Abstract

INTRODUCTION The Pragmatic Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial failed to demonstrate a mortality difference for hemorrhaging patients receiving a balanced (1:1:1) vs a 1:1:2 resuscitation at 24 hours and 30 days. Recent guidelines recommend earlier mortality end points for hemorrhage-control trials, and the use of contemporary statistical methods. The aim of this post hoc analysis of the PROPPR trial was to evaluate the impact of a balanced resuscitation strategy at early resuscitation time points using a Bayesian analytical framework. METHODS Bayesian hierarchical models were created to assess mortality differences at the 1, 3, 6, 12, 18, and 24 hours time points between study cohorts. Posterior probabilities and Bayes factors were calculated for each time point. RESULTS A 1:1:1 resuscitation displayed a 96%, 99%, 94%, 92%, 96%, and 94% probability for mortality benefit at 1, 3, 6, 12, 18, and 24 hours, respectively, when compared with a 1:1:2 approach. Associated Bayes factors for each respective time period were 21.2, 142, 14.9, 11.4, 26.4, and 15.5, indicating 'strong' to 'decisive' supporting evidence in favor of balanced transfusions. CONCLUSION This analysis provides evidence in support that a 1:1:1 resuscitation has a high probability of mortality benefit when compared with a 1:1:2 strategy, especially at the newly defined more proximate time points during the resuscitative period. Researchers should consider using Bayesian approaches, along with more proximate end points when assessing hemorrhage-related mortality, for the analysis of future clinical trials. LEVEL OF EVIDENCE Level III/Therapeutic.

Abstract

OBJECTIVES Transfusion of a high ratio of plasma to packed red blood cells (PRBC), to treat or prevent acute traumatic coagulopathy, has been associated with survival after major trauma. However, the effect of pre-hospital plasma on patient outcomes has been inconsistent. The aim of this pilot trial was to assess the feasibility of transfusing freeze-dried plasma with red blood cells (RBC) using a randomized controlled design in an Australian aeromedical pre-hospital setting. METHODS Patients attended by Helicopter Emergency Medical Service (HEMS) paramedics with suspected critical bleeding after trauma managed with pre-hospital RBC were randomized to receive two units of freeze-dried plasma (Lyoplas N-w) or standard care (no plasma). The primary outcome was the proportion of eligible patients enrolled and provided the intervention. Secondary outcomes included preliminary data on effectiveness, including mortality censored at 24 hours and at hospital discharge, and adverse events. RESULTS During the study period of 01 June to 31 October 2022, there were 25 eligible patients, of whom 20 (80%) were enrolled in the trial and 19 (76%) received the allocated intervention. Median time from randomization to hospital arrival was 92.5 mins (IQR 68-101.5). Mortality may have been lower in the freeze-dried plasma group at 24h (RR 0.24; 95%CI: 0.03 - 1.73) and at hospital discharge (RR 0.73; 95%CI: 0.24 - 2.27). No serious adverse events related to the trial interventions were reported. CONCLUSIONS This first reported experience of freeze-dried plasma use in Australia suggests pre-hospital administration is feasible. Given longer prehospital times typically associated with HEMS attendance, there is potential clinical benefit from this intervention and rationale for a definitive trial.

Abstract

BACKGROUND Management of bleeding trauma patients is still a difficult challenge. Massive transfusion (MT) requires resources to ensure the safety and timely delivery of blood products. Early prediction of MT need may be useful to shorten the time process of blood product preparation. The primary aim of this study was to assess the accuracy of shock index to predict the need for MT in adult patients with trauma. For the same population, we also assessed the accuracy of SI to predict mortality. METHODS This systematic review and meta-analysis was performed in accordance with the PRISMA guidelines. We performed a systematic search on MEDLINE, Scopus, and Web of Science from inception to March 2022. Studies were included if they reported MT or mortality with SI recorded at arrival in the field or the emergency department. The risk of bias was assessed using the QUADAS-2. RESULTS Thirty-five studies were included in the systematic review and meta-analysis, for a total of 670,728 patients. For MT the overall sensibility was 0.68 [0.57; 0.76], the overall specificity was 0.84 [0.79; 0.88] and the AUC was 0.85 [0.81; 0.88]. Positive and Negative Likelihood Ratio (LR+; LR-) were 4.24 [3.18-5.65] and 0.39 [0.29-0.52], respectively. For mortality the overall sensibility was 0.358 [0.238; 0.498] the overall specificity 0.742 [0.656; 0.813] and the AUC 0.553 (confidence region for sensitivity given specificity: [0.4014; 0.6759]; confidence region for specificity given sensitivity: [0.4799; 0.6332]). LR+ and LR- were 1.39 [1.36-1.42] and 0.87 [0.85-0.89], respectively. CONCLUSIONS Our study demonstrated that SI may have a limited role as the sole tool to predict the need for MT in adult trauma patients. SI is not accurate to predict mortality but may have a role to identify patients with a low risk of mortality.

Abstract

BACKGROUND Whole blood (WB) transfusion received renewed interest after recent armed conflicts. The effectiveness as compared to blood component transfusion (BCT) is however still topic of debate. Therefore, this study investigated the effect of WB ± BCT as compared to BCT transfusion on survival in trauma patients with acute hemorrhage. METHODS Studies published up to the 16th of January 2023, including patients with traumatic hemorrhage comparing WB ± BCT and BCT were included in meta-analysis. Sub analyses were performed on the effectiveness of WB in the treatment of civilian or military trauma patients, patients with massive hemorrhage and on platelet (PLT):Red Blood Cell (RBC), plasma:RBC and WB:RBC ratios. Methodological quality of studies was interpreted using the Cochrane risk of bias tool. The study protocol was registered in PROSPERO under number CRD42022296900. RESULTS Random effect pooled odds ratio (OR) for 24-hours mortality in civilian and military patients treated with WB as compared to BCT was 0.72 (95% CI 0.53-0.97). In sub analysis of studies conducted in civilian setting (n = 20), early (4-hours, 6-hours and Emergency Department) and 24-hours mortality was lower in WB groups compared BCT groups: OR 0.65 (95% CI 0.44 - 0.96) and OR 0.71 (0.52 - 0.98). No difference in late mortality (28-days, 30-days, in-hospital) was found. In military settings (n = 7) there was no difference in early, 24-hours or late mortality between groups. WB groups received significant higher PLT:RBC (p = 0.030) during early treatment and significant higher PLT:RBC and Plasma:RBC ratios during 24-hours of treatment (p = 0.031 and p = 0.007). The overall risk of bias in the majority of studies was judged as serious due to serious risk on confounding and selection bias, and unclear information regarding co-interventions. CONCLUSION Civilian trauma patients with acute traumatic hemorrhage treated with WB ± BCT as compared to BCT had lower odds on early and 24-hours mortality. Additionally, WB transfusion resulted in higher plt:RBC and plasma:RBC ratios. LEVEL OF EVIDENCE Level III, systematic review and meta-analysis.

Abstract

BACKGROUND The efficacies of fresh frozen plasma and coagulation factor transfusion have been widely evaluated in trauma-induced coagulopathy management during the acute post-injury phase. However, the efficacy of red blood cell transfusion has not been adequately investigated in patients with severe trauma, and the optimal hemoglobin target level during the acute post-injury and resuscitation phases remains unclear. Therefore, this study aimed to examine whether a restrictive transfusion strategy was clinically non-inferior to a liberal transfusion strategy during the acute post-injury phase. METHODS This cluster-randomized, crossover, non-inferiority multicenter trial was conducted at 22 tertiary emergency medical institutions in Japan and included adult patients with severe trauma at risk of major bleeding. The institutions were allocated a restrictive or liberal transfusion strategy (target hemoglobin levels: 7-9 or 10-12 g/dL, respectively). The strategies were applied to patients immediately after arrival at the emergency department. The primary outcome was 28-day survival after arrival at the emergency department. Secondary outcomes included transfusion volume, complication rates, and event-free days. The non-inferiority margin was set at 3%. RESULTS The 28-day survival rates of patients in the restrictive (n = 216) and liberal (n = 195) strategy groups were 92.1% and 91.3%, respectively. The adjusted odds ratio for 28-day survival in the restrictive versus liberal strategy group was 1.02 (95% confidence interval: 0.49-2.13). Significant non-inferiority was not observed. Transfusion volumes and hemoglobin levels were lower in the restrictive strategy group than in the liberal strategy group. No between-group differences were noted in complication rates or event-free days. CONCLUSIONS Although non-inferiority of the restrictive versus liberal transfusion strategy for 28-day survival was not statistically significant, the mortality and complication rates were similar between the groups. The restrictive transfusion strategy results in a lower transfusion volume. TRIAL REGISTRATION NUMBER umin.ac.jp/ctr: UMIN000034405, registration date: 8 October 2018.

Abstract

INTRODUCTION This systematic review and meta-analysis was conducted to compare outcomes, including transfusion volume, complications, intensive care unit length of stay, and mortality for adult civilian trauma patients transfused with whole blood (WB), components (COMP), or both (WB + COMP). METHODS A systematic review and meta-analysis were conducted using studies that evaluated outcomes of transfusion of WB, COMP, or WB + COMP for adult civilian trauma patients. A search of PubMed, Embase, and Cochrane from database inception to March 3, 2022 was conducted. The search resulted in 18,400 initial articles with 16 studies remaining after the removal of duplicates and screening for inclusion and exclusion criteria. RESULTS This study identified an increased risk of 24-h mortality with COMP versus WB + COMP (relative risk: 1.40 [1.10, 1.78]) and increased transfusion volumes of red blood cells with COMP versus WB at 6 and 24 h, respectively (-2.26 [-3.82, -0.70]; -1.94 [-3.22, -0.65] units). There were no differences in the calculated rates of infections or intensive care unit length of stay between WB and COMP, respectively (relative risks: 1.35 [0.53, 3.46]; -0.91 [-2.64, 0.83]). CONCLUSIONS Transfusion with WB + COMP is associated with lower 24-h mortality versus COMP and transfusion with WB is associated with a lower volume of red blood cells transfused at both 6 and 24 h. Based on these findings, greater utilization of whole blood in civilian adult trauma resuscitation may lead to improved mortality and reduced transfusion requirements.

Abstract

IMPORTANCE It is not clear which severely injured patients with hemorrhagic shock may benefit most from a 1:1:1 vs 1:1:2 (plasma:platelets:red blood cells) resuscitation strategy. Identification of trauma molecular endotypes may reveal subgroups of patients with differential treatment response to various resuscitation strategies. OBJECTIVE To derive trauma endotypes (TEs) from molecular data and determine whether these endotypes are associated with mortality and differential treatment response to 1:1:1 vs 1:1:2 resuscitation strategies. DESIGN, SETTING, AND PARTICIPANTS This was a secondary analysis of the Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) randomized clinical trial. The study cohort included individuals with severe injury from 12 North American trauma centers. The cohort was taken from the participants in the PROPPR trial who had complete plasma biomarker data available. Study data were analyzed on August 2, 2021, to October 25, 2022. EXPOSURES TEs identified by K-means clustering of plasma biomarkers collected at hospital arrival. MAIN OUTCOMES AND MEASURES An association between TEs and 30-day mortality was tested using multivariable relative risk (RR) regression adjusting for age, sex, trauma center, mechanism of injury, and injury severity score (ISS). Differential treatment response to transfusion strategy was assessed using an RR regression model for 30-day mortality by incorporating an interaction term for the product of endotype and treatment group adjusting for age, sex, trauma center, mechanism of injury, and ISS. RESULTS A total of 478 participants (median [IQR] age, 34.5 [25-51] years; 384 male [80%]) of the 680 participants in the PROPPR trial were included in this study analysis. A 2-class model that had optimal performance in K-means clustering was found. TE-1 (n = 270) was characterized by higher plasma concentrations of inflammatory biomarkers (eg, interleukin 8 and tumor necrosis factor α) and significantly higher 30-day mortality compared with TE-2 (n = 208). There was a significant interaction between treatment arm and TE for 30-day mortality. Mortality in TE-1 was 28.6% with 1:1:2 treatment vs 32.6% with 1:1:1 treatment, whereas mortality in TE-2 was 24.5% with 1:1:2 treatment vs 7.3% with 1:1:1 treatment (P for interaction = .001). CONCLUSIONS AND RELEVANCE Results of this secondary analysis suggest that endotypes derived from plasma biomarkers in trauma patients at hospital arrival were associated with a differential response to 1:1:1 vs 1:1:2 resuscitation strategies in trauma patients with severe injury. These findings support the concept of molecular heterogeneity in critically ill trauma populations and have implications for tailoring therapy for patients at high risk for adverse outcomes.

Abstract

BACKGROUND Time to treatment matters in traumatic haemorrhage but the optimal prehospital use of blood in major trauma remains uncertain. We investigated whether use of packed red blood cells (PRBC) and lyophilised plasma (LyoPlas) was superior to use of 0·9% sodium chloride for improving tissue perfusion and reducing mortality in trauma-related haemorrhagic shock. METHODS Resuscitation with pre-hospital blood products (RePHILL) is a multicentre, allocation concealed, open-label, parallel group, randomised, controlled, phase 3 trial done in four civilian prehospital critical care services in the UK. Adults (age ≥16 years) with trauma-related haemorrhagic shock and hypotension (defined as systolic blood pressure <90 mm Hg or absence of palpable radial pulse) were assessed for eligibility by prehospital critial care teams. Eligible participants were randomly assigned to receive either up to two units each of PRBC and LyoPlas or up to 1 L of 0·9% sodium chloride administered through the intravenous or intraosseous route. Sealed treatment packs which were identical in external appearance, containing PRBC-LyoPlas or 0·9% sodium chloride were prepared by blood banks and issued to participating sites according to a randomisation schedule prepared by the co-ordinating centre (1:1 ratio, stratified by site). The primary outcome was a composite of episode mortality or impaired lactate clearance, or both, measured in the intention-to-treat population. This study is completed and registered with ISRCTN.com, ISRCTN62326938. FINDINGS From Nov 29, 2016 to Jan 2, 2021, prehospital critical care teams randomly assigned 432 participants to PRBC-LyoPlas (n=209) or to 0·9% sodium chloride (n=223). Trial recruitment was stopped before it achieved the intended sample size of 490 participants due to disruption caused by the COVID-19 pandemic. The median follow-up was 9 days (IQR 1 to 34) for participants in the PRBC-LyoPlas group and 7 days (0 to 31) for people in the 0·9% sodium chloride group. Participants were mostly white (62%) and male (82%), had a median age of 38 years (IQR 26 to 58), and were mostly involved in a road traffic collision (62%) with severe injuries (median injury severity score 36, IQR 25 to 50). Before randomisation, participants had received on average 430 mL crystalloid fluids and tranexamic acid (90%). The composite primary outcome occurred in 128 (64%) of 199 participants randomly assigned to PRBC-LyoPlas and 136 (65%) of 210 randomly assigned to 0·9% sodium chloride (adjusted risk difference -0·025% [95% CI -9·0 to 9·0], p=0·996). The rates of transfusion-related complications in the first 24 h after ED arrival were similar across treatment groups (PRBC-LyoPlas 11 [7%] of 148 compared with 0·9% sodium chloride nine [7%] of 137, adjusted relative risk 1·05 [95% CI 0·46-2·42]). Serious adverse events included acute respiratory distress syndrome in nine (6%) of 142 patients in the PRBC-LyoPlas group and three (2%) of 130 in 0·9% sodium chloride group, and two other unexpected serious adverse events, one in the PRBC-LyoPlas (cerebral infarct) and one in the 0·9% sodium chloride group (abnormal liver function test). There were no treatment-related deaths. INTERPRETATION The trial did not show that prehospital PRBC-LyoPlas resuscitation was superior to 0·9% sodium chloride for adult patients with trauma related haemorrhagic shock. Further research is required to identify the characteristics of patients who might benefit from prehospital transfusion and to identify the optimal outcomes for transfusion trials in major trauma. The decision to commit to routine prehospital transfusion will require careful consideration by all stakeholders. FUNDING National Institute for Health Research Efficacy and Mechanism Evaluation.

Abstract

Our study aims to provide a synthesis of the best available evidence on the hemoglobin (hgb) red blood cell (RBC) transfusion thresholds in adult traumatic brain injury (TBI) patients, as well as describing the risk factors and outcomes associated with RBC transfusion in this population. A systematic review and meta-analysis was conducted using PubMed, Google Scholar, and Web of Science electronic databases according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to assess articles discussing RBC transfusion thresholds and describe complications secondary to transfusion in adult TBI patients in the perioperative period. Fifteen articles met search criteria and were reviewed for analysis. Compared to non-transfused, TBI patients who received transfusion tended to be primarily male patients with worse Injury Severity Score (ISS) and Glasgow Coma Scale. Further, the meta-analysis corroborated that transfused TBI patients are older (p = 0.04), have worse ISS scores (p = 0.001), receive more units of RBCs (p = 0.02), and have both higher mortality (p < 0.001) and complication rates (p < 0.0001). There were no differences identified in rates of hypertension, diabetes mellitus, and Abbreviated Injury Scale scores. Additionally, whereas many studies support restrictive (hgb <7 g/dL) transfusion thresholds over liberal (hgb <10 g/dL), our meta-analysis revealed no significant difference in mortality between those thresholds (p = 0.79). Current Class B/C level III evidence predominantly recommends against a liberal transfusion threshold of 10 g/dL for TBI patients (Class B/C level III), but our meta-analysis found no difference in survival between groups. There is evidence suggesting that an intermediate threshold between 7 and 9 g/dL, reflecting the physiological oxygen needs of cerebral tissue, may be worth exploring.

Abstract

BACKGROUND We sought to characterize if prehospital transfer origin from the scene of injury (SCENE) or from a referral emergency department (REF) alters the survival benefit attributable to prehospital plasma resuscitation in patients at risk of hemorrhagic shock. METHODS We performed a secondary analysis of data from a recently completed prehospital plasma clinical trial. All of the enrolled patients from either the SCENE or REF groups were included. The demographics, injury characteristics, shock severity and resuscitation needs were compared. The primary outcome was a 30-day mortality. Kaplan-Meier analysis and Cox-hazard regression were used to characterize the independent survival benefits of prehospital plasma for transport origin groups. RESULTS Of the 501 enrolled patients, the REF group patients (n = 111) accounted for 22% with the remaining (n = 390) originating from the scene. The SCENE group patients had higher injury severity and were more likely intubated prehospital. The REF group patients had longer prehospital times and received greater prehospital crystalloid and blood products. Kaplan-Meier analysis revealed a significant 30-day survival benefit associated with prehospital plasma in the SCENE group (P < .01) with no difference found in the REF group patients (P = .36). The Cox-regression verified after controlling for relevant confounders that prehospital plasma was independently associated with a 30-day survival in the SCENE group patients (hazard ratio 0.59; 95% confidence interval 0.39-0.89; P = .01) with no significant relationship found in the REF group patients (hazard ratio 1.03, 95% confidence interval 0.4-3.0). CONCLUSION Important differences across the SCENE and REF cohorts exist that are essential to understand when planning prehospital studies. Prehospital plasma is associated with a survival benefit primarily in SCENE group patients. The results are exploratory but suggest transfer origin may be an important determinant of prehospital plasma benefit.