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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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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.
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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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Platelet transfusions improve hemostasis and survival in a substudy of the prospective, randomized PROPPR trial
Cardenas JC, Zhang X, Fox EE, Cotton BA, Hess JR, Schreiber MA, Wade CE, Holcomb JB
Blood Advances. 2018;2((14)):1696-1704.
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Transfusing platelets during massive hemorrhage is debated because of a lack of high-quality evidence concerning outcomes in trauma patients. The objective of this study was to examine the effect of platelet transfusions on mortality in severely injured trauma patients. This work analyzed PROPPR (Pragmatic, Randomized Optimal Platelet and Plasma Ratios) trial patients who received only the first cooler of blood products, which either did or did not contain platelets. Primary outcomes were all-cause mortality at 24 hours and 30 days and hemostasis. Secondary outcomes included cause of death, complications, and hospital-, intensive care unit (ICU)-, and ventilator-free days. Continuous variables were compared using Wilcoxon rank sum tests. Categorical variables were compared using Fisher's exact tests. There were 261 PROPPR patients who achieved hemostasis or died before receiving a second cooler of blood products (137 received platelets and 124 did not). Patients who received platelets also received more total plasma (median, 3 vs 2 U; P < .05) by PROPPR intervention design. There were no differences in total red blood cell transfusions between groups. After controlling for plasma volume, patients who received platelets had significantly decreased 24-hour (5.8% vs 16.9%; P < .05) and 30-day mortality (9.5% vs 20.2%; P < .05). More patients in the platelet group achieved hemostasis (94.9% vs 73.4%; P < .01), and fewer died as a result of exsanguination (1.5% vs 12.9%; P < .01). Patients who received platelets had a shorter time on mechanical ventilation (P < .05); however, no differences in hospital- or ICU-free days were observed. In conclusion, early platelet administration is associated with improved hemostasis and reduced mortality in severely injured, bleeding patients. This trial was registered at www.clinicaltrials.gov as # NCT01545232.
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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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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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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
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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.
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The pragmatic randomized optimal platelet and plasma ratios trial: what does it mean for remote damage control resuscitation?
Yonge JD, Schreiber MA
Transfusion. 2016;56((Suppl 2)):S149-56.
Abstract
BACKGROUND Implications from the pragmatic, randomize, optimal platelet and plasma ratios (PROPPR) trial are critical for remote damage control resuscitation (DCR). Utilizing DCR principals in remote settings can combat early mortality from hemorrhage. Identifying the appropriate transfusion strategy is mandatory prior to adopting prehospital hemostatic resuscitation strategies. STUDY DESIGN AND METHODS The PROPPR study was examined in relation to the following questions: 1) Why is it important to have blood products in the prehospital setting?; 2) Which products should be investigated for prehospital hemostatic resuscitation?; 3) What is the appropriate ratio of blood product transfusion?; and 4) What are the appropriate indications for hemostatic resuscitation? RESULTS PROPPR demonstrates that early and balanced blood product transfusion ratios reduced mortality in all patients at 3 hours and death from exsanguination at 24 hours (p = 0.03). The median time to death from exsanguination was 2.3 hours, highlighting the need for point-of-injury DCR capabilities. A 1:1:1 transfusion ratio of plasma:platelets:packed red blood cells increased the percentage of patients achieving anatomic hemostasis (p = 0.006). PROPPR used the assessment of blood consumption score to identify patients likely to require ongoing hemostatic resuscitation. The critical administration threshold predicted patient mortality and identified patients likely to require ongoing hemostatic resuscitation. CONCLUSION A balanced resuscitation strategy demonstrates an early survival benefit, decreased death from exsanguination at 24 hours and a greater likelihood of achieving hemostasis in critically injured patients receiving a 1:1:1 ratio of plasma:platelets:PRBCs. This finding highlights the need to import DCR principals to remote locations.
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Transfusion of cryopreserved packed red blood cells is safe and effective after trauma: a prospective randomized trial
Schreiber MA, McCully BH, Holcomb JB, Robinson BR, Minei JP, Stewart R, Kiraly L, Gordon NT, Martin DT, Rick EA, et al
Annals of Surgery. 2015;262((3)):426-33.
Abstract
OBJECTIVES To determine the safety and efficacy of cryopreserved packed red blood cell (CPRBC) transfusion in trauma patients. BACKGROUND Liquid packed red blood cells (LPRBCs) have an abbreviated shelf-life and worsening storage lesion with age. CPRBCs are frozen 2 to 6 days after donation, stored up to 10 years, and are available for 14 days after thawing and washing. CPRBCs can be utilized in diverse settings, but the effect on clinical outcomes is unknown. METHODS We performed a prospective, randomized, double-blind study at 5 level 1 trauma centers. Stable trauma patients requiring transfusion were randomized to young LPRBCs (<14 storage days), old LPRBCs (>14 storage days), or CPRBCs. Tissue oxygenation (StO2), biochemical and inflammatory mediators were measured, and clinical outcomes were determined. RESULTS Two hundred fifty-six patients with well-matched injury severity and demographics (P > 0.2) were randomized (84 young, 86 old, and 86 CPRBCs). Pretransfusion and final hematocrits were similar (P > 0.68). Patients in all groups received the same number of units postrandomization (2 [1-4]; P > 0.05). There was no difference in the change in tissue oxygenation between groups. CPRBCs contained less alpha2-macrogobulin, haptoglobin, C-reactive protein, and serum amyloid P (P < 0.001). Organ failure, infection rate, and mortality did not differ between groups (P > 0.2). CONCLUSIONS Transfusion of CPRBCs is as safe and effective as transfusion of young and old LPRBCs and provides a mechanism to deliver PRBCs in a wide variety of settings.
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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: the PROPPR randomized clinical trial
Holcomb JB, Tilley BC, Baraniuk S, Fox EE, Wade CE, Podbielski JM, del Junco DJ, Brasel KJ, Bulger EM, Callcut RA, et al
Jama. 2015;313((5):):471-82.
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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.
PICO Summary
Population
Patients with severe trauma and major bleeding, enrolled in the Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial in 12 trauma centres in North America (n= 680).
Intervention
Plasma, platelets, and red blood cells in a 1:1:1 ratio (n= 338).
Comparison
Plasma, platelets, and red blood cells in a 1:1:2 ratio (n= 342).
Outcome
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%]) or at 30 days (22.4% vs. 26.1%, respectively; difference -3.7% [95% CI -10.2% to 2.7%]). 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%]). More patients in the 1:1:1 group achieved haemostasis than in the 1:1:2 group (86% vs. 78% respectively). Despite the 1:1:1 group receiving more plasma (median of 7 U vs. 5 U) and platelets (12 U vs. 6 U) 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.