Erin E. Fox

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

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.

Clinical and mechanistic drivers of acute traumatic coagulopathy.

BACKGROUND Acute traumatic coagulopathy (ATC) occurs after severe injury and shock and is associated with increased bleeding, morbidity, and mortality. The effects of ATC and hemostatic resuscitation on outcome are not well-explored. The PRospective Observational Multicenter Major Trauma Transfusion (PROMMTT) study provided a unique opportunity to characterize coagulation and the effects of resuscitation on ATC after severe trauma. METHODS Blood samples were collected upon arrival on a subset of PROMMTT patients. Plasma clotting factor levels were prospectively assayed for coagulation factors. These data were analyzed with comprehensive PROMMTT clinical data. RESULTS There were 1,198 patients with laboratory results, of whom 41.6% were coagulopathic. Using international normalized ratio of 1.3 or greater, 41.6% of patients (448) were coagulopathic, while 20.5% (214) were coagulopathic using partial thromboplastin time of 35 or greater. Coagulopathy was primarily associated with a combination of an Injury Severity Score (ISS) of greater than 15 and a base deficit (BD) of less than −6 (p < 0.05). Regression modeling for international normalized ratio–based coagulopathy shows that prehospital crystalloid (odds ratio [OR], 1.05), ISS (OR, 1.03), Glasgow Coma Scale (GCS) score (OR, 0.93), heart rate (OR, 1.08), systolic blood pressure (OR, 0.96), BD (OR, 0.92), and temperature (OR, 0.84) were significant predictors of coagulopathy (all p < 0.03). A subset of 165 patients had blood samples collected and coagulation factor analysis performed. Elevated ISS and BD were associated with elevation of aPC and depletion of factors (all p < 0.05). Reductions in factors I, II, V, VIII and an increase in aPC drive ATC (all p < 0.04). Similar results were found for partial thromboplastin time–defined coagulopathy. CONCLUSION ATC is associated with the depletion of factors I, II, V, VII, VIII, IX, and X and is driven by the activation of the protein C system. These data provide additional mechanistic understanding of the drivers of coagulation abnormalities after injury. Further understanding of the drivers of ATC and the effects of resuscitation can guide factor-guided resuscitation and correction of coagulopathy after injury. LEVEL OF EVIDENCE Epidemiologic/prognostic study, level IV.

Making thawed universal donor plasma available rapidly for massively bleeding trauma patients: experience from the Pragmatic, Randomized Optimal Platelets and Plasma Ratios (PROPPR) trial

The Pragmatic, Randomized Optimal Platelets and Plasma Ratios (PROPPR) trial was a randomized clinical trial comparing survival after transfusion of two different blood component ratios for emergency resuscitation of traumatic massive hemorrhage. Transfusion services supporting the study were expected to provide thawed plasma, platelets, and red blood cells within 10 minutes of request.

Defining when to initiate massive transfusion: A validation study of individual massive transfusion triggers in PROMMTT patients

BACKGROUND Early predictors of massive transfusion (MT) would prevent undertriage of patients likely to require MT. This study validates triggers using the Prospective Observational Multicenter Major Trauma Transfusion (PROMMTT) study. METHODS All enrolled patients in PROMMTT were analyzed. The initial emergency department value for each trigger (international normalized ratio [INR], systolic blood pressure, hemoglobin, base deficit, positive result for Focused Assessment for the Sonography of Trauma examination, heart rate, temperature, and penetrating injury mechanism) was compared for patients receiving MT (≥10 U of packed red blood cells in 24 hours) versus no MT. Adjusted odds ratios (ORs) for MT are reported using multiple logistic regression. If all triggers were known, a Massive Transfusion Score (MTS) was created, with 1 point assigned for each met trigger. RESULTS A total of 1,245 patients were prospectively enrolled with 297 receiving an MT. Data were available for all triggers in 66% of the patients including 67% of the MTs (199 of 297). INR was known in 87% (1,081 of 1,245). All triggers except penetrating injury mechanism and heart rate were valid individual predictors of MT, with INR as the most predictive (adjusted OR, 2.5; 95% confidence interval, 1.7–3.7). For those with all triggers known, a positive INR trigger was seen in 49% receiving MT. Patients with an MTS of less than 2 were unlikely to receive MT (negative predictive value, 89%). If any two triggers were present (MTS ≥ 2), sensitivity for predicting MT was 85%. MT was present in 33% with an MTS of 2 greater compared with 11% of those with MTS of less than 2 (OR, 3.9; 95% confidence interval, 2.6–5.8; p < 0.0005). CONCLUSION Parameters that can be obtained early in the initial emergency department evaluation are valid predictors for determining the likelihood of MT. LEVEL OF EVIDENCE Diagnostic, level II.

Prehospital intravenous fluid is associated with increased survival in trauma patients.

BACKGROUND Delivery of intravenous crystalloid fluids (IVF) remains a tradition-based priority during prehospital resuscitation of trauma patients. Hypotensive and targeted resuscitation algorithms have been shown to improve patient outcomes. We hypothesized that receiving any prehospital IVF is associated with increased survival in trauma patients compared with receiving no prehospital IVF. METHODS Prospective data from 10 Level 1 trauma centers were collected. Patient demographics, prehospital IVF volume, prehospital and emergency department vital signs, lifesaving interventions, laboratory values, outcomes, and complications were collected and analyzed. Patients who did or did not receive prehospital IVF were compared. Tests for nonparametric data were used to assess significant differences between groups (p ⩽ 0.05). Cox regression analyses were performed to determine the independent influence of IVF on outcome and complications. RESULTS The study population consisted of 1,245 trauma patients; 45 were excluded owing to incomplete data; 84% (n = 1,009) received prehospital IVF, and 16% (n = 191) did not. There was no difference between the groups with respect to sex, age, and Injury Severity Score (ISS). The on-scene systolic blood pressure was lower in the IVF group (110 mm Hg vs. 100 mm Hg, p < 0.04) and did not change significantly after IVF, measured at emergency department admission (110 mm Hg vs. 105 mm Hg, p = 0.05). Hematocrit/hemoglobin, fibrinogen, and platelets were lower (p < 0.05), and prothrombin time/international normalized ratio and partial thromboplastin time were higher (p < 0.001) in the IVF group. The IVF group received a median fluid volume of 700 mL (interquartile range, 300–1,300). The Cox regression revealed that prehospital fluid administration was associated with increased survival (hazard ratio, 0.84; 95% confidence interval, 0.72–0.98; p = 0.03). Site differences in ISS and fluid volumes were demonstrated (p < 0.001). CONCLUSION Prehospital IVF volumes commonly used by PRospective Observational Multicenter Massive Transfusion Study (PROMMTT) investigators do not result in increased systolic blood pressure but are associated with decreased in-hospital mortality in trauma patients compared with patients who did not receive prehospital IVF. LEVEL OF EVIDENCE Therapeutic study, level IV.

Early resuscitation intensity as a surrogate for bleeding severity and early mortality in the PROMMTT study.

BACKGROUND The classic definition of massive transfusion, 10 or more units of red blood cells (RBCs) in 24 hours, has never been demonstrated as a valid surrogate for severe hemorrhage and can introduce survival bias. In addition, the definition fails to capture other products that the clinician may have immediately available, and may use, during the initial resuscitation. Assuming that units of resuscitative fluids reflect patient illness, our objective was to identify a rate of resuscitation intensity (RI) that could serve as an early surrogate of sickness for patients with substantial bleeding after injury. METHODS Adult patients surviving at least 30 minutes after admission and receiving one or more RBCs within 6 hours of admission from 10 US Level 1 trauma centers were enrolled in the PRospective Observational Multicenter Major Trauma Transfusion (PROMMTT) study. Total fluid units were calculated as the sum of the number of crystalloid units (1 L = 1 U), colloids (0.5 L = 1 U), and blood products (1 RBC = 1 U, 1 plasma = 1 U, 6 pack platelets = 1 U). Univariable and multivariable logistic regressions were used to evaluate associations between RI and 6-hour mortality, adjusting for age, center, penetrating injury, weighted Revised Trauma Score (RTS), and Injury Severity Score (ISS). RESULTS A total of 1,096 eligible patients received resuscitative fluids within 30 minutes, including 620 transfused with blood products. Despite varying products used, the total fluid RI was similar across all sites (3.2 ± 2.5 U). Patients who received four or more units of any resuscitative fluid had a 6-hour mortality rate of 14.4% versus 4.5% in patients who received less than 4 U. The adjusted odds ratio of 6-hour mortality for patients receiving 4 U or more within 30 minutes was 2.1 (95% confidence interval, 1.2–3.5). CONCLUSION Resuscitation with four or more units of any fluid was significantly associated with 6-hour mortality. This study suggests that early RI regardless of fluid type can be used as a surrogate for sickness and mortality in severely bleeding patients. LEVEL OF EVIDENCE Epidemiologic/prognostic study, level III.

Coordination and management of multicenter clinical studies in trauma: Experience from the PRospective Observational Multicenter Major Trauma Transfusion (PROMMTT) Study☆

AIM Early death due to hemorrhage is a major consequence of traumatic injury. Transfusion practices differ among hospitals and it is unknown which transfusion practices improve survival. This report describes the experience of the PRospective Observational Multicenter Major Trauma Transfusion (PROMMTT) Study Data Coordination Center in designing and coordinating a study to examine transfusion practices at ten Level 1 trauma centers in the US. METHODS PROMMTT was a multisite prospective observational study of severely injured transfused trauma patients. The clinical sites collected real-time information on the timing and amounts of blood product infusions as well as colloids and crystalloids, vital signs, initial diagnostic and clinical laboratory tests, life saving interventions and other clinical care data. RESULTS Between July 2009 and October 2010, PROMMTT screened 12,561 trauma admissions and enrolled 1245 patients who received one or more blood transfusions within 6h of Emergency Department (ED) admission. A total of 297 massive transfusions were observed over the course of the study at a combined rate of 5.0 massive transfusion patients/week. CONCLUSION PROMMTT is the first multisite study to collect real-time prospective data on trauma patients requiring transfusion. Support from the Department of Defense and collaborative expertise from the ten participating centers helped to demonstrate the feasibility of prospective trauma transfusion studies. The observational data collected from this study will be an invaluable resource for research in trauma surgery and it will guide the design and conduct of future randomized trials.

Resuscitate early with plasma and platelets or balance blood products gradually: findings from the PROMMTT study.

BACKGROUND The trauma transfusion literature has yet to resolve which is more important for hemorrhaging patients, transfusing plasma and platelets along with red blood cells (RBCs) early in resuscitation or gradually balancing blood product ratios. In a previous report of PROMMTT results, we found (1) plasma and platelet:RBC ratios increased gradually during the 6 hours following admission, and (2) patients achieving ratios more than 1:2 (relative to ratios <1:2) had significantly decreased 6-hour to 24-hour mortality adjusting for baseline and time-varying covariates. To differentiate the association of in-hospital mortality with early plasma or platelet transfusion from that with delayed but gradually balanced ratios, we developed a separate analytic approach. METHODS Using PROMMTT data and multilevel logistic regression to adjust for center effects, we related in-hospital mortality to the early receipt of plasma or platelets within the first three to six transfusion units (including RBCs) and 2.5 hours of admission. We adjusted for the same covariates as in our previous report: Injury Severity Score (ISS), age, time and total number of blood product transfusions upon entry to the analysis cohort, and bleeding from the head, chest, or limb. RESULTS Of 1,245 PROMMTT patients, 619 were eligible for this analysis. Early plasma was associated with decreased 24-hour and 30-day mortality (adjusted odds ratios of 0.47 [p = 0.009] and 0.44 [p = 0.002], respectively). Too few patients (24) received platelets early for meaningful assessment. In the subgroup of 222 patients receiving no early plasma but continuing transfusions beyond Hour 2.5, achieving gradually balanced plasma and platelet:RBC ratios of 1:2 or greater by Hour 4 was not associated with 30-day mortality (adjusted odds ratios of 0.9 and 1.1, respectively). There were no significant center effects. CONCLUSION Plasma transfusion early in resuscitation had a protective association with mortality, whereas delayed but gradually balanced transfusion ratios did not. Further research will require considerably larger numbers of patients receiving platelets early. LEVEL OF EVIDENCE Therapeutic study, level IV.

Damage control resuscitation in patients with severe traumatic hemorrhage: A practice management guideline from the Eastern Association for the Surgery of Trauma.

Background The resuscitation of severely injured bleeding patients has evolved into a multi-modal strategy termed damage control resuscitation (DCR). This guideline evaluates several aspects of DCR including the role of massive transfusion (MT) protocols, the optimal target ratio of plasma (PLAS) and platelets (PLT) to red blood cells (RBC) during DCR, and the role of recombinant activated factor VII (rVIIa) and tranexamic acid (TXA). Methods Using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology, a subcommittee of the Practice Management Guidelines (PMG) Section of EAST conducted a systematic review using MEDLINE and EMBASE. Articles in English from1985 through 2015 were considered in evaluating four PICO questions relevant to DCR. Result A total of 37 studies were identified for analysis, of which 31 met criteria for quantitative meta-analysis. In these studies, mortality decreased with use of an MT/DCR protocol vs. no protocol (OR 0.61, 95% CI 0.43–0.87, p = 0.006) and with a high ratio of PLAS:RBC and PLT:RBC (relatively more PLAS and PLT) vs. a low ratio (OR 0.60, 95% CI 0.46–0.77, p < 0.0001; OR 0.44, 95% CI 0.28–0.71, p = 0.0003). Mortality and blood product use were no different with either rVIIa vs. no rVIIa or with TXA vs. no TXA. Conclusion DCR can significantly improve outcomes in severely injured bleeding patients. After a review of the best available evidence, we recommend the use of a MT/DCR protocol in hospitals that manage such patients and recommend that the protocol target a high ratio of PLAS and PLT to RBC. This is best achieved by transfusing equal amounts of RBC, PLAS, and PLT during the early, empiric phase of resuscitation. We cannot recommend for or against the use of rVIIa based on the available evidence. Finally, we conditionally recommend the in-hospital use of TXA early in the management of severely injured bleeding patients.

The PRospective Observational Multicenter Major Trauma Transfusion (PROMMTT) study.

T PRospective Observational Multicenter Major Trauma Transfusion (PROMMTT) study examined the timing of transfusions during the treatment of adult civilian trauma patients. We believe this is the first trauma study to capture data in real time on the timing and sequence of blood product infusions. Multiple previous retrospective studies had described transfusion and outcomes, but it was apparent that to design a high-quality prospective randomized intervention study, prospective observational data were required. Funded by the US Army Medical Research and Materiel Command, PROMMTT prospectively enrolled 1,245 adult trauma patients who received at least 1 U of red blood cells (RBCs) within 6 hours of admission among 10 nationwide Level 1 trauma centers between July 2, 2009, and October 15, 2010. Detailed description of the study design is available in Rahbar et al. The primary results of the study demonstrated that the median time to hemorrhagic death was 2.6 hours, increased plasma: RBC ratios were associated with improved early outcomes, and rapidly bleeding patients usually do not receive plasma and especially platelets for up to 3 hours after admission. The local principal investigators as well as investigators from the PROMMTT Data Coordinating Center (DCC) had extensive experience in designing, implementing, and analyzing studies within trauma and other clinical specialties, but the results revealed many misconceptions regarding transfusions in acutely bleeding trauma patients. Before PROMMTT, we thought that plasma, platelets, and RBCs were transfused early in a uniform ratio throughout resuscitation. PROMMTT data proved this idea false. In fact, transfusion patterns varied both within and between patients, with few patients receiving a balanced infusion of products, in any constant ratio. We also believed that clinical practice would be similar across the 10 Level 1 trauma centers, and we were wrong about that as well. There was variance in the time of blood product administration as well in the ratios between centers. We did expect and show that rapidly bleeding trauma patients could be enrolled quickly, demonstrating that studies in bleeding trauma patients were feasible. Data from PROMMTTwere used to inform the design of the follow-up randomized clinical trial, the Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) study, which is expected to provide Level 1 evidence to answer the question of whether transfusing a 1:1:1 (plasma:platelets:RBC) ratio provides a survival benefit compared to a ratio of 1:1:2. PROPPR is the culmination of a research program, which began with small retrospective military studies, continued with a multicenter retrospective study, then the multicenter prospective study PROMMTT. We believe that the systematic gathering and synthesis of data in this manner helps guide clinically relevant research programs by better defining and refining research questions at each point before a final randomized clinical trial. To date, three articles have been published from the PROMMTT data. The PROMMTT DCC also organized a symposium at the American Association for the Surgery of Trauma (AAST) annual meeting on September 11, 2012, in Kauai, Hawaii, where 19 PROMMTT articles were presented. The 15 articles in this supplement represent those that successfully passed through rigorous peer review and address crucial design and analysis issues currently facing trauma research. The articles run the gamut from regulatory issues, prehospital resuscitation, the impact of early versus late plasma use, laboratory-based profiles, the impact of crystalloid versus plasma