Seven deadly sins in trauma outcomes research

Junco, Deborah J. del; Fox, Erin E.; Camp, Elizabeth A.; Rahbar, Mohammad Hossein; Holcomb, John B.

doi:10.1097/ta.0b013e318298b0a4

Cited by 50 publications

(55 citation statements)

References 40 publications

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“…The trial addressed most of the limitations found in previous randomized trauma resuscitation trials, including lack of blinded treatment assignment, enrollment after bleeding slowed, survival and selection biases, and small sample size. 48,55–61 The trial was performed under exception from informed consent so that patients with severe bleeding could be enrolled rapidly and required that all blood products be immediately available for infusion within 10 minutes of calling the blood bank (Supplement 1). The selection criteria used in this study resulted in the rapid enrollment of patients who were severely bleeding, critically injured, in shock, and transfused with a median greater than 19 U of blood products.…”

Section: Discussionmentioning

confidence: 99%

Transfusion of Plasma, Platelets, and Red Blood Cells in a 1:1:1 vs a 1:1:2 Ratio and Mortality in Patients With Severe Trauma

Holcomb¹,

Tilley

Baraniuk

et al. 2015

JAMA

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IMPORTANCE Severely injured patients experiencing hemorrhagic shock often require massive transfusion. Earlier transfusion with higher blood product ratios (plasma, platelets, and red blood cells), defined as damage control resuscitation, has been associated with improved outcomes; however, there have been no large multicenter clinical trials. OBJECTIVE To determine the effectiveness and safety of transfusing patients with severe trauma and major bleeding using plasma, platelets, and red blood cells in a 1:1:1 ratio compared with a 1:1:2 ratio. DESIGN, SETTING, AND PARTICIPANTS Pragmatic, phase 3, multisite, randomized clinical trial of 680 severely injured patients who arrived at 1 of 12 level I trauma centers in North America directly from the scene and were predicted to require massive transfusion between August 2012 and December 2013. INTERVENTIONS Blood product ratios of 1:1:1 (338 patients) vs 1:1:2 (342 patients) during active resuscitation in addition to all local standard-of-care interventions (uncontrolled). MAIN OUTCOMES AND MEASURES Primary outcomes were 24-hour and 30-day all-cause mortality. Prespecified ancillary outcomes included time to hemostasis, blood product volumes transfused, complications, incidence of surgical procedures, and functional status. RESULTS No significant differences were detected in mortality at 24 hours (12.7% in 1:1:1 group vs 17.0% in 1:1:2 group; difference, −4.2% [95% CI, −9.6% to 1.1%]; P = .12) or at 30 days (22.4% vs 26.1%, respectively; difference, −3.7% [95% CI, −10.2% to 2.7%]; P = .26). Exsanguination, which was the predominant cause of death within the first 24 hours, was significantly decreased in the 1:1:1 group (9.2% vs 14.6% in 1:1:2 group; difference, −5.4% [95% CI, −10.4% to −0.5%]; P = .03). More patients in the 1:1:1 group achieved hemostasis than in the 1:1:2 group (86% vs 78%, respectively; P = .006). Despite the 1:1:1 group receiving more plasma (median of 7 U vs 5 U, P < .001) and platelets (12 U vs 6 U, P < .001) and similar amounts of red blood cells (9 U) over the first 24 hours, no differences between the 2 groups were found for the 23 prespecified complications, including acute respiratory distress syndrome, multiple organ failure, venous thromboembolism, sepsis, and transfusion-related complications. CONCLUSIONS AND RELEVANCE Among patients with severe trauma and major bleeding, early administration of plasma, platelets, and red blood cells in a 1:1:1 ratio compared with a 1:1:2 ratio did not result in significant differences in mortality at 24 hours or at 30 days. However, more patients in the 1:1:1 group achieved hemostasis and fewer experienced death due to exsanguination by 24 hours. Even though there was an increased use of plasma and platelets transfused in the 1:1:1 group, no other safety differences were identified between the 2 groups. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01545232

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Section: Discussionmentioning

confidence: 99%

Transfusion of Plasma, Platelets, and Red Blood Cells in a 1:1:1 vs a 1:1:2 Ratio and Mortality in Patients With Severe Trauma

Holcomb¹,

Tilley

Baraniuk

et al. 2015

JAMA

Self Cite

2,012

1,561

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“…Assigning patients at the opposite extremes of bleeding severity to the same 0-RBC subgroup reveals how the 24 hour RBC classification actually defeats the purpose of stratification, namely, to form more homogeneous patient subgroups. 1 …”

Section: Discussionmentioning

confidence: 99%

“…1,3,6,30 Because randomization was expected to balance potential confounders across study arms, the data were stratified by MT to reveal HSD modifying effects, or whether the MT subgroup benefited more than the alternate subgroups (receiving 1–9 and 0 RBCs, respectively). 11,12 Despite favorable HSD effects in the MT subgroup, opposite effects in the 0-RBC subgroup halted the pivotal trial early.…”

Section: Methodsmentioning

confidence: 99%

“…1–7 While randomization controls survival and other types of bias, 8 insidious collider bias continues to plague trauma trials as well as observational studies. Collider bias is a type of selection bias that is often introduced inadvertently into trauma resuscitation research by restriction, stratification or adjustment on a covariate that is a consequence (collider) rather than a cause (confounder) of both the treatment and outcome of interest.…”

Section: Introductionmentioning

confidence: 99%

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Collider bias in trauma comparative effectiveness research: The stratification blues for systematic reviews

Junco¹,

Bulger²,

Fox³

et al. 2015

Injury

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Background Collider bias, or stratifying data by a covariate consequence rather than cause (confounder) of treatment and outcome, plagues randomized and observational trauma research. Of the seven trials of prehospital hypertonic saline in dextran (HSD) that have been evaluated in systematic reviews, none found an overall between-group difference in survival, but four reported significant subgroup effects. We hypothesized that an avoidable type of collider bias often introduced inadvertently into trauma comparative effectiveness research could explain the incongruous findings. Methods The two most recent trials, a single-site pilot and a multi-site pivotal study, provided data for a secondary analysis to more closely examine the potential for collider bias. The two trials had followed the a priori statistical analysis plan to subgroup patients by a post-randomization covariate and well-established surrogate for bleeding severity, massive transfusion (MT), ≥10 units of red blood cells within 24 hours of admission. Despite favorable HSD effects in the MT subgroup, opposite effects in the non-transfused subgroup halted the pivotal trial early. In addition to analyzing the data from the two trials, we constructed causal diagrams and performed a meta-analysis of the results from all seven trials to assess the extent to which collider bias could explain null overall effects with subgroup heterogeneity. Results As in previous trials, HSD induced significantly greater increases in systolic blood pressure (SBP) from prehospital to admission than control crystalloid (p=0.003). Proportionately more HSD than control decedents accrued in the non-transfused subgroup, but with paradoxically longer survival. Despite different study populations and a span of over 20 years across the seven trials, the reported mortality effects were consistently null, summary RR=0.99 (p=0.864, homogeneity p=0.709). Conclusions HSD delayed blood transfusion by modifying standard triggers like SBP with no detectable effect on survival. The reported heterogeneous HSD effects in subgroups can be explained by collider bias that trauma researchers can avoid by improved covariate selection and data capture strategies.

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“…While early transfusion of plasma and platelets has been associated with improved outcomes [2,4–6], findings among observational studies seeking to identify optimum trauma transfusion protocols have been conflicting and difficult to interpret [7,8]. In earlier works [9,10], our group has identified major challenges in the design and statistical analysis of trauma transfusion studies.…”

Section: Introductionmentioning

confidence: 99%

Recurrent event frailty models reduced time-varying and other biases in evaluating transfusion protocols for traumatic hemorrhage

Choi

Rahbar

Ning

et al. 2016

Journal of Clinical Epidemiology

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Objective Transfusion research seeks to improve survival for severely injured and hemorrhaging patients using optimal plasma and platelet ratios over red blood cells (RBC). However, most published studies comparing different ratios are plagued with serious bias and ignore time-varying effects. We applied joint recurrent event frailty models to increase validity and clinical utility. Study Design and Setting Using the PRospective Observational Multicenter Major Trauma Transfusion (PROMMTT) study data, our joint random effects models estimated the association of 1) clinical covariates with transfusion rate intensities, and 2) varying plasma:RBC and platelet:RBC ratios with survival over the 24 hours after hospital admission. Along with survival time, baseline patient vital signs, laboratory values and longitudinal data on types and volumes of transfusions were included. Results Baseline systolic blood pressure, heart rate, pH and hemoglobin were significantly associated with RBC transfusion rates. Increased transfusion rates (per hour) of plasma (p=0.05), platelets (p<0.001) or RBCs were associated with increased 24-hour mortality. Higher ratios of plasma:RBC (p=0.107) and platelet:RBC (p<0.001) were associated with reduced mortality in a time-varying pattern (p<0.001). Conclusions The proposed joint analysis of transfusion rates and ratios offers a more valid statistical approach to evaluate survival effects in the presence of informative censoring by early death.

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Seven deadly sins in trauma outcomes research

Cited by 50 publications

References 40 publications

Transfusion of Plasma, Platelets, and Red Blood Cells in a 1:1:1 vs a 1:1:2 Ratio and Mortality in Patients With Severe Trauma

Transfusion of Plasma, Platelets, and Red Blood Cells in a 1:1:1 vs a 1:1:2 Ratio and Mortality in Patients With Severe Trauma

Collider bias in trauma comparative effectiveness research: The stratification blues for systematic reviews

Recurrent event frailty models reduced time-varying and other biases in evaluating transfusion protocols for traumatic hemorrhage

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