages 40 and 60. 18,37
- comorbidities. Asthma, autoimmune disease, and obesity have been associated with greater risk. 26,73,74 A survey cohort study 75 and a preprint cohort study 76 reported that anxiety, depression, and neurologic disabilities may also be risk factors. However, another cohort study reported no association between comorbidities and the presence of post-COVID-19 condition. 31
- specific symptoms during the acute phase. People who experience certain symptoms during the acute phase such as fatigue, shortness of breath, headache, voice hoarseness, and muscle aches and pains may be more likely to develop post-COVID-19. 18,26,65,77 - number of symptoms during the acute phase. Experiencing a higher number of different symptoms during the acute phase may be associated with developing post-COVID-19. 26,78,79 Other factors that have been investigated but show mixed findings include:
- ethnicity. Evidence on the association between ethnicity and the risk of developing post-COVID-19 condition has been mixed, 25,37, potentially due to high heterogeneity across studies. 83 This could be because of people from ethnic minority groups having less access to testing 84 or being underrepresented in survey studies. 51
- socioeconomic factors. Some studies indicate an association between socioeconomic factors (e.g., low income) and post-COVID-19 symptoms after 1 month but not beyond 2 months. 63,82 Data from the UK indicate that self-reported post-COVID-19 condition is highest among people from areas with higher deprivation (deprivation calculated by a composite score of neighbourhood level income, education, and health deprivation and disability). 60 These mixed findings may also be because of differences in access to testing or underrepresentation in surveys or the heterogeneity of post-COVID-19 symptoms. 63,82 Among children, a case series has reported that siblings and parents of children with post-COVID-19 condition may also report long-term symptoms, which could suggest genetic and/or environmental factors impacting the likelihood of developing post-COVID-19 condition. 85 One study using health administrative data reported that children who were symptomatic during the acute phase were more likely to develop post-COVID-19 symptoms compared to children who were asymptomatic. 86 The risk of developing MIS-C may be higher in children who are Black or Latino, male, and aged 6 to12 years, as well as children who had been hospitalized. 48,87 Overall, research assessing risk factors associated with developing post-COVID-19 condition in adults and children is developing and emerging findings should be interpreted with caution until rigorous studies have been completed.
# Prevention
Cochrane Rehabilitation has published a living systematic review, REH-COVER or Rehabilitation -COVID-19 Evidence-based Response, assessing rehabilitation for people with COVID-19. 88 Two cohort studies of early rehabilitation clinics treating people after the acute COVID-19 phase reported improvements in pulmonary symptoms and physical performance (e.g., 6-minute walking distance) when comparing participants before and after completing rehabilitation. 89,90 These studies were short-term interventions (8 weeks) for people who had been hospitalized. It is unclear how rehabilitation may affect people who had not been hospitalized, particularly people who present with ME/CFS-like symptoms such as post-exertional malaise (i.e., the worsening of symptoms after even minor physical, mental, or emotional exertion, also known as post-exertional symptom exacerbation) or exercise intolerance (i.e., reduced ability to exercise).
Pilot studies have assessed the efficacy of certain supplements; 91,92 however, due to limited evidence from larger studies, NICE currently does not recommend the use of over-the-counter supplements and vitamins for treating new or ongoing COVID-19 symptoms. 4
# Treatment and Management
Published guidelines from NICE, the CDC, and other research groups provide several options for treatment courses based on existing evidence that are primarily focused on symptoms management. 4,87, The CDC guidelines were published more recently than the NICE guidelines (June 2021 compared to December 2020) and draw on more recent data. The CDC guidelines also acknowledge that post-COVID-19 syndrome likely includes multiple syndromes and provides guidance based on research from other post-viral illnesses. 97 A rapid systematic review focused on care models for post-COVID-19 condition identified several studies from the US, UK, Spain, and Italy, with multiple common focuses across different models including: 61
- principles: multidisciplinary teams, integrated care, self-management, coordination of care, and evidence-based care
- medical specialists: pulmonary, cardiovascular, psychiatry and psychology, physiotherapy, occupational therapy, social work, neurology, primary care, nutrition, speech and language therapy
- components: standardized symptom assessment, referral system, follow-up system, virtual care, home-based care.
# Self-Management
NICE and a multidisciplinary clinical panel from the UK recommend that people suspected of having post-COVID-19 condition be provided with education and support for selfmanagement strategies. 4,98 Self-management strategies may include providing up-to-date information about the condition, helping to set realistic goals, and providing information on available supports like online support networks. 4 Certain symptoms may be self-managed, such as breathing exercises for shortness of breath. 97 Online resources providing selfmanagement advice, including the NHS's Your Covid Recovery, Post COVID-19 HUB by the Asthma UK and British Lung Foundation, and Long COVID Support created by a patient advocacy group have also been established. A program in Leeds, England introduced a fatigue management course delivered online that supports people with post-COVID-19 symptoms on how to manage their fatigue. 94
# Exercise
Evidence about exercise rehabilitation for people with post-COVID-19 is mixed and requires further assessment. Exercise may help reduce fatigue, a common post-COVID-19 symptom, 35 and may be helpful for people who had been bedridden (e.g., people who had been treated in the hospital or ICU) or people who had been hospitalized. 88 However, there is limited research on the impact of exercise for people who had not been hospitalized and there are also concerns that exercise may be harmful to some people with post-COVID-19 condition who may present with post-exertional malaise or exercise intolerance. 102,103 Because of concerns surrounding post-exertional malaise, as well as cardiac or pulmonary symptoms that may be exacerbated from vigorous exercise, post-COVID-19 condition guidelines from World Physiotherapy and the CDC recommend a cautious and conservative approach to exercise based on existing recommendations for ME/CFS. 97,102 World Physiotherapy's guidelines for post-COVID-19 condition and the CDC's guidelines for ME/CFS recommend pacing, also known as activity management, which is an intervention that focuses on balancing rest with activity, and staying within personal limits to avoid overexertion and worsening symptoms. 102,103 World Physiotherapy's report suggests that before recommending exercise, people with post-COVID-19 condition should be screened for post-exertional symptom exacerbation. 102 It also recommends against exercise rehabilitation for those with cardiac impairments, exertional oxygen desaturation (i.e., low oxygen levels during exertion), or autonomic nervous system dysfunction. 102 As post-COVID-19 condition may include multiple syndromes, exercise may be useful for treating certain syndromes but not others. Further research will be needed to determine who is most likely to benefit.
# Vaccination
For people who have not been vaccinated and develop post-COVID-19 condition, receiving a COVID-19 vaccine after the acute infection phase may help to reduce their post-COVID-19 symptoms. In a survey study by the LongCOVIDSOS group, of the respondents who received at least their first dose, 57% reported an overall improvement in symptoms, 25% saw no change, and 19% saw their symptoms worsen. 104 The study reported variation in which symptoms and how many symptoms improved. A preprint survey study reported that in a group of people with post-COVID-19 condition who had received at least 1 dose, 23% saw an increase in symptom resolution compared to 15% in matched unvaccinated individuals. 105 As some post-COVID-19 symptoms resolve with time, more studies are needed to determine if vaccinations, including receiving both doses, reduce post-COVID-19 symptoms and, if so, how this effect occurs. This topic is an active area of research. A non-randomized preprint study assessed the immune response of people who previously had COVID-19 (although it did not specifically include people who had post-COVID-19 symptoms) before and after vaccination and found immune system changes that could explain post-vaccination symptom improvement. 106 At least 1 study is in progress that is conducting immunological follow-up and surveys of people previously infected with COVID-19 to better understand the impact of vaccination on post-COVID-19 symptoms. 107 Research is also ongoing to determine if vaccines affect the risk of developing post-COVID-19 condition for people who have breakthrough infections (i.e., developed COVID-19 after being vaccinated). One survey study has found that people who are fully vaccinated have lower odds of having symptoms 28 days after a breakthrough infection compared to people who are not vaccinated. 108 Preliminary work suggests some people with breakthrough infections could have post-COVID-19 symptoms for at least 6 weeks.
# Models of Care
Research to understand features of different models of care associated with supporting people with post-COVID-19 is ongoing. Key features that have been recommended -based on evidence from 2 systematic reviews and published position statements of different health care providers -are multidisciplinary care and personalized care. 4,20,61,112,113 The range of symptoms and potential impact on multiple organ systems for post-COVID-19 condition means that people will likely benefit from receiving a range of services from various specialists coordinating and selecting appropriate care based on each person's unique set of symptoms. Researchers and guidelines suggest that diagnostic tests, rehabilitation, and management plans should be personalized. 4,50,98,112,114 Selected tests can be used to rule out other conditions and assess potential causes (e.g., chest X-ray for respiratory symptoms) to provide targeted treatment or referrals, where possible. 50,71,115 The use of technologies such as virtual visits may also help to easily access multiple specialists, especially for people experiencing fatigue who may find it difficult to make multiple clinic visits.
As research on post-COVID-19 condition continues to develop, comprehensive and standardized symptom assessment (such as using WHO's case report form 52 ) will help health care providers and researchers develop a clearer understanding of the effects of post-COVID-19 condition. Careful monitoring, follow-up, and open communication between health care providers, people with post-COVID-19 condition, and researchers has also been recommended to help determine what treatments work and for whom, to identify any adverse events so the treatment can be adjusted or withdrawn as needed, and to ensure cohesive and continuous care. 47,50,51,112,116 Some models of care that have been suggested or implemented, and their characteristics, are summarized in
# Ongoing Research
Research about post-COVID-19 condition is evolving at a rapid pace and different studies are ongoing in Canada and across the world to better understand the condition, its pathophysiology, effective treatments, and its impact on people's well-being. What follows is a description of some of the high-level research initiatives under way and the research questions being explored.
# Cause(s) and Diagnosis of Post-COVID-19 Condition
It is possible that there are multiple mechanisms of post-COVID-19 condition based on the range of symptoms, including damage from intensive treatment (i.e., PICS), lingering viral antigens, inflammatory damage, alterations to the immune system or autonomic nervous system, or COVID-19-specific pathophysiological changes. 87,93 Researchers are assessing damage to organ systems and abnormal biomarker levels to better understand the biologic mechanisms underlying post-COVID-19 symptoms. 115, The pathophysiology in children with post-COVID-19 condition is also unknown and further studies on post-COVID-19 condition in children has been identified as a research priority by the international research community. 125 A small pilot study from the UK has identified the presence of specific autoantibodies in people with post-COVID-19 condition that were not found in people who had not tested positive for COVID-19 or had recovered quickly and did not develop post-COVID-19 symptoms. 126 A blood test to diagnose post-COVID-19 condition may be developed based on these findings, allowing for a quicker diagnosis and therefore earlier access to appropriate treatment.
# Suggested Treatments
As research is under way to understand the physiologic mechanisms that may be causing post-COVID-19 symptoms (e.g., organ damage), targeted treatments may follow. Several potential treatments for post-COVID-19 condition have been suggested by emerging clinical guidelines and/or are being explored in research trials. Treatments that are used for other illnesses or conditions with similar symptoms are being considered. These treatments may be more likely to be investigated and could be included as part of clinical guidelines should they demonstrate efficacy in research trials. 127 For example:
- treatments for ME/CFS or mast cell activation syndrome 79,128,129 (e.g., extracorporeal apheresis, which has been tested by 1 clinic on 3 people with post-COVID-19 condition with CFS-like symptoms and appeared to improve symptoms) 130
- neuromuscular electrical stimulation for treating PICS 131
- photobiomodulation therapy, which has been used to treat various neurologic and psychological disorders, and could be used to treat similar symptoms in people with post-COVID-19 condition 132
- drugs that have been in development for other illnesses that have similar symptoms with post-COVID-19 condition; some are already under investigation as potential treatments for post-COVID-19 condition. 133,134 Other potential treatments are more exploratory and have been suggested by different research groups. These include polypharmacy (to treat post-COVID-19 condition's wide range of symptoms), 135 antibiotics, 136 corticosteroids (prednisolone), 137 personalized medicine by genetic testing, 136 and supplements (e.g., luteolin, vitamin C). 138,139 Some suggested treatments specific for pediatric post-COVID-19 condition have included those:
- for brain fog symptoms, providing the same treatment a child with a concussion would receive 140
- for MIS-C; currently, it is treated the same way as Kawasaki disease, although -as they may be separate conditions -it is unclear how effective that treatment is; antiinflammatory agents may be a useful option. 47
# Ongoing Systematic Reviews and Trials
Several systematic reviews on post-COVID-19 condition have been registered or are being updated regularly as living reviews. The Cochrane group has a rapid living systematic review on COVID-19 rehabilitation that is updated monthly and includes an interactive living evidence page that maps the included extracted studies. 88 The PROSPERO international prospective register of systematic reviews website also has a section dedicated to COVID-19 and, at the time of writing this report (September 9, 2021), has registered more than 100 systematic reviews related to post-COVID-19 condition. 141
Multiple trials are also under way around the world regarding developing a clearer understanding of the symptoms and best management of post-COVID-19 condition. In the UK, the National Institute for Health Research approved £19.6 million in July of 2021 for studies assessing post-COVID-19 condition's causes, symptoms, diagnosis, treatment, and rehabilitation. 142 A few examples include:
- the EU-COGER study, which will assess the recovery from COVID-19 in a geriatric population 143
- the longitudinal survey study from ISARIC -the International Severe Acute Respiratory and emerging Infection Consortium -to assess long-term outcomes 144
- the national UK HEAL-COVID trial, which is under way to identify treatments that can lead to better long-term outcomes for people who had been hospitalized for acute The U.S. National Library of Medicine's clinical trials registry has a dedicated section for COVID-19-related studies. 146 Developing a national surveillance system has also been recommended by WHO and international classifications of diseases (or ICD) codes have been developed to track post-COVID-19 condition. 8 More research using health administrative data with these codes may emerge with time.
In Canada, several cohort studies have been registered that aim to better understand the recovery trajectories of adults with COVID-19 using imaging, blood tests, functional tests, and/or questionnaires to understand symptoms, as well as quality of life (e.g., daily activity limitations). Two studies have also planned to establish a biobank to store biologic samples (e.g., DNA, saliva) for research. 147,150 Two studies plan to follow up after 1 year 149,150 and 1 study plans to follow up for 4 years. 148 A planned cohort study aims to assess the impact of lung ventilation and lung perfusion in adults who had COVID-19, which may help to better understand the specific injuries caused by intensive treatment and lead to the development of targeted treatments for people who received lung ventilation and/or perfusion. 151 Some of these studies will also stratify between mild and moderate/severe acute illness, which will develop a better understanding of the impact of acute infection severity on long-term outcomes. 148,150 The Canadian Institutes of Health Research (or CIHR) has a funding opportunity for its Emerging COVID-19 Research Gaps and Priorities competition, which includes including studies for post-COVID-19 condition, with some studies anticipated to begin by December 2021. 152
# Economic Impact
The economic impact and cost-effectiveness of post-COVID-19 treatment options and care models are not yet established, as they have only recently been launched. A rapid systematic review found 1 study that assessed the economic impact of post-COVID-19, which was focused on health care utilization outcomes and the proportion of people who were able to return to work. 61 The review also found 1 study that estimated the costs of implementing post-COVID-19 clinics in the UK. Further research on the health care costs of various specialists was recommended by the authors of the rapid systematic review. 61
# Considerations for Health Systems
Increase in Demand for Health Care Services
Although the prevalence estimates vary widely, between 14% 59 to 56%, 23,29 of people with COVID-19 experiencing new or persisting symptoms after 12 weeks, based on these estimates, as of August 2021 more than 100,000 people in Canada may have or could develop post-COVID-19 symptoms. Providing appropriate care to affected people, many of whom could also be health care professionals, could put additional pressures on health systems. A Canadian survey of 1,048 people with self-reported post-COVID-19 condition reported that 50% of respondents visited a health care provider 5 times over the past year and 30% of respondents visited more than 10 times. 51 As more people develop post-COVID-19 condition and/or become aware that their symptoms may be due to post-COVID-19 condition, additional resources may be needed to ensure that health care systems and providers are not overwhelmed. 95 A number of health care services could see increases in demand, including in:
- primary care. Many people will likely turn to their primary care providers first, regarding their suspected post-COVID-19 condition.
- multidisciplinary rehabilitation services. Post-COVID-19 condition can manifest with a variety of symptoms and will likely require various types of care from multiple specialists working in coordinated teams.
- prescription drugs. A US cohort study of health administrative data found that after 30 days, those who had COVID-19 had more billings for several drugs including pain medications, antidepressants, hypertensives, sedatives, and oral hypoglycemic drugs. 20
- mental health treatments and supports. As post-COVID-19 symptoms may include depression, anxiety, and/or PTSD, the use of psychological supports and treatment have been recommended by a clinical group from Italy. 112
- medical imaging procedures and blood tests. Clinical guidelines from NICE recommend that health care providers order bloodwork and/or imaging procedures to potentially determine causes of symptoms and rule out other illnesses as the cause of people's symptoms. 4
- intensive care in hospitals and/or ICUs. Cohort studies (including 1 preprint) found that about 17% of people who had been hospitalized for COVID-19 during the acute phase returned to the emergency department and 10% were re-hospitalized. 34,153 An estimated 70% to 80% of children with MIS-C may require admission to a pediatric ICU. 48 - nutritionist services. Education in nutrition may be needed to treat muscle loss and frailty from severe acute illness, as well as specific post-COVID-19 symptoms such as nausea or diarrhea. 87
- lung transplantations. There may be an increase in demand for lung transplantations due to the severe damage COVID-19 can cause to the lungs. 154
# Health Equity
In Canada and around the world, health equity has been an issue since before the onslaught of the COVID-19 pandemic, as discrimination and stigma based on factors such as ethnicity, sex and/or gender, and socioeconomics impacts people's health. 155 Many people experiencing vulnerabilities, such as people from diverse ethnic backgrounds and lower-income households, were at higher risk of being infected with COVID-19. 84,155 Thus, these groups may also have a high proportion of people with post-COVID-19 condition. Other groups at risk include people with disabilities, people experiencing homelessness or housing instability, or people living in correctional facilities. 97 Furthermore, these groups may be disproportionately impacted by post-COVID-19 condition, as they may be more likely to:
- work in jobs without sick leave and/or extended health benefits, and thus struggle to access needed treatment, which could lead to worsened health and greater health inequities
- struggle more financially if they or someone in their household becomes unable to work full-time
- find it challenging to access health services
- be misdiagnosed or have their post-COVID-19 symptoms dismissed (e.g., due to anxiety). 53,54 Some approaches suggested by the CDC and health policy researchers to address these inequities have been to:
- allocate resources to raise awareness of post-COVID-19 condition among marginalized groups and increase access to needed services 97
- provide training to health care providers surrounding sensitivity to and awareness of stigma, empathy, and the importance of completing a full clinical evaluation 97
- implement a primary care-based model to improve access to specialized services typically only covered by private insurance (e.g., physiotherapy) 84
- ensure services are easy to navigate (e.g., providing information in clear plain language) and culturally sensitive (e.g., being available in multiple languages or have interpreters available, culturally relevant and appropriate treatment plans)
- require minimal appointments to avoid interrupting work for those who do not have access to paid sick leave or who may live far from the clinic
- use telemedicine for easier scheduling, easier collection of information including symptoms (e.g., people can complete forms on their smartphones or computers in their free time at home or between work), and improve access (e.g., not requiring people to drive to a distant clinic). 95,113 As services are rolled out, they will need to continually be evaluated for any accessibility barriers and ensure that people are receiving high-quality, cost-effective, and culturally appropriate care. 84
# Patients' Perspectives and Experiences
Access to Care and Care Navigation
Although post-COVID-19 condition is now acknowledged as an issue by WHO and researchers, many people may be struggling to receive recognition of their condition and access appropriate care. 51,120 In a Canadian survey that ran in May of 2021, some participants reported health care professionals dismissing their symptoms and other people who received attention from their health care providers reported difficulties accessing care. 51 Because of diagnostic uncertainty, it may be challenging for people with post-COVID-19 condition to know where to seek care and for health care providers to know when and how to provide treatment. Providing health care services navigation support to people with suspected post-COVID-19 condition may be needed to prevent overwhelming hospitals or other health care services. Similarly, raising awareness about post-COVID-19 condition among health care providers and providing clear guidelines for self-management, testing, and treatment options may also help address challenges related to care navigation. Outlining care pathways may make care navigation simpler, less time-consuming, and less stressful for both health care providers and people with post-COVID-19. Systems may also need to consider how to minimize waiting times for receiving care. 156
# Quality of Life and Daily Activities
In addition to post-COVID-19 condition having an impact on people's health, it could impact their quality of life (QoL) and daily living. A systematic review and meta-analysis reported that post-COVID-19 condition was associated with lower health-related QoL, particularly in people who had been admitted to the ICU and people experiencing fatigue. 157 Approximately one-third of people in Canada who had been hospitalized for COVID-19 reported reduced QoL 3 months after symptom onset. 158 A prospective cohort study from Germany has suggested that lower QoL could continue for up to 12 months after symptom onset. 33 Reduced QoL could result from a variety of factors, such as general poorer health (e.g., fatigue) or cognitive difficulties such as memory difficulties and brain fog even among young people who had mild acute illness. 30,159 These symptoms could result in:
- limitations in day-to-day activities (e.g., being able to engage in social activities or hobbies, requiring assistance for personal care) 10, 25,160,161 - reduced ability to care for children and/or dependents 7
- reduced ability to work full-time (i.e., switching from full-time to part-time or taking leave from work), leading to financial stress, in particular for people who are less financially stable. 22,51 Estimates based on surveys of people self-reported to have post-COVID-19 who were working before their illness suggest that between 44% and 68% of people faced challenges to their work, either through reduced hours, taking leave, or not working. 22,162 One study reported that people with suspected post-COVID-19 condition were significantly more likely to not return to full-time work compared to people who developed COVID-19 but were able to recover within 12 weeks. 22 Post-COVID-19's impact on people's ability to return to work could have important implications for health and economic equity. While preliminary studies of rehabilitation programs indicate improved health outcomes for those who had been hospitalized, it is not known if rehabilitation helps people return to work more quickly. 88 Providing guidance and resources for people with post-COVID-19 condition and their educational institutes and workplaces may help to alleviate these difficulties. Studies that measure disability-adjusted life-years and quality-adjusted life-years will also likely be needed to better understand the burden of post-COVID-19 condition and help to quantify which treatment and management protocols are most clinically effective and cost-effective.
# Continuing Engagement
Patient support and self-help groups, including COVID Long-Haulers Canada and Long COVID Kids (which has groups in the US, UK, and Canada) are active. 8,163,164 People with post-COVID-19 condition have reported that these support groups have been invaluable in providing support and validation about their condition, and continue to help raise public awareness. 53,165,166 Advocacy groups are also calling on governments to set up working groups to address the needs of people with post-COVID-19 condition, commission urgent research, establish multidisciplinary clinics, ensure health care providers are able to provide appropriate treatment, and assess economic implications including providing long-term sick leave, financial support, and employer awareness. 166
# Implications for Children
Similar to adults, children with post-COVID-19 condition could experience a lower QoL through:
- being unable to engage in physical activities or only enjoying them occasionally and often having symptoms worsen afterwards 46
- lowered self-esteem due to their symptoms (e.g., rash) and inability to engage in activities with their peers
- being unable to attend school full-time or at all, which in turn can lead to poorer physical and mental health, as well as poorer academic performance. 44,85,165 This may be an issue especially for children and adolescents without access to supports (e.g., private tutoring) and may lead to greater inequalities that extend into adulthood (e.g., lowered chance to attend higher education, poorer job prospects). 167 As of the time of writing (September 2021), COVID-19 vaccines are not approved for children younger than 12 in Canada. Although uptake of vaccines by adults may help to reduce the spread of COVID-19, children can be at risk of infection, especially as public health restrictions ease in many jurisdictions. In addition to the risk of children being infected and developing post-COVID-19 condition or MIS-C, their family and communities are also at risk.
An additional consideration about post-COVID-19 in children is related to developing back-to-school policies that allow children to safely return to school. It is unknown if and to what extent children may develop post-COVID-19 condition through asymptomatic spread in the school setting, especially among unvaccinated children younger than 12 years. 168 Many children and families are keen to return to full-time, in-person teaching, without the disruptions from the past school year that led to academic, psychological, and social development losses for children and adolescents, particularly those from marginalized and/or low-income families. 169 However, considerations will likely be needed to minimize the risks of COVID-19 infection and post-COVID-19 condition to children, their families, and communities. Protective measures including mask-wearing, ventilation, regular testing, small class sizes, and spaced classrooms could help to reduce these risks. 168
# Final Remarks
It has become increasingly clear that a significant portion of people who recover from acute COVID-19 will need care for weeks or months. Post-COVID-19 condition is a new area of research and evidence is still emerging. While many trials and reviews on the condition have been registered and are under way, it will take months and years before a clear picture of post-COVID-19 condition's cause(s) and natural history is available, as well as what constitutes the most clinically effective and cost-effective treatment and management options. Notable gaps in the evidence include a lack of health economics studies (e.g., the estimated costs that post-COVID-19 condition will put on the health care system and the costs and benefits of different care models, social support, and support systems for people with post-COVID-19 condition) and studies assessing children with post-COVID-19 condition. As jurisdictions in Canada and across the world continue to monitor the emerging evidence base, increasing recognition about post-COVID-19 condition, improving reporting about its prevalence, and addressing the research gaps can help to better prepare and equip health systems. 170 Moving forward, addressing health equity issues and engaging with people with post-COVID-19 condition will also likely be key. Collaborating with patient advocates has allowed researchers and health care providers to learn a great deal about post-COVID-19 condition, from its very existence to its range of complex symptoms. Continuing to involve a diverse range of people with lived experiences will help to develop a better understanding of post-COVID-19 condition and allow for the development of care that addresses their health and well-being. | The information in this document is intended to help Canadian health care decision-makers, health care professionals, health systems leaders, and policy-makers make well-informed decisions and thereby improve the quality of health care services. While patients and others may access this document, the document is made available for informational purposes only and no representations or warranties are made with respect to its fitness for any particular purpose. The information in this document should not be used as a substitute for professional medical advice or as a substitute for the application of clinical judgment in respect of the care of a particular patient or other professional judgment in any decision-making process. The Canadian Agency for Drugs and Technologies in Health (CADTH) does not endorse any information, drugs, therapies, treatments, products, processes, or services. While care has been taken to ensure that the information prepared by CADTH in this document is accurate, complete, and up to date as at the applicable date the material was first published by CADTH, CADTH does not make any guarantees to that effect. CADTH does not guarantee and is not responsible for the quality, currency, propriety, accuracy, or reasonableness of any statements, information, or conclusions contained in any third-party materials used in preparing this document. The views and opinions of third parties published in this document do not necessarily state or reflect those of CADTH. CADTH is not responsible for any errors, omissions, injury, loss, or damage arising from or relating to the use (or misuse) of any information, statements, or conclusions contained in or implied by the contents of this document or any of the source materials. This document may contain links to third-party websites. CADTH does not have control over the content of such sites. Use of third-party sites is governed by the third-party website owners' own terms and conditions set out for such sites. CADTH does not make any guarantee with respect to any information contained on such third-party sites and CADTH is not responsible for any injury, loss, or damage suffered as a result of using such third-party sites. CADTH has no responsibility for the collection, use, and disclosure of personal information by third-party sites. Subject to the aforementioned limitations, the views expressed herein do not necessarily reflect the views of Health Canada, Canada's provincial or territorial governments, other CADTH funders, or any third-party supplier of information. This document is prepared and intended for use in the context of the Canadian health care system. The use of this document outside of Canada is done so at the user's own risk.# List of Tables
# Key Messages
• Long-term symptoms after developing COVID-19, known as post-COVID-19 condition or colloquially as long COVID, is a new condition estimated to affect millions of people worldwide. While standard diagnostic criteria have not yet been developed, current estimates suggest that 21% to 23% of people suspected of having had COVID-19 may have symptoms 4 weeks after their COVID-19 infections and 14% may have symptoms 12 weeks post-infection. Among people with self-reported post-COVID-19, an estimated 40% may continue to experience symptoms for at least a year.
• To provide health care providers and people with post-COVID-19 condition advice regarding diagnosis and treatment, guidelines have been published by the National Institute for Health and Care Excellence (NICE) and by the Centers for Disease Control and Prevention (CDC). The CDC guidelines were published more recently and refer to newer data on post-COVID-19 condition.
• Post-COVID symptoms can affect multiple organ systems and symptoms may vary by patient characteristics such as age and sex, as well as change over time. Some people may develop more severe symptoms or have increased risk of developing other illnesses.
As there are currently no known unique symptoms and no tests available to diagnose post-COVID-19 syndrome, guidelines from NICE and the CDC recommend diagnosing based on symptoms, suspected previous COVID-19 infection, and ruling out other potential causes of symptoms.
• Current treatment recommendations focus on multidisciplinary care and personalized treatment to address the potential range of symptoms unique to each patient. Different methods of delivering treatment have been suggested and implemented around the world, including specialized post-COVID-19 clinics and integrating treatment into primary care.
• Post-COVID-19 condition can result in a reduced ability to work or attend school, and reduced independence, which can impact quality of life. These effects may have a disproportionate impact on disadvantaged groups, which will have important implications for health equity.
• Limited evidence on the clinical effectiveness and cost-effectiveness of therapies for post-COVID-19 condition was identified. However, many trials have been registered and are in progress to address this knowledge gap.
# Purpose
The purpose of this Horizon Scan is to present health care stakeholders in Canada with an overview of information related to long-term symptoms after a COVID-19 infection -often referred to as long COVID or post-COVID-19 condition. The Horizon Scan also aims to include ongoing or emerging research regarding this topic and how to treat, manage, or rehabilitate the symptoms of post-COVID-19. This report is not a systematic review and does not involve a critical appraisal or include a detailed summary of study findings. It is not intended to provide recommendations.
The content of this report was considered up to date as of September 9, 2021 and only citations retrieved before September 8, 2021 were considered for inclusion. Care has been taken to ensure that the information is accurate, but it should be noted that international scientific evidence about COVID-19 is changing and growing rapidly.
# Methods
A limited literature search was conducted by an information specialist on key resources including MEDLINE and Embase through Ovid, the Cochrane Database of Systematic Reviews, the international HTA database, the websites of Canadian and major international health technology agencies, as well as a focused internet search. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine's MeSH (Medical Subject Headings), and keywords. The main search concept was post-acute (sequelae of) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) -or long COVID -and synonyms. No filters were applied to limit the retrieval by study type. Where possible, retrieval was limited to the human population. The search was also limited to English-language documents published between January 1, 2019 and June 4, 2021.
Regular alerts updated the database literature searches until the publication of the final report.
One author screened the literature search results and reviewed the full text of all potentially relevant studies. Studies were considered for inclusion if the population was people with longterm symptoms after a confirmed or suspected COVID-19 infection. Preprint publications, conference abstracts, and grey literature were included when they provided additional information to that available in the published studies.
# Peer Review
A draft version of this bulletin was reviewed by 1 clinical expert.
# Background
The coronavirus disease 2019 has spread rapidly around the globe since it was first identified in late 2019. 1 Caused by the SARS-CoV-2 virus, it was initially characterized by WHO as a relatively short-term, acute disease. In March 2020, WHO stated that, on average, mild cases would recover 2 weeks after symptom onset, while severe cases would recover 3 to 6 weeks after symptom onset. 2 The focus was on severe cases, with mild cases expected to make a quick and full recovery. 3 However, some people were not experiencing the expected full recovery within that time frame and began to share their experiences on social media as early as March of 2020. 3 Online support groups were established and editorials were published by people experiencing these long-term symptoms. Dubbing themselves "long-haulers" experiencing "long COVID," the term "long COVID" moved from social media to print media and was formally acknowledged in name as an issue by WHO during the summer of 2020. 3 Since then, research related to this new condition is aiming to understand the long-term effects of long COVID, its prevalence and risk factors, and to determine the most effective models of treatment.
The evidence base about post-COVID-19 condition, also known as long COVID, is emerging. Its long-term effects on people and health systems are uncertain, but based on the latest estimates, hundreds of thousands of people in Canada and millions of people around the world may be affected. As the evidence base continues to evolve, the purpose of this bulletin is to provide health care decision-makers in Canada an awareness about:
• what is known about post-COVID-19 condition
• what the major emerging research questions being explored are
• what the important implications could be for health systems to consider.
What is Post-COVID-19 Condition?
Research on classifying post-COVID-19 condition is developing and at the time of this report consensus on the terminology had yet to be reached. "Acute COVID-19" is typically used to refer to the acute infection phase, defined as the period up to 4 weeks after being infected. 4 After 4 weeks, new or ongoing symptoms were initially referred to on social media as "long COVID" by people with these long-term symptoms. 3 WHO uses the term "post COVID-19 condition" but notes that multiple names have been used, including long COVID, chronic COVID syndrome, late sequelae of COVID-19, post-acute sequelae SARS-CoV-2 infection (PASC), and long haul COVID, among others. 5 Different groups may use slightly different definitions for any of these terms. 4 WHO is convening a multidisciplinary panel consisting of patients and patient advocates, clinicians, researchers, and other stakeholders to develop a clinical case definition of post-COVID-19 condition. 5,6 This report will also use "post-COVID-19 condition" to refer to symptoms beyond the acute infection phase (i.e., 4 weeks after being infected), while recognizing that some patient advocates may dislike the term post-COVID-19, as it may be interpreted as having no active disease process or suggest that they have recovered. 7 In this context, post-COVID-19 can be considered a short form of post-acute infection phase of COVID-19.
# Classifying Post-COVID-19 Condition
# By Time
A common method of describing the stages of post-COVID-19 condition has been by the amount of time a person has had symptoms or the time elapsed since contracting the SARS-CoV-2 infection. The National Institute for Health and Care Excellence (NICE), the Scottish Intercollegiate Guidelines Network, and the Royal College of General Practitioners use the following terms to characterize different stages of post-COVID-19 condition: 4,8 • ongoing symptomatic COVID-19: symptoms from 4 to 12 weeks after being infected
• post-COVID-19 syndrome: symptoms beyond 12 weeks, or continuing 3 months after infection.
However, these terms are not universally agreed upon; as previously mentioned, WHO uses "post COVID-19 condition" to refer to symptoms after 4 weeks. As another example, a research group from Spain proposed the following groupings:
• potentially infection-related symptoms (weeks 4 to 5)
• acute post-COVID-19 symptoms (weeks 5 to 12)
• long post-COVID-19 symptoms (weeks 12 to 24)
• persistent post-COVID-19 symptoms (beyond 24 weeks). 9 Generally, clinical groups are proposing that post-COVID-19 refers to new or persisting symptoms occurring after 4 to 5 weeks of the infection and lasting up to 12 weeks or longer.
# By Subtypes or Syndromes
Post-COVID-19 symptoms can vary widely across multiple organ systems, which may indicate that it consists of multiple subtypes or syndromes. It may include: 7,10 • Post-viral chronic fatigue syndrome (or myalgic encephalomyelitis/chronic fatigue syndrome [ME/CFS]). ME/CFS can occur after a viral infection and features some symptoms similar to post-COVID-19 condition (e.g., fatigue). 11
• Post-intensive care syndrome (PICS), also sometimes referred to as post-critical-illness syndrome. PICS is caused by medical treatment in the intensive care unit (ICU). 12 Its symptoms may include chronically impaired pulmonary function, neuromuscular weakness, and long-term psychological impacts. 8
• Post-traumatic stress disorder (PTSD). Acute illness and intense treatment can be deeply stressful experiences that may lead to increased risk of developing PTSD. Approximately 9% of people hospitalized for COVID-19, or 23% of those with post-COVID-19 condition, may develop PTSD symptoms. 13,14 • Exacerbation of a pre-existing health condition or disability. For example, a casecontrolled study reported that 7 months after hospital discharge for COVID-19, 53% of people who had pre-existing musculoskeletal pain reported that their pain had worsened. 15 • A unique post-acute COVID syndrome. 7,10 Other proposed methods of classifying people with post-COVID-19 condition are based on when the symptoms appear (i.e., persistent symptoms after acute infection or new symptoms that appear after the acute phase), by pathogenesis (e.g., residual damage from acute infection versus persistent immune activation), or by multiple factors. [16][17][18][19] Distinguishing between subtypes may help to provide targeted treatment options. For example, people experiencing symptoms related to prolonged mechanical ventilation in the ICU will likely require different treatment courses from people who developed symptoms caused by organ damage. However, limited published research on characterizing the different subtypes or potential syndromes with specific diagnostic criteria was identified. The ongoing initiative of WHO to develop clinical case definitions based on international consensus will help to standardize the different characterizations and identify specific subtypes that would be important for making treatment decisions. 5
# Symptoms
Symptoms of post-COVID-19 condition can vary widely due to COVID-19's ability to impact multiple organs, with some studies assessing over 200 possible post-COVID-19 symptoms with a broad range of reported prevalence estimates. 4,[20][21][22] People seeking care for post-COVID-19 condition may present with any combination of:
• generalized symptoms (e.g., fatigue, fever, pain)
• respiratory symptoms (e.g., breathlessness, cough)
• cardiovascular symptoms (e.g., chest tightness or pain, palpitations)
• neurologic symptoms (e.g., cognitive impairment [also sometimes referred to as "brain fog" or not being able to think clearly], headache, sleep disturbance, dizziness, delirium [in older patients])
• gastrointestinal symptoms (e.g., abdominal pain, nausea, diarrhea, anorexia, and reduced appetite [in older patients])
• musculoskeletal symptoms (e.g., joint and muscle pain)
• psychological or psychiatric symptoms (e.g., depression, anxiety)
• ear, nose, and throat symptoms (e.g., tinnitus, earache, sore throat, dizziness, loss of taste and/or smell)
• dermatological symptoms (e.g., skin rashes, hair loss).
Evidence from a preprint systematic review 23 suggests that 83% of people with confirmed COVID-19 may experience 1 or more symptoms after 4 to 12 weeks of their infections. These symptoms may include body and muscle aches, dyspnea (i.e., shortness of breath) or breathing difficulties, and weakness or fatigue, which have been reported by multiple studies. 21,[23][24][25][26][27][28][29] After 12 weeks, the systematic review reported that 56% of people may experience 1 or more symptoms, with fatigue being 1 of the most common symptoms and experienced by nearly half of people (47%). 23 Other new or persisting symptoms after 12 weeks include breathing difficulties or shortness of breath, post-exertional malaise (worsening of symptoms after physical or mental activity), cognitive dysfunction, reduced exercise capacity, and loss of taste and/or smell. 22,[30][31][32][33][34] The preprint systematic review noted that there is relatively little research examining the prevalence of symptoms after 12 weeks and that many studies have limited sample sizes (fewer than 200 people) and are often without comparison groups, increasing the risk of bias. 23 Without comparatives, studies are limited in attributing the reported symptoms specifically to post-COVID-19, as other pre-existing health conditions and factors may also be contributing to symptom occurrence. There may be differences by age, sex, and other factors, and symptoms may change over time, all of which warrants more in-depth and longer-term research. 21,22,30,32,35 While comparative studies are emerging, a large cohort study of adults (more than 73,000 with confirmed COVID-19) from the US found that people who had confirmed COVID-19 but were not hospitalized were more likely to develop a variety of other health conditions in the 6 months after their initial diagnosis compared to adults (matched based on age, sex, ethnicity, and other factors) who did not have a COVID-19 diagnosis and were also not hospitalized. 20 The study also found that people who had acquired COVID-19 were significantly more likely to be diagnosed with neurologic, respiratory, mental health, cardiovascular, and other health conditions over the follow-up period. 20 Evidence from 3 additional non-randomized studies comparing people who were hospitalized with COVID-19 to matched control (people who were hospitalized without COVID-19) also suggest that people who acquire COVID-19 may be more likely to develop other diseases in the long-term (defined variably), including respiratory, cardiovascular, and neurologic diseases, among other conditions and disorders. [36][37][38] Researchers are also investigating the similarities between post-COVID-19 condition and the long-term health consequences of previous coronaviruses, particularly the SARS outbreak in 2003 and Middle East respiratory syndrome. 39 One systematic review found that 6 months after hospital discharge, people who had SARS or Middle East respiratory syndrome had similar symptoms as post-COVID-19 condition including lung abnormalities, reduced exercise capacity, and psychological impairment. 40 An estimated 40% of people who had SARS had chronic fatigue 3.5 years after being diagnosed. 40 It is possible that a similar trend could be found for post-COVID-19 condition.
Overall, the emerging evidence about the type of symptoms and long-term health effects of post-COVID-19 condition suggests that many people can experience a heterogenous range of symptoms after their initial COVID-19 infection. The diversity, length, and severity of symptoms reported vary considerably in different studies and more research is needed to characterize the factors that may be associated with symptoms. 23 The emerging comparative studies examining the health effects of people who acquire COVID-19 to those who do not suggest that there could be a rise in other health conditions. However, longer-term research understanding the mechanisms of how COVID-19 may exacerbate or contribute to other conditions is needed.
# Pediatric Population
The effects of post-COVID-19 condition on children are more uncertain, with fewer studies compared to adults. Many studies of post-COVID-19 condition follow up with people who were hospitalized, but, as children are more likely to have mild symptoms or be asymptomatic, they are less likely to be hospitalized. 41 Children may also have been less likely to be tested for COVID-19 when testing recommendations were focused on symptomatic acute illness. Detecting post-COVID-19 in children can be complicated by differences in common post-COVID-19 symptoms between children and adults, by the fact that children may have more difficulty explaining specific symptoms (e.g., brain fog), by a lack of diagnostic criteria, and because of the variations of post-COVID-19 symptoms in children. 42 Like adults, post-COVID-19 symptoms in children can range widely: the most frequently reported symptoms include pain, breathing difficulties, fatigue, cough, and headache. [43][44][45] Other symptoms include insomnia, rash, and neuropsychiatric symptoms such as concentration difficulties. [43][44][45][46] A preprint survey study of children with symptoms lasting for more than 4 weeks reported that symptoms lasted, on average, for months and that 94% of study participants reported experiencing at least 4 symptoms. 46 Post-COVID-19 condition in children may include multiple subtypes or syndromes. Based on an analysis of 570 pediatric patients, the CDC suggested that there may be 3 subtypes: multisystem inflammatory syndrome in children (MIS-C), atypical Kawasaki disease, and pediatric post-COVID-19 condition. 47 MIS-C is a post-viral hyperinflammatory condition that affects multiple organ systems. Its symptoms typically occur 2 to 6 weeks after exposure to COVID-19 and can include persistent fever, gastrointestinal symptoms, cardiovascular symptoms, abdominal pain, and rash. 47,48 It has been compared to Kawasaki disease because of similarities in clinical presentation but differs on the average age and biomarker test results (e.g., neutrophil counts), which suggests that it could be a different disease. 47
# Diagnosis
Currently, post-COVID-19 condition is primarily diagnosed based on 2 factors: having been infected with COVID-19 in the past and presenting with post-COVID-19 symptoms. The Mayo Clinic released its definition and diagnostic criteria for post-COVID-19 condition, which includes several criteria to help health care providers determine probable or possible cases. 49 Guidelines from NICE and the Mayo Clinic, as well as a UK-based clinical practice guideline, state that a positive COVID-19 test (polymerase chain reaction, antibody, or antigen) or hospitalization due to COVID-19 should not be necessary to diagnose post-COVID-19 condition. Suspected previous COVID-19 illness (e.g., having symptoms closely linked to a COVID-19 infection) is an adequate reason to suspect post-COVID-19 condition as a cause for any new or ongoing symptoms beyond 4 weeks. 4,49,50 This flexibility is important because some people may have contracted COVID-19 but did not need to be hospitalized, did not get tested (e.g., certain areas had recommended people only get tested if they were symptomatic, or community testing may not have been available or accessible), or may have received a false-negative test result. People in Canada with post-COVID-19 condition have reported frustrations over not being able to access post-COVID-19 clinics because they did not have a positive test result despite their health care provider diagnosing them with post-COVID-19 condition after ruling out other likely causes. 51 The Mayo Clinic's criteria recommends looking for symptoms affecting at least 2 of 6 major organ symptoms (general, cardiac, respiratory, gastrointestinal, musculoskeletal, and neurologic), as well as for a decrease in functional status. 49 NICE recommends that health care providers consider any ongoing or new symptoms after acute COVID-19 as potentially being caused by post-COVID-19 condition, but also that people with suspected post-COVID-19 condition undergo tests to determine if their symptoms are being caused by another condition. 4 This will help prevent misdiagnosis by attributing symptoms to post-COVID-19 condition when these same symptoms may have another cause, and allow for targeted treatment where possible.
NICE also recommends that health care providers use a screening questionnaire during the consultation to develop a clearer understanding of each person's symptoms. 4 Specific populations (e.g., children and older adults) may not show the most common symptoms of post-COVID-19 condition, which should be taken into account during diagnosis. 4 WHO have also developed a post-COVID-19 case report form to help collect standardized clinical data from people suspected of having post-COVID-19 condition. 52 In the absence of diagnostic tests, providing health care professionals with training and education about recognizing post-COVID-19 condition will be important. In surveys, people have reported being misdiagnosed by having their symptoms attributed to anxiety or being dismissed by health care professionals. 53,54 This may be because of a lack of awareness of how to diagnose post-COVID-19 condition. Developing clear diagnosis criteria may help reduce misdiagnosis and improve access to care.
# Prevalence
Estimates of the prevalence of post-COVID-19 condition vary widely across studies. One systematic review noted that estimates ranged from 5% to 80%, 55 which may be due to various factors:
• study methodology (e.g., choosing to limit to people who had a positive COVID-19 test or were hospitalized for COVID-19, health administrative data versus survey data)
• a lack of a consistent definition for post-COVID-19 condition (e.g., timing [e.g., 4 weeks or 3 months; timing after infection versus after hospital discharge], what conditions and symptoms are considered to be caused by post-COVID-19 condition)
• local factors (e.g., COVID testing availability for different areas at different times).
# Prevalence in People With Positive COVID-19 Tests and/or People Hospitalized for COVID-19
Many studies focus on people with laboratory-confirmed COVID-19 and/or people who had been hospitalized for COVID-19. Two systematic reviews 23,29 (including 1 that has not yet been peer-reviewed 23 ) estimated that 63% to 84% of people with confirmed COVID-19 had symptoms 4 weeks after either diagnosis or hospitalization and 46% to 56% experienced symptoms after 12 weeks. Three cohort studies 32,34,56 reported that 33% to 39% of people may experience symptoms after 6 to 9 months. Two cohort studies 57,58 reported that 28% to 49% of people who had been hospitalized for COVID-19 experienced symptoms after 12 months.
Although estimates range widely, it appears that the prevalence decreases with time (i.e., fewer people report symptoms at 6 to 9 months compared to at 3 months), which may indicate that some people with post-COVID-19 condition will recover gradually over time. Studies of people who had been hospitalized during the acute phase tend to show a higher prevalence of post-COVID-19 condition compared to people who had milder acute illness and who did not require hospitalization. 7,21 Prevalence When Including Suspected COVID-19
A major limitation recognized by researchers and health care stakeholders is that there are people who may not have had access to COVID-19 testing. As emerging evidence indicates that people who were initially asymptomatic or had mild acute illness can develop post-COVID-19 condition, 21 understanding the prevalence among this subset of people is needed to better characterize the prevalence of people who have or could develop post-COVID-19 condition. Studies that include suspected cases, together with confirmed COVID-19 cases, estimate that 21% to 23% of people who had COVID-19 develop ongoing or new symptoms after 4 weeks or 30 days 21,59 and approximately 14% experience symptoms after 12 weeks. 59 Limited studies about longer-term (beyond 12 weeks) prevalence rates among this subset of people was identified. However, based on household surveys, the Office for National Statistics from the UK has estimated that among people who experience self-reported post-COVID-19 symptoms, 40% may continue to experience symptoms for at least 1 year. 60
# Prevalence in Canada
A rapid systematic review published in June 2021 estimated that 150,000 Canadians have post-COVID-19 condition, although it is unclear if this is limited to confirmed COVID-19. 61 A survey of 1,048 people in Canada with suspected or confirmed post-COVID-19 condition conducted by the COVID Long-Haulers Support Group Canada found that 80% of respondents had symptoms for more than 3 months and almost 50% had symptoms had symptoms for more than 11 months. 51
# Prevalence in Children
In cohort studies limited to children with a positive COVID-19 test, a survey study found that 4% of children aged 5 to 17 had symptoms beyond 4 weeks and 2% had symptoms beyond 8 weeks, 45 while another cohort study found that 13% of participants aged 15 or younger had symptoms after 6 months. 30 An Italian survey that included children without a confirmed COVID-19 test reported that 43% of children had symptoms for more than 60 days after infection. 43 The prevalence of MIS-C, a subtype of post-COVID-19 condition that may occur in some children, appears to be relatively low. One cohort study assessed 99 children (95 with a positive COVID-19 test) and estimated prevalence at around 2 cases per 100,000 children, 62 but the prevalence may be higher among children who had been hospitalized. 48 A survey study from Italy reported that about 2% of children who had COVID-19 developed MIS-C. 43 The variability in prevalence estimates between different studies may be due to low testing rates among children.
# Risk Factors
Understanding potential risk factors that may be associated with developing post-COVID-19 condition may help characterize the cause or causes of the condition, support the development and implementation of preventive interventions, and tailor treatment and management plans. However, a variation in how studies are defining the condition, a heterogenous and complex range of symptoms, and other factors have made it challenging to clearly determine specific risk factors. Retrospective and cross-sectional studies suggest that some potential risk factors for developing post-COVID-19 condition may include:
• severity of acute illness. People who were hospitalized may have a higher risk of developing or having a more severe post-COVID-19 condition compared to people who had milder symptoms. 7,20,21,23,55,63 Other studies have found no association. [64][65][66][67] Acute illness severity may be associated with specific post-COVID-19 symptoms or with PICS. 68
• female sex and older age. Females 26,39,55,69 and older people (defined variably) 26,55,67 may be associated with higher risk of developing post-COVID-19 condition, although others have also found no correlation. 31,67,70,71 Specific symptoms may vary by age and sex, and may change over time. 21,22,30,32,33,35,72 Symptoms may peak for people between ages 40 and 60. 18,37
• comorbidities. Asthma, autoimmune disease, and obesity have been associated with greater risk. 26,73,74 A survey cohort study 75 and a preprint cohort study 76 reported that anxiety, depression, and neurologic disabilities may also be risk factors. However, another cohort study reported no association between comorbidities and the presence of post-COVID-19 condition. 31
• specific symptoms during the acute phase. People who experience certain symptoms during the acute phase such as fatigue, shortness of breath, headache, voice hoarseness, and muscle aches and pains may be more likely to develop post-COVID-19. 18,26,65,77 • number of symptoms during the acute phase. Experiencing a higher number of different symptoms during the acute phase may be associated with developing post-COVID-19. 26,78,79 Other factors that have been investigated but show mixed findings include:
• ethnicity. Evidence on the association between ethnicity and the risk of developing post-COVID-19 condition has been mixed, 25,37,[80][81][82] potentially due to high heterogeneity across studies. 83 This could be because of people from ethnic minority groups having less access to testing 84 or being underrepresented in survey studies. 51
• socioeconomic factors. Some studies indicate an association between socioeconomic factors (e.g., low income) and post-COVID-19 symptoms after 1 month but not beyond 2 months. 63,82 Data from the UK indicate that self-reported post-COVID-19 condition is highest among people from areas with higher deprivation (deprivation calculated by a composite score of neighbourhood level income, education, and health deprivation and disability). 60 These mixed findings may also be because of differences in access to testing or underrepresentation in surveys or the heterogeneity of post-COVID-19 symptoms. 63,82 Among children, a case series has reported that siblings and parents of children with post-COVID-19 condition may also report long-term symptoms, which could suggest genetic and/or environmental factors impacting the likelihood of developing post-COVID-19 condition. 85 One study using health administrative data reported that children who were symptomatic during the acute phase were more likely to develop post-COVID-19 symptoms compared to children who were asymptomatic. 86 The risk of developing MIS-C may be higher in children who are Black or Latino, male, and aged 6 to12 years, as well as children who had been hospitalized. 48,87 Overall, research assessing risk factors associated with developing post-COVID-19 condition in adults and children is developing and emerging findings should be interpreted with caution until rigorous studies have been completed.
# Prevention
Cochrane Rehabilitation has published a living systematic review, REH-COVER or Rehabilitation -COVID-19 Evidence-based Response, assessing rehabilitation for people with COVID-19. 88 Two cohort studies of early rehabilitation clinics treating people after the acute COVID-19 phase reported improvements in pulmonary symptoms and physical performance (e.g., 6-minute walking distance) when comparing participants before and after completing rehabilitation. 89,90 These studies were short-term interventions (8 weeks) for people who had been hospitalized. It is unclear how rehabilitation may affect people who had not been hospitalized, particularly people who present with ME/CFS-like symptoms such as post-exertional malaise (i.e., the worsening of symptoms after even minor physical, mental, or emotional exertion, also known as post-exertional symptom exacerbation) or exercise intolerance (i.e., reduced ability to exercise).
Pilot studies have assessed the efficacy of certain supplements; 91,92 however, due to limited evidence from larger studies, NICE currently does not recommend the use of over-the-counter supplements and vitamins for treating new or ongoing COVID-19 symptoms. 4
# Treatment and Management
Published guidelines from NICE, the CDC, and other research groups provide several options for treatment courses based on existing evidence that are primarily focused on symptoms management. 4,87,[93][94][95][96][97] The CDC guidelines were published more recently than the NICE guidelines (June 2021 compared to December 2020) and draw on more recent data. The CDC guidelines also acknowledge that post-COVID-19 syndrome likely includes multiple syndromes and provides guidance based on research from other post-viral illnesses. 97 A rapid systematic review focused on care models for post-COVID-19 condition identified several studies from the US, UK, Spain, and Italy, with multiple common focuses across different models including: 61
• principles: multidisciplinary teams, integrated care, self-management, coordination of care, and evidence-based care
• medical specialists: pulmonary, cardiovascular, psychiatry and psychology, physiotherapy, occupational therapy, social work, neurology, primary care, nutrition, speech and language therapy
• components: standardized symptom assessment, referral system, follow-up system, virtual care, home-based care.
# Self-Management
NICE and a multidisciplinary clinical panel from the UK recommend that people suspected of having post-COVID-19 condition be provided with education and support for selfmanagement strategies. 4,98 Self-management strategies may include providing up-to-date information about the condition, helping to set realistic goals, and providing information on available supports like online support networks. 4 Certain symptoms may be self-managed, such as breathing exercises for shortness of breath. 97 Online resources providing selfmanagement advice, including the NHS's Your Covid Recovery, Post COVID-19 HUB by the Asthma UK and British Lung Foundation, and Long COVID Support created by a patient advocacy group have also been established. [99][100][101] A program in Leeds, England introduced a fatigue management course delivered online that supports people with post-COVID-19 symptoms on how to manage their fatigue. 94
# Exercise
Evidence about exercise rehabilitation for people with post-COVID-19 is mixed and requires further assessment. Exercise may help reduce fatigue, a common post-COVID-19 symptom, 35 and may be helpful for people who had been bedridden (e.g., people who had been treated in the hospital or ICU) or people who had been hospitalized. 88 However, there is limited research on the impact of exercise for people who had not been hospitalized and there are also concerns that exercise may be harmful to some people with post-COVID-19 condition who may present with post-exertional malaise or exercise intolerance. 102,103 Because of concerns surrounding post-exertional malaise, as well as cardiac or pulmonary symptoms that may be exacerbated from vigorous exercise, post-COVID-19 condition guidelines from World Physiotherapy and the CDC recommend a cautious and conservative approach to exercise based on existing recommendations for ME/CFS. 97,102 World Physiotherapy's guidelines for post-COVID-19 condition and the CDC's guidelines for ME/CFS recommend pacing, also known as activity management, which is an intervention that focuses on balancing rest with activity, and staying within personal limits to avoid overexertion and worsening symptoms. 102,103 World Physiotherapy's report suggests that before recommending exercise, people with post-COVID-19 condition should be screened for post-exertional symptom exacerbation. 102 It also recommends against exercise rehabilitation for those with cardiac impairments, exertional oxygen desaturation (i.e., low oxygen levels during exertion), or autonomic nervous system dysfunction. 102 As post-COVID-19 condition may include multiple syndromes, exercise may be useful for treating certain syndromes but not others. Further research will be needed to determine who is most likely to benefit.
# Vaccination
For people who have not been vaccinated and develop post-COVID-19 condition, receiving a COVID-19 vaccine after the acute infection phase may help to reduce their post-COVID-19 symptoms. In a survey study by the LongCOVIDSOS group, of the respondents who received at least their first dose, 57% reported an overall improvement in symptoms, 25% saw no change, and 19% saw their symptoms worsen. 104 The study reported variation in which symptoms and how many symptoms improved. A preprint survey study reported that in a group of people with post-COVID-19 condition who had received at least 1 dose, 23% saw an increase in symptom resolution compared to 15% in matched unvaccinated individuals. 105 As some post-COVID-19 symptoms resolve with time, more studies are needed to determine if vaccinations, including receiving both doses, reduce post-COVID-19 symptoms and, if so, how this effect occurs. This topic is an active area of research. A non-randomized preprint study assessed the immune response of people who previously had COVID-19 (although it did not specifically include people who had post-COVID-19 symptoms) before and after vaccination and found immune system changes that could explain post-vaccination symptom improvement. 106 At least 1 study is in progress that is conducting immunological follow-up and surveys of people previously infected with COVID-19 to better understand the impact of vaccination on post-COVID-19 symptoms. 107 Research is also ongoing to determine if vaccines affect the risk of developing post-COVID-19 condition for people who have breakthrough infections (i.e., developed COVID-19 after being vaccinated). One survey study has found that people who are fully vaccinated have lower odds of having symptoms 28 days after a breakthrough infection compared to people who are not vaccinated. 108 Preliminary work suggests some people with breakthrough infections could have post-COVID-19 symptoms for at least 6 weeks. [109][110][111]
# Models of Care
Research to understand features of different models of care associated with supporting people with post-COVID-19 is ongoing. Key features that have been recommended -based on evidence from 2 systematic reviews and published position statements of different health care providers -are multidisciplinary care and personalized care. 4,20,61,112,113 The range of symptoms and potential impact on multiple organ systems for post-COVID-19 condition means that people will likely benefit from receiving a range of services from various specialists coordinating and selecting appropriate care based on each person's unique set of symptoms. Researchers and guidelines suggest that diagnostic tests, rehabilitation, and management plans should be personalized. 4,50,98,112,114 Selected tests can be used to rule out other conditions and assess potential causes (e.g., chest X-ray for respiratory symptoms) to provide targeted treatment or referrals, where possible. 50,71,115 The use of technologies such as virtual visits may also help to easily access multiple specialists, especially for people experiencing fatigue who may find it difficult to make multiple clinic visits.
As research on post-COVID-19 condition continues to develop, comprehensive and standardized symptom assessment (such as using WHO's case report form 52 ) will help health care providers and researchers develop a clearer understanding of the effects of post-COVID-19 condition. Careful monitoring, follow-up, and open communication between health care providers, people with post-COVID-19 condition, and researchers has also been recommended to help determine what treatments work and for whom, to identify any adverse events so the treatment can be adjusted or withdrawn as needed, and to ensure cohesive and continuous care. 47,50,51,112,116 Some models of care that have been suggested or implemented, and their characteristics, are summarized in
# Ongoing Research
Research about post-COVID-19 condition is evolving at a rapid pace and different studies are ongoing in Canada and across the world to better understand the condition, its pathophysiology, effective treatments, and its impact on people's well-being. What follows is a description of some of the high-level research initiatives under way and the research questions being explored.
# Cause(s) and Diagnosis of Post-COVID-19 Condition
It is possible that there are multiple mechanisms of post-COVID-19 condition based on the range of symptoms, including damage from intensive treatment (i.e., PICS), lingering viral antigens, inflammatory damage, alterations to the immune system or autonomic nervous system, or COVID-19-specific pathophysiological changes. 87,93 Researchers are assessing damage to organ systems and abnormal biomarker levels to better understand the biologic mechanisms underlying post-COVID-19 symptoms. 115,[121][122][123][124] The pathophysiology in children with post-COVID-19 condition is also unknown and further studies on post-COVID-19 condition in children has been identified as a research priority by the international research community. 125 A small pilot study from the UK has identified the presence of specific autoantibodies in people with post-COVID-19 condition that were not found in people who had not tested positive for COVID-19 or had recovered quickly and did not develop post-COVID-19 symptoms. 126 A blood test to diagnose post-COVID-19 condition may be developed based on these findings, allowing for a quicker diagnosis and therefore earlier access to appropriate treatment.
# Suggested Treatments
As research is under way to understand the physiologic mechanisms that may be causing post-COVID-19 symptoms (e.g., organ damage), targeted treatments may follow. Several potential treatments for post-COVID-19 condition have been suggested by emerging clinical guidelines and/or are being explored in research trials. Treatments that are used for other illnesses or conditions with similar symptoms are being considered. These treatments may be more likely to be investigated and could be included as part of clinical guidelines should they demonstrate efficacy in research trials. 127 For example:
• treatments for ME/CFS or mast cell activation syndrome 79,128,129 (e.g., extracorporeal apheresis, which has been tested by 1 clinic on 3 people with post-COVID-19 condition with CFS-like symptoms and appeared to improve symptoms) 130
• neuromuscular electrical stimulation for treating PICS 131
• photobiomodulation therapy, which has been used to treat various neurologic and psychological disorders, and could be used to treat similar symptoms in people with post-COVID-19 condition 132
• drugs that have been in development for other illnesses that have similar symptoms with post-COVID-19 condition; some are already under investigation as potential treatments for post-COVID-19 condition. 133,134 Other potential treatments are more exploratory and have been suggested by different research groups. These include polypharmacy (to treat post-COVID-19 condition's wide range of symptoms), 135 antibiotics, 136 corticosteroids (prednisolone), 137 personalized medicine by genetic testing, 136 and supplements (e.g., luteolin, vitamin C). 138,139 Some suggested treatments specific for pediatric post-COVID-19 condition have included those:
• for brain fog symptoms, providing the same treatment a child with a concussion would receive 140
• for MIS-C; currently, it is treated the same way as Kawasaki disease, although -as they may be separate conditions -it is unclear how effective that treatment is; antiinflammatory agents may be a useful option. 47
# Ongoing Systematic Reviews and Trials
Several systematic reviews on post-COVID-19 condition have been registered or are being updated regularly as living reviews. The Cochrane group has a rapid living systematic review on COVID-19 rehabilitation that is updated monthly and includes an interactive living evidence page that maps the included extracted studies. 88 The PROSPERO international prospective register of systematic reviews website also has a section dedicated to COVID-19 and, at the time of writing this report (September 9, 2021), has registered more than 100 systematic reviews related to post-COVID-19 condition. 141
Multiple trials are also under way around the world regarding developing a clearer understanding of the symptoms and best management of post-COVID-19 condition. In the UK, the National Institute for Health Research approved £19.6 million in July of 2021 for studies assessing post-COVID-19 condition's causes, symptoms, diagnosis, treatment, and rehabilitation. 142 A few examples include:
• the EU-COGER study, which will assess the recovery from COVID-19 in a geriatric population 143
• the longitudinal survey study from ISARIC -the International Severe Acute Respiratory and emerging Infection Consortium -to assess long-term outcomes 144
• the national UK HEAL-COVID trial, which is under way to identify treatments that can lead to better long-term outcomes for people who had been hospitalized for acute The U.S. National Library of Medicine's clinical trials registry has a dedicated section for COVID-19-related studies. 146 Developing a national surveillance system has also been recommended by WHO and international classifications of diseases (or ICD) codes have been developed to track post-COVID-19 condition. 8 More research using health administrative data with these codes may emerge with time.
In Canada, several cohort studies have been registered that aim to better understand the recovery trajectories of adults with COVID-19 using imaging, blood tests, functional tests, and/or questionnaires to understand symptoms, as well as quality of life (e.g., daily activity limitations). [147][148][149][150] Two studies have also planned to establish a biobank to store biologic samples (e.g., DNA, saliva) for research. 147,150 Two studies plan to follow up after 1 year 149,150 and 1 study plans to follow up for 4 years. 148 A planned cohort study aims to assess the impact of lung ventilation and lung perfusion in adults who had COVID-19, which may help to better understand the specific injuries caused by intensive treatment and lead to the development of targeted treatments for people who received lung ventilation and/or perfusion. 151 Some of these studies will also stratify between mild and moderate/severe acute illness, which will develop a better understanding of the impact of acute infection severity on long-term outcomes. 148,150 The Canadian Institutes of Health Research (or CIHR) has a funding opportunity for its Emerging COVID-19 Research Gaps and Priorities competition, which includes including studies for post-COVID-19 condition, with some studies anticipated to begin by December 2021. 152
# Economic Impact
The economic impact and cost-effectiveness of post-COVID-19 treatment options and care models are not yet established, as they have only recently been launched. A rapid systematic review found 1 study that assessed the economic impact of post-COVID-19, which was focused on health care utilization outcomes and the proportion of people who were able to return to work. 61 The review also found 1 study that estimated the costs of implementing post-COVID-19 clinics in the UK. Further research on the health care costs of various specialists was recommended by the authors of the rapid systematic review. 61
# Considerations for Health Systems
Increase in Demand for Health Care Services
Although the prevalence estimates vary widely, between 14% 59 to 56%, 23,29 of people with COVID-19 experiencing new or persisting symptoms after 12 weeks, based on these estimates, as of August 2021 more than 100,000 people in Canada may have or could develop post-COVID-19 symptoms. Providing appropriate care to affected people, many of whom could also be health care professionals, could put additional pressures on health systems. A Canadian survey of 1,048 people with self-reported post-COVID-19 condition reported that 50% of respondents visited a health care provider 5 times over the past year and 30% of respondents visited more than 10 times. 51 As more people develop post-COVID-19 condition and/or become aware that their symptoms may be due to post-COVID-19 condition, additional resources may be needed to ensure that health care systems and providers are not overwhelmed. 95 A number of health care services could see increases in demand, including in:
• primary care. Many people will likely turn to their primary care providers first, regarding their suspected post-COVID-19 condition.
• multidisciplinary rehabilitation services. Post-COVID-19 condition can manifest with a variety of symptoms and will likely require various types of care from multiple specialists working in coordinated teams.
• prescription drugs. A US cohort study of health administrative data found that after 30 days, those who had COVID-19 had more billings for several drugs including pain medications, antidepressants, hypertensives, sedatives, and oral hypoglycemic drugs. 20
• mental health treatments and supports. As post-COVID-19 symptoms may include depression, anxiety, and/or PTSD, the use of psychological supports and treatment have been recommended by a clinical group from Italy. 112
• medical imaging procedures and blood tests. Clinical guidelines from NICE recommend that health care providers order bloodwork and/or imaging procedures to potentially determine causes of symptoms and rule out other illnesses as the cause of people's symptoms. 4
• intensive care in hospitals and/or ICUs. Cohort studies (including 1 preprint) found that about 17% of people who had been hospitalized for COVID-19 during the acute phase returned to the emergency department and 10% were re-hospitalized. 34,153 An estimated 70% to 80% of children with MIS-C may require admission to a pediatric ICU. 48 • nutritionist services. Education in nutrition may be needed to treat muscle loss and frailty from severe acute illness, as well as specific post-COVID-19 symptoms such as nausea or diarrhea. 87
• lung transplantations. There may be an increase in demand for lung transplantations due to the severe damage COVID-19 can cause to the lungs. 154
# Health Equity
In Canada and around the world, health equity has been an issue since before the onslaught of the COVID-19 pandemic, as discrimination and stigma based on factors such as ethnicity, sex and/or gender, and socioeconomics impacts people's health. 155 Many people experiencing vulnerabilities, such as people from diverse ethnic backgrounds and lower-income households, were at higher risk of being infected with COVID-19. 84,155 Thus, these groups may also have a high proportion of people with post-COVID-19 condition. Other groups at risk include people with disabilities, people experiencing homelessness or housing instability, or people living in correctional facilities. 97 Furthermore, these groups may be disproportionately impacted by post-COVID-19 condition, as they may be more likely to:
• work in jobs without sick leave and/or extended health benefits, and thus struggle to access needed treatment, which could lead to worsened health and greater health inequities
• struggle more financially if they or someone in their household becomes unable to work full-time
• find it challenging to access health services
• be misdiagnosed or have their post-COVID-19 symptoms dismissed (e.g., due to anxiety). 53,54 Some approaches suggested by the CDC and health policy researchers to address these inequities have been to:
• allocate resources to raise awareness of post-COVID-19 condition among marginalized groups and increase access to needed services 97
• provide training to health care providers surrounding sensitivity to and awareness of stigma, empathy, and the importance of completing a full clinical evaluation 97
• implement a primary care-based model to improve access to specialized services typically only covered by private insurance (e.g., physiotherapy) 84
• ensure services are easy to navigate (e.g., providing information in clear plain language) and culturally sensitive (e.g., being available in multiple languages or have interpreters available, culturally relevant and appropriate treatment plans)
• require minimal appointments to avoid interrupting work for those who do not have access to paid sick leave or who may live far from the clinic
• use telemedicine for easier scheduling, easier collection of information including symptoms (e.g., people can complete forms on their smartphones or computers in their free time at home or between work), and improve access (e.g., not requiring people to drive to a distant clinic). 95,113 As services are rolled out, they will need to continually be evaluated for any accessibility barriers and ensure that people are receiving high-quality, cost-effective, and culturally appropriate care. 84
# Patients' Perspectives and Experiences
Access to Care and Care Navigation
Although post-COVID-19 condition is now acknowledged as an issue by WHO and researchers, many people may be struggling to receive recognition of their condition and access appropriate care. 51,120 In a Canadian survey that ran in May of 2021, some participants reported health care professionals dismissing their symptoms and other people who received attention from their health care providers reported difficulties accessing care. 51 Because of diagnostic uncertainty, it may be challenging for people with post-COVID-19 condition to know where to seek care and for health care providers to know when and how to provide treatment. Providing health care services navigation support to people with suspected post-COVID-19 condition may be needed to prevent overwhelming hospitals or other health care services. Similarly, raising awareness about post-COVID-19 condition among health care providers and providing clear guidelines for self-management, testing, and treatment options may also help address challenges related to care navigation. Outlining care pathways may make care navigation simpler, less time-consuming, and less stressful for both health care providers and people with post-COVID-19. Systems may also need to consider how to minimize waiting times for receiving care. 156
# Quality of Life and Daily Activities
In addition to post-COVID-19 condition having an impact on people's health, it could impact their quality of life (QoL) and daily living. A systematic review and meta-analysis reported that post-COVID-19 condition was associated with lower health-related QoL, particularly in people who had been admitted to the ICU and people experiencing fatigue. 157 Approximately one-third of people in Canada who had been hospitalized for COVID-19 reported reduced QoL 3 months after symptom onset. 158 A prospective cohort study from Germany has suggested that lower QoL could continue for up to 12 months after symptom onset. 33 Reduced QoL could result from a variety of factors, such as general poorer health (e.g., fatigue) or cognitive difficulties such as memory difficulties and brain fog even among young people who had mild acute illness. 30,159 These symptoms could result in:
• limitations in day-to-day activities (e.g., being able to engage in social activities or hobbies, requiring assistance for personal care) 10, 25,160,161 • reduced ability to care for children and/or dependents 7
• reduced ability to work full-time (i.e., switching from full-time to part-time or taking leave from work), leading to financial stress, in particular for people who are less financially stable. 22,51 Estimates based on surveys of people self-reported to have post-COVID-19 who were working before their illness suggest that between 44% and 68% of people faced challenges to their work, either through reduced hours, taking leave, or not working. 22,162 One study reported that people with suspected post-COVID-19 condition were significantly more likely to not return to full-time work compared to people who developed COVID-19 but were able to recover within 12 weeks. 22 Post-COVID-19's impact on people's ability to return to work could have important implications for health and economic equity. While preliminary studies of rehabilitation programs indicate improved health outcomes for those who had been hospitalized, it is not known if rehabilitation helps people return to work more quickly. 88 Providing guidance and resources for people with post-COVID-19 condition and their educational institutes and workplaces may help to alleviate these difficulties. Studies that measure disability-adjusted life-years and quality-adjusted life-years will also likely be needed to better understand the burden of post-COVID-19 condition and help to quantify which treatment and management protocols are most clinically effective and cost-effective.
# Continuing Engagement
Patient support and self-help groups, including COVID Long-Haulers Canada and Long COVID Kids (which has groups in the US, UK, and Canada) are active. 8,163,164 People with post-COVID-19 condition have reported that these support groups have been invaluable in providing support and validation about their condition, and continue to help raise public awareness. 53,165,166 Advocacy groups are also calling on governments to set up working groups to address the needs of people with post-COVID-19 condition, commission urgent research, establish multidisciplinary clinics, ensure health care providers are able to provide appropriate treatment, and assess economic implications including providing long-term sick leave, financial support, and employer awareness. 166
# Implications for Children
Similar to adults, children with post-COVID-19 condition could experience a lower QoL through:
• being unable to engage in physical activities or only enjoying them occasionally and often having symptoms worsen afterwards 46
• lowered self-esteem due to their symptoms (e.g., rash) and inability to engage in activities with their peers
• being unable to attend school full-time or at all, which in turn can lead to poorer physical and mental health, as well as poorer academic performance. 44,85,165 This may be an issue especially for children and adolescents without access to supports (e.g., private tutoring) and may lead to greater inequalities that extend into adulthood (e.g., lowered chance to attend higher education, poorer job prospects). 167 As of the time of writing (September 2021), COVID-19 vaccines are not approved for children younger than 12 in Canada. Although uptake of vaccines by adults may help to reduce the spread of COVID-19, children can be at risk of infection, especially as public health restrictions ease in many jurisdictions. In addition to the risk of children being infected and developing post-COVID-19 condition or MIS-C, their family and communities are also at risk.
An additional consideration about post-COVID-19 in children is related to developing back-to-school policies that allow children to safely return to school. It is unknown if and to what extent children may develop post-COVID-19 condition through asymptomatic spread in the school setting, especially among unvaccinated children younger than 12 years. 168 Many children and families are keen to return to full-time, in-person teaching, without the disruptions from the past school year that led to academic, psychological, and social development losses for children and adolescents, particularly those from marginalized and/or low-income families. 169 However, considerations will likely be needed to minimize the risks of COVID-19 infection and post-COVID-19 condition to children, their families, and communities. Protective measures including mask-wearing, ventilation, regular testing, small class sizes, and spaced classrooms could help to reduce these risks. 168
# Final Remarks
It has become increasingly clear that a significant portion of people who recover from acute COVID-19 will need care for weeks or months. Post-COVID-19 condition is a new area of research and evidence is still emerging. While many trials and reviews on the condition have been registered and are under way, it will take months and years before a clear picture of post-COVID-19 condition's cause(s) and natural history is available, as well as what constitutes the most clinically effective and cost-effective treatment and management options. Notable gaps in the evidence include a lack of health economics studies (e.g., the estimated costs that post-COVID-19 condition will put on the health care system and the costs and benefits of different care models, social support, and support systems for people with post-COVID-19 condition) and studies assessing children with post-COVID-19 condition. As jurisdictions in Canada and across the world continue to monitor the emerging evidence base, increasing recognition about post-COVID-19 condition, improving reporting about its prevalence, and addressing the research gaps can help to better prepare and equip health systems. 170 Moving forward, addressing health equity issues and engaging with people with post-COVID-19 condition will also likely be key. Collaborating with patient advocates has allowed researchers and health care providers to learn a great deal about post-COVID-19 condition, from its very existence to its range of complex symptoms. Continuing to involve a diverse range of people with lived experiences will help to develop a better understanding of post-COVID-19 condition and allow for the development of care that addresses their health and well-being. | None | None |
c0f6e5c8a353ed55c302d2c6c10355d858a4ec29 | cma | None | cute aortic syndrome (AAS) is a life-threatening emergency, accounting for 1/2000 presentations of acute chest or back pain to the emergency department. 1 It is a clinical spectrum of diagnoses including aortic dissection, intramural hematoma and penetrating atherosclerotic ulcer at any location along the aorta. 1 The incidence of AAS is about 3 per 100 000 persons. 2,3 Many physicians do not consider AAS in their initial differential diagnosis, which is in part why 25% of patients with AAS are not diagnosed with the condition until 24 hours after presenting to the emergency department. 4 Prognosis is most favourable when patients are treated early, while they are clinically stable. Mortality follows a linear increase with diagnostic delay and can be as high as 2% per hour of delay. 5 The misdiagnosis rate during the initial emergency department visit for AAS (i.e., patient admitted for an alternative diagnosis and later diagnosed as AAS; discharged from the emergency department and presenting again with a diagnosis of AAS; or diagnosed on postmortem examination) is estimated to be as high as 38%. 4, Patients with suspected AAS are typically investigated with electrocardiogram (ECG)-gated contrast-enhanced computed tomography (CT). 2 Current use of this investigation in patients with a clinical suspicion for AAS is inefficient. 17,18 The unnecessary use of CT leads to a direct increase in health care costs but also an increase in contrast-associated complications (e.g., allergic reactions), increased length of emergency department stay or incidental findings requiring further follow-up, additional im aging and increased stress or anxiety for the patient. 17 Use of CT in a low-prevalence population can result in an increase in false-positives, which can lead to further testing, unnecessary transfer and even surgical intervention. 19 There are 2 high-quality guidelines related to the diagnosis of AAS, from the American Heart Association (2010) and the European Society of Cardiology (2014). 20,21 However, there is still considerable variation in how clinicians investigate for AAS in Canada. 17 This variation is likely multifactorial but may be a result of lack of key stakeholder involvement in the development of the guidelines or the difference in threshold for investigation within the Canadian health care system. 22,23 The aims of this guideline are to update the available guideline recommendations with current evidence; include key stakeholders to allow interpretation of the evidence in context of values and preferences; and make practice recommendations that are applicable to the Canadian health care system. The full guideline, including supplemental documents, is available at Appendix 1# Scope
The purpose of this guideline is to provide evidence-based recommendations about the diagnostic evaluation of patients with suspected AAS. Our definition of AAS does not include ruptured or leaking aortic aneurysms. This guideline is not applicable to pregnant patients, patients with recent (< 24 hr) cocaine use or patients younger than 18 years. The primary studies used to generate the recommendations either did not include these patients or did not report on their inclusion; therefore, the diagnostic accuracy of signs and symptoms for AAS are unknown within these populations.
We present diagnostic pathways based on the expected prevalence of AAS and provide guidance on testing based on clinically relevant and accepted thresholds for diagnostic error. The recommendations are further guided by principles of minimizing radiation exposure and the required number of diagnostic tests to meet the accepted thresholds, where possible. This guideline is intended to aid clinicians in selecting optimal diagnostic test(s) that are more likely to result in a diagnostic result, reduce the number of diagnostic tests and minimize exposure to radiation.
The target audience includes patients, emergency medicine physicians, family physicians, internists, radiologists, vascular surgeons, cardiothoracic surgeons, critical care physicians and decision-makers.
# Recommendations
The 4 recommendations in this guideline are divided into the following categories: assessment of pretest probability (risk factors, pain features, clinical suspicion and alternative diagnoses, and physical examination) and diagnostic strategy (low, medium and high pretest probability) (Table 1). The assessment of quality of studies informing this guideline is available in Appendix 2, at www.cmaj.ca/lookup/suppl/doi:10.1503/cmaj.200021/-/DC1.
The rationale behind optimal test thresholds and the prevalence estimates used in Bayesian modelling (as described in the Methods section, below) can be found in the full guideline (Appendix 1). Modifications to the American Heart Association and European Society of Cardiology guidelines are highlighted in the description of the recommendations below and in Table 3.
Table 2 and Figure 1 provide a framework for assessment of pretest probability and suggestions for further testing at moderate or high risk for AAS. Pretest probability is defined as the probability of a patient having the target disorder before a diagnostic test result is known. See Appendix 2 for the definitions used for each high-risk clinical finding associated with AAS.
# Assessment of pretest probability
The committee recommends that providers routinely evaluate any patient presenting with complaints that may represent AAS, to establish a pretest risk of disease that can then be used to guide diagnostic decisions. This process should include specific questions about risk factors and pain features, as well as a focused examination to identify findings that are associated with AAS (strong recommendation based on low certainty in the evidence of effects on clinical outcomes and moderate certainty in the evidence of diagnostic accuracy studies).
The committee suggests using historical pain, risk factors and physical examination findings to define a patient as having a low (≤ 0.5%), moderate (0.5%-5%) or high (> 5%) probability for AAS (conditional recommendation based on low certainty in the evidence of effects on clinical outcomes and low certainty in the evidence of diagnostic accuracy studies) (Table 2).
# Risk factors
Risk factors for AAS include connective tissue disease, aortic valve disease, recent aortic manipulation, aortic aneurysm (thoracic or abdominal, on chest radiograph, history or bedside echocardiography) and family history of AAS.
The European Society of Cardiology and American Heart Association guidelines on AAS specifically refer to thoracic aortic aneurysms as a risk factor. However, the International Registry of Acute Aortic Dissection database, a multicentre registry that includes more than 4000 cases, states that a known aortic aneurysm, either thoracic or abdominal, is associated with AAS. 24 Therefore, we updated the definition of aortic aneurysm in our assessment of pretest probability to include both abdominal and thoracic aneurysms as risk factors.
Patients may not be aware of the presence of an aortic aneurysm. Bedside ultrasound has been found to be accurate in the diagnosis of abdominal aortic aneurysms. 25 A multicentre prospective observational study including 839 patients (very lowquality evidence, downgraded for risk of bias and indirectness) showed moderate diagnostic accuracy (sensitivity 0.60, 95% confidence interval 0.51-0.68; specificity 0.85, 95% CI 0.83-0.88) for assessment of aneurysmal dilation of the aortic root. 26 Bedside ultrasound is operator dependent; therefore, the diagnostic accuracy may vary depending on the level of training. However, it is reasonable to examine those who are presenting with symptoms suggestive of AAS for the presence of an abdominal or thoracic aortic aneurysm in the visible portions of the aorta.
We found 7 observational (prospective and retrospective) studies including 659 patients (very low-or low-quality evidence, downgraded for substantial heterogeneity and imprecision) that suggest chest radiograph may also be helpful (sensitivity 0.79, 95% CI 0.70-0.85; specificity 0.56, 95% CI 0.41-0.70) in suggesting a possible thoracic aortic dilation. A systematic review of 9 studies (n = 551) found clinical examination is not sufficient in diagnosing rapid aortic expansion or a leaking, ruptured or dissecting aortic aneurysm. 33 Therefore, if a patient presents with pain and a known or newly diagnosed aortic aneurysm, they should undergo advanced imaging. This is a modification of the European Society of Cardiology and American Heart Association guidelines (Table 3).
# High-risk pain features
High-risk pain features for AAS include abrupt-onset or thunderclap pain, severe or worst-ever pain, tearing or ripping pain, migrating or radiating pain.
The American Heart Association guideline recommends that high-risk pain be defined as pain that is either severe or abrupt in onset, with a tearing, ripping, sharp or stabbing characteristic. Rogers and colleagues modified this recommendation to define high-risk pain as any abrupt, severe, tearing or ripping pain. 34 These modifications formed the basis of the high-risk pain section of the acute aortic dissection detection risk score. This tool was the result of expert consensus and was incorporated into the European Society of Cardiology guideline.
In contrast, the committee agreed that a patient with severe pain versus a patient with severe, abrupt-onset, tearing pain were not at the same pretest probability for AAS. We also thought that an increasing number of high-risk pain features was associated with an increased pretest probability for AAS; however, this was based entirely on expert consensus as we found no direct evidence on systematic review of the literature.
# Clinical suspicion or alternative diagnosis
Clinician suspicion for AAS or an alternative diagnosis is currently part of the American Heart Association and European Society of Cardiology guidelines; however, these guidelines suggest that consideration of an alternative diagnosis should take place after Table 1 (part 1 of 2): Recommendations for assessment of pretest probability and diagnostic strategy in acute aortic syndrome
# Recommendation
# Strength of recommendation and certainty of evidence
# Assessment of pretest probability
The committee recommends that providers routinely evaluate any patient presenting with complaints that may represent AAS, to establish a pretest risk of disease that can then be used to guide diagnostic decisions. This process should include specific questions about risk factors and pain features, as well as a focused examination to identify findings that are associated with AAS.
Strong recommendation based on low certainty in the evidence of effects on clinical outcomes and moderate certainty in the evidence of diagnostic accuracy studies.
The committee suggests using historical pain, risk factors and physical examination findings to define a patient as low (≤ 0.5%), moderate (0.5%-5%) or high (> 5%) probability for AAS (Table 2).
Conditional recommendation based on low certainty in the evidence of effects on clinical outcomes and low certainty in the evidence of diagnostic accuracy studies.
Technical remarks:
- An absence of any high-risk historical, risk factor or physical examination findings places the patient in a population with a very low prevalence for AAS.
- The panel recognized that different clinical features have different strengths of association with AAS.
- Clinical suspicion for an alternative diagnosis or for AAS is important in assessment of pretest probability.
- Patients with a low risk of AAS and no alternative diagnosis are still considered low risk.
- The panel suggests the presence of any clinical features strongly associated with AAS (hypotension, pulse deficit, neurologic deficit, new murmur of aortic regurgitation, aortic aneurysm) places the patient in a higher probability population.
- Clinical suspicion for an alternative diagnosis is useful in a moderate-risk group, but AAS should still be considered in the presence of multiple clinical features for AAS even if a suspicion for an alternative diagnosis exists.
- This assessment strategy assumes that the history and physical examination are carried out under optimal conditions in an oriented patient compliant to physical examination. If the patient is unable to provide an accurate history, pretest probability assessment will be affected.
# Diagnostic strategy
# Low pretest probability
The committee suggests no further testing in a population with a low pretest probability (prevalence of AAS of ≤ 0.5%).
Conditional recommendation based on low certainty in the evidence of effects on clinical outcomes and moderate certainty in the evidence of diagnostic accuracy studies.
Technical remarks:
- There are no prospectively validated clinical decision rules to assess pretest probability. Estimates are based on modelling of low-or moderatequality observational studies.
- The pathway relies on the ability to obtain an accurate history. The addition of D-dimer to the diagnostic pathway lowered the probability of AAS further, but also increased the number of false-positive CT scans above ideal thresholds.
# Intermediate pretest probability
The committee suggests using a strategy starting with D-dimer for excluding AAS in a population with an intermediate pretest probability (prevalence 0.5%-5%), followed by ECG-gated CT in patients with a positive D-dimer test. If D-dimer testing is not readily available, an alternative acceptable strategy includes performing ECG-gated CT alone.
Conditional recommendation for D-dimer based on low certainty in the evidence of effects on clinical outcomes and moderate certainty in the evidence about diagnostic accuracy studies. Conditional recommendation for ECG-gated CT aorta based on moderate certainty in the evidence of effects on clinical outcomes and moderate certainty in the evidence from diagnostic accuracy studies.
The committee suggests no further testing after a negative D-dimer test in a population with an intermediate pretest probability (prevalence 0.5%-5%).
The panel recommends no additional testing after a negative ECG-gated CT in a population with intermediate pretest probability prevalence.
Grading as per low pretest probability recommendation.
the assessment of pretest probability. In contrast, committee members agreed that this happens concurrently with assessment of historical risk features and should be included in initial pretest probability assessment. Results from a national survey supported this view, with respondents rating likelihood of AAS or of an alternative diagnosis as extremely important in the assessment of pretest probability, ranking higher than any pain characteristic, risk factor or physical examination finding. 35 There is no formal assessment of the diagnostic accuracy of clinical suspicion for AAS. We performed a systematic review and meta-analysis of studies reporting on misdiagnosis of AAS and found 12 studies with 3433 patients (very low-quality evidence, downgraded for variable patient population, definition of missed cases and reference standard among studies, along with inconsistency, imprecision and indirectness 6,7, .) The results of this meta-analysis (sensitivity 0.79, 95% CI 0.70-0.87; specificity 0.63, 95% CI 0.60-0.65) were incorporated into the summary estimate of diagnostic accuracy in Bayesian modelling (Appendix 1). Incorporating clinical suspicion into pretest probability assessment allowed for an improvement in specificity while keeping the miss rate below an acceptable threshold. Care should be taken if the alternative diagnosis being considered is acute coronary syndrome, stroke or an unconfirmed pulmonary embolism. These are the most common initial diagnoses in patients with a missed AAS. 4,9,10,13,16 Physical examination High-risk physical examination findings for AAS include new aortic regurgitation (auscultated murmur or bedside echocardiography), pulse deficit, neurologic deficit, hypotension or pericardial effusion on bedside echocardiography.
The American Heart Association and European Society of Cardiology guidelines report bilateral blood pressure differential as a high-risk feature for AAS. We found no direct studies exploring - There are no prospectively validated clinical decision rules to assess pretest probability. Estimates are based on modelling of low-or moderatequality observational studies.
- A decision to start with D-dimer testing assumes the results will be obtained in a timely manner and that the cost of D-dimer screening is offset by avoiding unnecessary ECG-gated CT aorta or transfer of patients at moderate pretest probability for AAS. If the D-dimer strategy is followed, a highly sensitive D-dimer assay is required.
- A negative D-dimer test (i.e., < 500 ng/mL) indicates a low probability (< 0.5%) of AAS and no additional testing is required.
- Caution should be used in patients presenting with > 24 h of symptoms as D-dimer can be falsely negative. Intramural hematoma without connection to circulation can lead to a false-negative D-dimer. D-dimer has limited utility in hospitalized patients and in certain patient populations (postsurgical, pregnant) because of the high frequency of positive D-dimer results with standard thresholds.
- The likelihood of a positive D-dimer test (> 500 ng/mL) increases with age; however, there are no studies reporting on the diagnostic accuracy of age-adjusted D-dimer testing for the diagnosis of AAS. Therefore, the standard threshold of > 500 ng/mL was used to indicate a positive test.
- ECG-gated CT of the aorta is the next step after a positive D-dimer result. AAS is a time-sensitive condition and CT should be expedited. The preference is for an ECG-gated scan. A negative ECG-gated CT rules out AAS.
The strategy assumes that test results are obtained under optimal conditions. Suboptimal CT results may require repeat testing or an alternate strategy.
# High pretest probability
The committee recommends using a strategy starting with ECG-gated CT for assessing patients suspected of having AAS in a population with a high pretest probability (prevalence ≥ 5%).
Strong recommendation for ECG-gated CT aorta based on moderate certainty in the evidence of effects on clinical outcomes and moderate certainty in the evidence of diagnostic accuracy studies.
The committee suggests not using a D-dimer test in a population with a high pretest probability (prevalence ≥ 5%).
Conditional recommendation against D-dimer based on low certainty in the evidence of effects on clinical outcomes and moderate certainty in the evidence of diagnostic accuracy studies.
Technical remarks:
- There are no prospectively validated clinical decision rules to assess for a pretest probability of > 5%. Estimates are based on modelling of lowor moderate-quality observational studies.
- CT should be ECG gated to avoid motion artifacts especially of the aortic root and ascending aorta. It is important to scan with and without contrast to rule out an intramural hematoma. Reconstruction to thinner slices (< 1 mm) and multiplanar reconstruction including sagittal oblique for thoracic aorta are recommended.
- The strategy assumes that test results are obtained under optimal conditions. Suboptimal CT results from improper technique (e.g., no gating, only unenhanced study or venous phase scanning) may require repeat testing.
- If CT is not feasible (e.g., contrast media allergy, severe renal impairment, or unavailability), MRI or TEE may be acceptable.
- In cases where clinical suspicion for AAS remains high with a negative initial CT, repeat ECG-gated CT should be considered. If repeat CT with proper technique is not feasible, additional testing with TEE or MRI may be considered.
Note: AAS = acute aortic syndrome, CT = computed tomography, ECG = electrocardiogram, MRI = magnetic resonance imaging, TEE = transesophageal echocardiography.
its independent association with AAS. Multiple studies analyzed it as a composite variable with pulse deficit or blood pressure differential. 39 We identified only 1 case-control study that showed bilateral blood pressure differential was significantly associated with AAS; however, it did not improve diagnostic accuracy in addition to pulse deficit. 40 As much as 20% of the general population will have a blood pressure differential. 41 The committee agreed that this finding may be useful to raise suspicion for AAS; thus, any patient presenting with a blood pressure differential should be assessed for their pretest probability of AAS. In the context of other pain, risk factors and physical examination findings, it likely does not add any benefit in assessment of pretest probability. Therefore, we removed bilateral blood pressure differential from the high-risk physical examination findings (Table 3).
A single-centre study of 839 patients (very low-quality evidence, downgraded for risk of bias and indirectness) suggests that bedside ultrasound is capable of diagnosing aortic regurgitation in AAS (sensitivity 0.1, 95% CI 0.06-0.16; specificity 0.93, 95% CI 0.91-0.95). 26 Diagnostic accuracy of bedside ultrasound for aortic regurgitation may vary between providers. This variation is also seen with clinical examination. Auscultation has moderate-to-low inter-rater reliability and diagnostic accuracy. 42,43 Therefore, the committee agreed that point-of-care ultrasonographic evidence of new aortic regurgitation in a patient presenting with symptoms suggestive of AAS is a highrisk examination finding, in addition to auscultation of a murmur consistent with aortic regurgitation. The use of point-ofcare ultrasound is meant to augment physical examination; therefore, if a provider is not trained in its use, it is simply omitted from pretest probability assessment. The addition of pointof-care ultrasonography is an update to the American Heart Association guideline, but is present in the European Society of Cardiology guideline (Table 3).
# Diagnostic strategy
# Low pretest probability
The committee suggests no further testing in a population with a low pretest probability (prevalence of AAS of ≤ 0.5%) (conditional recommendation based on low certainty in the evidence of effects on clinical outcomes and moderate certainty in the evidence of diagnostic accuracy studies).
# Intermediate pretest probability The committee suggests using a strategy starting with D-dimer testing for excluding AAS in a population with an intermediate pretest probability (prevalence 0.5%-5%), followed by ECG-gated CT in patients with a positive D-dimer test. If D-dimer testing is not readi ly available, an alternative acceptable strategy includes performing ECG-gated CT alone (conditional recommendation for D-dimer based on low certainty in the evidence of effects on clinical outcomes and moderate certainty in the evidence about diagnostic accuracy studies; conditional recommendation for ECG-gated CT based on moderate certainty in the evidence of effects on clinical outcomes and moderate certainty in the evidence from diagnostic accuracy studies).
# The committee suggests no further testing after a negative D-dimer test in a population with an intermediate pretest probability (prevalence 0.5%-5%). The panel recommends no additional testing after a negative ECG-gated CT in a population with an intermediate pretest probability (prevalence 0.5%-5%) (grading as per low pretest probability recommendation).
# High pretest probability
The committee recommends using a strategy starting with ECGgated CT for assessing patients suspected of having AAS in a population with a high pretest probability (prevalence ≥ 5%) (strong recommendation for ECG-gated CT based on moderate certainty in the evidence of effects on clinical outcomes and moderate certainty in the evidence of diagnostic accuracy studies).
# The committee suggests not using a D-dimer test in a population with a high pretest probability (prevalence ≥ 5%) (conditional recommendation against D-dimer based on low certainty in the evidence of effects on clinical outcomes and moderate certainty in the evidence of diagnostic accuracy studies).
# D-dimer testing
The recommendations for D-dimer testing are based on a metaanalysis of 22 studies with 3860 patients (Appendix 2). According to the QUADAS-2 (quality assessment of diagnostic accuracy studies) tool, 19/22 of the included studies had at least 1 domain rated as high risk of bias. The evidence was rated as very low for specificity (0.60, 95% CI 0.48-0.71) and moderate for sensitivity (0.95, 95% CI 0.90-0.99). There are 2 other meta-analyses that included only 5 of the 22 articles we included in the meta-analysis; their QUADAS assessments found a low or unclear risk of bias in most domains, leading to downgrading of the level of certainty. 44,45 ECG-gated CT of the aorta Acute aortic syndrome is a time-sensitive emergency and if a patient is deemed at high risk, an ECG-gated CT of the aorta should be expedited. We found 1 meta-analysis with a total of 3 studies. Although a small number of patients (n = 126) were included, there were no serious limitations in indirectness, inconsistency, imprecision or risk of bias.
Whenever available, ECG gating (prospective) should be used for imaging of suspected acute aortic syndrome, to avoid motion artifacts especially at the aortic root and ascending aorta. Scanning of the thoracic aorta without contrast is important to rule out intramural hematoma. Reconstruction to thinner slices (< 1 mm) and multiplanar reconstruction including sagittal oblique for thoracic aorta are suggested.
# Methods
We chose to adapt existing high-quality clinical practice guidelines previously developed by the American Heart Association and European Society of Cardiology using the Grading of Recommendations Assessment, Development and Evaluation (GRADE)-ADOLOPMENT (combined use of adoption, adaptation, and de novo development of recommendations) approach. 20,21,46 The overall guideline development process -including funding of the work, formation of participating groups, management of competing interests, internal and external review, and organizational approval -was guided by the Guidelines International Network-McMaster Guideline Development Checklist. 25 We structured our process to meet the recommendations for trustworthy guidelines by the National Academy of Medicine and the Guidelines International Network. The full details of the guideline methods are available in our complete guideline document (Appendix 1).
# Composition of participating groups
We recruited 21 people from across Canada to take part in developing the guideline as members of the guideline advisory committee. The advisory committee included emergency phys icians and nurses, cardiothoracic and vascular surgeons, cardiac anesthesiologists, critical care physicians, radiologists and 2 patients. We selected members based on their expertise and professional and geographic diversity, as well as practice environment (academic, community, rural or remote). Methodologists with expertise in evidence appraisal and guideline development were also included (R.O., J.Y., K.Y., E.L.). From members of the advisory committee, we appointed a guideline chair (R.O.) and a guideline coordination panel (S.M., D.A., P.J.).
We prepared and revised the guideline through an iterative process consisting of feedback and discussions until we achieved consensus. The advisory committee communicated through multiple teleconference meetings, emails and a 1-day, in-person meeting in late 2018. The coordination panel developed and graded the recommendations and assessed the certainty in the supporting evidence following the GRADE approach. 51,52 We used the in-person meeting to discuss the evidence-to-decision frameworks and come to consensus on the recommendations.
# Formulating specific clinical questions and determining outcomes of interest
The coordination panel used the GRADEpro Guideline Development Tool (www.gradepro.org) 51 to brainstorm, then prioritize the following questions addressed by this guideline: 1. What is the optimal test threshold (i.e., the likelihood of the disease where the benefits of testing outweigh the harms) for low-, moderate-or high-risk probability for AAS? 2. What is the optimal pretest probability assessment for AAS? 3. In a patient population with a low clinical probability of AAS, what is the optimal diagnostic strategy to evaluate for suspected AAS? 4. In a patient population with an intermediate clinical probability of AAS, what is the optimal diagnostic strategy to evaluate for suspected AAS? 5. In a patient population with a high clinical probability of AAS, what is the optimal diagnostic strategy to evaluate for suspected AAS? After the coordination panel prioritized the questions, the chair developed diagnostic pathways that were refined through an iterative process with input from the panel. The diagnostic pathways were based on signs and symptoms and additional testing for AAS.
We used these pathways to guide the evidence synthesis and recommendations. The coordination panel selected outcomes of interest for each question a priori, following the approach described in detail elsewhere. 52 In brief, the coordination panel brainstormed all possible outcomes, then rated their relative importance for decision-making according to the GRADE approach. 53 The coordination panel rated the following outcomes as critical for decision-making across the AAS diagnosis questions: missed diagnosis, increase in CT use, increase in D-dimer use and unnecessary transfer, in addition to the diagnostic accuracy outcomes (i.e., false-positive, false-negative, true-positive and true-negative test results).
The coordination panel in conjunction with the patient representatives placed higher value on reducing missed diagnosis for AAS without a substantial increase in radiation exposure to the patient if the diagnosis could be obtained using alternate methods with less radiation exposure. This decision is supported by a recent article assessing patient research priorities for AAS. 7 In most instances, there was no direct evidence assessing the effect of using 1 diagnostic pathway versus another on patient outcomes or directly comparing the accuracy of different diagnostic pathways. To make judgments about health care and patientrelated desirable and undesirable effects, the coordination panel reviewed all the potential pathways and determined the downstream consequences related to a particular test result, as well as the complications of testing itself. This review affected the degree of certainty in the recommendations.
# Evidence review
To support the guideline, systematic reviews were performed (R.O., S.M., N.F.) for studies of diagnostic accuracy and prevalence estimates, as per the Cochrane Handbook for Systematic Reviews of Interventions (www.handbook.cochrane.org). We searched the electronic databases MEDLINE andEmbase (1968-2018) with the assistance of a librarian, using a combination of Medical Subject Headings (MeSH) terms and keywords; there was no language restriction. The searches were updated March 2019 (no new studies were identified). For the full search strategy, see the evidence-to-decision framework document titled "What is the optimal assessment of pretest probability for AAS?" in Appendix A-1 of the full guideline (Appendix 1).
We used the QUADAS-2 tool to assess risk of bias for included studies. 54 We evaluated the quality of the evidence that met inclusion criteria following the GRADE approach, based on the following domains: risk of bias, precision, consistency and magnitude of the estimate of effects, directness of the evidence and risk of publication bias. 55 We categorized the certainty of evidence into 4 levels, ranging from very low to high. 53,55,56 In the absence of any data, the level of evidence was rated as very low, because it was based on expert consensus.
There is very little published evidence on diagnostic pathways related to AAS; therefore, the coordination panel developed simple Bayesian models to calculate test accuracy of different pathways with a different combination of signs, symptoms and tests. The model included data obtained from the systematic reviews for AAS prevalence and the pooled diagnostic test accuracy for different tests. We used this method to present the test results explicitly, while considering different prevalence estimates, multiple potential diagnostic pathways and different assumptions about the performance of the tests in different populations. We summarized the predicted overall test strategy results from the model and the quality of evidence assessed using the GRADE approach in evidence tables, which allowed for a comparison of the benefits and harms of different diagnostic strategies.
# Development of recommendations
For each guideline question, we created a GRADE "evidence-todecision" framework, using the GRADEpro Guideline Development Tool (www.gradepro.org). The evidence-to-decision table summarized the results of systematic reviews of the literature that were performed specifically for this guideline 58 (see full guideline at Appendix 1). The evidence-to-decision table addressed effects of interventions including potential benefits and harms of the diagnostic test, test accuracy, resource utilization, values and preferences (e.g., relative importance of outcomes), equity, feasibility and acceptability.
A 1-day in-person meeting for advisory committee members was held in Sudbury, Ontario, on Nov. 23, 2018. The meeting was used to discuss the proposed diagnostic pathways and evidenceto-decision frameworks and come to consensus with regard to the strength of recommendations.
Recommendations were based on the balance of benefits and harms, the quality of evidence, and patient values and preferences, as per GRADE methodology. The initial draft recommendations were prepared by R.O. Interpretation of the strength of recommendations can be found in Box 1. Consensus was achieved through discussion. Initial plans were to use online software for anonymous voting using a modified Delphi process; however, the coordination panel and the advisory committee decided that they would prefer open discussion. Unanimous consensus was reached on all draft recommendations.
# Clinical decision aid
We developed a clinical decision aid to compile the recommendations into a single tool (Table 2). We combined the Bayesian models for each sign and symptom together with our identified values and preferences and defined thresholds for advanced im aging or no further testing. We used thresholds for investigation
# Box 1: Interpretation of strong and conditional recommendations
The strength of a recommendation is expressed as either strong ("the guideline panel recommends ..."), or conditional ("the guideline panel suggests …") and is interpreted as shown below. 59
# Strong recommendation
- For patients: most individuals in this situation would want the recommended course of action, and only a small proportion would not.
- For clinicians: most individuals should receive the intervention or test. Formal decision aids are not likely to be needed to help individual patients make decisions consistent with their values and preferences.
- For policy-makers: the recommendation can be adopted as policy in most situations. Adherence to this recommendation according to the guideline could be used as a quality criterion or performance indicator.
- For researchers: the recommendation is supported by credible research or other convincing judgments that make additional research unlikely to alter the recommendation. On occasion, a strong recommendation is based on low-or very low-certainty evidence. 60
# Conditional recommendation
- For patients: the majority of individuals in this situation may want the suggested course of action, but many may not. Decision aids may be useful in helping patients to make decisions consistent with their individual risks, values and preferences.
- For clinicians: different choices will be appropriate for individual patients and clinicians must help each patient arrive at a management decision consistent with their values and preferences through shared decision-making. Decision aids may be useful in helping individuals to make decisions consistent with their individual risks, values and preferences.
- For policy-makers: policy-making will require substantial debate and involvement of various stakeholders. Performance measures about the suggested course of action should focus on whether an appropriate decision-making process is duly documented.
- For researchers: this recommendation is likely to be strengthened (for future updates or adaptation) by additional research. An evaluation of the conditions and criteria (and the related judgments, research evidence and additional considerations) that determined the conditional (rather than strong) recommendation will help identify possible research gaps.
informed by a national survey of emergency physicians to define low ( 5%, a value of 2. Further investigations (i.e., D-dimer testing, ECG-gated CT aorta) were then applied to the post-test probabilities to determine their utility. See the full guideline for the method used to generate the prevalence estimates and to define the test thresholds (Appendix 1).
# External review
The draft recommendations were distributed to more than 300 emergency medicine physicians, radiologists and surgeons for review in October 2019. The goal of the review was to obtain stakeholder feedback on the interpretation of the evidence, the strength of the recommendations and document layout.
Key stakeholder organizations also reviewed the guideline and supporting documents: the Canadian Association of Emergency Physicians, the Canadian Society of Cardiac Surgery, the Canadian Society of Vascular Surgery and the Canadian Society of Thoracic Radiology.
The coordinating panel revised the document to address pertinent comments by the stakeholder organizations and external reviewers. The advisory committee then reviewed and approved these revisions. Each stakeholder organization provided endorsement of the final document.
# Management of competing interests
Development of this guideline was wholly funded by the Alternate Funding Plan grant of the Northern Ontario Academic Medical Association, a nonprofit academic medical association. Members of the advisory committee received travel reimbursement for attendance at the in-person meeting. Members of the coordin ation panel received no other payments.
We managed competing interests of all participants according to recommendations of the Institute of Medicine and the Guidelines International Network. 48,50 Before appointment to the advisory committee, individuals disclosed both direct (financial) and indirect (nonfinancial) interests. Members of the coordination panel and chair reviewed the disclosures and judged which interests were conflicts and should be managed. At the time of appointment, the entire advisory committee had no direct competing interests, defined as no current material interest in any commercial entity with a product that could be affected by the guideline. After the guideline was completed, this process was repeated; no additional competing interests were reported.
# Implementation
Adaptation of these recommendations will likely be necessary in some circumstances; this document may serve as a basis for adaptation by local, regional or national guideline groups. For example, guideline implementation in an urban centre with 24-hour access to CT may differ from a rural or remote location that requires transfer of a patient with accompanying staff. These adaptations should be based on the associated evidenceto-decision frameworks. 46 Using a theory-driven, qualitative approach, we interviewed emergency medicine physicians from 4 urban and rural hospitals to describe current practice and to identify the barriers and facilitators to a standardized approach for investigating patients for AAS (Cait Dimitrew, Northern Ontario School of Medicine, Sudbury, Ontario; unpublished data 2020). Saturation of themes was achieved after 9 physician interviews.
We identified 3 barriers to implementation of this guideline: use of D-dimer and knowledge of rationale for its use in AAS is not widespread; the decision aid in the guideline was not in alignment with current practice or physician understanding of risk factors; and the complexity of the suggested decision aid in the guideline was a potential barrier to accurate application and desired outcomes.
We also identified 3 facilitators: publishing the guideline recommendations and decision aid would increase use and acceptability; availability of the decision aid and recommendations as an online tool would increase use; and clinicians were confident that the recommendations and decision tool would support clinic al decision-making and risk stratification and had the potential to reduce resource use (e.g., CT), particularly in rural settings.
# Suggested performance measures
Based on consensus of the advisory committee, we developed a suggested set of performance measures to accompany this guideline for consideration by providers and policy-makers: proportion of missed cases of AAS, time to diagnosis of AAS, emergency department disposition time, proportion of patients receiving a CT aorta, proportion of patients with D-dimer testing, and proportion of patients transferred for imaging or consultation.
# Updates
The guideline coordination panel will be responsible for updating the guideline every 5 years.
# Other guidelines
The recommendations in this guideline were adapted from the American Heart Association and European Society of Cardiology guidelines; comparison of the 3 guidelines is available in Table 3. All 3 guidelines recommend further testing depending on assessment of pretest probability. However, the importance of specific clinical features and results of investigations may be interpreted differently. Additionally, the recommended testing by pretest probability varies among the guidelines. These differences are based on the interpretation of evidence and the thresholds for investigations in different practice environments.
# Gaps in knowledge
The recommendations in this guideline are largely based on very low-or low-quality evidence and on modelled estimates for the popu lation prevalence of AAS. The evidence base would benefit from prospective data collection of important high-risk clinical variables in order to increase the quality of evidence. Prevalence and pretest probability are continuous variables but for modelling purposes, required input of a specific population prevalence. Prevalence estimates greatly different from those used in modelling will affect the recommendations. Future studies are needed to validate the diagnostic accuracy of this guideline's recommendations across a spectrum of disease prevalence in emergency departments.
# Conclusion
Acute aortic syndrome is a difficult-to-diagnose aortic emergency. We propose recommendations to aid clinicians in riskstratifying patients and, depending on risk level, suggest further investigations needed. This guideline is intended as a resource for practising clinicians, both as an evidence base and a guide to investigation for this high-risk aortic catastrophe.
Competing interests: Ashish Gupta reports receiving reimbursement of | cute aortic syndrome (AAS) is a life-threatening emergency, accounting for 1/2000 presentations of acute chest or back pain to the emergency department. 1 It is a clinical spectrum of diagnoses including aortic dissection, intramural hematoma and penetrating atherosclerotic ulcer at any location along the aorta. 1 The incidence of AAS is about 3 per 100 000 persons. 2,3 Many physicians do not consider AAS in their initial differential diagnosis, which is in part why 25% of patients with AAS are not diagnosed with the condition until 24 hours after presenting to the emergency department. 4 Prognosis is most favourable when patients are treated early, while they are clinically stable. Mortality follows a linear increase with diagnostic delay and can be as high as 2% per hour of delay. 5 The misdiagnosis rate during the initial emergency department visit for AAS (i.e., patient admitted for an alternative diagnosis and later diagnosed as AAS; discharged from the emergency department and presenting again with a diagnosis of AAS; or diagnosed on postmortem examination) is estimated to be as high as 38%. 4,[6][7][8][9][10][11][12][13][14][15][16] Patients with suspected AAS are typically investigated with electrocardiogram (ECG)-gated contrast-enhanced computed tomography (CT). 2 Current use of this investigation in patients with a clinical suspicion for AAS is inefficient. 17,18 The unnecessary use of CT leads to a direct increase in health care costs but also an increase in contrast-associated complications (e.g., allergic reactions), increased length of emergency department stay or incidental findings requiring further follow-up, additional im aging and increased stress or anxiety for the patient. 17 Use of CT in a low-prevalence population can result in an increase in false-positives, which can lead to further testing, unnecessary transfer and even surgical intervention. 19 There are 2 high-quality guidelines related to the diagnosis of AAS, from the American Heart Association (2010) and the European Society of Cardiology (2014). 20,21 However, there is still considerable variation in how clinicians investigate for AAS in Canada. 17 This variation is likely multifactorial but may be a result of lack of key stakeholder involvement in the development of the guidelines or the difference in threshold for investigation within the Canadian health care system. 22,23 The aims of this guideline are to update the available guideline recommendations with current evidence; include key stakeholders to allow interpretation of the evidence in context of values and preferences; and make practice recommendations that are applicable to the Canadian health care system. The full guideline, including supplemental documents, is available at Appendix 1# Scope
The purpose of this guideline is to provide evidence-based recommendations about the diagnostic evaluation of patients with suspected AAS. Our definition of AAS does not include ruptured or leaking aortic aneurysms. This guideline is not applicable to pregnant patients, patients with recent (< 24 hr) cocaine use or patients younger than 18 years. The primary studies used to generate the recommendations either did not include these patients or did not report on their inclusion; therefore, the diagnostic accuracy of signs and symptoms for AAS are unknown within these populations.
We present diagnostic pathways based on the expected prevalence of AAS and provide guidance on testing based on clinically relevant and accepted thresholds for diagnostic error. The recommendations are further guided by principles of minimizing radiation exposure and the required number of diagnostic tests to meet the accepted thresholds, where possible. This guideline is intended to aid clinicians in selecting optimal diagnostic test(s) that are more likely to result in a diagnostic result, reduce the number of diagnostic tests and minimize exposure to radiation.
The target audience includes patients, emergency medicine physicians, family physicians, internists, radiologists, vascular surgeons, cardiothoracic surgeons, critical care physicians and decision-makers.
# Recommendations
The 4 recommendations in this guideline are divided into the following categories: assessment of pretest probability (risk factors, pain features, clinical suspicion and alternative diagnoses, and physical examination) and diagnostic strategy (low, medium and high pretest probability) (Table 1). The assessment of quality of studies informing this guideline is available in Appendix 2, at www.cmaj.ca/lookup/suppl/doi:10.1503/cmaj.200021/-/DC1.
The rationale behind optimal test thresholds and the prevalence estimates used in Bayesian modelling (as described in the Methods section, below) can be found in the full guideline (Appendix 1). Modifications to the American Heart Association and European Society of Cardiology guidelines are highlighted in the description of the recommendations below and in Table 3.
Table 2 and Figure 1 provide a framework for assessment of pretest probability and suggestions for further testing at moderate or high risk for AAS. Pretest probability is defined as the probability of a patient having the target disorder before a diagnostic test result is known. See Appendix 2 for the definitions used for each high-risk clinical finding associated with AAS.
# Assessment of pretest probability
The committee recommends that providers routinely evaluate any patient presenting with complaints that may represent AAS, to establish a pretest risk of disease that can then be used to guide diagnostic decisions. This process should include specific questions about risk factors and pain features, as well as a focused examination to identify findings that are associated with AAS (strong recommendation based on low certainty in the evidence of effects on clinical outcomes and moderate certainty in the evidence of diagnostic accuracy studies).
The committee suggests using historical pain, risk factors and physical examination findings to define a patient as having a low (≤ 0.5%), moderate (0.5%-5%) or high (> 5%) probability for AAS (conditional recommendation based on low certainty in the evidence of effects on clinical outcomes and low certainty in the evidence of diagnostic accuracy studies) (Table 2).
# Risk factors
Risk factors for AAS include connective tissue disease, aortic valve disease, recent aortic manipulation, aortic aneurysm (thoracic or abdominal, on chest radiograph, history or bedside echocardiography) and family history of AAS.
The European Society of Cardiology and American Heart Association guidelines on AAS specifically refer to thoracic aortic aneurysms as a risk factor. However, the International Registry of Acute Aortic Dissection database, a multicentre registry that includes more than 4000 cases, states that a known aortic aneurysm, either thoracic or abdominal, is associated with AAS. 24 Therefore, we updated the definition of aortic aneurysm in our assessment of pretest probability to include both abdominal and thoracic aneurysms as risk factors.
Patients may not be aware of the presence of an aortic aneurysm. Bedside ultrasound has been found to be accurate in the diagnosis of abdominal aortic aneurysms. 25 A multicentre prospective observational study including 839 patients (very lowquality evidence, downgraded for risk of bias and indirectness) showed moderate diagnostic accuracy (sensitivity 0.60, 95% confidence interval [CI] 0.51-0.68; specificity 0.85, 95% CI 0.83-0.88) for assessment of aneurysmal dilation of the aortic root. 26 Bedside ultrasound is operator dependent; therefore, the diagnostic accuracy may vary depending on the level of training. However, it is reasonable to examine those who are presenting with symptoms suggestive of AAS for the presence of an abdominal or thoracic aortic aneurysm in the visible portions of the aorta.
We found 7 observational (prospective and retrospective) studies including 659 patients (very low-or low-quality evidence, downgraded for substantial heterogeneity and imprecision) that suggest chest radiograph may also be helpful (sensitivity 0.79, 95% CI 0.70-0.85; specificity 0.56, 95% CI 0.41-0.70) in suggesting a possible thoracic aortic dilation. [27][28][29][30][31][32] A systematic review of 9 studies (n = 551) found clinical examination is not sufficient in diagnosing rapid aortic expansion or a leaking, ruptured or dissecting aortic aneurysm. 33 Therefore, if a patient presents with pain and a known or newly diagnosed aortic aneurysm, they should undergo advanced imaging. This is a modification of the European Society of Cardiology and American Heart Association guidelines (Table 3).
# High-risk pain features
High-risk pain features for AAS include abrupt-onset or thunderclap pain, severe or worst-ever pain, tearing or ripping pain, migrating or radiating pain.
The American Heart Association guideline recommends that high-risk pain be defined as pain that is either severe or abrupt in onset, with a tearing, ripping, sharp or stabbing characteristic. Rogers and colleagues modified this recommendation to define high-risk pain as any abrupt, severe, tearing or ripping pain. 34 These modifications formed the basis of the high-risk pain section of the acute aortic dissection detection risk score. This tool was the result of expert consensus and was incorporated into the European Society of Cardiology guideline.
In contrast, the committee agreed that a patient with severe pain versus a patient with severe, abrupt-onset, tearing pain were not at the same pretest probability for AAS. We also thought that an increasing number of high-risk pain features was associated with an increased pretest probability for AAS; however, this was based entirely on expert consensus as we found no direct evidence on systematic review of the literature.
# Clinical suspicion or alternative diagnosis
Clinician suspicion for AAS or an alternative diagnosis is currently part of the American Heart Association and European Society of Cardiology guidelines; however, these guidelines suggest that consideration of an alternative diagnosis should take place after Table 1 (part 1 of 2): Recommendations for assessment of pretest probability and diagnostic strategy in acute aortic syndrome
# Recommendation
# Strength of recommendation and certainty of evidence
# Assessment of pretest probability
The committee recommends that providers routinely evaluate any patient presenting with complaints that may represent AAS, to establish a pretest risk of disease that can then be used to guide diagnostic decisions. This process should include specific questions about risk factors and pain features, as well as a focused examination to identify findings that are associated with AAS.
Strong recommendation based on low certainty in the evidence of effects on clinical outcomes and moderate certainty in the evidence of diagnostic accuracy studies.
The committee suggests using historical pain, risk factors and physical examination findings to define a patient as low (≤ 0.5%), moderate (0.5%-5%) or high (> 5%) probability for AAS (Table 2).
Conditional recommendation based on low certainty in the evidence of effects on clinical outcomes and low certainty in the evidence of diagnostic accuracy studies.
Technical remarks:
• An absence of any high-risk historical, risk factor or physical examination findings places the patient in a population with a very low prevalence for AAS.
• The panel recognized that different clinical features have different strengths of association with AAS.
• Clinical suspicion for an alternative diagnosis or for AAS is important in assessment of pretest probability.
• Patients with a low risk of AAS and no alternative diagnosis are still considered low risk.
• The panel suggests the presence of any clinical features strongly associated with AAS (hypotension, pulse deficit, neurologic deficit, new murmur of aortic regurgitation, aortic aneurysm) places the patient in a higher probability population.
• Clinical suspicion for an alternative diagnosis is useful in a moderate-risk group, but AAS should still be considered in the presence of multiple clinical features for AAS even if a suspicion for an alternative diagnosis exists.
• This assessment strategy assumes that the history and physical examination are carried out under optimal conditions in an oriented patient compliant to physical examination. If the patient is unable to provide an accurate history, pretest probability assessment will be affected.
# Diagnostic strategy
# Low pretest probability
The committee suggests no further testing in a population with a low pretest probability (prevalence of AAS of ≤ 0.5%).
Conditional recommendation based on low certainty in the evidence of effects on clinical outcomes and moderate certainty in the evidence of diagnostic accuracy studies.
Technical remarks:
• There are no prospectively validated clinical decision rules to assess pretest probability. Estimates are based on modelling of low-or moderatequality observational studies.
• The pathway relies on the ability to obtain an accurate history. The addition of D-dimer to the diagnostic pathway lowered the probability of AAS further, but also increased the number of false-positive CT scans above ideal thresholds.
# Intermediate pretest probability
The committee suggests using a strategy starting with D-dimer for excluding AAS in a population with an intermediate pretest probability (prevalence 0.5%-5%), followed by ECG-gated CT in patients with a positive D-dimer test. If D-dimer testing is not readily available, an alternative acceptable strategy includes performing ECG-gated CT alone.
Conditional recommendation for D-dimer based on low certainty in the evidence of effects on clinical outcomes and moderate certainty in the evidence about diagnostic accuracy studies. Conditional recommendation for ECG-gated CT aorta based on moderate certainty in the evidence of effects on clinical outcomes and moderate certainty in the evidence from diagnostic accuracy studies.
The committee suggests no further testing after a negative D-dimer test in a population with an intermediate pretest probability (prevalence 0.5%-5%).
The panel recommends no additional testing after a negative ECG-gated CT in a population with intermediate pretest probability prevalence.
Grading as per low pretest probability recommendation.
the assessment of pretest probability. In contrast, committee members agreed that this happens concurrently with assessment of historical risk features and should be included in initial pretest probability assessment. Results from a national survey supported this view, with respondents rating likelihood of AAS or of an alternative diagnosis as extremely important in the assessment of pretest probability, ranking higher than any pain characteristic, risk factor or physical examination finding. 35 There is no formal assessment of the diagnostic accuracy of clinical suspicion for AAS. We performed a systematic review and meta-analysis of studies reporting on misdiagnosis of AAS and found 12 studies with 3433 patients (very low-quality evidence, downgraded for variable patient population, definition of missed cases and reference standard among studies, along with inconsistency, imprecision and indirectness 6,7,[9][10][11][13][14][15][16][36][37][38] [see Appendix 2 for more details].) The results of this meta-analysis (sensitivity 0.79, 95% CI 0.70-0.87; specificity 0.63, 95% CI 0.60-0.65) were incorporated into the summary estimate of diagnostic accuracy in Bayesian modelling (Appendix 1). Incorporating clinical suspicion into pretest probability assessment allowed for an improvement in specificity while keeping the miss rate below an acceptable threshold. Care should be taken if the alternative diagnosis being considered is acute coronary syndrome, stroke or an unconfirmed pulmonary embolism. These are the most common initial diagnoses in patients with a missed AAS. 4,9,10,13,16 Physical examination High-risk physical examination findings for AAS include new aortic regurgitation (auscultated murmur or bedside echocardiography), pulse deficit, neurologic deficit, hypotension or pericardial effusion on bedside echocardiography.
The American Heart Association and European Society of Cardiology guidelines report bilateral blood pressure differential as a high-risk feature for AAS. We found no direct studies exploring • There are no prospectively validated clinical decision rules to assess pretest probability. Estimates are based on modelling of low-or moderatequality observational studies.
• A decision to start with D-dimer testing assumes the results will be obtained in a timely manner and that the cost of D-dimer screening is offset by avoiding unnecessary ECG-gated CT aorta or transfer of patients at moderate pretest probability for AAS. If the D-dimer strategy is followed, a highly sensitive D-dimer assay is required.
• A negative D-dimer test (i.e., < 500 ng/mL) indicates a low probability (< 0.5%) of AAS and no additional testing is required.
• Caution should be used in patients presenting with > 24 h of symptoms as D-dimer can be falsely negative. Intramural hematoma without connection to circulation can lead to a false-negative D-dimer. D-dimer has limited utility in hospitalized patients and in certain patient populations (postsurgical, pregnant) because of the high frequency of positive D-dimer results with standard thresholds.
• The likelihood of a positive D-dimer test (> 500 ng/mL) increases with age; however, there are no studies reporting on the diagnostic accuracy of age-adjusted D-dimer testing for the diagnosis of AAS. Therefore, the standard threshold of > 500 ng/mL was used to indicate a positive test.
• ECG-gated CT of the aorta is the next step after a positive D-dimer result. AAS is a time-sensitive condition and CT should be expedited. The preference is for an ECG-gated scan. A negative ECG-gated CT rules out AAS.
The strategy assumes that test results are obtained under optimal conditions. Suboptimal CT results may require repeat testing or an alternate strategy.
# High pretest probability
The committee recommends using a strategy starting with ECG-gated CT for assessing patients suspected of having AAS in a population with a high pretest probability (prevalence ≥ 5%).
Strong recommendation for ECG-gated CT aorta based on moderate certainty in the evidence of effects on clinical outcomes and moderate certainty in the evidence of diagnostic accuracy studies.
The committee suggests not using a D-dimer test in a population with a high pretest probability (prevalence ≥ 5%).
Conditional recommendation against D-dimer based on low certainty in the evidence of effects on clinical outcomes and moderate certainty in the evidence of diagnostic accuracy studies.
Technical remarks:
• There are no prospectively validated clinical decision rules to assess for a pretest probability of > 5%. Estimates are based on modelling of lowor moderate-quality observational studies.
• CT should be ECG gated to avoid motion artifacts especially of the aortic root and ascending aorta. It is important to scan with and without contrast to rule out an intramural hematoma. Reconstruction to thinner slices (< 1 mm) and multiplanar reconstruction including sagittal oblique for thoracic aorta are recommended.
• The strategy assumes that test results are obtained under optimal conditions. Suboptimal CT results from improper technique (e.g., no gating, only unenhanced study or venous phase scanning) may require repeat testing.
• If CT is not feasible (e.g., contrast media allergy, severe renal impairment, or unavailability), MRI or TEE may be acceptable.
• In cases where clinical suspicion for AAS remains high with a negative initial CT, repeat ECG-gated CT should be considered. If repeat CT with proper technique is not feasible, additional testing with TEE or MRI may be considered.
Note: AAS = acute aortic syndrome, CT = computed tomography, ECG = electrocardiogram, MRI = magnetic resonance imaging, TEE = transesophageal echocardiography.
its independent association with AAS. Multiple studies analyzed it as a composite variable with pulse deficit or blood pressure differential. 39 We identified only 1 case-control study that showed bilateral blood pressure differential was significantly associated with AAS; however, it did not improve diagnostic accuracy in addition to pulse deficit. 40 As much as 20% of the general population will have a blood pressure differential. 41 The committee agreed that this finding may be useful to raise suspicion for AAS; thus, any patient presenting with a blood pressure differential should be assessed for their pretest probability of AAS. In the context of other pain, risk factors and physical examination findings, it likely does not add any benefit in assessment of pretest probability. Therefore, we removed bilateral blood pressure differential from the high-risk physical examination findings (Table 3).
A single-centre study of 839 patients (very low-quality evidence, downgraded for risk of bias and indirectness) suggests that bedside ultrasound is capable of diagnosing aortic regurgitation in AAS (sensitivity 0.1, 95% CI 0.06-0.16; specificity 0.93, 95% CI 0.91-0.95). 26 Diagnostic accuracy of bedside ultrasound for aortic regurgitation may vary between providers. This variation is also seen with clinical examination. Auscultation has moderate-to-low inter-rater reliability and diagnostic accuracy. 42,43 Therefore, the committee agreed that point-of-care ultrasonographic evidence of new aortic regurgitation in a patient presenting with symptoms suggestive of AAS is a highrisk examination finding, in addition to auscultation of a murmur consistent with aortic regurgitation. The use of point-ofcare ultrasound is meant to augment physical examination; therefore, if a provider is not trained in its use, it is simply omitted from pretest probability assessment. The addition of pointof-care ultrasonography is an update to the American Heart Association guideline, but is present in the European Society of Cardiology guideline (Table 3).
# Diagnostic strategy
# Low pretest probability
The committee suggests no further testing in a population with a low pretest probability (prevalence of AAS of ≤ 0.5%) (conditional recommendation based on low certainty in the evidence of effects on clinical outcomes and moderate certainty in the evidence of diagnostic accuracy studies).
# Intermediate pretest probability The committee suggests using a strategy starting with D-dimer testing for excluding AAS in a population with an intermediate pretest probability (prevalence 0.5%-5%), followed by ECG-gated CT in patients with a positive D-dimer test. If D-dimer testing is not readi ly available, an alternative acceptable strategy includes performing ECG-gated CT alone (conditional recommendation for D-dimer based on low certainty in the evidence of effects on clinical outcomes and moderate certainty in the evidence about diagnostic accuracy studies; conditional recommendation for ECG-gated CT based on moderate certainty in the evidence of effects on clinical outcomes and moderate certainty in the evidence from diagnostic accuracy studies).
# The committee suggests no further testing after a negative D-dimer test in a population with an intermediate pretest probability (prevalence 0.5%-5%). The panel recommends no additional testing after a negative ECG-gated CT in a population with an intermediate pretest probability (prevalence 0.5%-5%) (grading as per low pretest probability recommendation).
# High pretest probability
The committee recommends using a strategy starting with ECGgated CT for assessing patients suspected of having AAS in a population with a high pretest probability (prevalence ≥ 5%) (strong recommendation for ECG-gated CT based on moderate certainty in the evidence of effects on clinical outcomes and moderate certainty in the evidence of diagnostic accuracy studies).
# The committee suggests not using a D-dimer test in a population with a high pretest probability (prevalence ≥ 5%) (conditional recommendation against D-dimer based on low certainty in the evidence of effects on clinical outcomes and moderate certainty in the evidence of diagnostic accuracy studies).
# D-dimer testing
The recommendations for D-dimer testing are based on a metaanalysis of 22 studies with 3860 patients (Appendix 2). According to the QUADAS-2 (quality assessment of diagnostic accuracy studies) tool, 19/22 of the included studies had at least 1 domain rated as high risk of bias. The evidence was rated as very low for specificity (0.60, 95% CI 0.48-0.71) and moderate for sensitivity (0.95, 95% CI 0.90-0.99). There are 2 other meta-analyses that included only 5 of the 22 articles we included in the meta-analysis; their QUADAS assessments found a low or unclear risk of bias in most domains, leading to downgrading of the level of certainty. 44,45 ECG-gated CT of the aorta Acute aortic syndrome is a time-sensitive emergency and if a patient is deemed at high risk, an ECG-gated CT of the aorta should be expedited. We found 1 meta-analysis with a total of 3 studies. Although a small number of patients (n = 126) were included, there were no serious limitations in indirectness, inconsistency, imprecision or risk of bias.
Whenever available, ECG gating (prospective) should be used for imaging of suspected acute aortic syndrome, to avoid motion artifacts especially at the aortic root and ascending aorta. Scanning of the thoracic aorta without contrast is important to rule out intramural hematoma. Reconstruction to thinner slices (< 1 mm) and multiplanar reconstruction including sagittal oblique for thoracic aorta are suggested.
# Methods
We chose to adapt existing high-quality clinical practice guidelines previously developed by the American Heart Association and European Society of Cardiology using the Grading of Recommendations Assessment, Development and Evaluation (GRADE)-ADOLOPMENT (combined use of adoption, adaptation, and de novo development of recommendations) approach. 20,21,46 The overall guideline development process -including funding of the work, formation of participating groups, management of competing interests, internal and external review, and organizational approval -was guided by the Guidelines International Network-McMaster Guideline Development Checklist. 25 We structured our process to meet the recommendations for trustworthy guidelines by the National Academy of Medicine and the Guidelines International Network. [47][48][49][50] The full details of the guideline methods are available in our complete guideline document (Appendix 1).
# Composition of participating groups
We recruited 21 people from across Canada to take part in developing the guideline as members of the guideline advisory committee. The advisory committee included emergency phys icians and nurses, cardiothoracic and vascular surgeons, cardiac anesthesiologists, critical care physicians, radiologists and 2 patients. We selected members based on their expertise and professional and geographic diversity, as well as practice environment (academic, community, rural or remote). Methodologists with expertise in evidence appraisal and guideline development were also included (R.O., J.Y., K.Y., E.L.). From members of the advisory committee, we appointed a guideline chair (R.O.) and a guideline coordination panel (S.M., D.A., P.J.).
We prepared and revised the guideline through an iterative process consisting of feedback and discussions until we achieved consensus. The advisory committee communicated through multiple teleconference meetings, emails and a 1-day, in-person meeting in late 2018. The coordination panel developed and graded the recommendations and assessed the certainty in the supporting evidence following the GRADE approach. 51,52 We used the in-person meeting to discuss the evidence-to-decision frameworks and come to consensus on the recommendations.
# Formulating specific clinical questions and determining outcomes of interest
The coordination panel used the GRADEpro Guideline Development Tool (www.gradepro.org) 51 to brainstorm, then prioritize the following questions addressed by this guideline: 1. What is the optimal test threshold (i.e., the likelihood of the disease where the benefits of testing outweigh the harms) for low-, moderate-or high-risk probability for AAS? 2. What is the optimal pretest probability assessment for AAS? 3. In a patient population with a low clinical probability of AAS, what is the optimal diagnostic strategy to evaluate for suspected AAS? 4. In a patient population with an intermediate clinical probability of AAS, what is the optimal diagnostic strategy to evaluate for suspected AAS? 5. In a patient population with a high clinical probability of AAS, what is the optimal diagnostic strategy to evaluate for suspected AAS? After the coordination panel prioritized the questions, the chair developed diagnostic pathways that were refined through an iterative process with input from the panel. The diagnostic pathways were based on signs and symptoms and additional testing for AAS.
We used these pathways to guide the evidence synthesis and recommendations. The coordination panel selected outcomes of interest for each question a priori, following the approach described in detail elsewhere. 52 In brief, the coordination panel brainstormed all possible outcomes, then rated their relative importance for decision-making according to the GRADE approach. 53 The coordination panel rated the following outcomes as critical for decision-making across the AAS diagnosis questions: missed diagnosis, increase in CT use, increase in D-dimer use and unnecessary transfer, in addition to the diagnostic accuracy outcomes (i.e., false-positive, false-negative, true-positive and true-negative test results).
The coordination panel in conjunction with the patient representatives placed higher value on reducing missed diagnosis for AAS without a substantial increase in radiation exposure to the patient if the diagnosis could be obtained using alternate methods with less radiation exposure. This decision is supported by a recent article assessing patient research priorities for AAS. 7 In most instances, there was no direct evidence assessing the effect of using 1 diagnostic pathway versus another on patient outcomes or directly comparing the accuracy of different diagnostic pathways. To make judgments about health care and patientrelated desirable and undesirable effects, the coordination panel reviewed all the potential pathways and determined the downstream consequences related to a particular test result, as well as the complications of testing itself. This review affected the degree of certainty in the recommendations.
# Evidence review
To support the guideline, systematic reviews were performed (R.O., S.M., N.F.) for studies of diagnostic accuracy and prevalence estimates, as per the Cochrane Handbook for Systematic Reviews of Interventions (www.handbook.cochrane.org). We searched the electronic databases MEDLINE andEmbase (1968-2018) with the assistance of a librarian, using a combination of Medical Subject Headings (MeSH) terms and keywords; there was no language restriction. The searches were updated March 2019 (no new studies were identified). For the full search strategy, see the evidence-to-decision framework document titled "What is the optimal assessment of pretest probability for AAS?" in Appendix A-1 of the full guideline (Appendix 1).
We used the QUADAS-2 tool to assess risk of bias for included studies. 54 We evaluated the quality of the evidence that met inclusion criteria following the GRADE approach, based on the following domains: risk of bias, precision, consistency and magnitude of the estimate of effects, directness of the evidence and risk of publication bias. 55 We categorized the certainty of evidence into 4 levels, ranging from very low to high. 53,55,56 In the absence of any data, the level of evidence was rated as very low, because it was based on expert consensus.
There is very little published evidence on diagnostic pathways related to AAS; therefore, the coordination panel developed simple Bayesian models to calculate test accuracy of different pathways with a different combination of signs, symptoms and tests. The model included data obtained from the systematic reviews for AAS prevalence and the pooled diagnostic test accuracy for different tests. We used this method to present the test results explicitly, while considering different prevalence estimates, multiple potential diagnostic pathways and different assumptions about the performance of the tests in different populations. We summarized the predicted overall test strategy results from the model and the quality of evidence assessed using the GRADE approach in evidence tables, which allowed for a comparison of the benefits and harms of different diagnostic strategies.
# Development of recommendations
For each guideline question, we created a GRADE "evidence-todecision" framework, using the GRADEpro Guideline Development Tool (www.gradepro.org). [56][57][58] The evidence-to-decision table summarized the results of systematic reviews of the literature that were performed specifically for this guideline 58 (see full guideline at Appendix 1). The evidence-to-decision table addressed effects of interventions including potential benefits and harms of the diagnostic test, test accuracy, resource utilization, values and preferences (e.g., relative importance of outcomes), equity, feasibility and acceptability.
A 1-day in-person meeting for advisory committee members was held in Sudbury, Ontario, on Nov. 23, 2018. The meeting was used to discuss the proposed diagnostic pathways and evidenceto-decision frameworks and come to consensus with regard to the strength of recommendations.
Recommendations were based on the balance of benefits and harms, the quality of evidence, and patient values and preferences, as per GRADE methodology. The initial draft recommendations were prepared by R.O. Interpretation of the strength of recommendations can be found in Box 1. Consensus was achieved through discussion. Initial plans were to use online software for anonymous voting using a modified Delphi process; however, the coordination panel and the advisory committee decided that they would prefer open discussion. Unanimous consensus was reached on all draft recommendations.
# Clinical decision aid
We developed a clinical decision aid to compile the recommendations into a single tool (Table 2). We combined the Bayesian models for each sign and symptom together with our identified values and preferences and defined thresholds for advanced im aging or no further testing. We used thresholds for investigation
# Box 1: Interpretation of strong and conditional recommendations
The strength of a recommendation is expressed as either strong ("the guideline panel recommends ..."), or conditional ("the guideline panel suggests …") and is interpreted as shown below. 59
# Strong recommendation
• For patients: most individuals in this situation would want the recommended course of action, and only a small proportion would not.
• For clinicians: most individuals should receive the intervention or test. Formal decision aids are not likely to be needed to help individual patients make decisions consistent with their values and preferences.
• For policy-makers: the recommendation can be adopted as policy in most situations. Adherence to this recommendation according to the guideline could be used as a quality criterion or performance indicator.
• For researchers: the recommendation is supported by credible research or other convincing judgments that make additional research unlikely to alter the recommendation. On occasion, a strong recommendation is based on low-or very low-certainty evidence. 60
# Conditional recommendation
• For patients: the majority of individuals in this situation may want the suggested course of action, but many may not. Decision aids may be useful in helping patients to make decisions consistent with their individual risks, values and preferences.
• For clinicians: different choices will be appropriate for individual patients and clinicians must help each patient arrive at a management decision consistent with their values and preferences through shared decision-making. Decision aids may be useful in helping individuals to make decisions consistent with their individual risks, values and preferences.
• For policy-makers: policy-making will require substantial debate and involvement of various stakeholders. Performance measures about the suggested course of action should focus on whether an appropriate decision-making process is duly documented.
• For researchers: this recommendation is likely to be strengthened (for future updates or adaptation) by additional research. An evaluation of the conditions and criteria (and the related judgments, research evidence and additional considerations) that determined the conditional (rather than strong) recommendation will help identify possible research gaps.
informed by a national survey of emergency physicians to define low (< 0.5%), intermediate (0.5%-5%) or high (< 5%) pretest probability groups. 35 Using Bayesian models, signs and symptoms were applied to a prevalence of 2% to generate a post-test probability. If the post-test probability was < 0.5%, the clinical variable was assigned a value of 0; if 0.5%-5%, a value of 1; and if > 5%, a value of 2. Further investigations (i.e., D-dimer testing, ECG-gated CT aorta) were then applied to the post-test probabilities to determine their utility. See the full guideline for the method used to generate the prevalence estimates and to define the test thresholds (Appendix 1).
# External review
The draft recommendations were distributed to more than 300 emergency medicine physicians, radiologists and surgeons for review in October 2019. The goal of the review was to obtain stakeholder feedback on the interpretation of the evidence, the strength of the recommendations and document layout.
Key stakeholder organizations also reviewed the guideline and supporting documents: the Canadian Association of Emergency Physicians, the Canadian Society of Cardiac Surgery, the Canadian Society of Vascular Surgery and the Canadian Society of Thoracic Radiology.
The coordinating panel revised the document to address pertinent comments by the stakeholder organizations and external reviewers. The advisory committee then reviewed and approved these revisions. Each stakeholder organization provided endorsement of the final document.
# Management of competing interests
Development of this guideline was wholly funded by the Alternate Funding Plan grant of the Northern Ontario Academic Medical Association, a nonprofit academic medical association. Members of the advisory committee received travel reimbursement for attendance at the in-person meeting. Members of the coordin ation panel received no other payments.
We managed competing interests of all participants according to recommendations of the Institute of Medicine and the Guidelines International Network. 48,50 Before appointment to the advisory committee, individuals disclosed both direct (financial) and indirect (nonfinancial) interests. Members of the coordination panel and chair reviewed the disclosures and judged which interests were conflicts and should be managed. At the time of appointment, the entire advisory committee had no direct competing interests, defined as no current material interest in any commercial entity with a product that could be affected by the guideline. After the guideline was completed, this process was repeated; no additional competing interests were reported.
# Implementation
Adaptation of these recommendations will likely be necessary in some circumstances; this document may serve as a basis for adaptation by local, regional or national guideline groups. For example, guideline implementation in an urban centre with 24-hour access to CT may differ from a rural or remote location that requires transfer of a patient with accompanying staff. These adaptations should be based on the associated evidenceto-decision frameworks. 46 Using a theory-driven, qualitative approach, we interviewed emergency medicine physicians from 4 urban and rural hospitals to describe current practice and to identify the barriers and facilitators to a standardized approach for investigating patients for AAS (Cait Dimitrew, Northern Ontario School of Medicine, Sudbury, Ontario; unpublished data 2020). Saturation of themes was achieved after 9 physician interviews.
We identified 3 barriers to implementation of this guideline: use of D-dimer and knowledge of rationale for its use in AAS is not widespread; the decision aid in the guideline was not in alignment with current practice or physician understanding of risk factors; and the complexity of the suggested decision aid in the guideline was a potential barrier to accurate application and desired outcomes.
We also identified 3 facilitators: publishing the guideline recommendations and decision aid would increase use and acceptability; availability of the decision aid and recommendations as an online tool would increase use; and clinicians were confident that the recommendations and decision tool would support clinic al decision-making and risk stratification and had the potential to reduce resource use (e.g., CT), particularly in rural settings.
# Suggested performance measures
Based on consensus of the advisory committee, we developed a suggested set of performance measures to accompany this guideline for consideration by providers and policy-makers: proportion of missed cases of AAS, time to diagnosis of AAS, emergency department disposition time, proportion of patients receiving a CT aorta, proportion of patients with D-dimer testing, and proportion of patients transferred for imaging or consultation.
# Updates
The guideline coordination panel will be responsible for updating the guideline every 5 years.
# Other guidelines
The recommendations in this guideline were adapted from the American Heart Association and European Society of Cardiology guidelines; comparison of the 3 guidelines is available in Table 3. All 3 guidelines recommend further testing depending on assessment of pretest probability. However, the importance of specific clinical features and results of investigations may be interpreted differently. Additionally, the recommended testing by pretest probability varies among the guidelines. These differences are based on the interpretation of evidence and the thresholds for investigations in different practice environments.
# Gaps in knowledge
The recommendations in this guideline are largely based on very low-or low-quality evidence and on modelled estimates for the popu lation prevalence of AAS. The evidence base would benefit from prospective data collection of important high-risk clinical variables in order to increase the quality of evidence. Prevalence and pretest probability are continuous variables but for modelling purposes, required input of a specific population prevalence. Prevalence estimates greatly different from those used in modelling will affect the recommendations. Future studies are needed to validate the diagnostic accuracy of this guideline's recommendations across a spectrum of disease prevalence in emergency departments.
# Conclusion
Acute aortic syndrome is a difficult-to-diagnose aortic emergency. We propose recommendations to aid clinicians in riskstratifying patients and, depending on risk level, suggest further investigations needed. This guideline is intended as a resource for practising clinicians, both as an evidence base and a guide to investigation for this high-risk aortic catastrophe.
#
Competing interests: Ashish Gupta reports receiving reimbursement of | None | None |
40b062187e5a4902793843379fecf59871977eab | cma | None | # Introduction
Interstitial lung disease (ILD) is a group of pulmonary diseases characterized by inflammation and fibrosis of the lung parenchyma. 1 The diagnosis of fibrotic ILD is challenging, with key diagnostic considerations described and recommendations provided in a recent Canadian Thoracic Society (CTS) Position Statement. 2 The management of patients with ILD is also complex and must be multi-faceted, including pharmacological and non-pharmacological therapies.
Current international guidelines focus on pharmacologic management of idiopathic pulmonary fibrosis (IPF). 3 There have been few published therapeutic recommendations pertaining to non-IPF fibrotic ILD. The goal of this position paper is to address these gaps by providing specific recommendations for the comprehensive management of fibrotic ILD, with an emphasis on the Canadian context. Objectives 1. To summarize the current scientific literature on the comprehensive management of fibrotic interstitial lung advocates. Finally, health care decision makers may also use this in policy processes to inform coverage decisions.
# Evidence search, appraisal and recommendation
The document was developed in accordance with the CTS requirements for a position statement (/ guideline-library), which is derived from the CTS guideline production methodology. 4 Authors used the AGREE II checklist to guide the development of this position statement. 5 The working group identified 9 clinically important questions pertaining to the management of fibrotic ILD. The expert group based those relevant questions on their own knowledge of the literature, existing guidelines and gaps to be addressed. The PICO (problem/ population, intervention, comparison, outcome) format was used when applicable to develop the questions by the co-chairs, then input from all coauthors was obtained through group discussion, and consensus was reached on the final key questions and topics. Pairs of coauthors were assigned specific sections of the paper and corresponding PICO questions based on their expertise, and conducted a search and review of the scientific literature using key word searches, supplemented by their own knowledge of relevant articles to be included. The literature was summarized and agreed upon by each pair of reviewers. Consensus was reached through emails and teleconferences, and all coauthors were in agreement with the final published key messages in this manuscript.
# Review
In accordance with the CTS Guideline Production Methodology, this position statement underwent both internal and external review. External review was conducted by two international ILD experts who were independently invited by the CTS to review this position statement. Each expert provided a detailed review and suggestions, and authors responded to these reviews in detail. Internal review was conducted by two members of the CTS Canadian Respiratory Guidelines Committee, who provided further feedback for consideration by authors. A member of the CTS Canadian Respiratory Guidelines Committee also assessed the statement with the AGREE II assessment tool, highlighting areas for improvement, which were then considered by authors. Original reviews and responses to reviews are posted along with the position statement and all authors' conflicts of interest at . The CTS Executive approved the final document for publication.
# Updating this statement
This position statement will be reviewed every three years or sooner by members of the CTS Interstitial Lung Disease Clinical Assembly, to determine the need for guideline updates, in accordance with the CTS Living Guideline Model (details available at / methodology).
# Summary of evidence and key messages
# ILD-targeted pharmacotherapy
Q1. What pharmacotherapies should be considered for the management of fibrotic ILD? Deciding on the most appropriate pharmacotherapy for fibrotic ILD requires an accurate diagnosis. 2 Pirfenidone and nintedanib are approved in Canada for the treatment of IPF and both anti-fibrotic medications have been recommended for the management of IPF in recent international guidelines. 3 Pirfenidone is a nonspecific anti-fibrotic agent thought to act on multiple targets along the fibrotic cascade. Pirfenidone at a dose of 2403 mg per day slows the decline in lung function compared to placebo, and pooled analyses of 3 randomized placebo-controlled trials also suggests a survival benefit and a reduced risk of respiratory-related hospitalizations. Nintedanib is a nonspecific tyrosine kinase inhibitor acting on different targets. Treatment at a dose of 300 mg daily slows decline in lung function compared to placebo. 9 Nintedanib significantly increased time to first exacerbation in one randomized controlled trial, but this finding was not replicated in a second trial. Pooled analysis showed a trend toward a reduction in mortality for patients treated with nintedanib compared to placebo, but this did not reach statistical significance. While no direct comparison between the two drugs exists so far, multiple post hoc analyses have suggested similar overall efficacy of pirfenidone and nintedanib. Anti-fibrotic medications were not tolerated in approximately 15-20% of the prospective clinical trial cohorts, indicating the need for close monitoring of potential toxicity. 6,7,9 Given their similar overall benefit, these medications are often prescribed based on their side effect profile and patient preference.
Anti-fibrotic medications are not currently recommended for other types of fibrotic ILD; however, several clinical trials are evaluating their potential role in non-IPF ILD. Other medications (eg, immunosuppressive agents such as mycophenolate mofetil, azathioprine, cyclophosphamide and rituximab, among others) are often used in non-IPF fibrotic ILDs based on longstanding practice patterns, observational studies, and randomized controlled trials that exist for some ILD subtypes. These studies collectively demonstrate a trend to disease slowing without reversal of existing fibrosis, but side effects are important and specific to each immunosuppressive agent. Review articles summarizing the evidence for immunosuppressive agents have been published elsewhere. 13 There are several unanswered questions including choice of agent and duration of therapy, and further work in the field is needed. Importantly, immunosuppressive medications have potential to cause harm in patients with IPF, 14 emphasizing the importance of establishing the correct diagnosis in patients with fibrotic ILD. 2 Referral to a tertiary care center for enrollment in clinical trials can be considered in selected cases of fibrotic ILD.
# Pulmonary rehabilitation
Q2. Should patients with fibrotic ILD be referred to pulmonary rehabilitation? Pulmonary rehabilitation (PR) is defined as a comprehensive structured exercise and education program for patients with chronic lung disease. 15 PR is weakly recommended in patients with IPF given the small number of well-controlled studies. 16 Despite this weak recommendation, 71% of PR programs in Canada accept patients with ILD. 17 Randomized controlled trials show that PR improves functional capacity (6-minute walk distance), dyspnea and quality of life in patients with ILD, 18,19 and may also improve depression, fatigue, anxiety, and muscle strength. In patients with chronic obstructive pulmonary disease (COPD), PR may also reduce the frequency and duration of hospitalization, improve social isolation and prolong survival; 25 however, it is unknown whether these additional benefits occur in patients with ILD. The impact of PR diminishes over time and patients with ILD may have less initial benefit and greater attenuation of this benefit compared to patients with COPD. 18,20,26 It is unknown whether ILD-specific programs would provide greater or longer-lasting benefits compared to conventional PR that is predominantly designed for patients with COPD.
Several studies have evaluated which ILD patients achieve the most benefit from PR. Two non-randomized cohort studies suggested greater and more sustained improvement in patients with milder ILD and in those who did not require oxygen at baseline. 22,27 Other cohort studies have suggested that patients with worse baseline functional capacity achieve the greatest benefits, with these studies unable to identify a specific population in which PR was ineffective. 20,23,28 The decision on when patients should be referred for PR is also impacted by the limited access to PR programs in most regions. 17
# Box 2. Pulmonary rehabilitation
Should patients with fibrotic ILD be referred to pulmonary rehabilitation? Key Messages:
- Patients with ILD should undergo pulmonary rehabilitation, as it improves walking distance, dyspnea, and quality of life. 2. In resource-limited settings, selected patients with advanced ILD, reduced functional capacity or pre-lung transplantation could be prioritized for pulmonary rehabilitation, as they may derive more benefits.
# Educational and exercise components of pulmonary rehabilitation
should be adapted for patients with ILD.
There are limited data on ILD-specific approaches to PR. Exercise-training protocols for ILD patients are generally similar to those for COPD: 30-60 minutes of aerobic and resistance training 2-3 times per week. Several studies have used initial exercise intensity settings similar to the approach taken for patients with COPD (eg, 60% of peak workload or 80% of 6-minute walk test speed). Despite the high prevalence of severe hypoxemia and cardiopulmonary comorbidities in fibrotic ILD, 29 a recent Cochrane review reported no adverse events in PR trials for these patients; 30 however, it may be necessary to provide supplemental oxygen more frequently to patients with ILD compared to other populations during exercise. Interval training or one-legged cycling may be appropriate for patients with severe dyspnea and/or hypoxemia, but these have not been adequately explored in ILD. There are also limited data on the magnitude of benefit from alternatives to standard PR programs (eg, home-based exercise programs); 21,31,32 however, these options may be appropriate in some patients. Two recent studies showed that the typical PR educational curriculum does not meet the needs of ILD patients, recommending additional information on ILD prognosis, medications, diagnostic tests, oxygen, management of dyspnea and advance care planning. 33,34 Oxygen supplementation Q3. When should the need for oxygen supplementation be evaluated and when should oxygen be initiated in patients with fibrotic ILD?
Patients with fibrotic ILD frequently develop hypoxemia in the later stages of disease due to multifactorial physiologic derangements including diffusion limitation, ventilation-perfusion mismatch, and abnormalities of the pulmonary vasculature. The diffusion capacity of the lung for carbon monoxide (DLCO) is the most important predictor of hypoxemia in fibrotic ILD, 29 and this is the primary objective measure that indicates the need to screen for both resting and exertional desaturation. Measurement of resting oxygen saturation is widely available and should be performed at each clinical visit using pulse oximetry, while measurement of ambulatory oxygenation is more resource-intensive and should be considered in selected patients. Common parameters that indicate the need for assessment of oxygenation include disease progression, exercise limitation, significant exertional dyspnea, reduced DLCO, polycythemia or pulmonary hypertension.
There are sparse and inconsistent data regarding the efficacy of supplemental oxygen in patients with fibrotic ILD. 38 Data supporting oxygen use in ILD patients with resting hypoxemia are mainly extrapolated from studies of non-ILD pulmonary disease that showed improved cardiac output, exercise endurance, dyspnea and survival; however, the only study assessing mortality in patients with IPF found no survival benefit. 45 There are similarly no high quality studies evaluating the role of supplemental ambulatory oxygen in patients with fibrotic ILD; however, several small studies suggest potential benefits on endurance time, walk distance and maximal workload. The potential adverse effects of unnecessary supplemental oxygen also remain poorly characterized. 49 Access to oxygen supplementation varies across Canada, in part because funding criteria are defined within provincial jurisdictions. 50,51 Given the weak and predominantly indirect data, the decision to initiate supplemental oxygen for patients with fibrotic ILD should be made on an individual basis, considering mobility level, patient preference, quality of life, and the likelihood of symptomatic and/or functional benefit. International guidelines recommend continuous oxygen supplementation for patients with IPF and resting oxygen saturation below 88%, a partial pressure of oxygen (PaO 2 ) < 55 mmHg, or a PaO 2 <60 mmHg combined with evidence of cor pulmonale. 16 Ambulatory oxygen supplementation is typically recommended for patients with exertional hypoxemia (oxygen saturation <88%) and an improvement in dyspnea or functional capacity on 6-minute walk test with the use of oxygen during exertion. 52,53
# Box 3. Oxygen supplementation
When should the need for oxygen supplementation be evaluated and when should oxygen be initiated in patients with fibrotic ILD? Key Messages:
- Patients with fibrotic ILD should be screened for resting hypoxemia at each clinical visit using pulse oximetry. 2. Continuous oxygen supplementation is recommended for all patients with resting hypoxemia (oxygen saturation <88%, PaO 2 <55mmHg, or PaO 2 <60mmHg with cor pulmonale), despite lack of supportive data in ILD specifically. 3. Selected patients with advanced fibrotic ILD and/or significant dyspnea (MMRC 3) should be assessed for exertional hypoxemia (oxygen saturation <88%) using oximetry during exercise (walk test, ambulation or exercise test). 4. Ambulatory oxygen supplementation should be considered for patients with fibrotic ILD and exertional hypoxemia (oxygen saturation <88%), who demonstrate clinical improvement on oxygen with the understanding that this will change based on regional reimbursement criteria.
# Lung transplantation
Q4. Which patients with fibrotic ILD should be referred to a lung transplant program? Fibrotic ILD is the most common indication for lung transplant in Canada. 54 Currently, there are 4 surgical lung transplant programs in Canada, located in Vancouver, Edmonton, Toronto, and Montreal, with follow-up care available in additional satellite clinics. In 2015, a total of 279 lung transplantations were performed in Canada and this number has been steadily increasing over the past decade. 55 A detailed review of patient selection, timing of referral, and other transplant-related considerations are provided in recent guidelines from the International Society for Heart and Lung Transplantation. 56 Referral to a lung transplant center should be considered in patients with fibrotic ILD based on significant benefits on quality of life and survival; 57,58 however, there are important considerations (eg, age, comorbidities) related to specific ILD subtypes that preclude lung transplantation in many patients. 59,60 Preliminary screening for significant coronary disease and malignancy should be undertaken before referral to transplant centers. In patients with connective tissue disease (CTD)-associated ILD, extra-pulmonary disease manifestations (joint involvement, esophageal dysmotility, myopathy, renal impairment and skin involvement leading to restriction) may impact suitability for transplantation and can influence long-term outcomes. However, recent observational studies suggest that overall post-transplant outcomes may be similar to that of other lung diseases in appropriately selected patients. 61,62 Although there is a theoretical concern that anti-fibrotic medications might increase the risk of peri-operative bleeding, the limited available data do not suggest clinically significant risks associated with these agents and they are not contraindicated in patients on transplantation waitlists. 63,64 Disease recurrence in the allograft lung has been described in some fibrotic ILDs, most frequently sarcoidosis, although survival after transplant does not appear to be impacted. 65
# Box 4. Lung transplantation
Which patients with fibrotic ILD should be referred to a lung transplant program?
Key Messages:
- Lung transplantation should be considered in all patients with fibrotic ILD; however, many patients will not be eligible for lung transplant on the basis of significant comorbidities. 2. CTD is not a contraindication to transplant, although the presence of significant extra-pulmonary disease may impact eligibility.
# Q5. When should patients with fibrotic ILD be referred for lung transplantation evaluation?
Given the poor prognosis of IPF and the variable and unpredictable course of the disease, international guidelines have advocated that potentially eligible patients be referred for lung transplantation evaluation at or shortly after the time of diagnosis. 16,56,66,67 Less data are available to guide optimal timing for lung transplantation referral in non-IPF fibrotic ILD. Guidelines suggest referral at the time of diagnosis regardless of lung function for idiopathic fibrotic nonspecific interstitial pneumonia (NSIP), similarly to IPF. 56 In other non-IPF ILDs, referral should be made in the setting of a forced vital capacity below 80%, DLCO below 40%, any oxygen requirement, or failure to respond to pharmacotherapy, 56,68 recognizing that the ideal timing of referral will vary between institutions based on the expected time from initial referral to transplantation. Direct communication between referring physicians and the transplant program is frequently helpful to optimize the timing and convey the urgency of referral. This is particularly important given the high waitlist mortality in Canada, with 45 deaths on the waiting list in 2016. 54 Median unadjusted survival after lung transplant for ILD in the ISHLT registry is 4.9 years compared to 9.2 and 5.8 years for cystic fibrosis and chronic obstructive pulmonary disease, respectively. 69 However, survival may vary across programs. Given the poor prognosis of many fibrotic ILDs, especially IPF, lung transplant likely conveys a survival benefit in the appropriately selected fibrotic ILD patient. 57 Lung transplant also confers very substantial health-related quality of life benefits for patients with ILD, although this is also somewhat lower than the benefits seen for other lung diseases. 58
# Box 5. Lung transplantation
When should patients with fibrotic ILD be referred for lung transplantation evaluation? Key messages:
- Referral for lung transplant evaluation should be made at, or shortly after time of diagnosis for patients with IPF and fibrotic NSIP, given the poor prognosis and unpredictable disease course. 2. For non-IPF fibrotic ILD, referral should be made in the setting of a forced vital capacity below 80%, DLCO below 40%, any oxygen requirement or failure to respond to pharmacotherapy. 3. Optimal timing of lung transplant referral will vary in individual programs based on the expected time from initial referral to transplantation.
Advance care planning Q6. When should advance care planning be discussed with patients with fibrotic ILD and their caregivers?
Advance care planning is the process of thinking about a patient's wishes for future health and personal care, with the goal to ensure that patients receive medical care that is consistent with their values, goals, and preferences during serious and chronic illness. 70 It involves sharing prognosis, exploring wishes for care and involving family and caregivers in the discussion. 71 Advance care planning can help ease decision-making by patients or by surrogate decision makers when a patient loses capacity (eg, during acute episodes). 72 The process is iterative and what is discussed often changes over the course of living with ILD. Elements of the advance care planning process are summarized in Table 1. It results in lower medical resource utilization at the end of life, improved patient quality of life near death, and improved quality of life for caregivers. 71,73 It may also reduce moral distress among health care providers with a recent study identifying lack of end-of-life conversations, inconsistent care plans and poor communication as causes of moral distress among providers in the intensive care unit. 74 Establishing "goals of care" is important after a diagnosis of fibrotic ILD is established and, particularly, in the presence of disease progression. Resuscitation preferences, other specific treatment-related decisions and the focus or aims of care (eg, seeking to prolong life, focusing on symptom relief) should be documented and are made in relation to the patient's own personal and individualized goals for his or her care. Clinicians should consider using the "surprise question" to assist with transitioning to Goals of Care discussions: 75 "Would I be surprised if this patient were to die within the next 12 months?" If the clinician's answer is "no," then it may be an appropriate time to review the patient's prognosis and re-elicit personal priorities in relation to his or her healthcare.
Clinicians can use information on patient preferences, goals of care, and values to make recommendations about interventions such as referral to palliative care. Palliative care should be integrated with disease-centered management early in the disease course of any severe and life limiting disease. 76 A recent retrospective study of 404 patients with IPF found that only 13.7% had a referral to palliative care, with 71% of these occurring within 30 days of death. 77 This suggests that palliative care involvement occurs late in the disease course for a large majority of patients with fibrotic ILD, if at all, despite the high palliative care needs in this population. 78 Palliative care may also be appropriate to ease symptom burden for patients with ILD who are actively listed for lung transplantation. 79
# Box 6. Advance care planning
When should advance care planning be discussed with patients with fibrotic ILD and their caregivers? Key messages:
- Advance care planning (see Table 1) should be initiated with all patients with fibrotic ILD during the course of their disease. 2. Prognosis and outcomes should be shared with patients and caregivers to assist with end-of-life decision-making and establishing goals of care.
# Symptom management
Q7. How should severe dyspnea be managed in patients with fibrotic ILD? Exertional dyspnea is present in virtually all patients with advanced ILD, and dyspnea can eventually occur at rest as well. Dyspnea reduces quality of life, increases depression and anxiety, 80 can result in loss of independence and social isolation and is an important predictor of prognosis in patients with ILD. 80,81 Although dyspnea is primarily determined by the severity of ILD, it is important to identify, investigate for and treat any potentially reversible causes of dyspnea (eg, concomitant infection, pulmonary embolism, heart failure, anemia). 82 There are many non-pharmacologic interventions that can improve dyspnea, including pacing, energy conservation, breathing retraining, body positioning, relaxation techniques, fans (external airflow) and cognitive behavioral therapy. 83,84 Randomized controlled trials have shown that pulmonary rehabilitation reduces dyspnea in patients with ILD and is, thus, an important symptom management strategy that is recommended in clinical practice guidelines. 16,18,30 There is less evidence for the role of pharmacotherapies for the palliation of dyspnea in fibrotic ILD. Opioids are the preferred choice in advanced disease, although the only study in an ILD population is an open-label case series of 11 elderly patients with advanced IPF in which a single, low dose of subcutaneous diamorphine resulted in a significant reduction in dyspnea compared to baseline without reducing respiratory rate. 85 There are higher-quality data showing the benefit of opioids to relieve dyspnea in other advanced lung diseases such as cancer and COPD, and recent guidelines thus recommend carefully titrated low dose oral opioids for palliation of severe dyspnea in patients with chronic respiratory disease. 77 There is currently no clear role for nebulized opioids in ILD or other advanced lung diseases. 86,87 Shortacting opioids with rapid onset of action (e.g., subcutaneous, sublingual, or nasal fentanyl) have theoretical appeal for exertional breathlessness; however, studies have also not shown consistent benefit, and larger trials are underway. 88 A starting dose of immediate release morphine 1.0-2.5 mg or hydromorphone 0.1 mg orally every 4-6 hours can be used as a starting dose. Escalation of dose and conversion to long acting formulations can be done in consultation with local Palliative Care experts. Benzodiazepines are not recommended for palliation of dyspnea based on a previous systematic review that did not identify a clear benefit in a variety of advanced lung diseases. 89
# Box 7. Symptom management
How should severe dyspnea be managed in patients with fibrotic ILD? Q8. How should intractable chronic cough be managed in patients with fibrotic ILD?
Cough is reported in up to 85% of patients with fibrotic ILD, 90,91 can lead to reduced health-related quality of life and social isolation and is an independent predictor of mortality. 90 Although the pathogenesis of cough has not been clearly established in patients with fibrotic ILD, increased sensitivity of sensory fibers to stretch and damage in the lungs is thought to play a role in IPF. 92 Cough is frequently attributed to ILD, but other factors may contribute to cough, with one study reporting that cough was related to a process other than the underlying ILD in up to 54% of patients. 93 Treating cough in patients with ILD is challenging and there are no high-quality studies that suggest a highly effective treatment for cough in ILD. In a small study of 43 patients, pirfenidone reduced cough frequency by 34% after 12 weeks of therapy. 94 A post-hoc analysis of recent pirfenidone clinical trials also suggested improvement in the prevalence of cough compared to placebo. 95 Opioids are frequently used to palliate cough in a variety of settings, but there are no randomized trials and only anecdotal reports of effectiveness in ILD. 85 An open-label trial of oral prednisolone at 40-60 mg daily for one month showed decreased cough severity in 6 IPF patients who had severe cough. 92 A phase II double blind crossover trial of low-dose thalidomide at 50-100 mg daily reported a significant improvement in cough-specific quality of life and in respiratory-related quality of life; 96 however, additional studies are needed to verify the efficacy and safety of this given the frequent contraindications and significant risk of adverse effects. The central-acting neuromodulator gabapentin, at doses up to 1800 mg per day, reduced cough severity in refractory chronic idiopathic cough in a blinded randomized controlled trial, 97 but has never been studied in ILD. Future trials are needed for these and other potential therapies of cough given the absence of any high quality data and the frequent toxicity of currently available options. Patient education, support, and advocacy Q9. What are the benefits of structured patient education and advocacy programs in fibrotic ILD? IPF and other fibrotic ILDs have a significant impact on patients' quality of life, family life, emotional and physical wellbeing. In many ILD centers, patient-centered management includes a large multidisciplinary team of physicians, nurses and other allied health professionals. 98 Patients rely on ILD nurses and physicians for support and information, but express the need for more accessible information on disease. 99 Patient advocacy groups can play an important role in supporting patients with chronic diseases, filling gaps in information and advocating for better care through different measures. A recent collaborative between physicians and advocacy group members identified several unmet needs in patients with IPF that could be filled by patient advocacy groups, including the need for improved access to reliable information, knowledgeable health care providers, access to treatment and holistic and palliative care. 100 Internet-based resources are easily and widely accessible tools that can facilitate patient-centered education and management; however, many IPF-related websites contain incorrect or outdated information and there is no way for patients to reliably identify which websites provide accurate information. 101 Self-management has been shown to be of benefit in COPD 102 and may similarly be of benefit in ILD despite the absence of supportive data. Patients should actively review websites for information such as when they were last updated, who sponsored the page and where the information originates. Patients should also be encouraged to discuss with their physician if the information they read conflicts with what they have learned in clinic. Physicians should also direct their patients to trustworthy medical information websites.
# Conclusion
Fibrotic ILDs are complex and heterogeneous diseases that have serious consequences on quality of life and survival. This position paper from the CTS Interstitial Lung Disease Clinical Assembly summarizes important issues and provides key messages relevant to the management of patients with fibrotic ILD. This work is limited by the lack of patient perspective, and ILD clinicians should remember that a patientcentered approach is of fundamental importance. Available evidence indicates the importance of a comprehensive approach to management that includes both pharmacologic and non-pharmacologic interventions that are ideally provided in a collaborative multidisciplinary setting. | # Introduction
Interstitial lung disease (ILD) is a group of pulmonary diseases characterized by inflammation and fibrosis of the lung parenchyma. 1 The diagnosis of fibrotic ILD is challenging, with key diagnostic considerations described and recommendations provided in a recent Canadian Thoracic Society (CTS) Position Statement. 2 The management of patients with ILD is also complex and must be multi-faceted, including pharmacological and non-pharmacological therapies.
Current international guidelines focus on pharmacologic management of idiopathic pulmonary fibrosis (IPF). 3 There have been few published therapeutic recommendations pertaining to non-IPF fibrotic ILD. The goal of this position paper is to address these gaps by providing specific recommendations for the comprehensive management of fibrotic ILD, with an emphasis on the Canadian context. Objectives 1. To summarize the current scientific literature on the comprehensive management of fibrotic interstitial lung advocates. Finally, health care decision makers may also use this in policy processes to inform coverage decisions.
# Evidence search, appraisal and recommendation
The document was developed in accordance with the CTS requirements for a position statement (https://cts-sct.ca/ guideline-library), which is derived from the CTS guideline production methodology. 4 Authors used the AGREE II checklist to guide the development of this position statement. 5 The working group identified 9 clinically important questions pertaining to the management of fibrotic ILD. The expert group based those relevant questions on their own knowledge of the literature, existing guidelines and gaps to be addressed. The PICO (problem/ population, intervention, comparison, outcome) format was used when applicable to develop the questions by the co-chairs, then input from all coauthors was obtained through group discussion, and consensus was reached on the final key questions and topics. Pairs of coauthors were assigned specific sections of the paper and corresponding PICO questions based on their expertise, and conducted a search and review of the scientific literature using key word searches, supplemented by their own knowledge of relevant articles to be included. The literature was summarized and agreed upon by each pair of reviewers. Consensus was reached through emails and teleconferences, and all coauthors were in agreement with the final published key messages in this manuscript.
# Review
In accordance with the CTS Guideline Production Methodology, this position statement underwent both internal and external review. External review was conducted by two international ILD experts who were independently invited by the CTS to review this position statement. Each expert provided a detailed review and suggestions, and authors responded to these reviews in detail. Internal review was conducted by two members of the CTS Canadian Respiratory Guidelines Committee, who provided further feedback for consideration by authors. A member of the CTS Canadian Respiratory Guidelines Committee also assessed the statement with the AGREE II assessment tool, highlighting areas for improvement, which were then considered by authors. Original reviews and responses to reviews are posted along with the position statement and all authors' conflicts of interest at https://cts-sct.ca/guidelinelibrary. The CTS Executive approved the final document for publication.
# Updating this statement
This position statement will be reviewed every three years or sooner by members of the CTS Interstitial Lung Disease Clinical Assembly, to determine the need for guideline updates, in accordance with the CTS Living Guideline Model (details available at https://cts-sct/guideline-library/ methodology).
# Summary of evidence and key messages
# ILD-targeted pharmacotherapy
Q1. What pharmacotherapies should be considered for the management of fibrotic ILD? Deciding on the most appropriate pharmacotherapy for fibrotic ILD requires an accurate diagnosis. 2 Pirfenidone and nintedanib are approved in Canada for the treatment of IPF and both anti-fibrotic medications have been recommended for the management of IPF in recent international guidelines. 3 Pirfenidone is a nonspecific anti-fibrotic agent thought to act on multiple targets along the fibrotic cascade. Pirfenidone at a dose of 2403 mg per day slows the decline in lung function compared to placebo, and pooled analyses of 3 randomized placebo-controlled trials also suggests a survival benefit and a reduced risk of respiratory-related hospitalizations. [6][7][8] Nintedanib is a nonspecific tyrosine kinase inhibitor acting on different targets. Treatment at a dose of 300 mg daily slows decline in lung function compared to placebo. 9 Nintedanib significantly increased time to first exacerbation in one randomized controlled trial, but this finding was not replicated in a second trial. Pooled analysis showed a trend toward a reduction in mortality for patients treated with nintedanib compared to placebo, but this did not reach statistical significance. While no direct comparison between the two drugs exists so far, multiple post hoc analyses have suggested similar overall efficacy of pirfenidone and nintedanib. Anti-fibrotic medications were not tolerated in approximately 15-20% of the prospective clinical trial cohorts, indicating the need for close monitoring of potential toxicity. 6,7,9 Given their similar overall benefit, these medications are often prescribed based on their side effect profile and patient preference.
Anti-fibrotic medications are not currently recommended for other types of fibrotic ILD; however, several clinical trials are evaluating their potential role in non-IPF ILD. Other medications (eg, immunosuppressive agents such as mycophenolate mofetil, azathioprine, cyclophosphamide and rituximab, among others) are often used in non-IPF fibrotic ILDs based on longstanding practice patterns, observational studies, and randomized controlled trials that exist for some ILD subtypes. These studies collectively demonstrate a trend to disease slowing without reversal of existing fibrosis, but side effects are important and specific to each immunosuppressive agent. [10][11][12] Review articles summarizing the evidence for immunosuppressive agents have been published elsewhere. 13 There are several unanswered questions including choice of agent and duration of therapy, and further work in the field is needed. Importantly, immunosuppressive medications have potential to cause harm in patients with IPF, 14 emphasizing the importance of establishing the correct diagnosis in patients with fibrotic ILD. 2 Referral to a tertiary care center for enrollment in clinical trials can be considered in selected cases of fibrotic ILD.
# Pulmonary rehabilitation
Q2. Should patients with fibrotic ILD be referred to pulmonary rehabilitation? Pulmonary rehabilitation (PR) is defined as a comprehensive structured exercise and education program for patients with chronic lung disease. 15 PR is weakly recommended in patients with IPF given the small number of well-controlled studies. 16 Despite this weak recommendation, 71% of PR programs in Canada accept patients with ILD. 17 Randomized controlled trials show that PR improves functional capacity (6-minute walk distance), dyspnea and quality of life in patients with ILD, 18,19 and may also improve depression, fatigue, anxiety, and muscle strength. [20][21][22][23][24] In patients with chronic obstructive pulmonary disease (COPD), PR may also reduce the frequency and duration of hospitalization, improve social isolation and prolong survival; 25 however, it is unknown whether these additional benefits occur in patients with ILD. The impact of PR diminishes over time and patients with ILD may have less initial benefit and greater attenuation of this benefit compared to patients with COPD. 18,20,26 It is unknown whether ILD-specific programs would provide greater or longer-lasting benefits compared to conventional PR that is predominantly designed for patients with COPD.
Several studies have evaluated which ILD patients achieve the most benefit from PR. Two non-randomized cohort studies suggested greater and more sustained improvement in patients with milder ILD and in those who did not require oxygen at baseline. 22,27 Other cohort studies have suggested that patients with worse baseline functional capacity achieve the greatest benefits, with these studies unable to identify a specific population in which PR was ineffective. 20,23,28 The decision on when patients should be referred for PR is also impacted by the limited access to PR programs in most regions. 17
# Box 2. Pulmonary rehabilitation
Should patients with fibrotic ILD be referred to pulmonary rehabilitation? Key Messages:
1. Patients with ILD should undergo pulmonary rehabilitation, as it improves walking distance, dyspnea, and quality of life. 2. In resource-limited settings, selected patients with advanced ILD, reduced functional capacity or pre-lung transplantation could be prioritized for pulmonary rehabilitation, as they may derive more benefits.
# Educational and exercise components of pulmonary rehabilitation
should be adapted for patients with ILD.
There are limited data on ILD-specific approaches to PR. Exercise-training protocols for ILD patients are generally similar to those for COPD: 30-60 minutes of aerobic and resistance training 2-3 times per week. Several studies have used initial exercise intensity settings similar to the approach taken for patients with COPD (eg, 60% of peak workload or 80% of 6-minute walk test speed). Despite the high prevalence of severe hypoxemia and cardiopulmonary comorbidities in fibrotic ILD, 29 a recent Cochrane review reported no adverse events in PR trials for these patients; 30 however, it may be necessary to provide supplemental oxygen more frequently to patients with ILD compared to other populations during exercise. Interval training or one-legged cycling may be appropriate for patients with severe dyspnea and/or hypoxemia, but these have not been adequately explored in ILD. There are also limited data on the magnitude of benefit from alternatives to standard PR programs (eg, home-based exercise programs); 21,31,32 however, these options may be appropriate in some patients. Two recent studies showed that the typical PR educational curriculum does not meet the needs of ILD patients, recommending additional information on ILD prognosis, medications, diagnostic tests, oxygen, management of dyspnea and advance care planning. 33,34 Oxygen supplementation Q3. When should the need for oxygen supplementation be evaluated and when should oxygen be initiated in patients with fibrotic ILD?
Patients with fibrotic ILD frequently develop hypoxemia in the later stages of disease due to multifactorial physiologic derangements including diffusion limitation, ventilation-perfusion mismatch, and abnormalities of the pulmonary vasculature. [35][36][37] The diffusion capacity of the lung for carbon monoxide (DLCO) is the most important predictor of hypoxemia in fibrotic ILD, 29 and this is the primary objective measure that indicates the need to screen for both resting and exertional desaturation. Measurement of resting oxygen saturation is widely available and should be performed at each clinical visit using pulse oximetry, while measurement of ambulatory oxygenation is more resource-intensive and should be considered in selected patients. Common parameters that indicate the need for assessment of oxygenation include disease progression, exercise limitation, significant exertional dyspnea, reduced DLCO, polycythemia or pulmonary hypertension.
There are sparse and inconsistent data regarding the efficacy of supplemental oxygen in patients with fibrotic ILD. 38 Data supporting oxygen use in ILD patients with resting hypoxemia are mainly extrapolated from studies of non-ILD pulmonary disease that showed improved cardiac output, exercise endurance, dyspnea and survival; [39][40][41][42][43][44] however, the only study assessing mortality in patients with IPF found no survival benefit. 45 There are similarly no high quality studies evaluating the role of supplemental ambulatory oxygen in patients with fibrotic ILD; however, several small studies suggest potential benefits on endurance time, walk distance and maximal workload. [46][47][48] The potential adverse effects of unnecessary supplemental oxygen also remain poorly characterized. 49 Access to oxygen supplementation varies across Canada, in part because funding criteria are defined within provincial jurisdictions. 50,51 Given the weak and predominantly indirect data, the decision to initiate supplemental oxygen for patients with fibrotic ILD should be made on an individual basis, considering mobility level, patient preference, quality of life, and the likelihood of symptomatic and/or functional benefit. International guidelines recommend continuous oxygen supplementation for patients with IPF and resting oxygen saturation below 88%, a partial pressure of oxygen (PaO 2 ) < 55 mmHg, or a PaO 2 <60 mmHg combined with evidence of cor pulmonale. 16 Ambulatory oxygen supplementation is typically recommended for patients with exertional hypoxemia (oxygen saturation <88%) and an improvement in dyspnea or functional capacity on 6-minute walk test with the use of oxygen during exertion. 52,53
# Box 3. Oxygen supplementation
When should the need for oxygen supplementation be evaluated and when should oxygen be initiated in patients with fibrotic ILD? Key Messages:
1. Patients with fibrotic ILD should be screened for resting hypoxemia at each clinical visit using pulse oximetry. 2. Continuous oxygen supplementation is recommended for all patients with resting hypoxemia (oxygen saturation <88%, PaO 2 <55mmHg, or PaO 2 <60mmHg with cor pulmonale), despite lack of supportive data in ILD specifically. 3. Selected patients with advanced fibrotic ILD and/or significant dyspnea (MMRC 3) should be assessed for exertional hypoxemia (oxygen saturation <88%) using oximetry during exercise (walk test, ambulation or exercise test). 4. Ambulatory oxygen supplementation should be considered for patients with fibrotic ILD and exertional hypoxemia (oxygen saturation <88%), who demonstrate clinical improvement on oxygen with the understanding that this will change based on regional reimbursement criteria.
# Lung transplantation
Q4. Which patients with fibrotic ILD should be referred to a lung transplant program? Fibrotic ILD is the most common indication for lung transplant in Canada. 54 Currently, there are 4 surgical lung transplant programs in Canada, located in Vancouver, Edmonton, Toronto, and Montreal, with follow-up care available in additional satellite clinics. In 2015, a total of 279 lung transplantations were performed in Canada and this number has been steadily increasing over the past decade. 55 A detailed review of patient selection, timing of referral, and other transplant-related considerations are provided in recent guidelines from the International Society for Heart and Lung Transplantation. 56 Referral to a lung transplant center should be considered in patients with fibrotic ILD based on significant benefits on quality of life and survival; 57,58 however, there are important considerations (eg, age, comorbidities) related to specific ILD subtypes that preclude lung transplantation in many patients. 59,60 Preliminary screening for significant coronary disease and malignancy should be undertaken before referral to transplant centers. In patients with connective tissue disease (CTD)-associated ILD, extra-pulmonary disease manifestations (joint involvement, esophageal dysmotility, myopathy, renal impairment and skin involvement leading to restriction) may impact suitability for transplantation and can influence long-term outcomes. However, recent observational studies suggest that overall post-transplant outcomes may be similar to that of other lung diseases in appropriately selected patients. 61,62 Although there is a theoretical concern that anti-fibrotic medications might increase the risk of peri-operative bleeding, the limited available data do not suggest clinically significant risks associated with these agents and they are not contraindicated in patients on transplantation waitlists. 63,64 Disease recurrence in the allograft lung has been described in some fibrotic ILDs, most frequently sarcoidosis, although survival after transplant does not appear to be impacted. 65
# Box 4. Lung transplantation
Which patients with fibrotic ILD should be referred to a lung transplant program?
Key Messages:
1. Lung transplantation should be considered in all patients with fibrotic ILD; however, many patients will not be eligible for lung transplant on the basis of significant comorbidities. 2. CTD is not a contraindication to transplant, although the presence of significant extra-pulmonary disease may impact eligibility.
# Q5. When should patients with fibrotic ILD be referred for lung transplantation evaluation?
Given the poor prognosis of IPF and the variable and unpredictable course of the disease, international guidelines have advocated that potentially eligible patients be referred for lung transplantation evaluation at or shortly after the time of diagnosis. 16,56,66,67 Less data are available to guide optimal timing for lung transplantation referral in non-IPF fibrotic ILD. Guidelines suggest referral at the time of diagnosis regardless of lung function for idiopathic fibrotic nonspecific interstitial pneumonia (NSIP), similarly to IPF. 56 In other non-IPF ILDs, referral should be made in the setting of a forced vital capacity below 80%, DLCO below 40%, any oxygen requirement, or failure to respond to pharmacotherapy, 56,68 recognizing that the ideal timing of referral will vary between institutions based on the expected time from initial referral to transplantation. Direct communication between referring physicians and the transplant program is frequently helpful to optimize the timing and convey the urgency of referral. This is particularly important given the high waitlist mortality in Canada, with 45 deaths on the waiting list in 2016. 54 Median unadjusted survival after lung transplant for ILD in the ISHLT registry is 4.9 years compared to 9.2 and 5.8 years for cystic fibrosis and chronic obstructive pulmonary disease, respectively. 69 However, survival may vary across programs. Given the poor prognosis of many fibrotic ILDs, especially IPF, lung transplant likely conveys a survival benefit in the appropriately selected fibrotic ILD patient. 57 Lung transplant also confers very substantial health-related quality of life benefits for patients with ILD, although this is also somewhat lower than the benefits seen for other lung diseases. 58
# Box 5. Lung transplantation
When should patients with fibrotic ILD be referred for lung transplantation evaluation? Key messages:
1. Referral for lung transplant evaluation should be made at, or shortly after time of diagnosis for patients with IPF and fibrotic NSIP, given the poor prognosis and unpredictable disease course. 2. For non-IPF fibrotic ILD, referral should be made in the setting of a forced vital capacity below 80%, DLCO below 40%, any oxygen requirement or failure to respond to pharmacotherapy. 3. Optimal timing of lung transplant referral will vary in individual programs based on the expected time from initial referral to transplantation.
Advance care planning Q6. When should advance care planning be discussed with patients with fibrotic ILD and their caregivers?
Advance care planning is the process of thinking about a patient's wishes for future health and personal care, with the goal to ensure that patients receive medical care that is consistent with their values, goals, and preferences during serious and chronic illness. 70 It involves sharing prognosis, exploring wishes for care and involving family and caregivers in the discussion. 71 Advance care planning can help ease decision-making by patients or by surrogate decision makers when a patient loses capacity (eg, during acute episodes). 72 The process is iterative and what is discussed often changes over the course of living with ILD. Elements of the advance care planning process are summarized in Table 1. It results in lower medical resource utilization at the end of life, improved patient quality of life near death, and improved quality of life for caregivers. 71,73 It may also reduce moral distress among health care providers with a recent study identifying lack of end-of-life conversations, inconsistent care plans and poor communication as causes of moral distress among providers in the intensive care unit. 74 Establishing "goals of care" is important after a diagnosis of fibrotic ILD is established and, particularly, in the presence of disease progression. Resuscitation preferences, other specific treatment-related decisions and the focus or aims of care (eg, seeking to prolong life, focusing on symptom relief) should be documented and are made in relation to the patient's own personal and individualized goals for his or her care. Clinicians should consider using the "surprise question" to assist with transitioning to Goals of Care discussions: 75 "Would I be surprised if this patient were to die within the next 12 months?" If the clinician's answer is "no," then it may be an appropriate time to review the patient's prognosis and re-elicit personal priorities in relation to his or her healthcare.
Clinicians can use information on patient preferences, goals of care, and values to make recommendations about interventions such as referral to palliative care. Palliative care should be integrated with disease-centered management early in the disease course of any severe and life limiting disease. 76 A recent retrospective study of 404 patients with IPF found that only 13.7% had a referral to palliative care, with 71% of these occurring within 30 days of death. 77 This suggests that palliative care involvement occurs late in the disease course for a large majority of patients with fibrotic ILD, if at all, despite the high palliative care needs in this population. 78 Palliative care may also be appropriate to ease symptom burden for patients with ILD who are actively listed for lung transplantation. 79
# Box 6. Advance care planning
When should advance care planning be discussed with patients with fibrotic ILD and their caregivers? Key messages:
1. Advance care planning (see Table 1) should be initiated with all patients with fibrotic ILD during the course of their disease. 2. Prognosis and outcomes should be shared with patients and caregivers to assist with end-of-life decision-making and establishing goals of care.
# Symptom management
Q7. How should severe dyspnea be managed in patients with fibrotic ILD? Exertional dyspnea is present in virtually all patients with advanced ILD, and dyspnea can eventually occur at rest as well. Dyspnea reduces quality of life, increases depression and anxiety, 80 can result in loss of independence and social isolation and is an important predictor of prognosis in patients with ILD. 80,81 Although dyspnea is primarily determined by the severity of ILD, it is important to identify, investigate for and treat any potentially reversible causes of dyspnea (eg, concomitant infection, pulmonary embolism, heart failure, anemia). 82 There are many non-pharmacologic interventions that can improve dyspnea, including pacing, energy conservation, breathing retraining, body positioning, relaxation techniques, fans (external airflow) and cognitive behavioral therapy. 83,84 Randomized controlled trials have shown that pulmonary rehabilitation reduces dyspnea in patients with ILD and is, thus, an important symptom management strategy that is recommended in clinical practice guidelines. 16,18,30 There is less evidence for the role of pharmacotherapies for the palliation of dyspnea in fibrotic ILD. Opioids are the preferred choice in advanced disease, although the only study in an ILD population is an open-label case series of 11 elderly patients with advanced IPF in which a single, low dose of subcutaneous diamorphine resulted in a significant reduction in dyspnea compared to baseline without reducing respiratory rate. 85 There are higher-quality data showing the benefit of opioids to relieve dyspnea in other advanced lung diseases such as cancer and COPD, and recent guidelines thus recommend carefully titrated low dose oral opioids for palliation of severe dyspnea in patients with chronic respiratory disease. 77 There is currently no clear role for nebulized opioids in ILD or other advanced lung diseases. 86,87 Shortacting opioids with rapid onset of action (e.g., subcutaneous, sublingual, or nasal fentanyl) have theoretical appeal for exertional breathlessness; however, studies have also not shown consistent benefit, and larger trials are underway. 88 A starting dose of immediate release morphine 1.0-2.5 mg or hydromorphone 0.1 mg orally every 4-6 hours can be used as a starting dose. Escalation of dose and conversion to long acting formulations can be done in consultation with local Palliative Care experts. Benzodiazepines are not recommended for palliation of dyspnea based on a previous systematic review that did not identify a clear benefit in a variety of advanced lung diseases. 89
# Box 7. Symptom management
How should severe dyspnea be managed in patients with fibrotic ILD? Q8. How should intractable chronic cough be managed in patients with fibrotic ILD?
Cough is reported in up to 85% of patients with fibrotic ILD, 90,91 can lead to reduced health-related quality of life and social isolation and is an independent predictor of mortality. 90 Although the pathogenesis of cough has not been clearly established in patients with fibrotic ILD, increased sensitivity of sensory fibers to stretch and damage in the lungs is thought to play a role in IPF. 92 Cough is frequently attributed to ILD, but other factors may contribute to cough, with one study reporting that cough was related to a process other than the underlying ILD in up to 54% of patients. 93 Treating cough in patients with ILD is challenging and there are no high-quality studies that suggest a highly effective treatment for cough in ILD. In a small study of 43 patients, pirfenidone reduced cough frequency by 34% after 12 weeks of therapy. 94 A post-hoc analysis of recent pirfenidone clinical trials also suggested improvement in the prevalence of cough compared to placebo. 95 Opioids are frequently used to palliate cough in a variety of settings, but there are no randomized trials and only anecdotal reports of effectiveness in ILD. 85 An open-label trial of oral prednisolone at 40-60 mg daily for one month showed decreased cough severity in 6 IPF patients who had severe cough. 92 A phase II double blind crossover trial of low-dose thalidomide at 50-100 mg daily reported a significant improvement in cough-specific quality of life and in respiratory-related quality of life; 96 however, additional studies are needed to verify the efficacy and safety of this given the frequent contraindications and significant risk of adverse effects. The central-acting neuromodulator gabapentin, at doses up to 1800 mg per day, reduced cough severity in refractory chronic idiopathic cough in a blinded randomized controlled trial, 97 but has never been studied in ILD. Future trials are needed for these and other potential therapies of cough given the absence of any high quality data and the frequent toxicity of currently available options. Patient education, support, and advocacy Q9. What are the benefits of structured patient education and advocacy programs in fibrotic ILD? IPF and other fibrotic ILDs have a significant impact on patients' quality of life, family life, emotional and physical wellbeing. In many ILD centers, patient-centered management includes a large multidisciplinary team of physicians, nurses and other allied health professionals. 98 Patients rely on ILD nurses and physicians for support and information, but express the need for more accessible information on disease. 99 Patient advocacy groups can play an important role in supporting patients with chronic diseases, filling gaps in information and advocating for better care through different measures. A recent collaborative between physicians and advocacy group members identified several unmet needs in patients with IPF that could be filled by patient advocacy groups, including the need for improved access to reliable information, knowledgeable health care providers, access to treatment and holistic and palliative care. 100 Internet-based resources are easily and widely accessible tools that can facilitate patient-centered education and management; however, many IPF-related websites contain incorrect or outdated information and there is no way for patients to reliably identify which websites provide accurate information. 101 Self-management has been shown to be of benefit in COPD 102 and may similarly be of benefit in ILD despite the absence of supportive data. Patients should actively review websites for information such as when they were last updated, who sponsored the page and where the information originates. Patients should also be encouraged to discuss with their physician if the information they read conflicts with what they have learned in clinic. Physicians should also direct their patients to trustworthy medical information websites.
# Conclusion
Fibrotic ILDs are complex and heterogeneous diseases that have serious consequences on quality of life and survival. This position paper from the CTS Interstitial Lung Disease Clinical Assembly summarizes important issues and provides key messages relevant to the management of patients with fibrotic ILD. This work is limited by the lack of patient perspective, and ILD clinicians should remember that a patientcentered approach is of fundamental importance. Available evidence indicates the importance of a comprehensive approach to management that includes both pharmacologic and non-pharmacologic interventions that are ideally provided in a collaborative multidisciplinary setting.
# Acknowledgments
The authors would like to thank CTS and the Executive Committee of the Canadian Respiratory Guidelines Committee for their thoughtful comments and input: Samir Gupta, Chris Licskai and Louis-Philippe Boulet. We would also like to acknowledge with deep appreciation our
# Editorial independence
The CTS Interstitial Lung Disease Clinical Assembly is accountable to the CTS Respiratory Guidelines Committee and the CTS Board of Directors. The CTS Interstitial Lung Disease Clinical Assembly is functionally and editorially independent from any funding sources of the CTS and does not receive any direct funding from external sources. The CTS receives unrestricted grants that are combined into a central operating account to facilitate the knowledge translation activities of the CTS Clinical Assemblies. No funders played a role in the collection, review, analysis or interpretation of the scientific literature or in any decisions regarding the key messages presented in this document.
# Disclosures statement
Members of the CTS Interstitial Lung Disease Clinical Assembly declared potential conflicts of interest at the time of appointment and these were updated throughout the process in accordance with the CTS Conflict of Interest Disclosure Policy. Individual member conflict of interest statements are posted at https://cts-sct.ca/guideline-library/. | None | None |
2e29354b2cb1822c96d2a17706199b51a9245c1b | cma | None | Medical cannabinoid products are widely used in Canada to treat medical symptoms of all kinds, and gastrointestinal (GI) symptoms are among the most commonly cited reasons for use (1). Cannabis is also widely used recreationally (2), and legalization of recreational use has occurred in Canada.
Currently, cannabis is not an approved therapeutic product in Canada. However, health care practitioners may authorize the use of cannabis in various forms or synthetic cannabinoids for the relief of symptoms associated with a variety of disorders which have not responded to conventional medical treatments. These include pain and spasticity due to multiple sclerosis; severe nausea and vomiting related to cancer chemotherapy; loss of appetite and body weight in cancer patients and patients with HIV/AIDS; chronic noncancer pain (mainly neuropathic); severe refractory cancer-associated pain; insomnia and depressed mood associated with chronic diseases (HIV/ AIDS, chronic noncancer pain); and symptoms encountered in the palliative/end-of-life setting (3). Yet, evidence supporting the safety and efficacy of cannabis for the treatment of many of these conditions is often limited and inconsistent.
Certainly, a biological rationale exists for cannabinoids to have possible benefit for GI symptoms based on its known physiologic actions (3,4) but research in the field has been hampered by its historical illegality, plus the inability to patent a natural product which is widely available. However, there are also concerns regarding potential adverse effects of acute and chronic cannabis use including dependence, tolerance, psychiatric disorders, poor school or work performance, nervous system disorders, vascular and cardiac disorders, carcinogenesis and gastrointestinal disorders such as cannabis hyperemesis syndrome (CHS) and fibrosis progression in chronic hepatitis C.
The pharmacodynamics and pharmacokinetics of inhaled and ingested cannabis are reasonably well known and are reviewed elsewhere (3). However, very few randomized clinical trials of cannabis exist for GI indications, and the evidence that does exist is typically low or very low quality (such as case series or open-label studies). Further hampering a clear picture is the lack of standardization of cannabinoid products, which may contain hundreds of bioactive compounds, of which most have unknown effects. Two cannabinoids are better understood and are typically used to guide prescribing (specifically delta-9 tetrahydrocannabidiol and cannabidiol ), but these also vary substantially across strains of cannabis. Variability in inhalation or ingestion methods can also dramatically affect levels and effects of bioactive substances in the body.
Given these factors, the Canadian Association of Gastroenterology (CAG) has determined that guidance is required on the issues of relevance for clinical practitioners in the area of cannabis benefits and harms and particularly so with the anticipation of increased recreational use in Canada and more widespread medical use worldwide.
# METHODS
The lack of prospective clinical trial data for GI indications of cannabis precludes the possibility of meta-analysis in most cases. It was anticipated that the quality of evidence would generally be low or very low, and for some statements, only indirect evidence would exist. Where appropriate, a nonexhaustive evidence review was undertaken (MEDLINE, full text only, English language, humans only, with keywords 'cannab*' and 'marijuana or hemp' with the disease state) to inform the statements. Literature of significant importance is cited, but readers will be directed to appropriate recent reviews for more comprehensive information. It should also be noted that the CAG position statement is based on the literature as it stands at this time and could be subject to change in the future. As the literature grows in the field of cannabis and GI, especially if and when new clinical trial data become available, it is possible that the recommendations may change. The position statements were reviewed and approved by the CAG Practice Affairs committee.
# General Statements
# Statement
Medical cannabis use should not replace Health Canadaapproved medical therapy for treatment of any gastroenterologic or hepatologic disease if the approved therapy is available and has not been used.
# Commentary
Pharmaceutical agents approved by Health Canada have been evaluated to very high standards with both preclinical testing and prospective trials in order to obtain an indication for use. Cannabinoid medications have a very limited scope of approved GI-related indications at this time: treatment of severe nausea and vomiting associated with cancer chemotherapy (dronabinol, nabilone) (5,6), AIDS-related anorexia associated with weight loss (dronabinol) (5), and intractable pain related to advanced cancer (nabiximols) (7). However, medical cannabis (as dried flower for inhalation, oil or other oral forms) is not an approved therapeutic substance per Health Canada, but there is a variety of conditions for which health care practitioners can authorize use (not limited in scope as long as a practitioner justifies its use in a medical document) (3).
The difference between treating a disease and managing the symptoms of a disease must be stated because patients and much of the lay literature available to the public do not necessarily distinguish between these aspects. Since the evidence for disease-modifying treatment with cannabis is scant to nonexistent for most indications, we recommend using recognized and approved therapies over cannabis. This is especially important in diseases where the risk of significant morbidity may occur with untreated or poorly treated disease (e.g., viral hepatitis, autoimmune hepatitis, inflammatory bowel disease, GI malignancies) and for which effective and approved treatments exist. Concurrent use of cannabis for symptom control alongside approved therapies may be reasonable, provided the risk of harm appears low.
# Statement
If patients decide to use cannabis recreationally or for a medical reason, they should only use product from a Canadian licensed producer (LP) to ensure quality, lack of contamination, and reliable potency information on the product.
# Commentary
Cannabis grown outside of licensed production facilities is typically not tested for contaminants, which may include fungi, pesticides or other adulterants (8). This is of particular concern if a patient is immunosuppressed. Dried flower or cannabis oil from LPs also has accurate information on potency of THC and CBD, which is essential for medical dosing. Finally, unregulated cannabis products (with the exception of authorized home production) are illegal.
# Inflammatory Bowel Disease
# Statement
Cannabis does not appear to alter the course of disease in IBD (for better or worse) based on current evidence.
# Commentary
Cannabis has long been described in terms of its ability to ameliorate a variety of gastrointestinal symptoms including anorexia, nausea, abdominal pain and diarrhea (9). These properties could potentially make it an attractive treatment for the common gastrointestinal symptoms associated with inflammatory bowel disease (IBD).
Cannabis as a potential therapeutic option that could target the aberrant gastrointestinal immune response associated with IBD is not without biologic plausibility. The gastrointestinal tract is replete with endocannabinoid receptors that have been demonstrated to participate in the regulation of motility and maintenance of the epithelial barrier (10,11). Moreover, amelioration of inflammation in a murine ileitis model has been demonstrated when the endogenous cannabinoid 2 receptor (CB2R) was stimulated with a receptor specific ligand (11).
Cannabidiol (CBD) is a key component of cannabis that lacks psychotropic properties but is likely responsible for many of the gastrointestinal effects of cannabis. It has recently been demonstrated in vitro to reduce inflammatory cytokine expression from human colonic cells of patients with IBD (12).
Data in humans with IBD have largely focused, until recently, on observational studies evaluating the demography of patients and the rationale for the use of cannabis in this patient population (13)(14)(15)(16)(17).
In one prospective study, 12% of patients with IBD were active users of cannabis, and 39% were past users. Of the users, 16% used for symptom control, the majority of whom reported a subjective benefit (16). In a cross-sectional study of Canadian IBD patients who used cannabis for symptom control, users were statistically more likely to have a history of chronic analgesic utilization, use other complementary therapies and have a history of abdominal surgery (15). Similarly, the self-reported use of cannabis was found to be associated with a history of surgical resection for Crohn's disease (CD) in a Canadian study (17). The association with abdominal surgery must be interpreted cautiously because it may reflect a desire for symptom control in a cohort of patients with more disabling symptoms related to a potentially more aggressive disease course rather than implying causality. Nevertheless, in the majority of studies, a significant proportion of patients subjectively felt that cannabis use was associated with improvements in symptom control. Moreover, users in the study by Lal et al. were more likely than nonusers to be interested in participating in a clinical trial evaluating cannabis use for the treatment of IBD (15).
Perhaps the most important question facing gastroenterologists is whether there is evidence to support the use of cannabis or cannabinoid as a therapeutic agent that influences the inflammatory disease activity, rather than just symptoms, in patients with IBD. This is an arena in which there is a relative paucity of data to guide clinicians, and a comprehensive overview is beyond the scope of this review.
The first study evaluating this question was a retrospective Israeli study, which reported the clinical symptoms and need for surgery in 30 patients with CD who used inhaled cannabis. The disease activity, as measured by a Harvey Bradshaw Index (HBI), was lower in patients who used cannabis, but no objective measures were otherwise recorded (18). The same group then conducted an eight-week prospective, placebo-controlled trial in 21 medically refractory CD patients comparing the use of inhaled cannabis cigarettes containing 115 mg of tetrahydrocannabinol (THC) with cigarettes from which THC had been extracted. At the end of the study, significantly more patients treated with THC achieved a 100-point reduction in the Crohn's disease activity index (CDAI) than those treated with THC-free cigarettes (19). The only objective measure of disease activity that was assessed was C-reactive protein which did not change over the study duration in either treatment group. The same group evaluated CBD alone as a therapeutic agent in a placebo-controlled, randomized controlled trial (RCT) in 20 patients with medically refractory CD and found that no change in the CDAI was observed over an eight-week period (20). All three of these studies were supported by an Israeli licensed producer of cannabis.
A multi-centre, double-blind randomized controlled trial from the United Kingdom evaluated 60 patients with mild to moderate ulcerative colitis who were treated with a CBD-rich botanical extract or placebo over a 10 week period. The primary endpoint was the proportion of patients in remission at the end of the study. A per-protocol analysis was required due to a higher proportion of protocol violations in the CBD-treated patients due to higher rates of non-adherence and adverse events in this group. By intention to treat analysis, the rates of clinical remission were not different between the two groups. In the per-protocol analysis, there was a statistically significant reduction in the partial Mayo score in the CBD treated group. However, the reduction in fecal calprotectin between the two groups did not differ by study end (21).
The most recent study was published in 2018 in abstract form only (22). The study was a randomized controlled trial comparing inhaled cigarettes containing 11.5 mg of THC with placebo (THC-free) cigarettes in 28 patients with medically refractory moderate UC. The primary endpoints included both clinical disease activity indices and endoscopic disease activity. Both disease activity and the endoscopic disease severity decreased significantly in the THC-treated group compared with the placebo-treated group after eight weeks of therapy. However, it is worth noting the baseline CRP and fecal calprotectin levels were numerically higher in the placebo-treated groups than in the treatment group. Furthermore, the quality of the study cannot be fully ascertained until published in full.
At present, evidence that use of cannabis is associated with objective measures of reduction of inflammation is largely lacking and limited to small studies with insufficient power to detect a clinically relevant difference. Large, randomized, placebo-controlled trials assessing objective outcome measures using standardized preparations of cannabis with long-term follow-up of safety and effectiveness are therefore needed. There is insufficient evidence to recommend the use of cannabis as an anti-inflammatory treatment option for IBD at this time.
# Hepatology
# Statement
Although cannabinoids have been associated with improved outcomes in nonalcoholic fatty liver disease and alcoholic fatty liver disease in epidemiological studies, there is insufficient data to support their use in these diseases.
# Commentary
Currently, there is limited information regarding the use of cannabis in liver disease. The majority of studies are cohort studies with only one small RCT to date; the literature in this field was recently reviewed by Goyal et al. (23).
Endocannabinoids are thought to affect the liver in several ways. First, they are associated with fat accumulation through increased lipogenesis throughout the body and decreased rates of lipolysis (24), further augmented by appetite stimulation. Secondly, cannabinoids are thought to act on the CB1 and CB2 receptors. The CB1 receptors are thought to be profibrotic (25) and associated with the development of nonalcoholic fatty liver disease (NAFLD) (26) and steatosis (27). On the other hand, CB2 receptors, which are upregulated in chronic liver disease (28), are thought to be protective against fibrosis but can increase steatosis (29).
# Alcoholic Liver Disease (ALD)
The use of cannabinoids with ALD may have a possible protective effect. In a mouse model, cannabinoids reduced inflammation, oxidative stress and steatosis in ALD (30). Current human data are based on analysis of the 2014 National Inpatient Sample (NIS) of patients with a history of past/current abusive alcohol use based on ICD-9 codes. In this cohort study, cannabis use was associated with decreased rates of alcoholic steatosis, hepatitis, cirrhosis and hepatocellular carcinoma (31). A major limitation of this study is that it is an administrative study reliant on correct coding for steatosis/hepatitis and cannabis use by ICD-9 codes, which may not be completely accurate. Further study in this area is needed.
# Nonalcoholic Fatty Liver Disease (NAFLD)
At this time, the only human studies looking at NAFLD are cross-sectional in nature using two American datasets: the NIS (32) and the National Health and Nutrition Examination Survey (NHANES) (33). In both studies, cannabis use was associated with a lower prevalence of NAFLD with odds ratios ranging between 0.49-0.68, with a potential dose-related effect (32). These studies are limited given that the diagnosis of NAFLD was made by either ICD-9 codes or abnormal liver tests with steatosis on ultrasound. Further, potential mechanisms of this effect have not been well established, and so further research is needed before a recommendation can be made on cannabis's potential use in NAFLD.
# Statement
Cannabis likely increases hepatic fibrosis and steatosis in patients mono-infected with hepatitis C, and so its use is not recommended.
# Commentary
At this point, there is no human data regarding the role of cannabis with chronic hepatitis B, but in vitro cannabis has no effect on the virus (34). The effect of cannabis in patients in chronic hepatitis C has been variable although in vitro; cannabinoids may have an antiviral effect on hepatitis C (34). Cannabis use in chronic hepatitis C has been associated with moderate to severe fibrosis (35), more rapid fibrosis progression (36) in two cohorts and higher rates of steatosis (37). Conversely, a more recent Canadian study found cannabis had no effect on steatosis nor fibrosis (38).
Historically, cannabis was used as an adjunct agent in hepatitis C treated with interferon and ribavirin. Cannabis use was linked with higher rates of treatment completion and cure (39,40). With the availability of extremely potent direct acting antiviral agents with minimal side effects, adjunct use of cannabis is not recommended.
In patients coinfected with hepatitis C and HIV, cannabis use was been found to reduce the rate of steatosis in a French cohort of 838 patients (41). Furthermore, this cohort suggests that cannabis can reduce the risk of insulin resistance in coinfected patients (42). The negative impact of cannabis on fibrosis seems to be attenuated in co-infected patients, with two North American cohort studies showing no association of smoking cannabis with advanced fibrosis (28,43). It should be noted that the Canadian series showed a possible signal of increased cannabis use being associated with higher risks of fibrosis progression (43). The different effects of cannabis between the co-infected groups and mono-infected groups is unclear, and further study is warranted.
# Statement
Cannabis or synthetic analogues are possibly hepatotoxic.
# Commentary
Cannabis has been associated with possible hepatotoxicity, with one small series showing an association with mildly abnormal ALT, AST and ALP levels (35-54%), hepatomegaly (57.7%) and splenomegaly (73.1%), although other etiologies of liver disease were not assessed in this study (44). There have been four case reports of liver failure associated with the use of either cannabis or synthetic analogues (45)(46)(47)(48), but two of the cases had other more likely etiologies than cannabis or an analogue (45,46).
# Statement
Cannabis use is not an absolute contraindication to liver transplantation, but its use should be assessed on a case by case basis; in the context of other addictions, cannabis use is not recommended.
# Commentary
The use of cannabis in the context of liver transplantation remains controversial, with a minority of North American programs transplanting patients who use cannabis (49). Concerns of its use include possible impact on graft survival, medication compliance and addictions (50). However, cannabis use does not seem to have an adverse impact on liver transplant waitlist survival in two retrospective case series from Michigan (51) and San Francisco (52).
We would suggest that although cannabis use is not an absolute contraindication to transplantation, its use should be assessed on a case by case basis. We would discourage its use recreationally, and the risks and benefits would need to be considered in the context of medical use. If individuals have a history of addictions including street drugs or alcohol, we would recommend abstinence from cannabis and completion of any recommended treatment program by an addictions specialist.
In summary, the impact of cannabis on liver disease remains unclear and seems to have variable effect depending on the underlying disease. Potentially, cannabinoids may have a future role in the management of NAFLD and ALD, but more studies are required. Given the totality of evidence, its use in patients with hepatitis C is not recommended. Cannabis by itself should not be an absolute contraindication to transplant assessment but should be assessed on a case by case basis; in the context of other addictions, its use would not be recommended.
# GI Symptom Control
# Statement
Cannabis and cannabinoids may be helpful for GI symptom control, especially short-term use for refractory nausea, vomiting, diarrhea or abdominal pain where conventional therapies have failed.
# Commentary
This concept is based on the approved indications for cannabis (5,6) and its mechanism of action (4,53). A meta-analysis of randomized controlled trials of cannabinoid use for symptom control (54) found moderate-quality evidence to support the use of cannabinoids for the treatment of chronic pain and low-quality evidence suggesting that cannabinoids were associated with improvements in nausea and vomiting due to chemotherapy and weight gain in HIV infection. However, efficacy in non-GI related chronic pain disorders does not necessarily equate to efficacy in functional GI disorders, such as irritable bowel syndrome or functional dyspepsia. The vast majority of these trials used oral formulations of cannabinoids, and adverse effects (typically mild) related to cannabis were common. Clinical trials for other GI disorders are awaited, and long-term effectiveness and safety of cannabis for chronic gut symptoms (i.e., functional gut disorders) remain unknown. Thus, cannabis or cannabinoids should not be considered first-line treatment for nausea, vomiting unrelated to chemotherapy, or any other off-label GI symptom.
# Cannabis hyperemesis syndrome
# Statement
Cessation of cannabis or cannabinoid use is recommended as the mainstay of treatment for cannabis hyperemesis syndrome (CHS).
# Commentary
Cannabis hyperemesis syndrome is a recently recognized disorder of cyclic vomiting associated with chronic cannabis use (55). Other features of CHS may include morning nausea, abdominal pain or frequent hot showers or baths for symptom relief. Patients typically have a history of daily cannabis use, often for years, before the onset of symptoms. Use was reported as inhaled in almost all reports, with no reports of CHS in patients with exclusive oral ingestion of (nonsynthetic) cannabinoids. Although population-based incidence data are not available, patients commonly present to emergency departments and GI practices as one of the most frequent causes of chronic nausea and vomiting in younger people (56) (C. N. Andrews, personal communication, October 2018). The cause is unknown at this time, although hypotheses suggest the cause may be multifactorial; altered cannabinoid metabolism, complex pharmacodynamics at the CB-1 receptor and genetic variability are all proposed to play a role.
Small case series have suggested a possible benefit for intravenous haloperidol and topical capsaicin cream for acute exacerbations of CHS, with lesser apparent effectiveness of standard anti-emetic therapy, but no controlled trials have been performed (55,57). Cessation of cannabis use appears to be the best treatment, although the quality of evidence is similarly very low (55). However, cessation has the advantage of longterm resolution of symptoms in some cases. Many patients may have a co-existing cannabis use disorder, which may limit their ability to stop using it (58).
# Risk Reduction
# Statement
Recently published Lower-Risk Cannabis Use Guidelines (LRCUG) (59) systematically reviewed available evidence and made 10 major recommendations for lower-risk use: (1) the most effective way to avoid cannabis use-related health risks is abstinence; (2) avoid early age initiation of cannabis use; (3) choose low-potency tetrahydrocannabinol (THC) or balanced THC-to-cannabidiol (CBD) ratio cannabis products; (4) abstain from using synthetic cannabinoids; (5) avoid combusted cannabis inhalation and give preference to nonsmoking use methods; (6) avoid deep or other risky inhalation practices; (7) avoid high-frequency (e.g., daily or near-daily) cannabis use; (8) abstain from cannabis-impaired driving; (9) populations at higher risk for cannabis use-related health problems should avoid use altogether; and (10) avoid combining previously mentioned risk behaviors (e.g., early initiation and high-frequency use).
(e.g., use frequency, administration method) in the short term. Specific evidence-based medical benefits from medical cannabinoid use may supersede general risk management considerations on a case-by-case basis. Otherwise, risk reduction concerns should generally outweigh perceived benefit where there is a lack of evidence. Any licensed physician in Canada may authorize the use of cannabis for medical purposes for a patient; therefore, the CAG recommends physicians familiarize themselves with important aspects to consider before authorizing a patient for medical use. Moreover, with recreational use being so common, it also behooves physicians to understand the risks involved for patients and to be able to counsel them accordingly. | #
Medical cannabinoid products are widely used in Canada to treat medical symptoms of all kinds, and gastrointestinal (GI) symptoms are among the most commonly cited reasons for use (1). Cannabis is also widely used recreationally (2), and legalization of recreational use has occurred in Canada.
Currently, cannabis is not an approved therapeutic product in Canada. However, health care practitioners may authorize the use of cannabis in various forms or synthetic cannabinoids for the relief of symptoms associated with a variety of disorders which have not responded to conventional medical treatments. These include pain and spasticity due to multiple sclerosis; severe nausea and vomiting related to cancer chemotherapy; loss of appetite and body weight in cancer patients and patients with HIV/AIDS; chronic noncancer pain (mainly neuropathic); severe refractory cancer-associated pain; insomnia and depressed mood associated with chronic diseases (HIV/ AIDS, chronic noncancer pain); and symptoms encountered in the palliative/end-of-life setting (3). Yet, evidence supporting the safety and efficacy of cannabis for the treatment of many of these conditions is often limited and inconsistent.
Certainly, a biological rationale exists for cannabinoids to have possible benefit for GI symptoms based on its known physiologic actions (3,4) but research in the field has been hampered by its historical illegality, plus the inability to patent a natural product which is widely available. However, there are also concerns regarding potential adverse effects of acute and chronic cannabis use including dependence, tolerance, psychiatric disorders, poor school or work performance, nervous system disorders, vascular and cardiac disorders, carcinogenesis and gastrointestinal disorders such as cannabis hyperemesis syndrome (CHS) and fibrosis progression in chronic hepatitis C.
The pharmacodynamics and pharmacokinetics of inhaled and ingested cannabis are reasonably well known and are reviewed elsewhere (3). However, very few randomized clinical trials of cannabis exist for GI indications, and the evidence that does exist is typically low or very low quality (such as case series or open-label studies). Further hampering a clear picture is the lack of standardization of cannabinoid products, which may contain hundreds of bioactive compounds, of which most have unknown effects. Two cannabinoids are better understood and are typically used to guide prescribing (specifically delta-9 tetrahydrocannabidiol [THC] and cannabidiol [CBD]), but these also vary substantially across strains of cannabis. Variability in inhalation or ingestion methods can also dramatically affect levels and effects of bioactive substances in the body.
Given these factors, the Canadian Association of Gastroenterology (CAG) has determined that guidance is required on the issues of relevance for clinical practitioners in the area of cannabis benefits and harms and particularly so with the anticipation of increased recreational use in Canada and more widespread medical use worldwide.
# METHODS
The lack of prospective clinical trial data for GI indications of cannabis precludes the possibility of meta-analysis in most cases. It was anticipated that the quality of evidence would generally be low or very low, and for some statements, only indirect evidence would exist. Where appropriate, a nonexhaustive evidence review was undertaken (MEDLINE, full text only, English language, humans only, with keywords 'cannab*' and 'marijuana or hemp' with the disease state) to inform the statements. Literature of significant importance is cited, but readers will be directed to appropriate recent reviews for more comprehensive information. It should also be noted that the CAG position statement is based on the literature as it stands at this time and could be subject to change in the future. As the literature grows in the field of cannabis and GI, especially if and when new clinical trial data become available, it is possible that the recommendations may change. The position statements were reviewed and approved by the CAG Practice Affairs committee.
# General Statements
# Statement
Medical cannabis use should not replace Health Canadaapproved medical therapy for treatment of any gastroenterologic or hepatologic disease if the approved therapy is available and has not been used.
# Commentary
Pharmaceutical agents approved by Health Canada have been evaluated to very high standards with both preclinical testing and prospective trials in order to obtain an indication for use. Cannabinoid medications have a very limited scope of approved GI-related indications at this time: treatment of severe nausea and vomiting associated with cancer chemotherapy (dronabinol, nabilone) (5,6), AIDS-related anorexia associated with weight loss (dronabinol) (5), and intractable pain related to advanced cancer (nabiximols) (7). However, medical cannabis (as dried flower for inhalation, oil or other oral forms) is not an approved therapeutic substance per Health Canada, but there is a variety of conditions for which health care practitioners can authorize use (not limited in scope as long as a practitioner justifies its use in a medical document) (3).
The difference between treating a disease and managing the symptoms of a disease must be stated because patients and much of the lay literature available to the public do not necessarily distinguish between these aspects. Since the evidence for disease-modifying treatment with cannabis is scant to nonexistent for most indications, we recommend using recognized and approved therapies over cannabis. This is especially important in diseases where the risk of significant morbidity may occur with untreated or poorly treated disease (e.g., viral hepatitis, autoimmune hepatitis, inflammatory bowel disease, GI malignancies) and for which effective and approved treatments exist. Concurrent use of cannabis for symptom control alongside approved therapies may be reasonable, provided the risk of harm appears low.
# Statement
If patients decide to use cannabis recreationally or for a medical reason, they should only use product from a Canadian licensed producer (LP) to ensure quality, lack of contamination, and reliable potency information on the product.
# Commentary
Cannabis grown outside of licensed production facilities is typically not tested for contaminants, which may include fungi, pesticides or other adulterants (8). This is of particular concern if a patient is immunosuppressed. Dried flower or cannabis oil from LPs also has accurate information on potency of THC and CBD, which is essential for medical dosing. Finally, unregulated cannabis products (with the exception of authorized home production) are illegal.
# Inflammatory Bowel Disease
# Statement
Cannabis does not appear to alter the course of disease in IBD (for better or worse) based on current evidence.
# Commentary
Cannabis has long been described in terms of its ability to ameliorate a variety of gastrointestinal symptoms including anorexia, nausea, abdominal pain and diarrhea (9). These properties could potentially make it an attractive treatment for the common gastrointestinal symptoms associated with inflammatory bowel disease (IBD).
Cannabis as a potential therapeutic option that could target the aberrant gastrointestinal immune response associated with IBD is not without biologic plausibility. The gastrointestinal tract is replete with endocannabinoid receptors that have been demonstrated to participate in the regulation of motility and maintenance of the epithelial barrier (10,11). Moreover, amelioration of inflammation in a murine ileitis model has been demonstrated when the endogenous cannabinoid 2 receptor (CB2R) was stimulated with a receptor specific ligand (11).
Cannabidiol (CBD) is a key component of cannabis that lacks psychotropic properties but is likely responsible for many of the gastrointestinal effects of cannabis. It has recently been demonstrated in vitro to reduce inflammatory cytokine expression from human colonic cells of patients with IBD (12).
Data in humans with IBD have largely focused, until recently, on observational studies evaluating the demography of patients and the rationale for the use of cannabis in this patient population (13)(14)(15)(16)(17).
In one prospective study, 12% of patients with IBD were active users of cannabis, and 39% were past users. Of the users, 16% used for symptom control, the majority of whom reported a subjective benefit (16). In a cross-sectional study of Canadian IBD patients who used cannabis for symptom control, users were statistically more likely to have a history of chronic analgesic utilization, use other complementary therapies and have a history of abdominal surgery (15). Similarly, the self-reported use of cannabis was found to be associated with a history of surgical resection for Crohn's disease (CD) in a Canadian study (17). The association with abdominal surgery must be interpreted cautiously because it may reflect a desire for symptom control in a cohort of patients with more disabling symptoms related to a potentially more aggressive disease course rather than implying causality. Nevertheless, in the majority of studies, a significant proportion of patients subjectively felt that cannabis use was associated with improvements in symptom control. Moreover, users in the study by Lal et al. were more likely than nonusers to be interested in participating in a clinical trial evaluating cannabis use for the treatment of IBD (15).
Perhaps the most important question facing gastroenterologists is whether there is evidence to support the use of cannabis or cannabinoid as a therapeutic agent that influences the inflammatory disease activity, rather than just symptoms, in patients with IBD. This is an arena in which there is a relative paucity of data to guide clinicians, and a comprehensive overview is beyond the scope of this review.
The first study evaluating this question was a retrospective Israeli study, which reported the clinical symptoms and need for surgery in 30 patients with CD who used inhaled cannabis. The disease activity, as measured by a Harvey Bradshaw Index (HBI), was lower in patients who used cannabis, but no objective measures were otherwise recorded (18). The same group then conducted an eight-week prospective, placebo-controlled trial in 21 medically refractory CD patients comparing the use of inhaled cannabis cigarettes containing 115 mg of tetrahydrocannabinol (THC) with cigarettes from which THC had been extracted. At the end of the study, significantly more patients treated with THC achieved a 100-point reduction in the Crohn's disease activity index (CDAI) than those treated with THC-free cigarettes (19). The only objective measure of disease activity that was assessed was C-reactive protein which did not change over the study duration in either treatment group. The same group evaluated CBD alone as a therapeutic agent in a placebo-controlled, randomized controlled trial (RCT) in 20 patients with medically refractory CD and found that no change in the CDAI was observed over an eight-week period (20). All three of these studies were supported by an Israeli licensed producer of cannabis.
A multi-centre, double-blind randomized controlled trial from the United Kingdom evaluated 60 patients with mild to moderate ulcerative colitis who were treated with a CBD-rich botanical extract or placebo over a 10 week period. The primary endpoint was the proportion of patients in remission at the end of the study. A per-protocol analysis was required due to a higher proportion of protocol violations in the CBD-treated patients due to higher rates of non-adherence and adverse events in this group. By intention to treat analysis, the rates of clinical remission were not different between the two groups. In the per-protocol analysis, there was a statistically significant reduction in the partial Mayo score in the CBD treated group. However, the reduction in fecal calprotectin between the two groups did not differ by study end (21).
The most recent study was published in 2018 in abstract form only (22). The study was a randomized controlled trial comparing inhaled cigarettes containing 11.5 mg of THC with placebo (THC-free) cigarettes in 28 patients with medically refractory moderate UC. The primary endpoints included both clinical disease activity indices and endoscopic disease activity. Both disease activity and the endoscopic disease severity decreased significantly in the THC-treated group compared with the placebo-treated group after eight weeks of therapy. However, it is worth noting the baseline CRP and fecal calprotectin levels were numerically higher in the placebo-treated groups than in the treatment group. Furthermore, the quality of the study cannot be fully ascertained until published in full.
At present, evidence that use of cannabis is associated with objective measures of reduction of inflammation is largely lacking and limited to small studies with insufficient power to detect a clinically relevant difference. Large, randomized, placebo-controlled trials assessing objective outcome measures using standardized preparations of cannabis with long-term follow-up of safety and effectiveness are therefore needed. There is insufficient evidence to recommend the use of cannabis as an anti-inflammatory treatment option for IBD at this time.
# Hepatology
# Statement
Although cannabinoids have been associated with improved outcomes in nonalcoholic fatty liver disease and alcoholic fatty liver disease in epidemiological studies, there is insufficient data to support their use in these diseases.
# Commentary
Currently, there is limited information regarding the use of cannabis in liver disease. The majority of studies are cohort studies with only one small RCT to date; the literature in this field was recently reviewed by Goyal et al. (23).
Endocannabinoids are thought to affect the liver in several ways. First, they are associated with fat accumulation through increased lipogenesis throughout the body and decreased rates of lipolysis (24), further augmented by appetite stimulation. Secondly, cannabinoids are thought to act on the CB1 and CB2 receptors. The CB1 receptors are thought to be profibrotic (25) and associated with the development of nonalcoholic fatty liver disease (NAFLD) (26) and steatosis (27). On the other hand, CB2 receptors, which are upregulated in chronic liver disease (28), are thought to be protective against fibrosis but can increase steatosis (29).
# Alcoholic Liver Disease (ALD)
The use of cannabinoids with ALD may have a possible protective effect. In a mouse model, cannabinoids reduced inflammation, oxidative stress and steatosis in ALD (30). Current human data are based on analysis of the 2014 National Inpatient Sample (NIS) of patients with a history of past/current abusive alcohol use based on ICD-9 codes. In this cohort study, cannabis use was associated with decreased rates of alcoholic steatosis, hepatitis, cirrhosis and hepatocellular carcinoma (31). A major limitation of this study is that it is an administrative study reliant on correct coding for steatosis/hepatitis and cannabis use by ICD-9 codes, which may not be completely accurate. Further study in this area is needed.
# Nonalcoholic Fatty Liver Disease (NAFLD)
At this time, the only human studies looking at NAFLD are cross-sectional in nature using two American datasets: the NIS (32) and the National Health and Nutrition Examination Survey (NHANES) (33). In both studies, cannabis use was associated with a lower prevalence of NAFLD with odds ratios ranging between 0.49-0.68, with a potential dose-related effect (32). These studies are limited given that the diagnosis of NAFLD was made by either ICD-9 codes or abnormal liver tests with steatosis on ultrasound. Further, potential mechanisms of this effect have not been well established, and so further research is needed before a recommendation can be made on cannabis's potential use in NAFLD.
# Statement
Cannabis likely increases hepatic fibrosis and steatosis in patients mono-infected with hepatitis C, and so its use is not recommended.
# Commentary
At this point, there is no human data regarding the role of cannabis with chronic hepatitis B, but in vitro cannabis has no effect on the virus (34). The effect of cannabis in patients in chronic hepatitis C has been variable although in vitro; cannabinoids may have an antiviral effect on hepatitis C (34). Cannabis use in chronic hepatitis C has been associated with moderate to severe fibrosis (35), more rapid fibrosis progression (36) in two cohorts and higher rates of steatosis (37). Conversely, a more recent Canadian study found cannabis had no effect on steatosis nor fibrosis (38).
Historically, cannabis was used as an adjunct agent in hepatitis C treated with interferon and ribavirin. Cannabis use was linked with higher rates of treatment completion and cure (39,40). With the availability of extremely potent direct acting antiviral agents with minimal side effects, adjunct use of cannabis is not recommended.
In patients coinfected with hepatitis C and HIV, cannabis use was been found to reduce the rate of steatosis in a French cohort of 838 patients (41). Furthermore, this cohort suggests that cannabis can reduce the risk of insulin resistance in coinfected patients (42). The negative impact of cannabis on fibrosis seems to be attenuated in co-infected patients, with two North American cohort studies showing no association of smoking cannabis with advanced fibrosis (28,43). It should be noted that the Canadian series showed a possible signal of increased cannabis use being associated with higher risks of fibrosis progression (43). The different effects of cannabis between the co-infected groups and mono-infected groups is unclear, and further study is warranted.
# Statement
Cannabis or synthetic analogues are possibly hepatotoxic.
# Commentary
Cannabis has been associated with possible hepatotoxicity, with one small series showing an association with mildly abnormal ALT, AST and ALP levels (35-54%), hepatomegaly (57.7%) and splenomegaly (73.1%), although other etiologies of liver disease were not assessed in this study (44). There have been four case reports of liver failure associated with the use of either cannabis or synthetic analogues (45)(46)(47)(48), but two of the cases had other more likely etiologies than cannabis or an analogue (45,46).
# Statement
Cannabis use is not an absolute contraindication to liver transplantation, but its use should be assessed on a case by case basis; in the context of other addictions, cannabis use is not recommended.
# Commentary
The use of cannabis in the context of liver transplantation remains controversial, with a minority of North American programs transplanting patients who use cannabis (49). Concerns of its use include possible impact on graft survival, medication compliance and addictions (50). However, cannabis use does not seem to have an adverse impact on liver transplant waitlist survival in two retrospective case series from Michigan (51) and San Francisco (52).
We would suggest that although cannabis use is not an absolute contraindication to transplantation, its use should be assessed on a case by case basis. We would discourage its use recreationally, and the risks and benefits would need to be considered in the context of medical use. If individuals have a history of addictions including street drugs or alcohol, we would recommend abstinence from cannabis and completion of any recommended treatment program by an addictions specialist.
In summary, the impact of cannabis on liver disease remains unclear and seems to have variable effect depending on the underlying disease. Potentially, cannabinoids may have a future role in the management of NAFLD and ALD, but more studies are required. Given the totality of evidence, its use in patients with hepatitis C is not recommended. Cannabis by itself should not be an absolute contraindication to transplant assessment but should be assessed on a case by case basis; in the context of other addictions, its use would not be recommended.
# GI Symptom Control
# Statement
Cannabis and cannabinoids may be helpful for GI symptom control, especially short-term use for refractory nausea, vomiting, diarrhea or abdominal pain where conventional therapies have failed.
# Commentary
This concept is based on the approved indications for cannabis (5,6) and its mechanism of action (4,53). A meta-analysis of randomized controlled trials of cannabinoid use for symptom control (54) found moderate-quality evidence to support the use of cannabinoids for the treatment of chronic pain and low-quality evidence suggesting that cannabinoids were associated with improvements in nausea and vomiting due to chemotherapy and weight gain in HIV infection. However, efficacy in non-GI related chronic pain disorders does not necessarily equate to efficacy in functional GI disorders, such as irritable bowel syndrome or functional dyspepsia. The vast majority of these trials used oral formulations of cannabinoids, and adverse effects (typically mild) related to cannabis were common. Clinical trials for other GI disorders are awaited, and long-term effectiveness and safety of cannabis for chronic gut symptoms (i.e., functional gut disorders) remain unknown. Thus, cannabis or cannabinoids should not be considered first-line treatment for nausea, vomiting unrelated to chemotherapy, or any other off-label GI symptom.
# Cannabis hyperemesis syndrome
# Statement
Cessation of cannabis or cannabinoid use is recommended as the mainstay of treatment for cannabis hyperemesis syndrome (CHS).
# Commentary
Cannabis hyperemesis syndrome is a recently recognized disorder of cyclic vomiting associated with chronic cannabis use (55). Other features of CHS may include morning nausea, abdominal pain or frequent hot showers or baths for symptom relief. Patients typically have a history of daily cannabis use, often for years, before the onset of symptoms. Use was reported as inhaled in almost all reports, with no reports of CHS in patients with exclusive oral ingestion of (nonsynthetic) cannabinoids. Although population-based incidence data are not available, patients commonly present to emergency departments and GI practices as one of the most frequent causes of chronic nausea and vomiting in younger people (56) (C. N. Andrews, personal communication, October 2018). The cause is unknown at this time, although hypotheses suggest the cause may be multifactorial; altered cannabinoid metabolism, complex pharmacodynamics at the CB-1 receptor and genetic variability are all proposed to play a role.
Small case series have suggested a possible benefit for intravenous haloperidol and topical capsaicin cream for acute exacerbations of CHS, with lesser apparent effectiveness of standard anti-emetic therapy, but no controlled trials have been performed (55,57). Cessation of cannabis use appears to be the best treatment, although the quality of evidence is similarly very low (55). However, cessation has the advantage of longterm resolution of symptoms in some cases. Many patients may have a co-existing cannabis use disorder, which may limit their ability to stop using it (58).
# Risk Reduction
# Statement
Recently published Lower-Risk Cannabis Use Guidelines (LRCUG) (59) systematically reviewed available evidence and made 10 major recommendations for lower-risk use: (1) the most effective way to avoid cannabis use-related health risks is abstinence; (2) avoid early age initiation of cannabis use; (3) choose low-potency tetrahydrocannabinol (THC) or balanced THC-to-cannabidiol (CBD) ratio cannabis products; (4) abstain from using synthetic cannabinoids; (5) avoid combusted cannabis inhalation and give preference to nonsmoking use methods; (6) avoid deep or other risky inhalation practices; (7) avoid high-frequency (e.g., daily or near-daily) cannabis use; (8) abstain from cannabis-impaired driving; (9) populations at higher risk for cannabis use-related health problems should avoid use altogether; and (10) avoid combining previously mentioned risk behaviors (e.g., early initiation and high-frequency use).
(e.g., use frequency, administration method) in the short term. Specific evidence-based medical benefits from medical cannabinoid use may supersede general risk management considerations on a case-by-case basis. Otherwise, risk reduction concerns should generally outweigh perceived benefit where there is a lack of evidence. Any licensed physician in Canada may authorize the use of cannabis for medical purposes for a patient; therefore, the CAG recommends physicians familiarize themselves with important aspects to consider before authorizing a patient for medical use. Moreover, with recreational use being so common, it also behooves physicians to understand the risks involved for patients and to be able to counsel them accordingly.
# Acknowledgements
The authors would like to thank Ms. Lynn Wilsack for bibliographic assistance with this manuscript.
# Commentary
The LRCUG would generally apply to recreational use, while recognizing that medical use for GI disorders may require or result in noncompliance with select recommendation details
# Conflicts of Interest
CNA has received honoraria from Allergan, Lupin Pharma, and Pendopharm; he is on advisory boards for Allergan, Lupin Pharma and Newstrike Brands and has received research support from Allergan, Janssen, and Regeneron; he is a director of Callitas Health Inc. and a principal of Visceral Therapeutics, Inc. SD has received honoraria from Janssen, Abbvie, Takeda and Ferring, and he is on advisory boards for Janssen, Abbvie, Takeda, Ferring and Pfizer. BLF has received in-kind donation of Sativex from GW Pharma for NIH-and CIHR-funded projects related to cannabis use disorder, in-kind donation of product from Prairie Plant Systems for CIHR-funded studies related to impact of cannabis on driving, and funding from Canopy Health Innovation (grant and supply) for a project related to medical use of cannabis. BF has received research funding and support from and scientific consulting work for public entities only (e.g., CIHR, Health Canada). FT is on advisory boards for AbbVie Canada, Janssen Canada, Takeda, Pfizer and Akcea Therapeutics. MS has received honoraria from Allergan, Bionorica, Weber&Weber, Astellas, Falk-Foundation, Dr Schwabe and Bayer; he is on advisory boards for Bayer, Bionorica, Pfizer, MSD and is owner of Digesta Publishing. SEC is on the advisory board for Allergan and has received research support from Gilead Sciences, Genfit, Boehringer Ingelheim, Allergan and Bristol-Myers Squibb. | None | None |
710873b964e397d3bbaec1daba8f253a25a493de | cma | None | # Background
Merkel cell carcinoma (MCC) is a rare neuroendocrine tumour that accounts for a small proportion of cutaneous malignancies. MCC typically presents as a fleshy nodule with a red or blue discoloration 1 and the majority occur in the head and neck region 2 . Patients are generally older (mean patient age 75 years), often immunocompromised, fair-skinned women 3,4 . Ultraviolet radiation may be an etiological factor in MCC as most tumours are located on sun-exposed areas of the skin 5,6 . Heath developed the AEIOU mnemonic for clinical features associated with Merkel cell carcinoma. In his study 89% of patients presented with 3 or more of the AEIOU clinical features (asymptomatic, expanding rapidly, immune suppressed, older than 50 years of age, UV exposed site) 7 . There is mounting evidence that the tumour is due to reactivation of a latent viral infection, as polyomavirus particles are present in the majority of cases (i.e., up to 80%) 1 .
Merkel cell carcinoma is an aggressive tumour associated with a high rate of recurrence and carries a poor prognosis. The overall 5-year survival rates range from 30 to 64% 5,8 . The local recurrence rate is 26-44% after primary treatment. As many as 30% of patients have regional lymph node involvement at the time of diagnosis with a 55% rate of regional lymph node relapse after treatment and a 34-49% rate of distant metastasis . There have been reports of patients with spontaneous resolution of MCC . Almost all patients with visceral metastasis (stage IV) eventually die of the disease 17 . Given the relative rarity of the tumour, no large multicentre randomized trials have been conducted to assess staging, treatment modality, recurrence rate, and overall survival. Therefore, there is little evidence to guide practice for MCC. The purpose of this guideline is to provide recommendations on the management of MCC in Alberta. Whenever possible recommendations are evidence-based and when insufficient evidence exists provincial consensus has been used to guide practice.
# Guideline Questions
- What is the widely accepted staging classification for Merkel cell carcinoma (MCC)?
- What is the most appropriate treatment for MCC Stage I-IV?
- What are the management strategies for recurrence of MCC?
- How should a patient with MCC be followed?
# Search Strategy
The MEDLINE, CINAHL, Cochrane, ASCO abstracts and proceedings, and PubMed databases were searched for practice guidelines, systematic reviews, and clinical trials relevant to the topic. In addition, individual guideline organizations were searched for relevant practice guidelines. Search terms included 'Merkel cell carcinoma' and 'skin or cutaneous'. Non-English publications were excluded, as well as publications that included less than ten patients with Merkel cell carcinoma. The original search included publications from the year 1966 and onward with subsequent updates covering publications from the date of the last search through the date on which the update was conducted. The latest update searched MEDLINE and PubMed databases (January 2015 through December 2018) and retrieved 261 articles. A total of 12 relevant articles were identified. In addition, four clinical practice guidelines were identified from European Dermatology Forum and European Association of Dermato-Oncology, Fred Hutchinson Cancer Research Center, the National Comprehensive Cancer Network and the National Institute for Health and Care Excellence.
# Target Population
The recommendations outlined in this guideline apply to adults over the age of 18 years with Merkel cell carcinoma of the skin. Different principles may apply to patients with other cutaneous malignancies (i.e., melanoma, basal cell carcinoma, etc.) and those with Merkel cell carcinoma of non-cutaneous origin or who present with metastatic Merkel cell carcinoma from an unknown primary. Different principles may apply to pediatric patients as well.
# Recommendations
Merkel cell carcinoma is an uncommon cancer and there is a lack of strong evidence to guide practice. Recommendations included are based on available evidence (e.g., poor quality evidence such as case series) and Provincial Tumour Team consensus. Treatment should be individualized based on patients and disease factors.
# Staging and Work-up
- Patients should be staged using the 8 th Edition American Joint Committee on Cancer staging system for MCC, see Appendix A 18,19 . - History, physical examination, and relevant investigation should guide further treatment.
- Imaging where clinical evidence suggests metastases. FDG-PET/CT scan is preferred, body CT is an alternative if the former is not available.
# Summary of Treatment Options
The treatment of choice for MCC is surgical resection. The tumour is both radiosensitive and chemosensitive, raising the possibility of other strategies in treating this condition. As such patients would benefit from management in multidisciplinary settings.
# Surgery:
- Wide local excision (i.e., intra-operative margins of 2 cm if possible, with the final goal being histologically clear pathological margins) is recommended whenever possible. - Mohs micrographic surgery is appropriate as a tissue-sparing technique when the tumour is in a sensitive area such as head and neck area and there are concerns of functional impairment from too radical an excision, provided the tumour is de-bulked first and submitted for pathological review using permanent sections. Evaluation of re-excision specimens should include a comment to the extent of clear margins. - Sentinel lymph node biopsy (protocol below) should be performed simultaneously with excision if possible. - Standard requirements to be included in the pathology report have been defined by the College of American Pathologists and can be found in the Appendix B.
- The need for complete lymph node dissection should be at the discretion of the surgeon based on comorbidity factors, age, and whether there is a high probability of persistent disease
# Radiation:
- Local radiation therapy can be considered in patients who are deemed to be poor operative candidates, who refuse surgery, or who have metastatic disease. In those patients without distant metastatic disease, they are offered primary radiotherapy to a high dose (55-66 Gy to the primary site and the draining regional lymphatics, delivered in 2-2.5 Gy/ day fractions). Concurrent chemotherapy using cisplatin or carboplatin plus etoposide will be considered in these cases. - In patients with metastatic disease and uncontrolled primary disease, patients will be offered palliative radiotherapy to achieve local control. - Adjuvant radiation therapy to the primary site and to the regional lymph node basin should be considered, especially when high risk features are present, including T2 disease, surgical margins less than 0.5cm, lymphvascular invasion, or perineural invasion. All Mohs surgery patients should be consulted for discussion about radiotherapy, since margin status is usually unclear. Adjuvant treatment will be delivered to primary with or without nodes to a dose of 50-55Gy in 2-2.5Gy fractions. In cases with gross margin involvement, a boost will be considered. - As an alternative to adjuvant radiation therapy, observation following surgery could be considered in select patients (i.e., small primary, widely excised, no risk factors). - Other than on the face, wide margins of 5 cm around the primary site should be used, because of risk of satellite development.
# Chemotherapy:
- Adjuvant chemotherapy is not recommended unless administered to debulk disease with radiotherapy. - Chemotherapy can be used on a case-by-case basis for regional or disseminated disease:
- Cisplatin ± etoposide (regional or disseminated)
- Carboplatin ± etoposide (regional or disseminated)
- Topotecan (disseminated)
# Immunotherapy:
- Recommended option for disseminated disease: avelumab, pembrolizumab, nivolumab.
- Avelumab dose: 10 mg/kg every 2 weeks by intravenous infusion over 60 minutes.
# Summary of Clinical Scenarios
A. Clinical Node-Negative:
- Sentinel lymph node biopsy recommended prior to surgical removal of the primary tumour.
- Wide local excision with clear margins.
- Postoperative radiation therapy of the primary site or observation (limited to small primary lesions <1 cm, that have been widely excised and no adverse risk factors). - Positive sentinel lymph node biopsy:
- Recommended multidisciplinary tumour board consultation, baseline imagine, participation in clinical trial, and lymph node dissection and/or radiation therapy to the nodal basin. - Adjuvant radiation therapy after lymph node dissection for patients with multiple nodes and/or presence of extrascapsular extension. - Negative sentinel lymph node biopsy:
- Observation of nodal basin.
# B. Clinical Node-Positive:
- Confirm diagnosis by fine-needle aspiration or core biopsy with appropriate immunopanel.
- Recommend imaging with FDG PET/CT where possible.
- If no distant metastasis, recommend multidisciplinary tumour board consultation and lymph node dissection with radiation therapy (dose of 50-60 Gy if extracapsular extension is detected or multiple nodes involved). - Lymph node dissection is the preferred approach for first line treatment.
- Open biopsy to confirm initial negative biopsy may be considered.
# C. Metastatic:
- Multidisciplinary tumour board consultation to consider: immunotherapy preferred or combination of chemotherapy, radiation therapy or surgery as palliative care. - Full imaging work up.
- Management should be individually tailored.
- Clinical trial is preferred.
# Follow-up
- Physical exam including complete skin exam and regional lymph node exam.
- Imaging performed at the discretion of treating physician (FDG-PET/CT, MRI, neck/ chest/ abdomen/ pelvis CT). - Frequency:
- Year 1-2: every 4 months - Years 3-5: every 6 months
# Management of Recurrences
- Local or regional recurrences: individualize treatment.
- Disseminated recurrence: patients should be monitored closely for recurrence of locoregional or distant disease. Lymph node or distant metastatic disease has a uniformly grave prognosis; however, there may be a role for chemotherapy in prolonging survival.
- Given the complex issues in dealing with this aggressive tumour, patients are best served by being cared for in a tertiary care setting with a multidisciplinary approach.
# Sentinel Lymph Node Biopsy Protocol
Lymph node deposits of metastatic MCC may be difficult to identify on routine hematoxylin and eosin (H&E)-stained sections. As for melanoma and breast carcinoma, the use of immunohistochemistry has been shown to increase the sensitivity of identifying occult lymph node metastases 20 .
Based on recommendations from the College of American Pathologists 21 and discussions with M.D.
Anderson Cancer Center 22 , the following protocol is suggested:
- Bisect sentinel lymph node.
- If initial H&E section is negative, then cut 200 µm into block and repeat H&E stain.
- Perform anti-keratin immunohistochemistry, preferably using an antibody cocktail, including antibody against low-molecular weight keratin (e.g. Cam 5.2). - If any concerns regarding non-epithelial keratin staining, anti-cytokeratin 20 immunohistochemistry can be performed.
The number, size, and intra-nodal location of any metastatic deposits of MCC should be documented in the final pathology report (see Appendix B).
# Discussion
# Presentation and Work-Up
MCC is rarely suspected at the time of initial presentation. Heath developed the AEIOU mnemonic for clinical features associated with Merkel cell carcinoma. In his study 89% of patients presented with 3 or more of the AEIOU clinical features (asymptomatic, expanding rapidly, immune suppressed, older than 50 years of age, UV exposed site) 7 . It generally presents as cutaneous disease only, however, some patients present with evidence of regional or distant metastasis. The most common location of metastasis are the draining lymph node basin (27-60%), distant skin (9-30%), lung (10-23%), central nervous system (18%), bone (10-15%), and liver (30%) 23,24 . Other reported areas of distant metastasis include testis, pancreas, heart, bone marrow, pleura, parotid, gastrointestinal tract, prostate and bladder. The clinical differential diagnosis for MCC includes basal cell carcinoma, squamous cell carcinoma, cyst, pyogenic granuloma, amelanotic malignant melanoma, lymphoma cutis, and lipoma.
The work-up for MCC includes physical examination, biopsy, and imaging. The primary skin lesion is generally asymptomatic. Patients with disseminated disease may have constitutional symptoms (e.g. fatigue), localizing signs (e.g. hemoptysis, neurologic defect, adenopathy secondary to metastasis), or both. MCC most commonly presents as a blue or red solitary, dome-shaped nodule or firm plaque. Lesions are most often smaller than 2 cm in greatest dimension, but may exceed 15 cm in diameter 25 .
Lesions on the head and neck typically are smaller than lesions in other locations 5 . The most common locations for MCC include the head and neck region and the extremities; however, any mucosal or cutaneous site may be affected. The surface is often shiny with telangiectasias. Ulceration is uncommon.
Biopsy includes hematoxylin and eosin staining, as well as immunohistochemistry (i.e. CK-20, CK-7, and/or thyroid transcription factor-1). For diagnostic imaging FDG-PET/CT scans are indicated to detect distant metastases. A meta-analysis of six studies reported the sensitivity and specificity of FDG-PET/CT as 90% and 98%, respectively 26 . A prospective study found similar results with 56 scans of patients with MCC and that FDG-PET/CT imaging lead to a change in patient management in approximately a third of patients 27 . The following additional tests may also be indicated: sentinel lymph node biopsy (SLNB) to determine the presence or absence of lymph node disease (e.g. all blue stained nodes and nodes with radioactive counts exceeding 10% of the ex vivo count of the hottest lymph node), and additional studies as clinically indicated (i.e. CT scan of chest/abdomen).
# Treatment
MCC is an uncommon skin cancer in the larger group of small cell neuroendocrine tumours and therefore there is limited evidence to guide practice for MCC. While the most common neuroendocrine tumour, small cell lung cancer, has a variety of treatment modalities including hypoor hyper-fractionated radiation therapy with concurrent chemotherapy, chemotherapy alone, prophylactic whole brain radiotherapy, and consolidative radiation for responders to chemotherapy, it is not clear what the optimal treatment modalities, combination, sequencing, and techniques are for MCC.
Primary therapy for MCC consists of surgery, including wide local excision with intra-operative margins of 2 cm when possible (at least 1 cm margin) 3 , to achieve histologically clear pathological margins whenever possible. Mohs micrographic surgery can be considered as a tissue-sparing technique when the tumour is located in an area such as the head and neck where extensive surgery may lead to functional impairment or greatly affect cosmesis 28,29 . Nodal assessment with SLNB should be performed simultaneously with excision if possible, as information gained from the biopsy predicts the need for further treatment 30 . A SEER analysis of 1193 patients with stage I-II MCC showed that five-year MCC-specific survival was increased in patients who underwent SLNB as compared to those who didn't (79.2% vs. 73.8%; p=0.004) 31 . A meta-analysis, of seven studies and found SLNB significantly predicted better disease free survival for clinically node negative patients than nodal observation (HR 1.61, 95% CI 1.05-2.46) 32 . Completion lymph node dissection or radiation therapy or both should be given to the nodal basin if the SLNB is positive 33 . A review of a prospective database of 364 patients with stage I-III MCC who underwent complete resection with or without adjuvant local radiation therapy (23%), lymph node radiation therapy (23%), and chemotherapy (15%) found that among 108 recurrences, the majority (80%) occurred in patients who had clinically involved lymph nodes or patients who did not undergo pathologic lymph node evaluation 30 .
Definitive radiation therapy is a reasonable treatment for unresectable stage I-III MCC. A systemic review of 18 articles assessed the relapse and death rates of 48 stage I/II and 20 stage III MCC patients receiving either local or local-regional irradiation 34 . This study found that stage I/II patients treated with local irradiation had a relapse rate of 25% and 4% of patients died from MCC, and those treated with local-regional irradiation had a relapse rate of 21% and 8% died from MCC. Stage III patients treated with local-regional irradiation had a 60% relapse rate and 35% of patients died from MCC. A similar systemic review of 23 articles found a cumulative post radiation in-field recurrence rate of 11.7% 35 . There was no association between radiation dose and recurrence (p=0.197).
Adjuvant radiation therapy to the primary site should be considered for MCC 36 . An analysis of SEER data from patients with histologically confirmed MCC who underwent surgical resection with or without adjuvant radiation therapy evaluated MCC-specific and overall survival 37 . This study found that patients who received radiation therapy had improved overall survival (p=0.03) but not MCCspecific survival (p=0.26). A similar retrospective study found that on multivariate analysis, radiation therapy was associated with improved overall survival (HR 0.53, 95% CI 0.31-0.93; p=0.030) and MCC-specific survival (HR 0.42, 95% CI 0.26-0.70; p=0.001) 38 . Another retrospective study found the opposite to be true; improved cancer-specific survival (65% vs. 49%; p=0.03) but not overall survival (56% vs. 46%; p=0.20) with adjuvant radiation therapy in 180 patients with mostly localized MCC 39 . Adjuvant radiation therapy is indicated in patients with nodal disease (i.e., clinically positive or identified by SLNB). Patients who do not undergo SLNB can be considered for adjuvant radiation therapy 36 . A randomized controlled trial in stage I patients treated by wide local excision and local radiation therapy, plus regional adjuvant radiation therapy or observation found no significant improvement in overall survival (p=0.989) or progression-free survival (p=0.4) with regional radiation therapy. However, the regional recurrence rate was reduced (0% vs. 16.7%; p=0.007) with treatment 40 .
While there is limited evidence to support adjuvant chemotherapy in patients with MCC, adjuvant chemotherapy can be considered in patients with advanced disease including those with a positive SLNB 41 . Some patients do respond to chemotherapy, but toxicity must be weighed against the benefits. Agents that have been used include cisplatin or carboplatin, etoposide, and topotecan (in older patients) . Metastatic MCC should also be considered for chemotherapy 47 .
Systemic immunotherapy should be considered as a treatment option for disseminated disease.
Phase II of the JAVELIN Merkel 200 trial studied Avelumab in patients with metastatic MCC either as 1 st line therapy 48 or in chemotherapy-refractory MCC . In patients with no prior systemic therapy, after a median follow-up of 5.1 months (range 0.3-11.3 months), the overall response rate was 62.1%, and 83% of patients had a duration of response of at least 6 months 48 . In patients treated with avelumab after progression on chemotherapy, the overall response rate was 33.0% after a minimum follow up of 12 months. At the time of data cut-off, 72.4% of responses were ongoing 51 ___ pNX: Regional lymph nodes cannot be assessed (eg, previously removed for another reason or NOT removed for pathological evaluation) not examined pathologically ___ pN0: No regional lymph nodes metastasis detected on pathological evaluation ___ pN1: Metastasis in regional lymph node(s) ___ pN1a(sn): Clinically occult regional lymph node metastasis identified only by sentinel lymph node biopsy ___ pN1b: Clinically and/or radiologically detected regional lymph node metastasis # ___ pN2: In transit metastasis without lymph node metastasis ___ pN3: In transit metastasis with lymph node metastasis # note: the pN1b, subcategory is dependent on clinical information that may be unavailable to the pathologist. If this information is not available, the parent category (pN1) should be selected.
# Distant Metastasis (pM) (required only if confirmed pathologically in this case)
___ pM1: Distant metastasis microscopically confirmed ___ pM1a: Metastasis to distant skin, distant subcutaneous tissues, or distant lymph nodes microscopically confirmed ___ pM1b: Metastasis to lung, microscopically confirmed ___ pM1c: Metastasis to all other distant sites, microscopically confirmed Specify site(s), if known: ________________________________ +Additional Pathologic Findings (optional) +Specify: ______________________________ + Comment(s):
- Data elements preceded by this symbol are not required for accreditation purposes. These optional elements may be clinically important but are not yet validated or regularly used in patient management
# Appendix A:
AJCC (8th Edition) Anatomic Stage/Prognostic Groups for Merkel Cell Carcinoma 18 Primary Tumor (T) TX Primary tumor cannot be assessed T0 No evidence of primary tumor Tis In situ primary tumor T1 ≤ 2 cm maximum tumor diameter T2 > 2 cm but ≤ 5 cm maximum tumor diameter T3 > 5 cm maximum tumor diameter T4 Primary tumor invades bone, muscle, fascia, or cartilage Regional Lymph Nodes (N) Clinical (N) NX Regional nodes cannot be assessed N0 No regional node metastasis N1 Metastasis in regional lymph node(s) N2 In transit metastasis a without lymph node metastasis N3 In-transit metastasis a with lymph node metastasis Pathological (pN) pNX Regional lymph nodes cannot be assessed pN0 No regional lymph node metastasis pN1 Metastasis in regional lymph node(s) pN1a(sn) Clinically occult regional lymph node metastasis identified only by sentinel lymph node biopsy pN1a Clinically occult regional lymph node metastasis following lymph node dissection pN1b Clinically and/or radiologically detected regional lymph node metastasis microscopically confirmed pN2 In-transit metastasis a without lymph node metastasis pN3 In-transit metastasis a with lymph node metastasis
# Distant Metastasis (M) Clinical (M) M0
No distant metastasis M1 Distant metastasis M1a distant skin, distant subcutaneous tissues, or distant lymph nodes M1b to lung M1c to all other visceral sites Pathological (M) M0 No distant metastasis pM1 Distant metastasis microscopically confirmed pM1a Metastasis to distant skin, distant subcutaneous tissue, or distant lymph node(s), microscopically confirmed pM1b Metastasis to lung, microscopically confirmed pM1c Metastasis to all other distant sites, microscopically confirmed a In transit metastasis: a tumor distinct from the primary lesion and located either (1) between the primary lesion and the draining regional lymph nodes or (2) distal to the primary lesion. | # Background
Merkel cell carcinoma (MCC) is a rare neuroendocrine tumour that accounts for a small proportion of cutaneous malignancies. MCC typically presents as a fleshy nodule with a red or blue discoloration 1 and the majority occur in the head and neck region 2 . Patients are generally older (mean patient age 75 years), often immunocompromised, fair-skinned women 3,4 . Ultraviolet radiation may be an etiological factor in MCC as most tumours are located on sun-exposed areas of the skin 5,6 . Heath developed the AEIOU mnemonic for clinical features associated with Merkel cell carcinoma. In his study 89% of patients presented with 3 or more of the AEIOU clinical features (asymptomatic, expanding rapidly, immune suppressed, older than 50 years of age, UV exposed site) 7 . There is mounting evidence that the tumour is due to reactivation of a latent viral infection, as polyomavirus particles are present in the majority of cases (i.e., up to 80%) 1 .
Merkel cell carcinoma is an aggressive tumour associated with a high rate of recurrence and carries a poor prognosis. The overall 5-year survival rates range from 30 to 64% 5,8 . The local recurrence rate is 26-44% after primary treatment. As many as 30% of patients have regional lymph node involvement at the time of diagnosis with a 55% rate of regional lymph node relapse after treatment and a 34-49% rate of distant metastasis [9][10][11][12][13] . There have been reports of patients with spontaneous resolution of MCC [14][15][16] . Almost all patients with visceral metastasis (stage IV) eventually die of the disease 17 . Given the relative rarity of the tumour, no large multicentre randomized trials have been conducted to assess staging, treatment modality, recurrence rate, and overall survival. Therefore, there is little evidence to guide practice for MCC. The purpose of this guideline is to provide recommendations on the management of MCC in Alberta. Whenever possible recommendations are evidence-based and when insufficient evidence exists provincial consensus has been used to guide practice.
# Guideline Questions
• What is the widely accepted staging classification for Merkel cell carcinoma (MCC)?
• What is the most appropriate treatment for MCC Stage I-IV?
• What are the management strategies for recurrence of MCC?
• How should a patient with MCC be followed?
# Search Strategy
The MEDLINE, CINAHL, Cochrane, ASCO abstracts and proceedings, and PubMed databases were searched for practice guidelines, systematic reviews, and clinical trials relevant to the topic. In addition, individual guideline organizations were searched for relevant practice guidelines. Search terms included 'Merkel cell carcinoma' and 'skin or cutaneous'. Non-English publications were excluded, as well as publications that included less than ten patients with Merkel cell carcinoma. The original search included publications from the year 1966 and onward with subsequent updates covering publications from the date of the last search through the date on which the update was conducted. The latest update searched MEDLINE and PubMed databases (January 2015 through December 2018) and retrieved 261 articles. A total of 12 relevant articles were identified. In addition, four clinical practice guidelines were identified from European Dermatology Forum and European Association of Dermato-Oncology, Fred Hutchinson Cancer Research Center, the National Comprehensive Cancer Network and the National Institute for Health and Care Excellence.
# Target Population
The recommendations outlined in this guideline apply to adults over the age of 18 years with Merkel cell carcinoma of the skin. Different principles may apply to patients with other cutaneous malignancies (i.e., melanoma, basal cell carcinoma, etc.) and those with Merkel cell carcinoma of non-cutaneous origin or who present with metastatic Merkel cell carcinoma from an unknown primary. Different principles may apply to pediatric patients as well.
# Recommendations
Merkel cell carcinoma is an uncommon cancer and there is a lack of strong evidence to guide practice. Recommendations included are based on available evidence (e.g., poor quality evidence such as case series) and Provincial Tumour Team consensus. Treatment should be individualized based on patients and disease factors.
# Staging and Work-up
• Patients should be staged using the 8 th Edition American Joint Committee on Cancer staging system for MCC, see Appendix A 18,19 . • History, physical examination, and relevant investigation should guide further treatment.
• Imaging where clinical evidence suggests metastases. FDG-PET/CT scan is preferred, body CT is an alternative if the former is not available.
# Summary of Treatment Options
The treatment of choice for MCC is surgical resection. The tumour is both radiosensitive and chemosensitive, raising the possibility of other strategies in treating this condition. As such patients would benefit from management in multidisciplinary settings.
# Surgery:
• Wide local excision (i.e., intra-operative margins of 2 cm if possible, with the final goal being histologically clear pathological margins) is recommended whenever possible. • Mohs micrographic surgery is appropriate as a tissue-sparing technique when the tumour is in a sensitive area such as head and neck area and there are concerns of functional impairment from too radical an excision, provided the tumour is de-bulked first and submitted for pathological review using permanent sections. Evaluation of re-excision specimens should include a comment to the extent of clear margins. • Sentinel lymph node biopsy (protocol below) should be performed simultaneously with excision if possible. • Standard requirements to be included in the pathology report have been defined by the College of American Pathologists and can be found in the Appendix B.
• The need for complete lymph node dissection should be at the discretion of the surgeon based on comorbidity factors, age, and whether there is a high probability of persistent disease
# Radiation:
• Local radiation therapy can be considered in patients who are deemed to be poor operative candidates, who refuse surgery, or who have metastatic disease. In those patients without distant metastatic disease, they are offered primary radiotherapy to a high dose (55-66 Gy to the primary site and the draining regional lymphatics, delivered in 2-2.5 Gy/ day fractions). Concurrent chemotherapy using cisplatin or carboplatin plus etoposide will be considered in these cases. • In patients with metastatic disease and uncontrolled primary disease, patients will be offered palliative radiotherapy to achieve local control. • Adjuvant radiation therapy to the primary site and to the regional lymph node basin should be considered, especially when high risk features are present, including T2 disease, surgical margins less than 0.5cm, lymphvascular invasion, or perineural invasion. All Mohs surgery patients should be consulted for discussion about radiotherapy, since margin status is usually unclear. Adjuvant treatment will be delivered to primary with or without nodes to a dose of 50-55Gy in 2-2.5Gy fractions. In cases with gross margin involvement, a boost will be considered. • As an alternative to adjuvant radiation therapy, observation following surgery could be considered in select patients (i.e., small primary, widely excised, no risk factors). • Other than on the face, wide margins of 5 cm around the primary site should be used, because of risk of satellite development.
# Chemotherapy:
• Adjuvant chemotherapy is not recommended unless administered to debulk disease with radiotherapy. • Chemotherapy can be used on a case-by-case basis for regional or disseminated disease:
• Cisplatin ± etoposide (regional or disseminated)
• Carboplatin ± etoposide (regional or disseminated)
• Topotecan (disseminated)
# Immunotherapy:
• Recommended option for disseminated disease: avelumab, pembrolizumab, nivolumab.
• Avelumab dose: 10 mg/kg every 2 weeks by intravenous infusion over 60 minutes.
# Summary of Clinical Scenarios
A. Clinical Node-Negative:
• Sentinel lymph node biopsy recommended prior to surgical removal of the primary tumour.
• Wide local excision with clear margins.
• Postoperative radiation therapy of the primary site or observation (limited to small primary lesions <1 cm, that have been widely excised and no adverse risk factors). • Positive sentinel lymph node biopsy:
• Recommended multidisciplinary tumour board consultation, baseline imagine, participation in clinical trial, and lymph node dissection and/or radiation therapy to the nodal basin. • Adjuvant radiation therapy after lymph node dissection for patients with multiple nodes and/or presence of extrascapsular extension. • Negative sentinel lymph node biopsy:
• Observation of nodal basin.
# B. Clinical Node-Positive:
• Confirm diagnosis by fine-needle aspiration or core biopsy with appropriate immunopanel.
• Recommend imaging with FDG PET/CT where possible.
• If no distant metastasis, recommend multidisciplinary tumour board consultation and lymph node dissection with radiation therapy (dose of 50-60 Gy if extracapsular extension is detected or multiple nodes involved). • Lymph node dissection is the preferred approach for first line treatment.
• Open biopsy to confirm initial negative biopsy may be considered.
# C. Metastatic:
• Multidisciplinary tumour board consultation to consider: immunotherapy preferred or combination of chemotherapy, radiation therapy or surgery as palliative care. • Full imaging work up.
• Management should be individually tailored.
• Clinical trial is preferred.
# Follow-up
• Physical exam including complete skin exam and regional lymph node exam.
• Imaging performed at the discretion of treating physician (FDG-PET/CT, MRI, neck/ chest/ abdomen/ pelvis CT). • Frequency:
• Year 1-2: every 4 months • Years 3-5: every 6 months
# Management of Recurrences
• Local or regional recurrences: individualize treatment.
• Disseminated recurrence: patients should be monitored closely for recurrence of locoregional or distant disease. Lymph node or distant metastatic disease has a uniformly grave prognosis; however, there may be a role for chemotherapy in prolonging survival.
• Given the complex issues in dealing with this aggressive tumour, patients are best served by being cared for in a tertiary care setting with a multidisciplinary approach.
# Sentinel Lymph Node Biopsy Protocol
Lymph node deposits of metastatic MCC may be difficult to identify on routine hematoxylin and eosin (H&E)-stained sections. As for melanoma and breast carcinoma, the use of immunohistochemistry has been shown to increase the sensitivity of identifying occult lymph node metastases 20 .
Based on recommendations from the College of American Pathologists 21 and discussions with M.D.
Anderson Cancer Center 22 , the following protocol is suggested:
• Bisect sentinel lymph node.
• If initial H&E section is negative, then cut 200 µm into block and repeat H&E stain.
• Perform anti-keratin immunohistochemistry, preferably using an antibody cocktail, including antibody against low-molecular weight keratin (e.g. Cam 5.2). • If any concerns regarding non-epithelial keratin staining, anti-cytokeratin 20 immunohistochemistry can be performed.
The number, size, and intra-nodal location of any metastatic deposits of MCC should be documented in the final pathology report (see Appendix B).
# Discussion
# Presentation and Work-Up
MCC is rarely suspected at the time of initial presentation. Heath developed the AEIOU mnemonic for clinical features associated with Merkel cell carcinoma. In his study 89% of patients presented with 3 or more of the AEIOU clinical features (asymptomatic, expanding rapidly, immune suppressed, older than 50 years of age, UV exposed site) 7 . It generally presents as cutaneous disease only, however, some patients present with evidence of regional or distant metastasis. The most common location of metastasis are the draining lymph node basin (27-60%), distant skin (9-30%), lung (10-23%), central nervous system (18%), bone (10-15%), and liver (30%) 23,24 . Other reported areas of distant metastasis include testis, pancreas, heart, bone marrow, pleura, parotid, gastrointestinal tract, prostate and bladder. The clinical differential diagnosis for MCC includes basal cell carcinoma, squamous cell carcinoma, cyst, pyogenic granuloma, amelanotic malignant melanoma, lymphoma cutis, and lipoma.
The work-up for MCC includes physical examination, biopsy, and imaging. The primary skin lesion is generally asymptomatic. Patients with disseminated disease may have constitutional symptoms (e.g. fatigue), localizing signs (e.g. hemoptysis, neurologic defect, adenopathy secondary to metastasis), or both. MCC most commonly presents as a blue or red solitary, dome-shaped nodule or firm plaque. Lesions are most often smaller than 2 cm in greatest dimension, but may exceed 15 cm in diameter 25 .
Lesions on the head and neck typically are smaller than lesions in other locations 5 . The most common locations for MCC include the head and neck region and the extremities; however, any mucosal or cutaneous site may be affected. The surface is often shiny with telangiectasias. Ulceration is uncommon.
Biopsy includes hematoxylin and eosin staining, as well as immunohistochemistry (i.e. CK-20, CK-7, and/or thyroid transcription factor-1). For diagnostic imaging FDG-PET/CT scans are indicated to detect distant metastases. A meta-analysis of six studies reported the sensitivity and specificity of FDG-PET/CT as 90% and 98%, respectively 26 . A prospective study found similar results with 56 scans of patients with MCC and that FDG-PET/CT imaging lead to a change in patient management in approximately a third of patients 27 . The following additional tests may also be indicated: sentinel lymph node biopsy (SLNB) to determine the presence or absence of lymph node disease (e.g. all blue stained nodes and nodes with radioactive counts exceeding 10% of the ex vivo count of the hottest lymph node), and additional studies as clinically indicated (i.e. CT scan of chest/abdomen).
# Treatment
MCC is an uncommon skin cancer in the larger group of small cell neuroendocrine tumours and therefore there is limited evidence to guide practice for MCC. While the most common neuroendocrine tumour, small cell lung cancer, has a variety of treatment modalities including hypoor hyper-fractionated radiation therapy with concurrent chemotherapy, chemotherapy alone, prophylactic whole brain radiotherapy, and consolidative radiation for responders to chemotherapy, it is not clear what the optimal treatment modalities, combination, sequencing, and techniques are for MCC.
Primary therapy for MCC consists of surgery, including wide local excision with intra-operative margins of 2 cm when possible (at least 1 cm margin) 3 , to achieve histologically clear pathological margins whenever possible. Mohs micrographic surgery can be considered as a tissue-sparing technique when the tumour is located in an area such as the head and neck where extensive surgery may lead to functional impairment or greatly affect cosmesis 28,29 . Nodal assessment with SLNB should be performed simultaneously with excision if possible, as information gained from the biopsy predicts the need for further treatment 30 . A SEER analysis of 1193 patients with stage I-II MCC showed that five-year MCC-specific survival was increased in patients who underwent SLNB as compared to those who didn't (79.2% vs. 73.8%; p=0.004) 31 . A meta-analysis, of seven studies and found SLNB significantly predicted better disease free survival for clinically node negative patients than nodal observation (HR 1.61, 95% CI 1.05-2.46) 32 . Completion lymph node dissection or radiation therapy or both should be given to the nodal basin if the SLNB is positive 33 . A review of a prospective database of 364 patients with stage I-III MCC who underwent complete resection with or without adjuvant local radiation therapy (23%), lymph node radiation therapy (23%), and chemotherapy (15%) found that among 108 recurrences, the majority (80%) occurred in patients who had clinically involved lymph nodes or patients who did not undergo pathologic lymph node evaluation 30 .
Definitive radiation therapy is a reasonable treatment for unresectable stage I-III MCC. A systemic review of 18 articles assessed the relapse and death rates of 48 stage I/II and 20 stage III MCC patients receiving either local or local-regional irradiation 34 . This study found that stage I/II patients treated with local irradiation had a relapse rate of 25% and 4% of patients died from MCC, and those treated with local-regional irradiation had a relapse rate of 21% and 8% died from MCC. Stage III patients treated with local-regional irradiation had a 60% relapse rate and 35% of patients died from MCC. A similar systemic review of 23 articles found a cumulative post radiation in-field recurrence rate of 11.7% 35 . There was no association between radiation dose and recurrence (p=0.197).
Adjuvant radiation therapy to the primary site should be considered for MCC 36 . An analysis of SEER data from patients with histologically confirmed MCC who underwent surgical resection with or without adjuvant radiation therapy evaluated MCC-specific and overall survival 37 . This study found that patients who received radiation therapy had improved overall survival (p=0.03) but not MCCspecific survival (p=0.26). A similar retrospective study found that on multivariate analysis, radiation therapy was associated with improved overall survival (HR 0.53, 95% CI 0.31-0.93; p=0.030) and MCC-specific survival (HR 0.42, 95% CI 0.26-0.70; p=0.001) 38 . Another retrospective study found the opposite to be true; improved cancer-specific survival (65% vs. 49%; p=0.03) but not overall survival (56% vs. 46%; p=0.20) with adjuvant radiation therapy in 180 patients with mostly localized MCC 39 . Adjuvant radiation therapy is indicated in patients with nodal disease (i.e., clinically positive or identified by SLNB). Patients who do not undergo SLNB can be considered for adjuvant radiation therapy 36 . A randomized controlled trial in stage I patients treated by wide local excision and local radiation therapy, plus regional adjuvant radiation therapy or observation found no significant improvement in overall survival (p=0.989) or progression-free survival (p=0.4) with regional radiation therapy. However, the regional recurrence rate was reduced (0% vs. 16.7%; p=0.007) with treatment 40 .
While there is limited evidence to support adjuvant chemotherapy in patients with MCC, adjuvant chemotherapy can be considered in patients with advanced disease including those with a positive SLNB 41 . Some patients do respond to chemotherapy, but toxicity must be weighed against the benefits. Agents that have been used include cisplatin or carboplatin, etoposide, and topotecan (in older patients) [42][43][44][45][46] . Metastatic MCC should also be considered for chemotherapy 47 .
Systemic immunotherapy should be considered as a treatment option for disseminated disease.
Phase II of the JAVELIN Merkel 200 trial studied Avelumab in patients with metastatic MCC either as 1 st line therapy 48 or in chemotherapy-refractory MCC [49][50][51] . In patients with no prior systemic therapy, after a median follow-up of 5.1 months (range 0.3-11.3 months), the overall response rate was 62.1%, and 83% of patients had a duration of response of at least 6 months 48 . In patients treated with avelumab after progression on chemotherapy, the overall response rate was 33.0% after a minimum follow up of 12 months. At the time of data cut-off, 72.4% of responses were ongoing 51 ___ pNX: Regional lymph nodes cannot be assessed (eg, previously removed for another reason or NOT removed for pathological evaluation) not examined pathologically ___ pN0: No regional lymph nodes metastasis detected on pathological evaluation ___ pN1: Metastasis in regional lymph node(s) ___ pN1a(sn): Clinically occult regional lymph node metastasis identified only by sentinel lymph node biopsy ___ pN1b: Clinically and/or radiologically detected regional lymph node metastasis # ___ pN2: In transit metastasis without lymph node metastasis ___ pN3: In transit metastasis with lymph node metastasis # note: the pN1b, subcategory is dependent on clinical information that may be unavailable to the pathologist. If this information is not available, the parent category (pN1) should be selected.
# Distant Metastasis (pM) (required only if confirmed pathologically in this case)
___ pM1: Distant metastasis microscopically confirmed ___ pM1a: Metastasis to distant skin, distant subcutaneous tissues, or distant lymph nodes microscopically confirmed ___ pM1b: Metastasis to lung, microscopically confirmed ___ pM1c: Metastasis to all other distant sites, microscopically confirmed Specify site(s), if known: ________________________________ +Additional Pathologic Findings (optional) +Specify: ______________________________ + Comment(s):
+ Data elements preceded by this symbol are not required for accreditation purposes. These optional elements may be clinically important but are not yet validated or regularly used in patient management
# Appendix A:
AJCC (8th Edition) Anatomic Stage/Prognostic Groups for Merkel Cell Carcinoma 18 Primary Tumor (T) TX Primary tumor cannot be assessed T0 No evidence of primary tumor Tis In situ primary tumor T1 ≤ 2 cm maximum tumor diameter T2 > 2 cm but ≤ 5 cm maximum tumor diameter T3 > 5 cm maximum tumor diameter T4 Primary tumor invades bone, muscle, fascia, or cartilage Regional Lymph Nodes (N) Clinical (N) NX Regional nodes cannot be assessed N0 No regional node metastasis N1 Metastasis in regional lymph node(s) N2 In transit metastasis a without lymph node metastasis N3 In-transit metastasis a with lymph node metastasis Pathological (pN) pNX Regional lymph nodes cannot be assessed pN0 No regional lymph node metastasis pN1 Metastasis in regional lymph node(s) pN1a(sn) Clinically occult regional lymph node metastasis identified only by sentinel lymph node biopsy pN1a Clinically occult regional lymph node metastasis following lymph node dissection pN1b Clinically and/or radiologically detected regional lymph node metastasis microscopically confirmed pN2 In-transit metastasis a without lymph node metastasis pN3 In-transit metastasis a with lymph node metastasis
# Distant Metastasis (M) Clinical (M) M0
No distant metastasis M1 Distant metastasis M1a distant skin, distant subcutaneous tissues, or distant lymph nodes M1b to lung M1c to all other visceral sites Pathological (M) M0 No distant metastasis pM1 Distant metastasis microscopically confirmed pM1a Metastasis to distant skin, distant subcutaneous tissue, or distant lymph node(s), microscopically confirmed pM1b Metastasis to lung, microscopically confirmed pM1c Metastasis to all other distant sites, microscopically confirmed a In transit metastasis: a tumor distinct from the primary lesion and located either (1) between the primary lesion and the draining regional lymph nodes or (2) distal to the primary lesion. | None | None |
37cd5f8aaef4830d99bc1a3a2985950f7042a470 | cma | None | Note: It is the policy of the Canadian Psychiatric Association to review each position paper, policy statement and clinical practice guideline every five years after publication or last review. Any such document that has been published more than five years ago and does not explicitly state it has been reviewed and retained as an official document of the CPA, either with revisions or as originally published, should be considered as a historical reference document only.#
T he novel coronavirus disease 2019 (COVID- 19) pandemic has dramatically altered the lives of Canadians on various levels. As of the end of October 2020, COVID-19 cases surpassed the 100,000 count in Canada, with regional differences in the burden of the pandemic. As a result of necessary public health measures, psychiatrists and psychiatry residents have had to quickly adapt both in the personal and professional domains to a global situation that is rife with uncertainty and upheaval. This will continue to have implications with regards to general psychiatric care, the psychiatry workforce, access to psychiatric services, public health policies, and research agendas.
Patients with psychiatric disorders are differentially affected by COVID-19. Emerging evidence suggests patients suffering from psychiatric illness experience a distinct burden of the COVID-19 disease; several explanatory mechanisms have been posited to explain this association. First, both COVID-19 infection and psychiatric illness are associated with lower socioeconomic status and structural inequities. Second, patients with psychiatric illness experience many barriers to accessing health care as a result of stigma, reduced health literacy, or reduced ability to self-monitor for symptoms. 1,2 They also may have greater difficulty observing public health measures, such as hand hygiene, physical distancing, or selfisolation, due to symptom domains (e.g., behavioural disorganization, impaired judgement, lack of insight) or lack of necessary resources (e.g., poor housing conditions, low social supports). 3,4 Notably, within the inpatient psychiatric setting, greater infectious rates have been observed. It has been suggested that the design of the psychiatric inpatient units, wherein many spaces are shared and patients often interact in group activities, may render particularly challenging the implementation of COVID-19 infectious protocols. 5,6 Further, many patients experience generally poorer health status due to lifestyle factors (e.g., smoking) and comorbid general medical conditions (e.g., diabetes mellitus, lung disease). 2 Some psychotropic medications may confer a theoretical immunosuppressant effect (e.g., clozapine). 7 Finally, when patients with preexisting psychiatric illness become infected with COVID-19, they demonstrate a worsening of psychiatric symptoms and thus may warrant greater clinical attention.
Patients infected with COVID-19 are at risk of psychiatric sequelae. They may develop psychiatric symptoms both in the acute and post-acute phases of illness (e.g., post-traumatic stress and depressive symptoms). 8 Many medications used to treat COVID-19, such as antivirals, may not only have psychiatric side effects but may also interact with commonly used psychotropic medications. 9 In tandem, the pandemic has led to unprecedented levels of anxiety, uncertainty, and fear, with public health measures such as quarantine, physical distancing, and sheltering in place, contributing to increased levels of stress. In the first stage of the pandemic, there was a significant reduction in searches related to suicide, anxiety, and hopelessness; however, with prolonged public health measures and economic difficulties, there may be an increase in suicide rates, as was seen with the 2003 SARS epidemic in Hong Kong. 10 As such, there is an anticipated mental health wave of the pandemic, wherein it is projected that portions of the population that might have previously been mentally healthy will suffer mental health sequelae. Already there is evidence within the general public of lower psychological well-being, as well as higher scores of self-reported post-traumatic symptoms, anxiety, and depression. 8,11,12 Notably, children are felt to be vulnerable biologically and psychosocially to the impacts of the pandemic, with particular concern that measures may affect the development of prosocial skills longitudinally. 13 Early evidence from a survey of youth in clinical and community samples suggests that, in addition to a perceived deterioration in mental health, there are substantial mental health service disruptions and unmet support needs. 14 Taken together, this context has important implications for Canadian psychiatry across the domains of general psychiatric care, the psychiatric workforce, access to psychiatric services, public health policies, and research agendas.
# Recommendations
# General care for patients with psychiatric illness
- Psychiatrists represent important collaborators in the provision of high-quality care for patients infected with COVID-19, both in the acute and post-acute phases of the illness, as well as collaborators in the development of a pandemic response.
- COVID-19 testing efforts should involve targeted outreach to high-risk populations, including patients with psychiatric illness.
- Psychiatric care represents an important opportunity for public health promotion. Psychiatrists should aim to review up-to-date public health recommendations as part of routine care and psychoeducation with their patient population.
- There is evidence that chronic medical conditions are often not well managed in patients with psychiatric illness. During the pandemic, the care of chronic medical conditions has been delayed in general. Special consideration should be given to the risk that patients with psychiatric illness receive delayed cared for chronic medical conditions during the pandemic, thereby increasing the risk of worsening medical conditions.
- Special consideration should be given to the geriatric psychiatry population. This population remains particularly vulnerable to complications from COVID-19 infection, yet they may face greater difficulties accessing telehealth services, compounding the risk of social isolation. Governments, institutions, and psychiatrists should pay special attention to this population's vulnerability in developing the pandemic response.
- Special consideration should be given to the child and adolescent psychiatry population.
Although this population may experience milder symptoms and a lower fatality rate, secondary to COVID-19 infection, they may be more impacted psychosocially by public health measures during critical periods of development. However, this population may demonstrate greater acceptability of such service models as telepsychiatry and other forms of Internet-based care. 15 Governments, institutions, pediatricians, and psychiatrists should give special attention to this population's vulnerability in responding to mental health needs both during and following the pandemic.
- Special consideration should be given to the forensic psychiatry population. This population remains particularly vulnerable to COVID-19 infection, particularly within the setting of secure care, given the enclosed facilities, the requirement of high staff to patient ratio, and the behaviours of this group. 16 Institutions and psychiatrists should consider these particularities in developing infectious protocols that are adapted to this population.
# Psychiatric workforce
- Clinical facilities and institutions must ensure adequate access to necessary personal protective equipment and training for all staff providing psychiatric care.
- In the face of acute demand on the health care system, governments may seek to redeploy psychiatrists and psychiatry residents to other medical services for COVID-19 'relief care.' Psychiatric services remain essential services as part of the pandemic response, and redeployment measures should reflect this. Psychiatrists should be able to provide the same level of services, as some are predicting a wave of increased demand on mental health services as a result of the COVID-19 pandemic.
- In Canada, psychiatrists are relatively older, compared to other medical specialties' workforces. 17 As such, many have had to limit clinical activities within hospital settings due to the personal risk of COVID-19 infection. Regulatory agencies, professional psychiatric associations, and residency training programs should collaborate to ensure workforce planning measures are put in place to respond to the pandemic's anticipated impact on the psychiatry workforce. This may include temporary measures to adapt licensing requirements and advocacy surrounding the training needs of psychiatry residents, to ensure an adequate supply of new psychiatry graduates.
- Health care workers, who are currently frontline responders in this pandemic, have been found to be particularly at risk of psychological distress, depression, anxiety, and insomnia. Health care professionals are at greater risk of trauma and, therefore, post-traumatic stress disorder. 4 Professional organizations and institutions should provide additional support for physicians, including psychiatrists, to ensure their well-being during a time of greater risk and burden. This can include, but should not be limited to, resources for stress management, peer support, and access to mental health supports.
# Access to psychiatric services
- Telepsychiatry has been presented as a solution to mitigate the repercussions of physical distancing measures and isolation protocols, allowing for reduced person-to-person contact and therefore reduced propagation of the virus. 18,19 Not all patients with psychiatric illness may have the financial resources nor digital literacy to effectively use telehealth platforms on an outpatient basis. Thus, institutions, governments, and psychiatrists must promote clinical practices that do not disproportionately disadvantage patients with limited access to telehealth.
- Electroconvulsive therapy (ECT) is highly effective in treatment-resistant psychiatric illnesses ranging from mood disorders to psychotic disorders. During the pandemic, elective procedures have been suspended as a means of health systems planning for pandemic response. However, ECT is considered an urgent and necessary treatment in some cases.
As such, institutional administrators, anesthetists, and psychiatrists should work collaboratively to minimize the impact of public health measures on the continued provision of essential ECT treatments, as well as to develop a need-stratification model to ensure equitable use of this treatment modality in the face of more limited access. Other measures should also be considered when ECT is not available, such as, but not limited to, ketamine infusion and repetitive transcranial magnetic stimulation (rTMS).
- Psychiatrists should consider neuromodulation treatment protocols that reduce the risk of viral transmission (e.g., shorter duration of treatment, reduced frequency of in-person contact), while still ensuring safe and high-quality patient care. Psychiatrists and institutions should seek to ensure that treatment facilities used for neuromodulation promote safety precautions, including sanitation of equipment and adequate personal protective equipment.
- Inpatient psychiatric facilities should consider employing such technologies as videoconferencing and telehealth, to mitigate the impact of infectious protocols (e.g., discontinuation of visitors, isolation procedures) on the quality of psychiatric inpatient care.
- Adherence-promoting treatment strategies, such as long-acting injectable antipsychotics, should be preserved as essential clinical services, given their role in preventing relapse of psychiatric illnesses.
- Patients suffering from addictions may be at increased risk of relapse, substance use, overdose, withdrawal, reduced help seeking, disengagement, or non-adherence to treatment regimens in the face of greater anxiety, physical distancing, and social isolation experienced during the COVID-19 pandemic. Further, there may be reduced accessibility of outpatient addictions services and harm-reduction practices (e.g., safe injection sites). 4,20 As such, institutions, governments, and psychiatrists must promote clinical practices and innovative service delivery models that continue to meet the needs of this high-risk patient population.
- The anticipated impact of the pandemic on mental health systems, in addition to the changes in mental health human resources, will require the proactive development of policies aimed at mitigating the impact of these factors on the capacity of Canadian mental health systems.
# Public health policies
- Pandemic response plans must consider the mental health implications of the COVID-19 pandemic. Public health measures must balance both the risks and benefits to physical and mental domains of health for the general population, as well as more marginalized and at-risk populations, such as those with severe and persistent mental illness. Mental health expertise must be sought and consulted in the development of these policies.
- When patients with psychiatric illness do not conform to public health measures, such as quarantine, psychiatrists may be posed with the ethical and legal challenge of considering involuntary hospitalization to protect the public good or reporting the patient's behaviour to public health officials. 16 Ethical and legal expertise should be sought to develop policies to guide psychiatrists in these situations and to ensure that clinical practice respects patient rights. Legislations under public health law can be considered in addition to mental health law when applicable.
- Those recovering from COVID-19 infection, including health care workers, may face stigma by the general public. Public health education initiatives should seek to combat this stigma.
# Research agendas
- Research should seek to better elucidate the mechanisms through which patients with psychiatric illness experience a greater burden of COVID-19 disease and identify specific public health interventions for this clinical population, such as regular screening.
- The current pandemic represents an unprecedented opportunity to evaluate the impact of the crisis response on the quality and value of mental health outcomes. Research should be conducted to understand this impact as a means of informing policy responses to future public health crises. | Note: It is the policy of the Canadian Psychiatric Association to review each position paper, policy statement and clinical practice guideline every five years after publication or last review. Any such document that has been published more than five years ago and does not explicitly state it has been reviewed and retained as an official document of the CPA, either with revisions or as originally published, should be considered as a historical reference document only.#
T he novel coronavirus disease 2019 (COVID- 19) pandemic has dramatically altered the lives of Canadians on various levels. As of the end of October 2020, COVID-19 cases surpassed the 100,000 count in Canada, with regional differences in the burden of the pandemic. As a result of necessary public health measures, psychiatrists and psychiatry residents have had to quickly adapt both in the personal and professional domains to a global situation that is rife with uncertainty and upheaval. This will continue to have implications with regards to general psychiatric care, the psychiatry workforce, access to psychiatric services, public health policies, and research agendas.
Patients with psychiatric disorders are differentially affected by COVID-19. Emerging evidence suggests patients suffering from psychiatric illness experience a distinct burden of the COVID-19 disease; several explanatory mechanisms have been posited to explain this association. First, both COVID-19 infection and psychiatric illness are associated with lower socioeconomic status and structural inequities. Second, patients with psychiatric illness experience many barriers to accessing health care as a result of stigma, reduced health literacy, or reduced ability to self-monitor for symptoms. 1,2 They also may have greater difficulty observing public health measures, such as hand hygiene, physical distancing, or selfisolation, due to symptom domains (e.g., behavioural disorganization, impaired judgement, lack of insight) or lack of necessary resources (e.g., poor housing conditions, low social supports). 3,4 Notably, within the inpatient psychiatric setting, greater infectious rates have been observed. It has been suggested that the design of the psychiatric inpatient units, wherein many spaces are shared and patients often interact in group activities, may render particularly challenging the implementation of COVID-19 infectious protocols. 5,6 Further, many patients experience generally poorer health status due to lifestyle factors (e.g., smoking) and comorbid general medical conditions (e.g., diabetes mellitus, lung disease). 2 Some psychotropic medications may confer a theoretical immunosuppressant effect (e.g., clozapine). 7 Finally, when patients with preexisting psychiatric illness become infected with COVID-19, they demonstrate a worsening of psychiatric symptoms and thus may warrant greater clinical attention.
Patients infected with COVID-19 are at risk of psychiatric sequelae. They may develop psychiatric symptoms both in the acute and post-acute phases of illness (e.g., post-traumatic stress and depressive symptoms). 8 Many medications used to treat COVID-19, such as antivirals, may not only have psychiatric side effects but may also interact with commonly used psychotropic medications. 9 In tandem, the pandemic has led to unprecedented levels of anxiety, uncertainty, and fear, with public health measures such as quarantine, physical distancing, and sheltering in place, contributing to increased levels of stress. In the first stage of the pandemic, there was a significant reduction in searches related to suicide, anxiety, and hopelessness; however, with prolonged public health measures and economic difficulties, there may be an increase in suicide rates, as was seen with the 2003 SARS epidemic in Hong Kong. 10 As such, there is an anticipated mental health wave of the pandemic, wherein it is projected that portions of the population that might have previously been mentally healthy will suffer mental health sequelae. Already there is evidence within the general public of lower psychological well-being, as well as higher scores of self-reported post-traumatic symptoms, anxiety, and depression. 8,11,12 Notably, children are felt to be vulnerable biologically and psychosocially to the impacts of the pandemic, with particular concern that measures may affect the development of prosocial skills longitudinally. 13 Early evidence from a survey of youth in clinical and community samples suggests that, in addition to a perceived deterioration in mental health, there are substantial mental health service disruptions and unmet support needs. 14 Taken together, this context has important implications for Canadian psychiatry across the domains of general psychiatric care, the psychiatric workforce, access to psychiatric services, public health policies, and research agendas.
# Recommendations
# General care for patients with psychiatric illness
• Psychiatrists represent important collaborators in the provision of high-quality care for patients infected with COVID-19, both in the acute and post-acute phases of the illness, as well as collaborators in the development of a pandemic response.
• COVID-19 testing efforts should involve targeted outreach to high-risk populations, including patients with psychiatric illness.
• Psychiatric care represents an important opportunity for public health promotion. Psychiatrists should aim to review up-to-date public health recommendations as part of routine care and psychoeducation with their patient population.
• There is evidence that chronic medical conditions are often not well managed in patients with psychiatric illness. During the pandemic, the care of chronic medical conditions has been delayed in general. Special consideration should be given to the risk that patients with psychiatric illness receive delayed cared for chronic medical conditions during the pandemic, thereby increasing the risk of worsening medical conditions.
• Special consideration should be given to the geriatric psychiatry population. This population remains particularly vulnerable to complications from COVID-19 infection, yet they may face greater difficulties accessing telehealth services, compounding the risk of social isolation. Governments, institutions, and psychiatrists should pay special attention to this population's vulnerability in developing the pandemic response.
• Special consideration should be given to the child and adolescent psychiatry population.
Although this population may experience milder symptoms and a lower fatality rate, secondary to COVID-19 infection, they may be more impacted psychosocially by public health measures during critical periods of development. However, this population may demonstrate greater acceptability of such service models as telepsychiatry and other forms of Internet-based care. 15 Governments, institutions, pediatricians, and psychiatrists should give special attention to this population's vulnerability in responding to mental health needs both during and following the pandemic.
• Special consideration should be given to the forensic psychiatry population. This population remains particularly vulnerable to COVID-19 infection, particularly within the setting of secure care, given the enclosed facilities, the requirement of high staff to patient ratio, and the behaviours of this group. 16 Institutions and psychiatrists should consider these particularities in developing infectious protocols that are adapted to this population.
# Psychiatric workforce
• Clinical facilities and institutions must ensure adequate access to necessary personal protective equipment and training for all staff providing psychiatric care.
• In the face of acute demand on the health care system, governments may seek to redeploy psychiatrists and psychiatry residents to other medical services for COVID-19 'relief care.' Psychiatric services remain essential services as part of the pandemic response, and redeployment measures should reflect this. Psychiatrists should be able to provide the same level of services, as some are predicting a wave of increased demand on mental health services as a result of the COVID-19 pandemic.
• In Canada, psychiatrists are relatively older, compared to other medical specialties' workforces. 17 As such, many have had to limit clinical activities within hospital settings due to the personal risk of COVID-19 infection. Regulatory agencies, professional psychiatric associations, and residency training programs should collaborate to ensure workforce planning measures are put in place to respond to the pandemic's anticipated impact on the psychiatry workforce. This may include temporary measures to adapt licensing requirements and advocacy surrounding the training needs of psychiatry residents, to ensure an adequate supply of new psychiatry graduates.
• Health care workers, who are currently frontline responders in this pandemic, have been found to be particularly at risk of psychological distress, depression, anxiety, and insomnia. Health care professionals are at greater risk of trauma and, therefore, post-traumatic stress disorder. 4 Professional organizations and institutions should provide additional support for physicians, including psychiatrists, to ensure their well-being during a time of greater risk and burden. This can include, but should not be limited to, resources for stress management, peer support, and access to mental health supports.
# Access to psychiatric services
• Telepsychiatry has been presented as a solution to mitigate the repercussions of physical distancing measures and isolation protocols, allowing for reduced person-to-person contact and therefore reduced propagation of the virus. 18,19 Not all patients with psychiatric illness may have the financial resources nor digital literacy to effectively use telehealth platforms on an outpatient basis. Thus, institutions, governments, and psychiatrists must promote clinical practices that do not disproportionately disadvantage patients with limited access to telehealth.
• Electroconvulsive therapy (ECT) is highly effective in treatment-resistant psychiatric illnesses ranging from mood disorders to psychotic disorders. During the pandemic, elective procedures have been suspended as a means of health systems planning for pandemic response. However, ECT is considered an urgent and necessary treatment in some cases.
As such, institutional administrators, anesthetists, and psychiatrists should work collaboratively to minimize the impact of public health measures on the continued provision of essential ECT treatments, as well as to develop a need-stratification model to ensure equitable use of this treatment modality in the face of more limited access. Other measures should also be considered when ECT is not available, such as, but not limited to, ketamine infusion and repetitive transcranial magnetic stimulation (rTMS).
• Psychiatrists should consider neuromodulation treatment protocols that reduce the risk of viral transmission (e.g., shorter duration of treatment, reduced frequency of in-person contact), while still ensuring safe and high-quality patient care. Psychiatrists and institutions should seek to ensure that treatment facilities used for neuromodulation promote safety precautions, including sanitation of equipment and adequate personal protective equipment.
• Inpatient psychiatric facilities should consider employing such technologies as videoconferencing and telehealth, to mitigate the impact of infectious protocols (e.g., discontinuation of visitors, isolation procedures) on the quality of psychiatric inpatient care.
• Adherence-promoting treatment strategies, such as long-acting injectable antipsychotics, should be preserved as essential clinical services, given their role in preventing relapse of psychiatric illnesses.
• Patients suffering from addictions may be at increased risk of relapse, substance use, overdose, withdrawal, reduced help seeking, disengagement, or non-adherence to treatment regimens in the face of greater anxiety, physical distancing, and social isolation experienced during the COVID-19 pandemic. Further, there may be reduced accessibility of outpatient addictions services and harm-reduction practices (e.g., safe injection sites). 4,20 As such, institutions, governments, and psychiatrists must promote clinical practices and innovative service delivery models that continue to meet the needs of this high-risk patient population.
• The anticipated impact of the pandemic on mental health systems, in addition to the changes in mental health human resources, will require the proactive development of policies aimed at mitigating the impact of these factors on the capacity of Canadian mental health systems.
# Public health policies
• Pandemic response plans must consider the mental health implications of the COVID-19 pandemic. Public health measures must balance both the risks and benefits to physical and mental domains of health for the general population, as well as more marginalized and at-risk populations, such as those with severe and persistent mental illness. Mental health expertise must be sought and consulted in the development of these policies.
• When patients with psychiatric illness do not conform to public health measures, such as quarantine, psychiatrists may be posed with the ethical and legal challenge of considering involuntary hospitalization to protect the public good or reporting the patient's behaviour to public health officials. 16 Ethical and legal expertise should be sought to develop policies to guide psychiatrists in these situations and to ensure that clinical practice respects patient rights. Legislations under public health law can be considered in addition to mental health law when applicable.
• Those recovering from COVID-19 infection, including health care workers, may face stigma by the general public. Public health education initiatives should seek to combat this stigma.
# Research agendas
• Research should seek to better elucidate the mechanisms through which patients with psychiatric illness experience a greater burden of COVID-19 disease and identify specific public health interventions for this clinical population, such as regular screening.
• The current pandemic represents an unprecedented opportunity to evaluate the impact of the crisis response on the quality and value of mental health outcomes. Research should be conducted to understand this impact as a means of informing policy responses to future public health crises. | None | None |
f8dcf4a77d832a2408514ee8c52062c6f6006bdd | cma | None | # Background
Urinary bladder cancer is the fourth most common cancer among men and accounts for 8% of all new male cancer cases. Urinary bladder cancer is less common among women (ranked 11th) and accounts for less than 3% of all new female cancer cases. Statistics Canada estimates that in 2020 there were approximately 12,200 new cases of bladder cancer and 2,600 deaths associated with bladder cancer in Canada. 1 Smoking is estimated to account for between 34% and 50% of all bladder cancers. 2,3 There are several histological types of bladder cancer. Urothelial carcinoma (also known as transitional cell carcinoma, henceforth referred to as urothelial) is the most common subtype, accounting for more than 90% of all cases in North America. Other histologic variants include squamous differentiation, glandular differentiation, nested pattern, microcystic, micropapillary, lymphoepithelioma-like, plasmacytoid and lymphoma-like, sarcomatoid/carcinosarcoma, giant cell, trophoblastic differentiation, clear cell, lipid cell, and undifferentiated. 4 Other important histologic variants include adenocarcinoma (urachal and non-urachal) and small cell carcinoma. Less commonly, urothelial cancers can arise in other parts of the urinary tract including the renal pelvis, ureter and urethra.
Staging of bladder cancer is currently based on the eighth edition (2017) of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual. 5 One of the major updates from the seventh edition (2010) is that lymph node involvement limited to the true pelvis and/or common iliac lymph nodes (N1-N3) in combination with a T1-T4a primary tumour now constitutes stage III disease (previously stage IV). A detailed description of the staging system can be found in the Appendix.
The objective of this guideline is to provide physicians with the latest, evidence-based management strategies for muscle-invasive bladder cancer in Alberta. Guidelines for non-muscle-invasive bladder cancer, locally advanced/metastatic bladder cancer, and upper tract urothelial cancer are available separately.
# Target Population
Adult patients (age ≥18 years) with a diagnosis of non-metastatic, muscle-invasive bladder cancer, including patients with a single regional lymph node metastasis in the true pelvis (T2a-T4a, N0-1, M0
# Therapy with curative intent:
-All patients should be discussed in a multidisciplinary setting, and be made aware of their curative intent treatment options.
-Either a surgical (radical cystectomy with bilateral and extended lymph node dissection with urinary diversion or neobladder reconstruction OR trimodality bladder-preserving approach can be considered. -In patients unable to tolerate either a surgical or bladder-preserving approach due to medical comorbidities, poor performance status, or patient choice, consider TURBT +/-radiotherapy or chemotherapy, TURBT alone, radiotherapy alone, or chemotherapy alone, although the odds of cure are low.
# A. Neoadjuvant chemotherapy i.
Neoadjuvant chemotherapy is considered standard of care prior to radical cystectomy in patients with muscle-invasive urothelial bladder cancer. It may also be considered on a case-by-case basis for patients who are planned to receive a bladder preservation / combined modality approach.
ii. Where possible, neoadjuvant chemotherapy is strongly preferred over adjuvant chemotherapy.
iii. Neoadjuvant chemotherapy should be cisplatin-based combination therapy. Options include cisplatin-gemcitabine or dose-dense MVAC. 19,20 A total of 4 cycles should be planned. 21,22 A standard dosing option for each regimen is provided below: a. vi. For patients receiving cisplatin-gemcitabine, a CT scan of abdomen and pelvis should be performed after 2 cycles to exclude progression. If disease progression has occurred, then neoadjuvant chemotherapy should be abandoned and the patient should be taken to surgery if feasible.
# B. Radical cystectomy with bilateral pelvic lymph node dissection
i. Radical cystectomy with bilateral pelvic lymph node dissection (PLND), followed by urinary diversion. Options for urinary diversion include continent reservoir and conduit diversion. There are insufficient data to recommend one procedure over another.
ii. Ileal neobladder reconstruction can be considered in carefully selected patients with bladder-confined, node-negative urothelial carcinoma with good kidney and liver function. 25,26 iii. Extended template PLND can include the presacral and common iliac lymph nodes to the aortic bifurcation. iv. Non-urothelial histologies should be considered on a case-by-case basis and discussed in multi-disciplinary tumor boards/rounds. v. All patients who are eligible for cisplatin-based chemotherapy should have the opportunity to discuss neoadjuvant therapy with a medical oncologist before surgery, as this has been shown to result in improved survival versus surgery alone 32,33 (see section A above).
vi. In cases where neoadjuvant chemotherapy was not received and/or completed, adjuvant chemotherapy can be considered on a case-by-case basis pending postsurgical pathology (see section D below).
C. Bladder preservation / combined modality approach i. Bladder preservation therapy is best suited for those with a solitary lesion which has been maximally resected with TURBT and the following features: no CIS, no evidence of hydronephrosis, urothelial histology, adequate bladder volume, clinically negative lymph nodes, and absence of significant lower urinary tract irritative symptoms. 21,22,34 ii. Optimal bladder preservation strategies consist of radiotherapy combined with concurrent chemotherapy following a maximal TURBT. 35 iii. Prior to bladder preservation there should be a complete resection of the bladder tumour; if more than eight weeks have elapsed since TURBT, or symptoms are recurrent, consider repeat cystoscopy/ TURBT prior to initiation of concurrent chemoradiation if safely possible. viii. Prior to definitive chemoradiation, neoadjuvant chemotherapy may be considered on a case-by-case basis, although there is no level I evidence to support this (see section A above). iv. Radiotherapy should be delivered to the whole bladder (+/-regional nodes to at least 40 Gy), followed by a bladder/ tumour boost to at least 60 Gy in conventional fractionation; altered fractionation regimens, such as 50-52.5 Gy in 20 fractions may also be considered. v. In cystectomy candidates, second-look cystoscopy +/-biopsy and urine cytology is recommended after 40-50 Gy to ensure response. If no response, bladder preservation approach should be abandoned and salvage cystectomy should be considered. vi. Commonly used concurrent chemotherapy regimens include: weekly cisplatin, 5-FU plus Mitomycin C. 36,37 ii. Adjuvant chemotherapy should be considered for patients with resected urothelial carcinoma with either pT3-T4 or pN1-3 disease on pathology review of the surgical specimen.
iii. Adjuvant chemotherapy with a cisplatin-based regimen is recommended. 38,39
# B. Bladder preservation approach i.
Patients undergoing a bladder preservation, combined modality approach should be followed in similar fashion to patients treated with a surgical approach, with the addition of regular, lifelong cystoscopic surveillance as per the following schedule: a. Cystoscopy +/-biopsy and cytology q3 months for first 2 years, then every 6 months for the next 2 years, then annually thereafter. ii. Superficial recurrences of bladder cancer may be treated as per other non-muscleinvasive bladder cancers (see separate guidelines) or with salvage cystectomy with bilateral pelvic lymphadenectomy. iii. Muscle-invasive recurrences are recommended to be treated with salvage cystectomy and bilateral pelvic lymphadenectomy (see section 2B above).
# Special situations
A. Non-urothelial histology i. All pathology reported to have variant histology should be reviewed by an expert GU pathologist.
ii. All patients with pure non-urothelial histology should be discussed in a multidisciplinary setting.
iii. Given that pure non-urothelial histologies are generally less sensitive to chemotherapy, (neo)adjuvant treatment is generally not recommended. The major exceptions to this are small cell carcinoma (see below) and micropapillary histology.
iv. Radical cystectomy is strongly preferred over bladder-preserving, combined modality approaches for pure non-urothelial histologies. B. Urachal adenocarcinomas i. Partial cystectomy may be considered as an alternative to radical cystectomy, provided that adequate margins can be maintained.
ii. Cystectomy should be performed with en bloc resection of the urachal ligament and umbilicus. Bilateral pelvic lymphadenectomy should also be performed.
iii. As with other non-urothelial histologies, neoadjuvant chemotherapy and bladderpreserving, combined modality approaches are not recommended. iv. It is recommended that these patients are discussed at multidisciplinary rounds postoperatively and are referred to medical oncology for consideration of adjuvant chemotherapy, though there is no level I evidence to support the use of adjuvant chemotherapy. C. Small cell carcinoma of the bladder i. Small cell carcinoma (including any percentage small cell histology, and early stage (i.e T1) disease) of the bladder is recommended to be managed as follows: a) All patients should be discussed in multidisciplinary rounds. Treatment recommendations include neoadjuvant chemotherapy with platinum etoposide followed by definitive surgical resection or combined modality therapy analogous to pulmonary small cell carcinoma. 42,43 b) For patients who did not receive neoadjuvant chemotherapy prior to definitive local therapy, adjuvant chemotherapy with 4 cycles of platinum-etoposide is recommended. c) Baseline staging brain imaging can be considered in asymptomatic patients given the higher risk of brain metastases versus conventional urothelial bladder cancer. It is recommended in patients with higher-risk disease (e.g. T3+, N+ or M+).
d) The role of prophylactic cranial irradiation (PCI) following definitive therapy is unclear. In the absence of data demonstrating clear benefit, PCI is generally not recommended in this setting. e) For patients who develop metastatic disease, guidelines for management of metastatic small cell carcinoma of the lung should be followed.
# Discussion
For muscle-invasive bladder cancer (T2-T4a, N0-1, M0), therapy with curative intent typically includes either a radical cystectomy with full bilateral pelvic LN dissection, followed by urinary diversion or neobladder reconstruction or a bladder preservation approach (i.e. complete tumour resection followed by radiotherapy and concurrent chemotherapy). There are no modern-era randomized trials to support one approach over the other; however, some patients (e.g. those with adequate renal function, no hydronephrosis, urothelial histology, T2 tumour <5 cm, no CIS, pT0 after a second TURBT, and with a proper bladder capacity and function) 44 may be better suited for bladder preservation while others (i.e. not meeting criteria above) are better suited for radical cystectomy. For patients unable to tolerate or unwilling to undergo either approach, options include: TURBT ± radiotherapy or chemotherapy, TURBT alone, radiotherapy alone, or chemotherapy alone.
Pelvic LN dissection should include the presacral and common iliac lymph nodes to the aortic bifurcation (i.e., extended template). There are data to show that the lymph node metastasis detection rate is higher with extended template pelvic LN dissection than with limited or standard pelvic LN dissection: Heidenreich, et. al. reported 27% detection for extended vs. 12% for standard; 27 Bader, et. al. reported 24% for extended; 28 Allaf, et. al. reported 3% for extended vs. 1% for limited; 29 and Dhar, et. al. reported 26% for extended vs. 13% for limited. 30 The 5-year recurrence-free survival rate for extended is higher than that of limited (71% vs. 63% for pT2pN0-2 and 49% vs. 19% for pT3pN0-2; p<.0001). 30 These results were confirmed in a meta-analysis of 2,824 patients which showed a significantly better recurrence-free survival in extended pelvic LN dissection vs. non-extended pelvic LN dissection (HR 0.65; p<.001). 45 In patients for whom the surgical approach is appropriate, and who are eligible for cisplatin-based combination chemotherapy, the option of neoadjuvant chemotherapy should be discussed; if chemotherapy in the neoadjuvant setting is deemed inappropriate, adjuvant administration should instead be considered (see below).
In patients for whom the bladder-preserving approach is recommended, TURBT should be performed prior to the initiation of concurrent chemoradiation. A prospective study among patients with urothelial carcinoma (T2-T3, Nx, M0; n=33) who underwent maximum TURBT followed by three cycles of adjuvant chemotherapy (e.g. methotrexate, vinblastine, adriamycin and cisplatin; MVAC), followed by radical radiotherapy, demonstrated a response rate of 46.4% overall (39.3% complete; 7.1% partial) and disease free and overall survival rates of 39.3% and 64.3%, respectively, after 12 months of follow-up. Response and survival were positively associated with a lower tumour stage (P=.001) and completeness of TURBT (P=.001). 46 Similar results were reported in another study among patients with T2-T4 bladder cancer (n=74) who underwent either: three cycles of neoadjuvant methotrexate, cisplatin, and vinblastine (MCV) chemotherapy followed by radiotherapy (60 Gy) or concurrent chemoradiotherapy (64.8 Gy with weekly cisplatin). With a mean follow-up of 54 months, the actuarial 5-year overall survival and overall survival with bladder preservation rates were 72% and 60%, respectively; there were no significant differences in the incidence of superficial, muscle-invasive, or distant recurrences. 47 In patients (n=123) with muscle-invasive bladder cancer (T2-T4a), the addition of neoadjuvant chemotherapy (two cycles) with methotrexate, cisplatin, and vinblastine did not improve overall survival or distant metastases rates, as compared to pelvic irradiation (39.6 Gy) with concurrent cisplatin (two cycles q three weeks) alone. The actuarial 5-year overall survival rate was 48% for patients receiving neoadjuvant chemotherapy (versus 49% for those who didn't); the 5-year distant metastasis rate was 33% for those who received neoadjuvant chemotherapy (versus 39% for those who didn't). 21 Salvage cystectomy should be performed in patients with invasive residual disease or recurrence. 48,49 A multicenter, phase III trial among patients with muscle-invasive bladder cancer (N=360) compared radiotherapy alone to radiotherapy with concurrent chemotherapy (5-fluorouracil; 500 mg/m 2 during fractions 1-5 and 16-20 and mitomycin-C; 12 mg/m 2 on day 1). Two-year locoregional disease-free survival was 67% (95% CI 59-74) for chemoradiotherapy and 54% (95% CI 46-62) for radiotherapy alone. Five-year overall survival was 48% (95% CI 40-55) for chemoradiotherapy and 35% (95% CI 28-43) for radiotherapy alone (p=0.16). 37 A recent randomized controlled trial compared post-TURBT (maximal) whole-pelvis concurrent chemoradiotherapy with bladder-only concurrent chemoradiotherapy (45 Gy in 25 fractions plus 20 Gy boost, with weekly cisplatin 40 mg/m 2 ), among patients with muscle-invasive, node-negative disease (n=230). The 5-year disease-free survival rates (47.1% vs. 46.9%; p=.5), 5-year overall survival rates (52.9% vs. 51.0%; p=.8), and bladder preservation rates (58.9% vs. 57.1%; p=.8) were not different between groups. 13 These data suggest that bladder-only concurrent chemoradiotherapy may be an option for patients with potentially lower morbidity than whole-pelvis chemoradiotherapy.
Neoadjuvant chemotherapy is cisplatinum-based combination therapy (e.g. cisplatin-gemcitabine or dose-dense MVAC).
A trial among stage T2-T4a, N0 patients (n=307) who were treated with radical cystectomy alone or preceded by three cycles of neoadjuvant chemotherapy (e.g. methotrexate, vinblastine, doxorubicin, and cisplatin) showed that median survival was increased among patients who received neoadjuvant chemotherapy (77 vs. 46 months; P=.06); furthermore, the presence of residual disease was decreased significantly (15 vs. 38%; P<.001) among those who received neoadjuvant chemotherapy. 32 Another study in patients with T2-T4aNXM0 disease (n=309) showed that neoadjuvant chemotherapy with three courses of cisplatin and methotrexate also increased overall survival (53 vs. 46%) at a median follow-up of 5.3 years. 50 However, given that both cisplatingemcitabine and dose-dense MVAC have been shown to have improved tolerability with similar outcomes as compared to conventional MVAC in the advanced/metastatic setting for urothelial cancer, 51,52 these regimens have been adopted as standard of care neoadjuvant regimens, despite the lack of level I evidence. Though there are no randomized trials comparing these chemotherapy regimens in the neoadjuvant setting, retrospective studies have not identified a substantial difference between regimens. 53,54 In addition, there are 2 single-arm phase II studies of ddMVAC which suggest this regimen is feasible and effective, with pathologic downstaging to non-muscle invasive disease in 49%-52% of patients. 19,20 In summary, it is currently recommended that neoadjuvant chemotherapy consist of either 4 cycles of cisplatin-gemcitabine or 4 cycles of ddMVAC.
A meta-analysis of over 3000 T2-T4a patients in whom definitive therapy (surgery or radiotherapy) was given either by itself or with neoadjuvant chemotherapy demonstrated a survival advantage for neoadjuvant treatment. Neoadjuvant chemotherapy, regardless of the type of local treatment that followed, resulted in a 14% reduction in the risk of death and 5% absolute increase in overall survival at five years. 33 Patients with contraindications to cisplatinum should proceed directly to definitive therapy, as the use of carboplatinum-based neoadjuvant combinations is not advised. 32,33, Pure non-urothelial histologies are generally less sensitive to chemotherapy and therefore neoadjuvant chemotherapy is generally avoided in this patient population. The major exception to this is micropapillary bladder cancer, which should be treated similarly to urothelial bladder cancer in terms of perioperative chemotherapy.
A CT scan of the abdomen and pelvis should precede cystectomy. In patients who have already undergone cystectomy, adjuvant cisplatinum-based combination chemotherapy (using the same regimens as outlined for neoadjuvant chemotherapy above) should be offered. In cases where a cystectomy has already been performed, there is less rigorous evidence for adjuvant chemotherapy.
A Canadian population-based outcome study demonstrated that use of adjuvant chemotherapy was associated with improved OS (HR 0.71, 95% CI 0.62-0.81) and cancer-specific survival (HR 0.73, 95% CI 0.64-0.84). 70 In addition, a Cochrane Collaboration meta-analysis of adjuvant chemotherapy for invasive bladder cancer reported a 25% relative reduction in the risk of death for chemotherapy compared to that on control; 71 however, power was limited in this study.
Adjuvant immunotherapy has been evaluated and further studies are ongoing. In a placebo-controlled phase III trial of over 700 patients with urothelial carcinoma (UC) and high-risk disease after radical cystectomy, 40 one year of adjuvant nivolumab improved disease-free survival (median 21 versus 11 months). Data on overall survival is pending. This study included patients with muscleinvasive or node-positive disease after receiving neoadjuvant chemotherapy, or those with extravesicular extension or node-positive disease who did not receive neoadjuvant chemotherapy and were ineligible for or refused adjuvant cisplatin-based chemotherapy. This has been Health Canada approved and is currently available by patient support program. Other studies in this setting have not demonstrated improvements in survival and further studies are ongoing.
Appendix A: Cancer Staging Manual (American Joint Committee on Cancer, 2017)
TNM staging of Bladder Cancer (AJCC/UICC TNM classification of malignant tumours, 8 th edition) 72 Primary Tumour (T) TX Primary tumour cannot be assessed T0
No evidence of primary tumour Ta Non-invasive papillary carcinoma Tis Urothelial carcinoma in situ: "Flat tumor" T1 Tumour invades lamina propria (subepithelial connective tissue) T2
Tumour invades muscularis propria pT2a
Tumour invades superficial muscularis propria (inner half) pT2b
Tumour | # Background
Urinary bladder cancer is the fourth most common cancer among men and accounts for 8% of all new male cancer cases. Urinary bladder cancer is less common among women (ranked 11th) and accounts for less than 3% of all new female cancer cases. Statistics Canada estimates that in 2020 there were approximately 12,200 new cases of bladder cancer and 2,600 deaths associated with bladder cancer in Canada. 1 Smoking is estimated to account for between 34% and 50% of all bladder cancers. 2,3 There are several histological types of bladder cancer. Urothelial carcinoma (also known as transitional cell carcinoma, henceforth referred to as urothelial) is the most common subtype, accounting for more than 90% of all cases in North America. Other histologic variants include squamous differentiation, glandular differentiation, nested pattern, microcystic, micropapillary, lymphoepithelioma-like, plasmacytoid and lymphoma-like, sarcomatoid/carcinosarcoma, giant cell, trophoblastic differentiation, clear cell, lipid cell, and undifferentiated. 4 Other important histologic variants include adenocarcinoma (urachal and non-urachal) and small cell carcinoma. Less commonly, urothelial cancers can arise in other parts of the urinary tract including the renal pelvis, ureter and urethra.
Staging of bladder cancer is currently based on the eighth edition (2017) of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual. 5 One of the major updates from the seventh edition (2010) is that lymph node involvement limited to the true pelvis and/or common iliac lymph nodes (N1-N3) in combination with a T1-T4a primary tumour now constitutes stage III disease (previously stage IV). A detailed description of the staging system can be found in the Appendix.
The objective of this guideline is to provide physicians with the latest, evidence-based management strategies for muscle-invasive bladder cancer in Alberta. Guidelines for non-muscle-invasive bladder cancer, locally advanced/metastatic bladder cancer, and upper tract urothelial cancer are available separately.
# Target Population
Adult patients (age ≥18 years) with a diagnosis of non-metastatic, muscle-invasive bladder cancer, including patients with a single regional lymph node metastasis in the true pelvis (T2a-T4a, N0-1, M0
# Therapy with curative intent:
-All patients should be discussed in a multidisciplinary setting, and be made aware of their curative intent treatment options.
-Either a surgical (radical cystectomy with bilateral and extended lymph node dissection with urinary diversion or neobladder reconstruction [6][7][8][9][10][11][12] OR trimodality bladder-preserving approach can be considered. [13][14][15][16][17][18] -In patients unable to tolerate either a surgical or bladder-preserving approach due to medical comorbidities, poor performance status, or patient choice, consider TURBT +/-radiotherapy or chemotherapy, TURBT alone, radiotherapy alone, or chemotherapy alone, although the odds of cure are low.
# A. Neoadjuvant chemotherapy i.
Neoadjuvant chemotherapy is considered standard of care prior to radical cystectomy in patients with muscle-invasive urothelial bladder cancer. It may also be considered on a case-by-case basis for patients who are planned to receive a bladder preservation / combined modality approach.
ii. Where possible, neoadjuvant chemotherapy is strongly preferred over adjuvant chemotherapy.
iii. Neoadjuvant chemotherapy should be cisplatin-based combination therapy. Options include cisplatin-gemcitabine or dose-dense MVAC. 19,20 A total of 4 cycles should be planned. 21,22 A standard dosing option for each regimen is provided below: a. vi. For patients receiving cisplatin-gemcitabine, a CT scan of abdomen and pelvis should be performed after 2 cycles to exclude progression. If disease progression has occurred, then neoadjuvant chemotherapy should be abandoned and the patient should be taken to surgery if feasible.
# B. Radical cystectomy with bilateral pelvic lymph node dissection
i. Radical cystectomy with bilateral pelvic lymph node dissection (PLND), followed by urinary diversion. Options for urinary diversion include continent reservoir and conduit diversion. There are insufficient data to recommend one procedure over another.
ii. Ileal neobladder reconstruction can be considered in carefully selected patients with bladder-confined, node-negative urothelial carcinoma with good kidney and liver function. 25,26 iii. Extended template PLND can include the presacral and common iliac lymph nodes to the aortic bifurcation. [27][28][29][30][31] iv. Non-urothelial histologies should be considered on a case-by-case basis and discussed in multi-disciplinary tumor boards/rounds. v. All patients who are eligible for cisplatin-based chemotherapy should have the opportunity to discuss neoadjuvant therapy with a medical oncologist before surgery, as this has been shown to result in improved survival versus surgery alone 32,33 (see section A above).
vi. In cases where neoadjuvant chemotherapy was not received and/or completed, adjuvant chemotherapy can be considered on a case-by-case basis pending postsurgical pathology (see section D below).
C. Bladder preservation / combined modality approach i. Bladder preservation therapy is best suited for those with a solitary lesion which has been maximally resected with TURBT and the following features: no CIS, no evidence of hydronephrosis, urothelial histology, adequate bladder volume, clinically negative lymph nodes, and absence of significant lower urinary tract irritative symptoms. 21,22,34 ii. Optimal bladder preservation strategies consist of radiotherapy combined with concurrent chemotherapy following a maximal TURBT. 35 iii. Prior to bladder preservation there should be a complete resection of the bladder tumour; if more than eight weeks have elapsed since TURBT, or symptoms are recurrent, consider repeat cystoscopy/ TURBT prior to initiation of concurrent chemoradiation if safely possible. viii. Prior to definitive chemoradiation, neoadjuvant chemotherapy may be considered on a case-by-case basis, although there is no level I evidence to support this (see section A above). iv. Radiotherapy should be delivered to the whole bladder (+/-regional nodes to at least 40 Gy), followed by a bladder/ tumour boost to at least 60 Gy in conventional fractionation; altered fractionation regimens, such as 50-52.5 Gy in 20 fractions may also be considered. v. In cystectomy candidates, second-look cystoscopy +/-biopsy and urine cytology is recommended after 40-50 Gy to ensure response. If no response, bladder preservation approach should be abandoned and salvage cystectomy should be considered. vi. Commonly used concurrent chemotherapy regimens include: weekly cisplatin, 5-FU plus Mitomycin C. 36,37 ii. Adjuvant chemotherapy should be considered for patients with resected urothelial carcinoma with either pT3-T4 or pN1-3 disease on pathology review of the surgical specimen.
iii. Adjuvant chemotherapy with a cisplatin-based regimen is recommended. 38,39
# B. Bladder preservation approach i.
Patients undergoing a bladder preservation, combined modality approach should be followed in similar fashion to patients treated with a surgical approach, with the addition of regular, lifelong cystoscopic surveillance as per the following schedule: a. Cystoscopy +/-biopsy and cytology q3 months for first 2 years, then every 6 months for the next 2 years, then annually thereafter. ii. Superficial recurrences of bladder cancer may be treated as per other non-muscleinvasive bladder cancers (see separate guidelines) or with salvage cystectomy with bilateral pelvic lymphadenectomy. iii. Muscle-invasive recurrences are recommended to be treated with salvage cystectomy and bilateral pelvic lymphadenectomy (see section 2B above).
# Special situations
A. Non-urothelial histology i. All pathology reported to have variant histology should be reviewed by an expert GU pathologist.
ii. All patients with pure non-urothelial histology should be discussed in a multidisciplinary setting.
iii. Given that pure non-urothelial histologies are generally less sensitive to chemotherapy, (neo)adjuvant treatment is generally not recommended. The major exceptions to this are small cell carcinoma (see below) and micropapillary histology.
iv. Radical cystectomy is strongly preferred over bladder-preserving, combined modality approaches for pure non-urothelial histologies. B. Urachal adenocarcinomas i. Partial cystectomy may be considered as an alternative to radical cystectomy, provided that adequate margins can be maintained.
ii. Cystectomy should be performed with en bloc resection of the urachal ligament and umbilicus. Bilateral pelvic lymphadenectomy should also be performed.
iii. As with other non-urothelial histologies, neoadjuvant chemotherapy and bladderpreserving, combined modality approaches are not recommended. iv. It is recommended that these patients are discussed at multidisciplinary rounds postoperatively and are referred to medical oncology for consideration of adjuvant chemotherapy, though there is no level I evidence to support the use of adjuvant chemotherapy. C. Small cell carcinoma of the bladder i. Small cell carcinoma (including any percentage small cell histology, and early stage (i.e T1) disease) of the bladder is recommended to be managed as follows: a) All patients should be discussed in multidisciplinary rounds. Treatment recommendations include neoadjuvant chemotherapy with platinum etoposide followed by definitive surgical resection or combined modality therapy analogous to pulmonary small cell carcinoma. 42,43 b) For patients who did not receive neoadjuvant chemotherapy prior to definitive local therapy, adjuvant chemotherapy with 4 cycles of platinum-etoposide is recommended. c) Baseline staging brain imaging can be considered in asymptomatic patients given the higher risk of brain metastases versus conventional urothelial bladder cancer. It is recommended in patients with higher-risk disease (e.g. T3+, N+ or M+).
d) The role of prophylactic cranial irradiation (PCI) following definitive therapy is unclear. In the absence of data demonstrating clear benefit, PCI is generally not recommended in this setting. e) For patients who develop metastatic disease, guidelines for management of metastatic small cell carcinoma of the lung should be followed.
# Discussion
For muscle-invasive bladder cancer (T2-T4a, N0-1, M0), therapy with curative intent typically includes either a radical cystectomy with full bilateral pelvic LN dissection, followed by urinary diversion or neobladder reconstruction [6][7][8][9][10][11][12] or a bladder preservation approach (i.e. complete tumour resection followed by radiotherapy and concurrent chemotherapy). [13][14][15][16][17][18] There are no modern-era randomized trials to support one approach over the other; however, some patients (e.g. those with adequate renal function, no hydronephrosis, urothelial histology, T2 tumour <5 cm, no CIS, pT0 after a second TURBT, and with a proper bladder capacity and function) 44 may be better suited for bladder preservation while others (i.e. not meeting criteria above) are better suited for radical cystectomy. For patients unable to tolerate or unwilling to undergo either approach, options include: TURBT ± radiotherapy or chemotherapy, TURBT alone, radiotherapy alone, or chemotherapy alone.
Pelvic LN dissection should include the presacral and common iliac lymph nodes to the aortic bifurcation (i.e., extended template). There are data to show that the lymph node metastasis detection rate is higher with extended template pelvic LN dissection than with limited or standard pelvic LN dissection: Heidenreich, et. al. reported 27% detection for extended vs. 12% for standard; 27 Bader, et. al. reported 24% for extended; 28 Allaf, et. al. reported 3% for extended vs. 1% for limited; 29 and Dhar, et. al. reported 26% for extended vs. 13% for limited. 30 The 5-year recurrence-free survival rate for extended is higher than that of limited (71% vs. 63% for pT2pN0-2 and 49% vs. 19% for pT3pN0-2; p<.0001). 30 These results were confirmed in a meta-analysis of 2,824 patients which showed a significantly better recurrence-free survival in extended pelvic LN dissection vs. non-extended pelvic LN dissection (HR 0.65; p<.001). 45 In patients for whom the surgical approach is appropriate, and who are eligible for cisplatin-based combination chemotherapy, the option of neoadjuvant chemotherapy should be discussed; if chemotherapy in the neoadjuvant setting is deemed inappropriate, adjuvant administration should instead be considered (see below).
In patients for whom the bladder-preserving approach is recommended, TURBT should be performed prior to the initiation of concurrent chemoradiation. A prospective study among patients with urothelial carcinoma (T2-T3, Nx, M0; n=33) who underwent maximum TURBT followed by three cycles of adjuvant chemotherapy (e.g. methotrexate, vinblastine, adriamycin and cisplatin; MVAC), followed by radical radiotherapy, demonstrated a response rate of 46.4% overall (39.3% complete; 7.1% partial) and disease free and overall survival rates of 39.3% and 64.3%, respectively, after 12 months of follow-up. Response and survival were positively associated with a lower tumour stage (P=.001) and completeness of TURBT (P=.001). 46 Similar results were reported in another study among patients with T2-T4 bladder cancer (n=74) who underwent either: three cycles of neoadjuvant methotrexate, cisplatin, and vinblastine (MCV) chemotherapy followed by radiotherapy (60 Gy) or concurrent chemoradiotherapy (64.8 Gy with weekly cisplatin). With a mean follow-up of 54 months, the actuarial 5-year overall survival and overall survival with bladder preservation rates were 72% and 60%, respectively; there were no significant differences in the incidence of superficial, muscle-invasive, or distant recurrences. 47 In patients (n=123) with muscle-invasive bladder cancer (T2-T4a), the addition of neoadjuvant chemotherapy (two cycles) with methotrexate, cisplatin, and vinblastine did not improve overall survival or distant metastases rates, as compared to pelvic irradiation (39.6 Gy) with concurrent cisplatin (two cycles q three weeks) alone. The actuarial 5-year overall survival rate was 48% for patients receiving neoadjuvant chemotherapy (versus 49% for those who didn't); the 5-year distant metastasis rate was 33% for those who received neoadjuvant chemotherapy (versus 39% for those who didn't). 21 Salvage cystectomy should be performed in patients with invasive residual disease or recurrence. 48,49 A multicenter, phase III trial among patients with muscle-invasive bladder cancer (N=360) compared radiotherapy alone to radiotherapy with concurrent chemotherapy (5-fluorouracil; 500 mg/m 2 during fractions 1-5 and 16-20 and mitomycin-C; 12 mg/m 2 on day 1). Two-year locoregional disease-free survival was 67% (95% CI 59-74) for chemoradiotherapy and 54% (95% CI 46-62) for radiotherapy alone. Five-year overall survival was 48% (95% CI 40-55) for chemoradiotherapy and 35% (95% CI 28-43) for radiotherapy alone (p=0.16). 37 A recent randomized controlled trial compared post-TURBT (maximal) whole-pelvis concurrent chemoradiotherapy with bladder-only concurrent chemoradiotherapy (45 Gy in 25 fractions plus 20 Gy boost, with weekly cisplatin 40 mg/m 2 ), among patients with muscle-invasive, node-negative disease (n=230). The 5-year disease-free survival rates (47.1% vs. 46.9%; p=.5), 5-year overall survival rates (52.9% vs. 51.0%; p=.8), and bladder preservation rates (58.9% vs. 57.1%; p=.8) were not different between groups. 13 These data suggest that bladder-only concurrent chemoradiotherapy may be an option for patients with potentially lower morbidity than whole-pelvis chemoradiotherapy.
Neoadjuvant chemotherapy is cisplatinum-based combination therapy (e.g. cisplatin-gemcitabine or dose-dense MVAC).
A trial among stage T2-T4a, N0 patients (n=307) who were treated with radical cystectomy alone or preceded by three cycles of neoadjuvant chemotherapy (e.g. methotrexate, vinblastine, doxorubicin, and cisplatin) showed that median survival was increased among patients who received neoadjuvant chemotherapy (77 vs. 46 months; P=.06); furthermore, the presence of residual disease was decreased significantly (15 vs. 38%; P<.001) among those who received neoadjuvant chemotherapy. 32 Another study in patients with T2-T4aNXM0 disease (n=309) showed that neoadjuvant chemotherapy with three courses of cisplatin and methotrexate also increased overall survival (53 vs. 46%) at a median follow-up of 5.3 years. 50 However, given that both cisplatingemcitabine and dose-dense MVAC have been shown to have improved tolerability with similar outcomes as compared to conventional MVAC in the advanced/metastatic setting for urothelial cancer, 51,52 these regimens have been adopted as standard of care neoadjuvant regimens, despite the lack of level I evidence. Though there are no randomized trials comparing these chemotherapy regimens in the neoadjuvant setting, retrospective studies have not identified a substantial difference between regimens. 53,54 In addition, there are 2 single-arm phase II studies of ddMVAC which suggest this regimen is feasible and effective, with pathologic downstaging to non-muscle invasive disease in 49%-52% of patients. 19,20 In summary, it is currently recommended that neoadjuvant chemotherapy consist of either 4 cycles of cisplatin-gemcitabine or 4 cycles of ddMVAC.
A meta-analysis of over 3000 T2-T4a patients in whom definitive therapy (surgery or radiotherapy) was given either by itself or with neoadjuvant chemotherapy demonstrated a survival advantage for neoadjuvant treatment. Neoadjuvant chemotherapy, regardless of the type of local treatment that followed, resulted in a 14% reduction in the risk of death and 5% absolute increase in overall survival at five years. 33 Patients with contraindications to cisplatinum should proceed directly to definitive therapy, as the use of carboplatinum-based neoadjuvant combinations is not advised. 32,33,[55][56][57][58][59][60][61][62][63][64][65][66][67][68][69] Pure non-urothelial histologies are generally less sensitive to chemotherapy and therefore neoadjuvant chemotherapy is generally avoided in this patient population. The major exception to this is micropapillary bladder cancer, which should be treated similarly to urothelial bladder cancer in terms of perioperative chemotherapy.
A CT scan of the abdomen and pelvis should precede cystectomy. In patients who have already undergone cystectomy, adjuvant cisplatinum-based combination chemotherapy (using the same regimens as outlined for neoadjuvant chemotherapy above) should be offered. In cases where a cystectomy has already been performed, there is less rigorous evidence for adjuvant chemotherapy.
A Canadian population-based outcome study demonstrated that use of adjuvant chemotherapy was associated with improved OS (HR 0.71, 95% CI 0.62-0.81) and cancer-specific survival (HR 0.73, 95% CI 0.64-0.84). 70 In addition, a Cochrane Collaboration meta-analysis of adjuvant chemotherapy for invasive bladder cancer reported a 25% relative reduction in the risk of death for chemotherapy compared to that on control; 71 however, power was limited in this study.
Adjuvant immunotherapy has been evaluated and further studies are ongoing. In a placebo-controlled phase III trial of over 700 patients with urothelial carcinoma (UC) and high-risk disease after radical cystectomy, 40 one year of adjuvant nivolumab improved disease-free survival (median 21 versus 11 months). Data on overall survival is pending. This study included patients with muscleinvasive or node-positive disease after receiving neoadjuvant chemotherapy, or those with extravesicular extension or node-positive disease who did not receive neoadjuvant chemotherapy and were ineligible for or refused adjuvant cisplatin-based chemotherapy. This has been Health Canada approved and is currently available by patient support program. Other studies in this setting have not demonstrated improvements in survival and further studies are ongoing.
#
Appendix A: Cancer Staging Manual (American Joint Committee on Cancer, 2017)
TNM staging of Bladder Cancer (AJCC/UICC TNM classification of malignant tumours, 8 th edition) 72 Primary Tumour (T) TX Primary tumour cannot be assessed T0
No evidence of primary tumour Ta Non-invasive papillary carcinoma Tis Urothelial carcinoma in situ: "Flat tumor" T1 Tumour invades lamina propria (subepithelial connective tissue) T2
Tumour invades muscularis propria pT2a
Tumour invades superficial muscularis propria (inner half) pT2b
Tumour | None | None |
57dbbbf52b53175b56be34376dcfedf7f7f585af | cma | None | # BACKGROUND
Spasticity is a common sequela of upper motor neuron conditions that can reduce quality of life, impair function, and heighten economic burden. 1 Identification and treatment of problematic spasticity is key in order to decrease impairments including contracture formation, pain, skin breakdown, and functional decline and to limit disability. 2 The COVID-19 pandemic has affected health-care systems worldwide including physical medicine and rehabilitation (PMR) and neurology practices in Canada. Inpatient hospital care for the management of patients with COVID-19 has been prioritized, while elective surgeries and outpatient clinics have been limited or canceled as part of resource allocation management and mitigation of risks during the pandemic. Subsequently, the delivery of outpatient spasticity care in the PMR and neurology setting has been directly impacted. 6 The great majority of Canadian spasticity outpatient clinics have been canceled or are now predominantly administered through telemedicine, which has led to a dramatic reduction in patient volume.
As the pandemic evolves, there is a possibility of continuous or intermittent physical distancing being required until a vaccine becomes available. 7 For this reason, a COVID-19 spasticity task force was created. This task force is comprised of 17 Canadian experts in the field of spasticity management. These 16 PMR specialists and 1 neurologist have collaborated extensively regarding spasticity clinical practice, research, and education for more than 10 years nationally and internationally. Our task force experts have academic appointments from 10 Canadian universities and representation at the executive level in the Canadian Association of Physical Medicine and Rehabilitation, Canadian Advances in Neuro-Orthopedics for Spasticity Congress, and Canadian Stroke Best Practices Advisory Committee. There was an attempt for geographic diversity by seeking representation from all provinces with spasticity clinics, but we lacked representation from Nova Scotia, Prince Edward Island, and Newfoundland and the territories. We did not specifically attempt to attain gender diversity. Almost all spasticity clinics in Canada are run by physiatrists while only a very small number are headed by neurologists, hence the majority of task force members are physiatrists.
The COVID-19 spasticity task force conducted their first webbased meeting on April 21, 2020, during which consensus was obtained based on expert opinion for strategies to optimize spasticity outpatient care during the pandemic. Subsequent web-based, telephone, and email discussions regarding regional approaches to the response and procedures of spasticity clinics during the pandemic were conducted and the conclusions are included in our guidance paper. Our task force recommends that clinicians continue to deliver spasticity management via telemedicine for both follow-up care and new patient assessments during this pandemic.
We have also identified a subset of patients that require inperson assessment and access to treatment modalities such as intrathecal baclofen pump therapy, focal chemodenervation, and orthotic adjustments.
In this practical guidance paper, we outline a triaging strategy to determine the urgency of managing spasticity patients inperson versus using telemedicine. We provide strategies to best protect patients, physicians, caregivers, and staff from possible exposure to COVID-19 during outpatient visits. We acknowledge that there may be significant regional differences in personal protective equipment (PPE) access and restrictions regarding provision of care for outpatient clinics. Practitioners should refer to their local and hospital guidelines to ensure that they are in compliance with current recommendations, and our suggestions should be adapted accordingly.
# PATIENT SELECTION FOR TELEMEDICINE VERSUS IN-PERSON ASSESSMENTS
Spasticity clinics should not be canceled. Our opinion is that the majority of our spasticity patients should be assessed by telemedicine as a temporary measure. This includes patients who are treated without interventional procedures, those who are treated with oral antispasmodics and/or were recently injected with botulinum toxin or phenol, and those who are stable on intrathecal baclofen treatment.
Telemedicine can be used to gather a history, assess function, perform basic physical exam evaluation, and establish and monitor treatment goals. 8 It can also be used to help with stretching, range of motion, and spasticity education prior to in-person assessment. Telemedicine is obviously limited due to the inability to perform a full physical examination to adequately assess spasticity, tone, and contracture, and in certain clinical scenarios, in-person assessment becomes essential to ensure appropriate treatment.
# TRIAGING STRATEGY FOR IN-PERSON ASSESSMENT
We estimate that approximately 10%-30% of spasticity patients will require an in-person assessment. It is important to carefully triage this group to determine the urgency for spasticity assessments in order to reduce unnecessary exposure to COVID-19, to conserve PPE, and to help decrease medical complications and emergency visits.
We propose the following patient triage strategy based on tiers of urgency (see Figure 1):
- The URGENT GROUP classified as a need for in-person assessment/intervention within 48 hours of contacting the clinic/physician with clinical scenarios including ○ patients requiring intrathecal baclofen pump refills to avoid withdrawal; ○ patients experiencing symptoms or signs of intrathecal baclofen underdosing or overdosing; ○ patients experiencing symptoms or signs of baclofen pump device failure.
- The SEMI-URGENT GROUP classified as a need for inperson assessment between 48 hours and 4 weeks and includes clinical scenarios where spasticity is worsening over the last 4 weeks and is associated with
○ deteriorating functions such as mobility (including falls and difficulty with transfers), perineal care/hygiene with increased caregiver needs, and/or inability to function independently; ○ increasing severe pain that is uncontrolled with other measures and has previously responded to chemodenervation; ○ increased risk of joint dislocation; ○ development of new or worsening pressure ulcer or wound; ○ inability to don and doff orthoses required for function; ○ impaired seating with increased pain and/or high risk of skin breakdown; ○ loss of joint range of motion affecting function, skin breakdown, and/or contracture development.
- The NON-URGENT GROUP classified as patients who can wait up to or beyond 3 months for reassessment and be seen as needed through telemedicine.
For patients who are asymptomatic (of COVID-19) and in the urgent or semi-urgent groups:
- Assume that asymptomatic transmission of COVID-19 is possible, and therefore use appropriate PPE for all in-person encounters to protect both patients and health-care providers.
- The WHO guidelines for use of PPE advise using surgical mask, goggles/face-shield/visor, gloves, and gown when treating/injecting patients in the outpatient setting. 9 For patients in the urgent group who are suspected or confirmed COVID-19 positive:
- Urgent in-person assessment and treatment must be undertaken if there are intrathecal pump delivery system concerns or intrathecal baclofen refills needed.
- Strict PPE and safety precautions adhering to local guidelines on how COVID-19 positive patients are to be managed need to be in place.
For patients in the semi-urgent group who are suspected or confirmed COVID-19 positive:
- Assess with telemedicine and plan for in-person assessment once asymptomatic (defined as 10 days from symptom onset AND no fever without fever-reducing medication AND symptom resolution with the exception of post-viral cough). 4,10 THE CANADIAN JOURNAL OF NEUROLOGICAL SCIENCES - In the scenario where in-person treatment is required, ensure strict PPE and safety precautions adhering to local guidelines on how COVID-19 positive patients are to be managed.
# Setup of Outpatient Clinics During Pandemic
- Patient screening ○ Screen patients by phone prior to in-person assessments to ensure no COVID-19 symptoms, including fever, cough, shortness of breath, chills, muscle pain, new loss of taste or smell, vomiting or diarrhea, and/or sore throat or close contacts who are ill prior to attending. 11 Advise patients to use the local health authority self-assessment tool. ○ Ask if any family members are ill or COVID-19 positive or if they have had recent travel or exposure to a person who is COVID-19 positive; if so, delay the in-person clinic visit, offer telemedicine visit, and reassess in a timely fashion. ○ Given the current outbreaks in long-term care (LTC) facilities, we recommend not to transfer patients from LTC or other assisted living and group home settings to outpatient clinics during the pandemic unless urgent or semi-urgent. Telemedicine can be used to triage these patients into whether they may require urgent or semiurgent in-person assessment. At the time of this publication, patients in LTC settings are not allowed to be transferred for non-urgent outpatient appointments in many regions of Canada. ○ Assess the need for an overhead lift to transfer a patient.
Consider options to prepare the patient to be treated in their wheelchair if possible, such as loose clothing and tilt in space wheelchair. ○ Staff should acquire all patient information by telephone and limit interactions for information with patients during the in-person visit. ○ Arrangements for all follow-up appointments should be made by telephone to limit face-to-face interaction with front office staff.
- Staff education regarding PPE and safety protocols ○ Bring clean work clothes/scrubs/shoes for the clinic and another set of clothes for home. ○ Prior to leaving work or once home, shower and change into another set of clothing to decrease risk of transmission to family members/others living together. ○ Hand washing with soap and water or disinfecting gel is essential before and after every patient contact. ○ Ensure surgical masks, gloves, goggles/face visors fit properly before in-person contact with patients. Goggles/ face visors (should be cleaned after each patient encounter) and masks can be reused for the day if not soiled or damaged.
Triage for spasƟcity paƟents who are asymptomaƟc (of COVID-19) *
# NON-URGENT SEMI-URGENT (48 hours -4 weeks) URGENT (<48 hours)
PaƟents who can wait up to or beyond 3 months for re-assessment and be seen as needed through telemedicine ○ Wear a gown if available (ideally water-resistant) on top of scrubs or clothing when in contact with patients. ○ N95 masks and face visors are recommended for highrisk encounters (i.e., aerosol generating procedures for patients). 9 ○ Appropriately dispose of gloves and gown after each procedure. ○ When seeing patients with dysphagia and/or facial weakness use a full-face visor due to the potential for increased droplet risk. - Patient education ○ Before arrival, explain the changes in place in the clinic during the pandemic and reinforce the need for physical distancing.
○ Advise the patient to bring a mask, which may be homemade, or provide a mask upon arrival to the clinic. ○ Advise no visitors or family members during the consultation/procedure unless essential (e.g., requiring support as a result of cognitive/language dysfunction). ○ Advise not to bring purses/bags/unnecessary items to the clinic. ○ Advise patients to wear clothing that is easily removable or accessible to reduce preparation time and potentially avoid the need for the use of an overhead lift to expose targeted regions.
# CONCLUSION
It is essential to provide timely spasticity management while protecting patients and multidisciplinary spasticity teams from COVID-19 exposure.
Telemedicine is an effective tool for triage, assessment, and teaching for the majority of patients. However, there will be patients that require in-person contact for spasticity management procedures in order to maintain function and reduce the risk of significant complications and emergency department visits during this pandemic.
Triaging patients into non-urgent versus semi-urgent or urgent groups is essential to determine the need for in-person assessment. Patient education regarding changes in the delivery of spasticity care during the pandemic, staff education regarding PPE, triage protocols, room setup for examination and injection procedures, and outpatient clinic logistics are key in successfully treating spasticity during this pandemic. It is crucial to remember that our purpose is to maximize targeted and appropriate care to all patients during this unprecedented time and as spasticity specialists we will strive to safely provide the best possible care. | # BACKGROUND
Spasticity is a common sequela of upper motor neuron conditions that can reduce quality of life, impair function, and heighten economic burden. 1 Identification and treatment of problematic spasticity is key in order to decrease impairments including contracture formation, pain, skin breakdown, and functional decline and to limit disability. 2 The COVID-19 pandemic has affected health-care systems worldwide including physical medicine and rehabilitation (PMR) and neurology practices in Canada. [3][4][5] Inpatient hospital care for the management of patients with COVID-19 has been prioritized, while elective surgeries and outpatient clinics have been limited or canceled as part of resource allocation management and mitigation of risks during the pandemic. Subsequently, the delivery of outpatient spasticity care in the PMR and neurology setting has been directly impacted. 6 The great majority of Canadian spasticity outpatient clinics have been canceled or are now predominantly administered through telemedicine, which has led to a dramatic reduction in patient volume.
As the pandemic evolves, there is a possibility of continuous or intermittent physical distancing being required until a vaccine becomes available. 7 For this reason, a COVID-19 spasticity task force was created. This task force is comprised of 17 Canadian experts in the field of spasticity management. These 16 PMR specialists and 1 neurologist have collaborated extensively regarding spasticity clinical practice, research, and education for more than 10 years nationally and internationally. Our task force experts have academic appointments from 10 Canadian universities and representation at the executive level in the Canadian Association of Physical Medicine and Rehabilitation, Canadian Advances in Neuro-Orthopedics for Spasticity Congress, and Canadian Stroke Best Practices Advisory Committee. There was an attempt for geographic diversity by seeking representation from all provinces with spasticity clinics, but we lacked representation from Nova Scotia, Prince Edward Island, and Newfoundland and the territories. We did not specifically attempt to attain gender diversity. Almost all spasticity clinics in Canada are run by physiatrists while only a very small number are headed by neurologists, hence the majority of task force members are physiatrists.
The COVID-19 spasticity task force conducted their first webbased meeting on April 21, 2020, during which consensus was obtained based on expert opinion for strategies to optimize spasticity outpatient care during the pandemic. Subsequent web-based, telephone, and email discussions regarding regional approaches to the response and procedures of spasticity clinics during the pandemic were conducted and the conclusions are included in our guidance paper. Our task force recommends that clinicians continue to deliver spasticity management via telemedicine for both follow-up care and new patient assessments during this pandemic.
We have also identified a subset of patients that require inperson assessment and access to treatment modalities such as intrathecal baclofen pump therapy, focal chemodenervation, and orthotic adjustments.
In this practical guidance paper, we outline a triaging strategy to determine the urgency of managing spasticity patients inperson versus using telemedicine. We provide strategies to best protect patients, physicians, caregivers, and staff from possible exposure to COVID-19 during outpatient visits. We acknowledge that there may be significant regional differences in personal protective equipment (PPE) access and restrictions regarding provision of care for outpatient clinics. Practitioners should refer to their local and hospital guidelines to ensure that they are in compliance with current recommendations, and our suggestions should be adapted accordingly.
# PATIENT SELECTION FOR TELEMEDICINE VERSUS IN-PERSON ASSESSMENTS
Spasticity clinics should not be canceled. Our opinion is that the majority of our spasticity patients should be assessed by telemedicine as a temporary measure. This includes patients who are treated without interventional procedures, those who are treated with oral antispasmodics and/or were recently injected with botulinum toxin or phenol, and those who are stable on intrathecal baclofen treatment.
Telemedicine can be used to gather a history, assess function, perform basic physical exam evaluation, and establish and monitor treatment goals. 8 It can also be used to help with stretching, range of motion, and spasticity education prior to in-person assessment. Telemedicine is obviously limited due to the inability to perform a full physical examination to adequately assess spasticity, tone, and contracture, and in certain clinical scenarios, in-person assessment becomes essential to ensure appropriate treatment.
# TRIAGING STRATEGY FOR IN-PERSON ASSESSMENT
We estimate that approximately 10%-30% of spasticity patients will require an in-person assessment. It is important to carefully triage this group to determine the urgency for spasticity assessments in order to reduce unnecessary exposure to COVID-19, to conserve PPE, and to help decrease medical complications and emergency visits.
We propose the following patient triage strategy based on tiers of urgency (see Figure 1):
• The URGENT GROUP classified as a need for in-person assessment/intervention within 48 hours of contacting the clinic/physician with clinical scenarios including ○ patients requiring intrathecal baclofen pump refills to avoid withdrawal; ○ patients experiencing symptoms or signs of intrathecal baclofen underdosing or overdosing; ○ patients experiencing symptoms or signs of baclofen pump device failure.
• The SEMI-URGENT GROUP classified as a need for inperson assessment between 48 hours and 4 weeks and includes clinical scenarios where spasticity is worsening over the last 4 weeks and is associated with
○ deteriorating functions such as mobility (including falls and difficulty with transfers), perineal care/hygiene with increased caregiver needs, and/or inability to function independently; ○ increasing severe pain that is uncontrolled with other measures and has previously responded to chemodenervation; ○ increased risk of joint dislocation; ○ development of new or worsening pressure ulcer or wound; ○ inability to don and doff orthoses required for function; ○ impaired seating with increased pain and/or high risk of skin breakdown; ○ loss of joint range of motion affecting function, skin breakdown, and/or contracture development.
• The NON-URGENT GROUP classified as patients who can wait up to or beyond 3 months for reassessment and be seen as needed through telemedicine.
For patients who are asymptomatic (of COVID-19) and in the urgent or semi-urgent groups:
• Assume that asymptomatic transmission of COVID-19 is possible, and therefore use appropriate PPE for all in-person encounters to protect both patients and health-care providers.
• The WHO guidelines for use of PPE advise using surgical mask, goggles/face-shield/visor, gloves, and gown when treating/injecting patients in the outpatient setting. 9 For patients in the urgent group who are suspected or confirmed COVID-19 positive:
• Urgent in-person assessment and treatment must be undertaken if there are intrathecal pump delivery system concerns or intrathecal baclofen refills needed.
• Strict PPE and safety precautions adhering to local guidelines on how COVID-19 positive patients are to be managed need to be in place.
For patients in the semi-urgent group who are suspected or confirmed COVID-19 positive:
• Assess with telemedicine and plan for in-person assessment once asymptomatic (defined as 10 days from symptom onset AND no fever without fever-reducing medication AND symptom resolution with the exception of post-viral cough). 4,10 THE CANADIAN JOURNAL OF NEUROLOGICAL SCIENCES • In the scenario where in-person treatment is required, ensure strict PPE and safety precautions adhering to local guidelines on how COVID-19 positive patients are to be managed.
# Setup of Outpatient Clinics During Pandemic
• Patient screening ○ Screen patients by phone prior to in-person assessments to ensure no COVID-19 symptoms, including fever, cough, shortness of breath, chills, muscle pain, new loss of taste or smell, vomiting or diarrhea, and/or sore throat or close contacts who are ill prior to attending. 11 Advise patients to use the local health authority self-assessment tool. ○ Ask if any family members are ill or COVID-19 positive or if they have had recent travel or exposure to a person who is COVID-19 positive; if so, delay the in-person clinic visit, offer telemedicine visit, and reassess in a timely fashion. ○ Given the current outbreaks in long-term care (LTC) facilities, we recommend not to transfer patients from LTC or other assisted living and group home settings to outpatient clinics during the pandemic unless urgent or semi-urgent. Telemedicine can be used to triage these patients into whether they may require urgent or semiurgent in-person assessment. At the time of this publication, patients in LTC settings are not allowed to be transferred for non-urgent outpatient appointments in many regions of Canada. ○ Assess the need for an overhead lift to transfer a patient.
Consider options to prepare the patient to be treated in their wheelchair if possible, such as loose clothing and tilt in space wheelchair. ○ Staff should acquire all patient information by telephone and limit interactions for information with patients during the in-person visit. ○ Arrangements for all follow-up appointments should be made by telephone to limit face-to-face interaction with front office staff.
• Staff education regarding PPE and safety protocols ○ Bring clean work clothes/scrubs/shoes for the clinic and another set of clothes for home. ○ Prior to leaving work or once home, shower and change into another set of clothing to decrease risk of transmission to family members/others living together. ○ Hand washing with soap and water or disinfecting gel is essential before and after every patient contact. ○ Ensure surgical masks, gloves, goggles/face visors fit properly before in-person contact with patients. Goggles/ face visors (should be cleaned after each patient encounter) and masks can be reused for the day if not soiled or damaged.
Triage for spasƟcity paƟents who are asymptomaƟc (of COVID-19) *
# NON-URGENT SEMI-URGENT (48 hours -4 weeks) URGENT (<48 hours)
PaƟents who can wait up to or beyond 3 months for re-assessment and be seen as needed through telemedicine ○ Wear a gown if available (ideally water-resistant) on top of scrubs or clothing when in contact with patients. ○ N95 masks and face visors are recommended for highrisk encounters (i.e., aerosol generating procedures for patients). 9 ○ Appropriately dispose of gloves and gown after each procedure. ○ When seeing patients with dysphagia and/or facial weakness use a full-face visor due to the potential for increased droplet risk. • Patient education ○ Before arrival, explain the changes in place in the clinic during the pandemic and reinforce the need for physical distancing.
•
○ Advise the patient to bring a mask, which may be homemade, or provide a mask upon arrival to the clinic. ○ Advise no visitors or family members during the consultation/procedure unless essential (e.g., requiring support as a result of cognitive/language dysfunction). ○ Advise not to bring purses/bags/unnecessary items to the clinic. ○ Advise patients to wear clothing that is easily removable or accessible to reduce preparation time and potentially avoid the need for the use of an overhead lift to expose targeted regions.
# CONCLUSION
It is essential to provide timely spasticity management while protecting patients and multidisciplinary spasticity teams from COVID-19 exposure.
Telemedicine is an effective tool for triage, assessment, and teaching for the majority of patients. However, there will be patients that require in-person contact for spasticity management procedures in order to maintain function and reduce the risk of significant complications and emergency department visits during this pandemic.
Triaging patients into non-urgent versus semi-urgent or urgent groups is essential to determine the need for in-person assessment. Patient education regarding changes in the delivery of spasticity care during the pandemic, staff education regarding PPE, triage protocols, room setup for examination and injection procedures, and outpatient clinic logistics are key in successfully treating spasticity during this pandemic. It is crucial to remember that our purpose is to maximize targeted and appropriate care to all patients during this unprecedented time and as spasticity specialists we will strive to safely provide the best possible care.
# ACKNOWLEDGMENTS
The authors would like to thank Dr. Stacy Bhola-Reebye for reviewing the manuscript for grammar and syntax.
# FUNDING
No funding was received for development of this guidance paper from commercial interests including medical device or pharmaceutical companies.
# CONFLICT OF INTEREST
The development of the COVID-19 spasticity task force guidance paper has not been funded by any commercial interests, including pharmaceutical and medical device companies.
# DISCLOSURES
Dr. Rajiv Reebye reports personal fees and other from Allergan, Ipsen, and Merz, outside the submitted work.
Dr. Heather Finlayson reports personal fees and nonfinancial support from Allergan and personal fees from Ipsen, outside the submitted work.
Curtis May has nothing to disclose. Dr. Lalith Satkunam reports nonfinancial support from Allergan, grants and nonfinancial support from Merz, and nonfinancial support from Ipsen, outside the submitted work.
THE CANADIAN JOURNAL OF NEUROLOGICAL SCIENCES Dr. Theodore Wein reports grants from Ipsen and Allergan, during the conduct of the study, and grants, personal fees, and other from Allergan and Ipsen, outside the submitted work.
Dr. Thomas Miller reports personal fees from Allergan, Merz, and Ipsen, during the conduct of the study.
Dr. Chris Boulias reports grants from Ipsen during the conduct of the study, and grants from Ipsen, Allergan, Merz, outside the submitted work
Dr. Colleen O'Connell reports grants from Allergan, grants and personal fees from Ipsen, and other from Merz, outside the submitted work.
Dr. Anibal Bohorquez reports personal fees and nonfinancial support from Allergan, Ipsen, and Merz, outside the submitted work.
Dr. Sean Dukelow reports grants from CIHR, grants from Heart and Stroke Foundation, personal fees from Prometheus Medical, personal fees from Ipsen, and personal fees from Merz, outside the submitted work.
Dr. Karen Ethans reports personal fees from Allergan and Ipsen, outside the submitted work.
Dr. Farooq Ismail reports personal fees from Allergan, Merz, and Ipsen, outside the submitted work.
Dr. Waill Khalil has nothing to disclose. Dr. Omar Khan reports grants, personal fees, and nonfinancial support from Allergan, Ipsen, and Merz, outside the submitted work.
Dr. Philippe Lagnau has nothing to disclose. Dr.
Stephen McNeil reports grants and personal fees from Allergan and Merz, and personal fees from Ipsen, outside the submitted work.
Dr. Patricia Mills reports grants and nonfinancial support from Allergan, Ipsen, and Merz, outside the submitted work.
Dr. Geneviève Sirois reports other from advisory board and expert opinion and lecture for pharma industry (Allergan, Ipsen, Merz), outside the submitted work.
Dr. Paul Winston reports grants, personal fees, and nonfinancial support from Allergan, Ipsen, and Merz, outside the submitted work.
# STATEMENT OF AUTHORSHIP
RR led development of the content and drafted the manuscript; HF drafted the manuscript and coordinated the Task Force's feedback; CM drafted the figure and provided input on the content of the article, and helped RR and HF compile task force feedback and comments; the remaining coauthors provided key input on the guidance and content of the article. | None | None |
90318022df4d2b1d2511a27ee93c396fc3a58231 | cma | None | Note: It is the policy of the Canadian Psychiatric Association to review each position paper, policy statement and clinical practice guideline every five years after publication or last review. Any such document that has been published more than five years ago and does not explicitly state it has been reviewed and retained as an official document of the CPA, either with revisions or as originally published, should be considered as a historical reference document only.#
C anadian society recognizes that people have certain rights protected by the Canadian Charter of Rights and Freedoms. These include the right to life, liberty and security, and not to be subjected to cruel and unusual treatment or punishment. 1 Charter rights, including the right to self-determination and autonomy, may be infringed on in emergent and specific circumstances when acute mental illness manifests. The provinces and territories have various mental health and associated acts that allow for the restraint or detention of people with acute mental illness when they or others are at risk.
A definition of restrain is, "to place the person under control by the minimal use of such force, mechanical means or chemicals as is reasonable having regard to the person's physical and mental condition." 2 Restraint is not treatment as restraint is the temporary use of force to protect the patient or others. Seclusion involves the confinement of the person in a room or area from which free exit is prevented.
In certain, even more specific circumstances, the mental state of the person may require restraint or seclusion of the person to prevent harm. This type of emergency intervention is not only a further deprivation of liberty but also has associated risks to the person. Thus, their use should be only in clearly defined and specific situations when no alternatives exist.
An ideal world would be one in which detention under mental acts, seclusion and restraint are unneeded. 3 We, as a society and as a profession, should strive to move in that direction. However, not only are we not yet at that point but the business of acute and emergency psychiatry comes with the risk of physical harm to patients, staff and co-patients. All involved, including staff, also have a right to care and safety. However, should either restraint or seclusion be required, they should only be used in emergency situations when all appropriate, less restrictive measures have been exhausted or when the intervention is required to prevent immediate harm to the person or to others. It is important that staff is trained in crisis de-escalation and risk-reduction techniques. Attention should also be given to patient mix, space, layout, funding, treatment alternatives and recreational activities, among other factors that may reduce seclusion and restraint.
Each facility that uses this type of intervention should ensure that up-to-date policies are in place and that staff is familiar with them. Local policies should be in accordance with provincial, professional and national standards for the use of seclusion and restraint. Attention to best practices, including regular physician review, needs to take place.
Safeguards should include the need for a physician order and examination, regular observations, short time frames, humane settings and external reviews if the intervention extends beyond certain time periods. All efforts should be expended to review incidents requiring seclusion or restraint, and intervention should take place to prevent further use. 4,5 Formal tracking and monitoring of the use of all seclusion and restraint should occur wherever seclusion and or restraint are used. Research into mechanisms to reduce or shorten seclusion/restraint should be encouraged and supported.
As a profession, we should strive to continue to treat all our patients in a humane and fair manner, respecting their rights and freedoms. Ideally, no person should lose their right to liberty and freedom, but, unfortunately, acute mental illness may make that impossible, albeit for brief periods. The use of seclusion and restraint should be emergency measures used when all others fail or are unsuitable. These interventions may be essential to protect not only the patient but also others, including co-patients, members of the public and staff. If and when used, current monitored safeguards must be in place. | Note: It is the policy of the Canadian Psychiatric Association to review each position paper, policy statement and clinical practice guideline every five years after publication or last review. Any such document that has been published more than five years ago and does not explicitly state it has been reviewed and retained as an official document of the CPA, either with revisions or as originally published, should be considered as a historical reference document only.#
C anadian society recognizes that people have certain rights protected by the Canadian Charter of Rights and Freedoms. These include the right to life, liberty and security, and not to be subjected to cruel and unusual treatment or punishment. 1 Charter rights, including the right to self-determination and autonomy, may be infringed on in emergent and specific circumstances when acute mental illness manifests. The provinces and territories have various mental health and associated acts that allow for the restraint or detention of people with acute mental illness when they or others are at risk.
A definition of restrain is, "to place the person under control by the minimal use of such force, mechanical means or chemicals as is reasonable having regard to the person's physical and mental condition." 2 Restraint is not treatment as restraint is the temporary use of force to protect the patient or others. Seclusion involves the confinement of the person in a room or area from which free exit is prevented.
In certain, even more specific circumstances, the mental state of the person may require restraint or seclusion of the person to prevent harm. This type of emergency intervention is not only a further deprivation of liberty but also has associated risks to the person. Thus, their use should be only in clearly defined and specific situations when no alternatives exist.
An ideal world would be one in which detention under mental acts, seclusion and restraint are unneeded. 3 We, as a society and as a profession, should strive to move in that direction. However, not only are we not yet at that point but the business of acute and emergency psychiatry comes with the risk of physical harm to patients, staff and co-patients. All involved, including staff, also have a right to care and safety. However, should either restraint or seclusion be required, they should only be used in emergency situations when all appropriate, less restrictive measures have been exhausted or when the intervention is required to prevent immediate harm to the person or to others. It is important that staff is trained in crisis de-escalation and risk-reduction techniques. Attention should also be given to patient mix, space, layout, funding, treatment alternatives and recreational activities, among other factors that may reduce seclusion and restraint.
Each facility that uses this type of intervention should ensure that up-to-date policies are in place and that staff is familiar with them. Local policies should be in accordance with provincial, professional and national standards for the use of seclusion and restraint. Attention to best practices, including regular physician review, needs to take place.
Safeguards should include the need for a physician order and examination, regular observations, short time frames, humane settings and external reviews if the intervention extends beyond certain time periods. All efforts should be expended to review incidents requiring seclusion or restraint, and intervention should take place to prevent further use. 4,5 Formal tracking and monitoring of the use of all seclusion and restraint should occur wherever seclusion and or restraint are used. Research into mechanisms to reduce or shorten seclusion/restraint should be encouraged and supported.
As a profession, we should strive to continue to treat all our patients in a humane and fair manner, respecting their rights and freedoms. Ideally, no person should lose their right to liberty and freedom, but, unfortunately, acute mental illness may make that impossible, albeit for brief periods. The use of seclusion and restraint should be emergency measures used when all others fail or are unsuitable. These interventions may be essential to protect not only the patient but also others, including co-patients, members of the public and staff. If and when used, current monitored safeguards must be in place. | None | None |
1a08d974f3eba6c2362e47ac07e57d0b84b7e882 | cma | None | A new respiratory diseasecoronavirus disease 2019 (COVID-19)is spreading globally and there have been instances of COVID-19 spread in communities across the globe. The novel coronavirus COVID-19 may be introduced into an Adult Residential Facility (ARF) through individuals, such as residents, visitors and staff, with a link to International travel or to cases within the community. Staff members in ARFs have a critical role to play in identifying and managing potential cases of COVID-19. There are basic steps an ARF can take to help prevent the introduction or spread of viral infections like COVID-19. For information regarding COVID-19, visit the Canada.ca and WHO web site and the Government of New Brunswick (GNB) Coronavirus web site: www.gnb.ca/coronavirus- Fever (signs or history of fever) and/or - Cough (new or exacerbated chronic) Other symptoms may include:If a resident is experiencing symptoms of COVID-19, follow the ARF Clinical Care Pathways document and the control measures below. Residents that are symptomatic should be considered priority for testing for COVID-19.#
- Control access o Need to buzz in, check in with operator or designate before entering o Post signs at the entrance of the building instructing visitors not to visit. o Empower staff to politely ask visitors to leave. - Stringent active screening of employees at entry of facility.
- Exclude staff who have symptoms of respiratory infection from work. o Exclude staff who have travelled outside of New Brunswick. They should be excluded for 14 days from when they arrived back in New Brunswick.
- Monitor residents for respiratory symptoms and/or fever.
- Support hand and respiratory hygiene, as well as cough etiquette by residents, visitors, and employees. - Restrict residents with fever or acute respiratory symptoms to their room (See Appendix A). - Residents should maintain social distancing of 2 meters from others at all time.
# Hand Hygiene
Hand washing is an effective way to reduce microbial contamination of hands and should be part of the daily routine of residents, staff and visitors. Soap and water should always be used if hands are visibly soiled and after personal toileting. Use of an alcohol-based hand rub between 60-90% ethyl alcohol (70% or greater is best against non-enveloped viruses such as norovirus) is also appropriate and is the method of choice for health care settings. Waterless products that contain either no alcohol or alcohol in concentrations of less than 70% should not be used for hand hygiene.
- Ensure access to handwashing facilities following toileting and before meals or food preparation.
- Educate residents on how and when to wash their hands - Assist residents with hand hygiene where required.
- Ensure alcohol-based hand rub is available and maintained at the point of care, ideally both inside and outside of residents' room. - Ensure alcohol-based hand rub is located and maintained at entrances to the facility. - Soap and water are required if hands are visibly soiled and after personal toileting.
- Make sure tissues are available and any sink is well-stocked with soap and paper towels for hand washing. - Post signage directing all persons entering the building to wash their hands.
- Educate staff on the 4 critical moments for hand hygiene and review on a regular basis. - See Appendix B for directions for staff and Appendix C for residents and visitors regarding hand hygiene.
# Respiratory Hygiene
- Respiratory hygiene should be encouraged for residents who have respiratory symptoms. - Contain respiratory secretions by using tissues to cover the mouth and nose during coughing/sneezing, with prompt disposal into a no touch waste receptacle. - Cover the mouth and nose during coughing/sneezing against a sleeve/shoulder if tissues are not available. - Turn the head away from others when coughing/sneezing. - Maintain a spatial separation of 2 meters between residents with respiratory symptoms.
# Personal Protective Equipment (PPE)
Any aerosol-generating medical procedures (AGMP) performed on patients with suspect or confirmed COVID-19 require additional precautions including use of N95 respirator. Any AGMP should be avoided in the home environment. If an AGMP is required, consideration should be given to transferring the case/PUI to hospital due to the need for Additional Precautions.
AGMPs include:
- non-invasive positive pressure ventilation (CPAP, BiPAP)
- nebulized therapy Oxygen therapy is not considered an AGMP.
Provide the right supplies to ensure easy and correct use of PPE. (see Appendix D)
- Use of personal protective equipment (PPE) for asymptomatic patient care is not indicated. - Staff should wear disposable gloves when in direct contact with the ill person, or when in direct contact with the ill person's environment as well as soiled materials and surfaces. Hand hygiene should be performed before putting gloves on and after removing them - Post signs on the door or wall outside of the resident room that clearly describe the type of precautions needed and required PPE. - Make PPE, including procedure facemasks, eye protection, gowns, and gloves, available immediately outside of the resident room if required. - Position a trash can near the exit inside any resident room to make it easy for employees to discard PPE. - Residents who are not sick are discouraged from using facemasks.
# Staff:
- Provide staff with training and reminders on hand hygiene, proper use of PPE and their responsibility to monitor respiratory symptoms and stay home when sick. - Ensure staff have access to information on COVID-19, infection prevention and control precautions and have a chance to practice putting on and taking off protective equipment PHAC Infection Prevention Control Measures - Should staff develop symptoms while at work they should immediately exclude themselves from the resident environment, don a medical / procedure mask, clean their hands, and notify their supervisor, and call 1-833-475-0724. - If a staff is in contact with a known person with COVID-19 they should self-isolate at home for 14 days and monitor their symptoms. - If a staff is a contact of someone who travelled outside New Brunswick, they should selfmonitor for 14 days and self-isolate if develop symptoms.
- Health Care workers and staff that are symptomatic (new onset/exacerbation of chronic cough or fever) and provide direct patient contact should be tested for COVID-19 regardless of travel history, and they should stay off work and self-isolate until test results are negative. - A dedicated telephone line has been set up for Health Care workers and staff to call should they develop symptoms compatible with COVID-19; (new onset/exacerbation of chronic cough or fever) at 1-833-475-0724. - Plan for fluctuating staffing levels by identifying essential functions and creating plans for continuity of operations. - Staff should avoid working in different facilities when possible.
- If there is an outbreak in one of the facilities, restrict staff from moving around to a different facility.
- Consider what your residential care facility would require to maintain critical operations.
- Cross-train personnel to perform essential functions so the workplace can operate even if key staff are absent.
# Communication:
- Prepare and practice calm, reassuring and accurate communication with residents, their families and other stakeholders. Acknowledge the seriousness of the situation and the feelings of fear and anxiety that might produce. Share only the facts from trusted sources: o www.gnb/coronavirus o
- Keep residents and employees informed if a case of COVID-19 is identified in the ARF.
- Describe what actions the facility is taking to protect them, including answering their questions and explaining what they can do to protect themselves and their fellow staff and residents.
- Staff should monitor Public Health information to understand COVID-19 activity in their community to help inform their evaluation of individuals with unknown respiratory illness.
If there is transmission of COVID-19 in the community, in addition to implementing the precautions described above for residents with acute respiratory infection, facilities may also consult with public health authorities for additional guidance if required.
# Ill Residents:
Early epidemiologic evidence suggests that the majority of people who develop COVID-19 will have mild illness and may not require care in a hospital. It is important that people who do not require hospital-level care convalesce at home as long as effective self-isolation and appropriate monitoring (i.e. for worsening of illness) can be provided.
- Restrict residents with fever or acute respiratory symptoms to their room. If they must leave the room for medically necessary procedures, have them wear a medical / procedure facemask (if tolerated).
# April 4, 2020
Office of the Chief Medical Officer of Health
- In general, for care of residents with undiagnosed respiratory infection or COVID-19 use standard, contact, and droplet precautions with eye protection.
# Environment:
Environmental cleaning of the ill resident's room
- Clean and disinfect the room twice a day with special attention to all horizontal and frequently touched surfaces for the duration of illness. - Ensure all staff responsible for the environment adhere to required cleaning and disinfection practices. - Increased frequency of cleaning and disinfecting high-touch surfaces is significant in controlling the spread of microorganisms during a respiratory infection outbreak. Environmental cleaning products registered in Canada with a Drug Identification Number (DIN) and labelled as a broad-spectrum virucide are sufficient for use. All surfaces, especially those that are horizontal and frequently touched, should be cleaned and disinfected at least twice daily and when soiled.
# Resident care equipment
- Ensure all staff responsible for utilizing resident care equipment is adhering to required cleaning and disinfection practices. - All shared equipment is cleaned and disinfected before reuse by another resident.
- Appropriate cleaning techniques are used.
- Appropriate disinfection solutions are used.
- Ensure correct disinfectant concentration per manufacturer's directions.
- Ensure correct wet contact times.
- Electronic games, toys/games, personal effects are not to be shared.
- All care equipment (e.g., thermometers, blood pressure cuff, commodes, etc.) used with an ill resident should be dedicated to that resident. - Single person/resident devices are discarded after use with one resident (may be more than one use). - Single use devices are discarded in a waste receptacle after a single use on one resident.
# Laundry
- Contaminated laundry should be placed into a laundry bag or basket with a plastic liner and should not be shaken. - Gloves and a medical/procedure mask should be worn when in direct contact with contaminated laundry. - Clothing and linens belonging to the ill person can be washed together with other laundry, using regular laundry soap and hot water (60-90°C). - Laundry should be thoroughly dried.
- Hand hygiene should be performed after handling contaminated laundry and after April 4, 2020
Office of the Chief Medical Officer of Health removing gloves. - If the laundry container comes in contact with contaminated laundry, it should be disinfected Cohorting:
- Consider identifying dedicated employees to care for COVID-19 patients - Residents suspected or confirmed to have COVID-19 should be cared for in single rooms if possible. - Perform a risk assessment to determine resident placement and/ or suitability for cohorting when single rooms are limited. - Consider cohorting residents and staff to the affected unit/wing to ensure there is no contact with the staff/residents in the unaffected units/wings. If possible, further cohort staff, so one group cares for the ill residents and a second cohort cares for the non-ill residents on the affected unit/wing. - If cohorting is not possible in a shared room, privacy curtains should be drawn between beds. When possible there should be a minimum of two meters between the beds. - Residents who have recovered from COVID-19 can be cohorted with either group.
- Post infection control signage at the room entrance indicating droplet and contact precautions are required upon entry of the room. - When cohorting each resident must be isolated separately. Hand hygiene and a change of gown and gloves is required between contact with each resident and/or a resident's environment.
Admissions, Readmissions, Transfers:
- Notify facilities and Ambulance NB prior to transferring a resident with an acute respiratory illness, including suspected or confirmed COVID-19, to a higher level of care and advise of the required precautions for the resident being transported. - Admission with a resident diagnosed with COVID-19 into a ARF is not recommended.
- Movement/ transport of residents with suspected or confirmed C O V I D -19should be restricted to essential medical reasons. - Residents with COVID-19 who must leave their room for essential medical reasons should adhere to respiratory and hand hygiene and wear a mask. - Should it be necessary to readmit residents who have not had COVID-19 into a facility where there is a case of COVID-19 consult with the MOH.
# Communal /Social Activities:
- Cancel or re-schedule some or all social/group activities as needed - Restrict all well residents to their rooms as much as possible.
- Minimize activities to essential activities only. Such essential activities should be defined in advance consider the full spectrum of resident care needs (physical, mental, psychological). - Serve in-room meals to residents - Avoid touching your eyes, nose and mouth.
- Cough/sneeze into the band of your arm, not your hand, or into a tissue. Dispose of tissues in a lined waste container. - Individuals providing care can wear disposable gloves when in direct contact with the person in isolation, or when in direct contact with soiled materials and surfaces.
# Avoid contaminating common items and surfaces
- Do not share personal items with others, such as toothbrushes, towels, bed linen, utensils or electronic devices. - At least once daily, clean and disinfect surfaces that you touch often, like toilets, bedside tables, doorknobs, phones and television remotes using a diluted bleach solution (1 part bleach and 9 parts water) or regular household disinfectants. Household disinfects should have a DIN number and state that they are effective against viruses. - Clothing and linens belonging to the person in isolation can be washed together with other laundry, using regular laundry soap and hot water (60-90°C). Laundry should be thoroughly dried. Laundry containers can be disinfected as above.
- Place contaminated items that cannot be cleaned in a lined container, secure the contents and dispose of them with other household waste. - Put the lid of the toilet down before flushing.
# Monitor your symptoms daily
- Monitor your health and symptoms daily.
- Record your temperature daily. If you are taking medication to reduce fever (e.g. acetaminophen/ Tylenol or ibuprofen/Advil), record your temperature at least 4 hours after your last dose of fever-reducing medicine. - If you develop symptoms or your symptoms get worse immediately contact Tele-care 8-1-1 or Public Health. Describe your symptoms and history. They will provide advice on what you should do.
# Care for yourself
- Get some rest, eat a balanced diet and nutritious food, and stay hydrated with fluids like water. Over the counter medication can be used to reduce fever and aches. - Staying at home and not being able to do normal everyday activities outside of the home can be socially isolating. Stay in touch with family and friends by phone or computer. - Call your employer/school administration and share what Public Health has asked you to do so alternative work/study arrangements can be made where possible.
Appendix A Instructions for Self-isolating
# Self-Isolation
You have been asked to isolate yourself because you might have been diagnosed with COVID-19 or you might be at risk of developing COVID-19. Self-isolation means staying at home and avoiding contact with other people to help prevent the spread of disease to others in your home and your community.
For the next 14 days, it is expected that you take the following measures:
# Limit contact with others
- Do not leave home unless absolutely necessary, such as to seek medical care.
- Do not go to school, work, other public areas or use public transportation (e.g., buses, taxis). - Arrange to have groceries and supplies dropped off at your door to minimize contact.
- Stay in a separate room and use a separate bathroom from others in your home, if possible.
- If you have to be in contact with others, keep at least 2 metres between yourself and the other person. Keep interactions brief. - Avoid contact with individuals with chronic conditions, compromised immune systems and older adults. - Avoid contact with pets if you live with other people that may also be touching the pet.
- Limit the number of caregivers.
# Keep your hands clean
- Wash your hands often with soap and water for at least 20 seconds, and dry with disposable paper towels or dry reusable towel, replacing it when it becomes wet.
- Wet your hands and apply liquid soap or clean bar soap - Rub your hands vigorously together, scrubbing all skin surfaces - Pay special attention to the areas around your nails and between your fingers - Continue scrubbing for at least twenty seconds (as long as it takes to sing the happy birthday song twice) - Rinse your hands and dry them well - You can also remove dirt with a wet wipe and then use an alcohol-based hand sanitizer.
- Wash your hands
- Before and after preparing food;
- Before and after eating;
- After using the toilet;
- After you cough or sneeze,
- Before and after using a surgical/procedure mask - After disposing of waste or handling contaminated laundry;
- Whenever hands look dirty.
# Appendix B: Hand Hygiene for staff
Hand hygiene is the single most effective measure to prevent the transmission of Health Care Associated Infections (HCAI). It has been documented that HCAIs kill 8,000-12,000 Canadians every year. Good hand hygiene saves lives and reduces the strain on our healthcare system.
Hands must be cleaned at the point of care and it is crucial that hand hygiene is performed at these 4 critical times:
- Before initial resident/resident environment contact. Follow these simple instructions when using an alcohol-based hand rub:
- Apply a measured pump of the product (enough of the product to cover all surfaces of the hand) into your open palm. 2. Rub into hands covering all surfaces including front and back of hands, between fingers, around nails (especially cuticles), thumbs and wrists. 3. Rub until dry.
Hands must be fully dry before touching the resident or the environment/equipment for the alcohol-based hand rub to be effective and to eliminate the extremely rare risk of flammability in the presence of an oxygen-enriched environment.
# Appendix C: Hand Hygiene for Residents and Visitors
Hand washing is the single best way to prevent spread of infection. It is estimated that 80% of common infections such as the cold and flu are spread by unwashed hands. Good hand washing technique is easy to learn.
If there is visible soiling, hands should be washed with soap and water.
# Follow these simple instructions when washing your hands with plain soap and water:
- Wet hands with warm water. 2. Apply soap and rub for 15 -20 secondsall surfaces including front and back of hands, between fingers, around nails (especially cuticles), thumbs and wrists. 3. Rinse well. 4. Dry with a paper towel. 5. Turn off faucet without re contaminating hands, for example, use towel to turn off taps.
Follow these simple instructions when using an alcohol based hand rub:
- Apply a measured pump of the product (enough of the product to cover all surfaces of the hand) into your open palm. 2. Rub into hands covering all surfaces including front and back of hands, between fingers, around nails (especially cuticles), thumbs and wrists. Eye protection is recommended to protect the mucous membranes of the eyes during care or activities likely to generate splashes or sprays of body fluids including respiratory secretions.
- Eye protection should be worn over prescription eye glasses. Prescription eye glasses alone are not adequate protection against respiratory droplets. - Protective eye wear should be put on after putting on a mask.
- After applying eye protection, gloves should be donned (see above).
- To remove eye protection, first remove gloves and perform hand hygiene. Then remove the eye protection by handling the arms of goggles or sides or back of face shield. The front of the goggles or face shield is considered contaminated. - Discard the eye protection into a plastic lined waste container. If the eye protection is not intended for single use, clean it with soap and water and then disinfect it with a bleach solution of one part bleach to 9 parts water, being mindful not to contaminate the environment with the eye protection. - Perform hand hygiene.
# Gloves
Disposable single use gloves should be worn when in direct contact with the ill person, cleaning contaminated surfaces, and handling items soiled with body fluids, including dishes, cutlery, clothing, laundry, and waste for disposal. Gloves are not a substitute for hand hygiene; caregivers must perform hand hygiene before and after putting on and taking off gloves.
- Gloves should be removed, hand hygiene performed, and new gloves applied when they become soiled during care. - To remove gloves safely, with one of your gloved hands pull off your glove for the opposite hand from the fingertips, as you are pulling, form your glove into a ball within the palm of your gloved hand. To remove your other glove, slide your ungloved hand in under the glove at the wrist and gently roll inside out, and away from your body. Avoid touching the outside of the gloves with your bare hands. - Gloves must be changed and hand hygiene performed when they are torn.
- Discard the gloves in a plastic-lined waste container.
- Perform hand hygiene.
- Double-gloving is not necessary.
Reusable utility gloves may be used; however, they must be cleaned with soap and water and decontaminated after each use with a bleach solution of one part bleach with nine parts water (to make a 0.5% sodium hypochlorite solution). | A new respiratory diseasecoronavirus disease 2019 (COVID-19)is spreading globally and there have been instances of COVID-19 spread in communities across the globe. The novel coronavirus COVID-19 may be introduced into an Adult Residential Facility (ARF) through individuals, such as residents, visitors and staff, with a link to International travel or to cases within the community. Staff members in ARFs have a critical role to play in identifying and managing potential cases of COVID-19. There are basic steps an ARF can take to help prevent the introduction or spread of viral infections like COVID-19. For information regarding COVID-19, visit the Canada.ca and WHO web site and the Government of New Brunswick (GNB) Coronavirus web site: www.gnb.ca/coronavirus• Fever (signs or history of fever) and/or • Cough (new or exacerbated chronic) Other symptoms may include:If a resident is experiencing symptoms of COVID-19, follow the ARF Clinical Care Pathways document and the control measures below. Residents that are symptomatic should be considered priority for testing for COVID-19.#
• Control access o Need to buzz in, check in with operator or designate before entering o Post signs at the entrance of the building instructing visitors not to visit. o Empower staff to politely ask visitors to leave. • Stringent active screening of employees at entry of facility.
o Exclude staff who have symptoms of respiratory infection from work. o Exclude staff who have travelled outside of New Brunswick. They should be excluded for 14 days from when they arrived back in New Brunswick.
• Monitor residents for respiratory symptoms and/or fever.
• Support hand and respiratory hygiene, as well as cough etiquette by residents, visitors, and employees. • Restrict residents with fever or acute respiratory symptoms to their room (See Appendix A). • Residents should maintain social distancing of 2 meters from others at all time.
# Hand Hygiene
Hand washing is an effective way to reduce microbial contamination of hands and should be part of the daily routine of residents, staff and visitors. Soap and water should always be used if hands are visibly soiled and after personal toileting. Use of an alcohol-based hand rub between 60-90% ethyl alcohol (70% or greater is best against non-enveloped viruses such as norovirus) is also appropriate and is the method of choice for health care settings. Waterless products that contain either no alcohol or alcohol in concentrations of less than 70% should not be used for hand hygiene.
• Ensure access to handwashing facilities following toileting and before meals or food preparation.
• Educate residents on how and when to wash their hands • Assist residents with hand hygiene where required.
• Ensure alcohol-based hand rub is available and maintained at the point of care, ideally both inside and outside of residents' room. • Ensure alcohol-based hand rub is located and maintained at entrances to the facility. • Soap and water are required if hands are visibly soiled and after personal toileting.
• Make sure tissues are available and any sink is well-stocked with soap and paper towels for hand washing. • Post signage directing all persons entering the building to wash their hands.
• Educate staff on the 4 critical moments for hand hygiene and review on a regular basis. • See Appendix B for directions for staff and Appendix C for residents and visitors regarding hand hygiene.
# Respiratory Hygiene
• Respiratory hygiene should be encouraged for residents who have respiratory symptoms. • Contain respiratory secretions by using tissues to cover the mouth and nose during coughing/sneezing, with prompt disposal into a no touch waste receptacle. • Cover the mouth and nose during coughing/sneezing against a sleeve/shoulder if tissues are not available. • Turn the head away from others when coughing/sneezing. • Maintain a spatial separation of 2 meters between residents with respiratory symptoms.
# Personal Protective Equipment (PPE)
Any aerosol-generating medical procedures (AGMP) performed on patients with suspect or confirmed COVID-19 require additional precautions including use of N95 respirator. Any AGMP should be avoided in the home environment. If an AGMP is required, consideration should be given to transferring the case/PUI to hospital due to the need for Additional Precautions.
AGMPs include:
• non-invasive positive pressure ventilation (CPAP, BiPAP)
• nebulized therapy Oxygen therapy is not considered an AGMP.
Provide the right supplies to ensure easy and correct use of PPE. (see Appendix D)
• Use of personal protective equipment (PPE) for asymptomatic patient care is not indicated. • Staff should wear disposable gloves when in direct contact with the ill person, or when in direct contact with the ill person's environment as well as soiled materials and surfaces. Hand hygiene should be performed before putting gloves on and after removing them • Post signs on the door or wall outside of the resident room that clearly describe the type of precautions needed and required PPE. • Make PPE, including procedure facemasks, eye protection, gowns, and gloves, available immediately outside of the resident room if required. • Position a trash can near the exit inside any resident room to make it easy for employees to discard PPE. • Residents who are not sick are discouraged from using facemasks.
# Staff:
• Provide staff with training and reminders on hand hygiene, proper use of PPE and their responsibility to monitor respiratory symptoms and stay home when sick. • Ensure staff have access to information on COVID-19, infection prevention and control precautions and have a chance to practice putting on and taking off protective equipment PHAC Infection Prevention Control Measures • Should staff develop symptoms while at work they should immediately exclude themselves from the resident environment, don a medical / procedure mask, clean their hands, and notify their supervisor, and call 1-833-475-0724. • If a staff is in contact with a known person with COVID-19 they should self-isolate at home for 14 days and monitor their symptoms. • If a staff is a contact of someone who travelled outside New Brunswick, they should selfmonitor for 14 days and self-isolate if develop symptoms.
• Health Care workers and staff that are symptomatic (new onset/exacerbation of chronic cough or fever) and provide direct patient contact should be tested for COVID-19 regardless of travel history, and they should stay off work and self-isolate until test results are negative. • A dedicated telephone line has been set up for Health Care workers and staff to call should they develop symptoms compatible with COVID-19; (new onset/exacerbation of chronic cough or fever) at 1-833-475-0724. • Plan for fluctuating staffing levels by identifying essential functions and creating plans for continuity of operations. • Staff should avoid working in different facilities when possible.
• If there is an outbreak in one of the facilities, restrict staff from moving around to a different facility.
• Consider what your residential care facility would require to maintain critical operations.
• Cross-train personnel to perform essential functions so the workplace can operate even if key staff are absent.
# Communication:
• Prepare and practice calm, reassuring and accurate communication with residents, their families and other stakeholders. Acknowledge the seriousness of the situation and the feelings of fear and anxiety that might produce. Share only the facts from trusted sources: o www.gnb/coronavirus o https://www.canada.ca/en/public-health/services/diseases/2019-novelcoronavirus-infection.html
• Keep residents and employees informed if a case of COVID-19 is identified in the ARF.
• Describe what actions the facility is taking to protect them, including answering their questions and explaining what they can do to protect themselves and their fellow staff and residents.
• Staff should monitor Public Health information to understand COVID-19 activity in their community to help inform their evaluation of individuals with unknown respiratory illness.
If there is transmission of COVID-19 in the community, in addition to implementing the precautions described above for residents with acute respiratory infection, facilities may also consult with public health authorities for additional guidance if required.
# Ill Residents:
Early epidemiologic evidence suggests that the majority of people who develop COVID-19 will have mild illness and may not require care in a hospital. It is important that people who do not require hospital-level care convalesce at home as long as effective self-isolation and appropriate monitoring (i.e. for worsening of illness) can be provided.
• Restrict residents with fever or acute respiratory symptoms to their room. If they must leave the room for medically necessary procedures, have them wear a medical / procedure facemask (if tolerated).
# April 4, 2020
Office of the Chief Medical Officer of Health
• In general, for care of residents with undiagnosed respiratory infection or COVID-19 use standard, contact, and droplet precautions with eye protection.
# Environment:
Environmental cleaning of the ill resident's room
• Clean and disinfect the room twice a day with special attention to all horizontal and frequently touched surfaces for the duration of illness. • Ensure all staff responsible for the environment adhere to required cleaning and disinfection practices. • Increased frequency of cleaning and disinfecting high-touch surfaces is significant in controlling the spread of microorganisms during a respiratory infection outbreak. Environmental cleaning products registered in Canada with a Drug Identification Number (DIN) and labelled as a broad-spectrum virucide are sufficient for use. All surfaces, especially those that are horizontal and frequently touched, should be cleaned and disinfected at least twice daily and when soiled.
# Resident care equipment
• Ensure all staff responsible for utilizing resident care equipment is adhering to required cleaning and disinfection practices. • All shared equipment is cleaned and disinfected before reuse by another resident.
• Appropriate cleaning techniques are used.
• Appropriate disinfection solutions are used.
• Ensure correct disinfectant concentration per manufacturer's directions.
• Ensure correct wet contact times.
• Electronic games, toys/games, personal effects are not to be shared.
• All care equipment (e.g., thermometers, blood pressure cuff, commodes, etc.) used with an ill resident should be dedicated to that resident. • Single person/resident devices are discarded after use with one resident (may be more than one use). • Single use devices are discarded in a waste receptacle after a single use on one resident.
# Laundry
• Contaminated laundry should be placed into a laundry bag or basket with a plastic liner and should not be shaken. • Gloves and a medical/procedure mask should be worn when in direct contact with contaminated laundry. • Clothing and linens belonging to the ill person can be washed together with other laundry, using regular laundry soap and hot water (60-90°C). • Laundry should be thoroughly dried.
• Hand hygiene should be performed after handling contaminated laundry and after April 4, 2020
Office of the Chief Medical Officer of Health removing gloves. • If the laundry container comes in contact with contaminated laundry, it should be disinfected Cohorting:
• Consider identifying dedicated employees to care for COVID-19 patients • Residents suspected or confirmed to have COVID-19 should be cared for in single rooms if possible. • Perform a risk assessment to determine resident placement and/ or suitability for cohorting when single rooms are limited. • Consider cohorting residents and staff to the affected unit/wing to ensure there is no contact with the staff/residents in the unaffected units/wings. If possible, further cohort staff, so one group cares for the ill residents and a second cohort cares for the non-ill residents on the affected unit/wing. • If cohorting is not possible in a shared room, privacy curtains should be drawn between beds. When possible there should be a minimum of two meters between the beds. • Residents who have recovered from COVID-19 can be cohorted with either group.
• Post infection control signage at the room entrance indicating droplet and contact precautions are required upon entry of the room. • When cohorting each resident must be isolated separately. Hand hygiene and a change of gown and gloves is required between contact with each resident and/or a resident's environment.
Admissions, Readmissions, Transfers:
• Notify facilities and Ambulance NB prior to transferring a resident with an acute respiratory illness, including suspected or confirmed COVID-19, to a higher level of care and advise of the required precautions for the resident being transported. • Admission with a resident diagnosed with COVID-19 into a ARF is not recommended.
• Movement/ transport of residents with suspected or confirmed C O V I D -19should be restricted to essential medical reasons. • Residents with COVID-19 who must leave their room for essential medical reasons should adhere to respiratory and hand hygiene and wear a mask. • Should it be necessary to readmit residents who have not had COVID-19 into a facility where there is a case of COVID-19 consult with the MOH.
# Communal /Social Activities:
• Cancel or re-schedule some or all social/group activities as needed • Restrict all well residents to their rooms as much as possible.
• Minimize activities to essential activities only. Such essential activities should be defined in advance consider the full spectrum of resident care needs (physical, mental, psychological). • Serve in-room meals to residents • Avoid touching your eyes, nose and mouth.
• Cough/sneeze into the band of your arm, not your hand, or into a tissue. Dispose of tissues in a lined waste container. • Individuals providing care can wear disposable gloves when in direct contact with the person in isolation, or when in direct contact with soiled materials and surfaces.
# Avoid contaminating common items and surfaces
• Do not share personal items with others, such as toothbrushes, towels, bed linen, utensils or electronic devices. • At least once daily, clean and disinfect surfaces that you touch often, like toilets, bedside tables, doorknobs, phones and television remotes using a diluted bleach solution (1 part bleach and 9 parts water) or regular household disinfectants. Household disinfects should have a DIN number and state that they are effective against viruses. • Clothing and linens belonging to the person in isolation can be washed together with other laundry, using regular laundry soap and hot water (60-90°C). Laundry should be thoroughly dried. Laundry containers can be disinfected as above.
• Place contaminated items that cannot be cleaned in a lined container, secure the contents and dispose of them with other household waste. • Put the lid of the toilet down before flushing.
# Monitor your symptoms daily
• Monitor your health and symptoms daily.
• Record your temperature daily. If you are taking medication to reduce fever (e.g. acetaminophen/ Tylenol or ibuprofen/Advil), record your temperature at least 4 hours after your last dose of fever-reducing medicine. • If you develop symptoms or your symptoms get worse immediately contact Tele-care 8-1-1 or Public Health. Describe your symptoms and history. They will provide advice on what you should do.
# Care for yourself
• Get some rest, eat a balanced diet and nutritious food, and stay hydrated with fluids like water. Over the counter medication can be used to reduce fever and aches. • Staying at home and not being able to do normal everyday activities outside of the home can be socially isolating. Stay in touch with family and friends by phone or computer. • Call your employer/school administration and share what Public Health has asked you to do so alternative work/study arrangements can be made where possible.
#
Appendix A Instructions for Self-isolating
# Self-Isolation
You have been asked to isolate yourself because you might have been diagnosed with COVID-19 or you might be at risk of developing COVID-19. Self-isolation means staying at home and avoiding contact with other people to help prevent the spread of disease to others in your home and your community.
For the next 14 days, it is expected that you take the following measures:
# Limit contact with others
• Do not leave home unless absolutely necessary, such as to seek medical care.
• Do not go to school, work, other public areas or use public transportation (e.g., buses, taxis). • Arrange to have groceries and supplies dropped off at your door to minimize contact.
• Stay in a separate room and use a separate bathroom from others in your home, if possible.
• If you have to be in contact with others, keep at least 2 metres between yourself and the other person. Keep interactions brief. • Avoid contact with individuals with chronic conditions, compromised immune systems and older adults. • Avoid contact with pets if you live with other people that may also be touching the pet.
• Limit the number of caregivers.
# Keep your hands clean
• Wash your hands often with soap and water for at least 20 seconds, and dry with disposable paper towels or dry reusable towel, replacing it when it becomes wet.
• Wet your hands and apply liquid soap or clean bar soap • Rub your hands vigorously together, scrubbing all skin surfaces • Pay special attention to the areas around your nails and between your fingers • Continue scrubbing for at least twenty seconds (as long as it takes to sing the happy birthday song twice) • Rinse your hands and dry them well • You can also remove dirt with a wet wipe and then use an alcohol-based hand sanitizer.
• Wash your hands
• Before and after preparing food;
• Before and after eating;
• After using the toilet;
• After you cough or sneeze,
• Before and after using a surgical/procedure mask • After disposing of waste or handling contaminated laundry;
• Whenever hands look dirty.
# Appendix B: Hand Hygiene for staff
Hand hygiene is the single most effective measure to prevent the transmission of Health Care Associated Infections (HCAI). It has been documented that HCAIs kill 8,000-12,000 Canadians every year. Good hand hygiene saves lives and reduces the strain on our healthcare system.
Hands must be cleaned at the point of care and it is crucial that hand hygiene is performed at these 4 critical times:
1. Before initial resident/resident environment contact. Follow these simple instructions when using an alcohol-based hand rub:
1. Apply a measured pump of the product (enough of the product to cover all surfaces of the hand) into your open palm. 2. Rub into hands covering all surfaces including front and back of hands, between fingers, around nails (especially cuticles), thumbs and wrists. 3. Rub until dry.
Hands must be fully dry before touching the resident or the environment/equipment for the alcohol-based hand rub to be effective and to eliminate the extremely rare risk of flammability in the presence of an oxygen-enriched environment.
# Appendix C: Hand Hygiene for Residents and Visitors
Hand washing is the single best way to prevent spread of infection. It is estimated that 80% of common infections such as the cold and flu are spread by unwashed hands. Good hand washing technique is easy to learn.
If there is visible soiling, hands should be washed with soap and water.
# Follow these simple instructions when washing your hands with plain soap and water:
1. Wet hands with warm water. 2. Apply soap and rub for 15 -20 secondsall surfaces including front and back of hands, between fingers, around nails (especially cuticles), thumbs and wrists. 3. Rinse well. 4. Dry with a paper towel. 5. Turn off faucet without re contaminating hands, for example, use towel to turn off taps.
Follow these simple instructions when using an alcohol based hand rub:
1. Apply a measured pump of the product (enough of the product to cover all surfaces of the hand) into your open palm. 2. Rub into hands covering all surfaces including front and back of hands, between fingers, around nails (especially cuticles), thumbs and wrists. Eye protection is recommended to protect the mucous membranes of the eyes during care or activities likely to generate splashes or sprays of body fluids including respiratory secretions.
• Eye protection should be worn over prescription eye glasses. Prescription eye glasses alone are not adequate protection against respiratory droplets. • Protective eye wear should be put on after putting on a mask.
• After applying eye protection, gloves should be donned (see above).
• To remove eye protection, first remove gloves and perform hand hygiene. Then remove the eye protection by handling the arms of goggles or sides or back of face shield. The front of the goggles or face shield is considered contaminated. • Discard the eye protection into a plastic lined waste container. If the eye protection is not intended for single use, clean it with soap and water and then disinfect it with a bleach solution of one part bleach to 9 parts water, being mindful not to contaminate the environment with the eye protection. • Perform hand hygiene.
# Gloves
Disposable single use gloves should be worn when in direct contact with the ill person, cleaning contaminated surfaces, and handling items soiled with body fluids, including dishes, cutlery, clothing, laundry, and waste for disposal. Gloves are not a substitute for hand hygiene; caregivers must perform hand hygiene before and after putting on and taking off gloves.
• Gloves should be removed, hand hygiene performed, and new gloves applied when they become soiled during care. • To remove gloves safely, with one of your gloved hands pull off your glove for the opposite hand from the fingertips, as you are pulling, form your glove into a ball within the palm of your gloved hand. To remove your other glove, slide your ungloved hand in under the glove at the wrist and gently roll inside out, and away from your body. Avoid touching the outside of the gloves with your bare hands. • Gloves must be changed and hand hygiene performed when they are torn.
• Discard the gloves in a plastic-lined waste container.
• Perform hand hygiene.
• Double-gloving is not necessary.
Reusable utility gloves may be used; however, they must be cleaned with soap and water and decontaminated after each use with a bleach solution of one part bleach with nine parts water (to make a 0.5% sodium hypochlorite solution). | None | None |
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