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A Systematic Review and Meta-Analysis of Sample Size Methodology for Traumatic Hemorrhage Trials
Ghossein J, Fernando SM, Rochwerg B, Inaba K, Lampron J, Tran A
The journal of trauma and acute care surgery. 2023
Abstract
BACKGROUND Trauma hemorrhage remains the most common cause of preventable mortality in trauma. In order to guide clinical practice, RCTs provide high-quality evidence to inform clinical decision making. The clinical relevance and inferences made by RCTs are dependent on assumptions made during sample size calculation. METHODS To describe the quality of methodology for sample size determination, we conducted a systemic review RCTs evaluating interventions that aim to improve survival in adults with trauma related hemorrhage. Estimated and actual outcome data is compared, including components of sample size determination. RESULTS A total of 13 RCTs were included. We noted a high rate of negative trial results (11 of 13 studies). Most studies were multi-center and conducted in North America, evaluating patients with blunt and penetrating injuries. The criteria for hemorrhagic shock varied across studies. All studies did not accurately estimate the mortality rate during sample size calculation. All but one study overestimated the mortality reduction during sample size calculation; the median absolute mortality reduction was 3%, compared to a target of 10%. Only the CRASH-2 study used a minimal clinically important different for treatment effect target. No RCTs employed prognostic enrichment. Most studies were terminated (8 of 13), mainly for futility. CONCLUSIONS Taken together, this review highlights that current clinical trial methodology is limited by imprecise control group risk estimates, overly optimistic treatment effect estimates and lack of transparent justification for such targets. These limitations result in studies at high risk for futility and potentially premature abandonment of promising therapies. Given the high morbidity and mortality of trauma-related hemorrhage, we recommend that future conduct of trauma RCTs incorporate 1) prognostic enrichment to inform baseline risk, (2) justify target treatment differences based on clinical importance and realistic estimates of feasibility, and (3) be transparent and provide justification for the assumptions made. LEVEL OF EVIDENCE Systematic Review/Meta Analysis; Level II.
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Earlier time to hemostasis is associated with decreased mortality and rate of complications: Results from the Pragmatic Randomized Optimal Platelet and Plasma Ratio trial
Chang R, Kerby JD, Kalkwarf KJ, Van Belle G, Fox EE, Cotton BA, Cohen MJ, Schreiber MA, Brasel K, Bulger EM, et al
The journal of trauma and acute care surgery. 2019;87(2):342-349
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BACKDROP Clinicians intuitively recognize that faster time to hemostasis is important in bleeding trauma patients, but these times are rarely reported. METHODS Prospectively collected data from the Pragmatic Randomized Optimal Platelet and Plasma Ratios trial were analyzed. Hemostasis was predefined as no intraoperative bleeding requiring intervention in the surgical field or resolution of contrast blush on interventional radiology (IR). Patients who underwent an emergent (within 90 minutes) operating room (OR) or IR procedure were included. Mixed-effects Poisson regression with robust error variance (controlling for age, Injury Severity Score, treatment arm, injury mechanism, base excess on admission [missing values estimated by multiple imputation], and time to OR/IR as fixed effects and study site as a random effect) with modified Bonferroni corrections tested the hypothesis that decreased time to hemostasis was associated with decreased mortality and decreased incidence of acute kidney injury (AKI), acute respiratory distress syndrome (ARDS), multiple-organ failure (MOF), sepsis, and venous thromboembolism. RESULTS Of 680 enrolled patients, 468 (69%) underwent an emergent procedure. Patients with decreased time to hemostasis were less severely injured, had less deranged base excess on admission, and lower incidence of blunt trauma (all p < 0.05). In 408 (87%) patients in whom hemostasis was achieved, every 15-minute decrease in time to hemostasis was associated with decreased 30-day mortality (RR, 0.97; 95% confidence interval [CI], 0.94-0.99), AKI (RR, 0.97; 95% CI, 0.96-0.98), ARDS (RR, 0.98; 95% CI, 0.97-0.99), MOF (RR, 0.94; 95% CI, 0.91-0.97), and sepsis (RR, 0.98; 95% CI, 0.96-0.99), but not venous thromboembolism (RR, 0.99; 95% CI, 0.96-1.03). CONCLUSION Earlier time to hemostasis was independently associated with decreased incidence of 30-day mortality, AKI, ARDS, MOF, and sepsis in bleeding trauma patients. Time to hemostasis should be considered as an endpoint in trauma studies and as a potential quality indicator. LEVEL OF EVIDENCE Therapeutic/care management, level III.
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A comparison of resuscitation intensity (RI) and critical administration threshold (CAT) in predicting early mortality among bleeding patients: a multicenter validation in 680 major transfusion patients
Meyer DE, Cotton BA, Fox EE, Stein D, Holcomb JB, Cohen M, Inaba K, Rahbar E
The Journal of Trauma and Acute Care Surgery. 2018;85((4):):691-696
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BACKGROUND To address deficiencies associated with the classic definition of massive transfusion, Critical Administration Threshold and Resuscitation Intensity were developed to better quantify the overall severity of illness and predict the need for transfusions and early mortality. We sought to evaluate these as more appropriate replacements for MT in defining mortality risk in patients undergoing major transfusions. METHODS Patients predicted to receive MT at 12 Level-1 trauma centers were randomized in the PROPPR trial. MT: ≥10U RBC in 24 hours; CAT+: ≥3U RBC in the first hour; and RI: total products in the first 30 minutes (1U RBC, 1U plasma, 1000mL crystalloid, 500mL colloid each valued at 1U). RI was evaluated as a continuous variable and dichotomized as RI4+, where RI≥4 U. Each metric was evaluated for its ability to predict mortality at 3, 6, and 24 hours, and at 30 days. RESULTS Of the 680 patients, 301 patients met MT definition, 521 were CAT+, and 445 were RI4+. Of those that died, 23% never reached MT threshold, but all were captured by CAT+ and RI4+. The 3-hr (9 vs. 9%), 6-hr (14 vs. 14%), 24-hr (17 vs. 18%), and 30-day mortality rates (28 vs. 29%) were similar between CAT+ and RI4+ patients. When RI was evaluated as a continuous variable, each unit increase was associated with a 20% increase in hemorrhage-related mortality (OR 1.20, 95% CI [1.15-1.29], p<0.05).CONCLUSIONBoth RI and CAT are valid surrogates for early mortality in patients undergoing major transfusion, capturing patients omitted by the MT definition. CAT+ showed the best sensitivity; RI4+ demonstrated better specificity and good PPV and NPV. While CAT+ may be suited for patients receiving a RBC-dominant resuscitation, RI4+ is more comprehensive. RI can also be used as a continuous variable to provide quantitative as well qualitative risk of death.LEVEL OF EVIDENCELevel III, Prognostic.
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The impact of hypothermia on outcomes in massively transfused patients
Lester ELW, Fox EE, Holcomb JB, Brasel KJ, Bulger EM, Cohen MJ, Cotton BA, Fabian TC, Kerby JD, O'Keefe T, et al
The Journal of Trauma and Acute Care Surgery. 2018
Abstract
BACKGROUND Hypothermia is associated with poor outcomes after injury. The relationship between hypothermia during contemporary large volume resuscitation and blood product consumption is unknown. We evaluated this association, and the predictive value of hypothermia on mortality. METHODS Patients predicted to receive massive transfusion at 12 Level-1 trauma centers, randomized in the PROPPR trial, were grouped into those who were hypothermic (<36 degrees Celsius) or normothermic (36-38.5 degrees Celsius) within the first 6 hours of Emergency department arrival. The impact of hypothermia or normothermia on the volume of blood product required during the first 24 hours was determined via negative binomial regression, adjusting for treatment arm, injury severity score, mechanism, demographics, pre-emergency department fluid volume, blood administered prior to becoming hypothermic, pulse and systolic blood pressure on arrival and the time exposed to hypothermic or normothermic temperatures. RESULTS Of 680 patients, 590 had a temperature measured during the first 6 hours in hospital, and 399 experienced hypothermia. The mean number of red blood cell units given to all patients in the first 24 hours of admission was 8.8 (95% CI 7.9-9.6). In multivariable analysis, every one-degree decrease in temperature below 36.0 degrees was associated with a 10% increase (incidence rate ratio [IRR] 0.90; 95% CI 0.89-0.92; p<0.00) in consumption of red blood cells during the first 24 hours of admission. There was no association between red blood cell administration and a temperature above 36 degrees. Hypothermia on arrival was an independent predictor of mortality, with an adjusted odds ratio of 2.7 (95% CI 1.7-4.5; p<0.00) for 24-hour and 1.8 (95% CI 1.3-2.4; p<0.00) for 30-day mortality. CONCLUSION Hypothermia is associated with increased in blood product consumption and mortality. These findings support the maintenance of normothermia in trauma patients, and suggests that further investigation on the impact of cooling or rewarming during massive transfusion is warranted. LEVEL OF EVIDENCE III Prognostic.
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A Novel, Perfused-Cadaver Simulation Model for Tourniquet Training in Military Medics
Grabo DJ Jr, Polk T, Strumwasser A, Inaba K, Foran C, Luther C, Minneti M, Kronstedt S, Wilson A, Demetriades D
Journal of special operations medicine : a peer reviewed journal for SOF medical professionals. 2018;18((4):):97-102.
Abstract
BACKGROUND Exsanguinating limb injury is a significant cause of preventable death on the battlefield and can be controlled with tourniquets. US Navy corpsmen rotating at the Navy Trauma Training Center receive instruction on tourniquets. We evaluated the effectiveness of traditional tourniquet instruction compared with a novel, perfused-cadaver, simulation model for tourniquet training. METHODS Corpsmen volunteering to participate were randomly assigned to one of two tourniquet training arms. Traditional training (TT) consisted of lectures, videos, and practice sessions. Perfused-cadaver training (PCT) included TT plus training using a regionally perfused cadaver. Corpsmen were evaluated on their ability to achieve hemorrhage control with tourniquet(s) using the perfused cadaver. Outcomes included (1) time to control hemorrhage, (2) correct placement of tourniquet(s), and (3) volume of simulated blood loss. Participants were asked about confidence in understanding indications and skills for tourniquets. RESULTS The 53 corpsmen enrolled in the study were randomly assigned as follows: 26 to the TT arm and 27 to the PCT arm. Corpsmen in the PCT group controlled bleeding with the first tourniquet more frequently (96% versus 83%; p < .03), were quicker to hemorrhage control (39 versus 45 seconds; p < .01), and lost less simulated blood (256mL versus 355mL; p < .01). There was a trend toward increased confidence in tourniquet application among all corpsmen. CONCLUSIONS Using a perfused- cadaver training model, corpsmen placed tourniquets more rapidly and with less simulated-blood loss than their traditional training counterparts. They were more likely to control hemorrhage with first tourniquet placement and gain confidence in this procedure. Additional studies are indicated to identify components of effective simulation training for tourniquets.
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Risk factors for the development of acute respiratory distress syndrome following hemorrhage
Robinson BRH, Cohen MJ, Holcomb JB, Pritts TA, Gomaa D, Fox EE, Branson RD, Callcut RA, Cotton BA, Schreiber MA, et al
Shock (Augusta, Ga.). 2017;50((3):):258-264
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BACKGROUND The Pragmatic Randomized Optimal Platelet and Plasma Ratios (PROPPR) study evaluated the effects of plasma and platelets on hemostasis and mortality after hemorrhage. The pulmonary consequences of resuscitation strategies that mimic whole blood, remain unknown. METHODS A secondary analysis of the PROPPR study was performed. Injured patients predicted to receive a massive transfusion were randomized to 1:1:1 vs. 1:1:2 plasma-platelet-RBC ratios at 12 Level I North American trauma centers. Patients with survival >24 hours, an ICU stay, and a recorded PaO2/FiO2 (P/F) ratio were included. ARDS was defined as a P/F ratio < 200, with bilateral pulmonary infiltrates, and adjudicated by investigators. RESULTS 454 patients were reviewed (230 received 1:1:1, 224 1:1:2). Age, sex, injury mechanism, and regional abbreviated injury scale (AIS) scores did not differ between cohorts. Tidal volume, PEEP, and lowest P/F ratio did not differ. No significant differences in ARDS rates (14.8 vs. 18.4%), ventilator-free (24 vs. 24) or ICU-free days (17.5 vs. 18), hospital length of stay (22 vs. 18 days), or 30-day mortality were found (28 vs. 28%). ARDS was associated with blunt injury (OR 3.61 [1.53-8.81] p < 0.01) and increasing chest AIS (OR 1.40 [1.15-1.71] p < 0.01). Each 500 mL of crystalloid infused during hours 0-6 was associated with a 9% increase in the rate of ARDS (OR 1.09 [1.04-1.14] p < 0.01). Blood given at 0-6 or 7-24 hours were not risk factors for lung injury. CONCLUSION Acute crystalloid exposure, but not blood products, is a potentially modifiable risk factor for the prevention of ARDS following hemorrhage.
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Damage control resuscitation in patients with severe traumatic hemorrhage: a practice management guideline from the Eastern Association for the Surgery of Trauma
Cannon JW, Khan MA, Raja AS, Cohen MJ, Como JJ, Cotton BA, Dubose JJ, Fox EE, Inaba K, Rodriguez CJ, et al
The Journal of Trauma and Acute Care Surgery. 2017;82((3)):605-617.
Abstract
BACKGROUND The resuscitation of severely injured bleeding patients has evolved into a multi-modal strategy termed damage control resuscitation (DCR). This guideline evaluates several aspects of DCR including the role of massive transfusion (MT) protocols, the optimal target ratio of plasma (PLAS) and platelets (PLT) to red blood cells (RBC) during DCR, and the role of recombinant activated factor VII (rVIIa) and tranexamic acid (TXA). METHODS Using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology, a subcommittee of the Practice Management Guidelines (PMG) Section of EAST conducted a systematic review using MEDLINE and EMBASE. Articles in English from1985 through 2015 were considered in evaluating four PICO questions relevant to DCR. RESULT A total of 37 studies were identified for analysis, of which 31 met criteria for quantitative meta-analysis. In these studies, mortality decreased with use of an MT/DCR protocol vs. no protocol (OR 0.61, 95% CI 0.43-0.87, p = 0.006) and with a high ratio of PLASRBC and PLT:RBC (relatively more PLAS and PLT) vs. a low ratio (OR 0.60, 95% CI 0.46-0.77, p < 0.0001; OR 0.44, 95% CI 0.28-0.71, p = 0.0003). Mortality and blood product use were no different with either rVIIa vs. no rVIIa or with TXA vs. no TXA. CONCLUSION DCR can significantly improve outcomes in severely injured bleeding patients. After a review of the best available evidence, we recommend the use of a MT/DCR protocol in hospitals that manage such patients and recommend that the protocol target a high ratio of PLAS and PLT to RBC. This is best achieved by transfusing equal amounts of RBC, PLAS, and PLT during the early, empiric phase of resuscitation. We cannot recommend for or against the use of rVIIa based on the available evidence. Finally, we conditionally recommend the in-hospital use of TXA early in the management of severely injured bleeding patients.
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Every minute counts: time to delivery of initial massive transfusion cooler and its impact on mortality
Meyer DE, Vincent LA, Fox EE, O'Keeffe T, Inaba K, Bulger E, Holcomb JB, Cotton BA
The Journal of Trauma and Acute Care Surgery. 2017;83((1):):19-24
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BACKGROUND ACS-TQIP Best Practices recommends initial massive transfusion (MT) cooler delivery within 15 minutes of protocol activation, with a goal of 10 minutes. The current study sought to examine the impact of timing of first cooler delivery on patient outcomes. METHODS Patients predicted to receive MT at 12 level-1 trauma centers were randomized to two separate transfusion ratios as described in the PROPPR trial. ABC score or clinician gestalt prediction of MT was used to randomize patients and call for initial study cooler. In this planned sub-analysis, the time to MT protocol activation and time to delivery of the initial cooler were evaluated. The impact of these times on mortality and time to hemostasis were examined using both Wilcoxon rank sum and linear and logistic regression. RESULTS Among 680 patients, the median time from patient arrival to MT protocol activation was 9 minutes with a median time from MT activation call to delivery of first cooler of 8 minutes. An increase in both time to MT activation and time to arrival of first cooler were associated with prolonged time to achieving hemostasis (coef 1.09, p=0.001 and coef. 1.16, p < 0.001, respectively). Increased time to MT activation and time to arrival of first cooler were associated with increased mortality (OR 1.02, p=0.009 and OR 1.02, p = 0.012, respectively). Controlling for injury severity, physiology, resuscitation intensity, and treatment arm (1:1:1 vs. 1:1:2), increased time to arrival of first cooler was associated with an increased mortality at 24-hours (OR 1.05, p = 0.035) and 30-days (OR 1.05, p = 0.016). CONCLUSIONS Delays in MT protocol activation and delays in initial cooler arrival were associated with prolonged time to achieve hemostasis and an increase in mortality. Independent of products ratios, every minute from time of MT protocol activation to time of initial cooler arrival increases odds of mortality by 5%. LEVEL OF EVIDENCE Level II, Prognostic.
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Outcomes after concomitant traumatic brain injury and hemorrhagic shock: a secondary analysis from the Pragmatic, Randomized Optimal Platelets and Plasma Ratios trial
Galvagno SM Jr, Fox EE, Appana SN, Baraniuk S, Bosarge PL, Bulger EM, Callcut RA, Cotton BA, Goodman M, Inaba K, et al
The Journal of Trauma and Acute Care Surgery. 2017;83((4)):668-674.
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BACKGROUND Often the clinician is faced with a diagnostic and therapeutic dilemma in patients with concomitant traumatic brain injury (TBI) and hemorrhagic shock (HS), as rapid deterioration from either can be fatal. Knowledge about outcomes after concomitant TBI and HS may help prioritize the emergent management of these patients. We hypothesized that patients with concomitant TBI and HS (TBI + HS) had worse outcomes and required more intensive care compared with patients with only one of these injuries. METHODS This is a post hoc analysis of the Pragmatic, Randomized Optimal Platelets and Plasma Ratios (PROPPR) trial. TBI was defined by a head Abbreviated Injury Scale score greater than 2. HS was defined as a base excess of -4 or less and/or shock index of 0.9 or greater. The primary outcome for this analysis was mortality at 30 days. Logistic regression, using generalized estimating equations, was used to model categorical outcomes. RESULTS Six hundred seventy patients were included. Patients with TBI + HS had significantly higher lactate (median, 6.3; interquartile range, 4.7-9.2) compared with the TBI group (median, 3.3; interquartile range, 2.3-4). TBI + HS patients had higher activated prothrombin times and lower platelet counts. Unadjusted mortality was higher in the TBI + HS (51.6%) and TBI (50%) groups compared with the HS (17.5%) and neither group (7.7%). Adjusted odds of death in the TBI and TBI + HS groups were 8.2 (95% confidence interval, 3.4-19.5) and 10.6 (95% confidence interval, 4.8-23.2) times higher, respectively. Ventilator, intensive care unit-free and hospital-free days were lower in the TBI and TBI + HS groups compared with the other groups. Patients with TBI + HS or TBI had significantly greater odds of developing a respiratory complication compared with the neither group. CONCLUSION The addition of TBI to HS is associated with worse coagulopathy before resuscitation and increased mortality. When controlling for multiple known confounders, the diagnosis of TBI alone or TBI+HS was associated with significantly greater odds of developing respiratory complications. LEVEL OF EVIDENCE Prognostic study, level II.
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Outcomes following concomitant traumatic brain injury and hemorrhagic shock: a secondary analysis from the PROPPR trial
Galvagno SM Jr, Fox EE, Appana SN, Baraniuk S, Bosarge PL, Bulger EM, Callcut RA, Cotton BA, Goodman M, Inaba K, et al
The Journal of Trauma and Acute Care Surgery. 2017;83((4):):668-674
Abstract
BACKGROUND Often the clinician is faced with a diagnostic and therapeutic dilemma in patients with concomitant traumatic brain injury (TBI) and hemorrhagic shock (HS), as rapid deterioration from either can be fatal. Knowledge about outcomes following concomitant TBI and HS may help prioritize the emergent management of these patients. We hypothesized that patients with concomitant TBI and HS (TBI+HS) had worse outcomes and required more intensive care compared to patients with only one of these injuries. METHODS This is a post-hoc analysis of the Pragmatic, Randomized Optimal Platelets and Plasma Ratios (PROPPR) trial. TBI was defined by a head abbreviated injury scale >2. HS was defined as a base excess ≤ -4 and/or shock index ≥ 0.9. The primary outcome for this analysis was mortality at 30 days. Logistic regression, using generalized estimating equations (GEE), was used to model categorical outcomes. RESULTS 670 patients were included. Patients with TBI+HS had significantly higher lactate (median 6.3; IQR 4.7,9.2) compared to the TBI group (median 3.3; IQR 2.3,4). TBI+HS patients had higher activated prothrombin times and lower platelet counts. Unadjusted mortality was higher in the TBI+HS (51.6%) and TBI (50%) groups compared to the HS (17.5%) and neither group (7.7%). Adjusted odds of death in the TBI and TBI+HS groups were 8.2 (95% CI, 3.4-19.5) and 10.6 (95% CI, 4.8-23.2) times higher, respectively. Ventilator, ICU- and hospital-free days were lower in the TBI and TBI+HS groups compared to the other groups. Patients with TBI+HS or TBI had significantly greater odds of developing a respiratory complication compared to the neither group. CONCLUSIONS The addition of TBI to HS is associated with worse coagulopathy prior to resuscitation, and increased mortality. When conrolling for multiple known confounders, the diagnosis of TBI alone or TBI+HS was associated with significantly greater odds of developing respiratory complications. STUDY TYPE prognostic study LEVEL OF EVIDENCE II.