Leukotriene B4-Neutrophil Elastase Axis Drives Neutrophil Reverse Transendothelial Cell Migration In Vivo.

Breaching endothelial cells (ECs) is a decisive step in the migration of leukocytes from the vascular lumen to the extravascular tissue, but fundamental aspects of this response remain largely unknown. We have previously shown that neutrophils can exhibit abluminal-to-luminal migration through EC junctions within mouse cremasteric venules and that this response is elicited following reduced expression and/or functionality of the EC junctional adhesion molecule-C (JAM-C). Here we demonstrate that the lipid chemoattractant leukotriene B4 (LTB4) was efficacious at causing loss of venular JAM-C and promoting neutrophil reverse transendothelial cell migration (rTEM) in vivo. Local proteolytic cleavage of EC JAM-C by neutrophil elastase (NE) drove this cascade of events as supported by presentation of NE to JAM-C via the neutrophil adhesion molecule Mac-1. The results identify local LTB4-NE axis as a promoter of neutrophil rTEM and provide evidence that this pathway can propagate a local sterile inflammatory response to become systemic.

Transforming research to improve therapies for trauma in the twenty-first century.

Improvements have been made in optimizing initial care of trauma patients, both in prehospital systems as well as in the emergency department, and these have also favorably affected longer term outcomes. However, as specific treatments for bleeding are largely lacking, many patients continue to die from hemorrhage. Also, major knowledge gaps remain on the impact of tissue injury on the host immune and coagulation response, which hampers the development of interventions to treat or prevent organ failure, thrombosis, infections or other complications of trauma. Thereby, trauma remains a challenge for intensivists. This review describes the most pressing research questions in trauma, as well as new approaches to trauma research, with the aim to bring improved therapies to the bedside within the twenty-first century.

Prothrombin complex concentrate (PCC) for treatment of trauma-induced coagulopathy: systematic review and meta-analyses.

BACKGROUND: Trauma-induced coagulopathy (TIC) is common in trauma patients with major hemorrhage. Prothrombin complex concentrate (PCC) is used as a potential treatment for the correction of TIC, but the efficacy, timing, and evidence to support its use in injured patients with hemorrhage are unclear. METHODS: A systematic search of published studies was performed on MEDLINE and EMBASE databases using standardized search equations. Ongoing studies were identified using clinicaltrials.gov. Studies investigating the use of PCC to treat TIC (on its own or in combination with other treatments) in adult major trauma patients were included. Studies involving pediatric patients, studies of only traumatic brain injury (TBI), and studies involving only anticoagulated patients were excluded. Primary outcomes were in-hospital mortality and venous thromboembolism (VTE). Pooled effects of PCC use were reported using random-effects model meta-analyses. Risk of bias was assessed for each study, and we used the Grading of Recommendations Assessment, Development, and Evaluation to assess the quality of evidence. RESULTS: After removing duplicates, 1745 reports were screened and nine observational studies and one randomized controlled trial (RCT) were included, with a total of 1150 patients receiving PCC. Most studies used 4-factor-PCC with a dose of 20-30U/Kg. Among observational studies, co-interventions included whole blood (n = 1), fibrinogen concentrate (n = 2), or fresh frozen plasma (n = 4). Outcomes were inconsistently reported across studies with wide variation in both measurements and time points. The eight observational studies included reported mortality with a pooled odds ratio of 0.97 [95% CI 0.56-1.69], and five reported deep venous thrombosis (DVT) with a pooled OR of 0.83 [95% CI 0.44-1.57]. When pooling the observational studies and the RCT, the OR for mortality and DVT was 0.94 [95% CI 0.60-1.45] and 1.00 [95% CI 0.64-1.55] respectively. CONCLUSIONS: Among published studies of TIC, PCCs did not significantly reduce mortality, nor did they increase the risk of VTE. However, the potential thrombotic risk remains a concern that should be addressed in future studies. Several RCTs are currently ongoing to further explore the efficacy and safety of PCC.

Association of red blood cells and plasma transfusion versus red blood cell transfusion only with survival for treatment of major traumatic hemorrhage in prehospital setting in England: a multicenter study.

BACKGROUND: In-hospital acute resuscitation in trauma has evolved toward early and balanced transfusion resuscitation with red blood cells (RBC) and plasma being transfused in equal ratios. Being able to deliver this ratio in prehospital environments is a challenge. A combined component, like leukocyte-depleted red cell and plasma (RCP), could facilitate early prehospital resuscitation with RBC and plasma, while at the same time improving logistics for the team. However, there is limited evidence on the clinical benefits of RCP. OBJECTIVE: To compare prehospital transfusion of combined RCP versus RBC alone or RBC and plasma separately (RBC + P) on mortality in trauma bleeding patients. METHODS: Data were collected prospectively on patients who received prehospital transfusion (RBC + thawed plasma/Lyoplas or RCP) for traumatic hemorrhage from six prehospital services in England (2018-2020). Retrospective data on patients who transfused RBC from 2015 to 2018 were included for comparison. The association between transfusion arms and 24-h and 30-day mortality, adjusting for age, injury mechanism, age, prehospital heart rate and blood pressure, was evaluated using generalized estimating equations. RESULTS: Out of 970 recruited patients, 909 fulfilled the study criteria (RBC + P = 391, RCP = 295, RBC = 223). RBC + P patients were older (mean age 42 vs 35 years for RCP and RBC), and 80% had a blunt injury (RCP = 52%, RBC = 56%). RCP and RBC + P were associated with lower odds of death at 24-h, compared to RBC alone (adjusted odds ratio [aOR] 0.69 [95%CI: 0.52; 0.92] and 0.60 [95%CI: 0.32; 1.13], respectively). The lower odds of death for RBC + P and RCP vs RBC were driven by penetrating injury (aOR 0.22 [95%CI: 0.10; 0.53] and 0.39 [95%CI: 0.20; 0.76], respectively). There was no association between RCP or RBC + P with 30-day survival vs RBC. CONCLUSION: Prehospital plasma transfusion for penetrating injury was associated with lower odds of death at 24-h compared to RBC alone. Large trials are needed to confirm these findings.

The CRYOSTAT2 trial: The rationale and study protocol for a multi-Centre, randomised, controlled trial evaluating the effects of early high-dose cryoprecipitate in adult patients with major trauma haemorrhage requiring major haemorrhage protocol activation.

OBJECTIVES: To describe the protocol for a multinational randomised, parallel, superiority trial, in which patients were randomised to receive early high-dose cryoprecipitate in addition to standard major haemorrhage protocol (MHP), or Standard MHP alone. BACKGROUND: Blood transfusion support for trauma-related major bleeding includes red cells, plasma and platelets. The role of concentrated sources of fibrinogen is less clear and has not been evaluated in large clinical trials. Fibrinogen is a key pro-coagulant factor that is essential for stable clot formation. A pilot trial had demonstrated that it was feasible to deliver cryoprecipitate as a source of fibrinogen within 90 min of admission. METHODS: Randomisation was via opaque sealed envelopes held securely in participating Emergency Departments or transfusion laboratories. Early cryoprecipitate, provided as 3 pools (equivalent to 15 single units of cryoprecipitate or 6 g fibrinogen supplementation), was transfused as rapidly as possible, and started within 90 min of admission. Participants in both arms received standard treatment defined in the receiving hospital MHP. The primary outcome measure was all-cause mortality at 28 days. Symptomatic thrombotic events including venous thromboembolism and arterial thrombotic events (myocardial infarction, stroke) were collected from randomisation up to day 28 or discharge from hospital. EQ5D-5Land Glasgow Outcome Score were completed at discharge and 6 months. All analyses will be performed on an intention to treat basis, with per protocol sensitivity analysis. RESULTS: The trial opened for recruitment in June 2017 and the final patient completed follow-up in May 2022. DISCUSSION: This trial will provide firmer evidence to evaluate the effectiveness and cost-effectiveness of early high-dose cryoprecipitate alongside the standard MHP in major traumatic haemorrhage.

Early and Empirical High-Dose Cryoprecipitate for Hemorrhage After Traumatic Injury: The CRYOSTAT-2 Randomized Clinical Trial.

Importance: Critical bleeding is associated with a high mortality rate in patients with trauma. Hemorrhage is exacerbated by a complex derangement of coagulation, including an acute fibrinogen deficiency. Management is fibrinogen replacement with cryoprecipitate transfusions or fibrinogen concentrate, usually administered relatively late during hemorrhage. Objective: To assess whether survival could be improved by administering an early and empirical high dose of cryoprecipitate to all patients with trauma and bleeding that required activation of a major hemorrhage protocol. Design, Setting, and Participants: CRYOSTAT-2 was an interventional, randomized, open-label, parallel-group controlled, international, multicenter study. Patients were enrolled at 26 UK and US major trauma centers from August 2017 to November 2021. Eligible patients were injured adults requiring activation of the hospital's major hemorrhage protocol with evidence of active hemorrhage, systolic blood pressure less than 90 mm Hg at any time, and receiving at least 1 U of a blood component transfusion. Intervention: Patients were randomly assigned (in a 1:1 ratio) to receive standard care, which was the local major hemorrhage protocol (reviewed for guideline adherence), or cryoprecipitate, in which 3 pools of cryoprecipitate (6-g fibrinogen equivalent) were to be administered in addition to standard care within 90 minutes of randomization and 3 hours of injury. Main Outcomes and Measures: The primary outcome was all-cause mortality at 28 days in the intention-to-treat population. Results: Among 1604 eligible patients, 799 were randomized to the cryoprecipitate group and 805 to the standard care group. Missing primary outcome data occurred in 73 patients (principally due to withdrawal of consent) and 1531 (95%) were included in the primary analysis population. The median (IQR) age of participants was 39 (26-55) years, 1251 (79%) were men, median (IQR) Injury Severity Score was 29 (18-43), 36% had penetrating injury, and 33% had systolic blood pressure less than 90 mm Hg at hospital arrival. All-cause 28-day mortality in the intention-to-treat population was 26.1% in the standard care group vs 25.3% in the cryoprecipitate group (odds ratio, 0.96 [95% CI, 0.75-1.23]; P = .74). There was no difference in safety outcomes or incidence of thrombotic events in the standard care vs cryoprecipitate group (12.9% vs 12.7%). Conclusions and Relevance: Among patients with trauma and bleeding who required activation of a major hemorrhage protocol, the addition of early and empirical high-dose cryoprecipitate to standard care did not improve all cause 28-day mortality. Trial Registration: ClinicalTrials.gov Identifier: NCT04704869; ISRCTN Identifier: ISRCTN14998314.

Emergency Department Resuscitative Endovascular Balloon Occlusion of the Aorta in Trauma Patients With Exsanguinating Hemorrhage: The UK-REBOA Randomized Clinical Trial.

Importance: Bleeding is the most common cause of preventable death after trauma. Objective: To determine the effectiveness of resuscitative endovascular balloon occlusion of the aorta (REBOA) when used in the emergency department along with standard care vs standard care alone on mortality in trauma patients with exsanguinating hemorrhage. Design, Setting, and Participants: Pragmatic, bayesian, randomized clinical trial conducted at 16 major trauma centers in the UK. Patients aged 16 years or older with exsanguinating hemorrhage were enrolled between October 2017 and March 2022 and followed up for 90 days. Intervention: Patients were randomly assigned (1:1 allocation) to a strategy that included REBOA and standard care (n = 46) or standard care alone (n = 44). Main Outcomes and Measures: The primary outcome was all-cause mortality at 90 days. Ten secondary outcomes included mortality at 6 months, while in the hospital, and within 24 hours, 6 hours, or 3 hours; the need for definitive hemorrhage control procedures; time to commencement of definitive hemorrhage control procedures; complications; length of stay; blood product use; and cause of death. Results: Of the 90 patients (median age, 41 years [IQR, 31-59 years]; 62 [69%] were male; and the median Injury Severity Score was 41 [IQR, 29-50]) randomized, 89 were included in the primary outcome analysis because 1 patient in the standard care alone group declined to provide consent for continued participation and data collection 4 days after enrollment. At 90 days, 25 of 46 patients (54%) had experienced all-cause mortality in the REBOA and standard care group vs 18 of 43 patients (42%) in the standard care alone group (odds ratio [OR], 1.58 [95% credible interval, 0.72-3.52]; posterior probability of an OR >1 [indicating increased odds of death with REBOA], 86.9%). Among the 10 secondary outcomes, the ORs for mortality and the posterior probabilities of an OR greater than 1 for 6-month, in-hospital, and 24-, 6-, or 3-hour mortality were all increased in the REBOA and standard care group, and the ORs were increased with earlier mortality end points. There were more deaths due to bleeding in the REBOA and standard care group (8 of 25 patients [32%]) than in standard care alone group (3 of 18 patients [17%]), and most occurred within 24 hours. Conclusions and Relevance: In trauma patients with exsanguinating hemorrhage, a strategy of REBOA and standard care in the emergency department does not reduce, and may increase, mortality compared with standard care alone. Trial Registration: isrctn.org Identifier: ISRCTN16184981.

Temporal Transitions in Fibrinolysis after Trauma: Adverse Outcome Is Principally Related to Late Hypofibrinolysis.

BACKGROUND: The relationship between late clinical outcomes after injury and early dynamic changes between fibrinolytic states is not fully understood. The authors hypothesized that temporal transitions in fibrinolysis states using rotational thromboelastometry (ROTEM) would aid stratification of adverse late clinical outcomes and improve understanding of how tranexamic acid modulates the fibrinolytic response and impacts mortality. METHODS: The authors conducted a secondary analysis of previously collected data from trauma patients enrolled into an ongoing prospective cohort study (International Standard Randomised Controlled Trial Number [ISRCTN] 12962642) at a major trauma center in the United Kingdom. ROTEM was performed on admission and at 24 h with patients retrospectively grouped into three fibrinolysis categories: tissue factor-activated ROTEM maximum lysis of less than 5% (low); tissue factor-activated ROTEM maximum lysis of 5 to 15% (normal); or tissue factor-activated ROTEM maximum lysis of more than 15% (high). Primary outcomes were multiorgan dysfunction syndrome and 28-day mortality. RESULTS: Seven-hundred thirty-one patients were included: 299 (41%) were treated with tranexamic acid and 432 (59%) were untreated. Two different cohorts with low-maximum lysis at 24 h were identified: (1) severe brain injury and (2) admission shock and hemorrhage. Multiple organ dysfunction syndrome was greatest in those with low-maximum lysis on admission and at 24 h, and late mortality was four times higher than in patients who remained normal during the first 24 h (7 of 42 [17%] vs. 9 of 223 [4%]; P = 0.029). Patients that transitioned to or remained in low-maximum lysis had increased odds of organ dysfunction (5.43 [95% CI, 1.43 to 20.61] and 4.85 [95% CI, 1.83 to 12.83], respectively). Tranexamic acid abolished ROTEM hyperfibrinolysis (high) on admission, increased the frequency of persistent low-maximum lysis (67 of 195 [34%]) vs. 8 of 79 [10%]; P = 0.002), and was associated with reduced early mortality (28 of 195 [14%] vs. 23 of 79 [29%]; P = 0.015). No increase in late deaths, regardless of fibrinolysis transition patterns, was observed. CONCLUSIONS: Adverse late outcomes are more closely related to 24-h maximum lysis, irrespective of admission levels. Tranexamic acid alters early fibrinolysis transition patterns, but late mortality in patients with low-maximum lysis at 24 h is not increased.

Coagulopathy Underlying Rotational Thromboelastometry Derangements in Trauma Patients: A Prospective Observational Multicenter Study.

BACKGROUND: Viscoelastic hemostatic assays such as rotational thromboelastometry (ROTEM) are used to guide treatment of trauma induced coagulopathy. The authors hypothesized that ROTEM derangements reflect specific coagulation factor deficiencies after trauma. METHODS: This was a secondary analysis of a prospective cohort study in six European trauma centers in patients presenting with full trauma team activation. Patients with dilutional coagulopathy and patients on anticoagulants were excluded. Blood was drawn on arrival for measurement of ROTEM, coagulation factor levels, and markers of fibrinolysis. ROTEM cutoff values to define hypocoagulability were as follows: EXTEM clotting time greater than 80 s, EXTEM clot amplitude at 5 min less than 40 mm, EXTEM lysis index at 30 min less than 85%, FIBTEM clot amplitude at 5 min less than 10 mm, and FIBTEM lysis index at 30 min less than 85%. Based on these values, patients were divided into seven deranged ROTEM profiles and compared to the reference group (ROTEM values within reference range). The primary endpoint was coagulation factors levels and fibrinolysis. RESULTS: Of 1,828 patients, 732 (40%) had ROTEM derangements, most often consisting of a combined decrease in EXTEM and FIBTEM clot amplitude at 5 min, that was present in 217 (11.9%) patients. While an isolated EXTEM clotting time greater than 80 s had no impact on mortality, all other ROTEM derangements were associated with increased mortality. Also, coagulation factor levels in this group were similar to those of patients with a normal ROTEM. Of coagulation factors, a decrease was most apparent for fibrinogen (with a nadir of 0.78 g/l) and for factor V levels (with a nadir of 22.8%). In addition, increased fibrinolysis can be present when the lysis index at 30 min is normal but EXTEM and FIBTEM clot amplitude at 5 min is decreased. CONCLUSIONS: Coagulation factor levels and mortality in the group with an isolated clotting time prolongation are similar to those of patients with a normal ROTEM. Other ROTEM derangements are associated with mortality and reflect a depletion of fibrinogen and factor V. Increased fibrinolysis can be present when the lysis index after 30 min is normal.

Embracing uncertainty in mass casualty incidents.

Uncertainty is the defining state of the first minutes and hours of a mass casualty event, yet decisions must be taken and actions must happen before the picture is complete. To move forwards in face of uncertainty, we must acknowledge that there will be insufficient information for us to be comfortable in our decisions and actions. We discuss here a range of solutions that allow us to tolerate, even flourish, in the midst of uncertainty.

Mass casualty medicine: time for a 21st century refresh.

Mass casualty events are on the rise globally, as we face increasing pressures from scarcity of resources, population growth, systemic inequalities, geopolitical instabilities, and polarised discourse. Although they are rare events for an individual practitioner, they are going to happen to someone, somewhere, this week, this month, this year. And whilst they are often the last consideration for healthcare systems under constant pressures from daily routine work, individuals, departments, hospitals, and systems have to step up effectively in times of crisis. Failure to do so can lead to suboptimal outcomes for casualties, and even perceived failures can have crippling consequences on staff, families, and communities for years.

Learning from terrorist mass casualty incidents: a global survey.

BACKGROUND: Reports published directly after terrorist mass casualty incidents frequently fail to capture difficulties that may have been encountered. An anonymised consensus-based platform may enable discussion and collaboration on the challenges faced. Our aim was to identify where to focus improvement for future responses. METHODS: We conducted a mixed methods study by email of clinicians' experiences of leading during terrorist mass casualty incidents. An initial survey identified features that worked well, or failed to, during terrorist mass casualty incidents plus ongoing challenges and changes that were implemented as a result. A follow-up, quantitative survey measured agreement between responses within each of the themes using a Likert scale. RESULTS: Thirty-three participants responded from 22 hospitals that had received casualties from a terrorist incident, representing 17 cities in low-middle, middle and high income countries. The first survey identified themes of sufficient (sometimes abundant) human resource, although coordination of staff was a challenge. Difficulties highlighted were communication, security, and management of blast injuries. The most frequently implemented changes were education on specific injuries, revising future plans and preparatory exercises. Persisting challenges were lack of time allocated to training and psychological well-being. The follow-up survey recorded highest agreement amongst correspondents on the need for re-triage at hospital (90% agreement), coordination roles (85% agreement), flexibility (100% agreement), and large-scale exercises (95% agreement). CONCLUSION: This survey collates international experience gained from clinicians managing terrorist mass casualty incidents. The organisation of human response, rather than consumption of physical supplies, emerged as the main finding. NHSH Clinical Effectiveness Unit project registration number: 2020/21-036.

Thrombelastography (TEG® 6s) early amplitudes predict maximum amplitude in severely injured trauma patients.

Severely injured trauma patients are often coagulopathic and early hemostatic resuscitation is essential. Previous studies have revealed linear relationships between thrombelastography (TEG®) five- and ten-min amplitudes (A5 and A10), and maximum amplitude (MA), using TEG® 5000 technology. We aimed to investigate the performance of A5 and A10 in predicting low MA in severely injured trauma patients and identify optimal cut-off values for hemostatic intervention based on early amplitudes, using the cartridge-based TEG® 6s technology. Adult trauma patients with hemorrhagic shock were included in the iTACTIC randomized controlled trial at six European Level I trauma centers between 2016 and 2018. After admission, patients were randomized to hemostatic therapy guided by conventional coagulation tests (CCT) or viscoelastic hemostatic assays (VHA). Patients with available admission-TEG® 6s data were included in the analysis, regardless of treatment allocation. Low MA was defined as <55 mm for Kaolin TEG® and RapidTEG®, and <17 mm for TEG® functional fibrinogen (FF). One hundred eighty-seven patients were included. Median time to MA was 20 (Kaolin TEG®), 21 (RapidTEG®) and 12 (TEG® FF) min. For Kaolin TEG®, the optimal Youden index (YI) was at A5 < 36 mm (100/93% sensitivity/specificity) and A10 < 47 mm (100/96% sensitivity/specificity). RapidTEG® optimal YI was at A5 < 34 mm (98/92% sensitivity/specificity) and A10 < 45 mm (96/95% sensitivity/specificity). TEG® FF optimal YI was at A5 < 12 mm (97/93% sensitivity/specificity) and A10 < 15 mm (97/99% sensitivity/specificity). In summary, we found that TEG® 6s early amplitudes were sensitive and specific predictors of MA in severely injured trauma patients. Intervening on early amplitudes can save valuable time in hemostatic resuscitation.

Histone H4 induces platelet ballooning and microparticle release during trauma hemorrhage.

Trauma hemorrhage is a leading cause of death and disability worldwide. Platelets are fundamental to primary hemostasis, but become profoundly dysfunctional in critically injured patients by an unknown mechanism, contributing to an acute coagulopathy which exacerbates bleeding and increases mortality. The objective of this study was to elucidate the mechanism of platelet dysfunction in critically injured patients. We found that circulating platelets are transformed into procoagulant balloons within minutes of injury, accompanied by the release of large numbers of activated microparticles which coat leukocytes. Ballooning platelets were decorated with histone H4, a damage-associated molecular pattern released in massive quantities after severe injury, and exposure of healthy platelets to histone H4 recapitulated the changes in platelet structure and function observed in trauma patients. This is a report of platelet ballooning in human disease and of a previously unrecognized mechanism by which platelets contribute to the innate response to tissue damage.

Shock-Driven Endotheliopathy in Trauma Patients Is Associated with Leucocyte Derived Extracellular Vesicles.

Endotheliopathy following trauma is associated with poor outcome, but the underlying mechanisms are unknown. This study hypothesized that an increased extracellular vesicle (EV) concentration is associated with endotheliopathy after trauma and that red blood cell (RBC) transfusion could further enhance endotheliopathy. In this post hoc sub study of a multicentre observational trial, 75 trauma patients were stratified into three groups based on injury severity score or shock. In patient plasma obtained at hospital admission and after transfusion of four RBC transfusions, markers for endotheliopathy were measured and EVs were labelled with anti CD41 (platelet EVs), anti CD235a (red blood cell EVs), anti CD45 (leucocyte EVs), anti CD144 (endothelial EVs) or anti CD62e (activated endothelial EVs) and EV concentrations were measured with flow cytometry. Statistical analysis was performed by a Kruskall Wallis test with Bonferroni correction or Wilcoxon rank test for paired data. In patients with shock, syndecan-1 and von Willebrand Factor (vWF) were increased compared to patients without shock. Additionally, patients with shock had increased red blood cell EV and leucocyte EV concentrations compared to patients without shock. Endotheliopathy markers correlated with leucocyte EVs (ρ = 0.263, p = 0.023), but not with EVs derived from other cells. Injury severity score had no relation with EV release. RBC transfusion increased circulating red blood cell EVs but did not impact endotheliopathy. In conclusion, shock is (weakly) associated with EVs from leucocytes, suggesting an immune driven pathway mediated (at least in part) by shock.

Early Identification of Trauma-induced Coagulopathy: Development and Validation of a Multivariable Risk Prediction Model.

OBJECTIVE: The aim of this study was to develop and validate a risk prediction tool for trauma-induced coagulopathy (TIC), to support early therapeutic decision-making. BACKGROUND: TIC exacerbates hemorrhage and is associated with higher morbidity and mortality. Early and aggressive treatment of TIC improves outcome. However, injured patients that develop TIC can be difficult to identify, which may compromise effective treatment. METHODS: A Bayesian Network (BN) prediction model was developed using domain knowledge of the causal mechanisms of TIC, and trained using data from 600 patients recruited into the Activation of Coagulation and Inflammation in Trauma (ACIT) study. Performance (discrimination, calibration, and accuracy) was tested using 10-fold cross-validation and externally validated on data from new patients recruited at 3 trauma centers. RESULTS: Rates of TIC in the derivation and validation cohorts were 11.8% and 11.0%, respectively. Patients who developed TIC were significantly more likely to die (54.0% vs 5.5%, P < 0.0001), require a massive blood transfusion (43.5% vs 1.1%, P < 0.0001), or require damage control surgery (55.8% vs 3.4%, P < 0.0001), than those with normal coagulation. In the development dataset, the 14-predictor BN accurately predicted this high-risk patient group: area under the receiver operating characteristic curve (AUROC) 0.93, calibration slope (CS) 0.96, brier score (BS) 0.06, and brier skill score (BSS) 0.40. The model maintained excellent performance in the validation population: AUROC 0.95, CS 1.22, BS 0.05, and BSS 0.46. CONCLUSIONS: A BN (http://www.traumamodels.com) can accurately predict the risk of TIC in an individual patient from standard admission clinical variables. This information may support early, accurate, and efficient activation of hemostatic resuscitation protocols.

Resolvin D1 Attenuates the Organ Injury Associated With Experimental Hemorrhagic Shock.

OBJECTIVE: To evaluate the potential changes in the plasma levels of resolvin D1 (RvD1) in patients with trauma and hemorrhage. Having found that trauma results in a profound reduction in plasma RvD1 in patients, we have then investigated the effects of RvD1 on the organ injury and dysfunction associated with hemorrhagic shock (HS) in the rat. BACKGROUND: HS is a common cause of death in trauma due to excessive systemic inflammation and multiple organ failure. RvD1 is a member of the resolvin family of pro-resolution mediators. METHODS: Blood samples were drawn from critically injured patients (n = 27, ACITII-prospective observational cohort study) within 2 hours of injury for targeted liquid chromatography tandem mass spectrometry. HS rats (removal of blood to reduce arterial pressure to 30 ±â€Š2 mm Hg, 90 minutes, followed by resuscitation) were treated with RvD1 (0.3 or 1 µg/kg intravenous (i.v.)) or vehicle (n = 7). Parameters of organ injury and dysfunction were determined. RESULTS: Plasma levels of RvD1 (mg/dL) were reduced in patients with trauma+HS (0.17 ±â€Š0.08) when compared with healthy volunteers (0.76 ±â€Š0.25) and trauma patients (0.62 ±â€Š0.20). In rats with HS, RvD1 attenuated the kidney dysfunction, liver injury, and tissue ischemia. RvD1 also reduced activation of the nuclear factor (NF)-κB pathway and reduced the expression of pro-inflammatory proteins such as inducible nitric oxide synthase, tumor necrosis factor-α, interleukin-1ß, and interleukin-6. CONCLUSION: Plasma RvD1 is reduced in patients with trauma-HS. In rats with HS, administration of synthetic RvD1 on resuscitation attenuated the multiple organ failure associated with HS by a mechanism that involves inhibition of the activation of NF-κB.

A Decade of Damage Control Resuscitation: New Transfusion Practice, New Survivors, New Directions.

OBJECTIVE: The aim of this study was to identify the effects of recent innovations in trauma major hemorrhage management on outcome and transfusion practice, and to determine the contemporary timings and patterns of death. BACKGROUND: The last 10 years have seen a research-led change in hemorrhage management to damage control resuscitation (DCR), focused on the prevention and treatment of trauma-induced coagulopathy. METHODS: A 10-year retrospective analysis of prospectively collected data of trauma patients who activated the Major Trauma Centre's major hemorrhage protocol (MHP) and received at least 1 unit of red blood cell transfusions (RBC). RESULTS: A total of 1169 trauma patients activated the MHP and received at least 1 unit of RBC, with similar injury and admission physiology characteristics over the decade. Overall mortality declined from 45% in 2008 to 27% in 2017, whereas median RBC transfusion rates dropped from 12 to 4 units (massive transfusion rates from 68% to 24%). The proportion of deaths within 24 hours halved (33%-16%), principally with a fall in mortality between 3 and 24 hours (30%-6%). Survivors are now more likely to be discharged to their own home (57%-73%). Exsanguination is still the principal cause of early deaths, and the mortality associated with massive transfusion remains high (48%). Late deaths are now split between those due to traumatic brain injury (52%) and multiple organ dysfunction (45%). CONCLUSIONS: There have been remarkable reductions in mortality after major trauma hemorrhage in recent years. Mortality rates continue to be high and there remain important opportunities for further improvements in these patients.

Evidence-Based and Clinically Relevant Outcomes for Hemorrhage Control Trauma Trials.

OBJECTIVE: To address the clinical and regulatory challenges of optimal primary endpoints for bleeding patients by developing consensus-based recommendations for primary clinical outcomes for pivotal trials in patients within 6 categories of significant bleeding, (1) traumatic injury, (2) intracranial hemorrhage, (3) cardiac surgery, (4) gastrointestinal hemorrhage, (5) inherited bleeding disorders, and (6) hypoproliferative thrombocytopenia. BACKGROUND: A standardized primary outcome in clinical trials evaluating hemostatic products and strategies for the treatment of clinically significant bleeding will facilitate the conduct, interpretation, and translation into clinical practice of hemostasis research and support alignment among funders, investigators, clinicians, and regulators. METHODS: An international panel of experts was convened by the National Heart Lung and Blood Institute and the United States Department of Defense on September 23 and 24, 2019. For patients suffering hemorrhagic shock, the 26 trauma working-group members met for almost a year, utilizing biweekly phone conferences and then an in-person meeting, evaluating the strengths and weaknesses of previous high quality studies. The selection of the recommended primary outcome was guided by goals of patient-centeredness, expected or demonstrated sensitivity to beneficial treatment effects, biologic plausibility, clinical and logistical feasibility, and broad applicability. CONCLUSIONS: For patients suffering hemorrhagic shock, and especially from truncal hemorrhage, the recommended primary outcome was 3 to 6-hour all-cause mortality, chosen to coincide with the physiology of hemorrhagic death and to avoid bias from competing risks. Particular attention was recommended to injury and treatment time, as well as robust assessments of multiple safety related outcomes.

Alterations in platelet behavior after major trauma: adaptive or maladaptive?

Platelets are damage sentinels of the intravascular compartment, initiating and coordinating the primary response to tissue injury. Severe trauma and hemorrhage induce profound alterations in platelet behavior. During the acute post-injury phase, platelets develop a state of impaired ex vivo agonist responsiveness independent of platelet count, associated with systemic coagulopathy and mortality risk. In patients surviving the initial insult, platelets become hyper-responsive, associated with increased risk of thrombotic events. Beyond coagulation, platelets constitute part of a sterile inflammatory response to injury: both directly through release of immunomodulatory molecules, and indirectly through modifying behavior of innate leukocytes. Both procoagulant and proinflammatory aspects have implications for secondary organ injury and multiple-organ dysfunction syndromes. This review details our current understanding of adaptive and maladaptive alterations in platelet biology induced by severe trauma, mechanisms underlying these alterations, potential platelet-focused therapies, and existing knowledge gaps and their research implications.