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

BACKGROUND Complement activation after trauma promotes hemostasis but is associated with increased morbidity and mortality. However, the specific pathways and downstream mediators remain unclear. Recently the anaphylatoxin C4a has been shown to bind to thrombin receptors. While plasma-based resuscitation has been shown to modify the endotheliopathy of trauma, it may provide complement zymogens that fuel ongoing inflammatory cascades. We sought to characterize the activation of complement after injury and the effect of fresh frozen plasma (FFP) on this inflammatory response. We hypothesized that trauma induces C4 activation, which is associated with worse outcomes and influenced by FFP resuscitation. METHODS Blood was collected from injured patients at a single Level I Trauma Center enrolled in the COMBAT randomized clinical trial. Proteomic analyses were performed through targeted liquid chromatography coupled with mass spectrometry. For the present observational study, concentrations of complement proteins were analyzed at multiple time points, compared between treatment groups, and correlated with outcomes. RESULTS C4 activation occurred over the first six hours post-injury with peak activation 6-24 hours. Tissue hypoperfusion, defined as base deficit >10 mEq/L, and requirement for massive transfusion were associated with greater C4 activation. C4 activation was associated with mortality, multiple organ failure, and longer ventilator requirement. Additionally, temporal trends of C1q, factor B, and C3 by outcome groups support the prevailing theory of primary classical pathway activation with alternative pathway amplification. Resuscitation with FFP over the first six hours was associated with increased C4 activation at 12 and 24 hours. CONCLUSIONS C4 activation has an important inflammatory role post-injury, and FFP has the potential to augment this complement activation during resuscitation. EVIDENCE Level III, Prognostic/Epidemiological.

Abstract

OBJECTIVES Determine associations between biomarkers of endotheliopathy, 24-hour fibrinolysis phenotypes and clinical outcomes after trauma. BACKGROUND The vascular endothelium is a critical regulator of hemostasis and organ function. The relationship between markers of endotheliopathy and fibrinolysis following trauma has not been evaluated. METHODS We performed a secondary analysis of prospectively collected biomarker data in the Pragmatic Randomized Optimal Platelet and Plasma Ratios (PROPPR) randomized controlled trial. We stratified subjects by 24-hour thromboelastography (TEG) percent clot lysis (LY30) and plasma D-dimer (DD) levels and evaluated differences in endotheliopathy biomarkers and clinical outcomes between subjects with one of four 24-hour fibrinolysis phenotypes: LY30 0.9-2.9% (LY30(norm)), LY30 >2.9% (LY30(high)), LY30 <0.9% and low DD (LY30(low)+DD(low)), and LY30 <0.9% and high DD (LY30(low)+DD(high)). RESULTS The analysis included 168 subjects with LY30(norm), 32 with LY30(high), 147 with LY30(low)+DD(low) and 124 with LY30(low)+DD(high). LY30(low)+DD(high) subjects had greater injury severity and a higher incidence of severe head injury, multiorgan failure (MOF), and mortality than the other phenotypes. All endotheliopathy biomarkers were significantly higher in the LY30(low)+DD(high) phenotype. Adjusting for injury severity, mechanism and head trauma, 24-hour angiopoietin-2 and soluble thrombomodulin were independently associated with the LY30(low)+DD(high) phenotype. Both endothelial biomarkers were discriminating for MOF. Subjects with thrombomodulin level >9.5 ng/mL and angiopoietin-2 level >3.6 ng/mL accounted for 64% of subjects who developed MOF. CONCLUSIONS In a multicenter trauma cohort, subjects with a fibrinolysis phenotype characterized by low TEG lysis and elevated DD 24 hours after injury have significantly worse endotheliopathy and clinical outcomes. Our findings support mechanistic evaluations of the role of the endothelium in fibrinolysis dysregulation that may drive late-stage organ injury.

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.

Abstract

BACKGROUND Optimal management for trauma-induced coagulopathy (TIC) is a clinical conundrum. In conjunction with the transfusion of fresh-frozen plasma (FFP), additional administration of prothrombin complex concentrate (PCC) was proposed to bring about further coagulative benefit. However, investigations evaluating the efficacy as well as corresponding side effects were scarce and inconsistent. The aim of this study was to systematically review current literature and to perform a meta-analysis comparing FFP+PCC with FFP alone. METHODS Web search followed by manual interrogation was performed to identify relevant literatures fulfilling the following criteria, subjects as TIC patients taking no baseline anticoagulants, without underlying coagulative disorders, and reported clinical consequences. Those comparing FFP alone with PCC alone were excluded. Comprehensive Meta-analysis software was utilized, and statistical results were delineated with odd ratio (OR), mean difference (MD), and 95% confidence interval (CI). I(2) was calculated to determine heterogeneity. The primary endpoint was set as all-cause mortality, while the secondary endpoint consisted of international normalized ratio (INR) correction, transfusion of blood product, and thrombosis rate. RESULTS One hundred and sixty-four articles were included for preliminary evaluation, 3 of which were qualified for meta-analysis. A total of 840 subjects were pooled for assessment. Minimal heterogeneity was present in the comparisons (I(2) < 25%). In the PCC + FFP cohort, reduced mortality rate was observed (OR: 0.631; 95% CI: 0.450-0.884, p = 0.007) after pooling. Meanwhile, INR correction time was shorter under PCC + FFP (MD: -608.300 mins, p < 0.001), whilst the rate showed no difference (p = 0.230). The PCC + FFP group is less likely to mandate transfusion of packed red blood cells (p < 0.001) and plasma (p < 0.001), but not platelet (p = 0.615). The incidence of deep vein thrombosis was comparable in the two groups (p = 0.460). CONCLUSIONS Compared with FFP only, PCC + FFP demonstrated better survival rate, favorable clinical recovery and no elevation of thromboembolism events after TIC.

Abstract

BACKGROUND Platelet transfusion during major hemorrhage is important and often embedded in massive transfusion protocols. However, the optimal ratio of platelets to erythrocytes (platelet rich plasma (PLT) :RBC ratio) remains unclear. We hypothesized that high PLT:RBC ratios, as compared to low PLT:RBC ratios, are associated with improved survival in patients requiring massive transfusion. METHODS Four databases (Pubmed, CINAHL, EMBASE and Cochrane) were systematically screened for literature published up to January 21, 2021 to determine the effect of PLT:RBC ratio on the primary outcome measure mortality at 1-6 and 24 hours and at 28-30 days. Studies comparing various PLT:RBC ratios were included in meta-analysis. Secondary outcomes included intensive care unit length of stay and in-hospital length of stay and total blood component use. The study protocol was registered in PROSPERO under number CRD42020165648. RESULTS The search identified a total of 8903 records. After removing duplicates second screening of title, abstract and full text a total of 59 articles were included in the analysis. Of these articles 12 were included in meta-analysis. Mortality at 1-6, 24-hours and 28-30 days was significantly lower for high PLT:RBC ratios as compared to low PLT:RBC ratios. CONCLUSIONS Higher PLT:RBC ratios are associated with significantly lower 1-6 hours, 24 hours, 28-30 days mortality as compared to lower PLT:RBC ratios. The optimal PLT:RBC ratio for massive transfusion in trauma patients is approximately 1:1. LEVEL OF EVIDENCE Systematic review and meta-analysis, therapeutic level III.

Abstract

BACKGROUND Hybrid operating theatres (OT) allow for simultaneous interventional radiology and operative procedures, serving as a one-stop facility for the treatment of severely injured patients. Several countries have adopted the use of the hybrid OT however their clinical impact in improving efficiency and quality of care remains unclear. This study systematically reviews the clinical impact of the hybrid OT for treatment of the severely injured. METHODS A literature review of the PubMed, Embase and Cochrane databases was performed to identify all published articles in English, from 1st January 2000 to 31st December 2020, reporting on the impact of a hybrid OT for severe trauma. Articles were also reviewed for references of interest. RESULTS Five studies reporting the clinical impact of the hybrid OT, in a total of 951 patients, were shortlisted. All were cohort studies that compared patient outcomes in the hybrid OT versus a conventional group. Out of 3 studies that assessed timeliness to intervention, one reported shorter time associated with the hybrid OT, while the other two reported no difference. Mortality outcomes were reported in 4 studies and showed no significant difference associated with treatment in the hybrid OT. Two studies revealed shorter total procedure times associated with the hybrid OT. Two out of 3 studies that evaluated blood transfusion requirements reported decreased transfusion rates in the hybrid OT group. Only 1 study examined complication rates and demonstrated morbidity benefits associated with the hybrid OT. CONCLUSION Establishment of a hybrid OT requires a significant capital investment as well as a highly functioning multi-disciplinary team. The cost-benefit ratio remains unclear. Future studies, preferably in the form of clinical trials, are required to evaluate its usefulness in improving timeliness to definitive haemorrhage control and outcomes in severe trauma.

Abstract

BACKGROUND Several factors can influence the outcome of severe head injuries including the patient's hemoglobin levels. There has often been a dilemma regarding levels of hemoglobin at which red cell blood transfusion (RCBT) should be performed. OBJECTIVE To systematically review the literature to determine the usefulness of management protocols that have hemoglobin levels <10 g/dL vs <7 g/dL as an RCBT criterion. METHODS Following the PRISMA statement, the search was constructed using terms and descriptors of the Medical Subject Heading (MeSH), combined with Boolean operators. Full text of these articles was studied, and outcome measures at 3-6 months were considered for patients who were given a RCBT at <10 g/dL or at 7 g/dL hemoglobin levels. RESULTS A total of 4 articles were found suitable for inclusion in the meta-analysis. RCBT below 7 g/dL was not associated with an increased risk of mortality as compared to RCBT using the value of less than 10 g/dL. RCBT at lower levels of hemoglobin was also not associated with a poor neurological outcome (GOS 4-5) but rather RCBT at lower levels lead to better outcomes (GOS 1-3) and the association was significant. CONCLUSION Allogenic RCBT was associated with poorer neurological outcomes, within a wide range of reported differences in the hemoglobin threshold to decide for RCBT in TBI patients. Restrictive RCBT strategy may be useful in moderate to severe TBI cases although the risk of anemia-induced cerebral injury needs further investigation regarding the risks and complications inherent to RCBT.

Abstract

BACKGROUND Patients with hemorrhagic shock from trauma often require balanced blood product transfusion with red blood cells, plasma, and platelets. Resuscitation with whole blood resuscitation is becoming a common practice. We performed a systematic review and meta-analysis of studies comparing whole blood transfusion with balanced component therapy in patients suffering from traumatic hemorrhagic shock. METHODS We searched MEDLINE Ovid, EMBASE, and the Cochrane Library for human studies comparing whole blood with component blood therapy published from January 2007 to June 2019. We included studies from both civilian and military settings and that reported 24-hour, in-hospital, or 30-day mortality. We followed the Preferred Reporting Items in Systematic Reviews and Meta-Analyses (PRISMA) guidelines, assessing study quality, publication bias, and heterogeneity. We used meta-analytic models to determine the associations (odds ratio [OR] with 95% confidence interval [CI]) between whole blood transfusion and (1) 24-hour mortality, and (2) in-hospital or 30-day mortality. RESULTS A total of 1759 identified studies, 12 (reporting on n = 8431 patients) met inclusion criteria. There was heterogeneity in the design, setting, interventions, and outcomes of the studies. On meta-analysis, whole blood transfusion was not associated with 24-hour mortality (OR = 0.83; 95% CI = 0.56-1.24) or in-hospital/30-day mortality (OR = 0.79; 95% CI = 0.48-1.31). CONCLUSION In this systematic review and meta-analysis, compared with conventional component transfusion, whole blood was not associated with 24-hour or in-hospital mortality. However, there were important limitations with and heterogeneity among the primary studies. Additional study is needed to determine the effectiveness of whole blood.

Abstract

BACKGROUND Our main objective was to review the literature to answer the following questions regarding pediatric massive transfusion (PMT) protocols: 1) How is PMT defined? 2) Which blood product ratios have been investigated and what is their effect on outcomes? 3) What evidence exists regarding PMT outcomes? METHODS The PRISMA guidelines were used. We searched PubMed, Google Scholar, Cochrane Library, EMBASE, Wiley Online Library, and Ovid. Articles were screened for inclusion based on relevance to PMT. Articles were assessed for study design, presence of established/tested PMT, PMT definition, PMT activation criteria, and Transfusion Ratios, for final determination of article inclusion. RESULTS Our search produced 3213 articles with 33 included for final review. Existing definitions of PMT are based on volume administered/kg but vary in timeframe criteria (over 4 hr vs 24 hr). Some studies have investigated "high" balanced transfusion ratios as seen in adults (1:1 FFP:pRBC) with a few showing statistically significant improvement in pediatric mortality vs lower ratios. PMT protocol implementation has not been shown to consistently reduce pediatric trauma mortality across multiple centers. However, other operational aspects such as reduced time to first transfusion are apparent benefits. CONCLUSIONS There is poor consensus over the definition of PMT. Definitions that involve early recognition have the most promise for practice and future studies. Evidence supporting an optimal blood product ratio in PMT is also lacking but trends towards supporting balanced approaches. Implementation of PMT protocols have been limited in showing significant improvement of overall pediatric trauma mortality but may reduce associated morbidity.