Training trends and Issues

1. Research the current trends in training and development and the implications for the training and development practitioner. The syllabus contains a list of training and development resources that are available through the Franklin University library. 2. Write a 3- to 5- page paper that analyzes three trends that you identified in your research. Discuss the implications that the ...

The Entrepreneurs Guide to Business Planning

The Entrepreneurs Guide to Business Planning Your plan must be for an idea that is linked to Life Sciences with a Biological component. The idea could be based on your undergraduate research project, a scientific paper you have read, a scientific product you have used, a published patent or your own idea. Examples include: new scientific equipment; providing a service ...

Topic: Public Administration

Write a short essay summarizing the basic facts and analyzing its relevance to contemporary public administration in light of public administration theory. *****The book to read is RICHARD J. STILLMAN, PUBLIC ADMINISTRATION: CONCEPTS AND CASES EIGHTH EDITION (BOSTON HOUGHTON MIFFLIN CO,. 2005) ****Please read the chapter but most of all USE THE CASE STUDY TO ANSWER THE QUESTION. PLEASE ...

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. ...

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