A systematic review of vasopressor blood pressure targets in critically ill adults with hypotension.

PURPOSE: Clinicians must balance the risks from hypotension with the potential adverse effects of vasopressors. Experts have recommended a mean arterial pressure (MAP) target of at least 65 mmHg, and higher in older patients and in patients with chronic hypertension or atherosclerosis. We conducted a systematic review of randomized-controlled trials comparing higher vs lower blood pressure targets for vasopressor therapy administered to hypotensive critically ill patients. METHODS: We searched MEDLINE®, EMBASE™, and the Cochrane Central Register of Controlled Trials for studies of higher vs lower blood pressure targets for vasopressor therapy in critically ill hypotensive adult patients. Two reviewers independently assessed trial eligibility based on titles and abstracts, and they then selected full-text reports. Outcomes, subgroups, and analyses were prespecified. We used GRADE (Grading of Recommendations Assessment, Development and Evaluation) to rate the overall confidence in the estimates of intervention effects. RESULTS: Of 8001 citations, we retrieved 57 full-text articles and ultimately included two randomized-controlled trials (894 patients). Higher blood pressure targets were not associated with lower mortality (relative risk [RR], 1.05; 95% confidence interval [CI], 0.90 to 1.23; P = 0.54), and neither age (P = 0.17) nor chronic hypertension (P = 0.32) modified the overall effect. Nevertheless, higher blood pressure targets were associated with a greater risk of new-onset supraventricular cardiac arrhythmia (RR, 2.08; 95% CI, 1.28 to 3.38; P < 0.01). CONCLUSION: Current evidence does not support a MAP target > 70 mmHg in hypotensive critically ill adult patients requiring vasopressor therapy.

How do network meta-analyses address intransitivity when assessing certainty of evidence: a systematic survey.

OBJECTIVES: To describe how systematic reviews with network meta-analyses (NMAs) that used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) NMA approach addressed intransitivity when assessing certainty of evidence. DESIGN: Systematic survey. DATA SOURCES: Medline, Embase and Cochrane Database of Systematic Reviews from September 2014 to October 2022. ELIGIBILITY CRITERIA: Systematic reviews of randomised controlled trials with aggregate data NMAs that used the GRADE NMA approach for assessing certainty of evidence. DATA EXTRACTION AND SYNTHESIS: We documented how reviewers described methods for addressing intransitivity when assessing certainty of evidence, how often they rated down for intransitivity and their explanations for rating down. RESULTS: Of the 268 eligible systematic reviews, 44.8% (120/268) mentioned intransitivity when describing methods for assessing the certainty of evidence. Of these, 28.3% (34/120) considered effect modifiers and from this subset, 67.6% (23/34) specified the effect modifiers; however, no systematic review noted how they chose the effect modifiers. 15.0% (18/120) mentioned looking for differences between the direct comparisons that inform the indirect estimate. No review specified a threshold for difference in effect modifiers between the direct comparisons that would lead to rating down for intransitivity. Reviewers noted rating down indirect evidence for intransitivity in 33.1% of systematic reviews, and noted intransitivity for network estimates in 23.0% of reviews. Authors provided an explanation for rating down for intransitivity in 59.6% (31/52) of the cases in which they rated down. Of the 31 in which they provided an explanation, 74.2% (23/31) noted they detected differences in effect modifiers and 67.7% (21/31) specified in what effect modifiers they detected differences. CONCLUSIONS: A third of systematic reviews with NMAs using the GRADE approach rated down for intransitivity. Limitations in reporting of methods to address intransitivity proved considerable. Whether the problem is that reviewers neglected to address rating down for transitivity at all, or whether they did consider but not report, is not clear. At minimum systematic reviews with NMAs need to improve their reporting practices regarding intransitivity; it may well be that they need to improve their practice in transitivity assessment. How to best address intransitivity may remain unclear for many reviewers thus additional GRADE guidance providing practical instructions for addressing intransitivity may be desirable.

Adverse effects of remdesivir, hydroxychloroquine and lopinavir/ritonavir when used for COVID-19: systematic review and meta-analysis of randomised trials.

BACKGROUND: To summarise specific adverse effects of remdesivir, hydroxychloroquine and lopinavir/ritonavir in patients with COVID-19. METHODS: We searched 32 databases through 27 October 2020. We included randomised trials comparing any of the drugs of interest to placebo or standard care, or against each other. We conducted fixed-effects pairwise meta-analysis and assessed the certainty of evidence using the grading of recommendations assessment, development and evaluation approach. RESULTS: We included 16 randomised trials which enrolled 8152 patients. For most interventions and outcomes the certainty of the evidence was very low to low except for gastrointestinal adverse effects from hydroxychloroquine, which was moderate certainty. Compared with standard care or placebo, low certainty evidence suggests that remdesivir may not have an important effect on acute kidney injury (risk difference (RD) 8 fewer per 1000, 95% CI 27 fewer to 21 more) or cognitive dysfunction/delirium (RD 3 more per 1000, 95% CI 12 fewer to 19 more). Low certainty evidence suggests that hydroxychloroquine may increase the risk of cardiac toxicity (RD 10 more per 1000, 95% CI 0 more to 30 more) and cognitive dysfunction/delirium (RD 33 more per 1000, 95% CI 18 fewer to 84 more), whereas moderate certainty evidence suggests hydroxychloroquine probably increases the risk of diarrhoea (RD 106 more per 1000, 95% CI 48 more to 175 more) and nausea and/or vomiting (RD 62 more per 1000, 95% CI 23 more to 110 more) compared with standard care or placebo. Low certainty evidence suggests lopinavir/ritonavir may increase the risk of diarrhoea (RD 168 more per 1000, 95% CI 58 more to 330 more) and nausea and/or vomiting (RD 160 more per 1000, 95% CI 100 more to 210 more) compared with standard care or placebo. DISCUSSION: Hydroxychloroquine probably increases the risk of diarrhoea and nausea and/or vomiting and may increase the risk of cardiac toxicity and cognitive dysfunction/delirium. Lopinavir/ritonavir may increase the risk of diarrhoea and nausea and/or vomiting. Remdesivir may have no important effect on risk of acute kidney injury or cognitive dysfunction/delirium. These findings provide important information to support the development of evidence-based management strategies for patients with COVID-19.

Use of tocilizumab and sarilumab alone or in combination with corticosteroids for covid-19: systematic review and network meta-analysis.

Objective: To compare the effects of interleukin 6 receptor blockers, tocilizumab and sarilumab, with or without corticosteroids, on mortality in patients with covid-19. Design: Systematic review and network meta-analysis. Data sources: World Health Organization covid-19 database, a comprehensive multilingual source of global covid-19 literature, and two prospective meta-analyses (up to 9 June 2021). Review methods: Trials in which people with suspected, probable, or confirmed covid-19 were randomised to interleukin 6 receptor blockers (with or without corticosteroids), corticosteroids, placebo, or standard care. The analysis used a bayesian framework and assessed the certainty of evidence using the GRADE approach. Results from the fixed effect meta-analysis were used for the primary analysis. Results: Of 45 eligible trials (20 650 patients) identified, 36 (19 350 patients) could be included in the network meta-analysis. Of 36 trials, 27 were at high risk of bias, primarily due to lack of blinding. Tocilizumab, in combination with corticosteroids, suggested a reduction in the risk of death compared with corticosteroids alone (odds ratio 0.79, 95% credible interval 0.70 to 0.88; 35 fewer deaths per 1000 people, 95% credible interval 52 fewer to 18 fewer per 1000; moderate certainty of evidence), as did sarilumab in combination with corticosteroids, compared with corticosteroids alone (0.73, 0.58 to 0.92; 43 fewer per 1000, 73 fewer to 12 fewer; low certainty). Tocilizumab and sarilumab, each in combination with corticosteroids, appeared to have similar effects on mortality when compared with each other (1.07, 0.86 to 1.34; eight more per 1000, 20 fewer to 35 more; low certainty). The effects of tocilizumab (1.12, 0.91 to 1.38; 20 more per 1000, 16 fewer to 59 more; low certainty) and sarilumab (1.07, 0.81 to 1.40; 11 more per 1000, 38 fewer to 55 more; low certainty), when used alone, suggested an increase in the risk of death. Conclusion: These findings suggest that in patients with severe or critical covid-19, tocilizumab, in combination with corticosteroids, probably reduces mortality, and that sarilumab, in combination with corticosteroids, might also reduce mortality. Tocilizumab and sarilumab, in combination with corticosteroids, could have similar effectiveness. Tocilizumab and sarilumab, when used alone, might not be beneficial.

Consistency of covid-19 trial preprints with published reports and impact for decision making: retrospective review.

Objective: To assess the trustworthiness (ie, complete and consistent reporting of key methods and results between preprint and published trial reports) and impact (ie, effects of preprints on meta-analytic estimates and the certainty of evidence) of preprint trial reports during the covid-19 pandemic. Design: Retrospective review. Data sources: World Health Organization covid-19 database and the Living Overview of the Evidence (L-OVE) covid-19 platform by the Epistemonikos Foundation (up to 3 August 2021). Main outcome measures: Comparison of characteristics of covid-19 trials with and without preprints, estimates of time to publication of covid-19 preprints, and description of differences in reporting of key methods and results between preprints and their later publications. For the effects of eight treatments on mortality and mechanical ventilation, the study comprised meta-analyses including preprints and excluding preprints at one, three, and six months after the first trial addressing the treatment became available either as a preprint or publication (120 meta-analyses in total, 60 of which included preprints and 60 of which excluded preprints) and assessed the certainty of evidence using the GRADE framework. Results: Of 356 trials included in the study, 101 were only available as preprints, 181 as journal publications, and 74 as preprints first and subsequently published in journals. The median time to publication of preprints was about six months. Key methods and results showed few important differences between trial preprints and their subsequent published reports. Apart from two (3.3%) of 60 comparisons, point estimates were consistent between meta-analyses including preprints versus those excluding preprints as to whether they indicated benefit, no appreciable effect, or harm. For nine (15%) of 60 comparisons, the rating of the certainty of evidence was different when preprints were included versus being excluded-the certainty of evidence including preprints was higher in four comparisons and lower in five comparisons. Conclusion: No compelling evidence indicates that preprints provide results that are inconsistent with published papers. Preprints remain the only source of findings of many trials for several months-an unsuitable length of time in a health emergency that is not conducive to treating patients with timely evidence. The inclusion of preprints could affect the results of meta-analyses and the certainty of evidence. Evidence users should be encouraged to consider data from preprints.

Patient values and preferences on valve replacement for aortic stenosis: a systematic review.

The review aims to summarise evidence addressing patients' values, preferences and practical issues on deciding between transcatheter aortic valve insertion (TAVI) and surgical aortic valve replacement (SAVR) for aortic stenosis. We searched databases and grey literature until June 2020. We included studies of adults with aortic stenosis eliciting values and preferences about treatment, excluding medical management or palliative care. Qualitative findings were synthesised using thematic analysis, and quantitative findings were narratively described. Evidence certainty was assessed using CERQual (Confidence in the Evidence from Reviews of Qualitative Research) and GRADE (Grading of Recommendations Assessment, Development and Evaluation). We included eight studies. Findings ranged from low to very low certainty. Most studies only addressed TAVI. Studies addressing both TAVI and SAVR reported on factors affecting patients' decision-making along with treatment effectiveness, instead of trade-offs between procedures. Willingness to accept risk varied considerably. To improve their health status, participants were willing to accept higher mortality risk than current evidence suggests for either procedure. No study explicitly addressed valve reintervention, and one study reported variability in willingness to accept shorter duration of known effectiveness of TAVI compared with SAVR. The most common themes were desire for symptom relief and improved function. Participants preferred minimally invasive procedures with shorter hospital stay and recovery. The current body of evidence on patients' values, preferences and practical issues related to aortic stenosis management is of suboptimal rigour and reports widely disparate results regarding patients' perceptions. These findings emphasise the need for higher quality studies to inform clinical practice guidelines and the central importance of shared decision-making to individualise care fitted to each patient.

Establishing thresholds for important benefits considering the harms of screening interventions.

CONTEXT AND OBJECTIVE: Standards for clinical practice guidelines require explicit statements regarding how values and preferences influence recommendations. However, no cancer screening guideline has addressed the key question of what magnitude of benefit people require to undergo screening, given its harms and burdens. This article describes the development of a new method for guideline developers to address this key question in the absence of high-quality evidence from published literature. SUMMARY OF METHOD: The new method was developed and applied in the context of a recent BMJ Rapid Recommendation clinical practice guideline for colorectal cancer (CRC) screening. First, we presented the guideline panel with harms and burdens (derived from a systematic review) associated with the CRC screening tests under consideration. Second, each panel member completed surveys documenting their views of expected benefits on CRC incidence and mortality that people would require to accept the harms and burdens of screening. Third, the panel discussed results of the surveys and agreed on thresholds for benefits at which the majority of people would choose screening. During these three steps, the panel had no access to the actual benefits of the screening tests. In step four, the panel was presented with screening test benefits derived from a systematic review of clinical trials and microsimulation modelling. The thresholds derived through steps one to three were applied to these benefits, and directly informed the panel's recommendations. CONCLUSION: We present the development and application of a new, four-step method enabling incorporation of explicit and transparent judgements of values and preferences in a screening guideline. Guideline panels should establish their view regarding the magnitude of required benefit, given burdens and harms, before they review screening benefits and make their recommendations accordingly. Making informed screening decisions requires transparency in values and preferences judgements that our new method greatly facilitates.

How do cancer screening guidelines trade off benefits versus harms and burdens of screening? A systematic survey.

OBJECTIVES: Cancer screening guidelines differ in their recommendations for or against screening. To be able to provide explicit recommendations, guidelines need to specify thresholds for the magnitude of benefits of screening, given its harms and burdens. We evaluated how current cancer screening guidelines address the relative importance of benefits versus harms and burdens of screening. DATA SOURCE: We searched the Guidelines International Network, International Guideline Library, ECRI Institute and Medline. Two pairs of reviewers independently performed guideline selection and data abstraction. ELIGIBILITY CRITERIA: We included all cancer screening guidelines published in English between January 2014 and April 2019. RESULTS: Of 68 eligible guidelines, 25 included a statement regarding the trade-off between screening benefits versus harms and burdens (14 guidelines), or a statement of direction of the net effect (defined as benefits minus harms or burdens) (13 guidelines). None of these 25 guidelines defined how large a screening benefit should be to recommend screening, given its harms and burdens. 11 guidelines performed an economic evaluation of screening. Of these, six identified a key benefit outcome; two specified a cost-effectiveness threshold for recommending a screening option. Eight guidelines commented on people's values and preferences regarding the trade-off between benefits versus harms and burdens. CONCLUSIONS: Current cancer screening guidelines fail to specify the values and preferences underlying their recommendations. No guidelines provide a threshold at which they believe the benefits of screening outweigh its harms and burdens. PROSPERO REGISTRATION NUMBER: CRD42019138590.

Antibiotics for uncomplicated skin abscesses: systematic review and network meta-analysis.

OBJECTIVE: To assess the impact of adjunctive antibiotic therapy on uncomplicated skin abscesses. DESIGN: Systematic review and network meta-analysis. DATA SOURCES: Medline, Embase, the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov. STUDY SELECTION: A BMJ Rapid Recommendation panel provided input on design, important outcomes and the interpretation of the results. Eligible randomised controlled trials (RCTs) included a comparison of antibiotics against no antibiotics or a comparison of different antibiotics in patients with uncomplicated skin abscesses, and reported outcomes prespecified by the linked guideline panel. REVIEW METHODS: Reviewers independently screened abstracts and full texts for eligibility, assessed risk of bias and extracted data. We performed random-effects meta-analyses that compared antibiotics with no antibiotics, along with a limited number of prespecified subgroup hypotheses. We also performed network meta-analysis with a Bayesian framework to compare effects of different antibiotics. Quality of evidence was assessed with The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. RESULTS: Fourteen RCTs including 4198 patients proved eligible. Compared with no antibiotics, antibiotics probably lower the risk of treatment failure (OR 0.58, 95% CI 0.37 to 0.90; low quality), recurrence within 1 month (OR 0.48, 95% CI 0.30 to 0.77; moderate quality), hospitalisation (OR 0.55, 95% CI 0.32 to 0.94; moderate quality) and late recurrence (OR 0.64, 95% CI 0.48 to 0.85; moderate quality). However, relative to no use, antibiotics probably increase the risk of gastrointestinal side effects (trimethoprim and sulfamethoxazole (TMP-SMX): OR 1.28, 95% CI 1.04 to 1.58; moderate quality; clindamycin: OR 2.29, 95% CI 1.35 to 3.88; high quality) and diarrhoea (clindamycin: OR 2.71, 95% CI 1.50 to 4.89; high quality). Cephalosporins did not reduce the risk of treatment failure compared with placebo (moderate quality). CONCLUSIONS: In patients with uncomplicated skin abscesses, moderate-to-high quality evidence suggests TMP-SMX or clindamycin confer a modest benefit for several important outcomes, but this is offset by a similar risk of adverse effects. Clindamycin has a substantially higher risk of diarrhoea than TMP-SMX. Cephalosporins are probably not effective.

Patent foramen ovale closure, antiplatelet therapy or anticoagulation in patients with patent foramen ovale and cryptogenic stroke: a systematic review and network meta-analysis incorporating complementary external evidence.

OBJECTIVE: To examine the relative impact of three management options in patients aged <60 years with cryptogenic stroke and a patent foramen ovale (PFO): PFO closure plus antiplatelet therapy, antiplatelet therapy alone and anticoagulation alone. DESIGN: Systematic review and network meta-analysis (NMA) supported by complementary external evidence. DATA SOURCES: Medline, EMBASE and Cochrane CENTRAL. STUDY SELECTION: Randomised controlled trials (RCTs) addressing PFO closure and/or medical therapies in patients with PFO and cryptogenic stroke. REVIEW METHODS: We conducted an NMA complemented with external evidence and rated certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. RESULTS: Ten RCTs in eight studies proved eligible (n=4416). Seven RCTs (n=3913) addressed PFO closure versus medical therapy. Of these, three (n=1257) addressed PFO closure versus antiplatelet therapy, three (n=2303) addressed PFO closure versus mixed antiplatelet and anticoagulation therapies and one (n=353) addressed PFO closure versus anticoagulation. The remaining three RCTs (n=503) addressed anticoagulant versus antiplatelet therapy. PFO closure versus antiplatelet therapy probably results in substantial reduction in ischaemic stroke recurrence (risk difference per 1000 patients over 5 years (RD): -87, 95% credible interval (CrI) -100 to -33; moderate certainty). Compared with anticoagulation, PFO closure may confer little or no difference in ischaemic stroke recurrence (low certainty) but probably has a lower risk of major bleeding (RD -20, 95% CrI -27 to -2, moderate certainty). Relative to either medical therapy, PFO closure probably increases the risk of persistent atrial fibrillation (RD 18, 95% CI +5 to +56, moderate certainty) and device-related adverse events (RD +36, 95% CI +23 to +50, high certainty). Anticoagulation, compared with antiplatelet therapy, may reduce the risk of ischaemic stroke recurrence (RD -71, 95% CrI -100 to +17, low certainty), but probably increases the risk of major bleeding (RD +12, 95% CrI -5 to +65, moderate certainty). CONCLUSIONS: In patients aged <60 years, PFO closure probably confers an important reduction in ischaemic stroke recurrence compared with antiplatelet therapy alone but may make no difference compared with anticoagulation. PFO closure incurs a risk of persistent atrial fibrillation and device-related adverse events. Compared with alternatives, anticoagulation probably increases major bleeding. PROSPERO REGISTRATION NUMBER: CRD42017081567.

Vasopressor use following traumatic injury: protocol for a systematic review.

INTRODUCTION: Worldwide, traumatic casualties are projected to exceed 8 million by year 2020. Haemorrhagic shock and brain injury are the leading causes of death following trauma. While intravenous fluids have traditionally been used to support organ perfusion in the setting of haemorrhage, recent investigations have suggested that restricting fluid therapy by tolerating more severe hypotension may improve survival. However, the safety of permissive hypotension remains uncertain, particularly among patients who have suffered a traumatic brain injury. Vasopressors preferentially vasoconstrict blood vessels that supply non-vital organs and capacitance vessels, thereby mobilising the unstressed blood volume. Used as fluid-sparing adjuncts, these drugs can complement resuscitative measures by correcting hypotension without diluting clotting factors or increasing the risk for tissue oedema. METHODS AND ANALYSIS: We will identify randomised control trials comparing early resuscitation with vasopressors versus placebo or standard care in adults following traumatic injury. Data sources will include MEDLINE, EMBASE, CENTRAL, clinical trial registries and conference proceedings. Two reviewers will independently determine trial eligibility. For each included trial, we will conduct duplicate independent data extraction and risk of bias assessment. We will assess the overall quality of the data for each individual outcome using the GRADE approach. ETHICS AND DISSEMINATION: We will report this review in accordance with the PRISMA statement. We will disseminate our findings at critical care and trauma conferences and through a publication in a peer-reviewed journal. We will also use this systematic review to create clinical guidelines (http://www.magicapp.org), which will be disseminated in a standalone publication. TRIAL REGISTRATION NUMBER: CRD42016033437.

Corticosteroids in sepsis: an updated systematic review and meta-analysis (protocol).

INTRODUCTION: Sepsis is associated with a dysregulated host response to infection and impaired endogenous corticosteroid metabolism. As such, therapeutic use of exogenous corticosteroids is a promising adjunctive intervention. Despite a large number of trials examining this research question, uncertainty persists regarding the effect of corticosteroids on survival in sepsis. Several large randomised controlled trials have been published recently prompting a re-evaluation of the available literature. METHODS AND ANALYSIS: A rigorous and reproducible search and screening process from a Cochrane review on the same topic was comprehensive to October 2014. We will search MEDLINE, EMBASE, LILACS, the Cochrane trial registry and clinicaltrials.gov for eligible randomised controlled trials investigating the use of corticosteroids in patients with sepsis from September 2014. Outcomes have been chosen by a semi-independent guideline panel, created in the context of a parallel BMJ Rapid Recommendation on the topic. This panel includes clinicians, content experts, methodologists and patient representatives, who will help identify patient-important outcomes that are critical for deciding whether to use or not use corticosteroids in sepsis. Two reviewers will independently screen and identify eligible studies; a third reviewer will resolve any disagreements. We will use RevMan to pool effect estimates from included studies for each outcome using a random-effect model. We will present the results as relative risk with 95% CI for dichotomous outcomes and as mean difference or standardised mean difference for continuous outcomes with 95% CI. We will assess the certainty of evidence at the outcome level using the Grading of Recommendations, Assessment, Development and Evaluation approach. We will conduct a priori subgroup analyses, which have been chosen by the parallel BMJ Rapid Recommendation panel. ETHICS AND DISSEMINATION: The aim of this systematic review is to summarise the updated evidence on the efficacy and safety of corticosteroids in patients with sepsis. TRIAL REGISTRATION NUMBER: CRD42017058537.

Early vasopressor use following traumatic injury: a systematic review.

OBJECTIVES: Current guidelines suggest limiting the use of vasopressors following traumatic injury; however, wide variations in practice exist. Although excessive vasoconstriction may be harmful, these agents may help reduce administration of potentially harmful resuscitation fluids. This systematic review aims to compare early vasopressor use to standard resuscitation in adults with trauma-induced shock. DESIGN: Systematic review. DATA SOURCES: We searched MEDLINE, EMBASE, ClinicalTrials.gov and the Central Register of Controlled Trials from inception until October 2016, as well as the proceedings of 10 relevant international conferences from 2005 to 2016. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials and controlled observational studies that compared the early vasopressor use with standard resuscitation in adults with acute traumatic injury. RESULTS: Of 8001 citations, we retrieved 18 full-text articles and included 6 studies (1 randomised controlled trial and 5 observational studies), including 2 published exclusively in abstract form. Across observational studies, vasopressor use was associated with increased short-term mortality, with unadjusted risk ratios ranging from 2.31 to 7.39. However, the risk of bias was considered high in these observational studies because patients who received vasopressors were systematically sicker than patients treated without vasopressors. One clinical trial (n=78) was too imprecise to yield meaningful results. Two clinical trials are currently ongoing. No study measured long-term quality of life or cognitive function. CONCLUSIONS: Existing data on the effects of vasopressors following traumatic injury are of very low quality according to the Grading of Recommendations, Assessment, Development and Evaluation methodology. With emerging evidence of harm associated with aggressive fluid resuscitation and, in selected subgroups of patients, with permissive hypotension, the alternatives to vasopressor therapy are limited. Observational data showing that vasopressors are part of usual care would provide a strong justification for high-quality clinical trials of early vasopressor use during trauma resuscitation. TRIAL REGISTRATION NUMBER: CRD42016033437.