The relative risks were calculated using a random-effects model with Mantel-Haenszel weighting. The size of data markers indicates the weight of the study. Error bars indicate 95% CIs.
aVasopressin (or analogue [ie, terlipressin, selepressin, or pituitrin]) + catecholamine vasopressors.
bRisk of bias categories for requirement for renal replacement therapy are the same as those for atrial fibrillation, as summarized in Table 1.
eAppendix 1. MEDLINE Search Strategy
eAppendix 2. EMBASE Search Strategy
eAppendix 3. Cochrane CENTRAL Search Strategy
eAppendix 4. Basis for Outcome Selection
eAppendix 5. Outcome Importance for Choice of Vasopressor in Patients With Vasodilatory Shock
eAppendix 6. Characteristics of Included Studies
eAppendix 7. Characteristics of Important Excluded Studies
eAppendix 8. Characteristics of Ongoing Studies
eAppendix 9. Risk of Bias Graphs: Review Authors’ Judgments About Each Risk of Bias Item Presented as Percentages Across All 23 Randomized Trials
eAppendix 10. Risk of Bias Summary: Review Authors’ Judgments About Each Risk of Bias Item for Each Included Study
eAppendix 11. Forest Plots for All Outcomes, Including Sensitivity Analyses
eAppendix 12. Funnel Plots
eAppendix 13. Reported lengths of stay in primary studies and transformation of median and interquartile range to mean and standarddeviation
eAppendix 14. Summary of Findings Table
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McIntyre WF, Um KJ, Alhazzani W, et al. Association of Vasopressin Plus Catecholamine Vasopressors vs Catecholamines Alone With Atrial Fibrillation in Patients With Distributive Shock: A Systematic Review and Meta-analysis. JAMA. 2018;319(18):1889–1900. doi:10.1001/jama.2018.4528
In patients with distributive shock (a condition due to excessive vasodilation, most frequently from severe infection), is the addition of vasopressin to catecholamine vasopressors superior to catecholamine vasopressors alone for atrial fibrillation?
In this systematic review and meta-analysis of 23 trials that included 3088 patients with distributive shock, the addition of vasopressin to catecholamine vasopressors compared with catecholamine vasopressors alone was significantly associated with a lower risk of atrial fibrillation (relative risk, 0.77).
Addition of vasopressin to catecholamines may offer a clinical advantage for prevention of atrial fibrillation.
Vasopressin is an alternative to catecholamine vasopressors for patients with distributive shock—a condition due to excessive vasodilation, most frequently from severe infection. Blood pressure support with a noncatecholamine vasopressor may reduce stimulation of adrenergic receptors and decrease myocardial oxygen demand. Atrial fibrillation is common with catecholamines and is associated with adverse events, including mortality and increased length of stay (LOS).
To determine whether treatment with vasopressin + catecholamine vasopressors compared with catecholamine vasopressors alone was associated with reductions in the risk of adverse events.
MEDLINE, EMBASE, and CENTRAL were searched from inception to February 2018. Experts were asked and meta-registries searched to identify ongoing trials.
Pairs of reviewers identified randomized clinical trials comparing vasopressin in combination with catecholamine vasopressors to catecholamines alone for patients with distributive shock.
Data Extraction and Synthesis
Two reviewers abstracted data independently. A random-effects model was used to combine data.
Main Outcomes and Measures
The primary outcome was atrial fibrillation. Other outcomes included mortality, requirement for renal replacement therapy (RRT), myocardial injury, ventricular arrhythmia, stroke, and LOS in the intensive care unit and hospital. Measures of association are reported as risk ratios (RRs) for clinical outcomes and mean differences for LOS.
Twenty-three randomized clinical trials were identified (3088 patients; mean age, 61.1 years [14.2]; women, 45.3%). High-quality evidence supported a lower risk of atrial fibrillation associated with vasopressin treatment (RR, 0.77 [95% CI, 0.67 to 0.88]; risk difference [RD], −0.06 [95% CI, −0.13 to 0.01]). For mortality, the overall RR estimate was 0.89 (95% CI, 0.82 to 0.97; RD, −0.04 [95% CI, −0.07 to 0.00]); however, when limited to trials at low risk of bias, the RR estimate was 0.96 (95% CI, 0.84 to 1.11). The overall RR estimate for RRT was 0.74 (95% CI, 0.51 to 1.08; RD, −0.07 [95% CI, −0.12 to −0.01]). However, in an analysis limited to trials at low risk of bias, RR was 0.70 (95% CI, 0.53 to 0.92, P for interaction = .77). There were no significant differences in the pooled risks for other outcomes.
Conclusions and Relevance
In this systematic review and meta-analysis, the addition of vasopressin to catecholamine vasopressors compared with catecholamines alone was associated with a lower risk of atrial fibrillation. Findings for secondary outcomes varied.
Quiz Ref IDIn distributive shock, widespread vasodilation leads to decreased systemic vascular resistances and mean arterial pressure (MAP).1 If not reversed, end-organ hypoperfusion results in significant morbidity; mortality rates reached 50% in observational studies conducted in 2013 and 2014.2,3 Sepsis is the most common cause of distributive shock. It can also occur after cardiovascular surgery, spinal cord injury, or arise as a consequence of anaphylaxis or prolonged hypoperfusion.1,4
Quiz Ref IDManaging distributive shock involves treating the underlying cause, volume resuscitation, and infusing vasopressors to maintain a perfusing blood pressure.5,6 Clinicians frequently use catecholaminergic vasopressors (eg, norepinephrine, epinephrine, dopamine, dobutamine). However, catecholamines have adverse effects including myocardial ischemia and arrhythmia,6-8 which may affect outcomes.9
Atrial fibrillation is a common adverse event in patients with distributive shock and is independently associated with morbidity, mortality, and increases in length of stay (LOS).10-12
Vasopressin, an endogenous peptide hormone, can also be used as a vasopressor. Patients with septic shock have relative vasopressin deficiency and exogenous administration of vasopressin raises blood pressure by increasing vascular tone.13 By reducing the requirement for catecholamines, it decreases the stimulation of arrhythmogenic myocardial β1-receptors and associated myocardial oxygen demand.7,14 This, among other mechanisms, may translate into a reduction in adverse events, including atrial fibrillation, injury to other organs, and death.7,15 The most recent Surviving Sepsis guidelines suggest adding vasopressin to norepinephrine to raise MAP to target, or adding vasopressin to decrease norepinephrine dosage (weak recommendations, moderate quality of evidence).5
The objective of this systematic review and meta-analysis was to determine the association between treatment with vasopressin in addition to catecholamine vasopressors on atrial fibrillation, morbidity, and mortality compared with catecholamines alone.
The study protocol was registered with PROSPERO (2017:CRD42017059058). The conduct and reporting of the study follow the PRISMA guidelines.
Randomized clinical trials were included, irrespective of publication status, date of publication, risk of bias, outcomes published, or language. Trials were included if they enrolled adults with distributive shock, including septic shock, post–cardiovascular surgery vasoplegia, neurogenic shock, and anaphylaxis. Included studies had to compare the administration of vasopressin (or analogues [eg, terlipressin, selepressin]) with or without concomitant catecholaminergic vasopressors with the administration of catecholaminergic vasopressors alone, irrespective of dose, duration, or co-intervention.
The primary outcome was atrial fibrillation. Secondary outcomes were mortality, requirement for renal replacement therapy (RRT), myocardial injury, ventricular arrhythmia, stroke, and LOS in the intensive care unit (ICU) and hospital (eAppendices 4-5 in the Supplement). Acute kidney injury and digital ischemia were post hoc outcomes.
The outcomes were accepted as defined by study authors. For mortality, mortality at 28 to 30 days, at longest follow-up, and in-hospital were considered equivalent; ICU mortality was not pooled. Under digital ischemia, limb ischemia and peripheral ischemia or cyanosis were included. Myocardial infarction, myocardial ischemia, troponin rise, and acute coronary syndrome were pooled under myocardial injury. Ventricular tachycardia and fibrillation were pooled as ventricular arrhythmia. Cerebrovascular accident was combined with stroke.
MEDLINE, EMBASE, and CENTRAL were searched for keywords describing the condition, intervention, or comparator from inception to February 25, 2018 (eAppendices 1-3 in the Supplement). An information specialist reviewed the search strategies.
Trial registries were searched for ongoing and unpublished clinical trials via http://www.isrctn.com using the multiple database search option metaRegister of Controlled Trials and the World Health Organization trial registry. Authors hand-searched the conference proceedings for the scientific sessions of the European Society of Intensive Care Medicine, the Society of Critical Care Medicine, and the American Thoracic Society in the last 2 years. The references of eligible papers were screened and experts were consulted to identify additional trials.
Two reviewers independently screened studies’ titles and abstracts for eligibility. Full papers of the potentially eligible studies were retrieved. The same 2 reviewers then independently screened full texts in duplicate and recorded the main reason for exclusion. Disagreements were resolved through discussion.
Independently, 2 reviewers abstracted data on intervention and outcome. They also recorded study and patient characteristics including age, sex, type of shock, and concomitant conditions (eg, cirrhosis, malignancy). They compared results and resolved disagreements by discussion with a third party. Authors were contacted to clarify ambiguities and to request data on outcomes missing in primary reports.
In duplicate, 2 review authors assessed risk of bias.16 In each trial, reviewers evaluated the following domains: sequence generation, allocation concealment, blinding of patients and personnel, blinding of outcome assessors, incomplete outcome data, and selective reporting. The results were compared and disagreements resolved by discussion. Performance and detection bias were assessed separately. All open-label studies were classified as being at high risk of performance bias. A priori, the decision was made to classify open-label designs as “likely low risk of bias” for detection bias for mortality, stroke, and LOS in the absence of other concerns, but to judge “likely high risk of bias” for detection bias for atrial fibrillation, RRT, digital ischemia, myocardial injury, and ventricular arrhythmia. For analysis and presentation purposes, risk of bias was dichotomized as high (or likely high) or low (or likely low).
For subgroup analyses, the study-level risk of bias was assessed for each outcome. If a study was at risk of selection, performance, detection, or reporting bias for that outcome, it was categorized as high risk of bias. Additionally, studies at risk of attrition bias were categorized as high risk of bias for mortality.
The main reported standard association measure for clinical outcomes was risk ratios (RRs) and mean differences for LOS. Risk difference and absolute risk difference were also calculated for clinical outcomes. The absolute risk difference was obtained by applying the RRs with 95% CIs to the baseline risk in the control group. To permit meta-analysis, if a study reporting on LOS provided a median and a measure of dispersion, this was converted to mean and standard deviation assuming a normal distribution.17
Clinical and methodological heterogeneity were assessed based on study characteristics. Statistical heterogeneity was measured with the I2 statistic. An I2 statistic greater than 50% was considered as showing substantial heterogeneity.16
RevMan (Cochrane Collaboration), version 5.3, was used to combine data quantitatively when clinical heterogeneity was nonsubstantial. A random-effects model with Mantel-Haenszel weighting was used because several comparisons were expected to show heterogeneity. After recognizing that a substantial proportion of the weight for atrial fibrillation was contributed by a single study,18 we combined data for this outcome with a fixed-effect model in a sensitivity analysis. For trials in which patients crossed over to the other treatment, the analysis was according to their first assigned group (intention-to-treat principle). Two-sided P values less than .05 were considered statistically significant.
Prespecified subgroup analyses were performed hypothesizing that patients with sepsis would derive greater benefit vs cardiovascular surgery. As a separate sensitivity analysis for RRT, the outcome definition was changed to acute kidney injury, as defined by study authors. P values for interaction between subgroups were tested.
The GRADE (Grades of Recommendation, Assessment, Development, and Evaluation) approach19 was used to grade the quality of evidence. GRADE appraises the confidence in estimates of effect by considering within-study risk of bias, directness of the evidence, heterogeneity of the data, precision of effect estimates, and risk of publication bias. Funnel plots of standard errors vs effect estimates were inspected for publication bias and small-study effects.
The electronic search resulted in 1210 unique citations (Figure 1). After reference and full-text screening, 23 studies met eligibility criteria. Details on excluded and included studies and 3 potentially relevant ongoing studies are available (eAppendices 6-8 in the Supplement).
The 23 studies that compared vasopressin in combination with catecholamines vs catecholamines alone included 3088 patients (mean age, 61.1 years [14.2]; women, 45.3%) (Table 1). Five trials were multicenter.30,33,37,39,40 Twenty-two studies included patients with septic shock.20-41 Two studies evaluated patients with post–cardiac surgery vasoplegia.18,28 Vasopressin was the intervention in 13 trials,18,23,24,27-30,33-37,39 whereas 9 studied terlipressin,20-22,25,26,32,35,38,41 1 studied selepressin,40 and 1 studied pituitrin (a mixture of vasopressin and oxytocin).31 One 3-group study compared vasopressin vs terlipressin vs norepinephrine alone.35 Five studies were published only as abstracts.18,21,27,36,38
Fifteen of 23 trials were not blinded (eAppendices 9-10 in the Supplement). Performance bias due to lack of blinding was judged to have an important effect on all outcomes; patients with distributive shock are critically ill and receiving many concomitant interventions that could be influenced by choice of concomitant vasopressor. Atrial fibrillation, myocardial injury, and digital ischemia are vulnerable to detection bias from differential capture and subjective interpretation; lack of blinding of clinicians and outcome assessors may influence these outcomes. The decision to start RRT could also be subjective. Other outcomes were judged to be at low risk of detection bias in the absence of blinding. Two studies were assessed to be at risk of selection bias due to inadequate randomization31,36; they did not describe their randomization process and had significant between-group imbalances. Nine studies (39%) reported the information necessary to make a definitive judgment for selection bias. Authors relied on imbalances between groups and overall methodological quality of the study to make this judgment. Attrition was found in 7 studies,18,25,30,31,36,40,41 and judged as having an effect on mortality (Table 2 and Figure 2A). Reporting bias was not detected. “Other bias” was judged to be present when studies were published as abstracts only. Prespecified sensitivity analyses were performed to assess the robustness of estimates to risk of bias if studies were dichotomized according to their risk of bias.
Pooling data from 13 studies (4 studies with 0 events in either group, 1462 patients, 374 events) demonstrated a significant reduction in the risk of atrial fibrillation associated with the administration of vasopressin (RR, 0.77 [95% CI, 0.67 to 0.88], I2 = 1%; risk difference [RD], −0.06 [95% CI, −0.13 to 0.01]) (Figure 2A). Based on the GRADE framework, this was judged to be high-quality evidence (eAppendix 13 in the Supplement). This result was driven by the study by Hajjar et al,18 which carried 74.8% of the weight. In absolute terms, the absolute effect is that 68 fewer people per 1000 patients (95% CI, 36 to 98) will experience atrial fibrillation when vasopressin is added to catecholaminergic vasopressors. In a sensitivity analysis excluding the 7 studies at high risk of bias for lack of blinding of outcome assessors,20,26-28,33,35 the estimate of effect was unchanged (eAppendix 11 in the Supplement). In a second sensitivity analysis, patients with sepsis and post–cardiac surgery were considered separately. For the subgroup of post–cardiac surgery patients,18,28 the resultant RR estimate was 0.77 (95% CI, 0.67 to 0.88), not significantly different than in patients with sepsis (RR, 0.76 [95% CI, 0.55 to 1.05], P for interaction = .97) (Table 2). Even though the crude rate of atrial fibrillation in this post–cardiac surgery population (73%) was considerably higher than in the sepsis studies (13%), the relative effect estimate was similar in both groups.
Mortality data were available from 17 studies (2904 patients, 1123 events) (Figure 2B). When pooled, the administration of vasopressin in addition to catecholamines was associated with a reduction in mortality (RR, 0.89 [95% CI, 0.82 to 0.97], P = .009, I2 = 0; RD, −0.04 [95% CI, −0.07 to 0.00]). In absolute terms, 45 lives (95% CI, 12 to 73) would be saved per 1000 patients treated with vasopressin. However, when limited to the 2 trials at low risk of bias (Table 3),24,39 the RR estimate was 0.96 (95% CI, 0.84 to 1.11).
Six trials with a total of 805 patients (222 events) reported on RRT (Figure 3A). When combined, vasopressin was associated with a reduced risk for RRT, but the pooled estimate did not reach statistical significance and showed substantial heterogeneity (RR, 0.74 [95% CI, 0.51 to 1.08], I2 = 70%; RD, −0.07 [95% CI, −0.12 to −0.01]; moderate-quality evidence). However, when the analysis was limited to the 2 trials at low risk of bias,24,30 the point estimate was similar, but vasopressin was associated with a significant reduction in the risk of RRT without evidence of heterogeneity (RR, 0.70 [95% CI, 0.53 to 0.92], I2 = 0%, P for interaction = .77).
Eleven studies (1957 patients, 133 events) reported on myocardial injury; 2 trials had event rates of 0 in both groups. There was no significant difference in the risk of myocardial injury with vasopressin (RR, 0.86 [95% CI, 0.63 to 1.17], I2 = 0%; RD, 0.00 [95% CI, −0.02 to 0.02]; low-quality evidence). After excluding studies at high risk of bias from open-label design,20,28,33,41 the estimate did not change significantly. Because surrogates were reported for myocardial injury (eg, altered ST segments), indirectness was rated as serious.
When 9 studies reporting on ventricular arrhythmia were pooled (837 patients, 87 events), the risk was not significantly different with vasopressin (RR, 0.93 [95% CI, 0.73 to 1.19], I2 = 0%; RD, 0.00 [95% CI, −0.02 to 0.01]; low-quality evidence). There was no significant difference when pooling data from 4 studies (1358 patients, 17 events) reporting on stroke (RR, 1.61 [95% CI, 0.53 to 4.95], I2 = 7%; RD, 0.01 [95% CI, −0.02 to 0.04]; moderate-quality evidence). LOS data were reported exclusively as medians with interquartile range and were transformed to estimate mean LOS with standard deviation. Hospital LOS was not significantly associated with vasopressin (8 studies, 1939 patients; mean difference, −1.14 days [95% CI, −3.60 to 1.32], I2=75%; low-quality evidence) (Table 4). Similarly, ICU LOS was not significantly associated with vasopressin (mean difference, −0.40 days [95% CI, −1.05 to 0.25], I2= 24%; moderate-quality evidence) when 11 studies were combined (2156 patients).
When 9 studies (1963 patients, 58 events) were pooled (Figure 3B), vasopressin in addition to catecholamines was associated with a significant increase in digital ischemia (RR, 2.38 [95% CI, 1.37 to 4.12], I2 = 0; RD, 0.02 [95% CI, −0.01 to 0.04]; moderate-quality evidence). In absolute terms, this means 24 more occurrences (95% CI, 6 to 55) of digital ischemia per 1000 patients treated with vasopressin. When the 4 studies at high risk of bias were excluded,23,26,29,41 the resultant estimate was not significantly different. Definitions varied for this outcome; however, when the analysis was limited to the 6 studies that specifically described “digital ischemia,”18,23,29,30,39,40 the resultant estimate did not change significantly. Thus, evidence was not downgraded for indirectness but, because it was a post hoc outcome, it was downgraded for risk of bias.
In a sensitivity analysis, the treatment effect for RRT was consistent, but not statistically significant when the definition was modified to acute kidney injury (5 trials; RR, 0.73 [95% CI, 0.46 to 1.17], I2 = 91%).
The assessment of publication bias was limited by small numbers of studies for most outcomes (eAppendix 12 in the Supplement). Visual inspection did not lead to concerns about publication bias.
Quiz Ref IDIn this systematic review and meta-analysis of randomized clinical trials, the administration of vasopressin in addition to catecholamine vasopressors in patients with distributive shock was associated with a significant reduction in the risk of atrial fibrillation when compared with catecholamines alone (high-quality evidence). Findings for other outcomes were not consistent. Although when all studies were combined the risk of mortality was lower with the addition of vasopressin, a sensitivity analysis limited to low risk of bias trials yielded a relative risk much closer to 1 and was not statistically significant.
To our knowledge, this systematic review is the first on the topic to include atrial fibrillation as an outcome. Prior reviews assessed arrhythmia,42,43 but this outcome has limited utility due to the variety of conditions that could be found under this heading. The reduction in atrial fibrillation associated with vasopressin was consistent across 2 subtypes of distributive shock and in sensitivity analyses restricted to studies at low risk of bias.
Quiz Ref IDVasopressin may have contributed to a reduction of atrial fibrillation by sparing the adrenergic stimulation provided by catecholaminergic vasopressors.6-8,14 This could have manifested in fewer patients developing atrial fibrillation or may have caused atrial fibrillation to be shorter in duration and lower in rate and, in consequence, less likely to be detected.
The approach to monitoring and ascertainment of atrial fibrillation in patients who are acutely ill affects the detection of this outcome.44 This limitation would need to be addressed to more precisely estimate event rates in this population and their association with vasopressin treatment. Quiz Ref IDThe clinical significance of atrial fibrillation in this population is not fully understood.44 Where atrial fibrillation in patients who are critically ill has been associated with worse outcomes, including death, causality has not been proven and the consequences on long-term prognosis in survivors are unknown.10,11,44
This review is one of few reviews to directly compare vasopressin + catecholamines against the current standard of care—catecholamines alone. Two systematic reviews with network meta-analyses found no difference in mortality in any comparison, including between vasopressin or terlipressin and norepinephrine.42,43 Another systematic review and meta-analysis concluded that treatment with noncatecholaminergic agents (including vasopressin and methylene blue) improved survival (RR, 0.88 [95% CI, 0.79 to 0.98]) in patients experiencing or “at risk” for distributive shock.45 In another systematic review and meta-analysis, mortality was significantly lower in patients with septic shock treated with vasopressin or terlipressin compared with norepinephrine (RR, 0.87 [95% CI, 0.78 to 0.97]).46 However, that review included 4 substudies of the Vasopressin and Septic Shock Trial (VASST) in the meta-analysis of mortality and did not assess evidence using GRADE.19,39,47
The theoretical basis for vasopressin administration stems from research identifying relative vasopressin deficiency in patients with distributive shock.13 Vasopressin administration could lower mortality by decreasing the need for catecholaminergic drugs and reducing their adverse effects including arrhythmia, preferentially perfusing the brain and renal vascular bed—the latter leading to reductions in acute kidney injury—and decreasing activation of both the renin-aldosterone-angiotensin system and neurohormonal processes, inhibiting proinflammatory cytokines, improving calcium handling, and potentiating endogenous glucocorticoids.47-50
For clinicians aiming for MAP, maintaining adequate blood flow while mitigating the risk of excessive vasoconstriction (the likely mechanism of digital ischemia) is also important. An understanding of the clinical effect of these events (ie, did they simply precipitate drug discontinuation or did they lead to permanent disability?) would be needed to evaluate trade-off against a decrease in mortality.
This systematic review also evaluated requirement for RRT. The significant reduction in need for RRT with vasopressin was limited to the pooled estimate for low risk of bias studies. Renal protection related to reduced activation of the renin-aldosterone-angiotensin system is one of the hypothesized benefits of vasopressin in distributive shock; creatinine clearance has been shown to improve when vasopressin was started early after the onset of distributive shock.33
This review included data from the relatively large and recently published Vasopressin vs Norepinephrine in Patients with Vasoplegic Shock after Cardiac Surgery (VANCS) and Effect of Early Vasopressin vs Norepinephrine on Kidney Failure in Patients With Septic Shock (VANISH) trials (751 patients total).18,30 Combining subtypes of distributive shock and considering vasopressin analogs allowed the inclusion of a larger number of studies. Bias in the review process was reduced by searching multiple databases without language restriction. Significant attempts were made to obtain clarification of published data and access to unpublished data.
This study has several limitations. First, subgroup analyses were restricted by the study-level nature of the data. Second, the quality of reporting for many studies was not sufficient to permit definitive judgments about risk of bias in all domains. Third, there are likely differences in the way vasopressors were initiated, titrated, and weaned between studies and approaches were infrequently described in detail. However, the general approach seemed to be to up-titrate vasopressin until the maximum dose or target MAP was reached and then to add or wean norepinephrine as needed to reach the target MAP.
In this meta-analysis, the addition of vasopressin to catecholamine vasopressors compared with catecholamines alone was associated with a lower risk of atrial fibrillation. However, findings for secondary outcomes varied.
Corresponding Author: Emilie P. Belley-Côté, MD, MSc, David Braley Cardiac, Vascular and Stroke Research Institute, 237 Barton St E, Room 1C1-5B, Hamilton, ON L8L 2X2, Canada (email@example.com).
Accepted for Publication: April 5, 2018.
Author Contributions: Drs Belley-Côté and McIntyre (McMaster University) had full access to all the data in the study, conducted the analyses, and take responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: McIntyre, Whitlock, Belley-Côté.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: McIntyre, Belley-Côté.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: McIntyre, Um, Whitlock, Belley-Côté.
Administrative, technical, or material support: McIntyre, Um, Lengyel, Gordon, Whitlock.
Supervision: Alhazzani, Hajjar, Healey, Whitlock, Belley-Côté.
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr McIntyre reported receiving grant funding from the Canadian Stroke Prevention Intervention Network and being a trainee member of the Cardiac Arrhythmia Network of Canada. Dr Gordon reported receiving grant funding from the National Institute for Health Research and Tenax Therapeutics; personal fees and nonfinancial support from Orion Pharma, Tenax Therapeutics, Ferring Pharmaceuticals, GlaxoSmithKline, and Bristol-Myers Squibb; and personal fees from Amomed Pharma. Dr Healey reported receiving grant funding from Medtronic and Bristol-Meyers Squibb/Pfizer. Dr Belley-Côté reported receiving grant funding from the Canadian Institutes of Health Research. No other disclosures were reported.
Additional Contributions: We thank the Guidelines in Intensive Care Development and Evaluation (GUIDE) Group (McMaster University) for methodological support; Neera Bhatnagar, MLIS (McMaster Health Sciences Library), for reviewing our search strategy; Yongning Ou, MSc (Population Health Research Institute), Shuhua Luo (Sick Kids Hospital), and Kevin An (McMaster University) for their assistance in assessing articles written in Chinese; the members of the McMaster Interdisciplinary Investigative Outcomes Node—Cardiac Sciences, Intensive Care and Anesthesia (McMaster University), for their methodological support; Bram Rochwerg, MD, MSc, Nancy Santesso, PhD, and Romina Brignardello-Petersen, PhD (all at McMaster University), for their tutoring and methodological support; and Kelsey McIntyre, RN (Hamilton Health Sciences), for her assistance with proofreading and data entry. They did not receive compensation for their contributions.
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