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Long-term (180-Day) Outcomes in Critically Ill Patients With COVID-19 in the REMAP-CAP Randomized Clinical Trial
Higgins AM, Berry LR, Lorenzi E, Murthy S, McQuilten Z, Mouncey PR, Al-Beidh F, Annane D, Arabi YM, Beane A, et al
Jama. 2022
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Editor's Choice
Abstract
IMPORTANCE The longer-term effects of therapies for the treatment of critically ill patients with COVID-19 are unknown. OBJECTIVE To determine the effect of multiple interventions for critically ill adults with COVID-19 on longer-term outcomes. DESIGN, SETTING, AND PARTICIPANTS Prespecified secondary analysis of an ongoing adaptive platform trial (REMAP-CAP) testing interventions within multiple therapeutic domains in which 4869 critically ill adult patients with COVID-19 were enrolled between March 9, 2020, and June 22, 2021, from 197 sites in 14 countries. The final 180-day follow-up was completed on March 2, 2022. INTERVENTIONS Patients were randomized to receive 1 or more interventions within 6 treatment domains: immune modulators (n = 2274), convalescent plasma (n = 2011), antiplatelet therapy (n = 1557), anticoagulation (n = 1033), antivirals (n = 726), and corticosteroids (n = 401). MAIN OUTCOMES AND MEASURES The main outcome was survival through day 180, analyzed using a bayesian piecewise exponential model. A hazard ratio (HR) less than 1 represented improved survival (superiority), while an HR greater than 1 represented worsened survival (harm); futility was represented by a relative improvement less than 20% in outcome, shown by an HR greater than 0.83. RESULTS Among 4869 randomized patients (mean age, 59.3 years; 1537 [32.1%] women), 4107 (84.3%) had known vital status and 2590 (63.1%) were alive at day 180. IL-6 receptor antagonists had a greater than 99.9% probability of improving 6-month survival (adjusted HR, 0.74 [95% credible interval {CrI}, 0.61-0.90]) and antiplatelet agents had a 95% probability of improving 6-month survival (adjusted HR, 0.85 [95% CrI, 0.71-1.03]) compared with the control, while the probability of trial-defined statistical futility (HR >0.83) was high for therapeutic anticoagulation (99.9%; HR, 1.13 [95% CrI, 0.93-1.42]), convalescent plasma (99.2%; HR, 0.99 [95% CrI, 0.86-1.14]), and lopinavir-ritonavir (96.6%; HR, 1.06 [95% CrI, 0.82-1.38]) and the probabilities of harm from hydroxychloroquine (96.9%; HR, 1.51 [95% CrI, 0.98-2.29]) and the combination of lopinavir-ritonavir and hydroxychloroquine (96.8%; HR, 1.61 [95% CrI, 0.97-2.67]) were high. The corticosteroid domain was stopped early prior to reaching a predefined statistical trigger; there was a 57.1% to 61.6% probability of improving 6-month survival across varying hydrocortisone dosing strategies. CONCLUSIONS AND RELEVANCE Among critically ill patients with COVID-19 randomized to receive 1 or more therapeutic interventions, treatment with an IL-6 receptor antagonist had a greater than 99.9% probability of improved 180-day mortality compared with patients randomized to the control, and treatment with an antiplatelet had a 95.0% probability of improved 180-day mortality compared with patients randomized to the control. Overall, when considered with previously reported short-term results, the findings indicate that initial in-hospital treatment effects were consistent for most therapies through 6 months.
PICO Summary
Population
Critically ill adults with COVID-19 enrolled in the REMAP-CAP trial in 14 countries (n= 4,869).
Intervention
One or more interventions within six treatment domains: immune modulators, convalescent plasma, antiplatelet therapy, anticoagulation, antivirals, and corticosteroids.
Comparison
Control.
Outcome
Among 4,869 randomized patients, 4,107 (84.3%) had known vital status and 2,590 (63.1%) were alive at day 180. IL-6 receptor antagonists had a greater than 99.9% probability of improving 6-month survival (adjusted HR, 0.74 (95% credible interval (CrI) 0.61 to 0.90)) and antiplatelet agents had a 95% probability of improving 6-month survival (adjusted HR, 0.85 (95% CrI 0.71 to 1.03)) compared with the control, while the probability of trial-defined statistical futility (HR >0.83) was high for therapeutic anticoagulation (99.9%; HR, 1.13 (95% CrI 0.93 to 1.42)), convalescent plasma (99.2%; HR, 0.99 (95% CrI 0.86 to 1.14)), and lopinavir-ritonavir (96.6%; HR, 1.06 (95% CrI 0.82 to 1.38)) and the probabilities of harm from hydroxychloroquine (96.9%; HR, 1.51 (95% CrI 0.98 to 2.29)) and the combination of lopinavir-ritonavir and hydroxychloroquine (96.8%; HR, 1.61 (95% CrI 0.97 to 2.67)) were high. The corticosteroid domain was stopped early prior to reaching a predefined statistical trigger; there was a 57.1% to 61.6% probability of improving 6-month survival across varying hydrocortisone dosing strategies.
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Effect of Convalescent Plasma on Organ Support-Free Days in Critically Ill Patients With COVID-19: A Randomized Clinical Trial
Estcourt LJ, Turgeon AF, McQuilten ZK, McVerry BJ, Al-Beidh F, Annane D, Arabi YM, Arnold DM, Beane A, Bégin P, et al
Jama. 2021
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Editor's Choice
Abstract
IMPORTANCE The evidence for benefit of convalescent plasma for critically ill patients with COVID-19 is inconclusive. OBJECTIVE To determine whether convalescent plasma would improve outcomes for critically ill adults with COVID-19. DESIGN, SETTING, AND PARTICIPANTS The ongoing Randomized, Embedded, Multifactorial, Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) enrolled and randomized 4763 adults with suspected or confirmed COVID-19 between March 9, 2020, and January 18, 2021, within at least 1 domain; 2011 critically ill adults were randomized to open-label interventions in the immunoglobulin domain at 129 sites in 4 countries. Follow-up ended on April 19, 2021. INTERVENTIONS The immunoglobulin domain randomized participants to receive 2 units of high-titer, ABO-compatible convalescent plasma (total volume of 550 mL ± 150 mL) within 48 hours of randomization (n = 1084) or no convalescent plasma (n = 916). MAIN OUTCOMES AND MEASURES The primary ordinal end point was organ support-free days (days alive and free of intensive care unit-based organ support) up to day 21 (range, -1 to 21 days; patients who died were assigned -1 day). The primary analysis was an adjusted bayesian cumulative logistic model. Superiority was defined as the posterior probability of an odds ratio (OR) greater than 1 (threshold for trial conclusion of superiority >99%). Futility was defined as the posterior probability of an OR less than 1.2 (threshold for trial conclusion of futility >95%). An OR greater than 1 represented improved survival, more organ support-free days, or both. The prespecified secondary outcomes included in-hospital survival; 28-day survival; 90-day survival; respiratory support-free days; cardiovascular support-free days; progression to invasive mechanical ventilation, extracorporeal mechanical oxygenation, or death; intensive care unit length of stay; hospital length of stay; World Health Organization ordinal scale score at day 14; venous thromboembolic events at 90 days; and serious adverse events. RESULTS Among the 2011 participants who were randomized (median age, 61 [IQR, 52 to 70] years and 645/1998 [32.3%] women), 1990 (99%) completed the trial. The convalescent plasma intervention was stopped after the prespecified criterion for futility was met. The median number of organ support-free days was 0 (IQR, -1 to 16) in the convalescent plasma group and 3 (IQR, -1 to 16) in the no convalescent plasma group. The in-hospital mortality rate was 37.3% (401/1075) for the convalescent plasma group and 38.4% (347/904) for the no convalescent plasma group and the median number of days alive and free of organ support was 14 (IQR, 3 to 18) and 14 (IQR, 7 to 18), respectively. The median-adjusted OR was 0.97 (95% credible interval, 0.83 to 1.15) and the posterior probability of futility (OR <1.2) was 99.4% for the convalescent plasma group compared with the no convalescent plasma group. The treatment effects were consistent across the primary outcome and the 11 secondary outcomes. Serious adverse events were reported in 3.0% (32/1075) of participants in the convalescent plasma group and in 1.3% (12/905) of participants in the no convalescent plasma group. CONCLUSIONS AND RELEVANCE Among critically ill adults with confirmed COVID-19, treatment with 2 units of high-titer, ABO-compatible convalescent plasma had a low likelihood of providing improvement in the number of organ support-free days. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02735707.
PICO Summary
Population
Critically ill patients with COVID-19 from 129 sites in 4 countries, enrolled in the ongoing REMAP-CAP trial (n= 2,011).
Intervention
2 units of high-titre, ABO-compatible convalescent plasma (n= 1,084).
Comparison
No convalescent plasma (n= 916).
Outcome
The median number of organ support-free days was 0 in the convalescent plasma group and 3 in the no convalescent plasma group. The in-hospital mortality rate was 37.3% for the convalescent plasma group and 38.4% for the no convalescent plasma group and the median number of days alive and free of organ support was 14 and 14, respectively. Serious adverse events were reported in 3% of participants in the convalescent plasma group and in 1.3% of participants in the no convalescent plasma group.
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Convalescent plasma for hospitalized patients with COVID-19: an open-label, randomized controlled trial
Bégin P, Callum J, Jamula E, Cook R, Heddle NM, Tinmouth A, Zeller MP, Beaudoin-Bussières G, Amorim L, Bazin R, et al
Nature Medicine. 2021
Abstract
The efficacy of convalescent plasma for coronavirus disease 2019 (COVID-19) is unclear. Although most randomized controlled trials have shown negative results, uncontrolled studies have suggested that the antibody content could influence patient outcomes. We conducted an open-label, randomized controlled trial of convalescent plasma for adults with COVID-19 receiving oxygen within 12 d of respiratory symptom onset ( NCT04348656 ). Patients were allocated 2:1 to 500 ml of convalescent plasma or standard of care. The composite primary outcome was intubation or death by 30 d. Exploratory analyses of the effect of convalescent plasma antibodies on the primary outcome was assessed by logistic regression. The trial was terminated at 78% of planned enrollment after meeting stopping criteria for futility. In total, 940 patients were randomized, and 921 patients were included in the intention-to-treat analysis. Intubation or death occurred in 199/614 (32.4%) patients in the convalescent plasma arm and 86/307 (28.0%) patients in the standard of care arm-relative risk (RR) = 1.16 (95% confidence interval (CI) 0.94-1.43, P = 0.18). Patients in the convalescent plasma arm had more serious adverse events (33.4% versus 26.4%; RR = 1.27, 95% CI 1.02-1.57, P = 0.034). The antibody content significantly modulated the therapeutic effect of convalescent plasma. In multivariate analysis, each standardized log increase in neutralization or antibody-dependent cellular cytotoxicity independently reduced the potential harmful effect of plasma (odds ratio (OR) = 0.74, 95% CI 0.57-0.95 and OR = 0.66, 95% CI 0.50-0.87, respectively), whereas IgG against the full transmembrane spike protein increased it (OR = 1.53, 95% CI 1.14-2.05). Convalescent plasma did not reduce the risk of intubation or death at 30 d in hospitalized patients with COVID-19. Transfusion of convalescent plasma with unfavorable antibody profiles could be associated with worse clinical outcomes compared to standard care.
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Effect of age of transfused red blood cells on neurologic outcome following traumatic brain injury (ABLE-tbi Study): a nested study of the Age of Blood Evaluation (ABLE) trial
Ruel-Laliberte J, Lessard Bonaventure P, Fergusson D, Lacroix J, Zarychanski R, Lauzier F, Tinmouth A, Hebert PC, Green R, Griesdale D, et al
Canadian Journal of Anaesthesia. 2019;66(6):696-705
Abstract
BACKGROUND Anemia is common in critically ill patients with traumatic brain injury, and often requires red blood cell transfusion. Studies suggest that prolonged storage causes lesions of the red blood cells, including a decreased ability to carry oxygen. Considering the susceptibility of the brain to hypoxemia, victims of traumatic brain injury may thus be more vulnerable to exposure to older red blood cells. METHODS Our study aimed to ascertain whether the administration of fresh red blood cells (seven days or less) results in a better neurologic outcome compared with standard red blood cells in critically ill patients with traumatic brain injury requiring transfusion. The Age of Blood Evaluation in traumatic brain injury (ABLE-tbi) study was a nested study within the ABLE study (ISRCTN44878718). Our primary outcome was the extended Glasgow Outcome Scale (GOSe) at six months. RESULTS In the ABLE study, 217 subjects suffered a traumatic brain injury: 110 in the fresh group, and 107 in the standard group. In the fresh group, 68 (73.1%) of the patients had an unfavourable neurologic outcome (GOSe <= 4) compared with 60 (64.5%) in the standard group (P = 0.21). Using a sliding dichotomy approach, we observed no overall effect of fresh red blood cells on neurologic outcome (odds ratio [OR], 1.34; 95% confidence interval [CI], 0.72 to 2.50; P = 0.35) but observed differences across prognostic bands with a decreased odds of unfavourable outcome in patients with the best prognosis at baseline (OR, 0.33; 95% CI, 0.11 to 0.96; P = 0.04) but an increased odds in those with intermediate and worst baseline prognosis (OR, 5.88; 95% CI,1.66 to 20.81; P = 0.006; and OR, 1.67; 95% CI, 0.53 to 5.30; P = 0.38, respectively). CONCLUSION Overall, transfusion of fresh red blood cells was not associated with a better neurologic outcome at six months in critically ill patients with traumatic brain injury. Nevertheless, we cannot exclude a differential effect according to the patient baseline prognosis. TRIAL REGISTRATION ABLE study (ISRCTN44878718); registered 22 August, 2008.
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Effect of Fresh vs Standard-issue Red Blood Cell Transfusions on Multiple Organ Dysfunction Syndrome in Critically Ill Pediatric Patients: A Randomized Clinical Trial
Spinella PC, Tucci M, Fergusson DA, Lacroix J, Hebert PC, Leteurtre S, Schechtman KB, Doctor A, Berg RA, Bockelmann T, et al
Jama. 2019;322(22):2179-2190
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Editor's Choice
Abstract
Importance: The clinical consequences of red blood cell storage age for critically ill pediatric patients have not been examined in a large, randomized clinical trial. Objective: To determine if the transfusion of fresh red blood cells (stored ≤7 days) reduced new or progressive multiple organ dysfunction syndrome compared with the use of standard-issue red blood cells in critically ill children. Design, Setting, and Participants: The Age of Transfused Blood in Critically-Ill Children trial was an international, multicenter, blinded, randomized clinical trial, performed between February 2014 and November 2018 in 50 tertiary care centers. Pediatric patients between the ages of 3 days and 16 years were eligible if the first red blood cell transfusion was administered within 7 days of intensive care unit admission. A total of 15568 patients were screened, and 13308 were excluded. Interventions: Patients were randomized to receive either fresh or standard-issue red blood cells. A total of 1538 patients were randomized with 768 patients in the fresh red blood cell group and 770 in the standard-issue group. Main Outcomes and Measures: The primary outcome measure was new or progressive multiple organ dysfunction syndrome, measured for 28 days or to discharge or death. Results: Among 1538 patients who were randomized, 1461 patients (95%) were included in the primary analysis (median age, 1.8 years; 47.3% girls), in which there were 728 patients randomized to the fresh red blood cell group and 733 to the standard-issue group. The median storage duration was 5 days (interquartile range [IQR], 4-6 days) in the fresh group vs 18 days (IQR, 12-25 days) in the standard-issue group (P < .001). There were no significant differences in new or progressive multiple organ dysfunction syndrome between fresh (147 of 728 [20.2%]) and standard-issue red blood cell groups (133 of 732 [18.2%]), with an unadjusted absolute risk difference of 2.0% (95% CI, -2.0% to 6.1%; P = .33). The prevalence of sepsis was 25.8% (160 of 619) in the fresh group and 25.3% (154 of 608) in the standard-issue group. The prevalence of acute respiratory distress syndrome was 6.6% (41 of 619) in the fresh group and 4.8% (29 of 608) in the standard-issue group. Intensive care unit mortality was 4.5% (33 of 728) in the fresh group vs 3.5 % (26 of 732) in the standard-issue group (P = .34). Conclusions and Relevance: Among critically ill pediatric patients, the use of fresh red blood cells did not reduce the incidence of new or progressive multiple organ dysfunction syndrome (including mortality) compared with standard-issue red blood cells. Trial Registration: ClinicalTrials.gov Identifier: NCT01977547.
PICO Summary
Population
Critically ill paediatric patients between the ages of 3 days and 16 years, (n=1461).
Intervention
Red blood cells stored </=y days (Fresh red blood cell group, (n=728).
Comparison
Delivery of oldest compatible red cell units available (Standard-issue red blood cells, (n=733).
Outcome
There were no significant differences in new or progressive multiple organ dysfunction syndrome between fresh (147 of 728 [20.2%]) and standard-issue red blood cell groups (133 of 732 [18.2%]), with an unadjusted absolute risk difference of 2.0%; P = .33). The prevalence of sepsis was 25.8% (160 of 619) in the fresh group and 25.3% (154 of 608) in the standard-issue group. The prevalence of acute respiratory distress syndrome was 6.6% (41 of 619) in the fresh group and 4.8% (29 of 608) in the standard-issue group. Intensive care unit mortality was 4.5% (33 of 728) in the fresh group vs 3.5 % (26 of 732) in the standard-issue group.
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The impact of perioperative red blood cell transfusions in patients undergoing liver resection: a systematic review
Bennett S, Baker LK, Martel G, Shorr R, Pawlik TM, Tinmouth A, McIsaac DI, Hebert PC, Karanicolas PJ, McIntyre L, et al
Hpb : the Official Journal of the International Hepato Pancreato Biliary Association. 2017;19((4):):321-330
Abstract
BACKGROUND Liver resection is associated with a high proportion of red blood cell transfusions. There is a proposed association between perioperative transfusions and increased risk of complications and tumor recurrence. This study reviews the evidence of this association in the literature. METHODS The Medline, EMBASE, and Cochrane databases were searched for clinical trials or observational studies of patients undergoing liver resection that compared patients who did and did not receive a perioperative red blood cell transfusion. Outcomes were mortality, complications, and cancer survival. RESULTS Twenty-two studies involving 6832 patients were included. All studies were retrospective, with no clinical trials. No studies were scored as low risk of bias. The overall proportion of patients transfused was 38.3%. After multivariate analysis, 1 of 5 studies demonstrated an association between transfusion and increased mortality; 5 of 6 demonstrated an association between transfusion and increased complications; and 10 of 18 demonstrated an association between transfusion and decreased cancer survival. CONCLUSION This review supports the evidence linking perioperative blood transfusions to negative outcomes. The most convincing association was with post-operative complications, some association with long-term cancer outcomes, and no convincing association with mortality. These findings support the initiation, and further study, of restrictive transfusion protocols.
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Red blood cell transfusion in patients with traumatic brain injury: a systematic review and meta-analysis
Boutin A, Chasse M, Shemilt M, Lauzier F, Moore L, Zarychanski R, Griesdale D, Desjardins P, Lacroix J, Fergusson D, et al
Transfusion Medicine Reviews. 2016;30((1)):15-24.
Abstract
Our objectives were to evaluate the frequency of red blood cell (RBC) transfusion in patients with traumatic brain injury (TBI) as well as potential determinants and outcomes associated with RBC transfusion in this population. We conducted a systematic review of cohort studies and randomized trials of patients with TBI. We searched Medline, Embase, the Cochrane Library, and BIOSIS databases from their inception up to April 2015. We selected studies of adult patients with acute TBI reporting data on RBC transfusions. Cumulative incidences of transfusion were pooled using random-effect models with a DerSimonian approach. To evaluate the association between RBC transfusion and potential determinants or clinical outcomes, we pooled risk ratios or mean differences with random-effect models and the Mantel-Haenszel method. We identified 24 eligible studies (17414 patients). After pooling data from 23 studies (7524 patients), approximately 36% (95% confidence interval [CI], 28-44; I(2) = 98%) of patients received RBC transfusion at some point during their hospital stay. Hemoglobin thresholds for transfusion were rarely available (reported in 9 studies) and varied from 6 to 10 g/dL. Glasgow Coma Scale scores at admission were lower in patients who were transfused than those who were not (3 cohort studies; 1371 patients; mean difference of 1.38 points [95% CI, 0.86-1.89]; I(2) = 12%). Mortality was not significantly different among transfused and nontransfused patients in univariate and multivariate meta-analyses. Hospital length of stay was longer among patients receiving RBC transfusion compared to those who did not (3 studies; n = 455; mean difference, 9.58 days [95% CI, 3.94-15.22]; I(2) = 74%). Results should be considered cautiously due to the high heterogeneity and high risk of confounding from the observational nature of included studies. Red blood cell transfusion is frequent in patients with TBI, and transfusion practices varied widely between studies. Current published data highlight the lack of clinical evidence guiding transfusion strategies in TBI. Copyright © 2015 Elsevier Inc. All rights reserved.
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Length of red blood cell storage and clinical outcomes in transfused critical ill adults – the Age of Blood Evaluation (ABLE) randomised controlled trial
Lacroix L, Hebert PC, Fergusson DA, Tinmouth A, Cook DJ, Marshall, JC, Clayton L, McIntyre L, Callum J, et al
Transfusion Medicine. 2015;25((Suppl. 1)):6.. Abstract No. S10
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Age of transfused blood in critically ill adults
Lacroix J, Hebert PC, Fergusson DA, Tinmouth A, Cook DJ, Marshall JC, Clayton L, McIntyre L, Callum J, Turgeon AF, et al
New England Journal of Medicine. 2015;372((15):):1410-8.
Abstract
BACKGROUND Fresh red cells may improve outcomes in critically ill patients by enhancing oxygen delivery while minimizing the risks of toxic effects from cellular changes and the accumulation of bioactive materials in blood components during prolonged storage. METHODS In this multicenter, randomized, blinded trial, we assigned critically ill adults to receive either red cells that had been stored for less than 8 days or standard-issue red cells (the oldest compatible units available in the blood bank). The primary outcome measure was 90-day mortality. RESULTS Between March 2009 and May 2014, at 64 centers in Canada and Europe, 1211 patients were assigned to receive fresh red cells (fresh-blood group) and 1219 patients were assigned to receive standard-issue red cells (standard-blood group). Red cells were stored a mean (+/-SD) of 6.1+/-4.9 days in the fresh-blood group as compared with 22.0+/-8.4 days in the standard-blood group (P<0.001). At 90 days, 448 patients (37.0%) in the fresh-blood group and 430 patients (35.3%) in the standard-blood group had died (absolute risk difference, 1.7 percentage points; 95% confidence interval [CI], -2.1 to 5.5). In the survival analysis, the hazard ratio for death in the fresh-blood group, as compared with the standard-blood group, was 1.1 (95% CI, 0.9 to 1.2; P=0.38). There were no significant between-group differences in any of the secondary outcomes (major illnesses; duration of respiratory, hemodynamic, or renal support; length of stay in the hospital; and transfusion reactions) or in the subgroup analyses. CONCLUSIONS Transfusion of fresh red cells, as compared with standard-issue red cells, did not decrease the 90-day mortality among critically ill adults. (Funded by the Canadian Institutes of Health Research and others; Current Controlled Trials number, ISRCTN44878718.).
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Red blood cell transfusion and mortality effect in aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis protocol
English SW, Chasse M, Turgeon AF, Tinmouth A, Boutin A, Pagliarello G, Fergusson D, McIntyre L
Systems Review. 2015;4((1)):41.
Abstract
BACKGROUND Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating disease that leads to important morbidity and mortality in a young patient population. Anemia following aSAH is common and may be exacerbated by the treatments instituted by clinicians as part of standard care. The role and optimal thresholds for red blood cell (RBC) transfusion in this patient population remains unknown. METHODS/DESIGN We will conduct a systematic review of the literature using MEDLINE, EMBASE, and EBM Reviews (including Cochrane Central databases) using a comprehensive search strategy for observational and interventional studies of RBC transfusion in aSAH. Our primary objective is to evaluate the association of RBC transfusion with mortality in aSAH patients. Secondary objectives include a) determining associations between RBC transfusion and poor neurologic outcome, b) defining an optimal RBC transfusion threshold in aSAH patients, and c) describing complications associated with RBC transfusion in aSAH patients. We plan a descriptive reporting of all included citations including study characteristics, methodological quality, and reported outcomes. Clinical and statistical heterogeneity observed between studies will be described. If appropriate, meta-analyses of suitable studies and interpretation of their results will be performed. Effect measures will be converted to obtain relative risks and odds ratios (RR and ORs) with 95% confidence intervals and pooled according to study design (randomized trials and observational studies respectively) using a random effects model. DISCUSSION This review will summarize the existing observational and trial evidence regarding RBC transfusion in aSAH patients. The analytical plan has made considerations for different study designs, both observational and interventional in nature, and will summarize the best available evidence to inform the end user and policy and guideline producers and to highlight areas in need of further study. SYSTEMATIC REVIEW REGISTRATION PROSPERO CRD42014014806.