Copyright 2015 American Medical Association. All rights reserved. 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 John B. Holcomb, MD; Barbara C. Tilley, PhD; Sarah Baraniuk, PhD; Erin E. Fox, PhD; Charles E. Wade, PhD; Jeanette M. Podbielski, RN; Deborah J. del Junco, PhD; Karen J. Brasel, MD, MPH; Eileen M. Bulger, MD; Rachael A. Callcut, MD, MSPH; Mitchell Jay Cohen, MD; Bryan A. Cotton, MD, MPH; Timothy C. Fabian, MD; Kenji Inaba, MD; Jeffrey D. Kerby, MD, PhD; Peter Muskat, MD; Terence O’Keeffe, MBChB, MSPH; Sandro Rizoli, MD, PhD; Bryce R. H. Robinson, MD; Thomas M. Scalea, MD; Martin A. Schreiber, MS; Deborah M. Stein, MD; Jordan A. Weinberg, MD; Jeannie L. Callum, MD; John R. Hess, MD, MPH; Nena Matijevic, PhD; Christopher N. Miller, MD; Jean-Francois Pittet, MD; David B. Hoyt, MD; Gail D. Pearson, MD, ScD; Brian Leroux, PhD; Gerald van Belle, PhD; for the PROPPR Study Group 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 JAMA. 2015;313(5):471-482. doi:10.1001/jama.2015.12 Supplemental content at jama.com Author Affiliations: Author affiliations are listed at the end of this article. Group Information: The Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) Study Group members are listed at the end of this article. Corresponding Author: John B. Holcomb, MD, Center for Translational Injury Research, University of Texas Health Science Center, 6410 Fannin St, Houston, TX 77030 (john.holcomb@uth.tmc.edu). Research Original Investigation (Reprinted) 471 Copyright 2015 American Medical Association. All rights reserved. Downloaded From: http://jama.jamanetwork.com/ by a UNIVERSITY OF SYDNEY LIBRARY User on 09/20/2015 Copyright 2015 American Medical Association. All rights reserved. I n the United States, injury is the leading cause of death among individuals between the ages of 1 and 44 years, it is the leading cause of years of life lost for those younger than 75 years, and it is the third leading cause of death overall.1 Deaths from injury have increased 23% during the last decade.2 Approximately 20% to 40% of trauma deaths occurring after hospital admission involve massive hemorrhage from truncal injury and are potentially preventable with rapid hemorrhage control and improved resuscitation techniques.3 Damage control resuscitation is defined as rapid hemorrhage control through early administration of blood products in a balanced ratio (1:1:1 for units of plasma to platelets to red blood cells [RBCs]; a ratio that is the closest approximation to reconstituted whole blood), prevention and immediate correction of coagulopathy, and minimization of crystalloid fluids.4 Damage control resuscitation was developed to treat intravascular volume deficits, the acute coagulopathy of trauma, preserve oxygen-carrying capacity, repair the endothelium, and prevent dilutional coagulopathy.4,5 Damage control resuscitation was codified as a US Department of Defense clinical practice guideline in 20046 and has become the standard of care for battlefield resuscitation that is now used in many civilian trauma centers. Damage control resuscitation principles have been associated with improved outcomes compared with more traditional transfusion practices.7-12 Conversely, other studies have reported beneficial outcomes across a wider range of blood product ratios or goal-directed approaches.13,14 However, concerns about the safety of exposing injured patients to large amounts of plasmacontaining blood products were difficult to address in previous retrospective studies. There are no large, multicenter, randomized clinical trials with survival as a primary end point that support optimal trauma resuscitation practices with approved blood products. As a result, there are multiple and often conflicting recommendations promulgated by various organizations.15-18The Prospective Observational Multicenter Major Trauma Transfusion (PROMMTT) study demonstrated that clinicians generally were transfusing patients with a blood product ratio of 1:1:1 or 1:1:2 and that early transfusion of plasma (within minutes of arrival to a trauma center) was associated with improved 6-hour survival after admission.10,19 The Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial was designed to address the effectiveness and safety of a 1:1:1 transfusion ratio compared with a 1:1:2 transfusion ratio in patients with trauma who were predicted to receive a massive transfusion. Methods Study Design and Intervention A pragmatic, phase 3, multisite, randomized trial, the PROPPR study compared the effectiveness and safety of a 1:1:1 transfusion ratio of plasma, platelets, and RBCs to a 1:1:2 ratio.20 Patients were randomized within each site, and the intervention consisted of containers of blood products prepared by each site’s blood bank and delivered to the bedside within 10 minutes (DJ Novak et al and the PROPPR Study Group, unpublished data, 2015; Supplement 1). The initial container was sealed to blind the physicians to treatment assignment. The patient was declared randomized when the seal was broken. The blood products were transfused in a prespecified order designed to maintain the appropriate assigned ratio. All containers for the 1:1:1 group included 6 U of plasma, 1 dose of platelets (a pool of 6 U on average), and 6 U of RBCs, which were transfused in the following order: platelets first, then alternating RBC and plasma units. The initial and all subsequent odd-numbered containers for the 1:1:2 group included 3 U of plasma, 0 doses of platelets, and 6 U of RBCs, which were transfused in the following order: alternating 2 U of RBCs and 1 U of plasma. The second and all subsequent even-numbered containers included 3 U of plasma, 1 dose of platelets (a pool of 6 U on average), and 6 U of RBCs, which were transfused in the following order: platelets first, then alternating 2 U of RBCs and 1 unit of plasma. Patients with multiple intravenous lines could receive blood products simultaneously, otherwise patients received products sequentially. Transfusion of all study blood products was stopped when clinically indicated, irrespective of ratio or partial blood container use.20Transfusion of study blood products ended in several ways: achievement of hemostasis, death, declaration of treatment futility, no need for further blood products after randomization, or protocol violations. No other resuscitation, pharmacological, or clinical treatment was controlled by the trial protocol (Supplement 1). The study was approved by the US Food and Drug Administration (FDA) (Investigational New Drug No. 14929), Health Canada, the Department of Defense, and all site institutional review boards. In addition, the study was monitored by an external data and safety monitoring board appointed by the National Heart, Lung, and Blood Institute and used exception from informed consent, including community consultation with delayed patient or legally authorized representative consent.21 Study Population Patients included in the PROPPR trial were severely injured and met the local criteria for highest level trauma activation at 1 of 12 participating level I trauma centers in North America. These site-specific criteria, reviewed by the American College of Surgeons, are based on heart rate, blood pressure, respiratory rate, and mechanism of injury and are used clinically to ensure trauma teams are present before these critically injured patients arrive at the emergency department. The research personnel were notified along with the trauma teams. The goal was to rapidly enroll patients with severe hemorrhage who were nonmoribund, regardless of injury type. To facilitate rapid identification of patients with severe bleeding, inclusion criteria included the patient having at least 1 U of any blood component transfused prior to hospital arrival or within 1 hour of admission and prediction by an Assessment of Blood Consumption score22 of 2 or greater or by physician judgment of the need for a massive transfusion (defined as ≥10 U of RBCs within 24 hours). The complete inclusion and exclusion criteria are listed in the Box. Research Original Investigation Transfusion in Patients With Severe Trauma 472 JAMA February 3, 2015 Volume 313, Number 5 (Reprinted) jama.com Copyright 2015 American Medical Association. All rights reserved. Downloaded From: http://jama.jamanetwork.com/ by a UNIVERSITY OF SYDNEY LIBRARY User on 09/20/2015 Copyright 2015 American Medical Association. All rights reserved. Outcomes and Other Variables of Interest The primary outcomes included absolute percentage group differences for 24-hour and 30-day mortality. These 2 outcome measures tested 2 separate questions regarding short-term effectiveness and long-term safety without adjustment for multiple comparisons per protocol.23 Each death was adjudicated by a clinician blinded to group assignment and external to the trial site and 1 or more causes of death were assigned. Ancillary outcomes were prespecified to evaluate the effectiveness and safety of the transfusion ratios and included (1) time to hemostasis; (2) the number and type of blood products used from randomization until hemostasis was achieved; (3) the number and type of blood products used after hemostasis was achieved up to 24 hours postadmission; (4) 23 complications; (5) hospital-, ventilator-, and ICU-free days (within the first 30 days or hospital discharge, whichever occurred first); (6) incidence of major surgical procedures; and (7) functional status at hospital discharge or 30 days, whichever occurred first, asmeasured by discharge destination and Glasgow Outcome Scale-Extended. Blood product ratios were calculated as 2 separate ratios: plasma to RBCs and platelets to RBCs. For example, a 1:1 ratio of plasma to RBCs is equivalent to 1.0 and represents equal total units of plasma and RBCs within the specified interval. A 1:2 ratio is equivalent to 0.5 and represents twice as many total RBC units as plasma units. Ratios for patients who received no RBCs within a specified interval cannot be calculated because the denominator is zero, and therefore are not included in the calculation of cumulative ratios of blood products in that interval. Race and Hispanic ethnicity were collected by patient self-report or hospital staff determination and were included to identify disparities in treatment or outcome. The Injury Severity Score is an anatomic scoring system used for patients with multiple injuries, correlates with mortality, and has a range of 0 (uninjured) to 75 (usually unsurvivable injuries).24 The critical administration threshold represents the trauma subset at highest risk of hemorrhagic mortality25 and denotes patients receiving more than 3 U of RBCs within at least 1 hour during the first 24 hours after admission. The Assessment of Blood Consumption score has a range of 0 to 4 with scores of 2 or greater associated with the need for a massive transfusion.22 Anatomic hemostasis in the operating room was defined as an objective assessment by the surgeon indicating that bleeding within the surgical field was controlled and no further hemostatic interventions were anticipated. In the interventional radiology suite, anatomic hemostasis was defined as achieving resolution of contrast blush after embolization. Sample Size The initial sample size of 580 was planned to detect a clinically meaningful 10% difference in 24-hour mortality (11% vs 21%) and a 12% difference in 30-day mortality (23% vs 35%), which was supported by prior data.26,27 Sample size was increased to 680 by the data and safety monitoring board according to the trial’s adaptive design. With 680 patients and given the final observedmortality proportions in the 1:1:1 group, the PROPPR trial had 95% power to detect the prespecified 10% difference at 24 hours and 92% power to detect the prespecified 12% difference at 30 days, if such differences existed. Statistical Analysis The primary analysis separately compared 24-hour and 30-day mortality in the 2 transfusion ratio groups using a 2-sided Mantel-Haenszel test adjusting for site. For the 4 patients missing a primary outcome, a sensitivity analysis using all possible combinations (n = 16) of outcomes was performed and a range of intent-to-treat P values for the hypotheticalMantel-Haenszel tests are presented.28The critical level for significance (P ≤ .044) was adjusted for 2 interim analyses, and all tests were conducted using 2-sided tests.29 In Cox analyses, the 4 patients missing a 30-day outcome were censored at the last known follow-up time.30 Lack of protocol compliance was measured by the per-patient percentage of blood products given out of order. A sensitivity analysis compared treatment groups excluding these patients. Box. Inclusion and Exclusion Criteria for the Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) Trial Eligible Patients Met All of the Following: Highest trauma level activation Estimated age of 15 years or older or weight of 50 kg or greater if age unknown Received directly from the injury scene Initiated transfusion of at least 1U ofblood component within the first hour of arrival or during prehospital transport Predicted to receive a massive transfusion by exceeding the threshold score of either the Assessment of Blood Consumption score of 2 or greater or based on the attending trauma physician’s judgment Patients Who Were Ineligible Met at Least 1 of the Following: Received a lifesaving intervention from an outside hospital or health care facility Had devastating injuries and expected to die within 1 hour of admission (eg, lethal traumatic brain injury) Directly admitted from a correctional facility Required a thoracotomy prior to receiving randomized blood products in the emergency department Younger than 15 years or weighed less than 50 kg if age unknown Known pregnancy in the emergency department Had burns covering greater than 20% total body surface area Suspected inhalation injury Received greater than 5 consecutiveminutes of cardiopulmonary resuscitation (with chest compressions) prior to arriving at the hospital or within the emergency department Known do-not-resuscitate order prior to randomization Enrolled in a concurrent, ongoing, interventional, randomized clinical trial Activated the opt-out process for the PROPPR trial (usually by wearing a bracelet given out at a community consent presentation) More than 3 U of red blood cells given before randomization Transfusion in Patients With Severe Trauma Original Investigation Research jama.com (Reprinted) JAMA February 3, 2015 Volume 313, Number 5 473 Copyright 2015 American Medical Association. All rights reserved. Downloaded From: http://jama.jamanetwork.com/ by a UNIVERSITY OF SYDNEY LIBRARY User on 09/20/2015 Copyright 2015 American Medical Association. All rights reserved. All analyses were generated using SAS version 9.3 (SAS Institute Inc). Additional details regarding the study design and analysis were published previously.20 Results From August 3, 2012, to December 2, 2013, a total of 14 313 highest-level trauma activations occurred at the 12 enrolling sites, of which 78% were screened. A total of 680 patients were randomized (338 to the 1:1:1 group and 342 to the 1:1:2 group; Figure 1). Randomized blood products were transfused to 669 patients. No differences were detected between treatment groups in baseline characteristics (Table 1). Themajority of patientsweremalewith similar ages in both groups. Patients in both groups were profoundly injured with a median Injury Severity Score of 26 and severely bleeding based on the critical administration threshold (87% positive based on this threshold overall). The initial hemoglobin level was 11.7 g/dL (37% had hemoglobin levels <11 g/dL) in the 1:1:1 group and 11.9 g/dL (38.8% had hemoglobin levels <11 g/dL) in the 1:1:2 group. Seventy-five percent of patients required an interventional radiology or operating room procedure within 2 hours of admission (data not shown). The primary trial outcomes of mortality at 24 hours and 30 days were obtained on 100% and 99.4% of patients, respectively. No significant differences in mortality were detected at 24 hours (12.7% in the 1:1:1 group vs 17.0% in the 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%) (Table 2).31 The range of intent-to-treat P values computed for all possible combinations of 30-day outcomes for the 4 patients with missing values did not change these results. The P values ranged from 0.21 to 0.36 (eTable 1 in Supplement 2). The Kaplan-Meier curves (Figure 2) show a separation in survival between the 2 treatment groups across the follow-up period, but the difference was not significant (unadjusted logrank test, P = .21). Sensitivity analyses excluding patients who received blood products given out of order yielded results similar to the main analysis. Themean percentages of intervention units given out of order per patient (protocol noncompliance) were significantly lower in the 1:1:1 group (4%; 95% CI, 3.2%-5.7%) vs the 1:1:2 group (7%; 95% CI, 6.1% to 8.5%) (P = .01). Exsanguination, the predominant cause of death within the first 24 hours, was decreased in the 1:1:1 group (9.2%) vs the 1:1:2 group (14.6%) (difference, −5.4% [95% CI, −10.4% to −0.5%], P = .03); the median time to death due to exsanguination was 106 minutes (interquartile range [IQR], 54 to 198 minutes) and 96 minutes (IQR, 43 to 194 minutes), respectively. From 24 hours through 30 days, the numbers of additional all-cause deaths were similar (32 for the 1:1:1 group vs 31 for the 1:1:2 group). Over 30 days, deaths due to exsanguination occurred in 10.7% of patients in the 1:1:1 group vs 14.7% in the 1:1:2 group, whereas deaths due to traumatic brain injury were 8.1% vs 10.3%, respectively. Additional causes of Figure 1. Flow of Patients in the Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) Trial 11185 Patients assessed for eligibility 10505 Excluded 7027 Did not receive at least 1 U of a blood component within the first hour after arrival or during prehospital transport 1655 Not received directly from the injury scene 882 Not predicted to receive a massive transfusion 277 Age <15 y (or weight <50 kg) 154 Patient improved, did not require further transfusion 130 Devastating injury, expected to die within 1 h of ED admission 129 PROPPR products not given within 2-h period 65 Patient did not require highest level of trauma activation 49 Received CPR for >5 min 48 Required an emergency thoracotomy 36 Institutionalized in prison 32 Fourth unit of RBCs was transfused before randomization 21 Other reasonsa 680 Randomized 30-d Mortality 18 Withdrew consentb 3 Lost to follow-up 338 Included in mortality analysis 30-d Mortality 17 Withdrew consentb 1 Lost to follow-up 342 Included in mortality analysis 24-h Mortality 3 Withdrew consentb 0 Lost to follow-up 338 Included in mortality analysis 24-h Mortality 2 Withdrew consentb 0 Lost to follow-up 342 Included in mortality analysis 338 Randomized to 1:1:1 group 342 Randomized to 1:1:2 group CPR indicates cardiopulmonary resuscitation; ED, emergency department; RBC, red blood cell. a Included patients with the following: 6 known pregnancies, 5 with physicians who refused to randomize, 4 with known do-not-resuscitate order prior to randomization, 3 with burns covering more than 20% of total body surface area, 1 with a documented inhalation injury, 1 who opted out upon arrival to the ED, 1 unknown reason. b The vital statistic data were obtained for patients who withdrew consent when available. Patients who withdrew consent at 24 hours are included in the count of those who withdrew at 30 days. Research Original Investigation Transfusion in Patients With Severe Trauma 474 JAMA February 3, 2015 Volume 313, Number 5 (Reprinted) jama.com Copyright 2015 American Medical Association. All rights reserved. Downloaded From: http://jama.jamanetwork.com/ by a UNIVERSITY OF SYDNEY LIBRARY User on 09/20/2015 Copyright 2015 American Medical Association. All rights reserved. death were infrequent and are shown in Table 3. More patients achieved anatomic hemostasis in the 1:1:1 group (86.1% vs 78.1% in the 1:1:2 group, P = .006) with a median time of 105 minutes (IQR, 64 to 179 minutes) vs 100 minutes (IQR, 56 to 181minutes), respectively (P = .44) in those who achieved anatomic hemostasis (Table 2). Cumulative transfusion ratios and the distribution of blood product amounts (prerandomization, during the intervention, and postintervention) are shown in Figure 3 and Figure 4. During the intervention, patients received median ratios of plasma to RBCs of 1.0 in the 1:1:1 group and 0.5 in the 1:1:2 group. The median ratios of platelets to RBCs during the Table 1. Patient Characteristics by Treatment Group 1:1:1 Group (n = 338) 1:1:2 Group (n = 342) Age, median (IQR), ya 34.5 (25 to 51) 34 (24 to 50) Male sex, No. (%) 263 (77.8) 283 (82.7) Race, No. (%)b White 210 (62.1) 224 (65.5) Black 94 (27.8) 93 (27.2) Other 35 (10.4) 25 (7.3) Hispanic ethnicity, No. (%)c 61 (18.0) 59 (17.3) Glasgow Coma Scale score, median (IQR) 14 (3 to 15) 14 (3 to 15) Systolic blood pressure, No. of patients 330 328 Median (IQR), mm Hgd 102 (81 to 126) 102 (80 to 125) No. (%) with ≤90 mm Hg 127 (38.5) 128 (39.0) Diastolic blood pressure, No. of patients 284 279 Median (IQR), mm Hgd 70 (53 to 90) 68 (50 to 91) Heart rate, No. of patients 336 341 Median (IQR), beats/mind 115 (97 to 135) 113 (93 to 130) No. (%) with ≥120 beats/min 148 (44.0) 152 (44.6) Respiratory rate, No. of patients 308 313 Median (IQR), breaths/min 20 (17.5 to 26.0) 20 (17 to 26) Assessment of Blood Consumption score ≥2, No. (%)22,e 215 (63.6) 223 (65.2) Mechanism of injury, No. (%) Any blunt injury 185 (54.7) 173 (50.6) Any penetrating injury 157 (46.4) 173 (50.6) Time to randomization, median (IQR), min 27.5 (17 to 47) 25.5 (16 to 41) Hemoglobin level, No. of patients 327 325 Median (IQR), g/dL 11.7 (10.1 to 13.4) 11.9 (10.1 to 13.2) No. (%) with ≤11 g/dL 121 (37.0) 126 (38.8) International normalized ratio, No. of patients 218 218 Median (IQR) 1.3 (1.2 to 1.5) 1.3 (1.2 to 1.5) No. (%) with ratio >1.5 57 (26.1) 59 (27.1) Thromboelastography R time, No. of patients 276 279 Median (IQR), min 3.8 (2.9 to 4.6) 3.8 (2.8 to 4.7) No. (%) with time >8 min 12 (4.3) 12 (4.3) Platelet count, No. of patients 317 317 Median (IQR), in thousands 213 (164 to 261) 212 (164 to 264) No. (%) with count <150 in thousands 54 (17.0) 60 (18.9) Base excess, No. of patients 318 301 Median (IQR), mmol/L −8 (−12.5 to −3.8) −8.5 (−12.8 to −4.7) No. (%) with score ≤−4 mmol/L 238 (74.8) 239 (79.4) Injury Severity Score, median (IQR)f 26.5 (17 to 41) 26 (17 to 38) Revised Trauma Score, No. of patientsg 303 304 Median (IQR) 6.8 (4.1 to 7.8) 6.4 (4.1 to 7.8) Resuscitation indicators, No. (%) Massive transfusionh 153 (45.3) 160 (46.8) Critical administration thresholdi 281 (83.1) 314 (91.8) Abbreviations: IQR, interquartile range; RBC, red blood cell. a One patient was missing a verified age so it was imputed using the median of the interval for estimated age. bMore than 1 race could be selected per patient, therefore percentages may exceed 100%. Other included American Indian/Alaskan Native/Aboriginal, Asian, Native Hawaiian/other Pacific Islander, other, and unknown. c Determined by either self-report from the patient or family or direct observation by medical staff. dPatients with blood pressure and heart rate that was not recorded, measured, detectable, or palpable were excluded from the median calculations and the Wilcoxon rank sum test. e The score range was 0 to 4. Patients with a score of 0 (n = 50) and 1 (n = 192) were enrolled in the trial as physician overrides, which was defined as a score of less than 2 and attending physician determination that a massive transfusion was needed. f The score range was 0 to 75. A score greater than 15 indicates major trauma. g The score range was 0 to 7.8. A higher score is associated with better survival probability. hDefined as 10 U or greater of RBCs received within first 24 hours. Includes observations made postrandomization. i Defined as 3 U or greater of RBCs received at least once per 1-hour interval during the first 24 1-hour periods. One patient in each treatment group did not receive any RBCs. Includes observations made postrandomization. Transfusion in Patients With Severe Trauma Original Investigation Research jama.com (Reprinted) JAMA February 3, 2015 Volume 313, Number 5 475 Copyright 2015 American Medical Association. All rights reserved. Downloaded From: http://jama.jamanetwork.com/ by a UNIVERSITY OF SYDNEY LIBRARY User on 09/20/2015 Copyright 2015 American Medical Association. All rights reserved. intervention were 1.5 for the 1:1:1 group and 0.4 for the 1:1:2 group. Higher cumulative plasma and platelet ratios in the 1:1:2 group vs the 1:1:1 group were seen during the postintervention period. Similar amounts of total blood products (median of 2 U) were delivered prerandomization to both groups (eFigure in Supplement 2). Themedian total blood product amounts transfused were 16 U in the 1:1:1 group and 15 U in the 1:1:2 group during the intervention period. Patients in the 1:1:1 group received fewer blood products during the postintervention period than the 1:1:2 group (median of 1 U vs 2 U, respectively). The median total for blood products transfused up to 24 hours after admission was 25.5 U in the 1:1:1 group and 19 U in the 1:1:2 group. Total plasma (median of 7 U in the 1:1:1 group vs 5 U in the 1:1:2 group, P < .001) and platelets (12 U vs 6 U, respectively, P < .001) transfused within the first 24 hours were higher in the 1:1:1 group, but similar for RBCs (9 U) (eTable 2 in Supplement 2). Use of tranexamic acid and other procoagulants was similar. Differences were not detected in any of the 23 complications at 30 days (Table 4), including acute respiratory distress syndrome, multiple organ failure, venous thromboembolism, sepsis, and transfusion-related complications. The overall rate of complications was high (89% of patients). One patient in the 1:1:1 group died from transfusion-associated circulatory overload. Significant differences between groups in the other ancillary outcomes focusing on safety were not detected and are shown in Table 2. Discussion Transfusion for patients with severe trauma and major bleeding has been predominantly guided by tradition rather than evidence from large, multicenter randomized trials. Over the last decade, transfusion therapy has undergone a significant change with many patients receiving less crystalloid and early, more balanced transfusion ratios attempting to reconstitute whole blood.4-12,27,32-41 This change has largely been associated with decreased transfusion amounts, fewer inflammatory complications, and improved survival.4-12,27,32-41 To our knowledge, the PROPPR trial was the first multicenter randomized trial using approved blood products to compare 2 transfusion ratioswithmortality as the primary end point. Among the 680 patients predicted to receive a massive transfusion and transfused with a 1:1:1 or 1:1:2 ratio, no significant differences in overall mortality at 24 hours or 30 days were detected. However, more patients achieved hemostasis in the Table 2. Trial Outcomes by Treatment Group 1:1:1 Group (n = 338) 1:1:2 Group (n = 342) Difference (95% CI), % Adjusted RR (95% CI) P Valuea 24-h Mortality, No. (%)b 43 (12.7) 58 (17.0) −4.2 (−9.6 to 1.1) 0.75 (0.52 to 1.08) .12 30-d Mortality, No. (%)b 75 (22.4) 89 (26.1) −3.7 (−10.2 to 2.7) 0.86 (0.65 to 1.12) .26 Achieved hemostasis No. (%) 291 (86.1) 267 (78.1) .006 Anatomic, median (IQR), minc 105 (64 to 179) 100 (56 to 181) .44 Hospital-free days, median (IQR)c,d 1 (0 to 17) 0 (0 to 16) .83 Ventilator-free daysd Total No. of patients 337 340 Median (IQR)c 8 (0 to 16) 7 (0 to 14) .14 ICU-free daysd Total No. of patients 337 340 Median (IQR)c 5 (0 to 11) 4 (0 to 10) .10 Incidence of primary surgical procedure 290 (85.8) 284 (83.0) 2.8 (−2.8 to 8.3) Disposition at 30 d, No. (%)e Home 118 (34.9) 105 (30.7) .37 Remained hospitalized 82 (24.3) 77 (22.5) Otherf 59 (17.5) 71 (20.8) Morgue 75 (22.2) 89 (26.0) Unknown 4 (1.2) 0 Glasgow Outcome Scale-Extended score Total No. of patientsg 30 28 Median (IQR)c 4 (3 to 6) 4.5 (3.5 to 7.0) .11 a Calculated using the Mantel-Haenszel test for binary outcomes measured from randomization, adjusting for site. bBreslow-Day test for homogeneity, χ 2 11: 24-hour P = .51, 30-day P = .65. c The van Elteren test31 was used to compare medians, adjusting for site. d Individuals who died within the first 24 hours from admission were assigned zero ICU-, ventilator-, and hospital-free days. e A generalized logit model was fit to test for treatment differences. f Includes long-term care facility, skilled nursing facility, rehabilitation facility, acute care hospital, assisted living, psychiatric facility, and jail. gObtained only on discharged patients who had a head injury. Research Original Investigation Transfusion in Patients With Severe Trauma 476 JAMA February 3, 2015 Volume 313, Number 5 (Reprinted) jama.com Copyright 2015 American Medical Association. All rights reserved. Downloaded From: http://jama.jamanetwork.com/ by a UNIVERSITY OF SYDNEY LIBRARY User on 09/20/2015 Copyright 2015 American Medical Association. All rights reserved. 1:1:1 group, fewer patientsdied of exsanguination, and this transfusion ratio appears to be safe.Results from thePROMMTT study showed that earlier use of higher amounts of plasma and platelets (albeit without consistent ratios) was associated with improved survival during the first 6 hours after admission.10,19Data from the PROPPR trial evaluated the effect of early transfusion of different but consistent ratios in patients predicted to receive a massive transfusion. Taken together, these data support early (withinminutes of hospital arrival) use of a 1:1:1 transfusion ratio in patients with rapid bleeding. Despite significant concerns that the 1:1:1 group would experience higher rates ofmultiple inflammatory-mediated complications such as acute respiratory distress syndrome, multiple organ failure, infection, venous thromboembolism, and sepsis,13,14,42-45 no differences were detected between the 2 treatment groups. Furthermore, the rates ofmultiple organ failure (5%) and acute respiratory distress syndrome (14%) were lower than in recent studies in similarly injured patient populations,46,47whichmay be attributable to delivering blood to the bedside earlier (median of 8minutes)20 and limited crysFigure 2. Kaplan-Meier Failure Curves for Mortality at 24 Hours and 30 Days 0.30 0.35 0.25 0.20 0.15 0.10 0.05 0 0 342 338 24 284 295 12 291 300 18 286 297 6 296 305 Probability of Death Time to Death From Randomization, h No. at risk 1:1:2 1:1:1 1 322 327 3 304 318 24-h Mortality 0.30 0.35 0.25 0.20 0.15 0.10 0.05 0 0 342 338 30 252 260 20 253 263 Probability of Death Time to Death From Randomization, d 10 261 269 30-d Mortality 1:1:2 Group 1:1:1 Group The colored areas indicate 95% confidence bands, which were calculated using the Hall-Wellner method. The Hall-Wellner bands extend to the last event (death) in each group. For 24-hour mortality, the Cox proportional hazards regression model, adjusted for site as a random effect, produced a hazard ratio (HR) of 0.72 (95% CI, 0.49-1.07). There were no patients lost to follow-up during the first 24 hours from randomization. For 30-day mortality, the Cox proportional hazards regression model, adjusted for site as a random effect, produced an HR of 0.83 (95% CI, 0.61-1.12). Between 24 hours and 30 days, 4 patients were lost to follow-up and were censored when they withdrew consent or were last known to be alive (3 in the 1:1:1 group and 1 in the 1:1:2 group). Table 3. Adjudicated Cause of Death by Treatment Group and Period From Randomization First 24 Hours 30 Days No. (%) Difference (95% CI),%a No. (%) Difference (95% CI), %a 1:1:1 Group (n = 338) 1:1:2 Group (n = 342) 1:1:1 Group (n = 335) 1:1:2 Group (n = 341) Total No. of deaths 43 58 75 89 Cause of deathb Exsanguination 31 (9.2) 50 (14.6) −5.4 (−10.4 to −0.5) 36 (10.7) 50 (14.7) −3.9 (−9.1 to 1.2) Traumatic brain injury 11 (3.3) 12 (3.5) −0.3 (−3.2 to 2.7) 27 (8.1) 35 (10.3) −2.2 (−6.7 to 2.2) Respiratory, pulmonary contusion, or tension pneumothorax 3 (0.9) 1 (0.3) 0.6 (−0.9 to 2.4) 5 (1.5) 2 (0.6) 0.9 (−0.8 to 3.0) Sepsis 0 0 0 (−1.1 to 1.1) 1 (0.3) 2 (0.6) −0.3 (−1.9 to 1.2) Multiple organ failure 0 0 0 (−1.1 to 1.1) 10 (3.0) 8 (2.3) 0.6 (−2.0 to 3.4) Type of cardiovascular event Stroke 0 1 (0.3) −0.3 (−1.7 to 0.9) 2 (0.6) 1 (0.3) 0.3 (−1.1 to 1.9) Myocardial infarction 1 (0.3) 1 (0.3) 0 (−1.4 to 1.4) 1 (0.3) 2 (0.6) −0.3 (−1.9 to 1.2) Pulmonary embolism 0 1 (0.3) −0.3 (−1.7 to 0.9) 0 1 (0.3) −0.3 (−1.7 to 0.9) Transfusion-related fatality 0 0 0 (−1.1 to 1.1) 1 (0.3) 0 0.3 (−0.8 to 1.7) a Calculated using exact unconditional methods based on the Farrington-Manning score statistic. bA patient may have had more than 1 cause of death. Transfusion in Patients With Severe Trauma Original Investigation Research jama.com (Reprinted) JAMA February 3, 2015 Volume 313, Number 5 477 Copyright 2015 American Medical Association. All rights reserved. Downloaded From: http://jama.jamanetwork.com/ by a UNIVERSITY OF SYDNEY LIBRARY User on 09/20/2015 Copyright 2015 American Medical Association. All rights reserved. talloid exposure (median, 6.3-6.6 L) during the first 24 hours of care. In this trial, the early availability of blood products administered within minutes of arrival using a transfusion ratio of 1:1:1 was associated with more patients achieving hemostasis and decreased hemorrhage-related deaths over the first 24 hours with no differences in complications. Therefore, patient safety was not compromised over 30 days. Transfusing patients based on an empirical ratio rather than guided solely by laboratory data (goal-directed) is considered controversial by some researchers.44,45,48 This trial was not designed to study this question. However, after the controlled, ratio-driven intervention was completed, clinicians treated patients based on local laboratory-guided standard-of-care practice.49 It appears that laboratorydirected catching up occurred in the 1:1:2 group with plasma and platelets approaching a cumulative ratio of 1:1:1. Other studies have shown similar results with laboratory-directed resuscitation.11 This catching up after the completion of randomized blood product transfusion may have decreased the ability to detect differences in mortality at 24 hours and 30 days or in the prespecified ancillary outcomes. Theconceptsofdamagecontrol resuscitation anddata from the PROMMTT study formed the biological basis of the PROPPR trial, ie, both early initiation (withinminutes of arrival) and increased ratios of plasma and platelets would decrease death from hemorrhage by improving hemostasis.4-12,27,32-41Recent trauma resuscitationstudieshavedemonstrated thatmost early deaths due to hemorrhage occur within 2 to 3 hours.3,10,27,50,51 The PROMMTT study demonstrated a median time to hemorrhagic death from admission of 2.6 hours,10 and in the PROPPR trial, the median time was 2.3 hours. In recognition of the known physiology of patients with major bleeding, the FDA recently recommended moving the end point of hemostasis in a pivotal phase 3 prothrombin complex concentrate trial to within 4 hours of the intervention.52 These data support recent recommendations by the FDA to include a 3-hour end point for intervention studies focusing on traumatic hemorrhage.53 In the current study, the FDA only allowed 2 separate primary end points (24 hours and 30 days) in recognition of the assumed time frame of death from hemorrhage after injury.3,10,54 However, most outcomes relevant to hemorrhage control occurred early (within the initial 2-3 hours after randomization). Thereafter, the number of patients who died was similar between groups, explaining the diminished effects at 24 hours and 30 days. This pattern of Figure 3. Distribution of Cumulative Blood Product Ratios Within Period up to 24 Hours After Admission 4.0 2.0 2.5 3.5 3.0 1.5 1.0 0.5 0 Ratio of Plasma to RBCs No. 1:1:1 1:1:2 Prerandomization 324 321 Postintervention 133 114 7.5 6.0 4.5 3.0 1.5 0 Ratio of Platelets to RBCs No. Prerandomization 324 321 Postintervention 133 114 Ratio of plasma to RBCs Ratio of platelets to RBCs During Intervention 326 332 During Intervention 326 332 Prerandomization blood products include those given prior to hospital arrival. Patients who received no red blood cells (RBCs) within an interval were excluded because RBCs are in the ratio denominator. The lower and upper edges of the boxes are the 25th and 75th percentiles, the whiskers extend to ± 1.5 × the interquartile range, and the points outside are the outliers. The thick line inside the box represents the median and the circle is the mean. Figure 4. Distribution of Blood Product Amounts Within Period up to 24 Hours After Admission 70 40 50 60 30 20 10 0 Amount Given, U Prerandomization No. 70 40 50 60 30 20 10 0 Amount Given, U During intervention No. RBCs 70 40 50 60 30 20 10 0 Amount Given, U Postintervention No. Plasma Platelets RBCs 316 Plasma Platelets 305 Plasma Platelets RBCs 342 Platelets 338 Plasma RBCs 1:1:1 Plasma Platelets 342 RBCs 1:1:2 1:1:1 1:1:2 1:1:1 1:1:2 Platelets RBCs 338 Plasma Prerandomization blood products include those given prior to hospital arrival. The lower and upper edges of the boxes are the 25th and 75th percentiles, the whiskers extend to ± 1.5 × the interquartile range, and the points outside are the outliers. The thick line inside the box represents the median and the circle is the mean. Five or 6 U pools of whole blood–derived platelets were considered equivalent to 1 U of apheresis platelets (eg, an adult dose of platelets). Research Original Investigation Transfusion in Patients With Severe Trauma 478 JAMA February 3, 2015 Volume 313, Number 5 (Reprinted) jama.com Copyright 2015 American Medical Association. All rights reserved. Downloaded From: http://jama.jamanetwork.com/ by a UNIVERSITY OF SYDNEY LIBRARY User on 09/20/2015 Copyright 2015 American Medical Association. All rights reserved. traumatic death is consistent with previous randomized resuscitation studies.51,55,56 This trial had a number of strengths. 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.48,55-61The 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. Separation of the ratio groupswasmaintained during the intervention period. Another strength of the trial was the high degree of compliance with treatment protocols while simultaneously caring for patients with severe injuries. Follow-up at 24 hours was complete in both intervention groups, and only 4 patients were lost to follow-up at 30 days. Additionally, we blinded clinicians to treatment assignment until infusion of randomized products and used direct observation for accurate data collection of blood product delivery. Limitations include power to detect differences smaller than the effect size we considered to be both clinically meaningful and affordable to study when we designed the trial. The PROPPR trial had 95% power to detect the prespecified 10% difference at 24 hours and 92% power to detect the prespecified 12% difference at 30 days, if such differences existed. As in many studies, observed mortality in the comparison group (1:1:2) was lower than expected, whereas in the 1:1:1 group, observed mortality was similar to what was projected. A total sample size of 2968 would have been required to detect the observed difference of 4.2% given the observed 24-hour mortality of 12.7% in the 1:1:1 group with 90% power. A further limitation is the inability to independently examine the effects of plasma and platelets on outcomes. To enroll patients withmassive bleeding, the protocol required transfusion of at least 1 U of any blood product and no more than 3 U of RBCs prior to randomization, resulting in an inability to use randomized blood products starting with the first transfusion. Table 4. Incidence of Prespecified Complications by Treatment Group 1:1:1 Group (n = 338) 1:1:2 Group (n = 342) Difference Between Groups in Percentage of Patients With Event, % (95% CI)c Total No. of Eventsa No. (%) of Patientsb Total No. of Eventsa No. (%) of Patientsb Systemic inflammatory response syndrome 265 231 (68.3) 239 216 (63.2) 5.2 (−2.1 to 12.3) Sepsis 110 99 (29.3) 102 91 (26.6) 2.7 (−4.2 to 9.5) Infection (urinary tract infection, wound, line, other) 155 98 (29.0) 146 106 (31.0) −2.0 (−8.9 to 5.0) Death 75 75 (22.2) 89 89 (26.0) −3.8 (−10.3 to 2.7) Acute kidney injury 87 74 (21.9) 93 85 (24.9) −3.0 (−9.4 to 3.5) Ventilator-associated pneumonia 70 62 (18.3) 65 58 (17.0) 1.4 (−4.4 to 7.2) Transfusion-related metabolic complication (hypocalcemia or hyperkalemia) 53 53 (15.7) 60 59 (17.3) −1.6 (−7.2 to 4.1) Acute lung injury 56 47 (13.9) 66 57 (16.7) −2.8 (−8.3 to 2.7) Acute respiratory distress syndrome 55 46 (13.6) 57 48 (14.0) −0.4 (−5.7 to 4.9) Deep vein thrombosis 28 25 (7.4) 24 24 (7.0) 0.4 (−3.6 to 4.4) Abdominal complication 29 24 (7.1) 23 22 (6.4) 0.7 (−3.3 to 4.6) Cardiac arrest 25 23 (6.8) 30 27 (7.9) −1.1 (−5.2 to 3.0) Multiple organ failure 24 20 (5.9) 18 15 (4.4) 1.5 (−1.9 to 5.1) Symptomatic pulmonary embolism 14 14 (4.1) 13 13 (3.8) 0.3 (−2.8 to 3.5) Additional bleeding after hemostasis requiring interventional radiology or operating room procedure 13 13 (3.8) 18 16 (4.7) −0.8 (−4.1 to 2.4) Asymptomatic pulmonary embolism 11 11 (3.3) 11 11 (3.2) 0 (−2.8 to 2.9) Stroke 9 8 (2.4) 11 11 (3.2) −0.8 (−3.6 to 1.8) Abdominal compartment syndrome 3 3 (0.9) 3 3 (0.9) 0 (−1.8 to 1.8) Delayed serological transfusion reaction 2 2 (0.6) 0 0 0.6 (−0.5 to 2.1) Transfusion-related allergic reactions 2 2 (0.6) 1 1 (0.3) 0.3 (−1.1 to 1.9) Hypernatremia (associated with hypertonic saline) 1 1 (0.3) 4 4 (1.2) −0.9 (−2.7 to 0.6) Febrile nonhemolytic transfusion reaction 1 1 (0.3) 1 1 (0.3) 0 (−1.4 to 1.4) Transfusion-associated circulatory overload 1 1 (0.3) 0 0 0.3 (−0.8 to 1.7) Myocardial infarction 0 0 2 2 (0.6) −0.6 (−2.1 to 0.6) Any prespecified complications 1089 297 (87.9) 1076 310 (90.6) −2.8 (−7.6 to 1.9) a A patient may have had multiple complications of the same type. bPercentages may add to more than 100% because a patient may have had more than 1 complication. c Calculated using exact unconditional methods based on the Farrington-Manning score statistic. Transfusion in Patients With Severe Trauma Original Investigation Research jama.com (Reprinted) JAMA February 3, 2015 Volume 313, Number 5 479 Copyright 2015 American Medical Association. All rights reserved. Downloaded From: http://jama.jamanetwork.com/ by a UNIVERSITY OF SYDNEY LIBRARY User on 09/20/2015 Copyright 2015 American Medical Association. All rights reserved. Even though the study was blinded until the opening of the containers, another limitation was that clinicians could not be blinded after the containers were opened without altering patient care. This trial was also limited by an inability to completely exclude patients with an unsurvivable brain injury; 23% of deaths at 24 hours and 38% of all deaths at 30 days were associated with traumatic brain injury. Last, the issue of competing risks of death from hemorrhage and traumatic brain injury in trauma studies that require rapid enrollment before definitive diagnosis of allmajor injuries is well-known and will continue to be an issue in future trauma studies unless novel regulatory, study design, or technological solutions are developed to solve this issue.3,54 Given the lower percentage of deaths from exsanguination and our failure to find differences in safety, clinicians should consider using a 1:1:1 transfusion protocol, starting with the initial units transfused while patients are actively bleeding, and then transitioning to laboratory-guided treatment once hemorrhage control is achieved. Future studies of hemorrhage control products, devices, and interventions should concentrate on the physiologically relevant period of active bleeding after injury and use acute complications and later deaths (24 hours and 30 days) as safety end points. Conclusions Among patients with severe trauma and major bleeding, early administration of plasma, platelets, and RBCs 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. ARTICLE INFORMATION Author Affiliations: Center for Translational Injury Research, Division of Acute Care Surgery, Department of Surgery, Medical School, University of Texas Health Science Center, Houston (Holcomb, Fox, Wade, Podbielski, del Junco, Cotton, Matijevic); Division of Biostatistics, School of Public Health, University of Texas Health Science Center, Houston (Tilley, Baraniuk); Division of Trauma and Critical Care, Department of Surgery, Medical College of Wisconsin, Milwaukee (Brasel); Division of Trauma and Critical Care, Department of Surgery, School of Medicine, University of Washington, Seattle (Bulger); Division of General Surgery, Department of Surgery, School of Medicine, University of California, San Francisco (Callcut, Cohen); Division of Trauma and Surgical Critical Care, Department of Surgery, College of Medicine, University of Tennessee Health Science Center, Memphis (Fabian, Weinberg); Division of Trauma and Critical Care, University of Southern California, Los Angeles (Inaba); Division of Trauma, Burns and Surgical Critical Care, Department of Surgery, School of Medicine, University of Alabama, Birmingham (Kerby); Division of Trauma/Critical Care, Department of Surgery, College of Medicine, University of Cincinnati, Cincinnati, Ohio (Muskat, Robinson); Division of Trauma, Critical Care and Emergency Surgery, Department of Surgery, University of Arizona, Tucson (O’Keeffe); Trauma and Acute Care Surgery, St Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada (Rizoli); R. Adams Cowley Shock Trauma Center, Program in Trauma, University of Maryland School of Medicine, Baltimore (Scalea, Stein); Division of Trauma, Critical Care and Acute Care Surgery, School of Medicine, Oregon Health & Science University, Portland (Schreiber); Sunnybrook Research Institute, Department of Clinical Pathology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada (Callum); Department of Laboratory Medicine, School of Medicine, University of Washington, Seattle (Hess); Department of Emergency Medicine, College of Medicine, University of Cincinnati, Cincinnati, Ohio (Miller); Division of Critical Care and Perioperative Medicine, Department of Anesthesiology, School of Medicine, University of Alabama, Birmingham (Pittet); American College of Surgeons, Chicago, Illinois (Hoyt); Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland (Pearson); Department of Biostatistics, School of Public Health, University of Washington, Seattle (Leroux, van Belle); Department of Environmental and Occupational Health Sciences, School of Public Health, University of Washington, Seattle (van Belle). Dr Brasel is now with the Division of Trauma, Critical Care and Acute Care Surgery, School of Medicine, Oregon Health & Science University, Portland. Dr Muskat is now with the Division of General Surgery, Department of Surgery, School of Medicine, University of California, San Francisco. Author Contributions: Drs Tilley and Baraniuk had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Holcomb, Tilley, Baraniuk, Wade, del Junco, Bulger, Cohen, Cotton, Kerby, Muskat, Rizoli, Robinson, Scalea, Schreiber, Stein, Callum, Hess, Miller, Pittet, Hoyt, Pearson, Leroux, van Belle. Acquisition, analysis, or interpretation of data: Tilley, Baraniuk, Fox, Wade, Podbielski, del Junco, Brasel, Bulger, Callcut, Cohen, Cotton, Fabian, Inaba, Kerby, Muskat, O’Keeffe, Rizoli, Robinson, Scalea, Schreiber, Stein, Weinberg, Callum, Hess, Matijevic, Miller, Pittet, Hoyt, Leroux, van Belle. Drafting of the manuscript: Holcomb, Tilley, Baraniuk, Fox, Wade, Podbielski, Callcut, Cohen, Cotton, Robinson, Stein, Hess, Pearson, van Belle. Critical revision of the manuscript for important intellectual content: Tilley, Baraniuk, Fox, Wade, del Junco, Brasel, Bulger, Callcut, Cohen, Cotton, Fabian, Inaba, Kerby, Muskat, O’Keeffe, Rizoli, Robinson, Scalea, Schreiber, Stein, Weinberg, Callum, Hess, Matijevic, Miller, Pittet, Hoyt, Pearson, Leroux, van Belle. Statistical analysis: Tilley, Baraniuk, Fox, Wade, Fabian, van Belle. Obtained funding: Holcomb, Wade, Cotton, Schreiber, van Belle. Administrative, technical, or material support: Tilley, Wade, Podbielski, del Junco, Bulger, Callcut, Cohen, Cotton, Kerby, Muskat, O’Keeffe, Rizoli, Robinson, Scalea, Stein, Weinberg, Callum, Hess, Matijevic, Miller, Pittet, Hoyt, Pearson, Leroux, Study supervision: Holcomb, Tilley, Wade, Bulger, Callcut, Muskat, Rizoli, Robinson, Schreiber, Weinberg, Callum, Hess, Matijevic, Pittet, Hoyt, van Belle. Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Rizoli reported receiving grant funding from TEM International and CSL Behring. Dr Stein reported serving as an advisor for Decisio Health for which she receives travel reimbursement. No other disclosures were reported. Funding/Support: This work was supported with grant U01HL077863 from the US National Heart, Lung, and Blood Institute and funding from the US Department of Defense, the Defence Research and Development Canada in partnership with the Canadian Institutes of Health Research-Institute of Circulatory and Respiratory Health (grant CRR- 120612). Role of the Funder/Sponsor: The US National Heart, Lung, and Blood Institute (NHLBI) and the US Department of Defense had a role in the study design but had no role in the conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. However, Dr Pearson is employed by the NHLBI and she did participate in the review and approval of the manuscript. Group Information: The PROPPR Study Group: Clinical Coordinating Center, University of Texas Health Science Center, Houston: John B. Holcomb, MD, Charles E. Wade, PhD, Deborah J. del Junco, PhD, Erin E. Fox, PhD, Nena Matijevic, PhD (laboratory committee co-chair), Jeanette M. Podbielski, RN, Angela M. Beeler, BS. Data Coordinating Center, University of Texas Health Science Center, Houston: Barbara C. Tilley, PhD, Sarah Baraniuk, PhD, Stacia M. DeSantis, PhD, Hongjian Zhu, PhD, Joshua Nixon, MS, Roann Seay, MS, Savitri N. Appana, MS, Hui Yang, MS, Michael O. Gonzalez, MS. Core Laboratory, University of Texas Health Science Center, Houston: Lisa Baer, MS, Research Original Investigation Transfusion in Patients With Severe Trauma 480 JAMA February 3, 2015 Volume 313, Number 5 (Reprinted) jama.com Copyright 2015 American Medical Association. All rights reserved. Downloaded From: http://jama.jamanetwork.com/ by a UNIVERSITY OF SYDNEY LIBRARY User on 09/20/2015 Copyright 2015 American Medical Association. All rights reserved. Yao-Wei Willa Wang, MD, Brittany S. Hula, MS, Elena Espino, BS, An Nguyen, BS, Nicholas Pawelczyk, BS, Kisha D. Arora-Nutall, BS, Rishika Sharma, MD, Jessica C. Cardenas, PhD, Elaheh Rahbar, PhD, Tyrone Burnett Jr, BS, David Clark, BS. Resuscitation Outcomes Consortium, University of Washington: Gerald van Belle, PhD, Susanne May, PhD, Brian Leroux, PhD, David Hoyt, MD, Judy Powell, BSN, RN, Kellie Sheehan, BSN. Systems Biology Committee, University of California, Berkeley: Alan Hubbard, PhD (co-chair), Adam P. Arkin, PhD. Transfusion Committee: John R. Hess, MD, MPH (co-chair, University of Washington), Jeannie L. Callum, MD (co-chair, Sunnybrook Health Sciences Centre). Anesthesiology Committee: Jean-Francois Pittet, MD (chair, University of Alabama, Birmingham). Emergency Medicine Committee: Christopher N. Miller, MD (chair, University of Cincinnati). PROPPR Clinical Sites (listed in order of number of patients enrolled): University of Texas Health Science Center, Houston: Bryan A. Cotton, MD, MPH, Laura Vincent, BSN, RN, CCRP, Timothy Welch, Tiffany Poole, DC, Evan G. Pivalizza, MD, Sam D. Gumbert, MD, Yu Bai, MD, PhD, James J. McCarthy, MD, Amy Noland, MD, Rhonda Hobbs, MT(ASCP)SBB. University of Washington: Eileen M. Bulger, MD, Patricia Klotz, RN, Lindsay Cattin, BA, Keir J. Warner, BS, Angela Wilson, BA, David Boman, BA, Nathan White, MD, MS, Andreas Grabinsky, MD, Jennifer A. Daniel-Johnson, MBBS. University of California, San Francisco: Mitchell Jay Cohen, MD (systems biology and laboratory committee co-chair), Rachael A. Callcut, MD, MSPH, Mary Nelson, RN, MPA, Brittney Redick, BA, Amanda Conroy, BA, Marc P. Steurer, MD, DESA, Preston C. Maxim, MD, Eberhard Fiebig, MD, Joanne Moore, Eireen Mallari, MT. University of Cincinnati: Peter Muskat, MD, Jay A. Johannigman, MD, Bryce R. H. Robinson, MD, Richard D. Branson, MSc, RRT, Dina Gomaa, BS, RRT, Christopher Barczak, BS, MT (ASCP), Suzanne Bennett, MD, Patricia M. Carey, MD, Helen Hancock, BS, MT(ASCP), Carolina Rodriguez, BA. University of Southern California: Kenji Inaba, MD, Jay G. Zhu, MD, Monica D. Wong, MS, Michael Menchine, MD, MPH, Kelly Katzberg, MD, FACEP, Sean O. Henderson, MD, Rodney McKeever, MD, Ira A. Shulman, MD, Janice M. Nelson, MD, Christopher W. Tuma, BA, MT(ASCP), SBB, Cheryl Y. Matsushita, BS, MT(ASCP). Shock, Trauma and Anesthesiology Research-Organized Research Center, R. Adams Cowley Shock Trauma Center, University of Maryland Medical Center: Thomas M. Scalea, MD, Deborah M. Stein, MD, MPH, Cynthia K. Shaffer, MS, MBA, Christine Wade, BA, Anthony V. Herrera, MS, Seeta Kallam, MBBS, Sarah E. Wade, BS, Samuel M. Galvagno Jr, DO, PhD, Magali J. Fontaine, MD, PhD, Janice M. Hunt, BS, MT(ASCP) SBB, Rhonda K. Cooke, MD. University of Tennessee Health Science Center, Memphis: Timothy C. Fabian, MD, Jordan A. Weinberg, MD, Martin A. Croce, MD, Suzanne Wilson, RN, Stephanie Panzer-Baggett, RN, Lynda WaddleSmith, BSN, Sherri Flax, MD. Medical College of Wisconsin: Karen J. Brasel, MD, MPH, Pamela Walsh, AS, CCRC, David Milia, MD, Allia Nelson, BS, BA, Olga Kaslow, MD, PhD, Tom P. Aufderheide, MD, MS, Jerome L. Gottschall, MD, Erica Carpenter, MLS(ASCP). University of Arizona: Terence O’Keeffe, MBChB, MSPH, Laurel L. Rokowski, RN, BSN, MKT, Kurt R. Denninghoff, MD, Daniel T. Redford, MD, Deborah J. Novak, MD, Susan Knoll, MS, MT(ASCP)SBB. University of Alabama, Birmingham: Jeffrey D. Kerby, MD, PhD, Patrick L. Bosarge, MD, Albert T. Pierce, MD, Carolyn R. Williams, RN, BSN, BSME, Shannon W. Stephens, EMTP, Henry E. Wang, MD, MS, Marisa B. Marques, MD. Oregon Health & Science University: Martin A. Schreiber, MD, Jennifer M. Watters, MD, Samantha J. Underwood, MS, Tahnee Groat, MPH, Craig Newgard, MD, MPH, Matthias Merkel, MD, PhD, Richard M. Scanlan, MD, Beth Miller, MT(ASCP)SBB. Sunnybrook Health Science Center: Sandro Rizoli, MD, PhD, Homer Tien, MD, Barto Nascimento, MD, MSc, CTBS, Sandy Trpcic, Skeeta Sobrian-Couroux, RN, CCRP, BHA, Marciano Reis, Adic Pérez, MD, Susan E. Belo, MD, PhD, Lisa Merkley, BA, MLT, CBTS, Connie Colavecchia, BSc, MLT. Disclaimer: The content is the sole responsibility of the authors and should not be construed as official or as reflecting the views of any of the sponsors. Additional Contributions: We thank the members of the data and safety monitoring board (Lance Becker, Charles Cairns, Ralph D’Agostino, Karl Jern, Nigel Key, Laurence McCullough, Jeremy Perkins, Herbert Wiedemann, Janet Wittes, and Jay Mason) and the external advisory committee (Kenneth G. Mann, Kathleen Brummel, Beth Hartwell, Charles Esmon, Morris Blajchman, Andrew P. Cap, Andrei Kindzelski, and Anthony E. Pusateri) for their time and effort. We also thank the Resuscitation Outcomes Consortium protocol review committee for their important contributions as well as COL Dallas Hack and COL Robert Vandre for their extraordinary commitment and unwavering support for this trial. We could not have successfully completed this study without the help of hundreds of unnamed clinical personnel and we thank them for their sustained efforts. Additional Information: We dedicate this work to the US Soldiers, Sailors, Airmen, and Marines who put their lives on the line every day. We hope this effort will help improve the care of seriously injured patients, both military and civilian. REFERENCES 1. US Centers for Disease Control and Prevention. Injury prevention and control: data and statistics, 2012. http://webappa.cdc.gov/cgi-bin/broker.exe. Accessed December 21, 2014. 2. Rhee P, Joseph B, Pandit V, et al. Increasing trauma deaths in the United States. Ann Surg. 2014; 260(1):13-21. 3. Tisherman SA, Schmicker RH, Brasel KJ, et al. Detailed description of all deaths in both the Shock and Traumatic Brain Injury Hypertonic Saline Trials of the Resuscitation Outcomes Consortium [published online July 28, 2014]. Ann Surg. doi:10 .1097/SLA.0b013e3181df0401. 4. Holcomb JB, Jenkins D, Rhee P, et al. Damage control resuscitation: directly addressing the early coagulopathy of trauma. J Trauma. 2007;62(2): 307-310. 5. Holcomb JB, Pati S. Optimal trauma resuscitation with plasma as the primary resuscitative fluid: the surgeon’s perspective. Hematology Am Soc Hematol Educ Program. 2013; 2013:656-659. 6. US Army Institute of Surgical Research. Joint Theater Trauma System Clinical Practice Guideline: damage control resuscitation at level IIb and III treatment facilities. http://www.usaisr.amedd.army .mil/assets/cpgs/Damage%20Control %20Resuscitation%20-%201%20Feb%202013 .pdf. Accessed December 21, 2014. 7. Borgman MA, Spinella PC, Perkins JG, et al. The ratio of blood products transfused affects mortality in patients receiving massive transfusions at a combat support hospital.J Trauma. 2007;63(4): 805-813. 8. Shaz BH, Dente CJ, Nicholas J, et al. Increased number of coagulation products in relationship to red blood cell products transfused improves mortality in trauma patients. Transfusion. 2010;50 (2):493-500. 9. Cotton BA, Reddy N, Hatch QM, et al. Damage control resuscitation is associated with a reduction in resuscitation volumes and improvement in survival in 390 damage control laparotomy patients. Ann Surg. 2011;254(4):598-605. 10. Holcomb JB, del Junco DJ, Fox EE, et al; PROMMTT Study Group. The Prospective, Observational, Multicenter, Major Trauma Transfusion (PROMMTT) study: comparative effectiveness of a time-varying treatment with competing risks.JAMA Surg. 2013;148(2):127-136. 11. Johansson PI, Sørensen AM, Larsen CF, et al. Low hemorrhage-related mortality in trauma patients in a level I trauma center employing transfusion packages and early thromboelastography-directed hemostatic resuscitation with plasma and platelets. Transfusion. 2013;53(12):3088-3099. 12. Langan NR, Eckert M, Martin MJ. Changing patterns of in-hospital deaths following implementation of damage control resuscitation practices in US forward military treatment facilities. JAMA Surg. 2014;149(9):904-912. 13. Scalea TM, Bochicchio KM, Lumpkins K, et al. Early aggressive use of fresh frozen plasma does not improve outcome in critically injured trauma patients. Ann Surg. 2008;248(4):578-584. 14. Johnson JL, Moore EE, Kashuk JL, et al. Effect of blood products transfusion on the development of postinjury multiple organ failure. Arch Surg. 2010;145(10):973-977. 15. American Society of Anesthesiologists Task Force on Perioperative Blood Transfusion and Adjuvant Therapies. Practice guidelines for perioperative blood transfusion and adjuvant therapies: an updated report by the American Society of Anesthesiologists Task Force on Perioperative Blood Transfusion and Adjuvant Therapies. Anesthesiology. 2006;105(1):198-208. 16. Dzik WH, Blajchman MA, Fergusson D, et al. Clinical review: Canadian National Advisory Committee on Blood and Blood Products—massive transfusion consensus conference 2011: report of the panel. Crit Care. 2011;15(6):242. 17. American Society of Anesthesiologists. Standards, guidelines, statements and other documents. https://www.asahq.org/For-Members /Standards-Guidelines-and-Statements.aspx. Accessed September 1, 2014. 18. Spahn DR, Bouillon B, Cerny V, et al. Management of bleeding and coagulopathy following major trauma: an updated European guideline. Crit Care. 2013;17(2):R76. 19. del Junco DJ, Holcomb JB, Fox EE, et al; PROMMTT Study Group. Resuscitate early with plasma and platelets or balance blood products Transfusion in Patients With Severe Trauma Original Investigation Research jama.com (Reprinted) JAMA February 3, 2015 Volume 313, Number 5 481 Copyright 2015 American Medical Association. All rights reserved. Downloaded From: http://jama.jamanetwork.com/ by a UNIVERSITY OF SYDNEY LIBRARY User on 09/20/2015 Copyright 2015 American Medical Association. All rights reserved.

Copyright 2015 American Medical Association. All rights reserved.
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
John B. Holcomb, MD; Barbara C. Tilley, PhD; Sarah Baraniuk, PhD; Erin E. Fox, PhD; Charles E. Wade, PhD; Jeanette M. Podbielski, RN;
Deborah J. del Junco, PhD; Karen J. Brasel, MD, MPH; Eileen M. Bulger, MD; Rachael A. Callcut, MD, MSPH; Mitchell Jay Cohen, MD;
Bryan A. Cotton, MD, MPH; Timothy C. Fabian, MD; Kenji Inaba, MD; Jeffrey D. Kerby, MD, PhD; Peter Muskat, MD; Terence O’Keeffe, MBChB, MSPH;
Sandro Rizoli, MD, PhD; Bryce R. H. Robinson, MD; Thomas M. Scalea, MD; Martin A. Schreiber, MS; Deborah M. Stein, MD; Jordan A. Weinberg, MD;
Jeannie L. Callum, MD; John R. Hess, MD, MPH; Nena Matijevic, PhD; Christopher N. Miller, MD; Jean-Francois Pittet, MD; David B. Hoyt, MD;
Gail D. Pearson, MD, ScD; Brian Leroux, PhD; Gerald van Belle, PhD; for the PROPPR Study Group
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
JAMA. 2015;313(5):471-482. doi:10.1001/jama.2015.12
Supplemental content at
jama.com
Author Affiliations: Author
affiliations are listed at the end of this
article.
Group Information: The Pragmatic,
Randomized Optimal Platelet and
Plasma Ratios (PROPPR) Study Group
members are listed at the end of this
article.
Corresponding Author: John B.
Holcomb, MD, Center for
Translational Injury Research,
University of Texas Health
Science Center, 6410 Fannin St,
Houston, TX 77030
(john.holcomb@uth.tmc.edu).
Research
Original Investigation
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I
n the United States, injury is the leading cause of death
among individuals between the ages of 1 and 44 years, it is
the leading cause of years of life lost for those younger than
75 years, and it is the third leading cause of death overall.1
Deaths from injury have increased 23% during the last decade.2
Approximately 20% to 40% of trauma deaths occurring after
hospital admission involve massive hemorrhage from truncal
injury and are potentially preventable with rapid hemorrhage
control and improved resuscitation techniques.3
Damage control resuscitation is defined as rapid hemorrhage
control through early administration of blood products
in a balanced ratio (1:1:1 for units of plasma to platelets to red
blood cells [RBCs]; a ratio that is the closest approximation to
reconstituted whole blood), prevention and immediate correction
of coagulopathy, and minimization of crystalloid
fluids.4 Damage control resuscitation was developed to treat
intravascular volume deficits, the acute coagulopathy of
trauma, preserve oxygen-carrying capacity, repair the endothelium,
and prevent dilutional coagulopathy.4,5
Damage control resuscitation was codified as a US Department
of Defense clinical practice guideline in 20046 and has
become the standard of care for battlefield resuscitation that
is now used in many civilian trauma centers. Damage control
resuscitation principles have been associated with improved
outcomes compared with more traditional transfusion
practices.7-12 Conversely, other studies have reported beneficial
outcomes across a wider range of blood product ratios or
goal-directed approaches.13,14 However, concerns about the
safety of exposing injured patients to large amounts of plasmacontaining
blood products were difficult to address in previous
retrospective studies.
There are no large, multicenter, randomized clinical trials
with survival as a primary end point that support optimal
trauma resuscitation practices with approved blood products.
As a result, there are multiple and often conflicting recommendations
promulgated by various organizations.15-18The
Prospective Observational Multicenter Major Trauma Transfusion
(PROMMTT) study demonstrated that clinicians generally
were transfusing patients with a blood product ratio of
1:1:1 or 1:1:2 and that early transfusion of plasma (within minutes
of arrival to a trauma center) was associated with improved
6-hour survival after admission.10,19
The Pragmatic, Randomized Optimal Platelet and Plasma
Ratios (PROPPR) trial was designed to address the effectiveness
and safety of a 1:1:1 transfusion ratio compared with a 1:1:2
transfusion ratio in patients with trauma who were predicted
to receive a massive transfusion.
Methods
Study Design and Intervention
A pragmatic, phase 3, multisite, randomized trial, the PROPPR
study compared the effectiveness and safety of a 1:1:1 transfusion
ratio of plasma, platelets, and RBCs to a 1:1:2 ratio.20 Patients
were randomized within each site, and the intervention
consisted of containers of blood products prepared by each
site’s blood bank and delivered to the bedside within 10 minutes
(DJ Novak et al and the PROPPR Study Group, unpublished
data, 2015; Supplement 1). The initial container was
sealed to blind the physicians to treatment assignment. The
patient was declared randomized when the seal was broken.
The blood products were transfused in a prespecified order designed
to maintain the appropriate assigned ratio.
All containers for the 1:1:1 group included 6 U of plasma,
1 dose of platelets (a pool of 6 U on average), and 6 U of RBCs,
which were transfused in the following order: platelets first,
then alternating RBC and plasma units. The initial and all
subsequent odd-numbered containers for the 1:1:2 group
included 3 U of plasma, 0 doses of platelets, and 6 U of RBCs,
which were transfused in the following order: alternating 2 U
of RBCs and 1 U of plasma. The second and all subsequent
even-numbered containers included 3 U of plasma, 1 dose of
platelets (a pool of 6 U on average), and 6 U of RBCs, which
were transfused in the following order: platelets first,
then alternating 2 U of RBCs and 1 unit of plasma. Patients
with multiple intravenous lines could receive blood products
simultaneously, otherwise patients received products
sequentially.
Transfusion of all study blood products was stopped when
clinically indicated, irrespective of ratio or partial blood container
use.20Transfusion of study blood products ended in several
ways: achievement of hemostasis, death, declaration of
treatment futility, no need for further blood products after randomization,
or protocol violations.
No other resuscitation, pharmacological, or clinical treatment
was controlled by the trial protocol (Supplement 1). The
study was approved by the US Food and Drug Administration
(FDA) (Investigational New Drug No. 14929), Health Canada,
the Department of Defense, and all site institutional review
boards. In addition, the study was monitored by an external
data and safety monitoring board appointed by the National
Heart, Lung, and Blood Institute and used exception from informed
consent, including community consultation with delayed
patient or legally authorized representative consent.21
Study Population
Patients included in the PROPPR trial were severely injured and
met the local criteria for highest level trauma activation at 1
of 12 participating level I trauma centers in North America.
These site-specific criteria, reviewed by the American College
of Surgeons, are based on heart rate, blood pressure, respiratory
rate, and mechanism of injury and are used clinically to
ensure trauma teams are present before these critically injured
patients arrive at the emergency department. The research
personnel were notified along with the trauma teams.
The goal was to rapidly enroll patients with severe hemorrhage
who were nonmoribund, regardless of injury type.
To facilitate rapid identification of patients with severe
bleeding, inclusion criteria included the patient having at least
1 U of any blood component transfused prior to hospital arrival
or within 1 hour of admission and prediction by an Assessment
of Blood Consumption score22 of 2 or greater or by
physician judgment of the need for a massive transfusion (defined
as ≥10 U of RBCs within 24 hours). The complete inclusion
and exclusion criteria are listed in the Box.
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Outcomes and Other Variables of Interest
The primary outcomes included absolute percentage group differences
for 24-hour and 30-day mortality. These 2 outcome
measures tested 2 separate questions regarding short-term effectiveness
and long-term safety without adjustment for multiple
comparisons per protocol.23 Each death was adjudicated
by a clinician blinded to group assignment and external
to the trial site and 1 or more causes of death were assigned.
Ancillary outcomes were prespecified to evaluate the effectiveness
and safety of the transfusion ratios and included
(1) time to hemostasis; (2) the number and type of blood products
used from randomization until hemostasis was achieved;
(3) the number and type of blood products used after hemostasis
was achieved up to 24 hours postadmission; (4) 23 complications;
(5) hospital-, ventilator-, and ICU-free days (within
the first 30 days or hospital discharge, whichever occurred
first); (6) incidence of major surgical procedures; and (7) functional
status at hospital discharge or 30 days, whichever occurred
first, asmeasured by discharge destination and Glasgow
Outcome Scale-Extended.
Blood product ratios were calculated as 2 separate ratios:
plasma to RBCs and platelets to RBCs. For example, a 1:1 ratio
of plasma to RBCs is equivalent to 1.0 and represents equal total
units of plasma and RBCs within the specified interval. A
1:2 ratio is equivalent to 0.5 and represents twice as many total
RBC units as plasma units. Ratios for patients who received no
RBCs within a specified interval cannot be calculated because
the denominator is zero, and therefore are not included
in the calculation of cumulative ratios of blood products
in that interval.
Race and Hispanic ethnicity were collected by patient
self-report or hospital staff determination and were included
to identify disparities in treatment or outcome. The Injury
Severity Score is an anatomic scoring system used for
patients with multiple injuries, correlates with mortality,
and has a range of 0 (uninjured) to 75 (usually unsurvivable
injuries).24 The critical administration threshold represents
the trauma subset at highest risk of hemorrhagic mortality25
and denotes patients receiving more than 3 U of RBCs within
at least 1 hour during the first 24 hours after admission. The
Assessment of Blood Consumption score has a range of 0 to
4 with scores of 2 or greater associated with the need for a
massive transfusion.22
Anatomic hemostasis in the operating room was defined
as an objective assessment by the surgeon indicating that bleeding
within the surgical field was controlled and no further hemostatic
interventions were anticipated. In the interventional
radiology suite, anatomic hemostasis was defined as
achieving resolution of contrast blush after embolization.
Sample Size
The initial sample size of 580 was planned to detect a clinically
meaningful 10% difference in 24-hour mortality (11% vs
21%) and a 12% difference in 30-day mortality (23% vs 35%),
which was supported by prior data.26,27 Sample size was increased
to 680 by the data and safety monitoring board according
to the trial’s adaptive design. With 680 patients and
given the final observedmortality proportions in the 1:1:1 group,
the PROPPR trial had 95% power to detect the prespecified 10%
difference at 24 hours and 92% power to detect the prespecified
12% difference at 30 days, if such differences existed.
Statistical Analysis
The primary analysis separately compared 24-hour and
30-day mortality in the 2 transfusion ratio groups using a
2-sided Mantel-Haenszel test adjusting for site. For the 4 patients
missing a primary outcome, a sensitivity analysis using
all possible combinations (n = 16) of outcomes was performed
and a range of intent-to-treat P values for the hypotheticalMantel-Haenszel
tests are presented.28The critical level
for significance (P ≤ .044) was adjusted for 2 interim analyses,
and all tests were conducted using 2-sided tests.29 In Cox
analyses, the 4 patients missing a 30-day outcome were censored
at the last known follow-up time.30 Lack of protocol compliance
was measured by the per-patient percentage of blood
products given out of order. A sensitivity analysis compared
treatment groups excluding these patients.
Box. Inclusion and Exclusion Criteria for the Pragmatic,
Randomized Optimal Platelet and Plasma Ratios (PROPPR) Trial
Eligible Patients Met All of the Following:
Highest trauma level activation
Estimated age of 15 years or older or weight of 50 kg or greater if age
unknown
Received directly from the injury scene
Initiated transfusion of at least 1U ofblood component within the first
hour of arrival or during prehospital transport
Predicted to receive a massive transfusion by exceeding the threshold
score of either the Assessment of Blood Consumption score of 2
or greater or based on the attending trauma physician’s judgment
Patients Who Were Ineligible Met at Least 1 of the Following:
Received a lifesaving intervention from an outside hospital or health
care facility
Had devastating injuries and expected to die within 1 hour of admission
(eg, lethal traumatic brain injury)
Directly admitted from a correctional facility
Required a thoracotomy prior to receiving randomized blood products
in the emergency department
Younger than 15 years or weighed less than 50 kg if age unknown
Known pregnancy in the emergency department
Had burns covering greater than 20% total body surface area
Suspected inhalation injury
Received greater than 5 consecutiveminutes of cardiopulmonary resuscitation
(with chest compressions) prior to arriving at the hospital
or within the emergency department
Known do-not-resuscitate order prior to randomization
Enrolled in a concurrent, ongoing, interventional, randomized clinical
trial
Activated the opt-out process for the PROPPR trial (usually by wearing
a bracelet given out at a community consent presentation)
More than 3 U of red blood cells given before randomization
Transfusion in Patients With Severe Trauma Original Investigation Research
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All analyses were generated using SAS version 9.3 (SAS Institute
Inc). Additional details regarding the study design and
analysis were published previously.20
Results
From August 3, 2012, to December 2, 2013, a total of 14 313
highest-level trauma activations occurred at the 12 enrolling
sites, of which 78% were screened. A total of 680 patients
were randomized (338 to the 1:1:1 group and 342 to the 1:1:2
group; Figure 1). Randomized blood products were transfused
to 669 patients. No differences were detected between
treatment groups in baseline characteristics (Table 1).
Themajority of patientsweremalewith similar ages in both
groups. Patients in both groups were profoundly injured with
a median Injury Severity Score of 26 and severely bleeding
based on the critical administration threshold (87% positive
based on this threshold overall). The initial hemoglobin level
was 11.7 g/dL (37% had hemoglobin levels <11 g/dL) in the 1:1:1
group and 11.9 g/dL (38.8% had hemoglobin levels <11 g/dL)
in the 1:1:2 group. Seventy-five percent of patients required an
interventional radiology or operating room procedure within
2 hours of admission (data not shown).
The primary trial outcomes of mortality at 24 hours and
30 days were obtained on 100% and 99.4% of patients, respectively.
No significant differences in mortality were detected at
24 hours (12.7% in the 1:1:1 group vs 17.0% in the 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%) (Table 2).31 The range of intent-to-treat P values computed
for all possible combinations of 30-day outcomes for the
4 patients with missing values did not change these results.
The P values ranged from 0.21 to 0.36 (eTable 1 in Supplement
2). The Kaplan-Meier curves (Figure 2) show a separation in survival
between the 2 treatment groups across the follow-up period,
but the difference was not significant (unadjusted logrank
test, P = .21).
Sensitivity analyses excluding patients who received blood
products given out of order yielded results similar to the main
analysis. Themean percentages of intervention units given out
of order per patient (protocol noncompliance) were significantly
lower in the 1:1:1 group (4%; 95% CI, 3.2%-5.7%) vs the
1:1:2 group (7%; 95% CI, 6.1% to 8.5%) (P = .01).
Exsanguination, the predominant cause of death within
the first 24 hours, was decreased in the 1:1:1 group (9.2%) vs
the 1:1:2 group (14.6%) (difference, −5.4% [95% CI, −10.4% to
−0.5%], P = .03); the median time to death due to exsanguination
was 106 minutes (interquartile range [IQR], 54 to 198
minutes) and 96 minutes (IQR, 43 to 194 minutes), respectively.
From 24 hours through 30 days, the numbers of additional
all-cause deaths were similar (32 for the 1:1:1 group vs
31 for the 1:1:2 group). Over 30 days, deaths due to exsanguination
occurred in 10.7% of patients in the 1:1:1 group vs 14.7%
in the 1:1:2 group, whereas deaths due to traumatic brain injury
were 8.1% vs 10.3%, respectively. Additional causes of
Figure 1. Flow of Patients in the Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) Trial
11185 Patients assessed for eligibility
10505 Excluded
7027 Did not receive at least 1 U of a blood component within
the first hour after arrival or during prehospital transport
1655 Not received directly from the injury scene
882 Not predicted to receive a massive transfusion
277 Age <15 y (or weight <50 kg)
154 Patient improved, did not require further transfusion
130 Devastating injury, expected to die within 1 h of ED admission
129 PROPPR products not given within 2-h period
65 Patient did not require highest level of trauma activation
49 Received CPR for >5 min
48 Required an emergency thoracotomy
36 Institutionalized in prison
32 Fourth unit of RBCs was transfused before randomization
21 Other reasonsa
680 Randomized
30-d Mortality
18 Withdrew consentb
3 Lost to follow-up
338 Included in mortality analysis
30-d Mortality
17 Withdrew consentb
1 Lost to follow-up
342 Included in mortality analysis
24-h Mortality
3 Withdrew consentb
0 Lost to follow-up
338 Included in mortality analysis
24-h Mortality
2 Withdrew consentb
0 Lost to follow-up
342 Included in mortality analysis
338 Randomized to 1:1:1 group 342 Randomized to 1:1:2 group
CPR indicates cardiopulmonary
resuscitation; ED, emergency
department; RBC, red blood cell.
a Included patients with the
following: 6 known pregnancies,
5 with physicians who refused to
randomize, 4 with known
do-not-resuscitate order prior to
randomization, 3 with burns
covering more than 20% of total
body surface area, 1 with a
documented inhalation injury, 1 who
opted out upon arrival to the ED,
1 unknown reason.
b The vital statistic data were
obtained for patients who withdrew
consent when available. Patients
who withdrew consent at 24 hours
are included in the count of those
who withdrew at 30 days.
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death were infrequent and are shown in Table 3. More patients
achieved anatomic hemostasis in the 1:1:1 group (86.1%
vs 78.1% in the 1:1:2 group, P = .006) with a median time of 105
minutes (IQR, 64 to 179 minutes) vs 100 minutes (IQR, 56 to
181minutes), respectively (P = .44) in those who achieved anatomic
hemostasis (Table 2).
Cumulative transfusion ratios and the distribution of
blood product amounts (prerandomization, during the intervention,
and postintervention) are shown in Figure 3 and
Figure 4. During the intervention, patients received median
ratios of plasma to RBCs of 1.0 in the 1:1:1 group and 0.5 in the
1:1:2 group. The median ratios of platelets to RBCs during the
Table 1. Patient Characteristics by Treatment Group
1:1:1 Group
(n = 338)
1:1:2 Group
(n = 342)
Age, median (IQR), ya 34.5 (25 to 51) 34 (24 to 50)
Male sex, No. (%) 263 (77.8) 283 (82.7)
Race, No. (%)b
White 210 (62.1) 224 (65.5)
Black 94 (27.8) 93 (27.2)
Other 35 (10.4) 25 (7.3)
Hispanic ethnicity, No. (%)c 61 (18.0) 59 (17.3)
Glasgow Coma Scale score, median (IQR) 14 (3 to 15) 14 (3 to 15)
Systolic blood pressure, No. of patients 330 328
Median (IQR), mm Hgd 102 (81 to 126) 102 (80 to 125)
No. (%) with ≤90 mm Hg 127 (38.5) 128 (39.0)
Diastolic blood pressure, No. of patients 284 279
Median (IQR), mm Hgd 70 (53 to 90) 68 (50 to 91)
Heart rate, No. of patients 336 341
Median (IQR), beats/mind 115 (97 to 135) 113 (93 to 130)
No. (%) with ≥120 beats/min 148 (44.0) 152 (44.6)
Respiratory rate, No. of patients 308 313
Median (IQR), breaths/min 20 (17.5 to 26.0) 20 (17 to 26)
Assessment of Blood Consumption score ≥2, No. (%)22,e 215 (63.6) 223 (65.2)
Mechanism of injury, No. (%)
Any blunt injury 185 (54.7) 173 (50.6)
Any penetrating injury 157 (46.4) 173 (50.6)
Time to randomization, median (IQR), min 27.5 (17 to 47) 25.5 (16 to 41)
Hemoglobin level, No. of patients 327 325
Median (IQR), g/dL 11.7 (10.1 to 13.4) 11.9 (10.1 to 13.2)
No. (%) with ≤11 g/dL 121 (37.0) 126 (38.8)
International normalized ratio, No. of patients 218 218
Median (IQR) 1.3 (1.2 to 1.5) 1.3 (1.2 to 1.5)
No. (%) with ratio >1.5 57 (26.1) 59 (27.1)
Thromboelastography R time, No. of patients 276 279
Median (IQR), min 3.8 (2.9 to 4.6) 3.8 (2.8 to 4.7)
No. (%) with time >8 min 12 (4.3) 12 (4.3)
Platelet count, No. of patients 317 317
Median (IQR), in thousands 213 (164 to 261) 212 (164 to 264)
No. (%) with count <150 in thousands 54 (17.0) 60 (18.9)
Base excess, No. of patients 318 301
Median (IQR), mmol/L −8 (−12.5 to −3.8) −8.5 (−12.8 to −4.7)
No. (%) with score ≤−4 mmol/L 238 (74.8) 239 (79.4)
Injury Severity Score, median (IQR)f 26.5 (17 to 41) 26 (17 to 38)
Revised Trauma Score, No. of patientsg 303 304
Median (IQR) 6.8 (4.1 to 7.8) 6.4 (4.1 to 7.8)
Resuscitation indicators, No. (%)
Massive transfusionh 153 (45.3) 160 (46.8)
Critical administration thresholdi 281 (83.1) 314 (91.8)
Abbreviations: IQR, interquartile
range; RBC, red blood cell.
a One patient was missing a verified
age so it was imputed using the
median of the interval for estimated
age.
bMore than 1 race could be selected
per patient, therefore percentages
may exceed 100%. Other included
American Indian/Alaskan
Native/Aboriginal, Asian, Native
Hawaiian/other Pacific Islander,
other, and unknown.
c Determined by either self-report
from the patient or family or direct
observation by medical staff.
dPatients with blood pressure and
heart rate that was not recorded,
measured, detectable, or palpable
were excluded from the median
calculations and the Wilcoxon rank
sum test.
e The score range was 0 to 4. Patients
with a score of 0 (n = 50) and 1
(n = 192) were enrolled in the trial as
physician overrides, which was
defined as a score of less than 2 and
attending physician determination
that a massive transfusion was
needed.
f The score range was 0 to 75. A score
greater than 15 indicates major
trauma.
g The score range was 0 to 7.8. A
higher score is associated with
better survival probability.
hDefined as 10 U or greater of RBCs
received within first 24 hours.
Includes observations made
postrandomization.
i Defined as 3 U or greater of RBCs
received at least once per 1-hour
interval during the first 24 1-hour
periods. One patient in each
treatment group did not receive any
RBCs. Includes observations made
postrandomization.
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intervention were 1.5 for the 1:1:1 group and 0.4 for the 1:1:2
group. Higher cumulative plasma and platelet ratios in the
1:1:2 group vs the 1:1:1 group were seen during the postintervention
period.
Similar amounts of total blood products (median of 2 U)
were delivered prerandomization to both groups (eFigure in
Supplement 2). Themedian total blood product amounts transfused
were 16 U in the 1:1:1 group and 15 U in the 1:1:2 group
during the intervention period. Patients in the 1:1:1 group received
fewer blood products during the postintervention period
than the 1:1:2 group (median of 1 U vs 2 U, respectively).
The median total for blood products transfused up to 24 hours
after admission was 25.5 U in the 1:1:1 group and 19 U in the
1:1:2 group. Total plasma (median of 7 U in the 1:1:1 group vs
5 U in the 1:1:2 group, P < .001) and platelets (12 U vs 6 U, respectively,
P < .001) transfused within the first 24 hours were
higher in the 1:1:1 group, but similar for RBCs (9 U) (eTable 2
in Supplement 2). Use of tranexamic acid and other procoagulants
was similar.
Differences were not detected in any of the 23 complications
at 30 days (Table 4), including acute respiratory distress
syndrome, multiple organ failure, venous thromboembolism,
sepsis, and transfusion-related complications. The overall
rate of complications was high (89% of patients). One patient
in the 1:1:1 group died from transfusion-associated
circulatory overload. Significant differences between groups
in the other ancillary outcomes focusing on safety were not
detected and are shown in Table 2.
Discussion
Transfusion for patients with severe trauma and major bleeding
has been predominantly guided by tradition rather than
evidence from large, multicenter randomized trials. Over the
last decade, transfusion therapy has undergone a significant
change with many patients receiving less crystalloid and early,
more balanced transfusion ratios attempting to reconstitute
whole blood.4-12,27,32-41 This change has largely been associated
with decreased transfusion amounts, fewer inflammatory
complications, and improved survival.4-12,27,32-41
To our knowledge, the PROPPR trial was the first multicenter
randomized trial using approved blood products to compare
2 transfusion ratioswithmortality as the primary end point.
Among the 680 patients predicted to receive a massive transfusion
and transfused with a 1:1:1 or 1:1:2 ratio, no significant
differences in overall mortality at 24 hours or 30 days were detected.
However, more patients achieved hemostasis in the
Table 2. Trial Outcomes by Treatment Group
1:1:1 Group
(n = 338)
1:1:2 Group
(n = 342) Difference (95% CI), % Adjusted RR (95% CI) P Valuea
24-h Mortality, No. (%)b 43 (12.7) 58 (17.0) −4.2 (−9.6 to 1.1) 0.75 (0.52 to 1.08) .12
30-d Mortality, No. (%)b 75 (22.4) 89 (26.1) −3.7 (−10.2 to 2.7) 0.86 (0.65 to 1.12) .26
Achieved hemostasis
No. (%) 291 (86.1) 267 (78.1) .006
Anatomic, median (IQR), minc 105 (64 to 179) 100 (56 to 181) .44
Hospital-free days, median (IQR)c,d 1 (0 to 17) 0 (0 to 16) .83
Ventilator-free daysd
Total No. of patients 337 340
Median (IQR)c 8 (0 to 16) 7 (0 to 14) .14
ICU-free daysd
Total No. of patients 337 340
Median (IQR)c 5 (0 to 11) 4 (0 to 10) .10
Incidence of primary surgical procedure 290 (85.8) 284 (83.0) 2.8 (−2.8 to 8.3)
Disposition at 30 d, No. (%)e
Home 118 (34.9) 105 (30.7)
.37
Remained hospitalized 82 (24.3) 77 (22.5)
Otherf 59 (17.5) 71 (20.8)
Morgue 75 (22.2) 89 (26.0)
Unknown 4 (1.2) 0
Glasgow Outcome Scale-Extended score
Total No. of patientsg 30 28
Median (IQR)c 4 (3 to 6) 4.5 (3.5 to 7.0) .11
a Calculated using the Mantel-Haenszel test for binary outcomes measured
from randomization, adjusting for site.
bBreslow-Day test for homogeneity, χ 2
11: 24-hour P = .51, 30-day P = .65.
c The van Elteren test31 was used to compare medians, adjusting for site.
d Individuals who died within the first 24 hours from admission were assigned
zero ICU-, ventilator-, and hospital-free days.
e A generalized logit model was fit to test for treatment differences.
f Includes long-term care facility, skilled nursing facility, rehabilitation
facility, acute care hospital, assisted living, psychiatric facility,
and jail.
gObtained only on discharged patients who had a head injury.
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1:1:1 group, fewer patientsdied of exsanguination, and this transfusion
ratio appears to be safe.Results from thePROMMTT study
showed that earlier use of higher amounts of plasma and platelets
(albeit without consistent ratios) was associated with improved
survival during the first 6 hours after admission.10,19Data
from the PROPPR trial evaluated the effect of early transfusion
of different but consistent ratios in patients predicted to receive
a massive transfusion. Taken together, these data support
early (withinminutes of hospital arrival) use of a 1:1:1 transfusion
ratio in patients with rapid bleeding.
Despite significant concerns that the 1:1:1 group would experience
higher rates ofmultiple inflammatory-mediated complications
such as acute respiratory distress syndrome, multiple
organ failure, infection, venous thromboembolism, and
sepsis,13,14,42-45 no differences were detected between the 2
treatment groups. Furthermore, the rates ofmultiple organ failure
(5%) and acute respiratory distress syndrome (14%) were
lower than in recent studies in similarly injured patient
populations,46,47whichmay be attributable to delivering blood
to the bedside earlier (median of 8minutes)20 and limited crysFigure
2. Kaplan-Meier Failure Curves for Mortality at 24 Hours and 30 Days
0.30
0.35
0.25
0.20
0.15
0.10
0.05
0
0
342
338
24
284
295
12
291
300
18
286
297
6
296
305
Probability of Death
Time to Death From Randomization, h
No. at risk
1:1:2
1:1:1
1
322
327
3
304
318
24-h Mortality
0.30
0.35
0.25
0.20
0.15
0.10
0.05
0
0
342
338
30
252
260
20
253
263
Probability of Death
Time to Death From Randomization, d
10
261
269
30-d Mortality
1:1:2 Group
1:1:1 Group
The colored areas indicate 95% confidence bands, which were calculated using
the Hall-Wellner method. The Hall-Wellner bands extend to the last event
(death) in each group. For 24-hour mortality, the Cox proportional hazards
regression model, adjusted for site as a random effect, produced a hazard ratio
(HR) of 0.72 (95% CI, 0.49-1.07). There were no patients lost to follow-up
during the first 24 hours from randomization. For 30-day mortality, the Cox
proportional hazards regression model, adjusted for site as a random effect,
produced an HR of 0.83 (95% CI, 0.61-1.12). Between 24 hours and 30 days, 4
patients were lost to follow-up and were censored when they withdrew consent
or were last known to be alive (3 in the 1:1:1 group and 1 in the 1:1:2 group).
Table 3. Adjudicated Cause of Death by Treatment Group and Period From Randomization
First 24 Hours 30 Days
No. (%)
Difference (95% CI),%a
No. (%)
Difference (95% CI), %a
1:1:1 Group
(n = 338)
1:1:2 Group
(n = 342)
1:1:1 Group
(n = 335)
1:1:2 Group
(n = 341)
Total No. of deaths 43 58 75 89
Cause of deathb
Exsanguination 31 (9.2) 50 (14.6) −5.4 (−10.4 to −0.5) 36 (10.7) 50 (14.7) −3.9 (−9.1 to 1.2)
Traumatic brain injury 11 (3.3) 12 (3.5) −0.3 (−3.2 to 2.7) 27 (8.1) 35 (10.3) −2.2 (−6.7 to 2.2)
Respiratory, pulmonary contusion,
or tension pneumothorax
3 (0.9) 1 (0.3) 0.6 (−0.9 to 2.4) 5 (1.5) 2 (0.6) 0.9 (−0.8 to 3.0)
Sepsis 0 0 0 (−1.1 to 1.1) 1 (0.3) 2 (0.6) −0.3 (−1.9 to 1.2)
Multiple organ failure 0 0 0 (−1.1 to 1.1) 10 (3.0) 8 (2.3) 0.6 (−2.0 to 3.4)
Type of cardiovascular event
Stroke 0 1 (0.3) −0.3 (−1.7 to 0.9) 2 (0.6) 1 (0.3) 0.3 (−1.1 to 1.9)
Myocardial infarction 1 (0.3) 1 (0.3) 0 (−1.4 to 1.4) 1 (0.3) 2 (0.6) −0.3 (−1.9 to 1.2)
Pulmonary embolism 0 1 (0.3) −0.3 (−1.7 to 0.9) 0 1 (0.3) −0.3 (−1.7 to 0.9)
Transfusion-related fatality 0 0 0 (−1.1 to 1.1) 1 (0.3) 0 0.3 (−0.8 to 1.7)
a Calculated using exact unconditional methods based on the Farrington-Manning score statistic.
bA patient may have had more than 1 cause of death.
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talloid exposure (median, 6.3-6.6 L) during the first 24 hours
of care. In this trial, the early availability of blood products administered
within minutes of arrival using a transfusion ratio
of 1:1:1 was associated with more patients achieving hemostasis
and decreased hemorrhage-related deaths over the first 24
hours with no differences in complications. Therefore, patient
safety was not compromised over 30 days.
Transfusing patients based on an empirical ratio rather
than guided solely by laboratory data (goal-directed) is considered
controversial by some researchers.44,45,48 This trial
was not designed to study this question. However, after the
controlled, ratio-driven intervention was completed, clinicians
treated patients based on local laboratory-guided
standard-of-care practice.49 It appears that laboratorydirected
catching up occurred in the 1:1:2 group with plasma
and platelets approaching a cumulative ratio of 1:1:1. Other
studies have shown similar results with laboratory-directed
resuscitation.11 This catching up after the completion of randomized
blood product transfusion may have decreased the
ability to detect differences in mortality at 24 hours and 30
days or in the prespecified ancillary outcomes.
Theconceptsofdamagecontrol resuscitation anddata from
the PROMMTT study formed the biological basis of the PROPPR
trial, ie, both early initiation (withinminutes of arrival) and increased
ratios of plasma and platelets would decrease death
from hemorrhage by improving hemostasis.4-12,27,32-41Recent
trauma resuscitationstudieshavedemonstrated thatmost early
deaths due to hemorrhage occur within 2 to 3 hours.3,10,27,50,51
The PROMMTT study demonstrated a median time to hemorrhagic
death from admission of 2.6 hours,10 and in the
PROPPR trial, the median time was 2.3 hours. In recognition
of the known physiology of patients with major bleeding, the
FDA recently recommended moving the end point of hemostasis
in a pivotal phase 3 prothrombin complex concentrate
trial to within 4 hours of the intervention.52 These data support
recent recommendations by the FDA to include a 3-hour
end point for intervention studies focusing on traumatic
hemorrhage.53
In the current study, the FDA only allowed 2 separate
primary end points (24 hours and 30 days) in recognition of
the assumed time frame of death from hemorrhage after
injury.3,10,54 However, most outcomes relevant to hemorrhage
control occurred early (within the initial 2-3 hours
after randomization). Thereafter, the number of patients
who died was similar between groups, explaining the
diminished effects at 24 hours and 30 days. This pattern of
Figure 3. Distribution of Cumulative Blood Product Ratios Within Period up to 24 Hours After Admission
4.0
2.0
2.5
3.5
3.0
1.5
1.0
0.5
0
Ratio of Plasma to RBCs
No.
1:1:1
1:1:2
Prerandomization
324 321
Postintervention
133 114
7.5
6.0
4.5
3.0
1.5
0
Ratio of Platelets to RBCs
No.
Prerandomization
324 321
Postintervention
133 114
Ratio of plasma to RBCs Ratio of platelets to RBCs
During
Intervention
326 332
During
Intervention
326 332
Prerandomization blood products
include those given prior to hospital
arrival. Patients who received no red
blood cells (RBCs) within an interval
were excluded because RBCs are in
the ratio denominator. The lower and
upper edges of the boxes are the
25th and 75th percentiles, the
whiskers extend to ± 1.5 × the
interquartile range, and the points
outside are the outliers. The thick line
inside the box represents the median
and the circle is the mean.
Figure 4. Distribution of Blood Product Amounts Within Period up to 24 Hours After Admission
70
40
50
60
30
20
10
0
Amount Given, U
Prerandomization
No.
70
40
50
60
30
20
10
0
Amount Given, U
During intervention
No.
RBCs
70
40
50
60
30
20
10
0
Amount Given, U
Postintervention
No.
Plasma Platelets RBCs
316
Plasma Platelets
305
Plasma Platelets RBCs
342
Platelets
338
Plasma RBCs
1:1:1
Plasma Platelets
342
RBCs
1:1:2 1:1:1 1:1:2 1:1:1 1:1:2
Platelets RBCs
338
Plasma
Prerandomization blood products include those given prior to hospital arrival.
The lower and upper edges of the boxes are the 25th and 75th percentiles, the
whiskers extend to ± 1.5 × the interquartile range, and the points outside are
the outliers. The thick line inside the box represents the median and the circle is
the mean. Five or 6 U pools of whole blood–derived platelets were considered
equivalent to 1 U of apheresis platelets (eg, an adult dose of platelets).
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traumatic death is consistent with previous randomized
resuscitation studies.51,55,56
This trial had a number of strengths. 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.48,55-61The 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. Separation of the ratio groupswasmaintained
during the intervention period.
Another strength of the trial was the high degree of compliance
with treatment protocols while simultaneously caring
for patients with severe injuries. Follow-up at 24 hours was
complete in both intervention groups, and only 4 patients were
lost to follow-up at 30 days. Additionally, we blinded clinicians
to treatment assignment until infusion of randomized
products and used direct observation for accurate data collection
of blood product delivery.
Limitations include power to detect differences smaller
than the effect size we considered to be both clinically meaningful
and affordable to study when we designed the trial. The
PROPPR trial had 95% power to detect the prespecified 10%
difference at 24 hours and 92% power to detect the prespecified
12% difference at 30 days, if such differences existed. As
in many studies, observed mortality in the comparison group
(1:1:2) was lower than expected, whereas in the 1:1:1 group, observed
mortality was similar to what was projected. A total
sample size of 2968 would have been required to detect the
observed difference of 4.2% given the observed 24-hour mortality
of 12.7% in the 1:1:1 group with 90% power. A further limitation
is the inability to independently examine the effects of
plasma and platelets on outcomes. To enroll patients withmassive
bleeding, the protocol required transfusion of at least 1 U
of any blood product and no more than 3 U of RBCs prior to
randomization, resulting in an inability to use randomized
blood products starting with the first transfusion.
Table 4. Incidence of Prespecified Complications by Treatment Group
1:1:1 Group (n = 338) 1:1:2 Group (n = 342) Difference Between
Groups in Percentage
of Patients With Event,
% (95% CI)c
Total No. of
Eventsa
No. (%) of
Patientsb
Total No. of
Eventsa
No. (%) of
Patientsb
Systemic inflammatory response syndrome 265 231 (68.3) 239 216 (63.2) 5.2 (−2.1 to 12.3)
Sepsis 110 99 (29.3) 102 91 (26.6) 2.7 (−4.2 to 9.5)
Infection (urinary tract infection, wound, line, other) 155 98 (29.0) 146 106 (31.0) −2.0 (−8.9 to 5.0)
Death 75 75 (22.2) 89 89 (26.0) −3.8 (−10.3 to 2.7)
Acute kidney injury 87 74 (21.9) 93 85 (24.9) −3.0 (−9.4 to 3.5)
Ventilator-associated pneumonia 70 62 (18.3) 65 58 (17.0) 1.4 (−4.4 to 7.2)
Transfusion-related metabolic complication (hypocalcemia
or hyperkalemia)
53 53 (15.7) 60 59 (17.3) −1.6 (−7.2 to 4.1)
Acute lung injury 56 47 (13.9) 66 57 (16.7) −2.8 (−8.3 to 2.7)
Acute respiratory distress syndrome 55 46 (13.6) 57 48 (14.0) −0.4 (−5.7 to 4.9)
Deep vein thrombosis 28 25 (7.4) 24 24 (7.0) 0.4 (−3.6 to 4.4)
Abdominal complication 29 24 (7.1) 23 22 (6.4) 0.7 (−3.3 to 4.6)
Cardiac arrest 25 23 (6.8) 30 27 (7.9) −1.1 (−5.2 to 3.0)
Multiple organ failure 24 20 (5.9) 18 15 (4.4) 1.5 (−1.9 to 5.1)
Symptomatic pulmonary embolism 14 14 (4.1) 13 13 (3.8) 0.3 (−2.8 to 3.5)
Additional bleeding after hemostasis requiring
interventional radiology or operating room procedure
13 13 (3.8) 18 16 (4.7) −0.8 (−4.1 to 2.4)
Asymptomatic pulmonary embolism 11 11 (3.3) 11 11 (3.2) 0 (−2.8 to 2.9)
Stroke 9 8 (2.4) 11 11 (3.2) −0.8 (−3.6 to 1.8)
Abdominal compartment syndrome 3 3 (0.9) 3 3 (0.9) 0 (−1.8 to 1.8)
Delayed serological transfusion reaction 2 2 (0.6) 0 0 0.6 (−0.5 to 2.1)
Transfusion-related allergic reactions 2 2 (0.6) 1 1 (0.3) 0.3 (−1.1 to 1.9)
Hypernatremia (associated with hypertonic saline) 1 1 (0.3) 4 4 (1.2) −0.9 (−2.7 to 0.6)
Febrile nonhemolytic transfusion reaction 1 1 (0.3) 1 1 (0.3) 0 (−1.4 to 1.4)
Transfusion-associated circulatory overload 1 1 (0.3) 0 0 0.3 (−0.8 to 1.7)
Myocardial infarction 0 0 2 2 (0.6) −0.6 (−2.1 to 0.6)
Any prespecified complications 1089 297 (87.9) 1076 310 (90.6) −2.8 (−7.6 to 1.9)
a A patient may have had multiple complications of the same type.
bPercentages may add to more than 100% because a patient may have had
more than 1 complication.
c Calculated using exact unconditional methods based on the
Farrington-Manning score statistic.
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Even though the study was blinded until the opening of
the containers, another limitation was that clinicians could not
be blinded after the containers were opened without altering
patient care. This trial was also limited by an inability to completely
exclude patients with an unsurvivable brain injury; 23%
of deaths at 24 hours and 38% of all deaths at 30 days were associated
with traumatic brain injury. Last, the issue of competing
risks of death from hemorrhage and traumatic brain injury
in trauma studies that require rapid enrollment before
definitive diagnosis of allmajor injuries is well-known and will
continue to be an issue in future trauma studies unless novel
regulatory, study design, or technological solutions are developed
to solve this issue.3,54
Given the lower percentage of deaths from exsanguination
and our failure to find differences in safety, clinicians
should consider using a 1:1:1 transfusion protocol, starting with
the initial units transfused while patients are actively bleeding,
and then transitioning to laboratory-guided treatment once
hemorrhage control is achieved. Future studies of hemorrhage
control products, devices, and interventions should concentrate
on the physiologically relevant period of active bleeding
after injury and use acute complications and later deaths
(24 hours and 30 days) as safety end points.
Conclusions
Among patients with severe trauma and major bleeding, early
administration of plasma, platelets, and RBCs 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.
ARTICLE INFORMATION
Author Affiliations: Center for Translational Injury
Research, Division of Acute Care Surgery,
Department of Surgery, Medical School, University
of Texas Health Science Center, Houston (Holcomb,
Fox, Wade, Podbielski, del Junco, Cotton,
Matijevic); Division of Biostatistics, School of Public
Health, University of Texas Health Science Center,
Houston (Tilley, Baraniuk); Division of Trauma and
Critical Care, Department of Surgery, Medical
College of Wisconsin, Milwaukee (Brasel); Division
of Trauma and Critical Care, Department of Surgery,
School of Medicine, University of Washington,
Seattle (Bulger); Division of General Surgery,
Department of Surgery, School of Medicine,
University of California, San Francisco (Callcut,
Cohen); Division of Trauma and Surgical Critical
Care, Department of Surgery, College of Medicine,
University of Tennessee Health Science Center,
Memphis (Fabian, Weinberg); Division of Trauma
and Critical Care, University of Southern California,
Los Angeles (Inaba); Division of Trauma, Burns and
Surgical Critical Care, Department of Surgery,
School of Medicine, University of Alabama,
Birmingham (Kerby); Division of Trauma/Critical
Care, Department of Surgery, College of Medicine,
University of Cincinnati, Cincinnati, Ohio (Muskat,
Robinson); Division of Trauma, Critical Care and
Emergency Surgery, Department of Surgery,
University of Arizona, Tucson (O’Keeffe); Trauma
and Acute Care Surgery, St Michael’s Hospital,
University of Toronto, Toronto, Ontario, Canada
(Rizoli); R. Adams Cowley Shock Trauma Center,
Program in Trauma, University of Maryland School
of Medicine, Baltimore (Scalea, Stein); Division of
Trauma, Critical Care and Acute Care Surgery,
School of Medicine, Oregon Health & Science
University, Portland (Schreiber); Sunnybrook
Research Institute, Department of Clinical
Pathology, Sunnybrook Health Sciences Centre,
Toronto, Ontario, Canada (Callum); Department of
Laboratory Medicine, School of Medicine,
University of Washington, Seattle (Hess);
Department of Emergency Medicine, College of
Medicine, University of Cincinnati, Cincinnati, Ohio
(Miller); Division of Critical Care and Perioperative
Medicine, Department of Anesthesiology, School of
Medicine, University of Alabama, Birmingham
(Pittet); American College of Surgeons, Chicago,
Illinois (Hoyt); Division of Cardiovascular Sciences,
National Heart, Lung, and Blood Institute, National
Institutes of Health, Bethesda, Maryland (Pearson);
Department of Biostatistics, School of Public
Health, University of Washington, Seattle (Leroux,
van Belle); Department of Environmental and
Occupational Health Sciences, School of Public
Health, University of Washington, Seattle
(van Belle). Dr Brasel is now with the Division of
Trauma, Critical Care and Acute Care Surgery,
School of Medicine, Oregon Health & Science
University, Portland. Dr Muskat is now with the
Division of General Surgery, Department of Surgery,
School of Medicine, University of California,
San Francisco.
Author Contributions: Drs Tilley and Baraniuk had
full access to all of the data in the study and take
responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design: Holcomb, Tilley,
Baraniuk, Wade, del Junco, Bulger, Cohen, Cotton,
Kerby, Muskat, Rizoli, Robinson, Scalea, Schreiber,
Stein, Callum, Hess, Miller, Pittet, Hoyt, Pearson,
Leroux, van Belle.
Acquisition, analysis, or interpretation of data: Tilley,
Baraniuk, Fox, Wade, Podbielski, del Junco, Brasel,
Bulger, Callcut, Cohen, Cotton, Fabian, Inaba, Kerby,
Muskat, O’Keeffe, Rizoli, Robinson, Scalea,
Schreiber, Stein, Weinberg, Callum, Hess, Matijevic,
Miller, Pittet, Hoyt, Leroux, van Belle.
Drafting of the manuscript: Holcomb, Tilley,
Baraniuk, Fox, Wade, Podbielski, Callcut, Cohen,
Cotton, Robinson, Stein, Hess, Pearson, van Belle.
Critical revision of the manuscript for important
intellectual content: Tilley, Baraniuk, Fox, Wade,
del Junco, Brasel, Bulger, Callcut, Cohen, Cotton,
Fabian, Inaba, Kerby, Muskat, O’Keeffe, Rizoli,
Robinson, Scalea, Schreiber, Stein, Weinberg,
Callum, Hess, Matijevic, Miller, Pittet, Hoyt,
Pearson, Leroux, van Belle.
Statistical analysis: Tilley, Baraniuk, Fox, Wade,
Fabian, van Belle.
Obtained funding: Holcomb, Wade, Cotton,
Schreiber, van Belle.
Administrative, technical, or material support: Tilley,
Wade, Podbielski, del Junco, Bulger, Callcut, Cohen,
Cotton, Kerby, Muskat, O’Keeffe, Rizoli, Robinson,
Scalea, Stein, Weinberg, Callum, Hess, Matijevic,
Miller, Pittet, Hoyt, Pearson, Leroux,
Study supervision: Holcomb, Tilley, Wade, Bulger,
Callcut, Muskat, Rizoli, Robinson, Schreiber,
Weinberg, Callum, Hess, Matijevic, Pittet, Hoyt,
van Belle.
Conflict of Interest Disclosures: The authors have
completed and submitted the ICMJE Form for
Disclosure of Potential Conflicts of Interest. Dr
Rizoli reported receiving grant funding from TEM
International and CSL Behring. Dr Stein reported
serving as an advisor for Decisio Health for which
she receives travel reimbursement. No other
disclosures were reported.
Funding/Support: This work was supported with
grant U01HL077863 from the US National Heart,
Lung, and Blood Institute and funding from the US
Department of Defense, the Defence Research and
Development Canada in partnership with the
Canadian Institutes of Health Research-Institute of
Circulatory and Respiratory Health (grant CRR-
120612).
Role of the Funder/Sponsor: The US National
Heart, Lung, and Blood Institute (NHLBI) and the
US Department of Defense had a role in the study
design but had no role in the conduct of the study;
collection, management, analysis, and
interpretation of the data; preparation, review, or
approval of the manuscript; and decision to submit
the manuscript for publication. However, Dr
Pearson is employed by the NHLBI and she did
participate in the review and approval of the
manuscript.
Group Information: The PROPPR Study Group:
Clinical Coordinating Center, University of Texas
Health Science Center, Houston: John B. Holcomb,
MD, Charles E. Wade, PhD, Deborah J. del Junco,
PhD, Erin E. Fox, PhD, Nena Matijevic, PhD
(laboratory committee co-chair), Jeanette M.
Podbielski, RN, Angela M. Beeler, BS. Data
Coordinating Center, University of Texas Health
Science Center, Houston: Barbara C. Tilley, PhD,
Sarah Baraniuk, PhD, Stacia M. DeSantis, PhD,
Hongjian Zhu, PhD, Joshua Nixon, MS, Roann Seay,
MS, Savitri N. Appana, MS, Hui Yang, MS, Michael O.
Gonzalez, MS. Core Laboratory, University of Texas
Health Science Center, Houston: Lisa Baer, MS,
Research Original Investigation Transfusion in Patients With Severe Trauma
480 JAMA February 3, 2015 Volume 313, Number 5 (Reprinted) jama.com
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Yao-Wei Willa Wang, MD, Brittany S. Hula, MS, Elena
Espino, BS, An Nguyen, BS, Nicholas Pawelczyk, BS,
Kisha D. Arora-Nutall, BS, Rishika Sharma, MD,
Jessica C. Cardenas, PhD, Elaheh Rahbar, PhD,
Tyrone Burnett Jr, BS, David Clark, BS. Resuscitation
Outcomes Consortium, University of Washington:
Gerald van Belle, PhD, Susanne May, PhD, Brian
Leroux, PhD, David Hoyt, MD, Judy Powell, BSN,
RN, Kellie Sheehan, BSN. Systems Biology
Committee, University of California, Berkeley: Alan
Hubbard, PhD (co-chair), Adam P. Arkin, PhD.
Transfusion Committee: John R. Hess, MD, MPH
(co-chair, University of Washington), Jeannie L.
Callum, MD (co-chair, Sunnybrook Health Sciences
Centre). Anesthesiology Committee: Jean-Francois
Pittet, MD (chair, University of Alabama,
Birmingham). Emergency Medicine Committee:
Christopher N. Miller, MD (chair, University of
Cincinnati). PROPPR Clinical Sites (listed in order of
number of patients enrolled): University of Texas
Health Science Center, Houston: Bryan A. Cotton,
MD, MPH, Laura Vincent, BSN, RN, CCRP, Timothy
Welch, Tiffany Poole, DC, Evan G. Pivalizza, MD,
Sam D. Gumbert, MD, Yu Bai, MD, PhD, James J.
McCarthy, MD, Amy Noland, MD, Rhonda Hobbs,
MT(ASCP)SBB. University of Washington: Eileen M.
Bulger, MD, Patricia Klotz, RN, Lindsay Cattin, BA,
Keir J. Warner, BS, Angela Wilson, BA, David Boman,
BA, Nathan White, MD, MS, Andreas Grabinsky, MD,
Jennifer A. Daniel-Johnson, MBBS. University of
California, San Francisco: Mitchell Jay Cohen, MD
(systems biology and laboratory committee
co-chair), Rachael A. Callcut, MD, MSPH, Mary
Nelson, RN, MPA, Brittney Redick, BA, Amanda
Conroy, BA, Marc P. Steurer, MD, DESA, Preston C.
Maxim, MD, Eberhard Fiebig, MD, Joanne Moore,
Eireen Mallari, MT. University of Cincinnati: Peter
Muskat, MD, Jay A. Johannigman, MD, Bryce R. H.
Robinson, MD, Richard D. Branson, MSc, RRT, Dina
Gomaa, BS, RRT, Christopher Barczak, BS, MT
(ASCP), Suzanne Bennett, MD, Patricia M. Carey,
MD, Helen Hancock, BS, MT(ASCP), Carolina
Rodriguez, BA. University of Southern California:
Kenji Inaba, MD, Jay G. Zhu, MD, Monica D. Wong,
MS, Michael Menchine, MD, MPH, Kelly Katzberg,
MD, FACEP, Sean O. Henderson, MD, Rodney
McKeever, MD, Ira A. Shulman, MD, Janice M.
Nelson, MD, Christopher W. Tuma, BA, MT(ASCP),
SBB, Cheryl Y. Matsushita, BS, MT(ASCP). Shock,
Trauma and Anesthesiology Research-Organized
Research Center, R. Adams Cowley Shock Trauma
Center, University of Maryland Medical Center:
Thomas M. Scalea, MD, Deborah M. Stein, MD,
MPH, Cynthia K. Shaffer, MS, MBA, Christine Wade,
BA, Anthony V. Herrera, MS, Seeta Kallam, MBBS,
Sarah E. Wade, BS, Samuel M. Galvagno Jr, DO, PhD,
Magali J. Fontaine, MD, PhD, Janice M. Hunt, BS,
MT(ASCP) SBB, Rhonda K. Cooke, MD. University of
Tennessee Health Science Center, Memphis:
Timothy C. Fabian, MD, Jordan A. Weinberg, MD,
Martin A. Croce, MD, Suzanne Wilson, RN,
Stephanie Panzer-Baggett, RN, Lynda WaddleSmith,
BSN, Sherri Flax, MD. Medical College of
Wisconsin: Karen J. Brasel, MD, MPH, Pamela
Walsh, AS, CCRC, David Milia, MD, Allia Nelson, BS,
BA, Olga Kaslow, MD, PhD, Tom P. Aufderheide, MD,
MS, Jerome L. Gottschall, MD, Erica Carpenter,
MLS(ASCP). University of Arizona: Terence
O’Keeffe, MBChB, MSPH, Laurel L. Rokowski, RN,
BSN, MKT, Kurt R. Denninghoff, MD, Daniel T.
Redford, MD, Deborah J. Novak, MD, Susan Knoll,
MS, MT(ASCP)SBB. University of Alabama,
Birmingham: Jeffrey D. Kerby, MD, PhD, Patrick L.
Bosarge, MD, Albert T. Pierce, MD, Carolyn R.
Williams, RN, BSN, BSME, Shannon W. Stephens,
EMTP, Henry E. Wang, MD, MS, Marisa B. Marques,
MD. Oregon Health & Science University: Martin A.
Schreiber, MD, Jennifer M. Watters, MD, Samantha
J. Underwood, MS, Tahnee Groat, MPH, Craig
Newgard, MD, MPH, Matthias Merkel, MD, PhD,
Richard M. Scanlan, MD, Beth Miller, MT(ASCP)SBB.
Sunnybrook Health Science Center: Sandro Rizoli,
MD, PhD, Homer Tien, MD, Barto Nascimento, MD,
MSc, CTBS, Sandy Trpcic, Skeeta Sobrian-Couroux,
RN, CCRP, BHA, Marciano Reis, Adic Pérez, MD,
Susan E. Belo, MD, PhD, Lisa Merkley, BA, MLT,
CBTS, Connie Colavecchia, BSc, MLT.
Disclaimer: The content is the sole responsibility of
the authors and should not be construed as official
or as reflecting the views of any of the sponsors.
Additional Contributions: We thank the members
of the data and safety monitoring board (Lance
Becker, Charles Cairns, Ralph D’Agostino, Karl Jern,
Nigel Key, Laurence McCullough, Jeremy Perkins,
Herbert Wiedemann, Janet Wittes, and Jay Mason)
and the external advisory committee (Kenneth G.
Mann, Kathleen Brummel, Beth Hartwell, Charles
Esmon, Morris Blajchman, Andrew P. Cap, Andrei
Kindzelski, and Anthony E. Pusateri) for their time
and effort. We also thank the Resuscitation
Outcomes Consortium protocol review committee
for their important contributions as well as
COL Dallas Hack and COL Robert Vandre for their
extraordinary commitment and unwavering
support for this trial. We could not have
successfully completed this study without the help
of hundreds of unnamed clinical personnel and we
thank them for their sustained efforts.
Additional Information: We dedicate this work to
the US Soldiers, Sailors, Airmen, and Marines who
put their lives on the line every day. We hope this
effort will help improve the care of seriously injured
patients, both military and civilian.
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