-
1.
Association of Trauma Molecular Endotypes With Differential Response to Transfusion Resuscitation Strategies
Thau MR, Liu T, Sathe NA, O'Keefe GE, Robinson BRH, Bulger E, Wade CE, Fox EE, Holcomb JB, Liles WC, et al
JAMA surgery. 2023
Abstract
IMPORTANCE It is not clear which severely injured patients with hemorrhagic shock may benefit most from a 1:1:1 vs 1:1:2 (plasma:platelets:red blood cells) resuscitation strategy. Identification of trauma molecular endotypes may reveal subgroups of patients with differential treatment response to various resuscitation strategies. OBJECTIVE To derive trauma endotypes (TEs) from molecular data and determine whether these endotypes are associated with mortality and differential treatment response to 1:1:1 vs 1:1:2 resuscitation strategies. DESIGN, SETTING, AND PARTICIPANTS This was a secondary analysis of the Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) randomized clinical trial. The study cohort included individuals with severe injury from 12 North American trauma centers. The cohort was taken from the participants in the PROPPR trial who had complete plasma biomarker data available. Study data were analyzed on August 2, 2021, to October 25, 2022. EXPOSURES TEs identified by K-means clustering of plasma biomarkers collected at hospital arrival. MAIN OUTCOMES AND MEASURES An association between TEs and 30-day mortality was tested using multivariable relative risk (RR) regression adjusting for age, sex, trauma center, mechanism of injury, and injury severity score (ISS). Differential treatment response to transfusion strategy was assessed using an RR regression model for 30-day mortality by incorporating an interaction term for the product of endotype and treatment group adjusting for age, sex, trauma center, mechanism of injury, and ISS. RESULTS A total of 478 participants (median [IQR] age, 34.5 [25-51] years; 384 male [80%]) of the 680 participants in the PROPPR trial were included in this study analysis. A 2-class model that had optimal performance in K-means clustering was found. TE-1 (n = 270) was characterized by higher plasma concentrations of inflammatory biomarkers (eg, interleukin 8 and tumor necrosis factor α) and significantly higher 30-day mortality compared with TE-2 (n = 208). There was a significant interaction between treatment arm and TE for 30-day mortality. Mortality in TE-1 was 28.6% with 1:1:2 treatment vs 32.6% with 1:1:1 treatment, whereas mortality in TE-2 was 24.5% with 1:1:2 treatment vs 7.3% with 1:1:1 treatment (P for interaction = .001). CONCLUSIONS AND RELEVANCE Results of this secondary analysis suggest that endotypes derived from plasma biomarkers in trauma patients at hospital arrival were associated with a differential response to 1:1:1 vs 1:1:2 resuscitation strategies in trauma patients with severe injury. These findings support the concept of molecular heterogeneity in critically ill trauma populations and have implications for tailoring therapy for patients at high risk for adverse outcomes.
-
2.
Dynamic Impact of Transfusion Ratios on Outcomes in Severely Injured Patients: Targeted Machine Learning Analysis of the PROPPR Randomized Clinical Trial
Nguyen M, Pirracchio R, Kornblith LZ, Callcut R, Fox EE, Wade CE, Schreiber M, Holcomb JB, Coyle J, Cohen M, et al
J Trauma Acute Care Surg. 2020
-
-
Free full text
-
Abstract
BACKGROUND Massive transfusion protocols to treat post-injury hemorrhage are based on pre-defined blood product transfusion ratios followed by goal-directed transfusion based on patient's clinical evolution. However, it remains unclear how these transfusion ratios impact patient outcomes over time from injury. METHODS The Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) is a phase 3, randomized controlled trial, across 12 level-I trauma centers in North America. From 2012 to 2013, 680 severely injured patients required massive transfusion. We used semi-parametric machine learning techniques and causal inference methods to augment the intent-to-treat analysis of PROPPR, estimating the dynamic relationship between transfusion ratios and outcomes: mortality and hemostasis at different time-points during the first 24 hours after admission. RESULTS In the intention-to-treat analysis, the 1:1:1 group tended to have decreased mortality, but with no statistical significance. For patients in whom hemostasis took longer than 2 hours, the 1:1:1 ratio was associated with a higher probability of hemostasis, statistically significant from the 4 hour on. In the per-protocol, actual-transfusion-ratios-received analysis, during four successive time intervals, no significant association was found between the actual ratios and mortality. When comparing patient groups who received both high plasma:PRBC and high platelet:PRBC ratios to the group of low ratios in both, the relative risk of achieving hemostasis was 2.49 (95% CI = 1.19-5.22) during the 3 hour after admission, suggesting a significant beneficial impact of higher transfusion ratios of plasma and platelets on hemostasis. CONCLUSIONS Our results suggest that the impact of transfusion ratios on hemostasis is dynamic. Overall, the transfusion ratios had no significant impact on mortality over time. However, receiving higher ratios of platelets and plasma relative to red blood cells hastens hemostasis in subjects who have yet to achieve hemostasis within 3 hours after hospital admission. LEVEL OF EVIDENCE Prognostic, level III.
-
3.
Sex-based differences in transfusion need after severe injury: Findings of the PROPPR study
McCrum ML, Leroux B, Fang T, Bulger E, Arbabi S, Wade CE, Fox E, Holcomb JB, Robinson B
Surgery. 2019
-
-
Free full text
-
Abstract
BACKGROUND Women are underrepresented in trauma research, and aggregated results of clinical trials may mask effects that differ by sex. It is unclear whether women respond differently to severe hemorrhage compared with men. We sought to evaluate sex-based differences in outcomes after severe trauma with hemorrhage. METHODS We performed a secondary analysis of the Pragmatic Randomized Optimal Platelet and Plasma Ratios trial. Trauma patients predicted to require massive transfusion were randomized to a 1:1:1 vs 1:1:2 plasma to platelet to red blood cell transfusion ratio. Analysis was performed according to sex, controlling for clinical characteristics and transfusion arm. RESULTS A total of 134 women and 546 men were analyzed. In multivariable analysis, there was no difference in mortality at 24 hours (hazard ratio for women 0.64, 95% confidence interval 0.34-1.23, P = .18) or in time to hemostasis (hazard ratio 1.10, 95% confidence interval 0.84-1.42, P = .49) by sex. We observed no difference between sexes in volume of blood products transfused during active hemorrhage. However, after anatomic hemostasis, women received lower volumes of all products, with a 38% reduction in fresh frozen plasma (mean ratio 0.62 (95% confidence interval 0.43-0.89, P = .01), 49% reduction in platelets (mean ratio 0.51, 95% confidence interval 0.33-0.79, P < .01) and 49% reduction in volume of red blood cells (mean ratio 0.51, 95% confidence interval 0.33-0.79, P < .01). CONCLUSION Mortality and time to hemostasis of trauma patients with hemorrhage did not differ by sex. Although there was no difference in transfusion requirement during active hemorrhage, once hemostasis was achieved, women received fewer units of all blood products than men. Further research is required to determine whether women exhibit differences in coagulation during and after severe traumatic hemorrhage.
-
4.
The effects of cryopreserved red blood cell transfusion on tissue oxygenation in obese trauma patients
McCully BH, Underwood SJ, Kiraly L, Holcomb JB, Robinson BRH, Minei JP, Stewart RM, Cotton BA, Gordon NT, Martin DT, et al
The Journal of Trauma and Acute Care Surgery. 2018;84((1)):104-111.
Abstract
BACKGROUND Low tissue oxygenation (StO2) is associated with poor outcomes in obese trauma patients. A novel treatment could be the transfusion of cryopreserved packed red blood cells (CPRBCs), which the in vitro biochemical profile favors red blood cell (RBC) function. We hypothesized that CPRBC transfusion improves StO2 in obese trauma patients. METHODS Two hundred forty-three trauma patients at five Level I trauma centers who required RBC transfusion were randomized to receive one to two units of liquid packed RBCs (LPRBCs) or CPRBCs. Demographics, injury severity, StO2, outcomes, and biomarkers of RBC function were compared in nonobese (body mass index [BMI] < 30) and obese (BMI ≥ 30) patients. StO2 was also compared between obese patients with BMI of 30 to 34.9 and BMI ≥ 35. StO2 was normalized and expressed as % change after RBC transfusion. A p value less than 0.05 indicated significance. RESULTS Patients with BMI less than 30 (n = 141) and BMI of 30 or greater (n = 102) had similar Injury Severity Score, Glasgow Coma Scale, and baseline StO2. Plasma levels of free hemoglobin, an index of RBC lysis, were lower in obese patients after CPRBC (125 [72-259] mug/mL) versus LPRBC transfusion (230 [178-388] mug/mL; p < 0.05). StO2 was similar in nonobese patients regardless of transfusion type, but improved in obese patients who received CPRBCs (104 +/- 1%) versus LPRPCs (99 +/- 1%, p < 0.05; 8 hours after transfusion). Subanalysis showed improved StO2 after CPRBC transfusion was specific to BMI of 35 or greater, starting 5 hours after transfusion (p < 0.05 vs. LPRBCs). CPRBCs did not improve clinical outcomes in either group. CONCLUSION CPRBC transfusion is associated with increased StO2 and lower free hemoglobin levels in obese trauma patients, but did not improve clinical outcomes. Future studies are needed to determine if CPRBC transfusion in obese patients attenuates hemolysis to improve StO2. LEVEL OF EVIDENCE Therapeutic, level IV.
-
5.
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
-
-
Free full text
-
Abstract
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.
-
6.
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.
-
7.
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
-
-
Free full text
-
Abstract
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.
-
8.
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.
-
9.
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
-
-
Free full text
-
Abstract
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.
-
10.
Damage control resuscitation and emergency laparotomy: findings from the PROPPR Study
Undurraga Perl VJ, Leroux B, Cook MR, Watson J, FairK, Martin DT, Kerby JD, Williams C, Inaba K, Wade CE, et al
The Journal of Trauma and Acute Care Surgery. 2016;80((4):):568-74; discussion 574-5
-
-
Free full text
-
Abstract
BACKGROUND The Pragmatic Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial has demonstrated that damage control resuscitation, a massive transfusion strategy targeting a balanced delivery of plasma-platelet-RBC in a ratio of 1:1:1, results in improved survival at 3 hours and a reduction in deaths due to exsanguination in the first 24 hours compared to a 1:1:2 ratio. In light of these findings, we hypothesized that patients receiving 1:1:1 ratio would have improved survival after emergency laparotomy. METHODS Severely injured patients predicted to receive a massive transfusion admitted to 12 level I North American trauma centers were randomized to 1:1:1 versus 1:1:2 as described in the PROPPR trial. From these patients, the subset that underwent an emergency laparotomy, defined previously in the literature as laparotomy within 90 minutes of arrival, were identified. We compared rates and timing of emergency laparotomy as well as post-surgical survival at 24-hours and 30-days. RESULTS Of the 680 enrolled patients, 613 underwent a surgical procedure, 397 underwent a laparotomy, and 346 underwent an emergency laparotomy. The percentages of patients undergoing emergency laparotomy were 51.5% (174/338) and 50.3% (172/342) for 1:1:1 and 1:1:2, respectively (p=0.20). Median time to laparotomy was 28 minutes in both treatment groups. Among patients undergoing an emergency laparotomy, the proportions of patients surviving to 24 hours and 30 days were similar between treatment arms, 24-hour survival was 86.8% (151/174) for 1:1:1 and 83.1% (143/172) for 1:1:2 (p=0.29), and 30-day 79.3% (138/174) for 1:1:1 and 75.0% (129/172) for 1:1:2 (p=0.30). CONCLUSIONS We found no evidence that resuscitation strategy affects whether a patient requires an emergency laparotomy, time to laparotomy, or subsequent survival. LEVEL OF EVIDENCE Level IV, therapeutic study.