Comments on: 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

Comments on: 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 https://www.rapidessayresearchers.com/essays/copyright-2015-american-medical-association-all-rights-reserved-transfusion-of-plasma-platelets-and-red-blood-cells-in-a-111-vs-a-112-ratio-and-mortality-in-patients-with-severe-trauma-the-pro/ We offer fast essays with the best content Tue, 26 Jul 2016 09:12:00 +0000 hourly 1 http://wordpress.org/?v=4.2.2