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In trauma patients, shock-induced endotheliopathy (SHINE) is associated with a poor prognosis. We have previously identified four metabolic phenotypes in a small cohort of trauma patients (N = 20) and displayed the intracellular metabolic profile of the endothelial cell by integrating quantified plasma metabolomic profiles into a genome-scale metabolic model (iEC-GEM). A retrospective observational study of 99 trauma patients admitted to a Level 1 Trauma Center. Mass spectrometry was conducted on admission samples of plasma metabolites. Quantified metabolites were analyzed by computational network analysis of the iEC-GEM. Four plasma metabolic phenotypes (A–D) were identified, of which phenotype D was associated with an increased injury severity score (p < 0.001); 90% (91.6%) of the patients who died within 72 h possessed this phenotype. The inferred EC metabolic patterns were found to be different between phenotype A and D. Phenotype D was unable to maintain adequate redox homeostasis. We confirm that trauma patients presented four metabolic phenotypes at admission. Phenotype D was associated with increased mortality. Different EC metabolic patterns were identified between phenotypes A and D, and the inability to maintain adequate redox balance may be linked to the high mortality.

Supplemental digital content is available in the text., BACKGROUND Damage-control resuscitation (DCR) improves survival in severely bleeding patients. However, deviating from balanced transfusion ratios during a resuscitation may limit this benefit. We hypothesized that maintaining a balanced resuscitation during DCR is independently associated with improved survival. METHODS This was a secondary analysis of the Prospective Observational Multicenter Major Trauma Transfusion (PROMMTT) study. Patients receiving >3 U of packed red blood cells (PRBCs) during any 1-hour period over the first 6 hours and surviving beyond 30 minutes were included. Linear regression assessed the effect of percent time in a high-ratio range on 24-hour survival. We identified an optimal ratio and percent of time above the target ratio threshold by Youden’s index. We compared patients with a 6-hour ratio above the target and above the percent time threshold (on-target) with all others (off-target). Kaplan-Meier analysis assessed the combined effect of blood product ratio and percent time over the target ratio on 24-hour and 30-day survival. Multivariable logistic regression identified factors independently associated with 24-hour and 30-day survival. RESULTS Of 1,245 PROMMTT patients, 524 met the inclusion criteria. Optimal targets were plasma/PRBC and platelet/PRBC of 0.75 (3:4) and ≥40% time spent over this threshold. For plasma/PRBC, on-target (n = 213) versus off-target (n = 311) patients were younger (median, 31 years; interquartile range, [22–50] vs. 40 [25–54]; p = 0.002) with similar injury burdens and presenting physiology. Similar patterns were observed for platelet/PRBC on-target (n = 116) and off-target (n = 408) patients. After adjusting for differences, on-target plasma/PRBC patients had significantly improved 24-hour (odds ratio, 2.25; 95% confidence interval, 1.20–4.23) and 30-day (odds ratio, 1.97; 95% confidence interval, 1.14–3.41) survival, while on-target platelet/PRBC patients did not. CONCLUSION Maintaining a high ratio of plasma/PRBC during DCR is independently associated with improved survival. Performance improvement efforts and prospective studies should capture time spent in a high-ratio range. LEVEL OF EVIDENCE Epidemiologic/prognostic study, level II; Therapeutic, level IV.

IMPORTANCE: Venous thromboembolism (VTE) affects 2% to 20% of recovering trauma patients, despite aggressive prophylaxis with enoxaparin. Antithrombin is a primary circulating anticoagulant and crucial component of enoxaparin thromboprophylaxis. Approximately 20% of trauma patients present with antithrombin deficiency (antithrombin activity

Introduction: Exsanguination remains a leading cause of preventable death in traumatically injured patients. To better treat hemorrhagic shock, hospitals have adopted massive transfusion protocols (MTPs) which accelerate the delivery of blood products to patients. There has been an increase in mass casualty events (MCE) worldwide over the past two decades. These events can overwhelm a responding hospitals supply of blood products. Using a computerized model, this study investigated the ability of US trauma centers (TCs) to meet the blood product requirements of MCEs. Methods: Cross-sectional survey data of on-hand blood products were collected from 16 US level-1 TCs. A discrete event simulation model of a TC was developed based on historic data of blood product consumption during MCEs. Each hospitals blood bank was evaluated across increasingly more demanding MCEs using modern MTPs to guide resuscitation efforts in massive transfusion (MT) patients. Results: A total of 9,000 simulations were performed on each TCs data. Under the least demanding MCE scenario, the median size MCE in which TCs failed to adequately meet blood product demand was 50 patients (IQR 20-90), considering platelets. Ten TCs exhaust their supply of platelets prior to red blood cells (RBCs) or plasma. Disregarding platelets, five TCs exhausted their supply of O- packed RBCs, six exhausted their AB plasma supply, and five had a mixed exhaustion picture. Conclusion: Assuming a TCs ability to treat patients is limited only by their supply of blood products, US level-1 TCs lack the on-hand blood products required to adequately treat patients following a MCE. Use of non-traditional blood products, which have a longer shelf life, may allow TCs to better meet the blood product requirement needs of patients following larger MCEs. Funding Agencies|Center for Translational Injury Research; John B Holmes Professorship in Clinical Sciences

On August 27 and 28, 2018, the American Burn Association, in conjunction with Underwriters Laboratories, convened a group of experts on burn and inhalation injury in Washington, DC. The goal of the meeting was to identify and discuss the existing knowledge, data, and modeling gaps related to understanding cutaneous thermal injury and inhalation injury due to exposure from a fire environment, and in addition, address two more areas proposed by the American Burn Association Research Committee that are critical to burn care but may have current translational research gaps (inflammatory response and hypermetabolic response). Representatives from the Underwriters Laboratories Firefighter Safety Research Institute and the Bureau of Alcohol, Tobacco, Firearms and Explosives Fire Research Laboratory presented the state of the science in their fields, highlighting areas that required further investigation and guidance from the burn community. Four areas were discussed by the full 24 participant group and in smaller groups: Basic and Translational Understanding of Inhalation Injury, Thermal Contact and Resulting Injury, Systemic Inflammatory Response and Resuscitation, and Hypermetabolic Response and Healing. A primary finding was the need for validating historic models to develop a set of reliable data on contact time and temperature and resulting injury. The working groups identified common areas of focus across each subtopic, including gaining an understanding of individual response to injury that would allow for precision medicine approaches. Predisposed phenotype in response to insult, the effects of age and sex, and the role of microbiomes could all be studied by employing multi-omic (systems biology) approaches.

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 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.

Background: The endotheliopathy of trauma (EoT) is associated with increased mortality following injury. Herein, we describe the plasma proteome related to EoT in order to provide insight into the role of the endothelium within the systemic response to trauma. Methods: 99 subjects requiring the highest level of trauma activation were included in the study. Enzyme-linked immunosorbent assays of endothelial and catecholamine biomarkers were performed on admission plasma samples, as well as untargeted proteome quantification utilizing high-performance liquid chromatography and tandem mass spectrometry. Results: Plasma endothelial and catecholamine biomarker abundance was elevated in EoT. Patients with EoT (n = 62) had an increased incidence of death within 24 h at 21% compared to 3% for non-EoT (n = 37). Proteomic analysis revealed that 52 out of 290 proteins were differentially expressed between the EoT and non-EoT groups. These proteins are involved in endothelial activation, coagulation, inflammation, and oxidative stress, and include known damage-associated molecular patterns (DAMPs) and intracellular proteins specific to several organs. Conclusions: We report a proteomic profile of EoT suggestive of a surge of DAMPs and inflammation driving nonspecific activation of the endothelial, coagulation, and complement systems with subsequent end-organ damage and poor clinical outcome. These findings support the utility of EoT as an index of cellular injury and delineate protein candidates for therapeutic intervention.

Purpose: Endotheliopathy of trauma (EoT), as defined by circulating levels of syndecan-1 ≥ 40 ng/mL, has been reported to be associated with significantly increased transfusion requirements and a doubled 30-day mortality. Increased shedding of the glycocalyx points toward the endothelial cell membrane composition as important for the clinical outcome being the rationale for this study. Results: The plasma metabolome of 95 severely injured trauma patients was investigated by mass spectrometry, and patients with EoT vs. non-EoT were compared by partial least square-discriminant analysis, identifying succinic acid as the top metabolite to differentiate EoT and non-EoT patients (VIP score = 3). EoT and non-EoT patients’ metabolic flux profile was inferred by integrating the corresponding plasma metabolome data into a genome-scale metabolic network reconstruction analysis and performing a functional study of the metabolic capabilities of each group. Model predictions showed a decrease in cholesterol metabolism secondary to impaired mevalonate synthesis in EoT compared to non-EoT patients. Intracellular task analysis indicated decreased synthesis of thromboxanA2 and leukotrienes, as well as a lower carnitine palmitoyltransferase I activity in EoT compared to non-EoT patients. Sensitivity analysis also showed a significantly high dependence of eicosanoid-associated metabolic tasks on alpha-linolenic acid as unique to EoT patients. Conclusions: Model-driven analysis of the endothelial cells’ metabolism identified potential novel targets as impaired thromboxane A2 and leukotriene synthesis in EoT patients when compared to non-EoT patients. Reduced thromboxane A2 and leukotriene availability in the microvasculature impairs vasoconstriction ability and may thus contribute to shock in EoT patients. These findings are supported by extensive scientific literature; however, further investigations are required on these findings.

Background: Superficial surgical site infections (S-SSIs) are common after trauma laparotomy, leading to morbidity, increased costs, and prolonged length of stay (LOS). Opportunities to mitigate S-SSI risks are limited to the intra-operative and post-operative periods. Accurate S-SSI risk stratification is paramount at the time of operation to inform immediate management. We aimed to develop a risk calculator to aid in surgical decision-making at the time of emergency laparotomy. Methods: A retrospective cohort study of patients requiring emergency trauma laparotomy between 2011 and 2017 at a single, level 1 trauma center was performed. Operative factors, skin management strategy, and outcomes were determined by chart review. Bayesian multilevel logistic regression was utilized to create a risk calculator with variables available upon closure of the laparotomy. Models were validated on a 30% test cohort and discrimination reported as an area under the receiver operating characteristics curve (AUROC). Results: Of 1,322 patients, the majority were male (77%) with median age of 33 years, injured by blunt mechanism (54%), and median injury severity score of 19. Eighty-eight (7%) patients developed an S-SSI. Patients who developed S-SSI had higher final lactate, blood loss, transfusion requirements, and wound classification. Patients with S-SSI more frequently had mesenteric or large bowel injury than those without S-SSI. Superficial SSI was associated with increased complications and prolonged length of stay (LOS). The S-SSI predictive model demonstrated moderate discrimination with an AUROC of 0.69 (95% confidence interval [CI], 0.56-0.81). Parameters contributing the most to the model were damage control laparotomy, full-thickness large bowel injury, and large bowel resection. Conclusion: A predictive model for S-SSI was built using factors available to the surgeon upon index emergency trauma laparotomy closure. This calculator may be used to standardize intra- and post-operative care and to identify high-risk patients in whom to test novel preventative strategies and improve overall outcomes for patients requiring emergency trauma laparotomy.

BackgroundAlthough widely used in treating severe abdominal trauma, damage control laparotomy (DCL) has not been assessed in any randomized controlled trial. We conducted a pilot trial among patients for whom our surgeons had equipoise and hypothesized that definitive laparotomy (DEF) would reduce major abdominal complications (MAC) or death within 30 days compared with DCL.MethodsEligible patients undergoing emergency laparotomy were randomized during surgery to DCL or DEF from July 2016 to May 2019. The primary outcome was MAC or death within 30 days. Prespecified frequentist and Bayesian analyses were performed.ResultsOf 489 eligible patients, 39 patients were randomized (DCL 18, DEF 21) and included. Groups were similar in demographics and mechanism of injury. The DEF group had a higher Injury Severity Score (DEF median 34 (IQR 20, 43) vs DCL 29 (IQR 22, 41)) and received more prerandomization blood products (DEF median red blood cells 8 units (IQR 6, 11) vs DCL 6 units (IQR 2, 11)). In unadjusted analyses, the DEF group had more MAC or death within 30 days (1.71, 95% CI 0.81 to 3.63, p=0.159) due to more deaths within 30 days (DEF 33% vs DCL 0%, p=0.010). Adjustment for Injury Severity Score and prerandomization blood products reduced the risk ratio for MAC or death within 30 days to 1.54 (95% CI 0.71 to 3.32, p=0.274). The Bayesian probability that DEF increased MAC or death within 30 days was 85% in unadjusted analyses and 66% in adjusted analyses.ConclusionThe findings of our single center pilot trial were inconclusive. Outcomes were not worse with DCL and, in fact, may have been better. A randomized clinical trial of DCL is feasible and a larger, multicenter trial is needed to compare DCL and DEF for patients with severe abdominal trauma.Level of evidenceLevel II.

Every year more than 500,000 deaths are attributed to trauma worldwide and severe hemorrhage is present in most of them. Transfused platelets have been shown to improve survival in trauma patients, although its mechanism is only partially known. Platelet derived-extracellular vesicles (PEVs) are small vesicles released from platelets upon activation and/or mechanical stimulation and many of the benefits attributed to platelets could be mediated through PEVs. Based on the available literature, we hypothesized that transfusion of human PEVs would promote hemostasis, reduce blood loss and attenuate the progression to hemorrhagic shock following severe trauma. In this study, platelet units from four different donors were centrifuged to separate platelets and PEVs. The pellets were washed to obtain plasma-free platelets to use in the rodent model. The supernatant was subjected to tangential flow filtration for isolation and purification of PEVs. PEVs were assessed by total count and particle size distribution by Nanoparticle Tracking Analysis (NTA) and characterized for cells of origin and expression of EV specific-surface and cytosolic markers by flow cytometry. The coagulation profile from PEVs was assessed by calibrated automated thrombography (CAT) and thromboelastography (TEG). A rat model of uncontrolled hemorrhage was used to compare the therapeutic effects of 8.7 × 108 fresh platelets (FPLT group, n = 8), 7.8 × 109 PEVs (PEV group, n = 8) or Vehicle (Control, n = 16) following severe trauma. The obtained pool of PEVs from 4 donors had a mean size of 101 ± 47 nm and expressed the platelet-specific surface marker CD41 and the EV specific markers CD9, CD61, CD63, CD81 and HSP90. All PEV isolates demonstrated a dose-dependent increase in the rate and amount of thrombin generated and overall clot strength. In vivo experiments demonstrated a 24% reduction in abdominal blood loss following liver trauma in the PEVs group when compared with the control group (9.9 ± 0.4 vs. 7.5 ± 0.5 mL, p ). The PEV group also exhibited improved outcomes in blood pressure, lactate level, base excess and plasma protein concentration compared to the Control group. Fresh platelets failed to improve these endpoints when compared to Controls. Altogether, these results indicate that human PEVs provide pro-hemostatic support following uncontrolled bleeding. As an additional therapeutic effect, PEVs improve the outcome following severe trauma by maintaining hemodynamic stability and attenuating the development of ischemia, base deficit, and cardiovascular shock.

In 2019, we implemented a pill-based, opioid-minimizing pain protocol and protocolized moderate sedation for dressing changes in order to decrease opioid exposure in burn patients. We hypothesized that these interventions would reduce inpatient opioid exposure without increasing acute pain scores. Two groups of consecutive patients admitted to the burn service were compared: Pre-group (from January 1, 2018 to July 31, 2019) and Post-group (from January 1, 2020 to June 30, 2020) from before and after the implementation of the protocols (from August 1, 2019 to December 31, 2019). We abstracted patient demographics and burn injury characteristics from the burn registry. We obtained opioid exposure and pain scale scores from the electronic medical record. The primary outcome was total morphine milligram equivalents (MMEs). Secondary outcomes included MMEs/day, pain domain-specific MMEs, and pain scores. Pain was estimated by creating a normalized pain score (range 0–1), which incorporated three different pain scales (Numeric Rating Scale, Behavioral Pain Scale, and Behavioral Pain Assessment Scale). Groups were compared using Wilcoxon rank-sum and chi-square tests. Treatment effects were estimated using Bayesian generalized linear models. There were no differences in demographics or burn characteristics between the Pre-group (n = 495) and Post-group (n = 174). The Post-group had significantly lower total MMEs (Post-group 110 MMEs [32, 325] vs Pre-group 230 [60, 840], P < .001), MMEs/day (Post-group 33 MMEs/day [15, 54] vs Pre-group 52 [27, 80], P < .001), and domain-specific total MMEs. No difference in average normalized pain scores was seen. Implementation of opioid-minimizing protocols for acute burn pain was associated with a significant reduction in inpatient opioid exposure without an increase in pain scores.

Background Administration of nonsteroidal anti-inflammatory drugs (NSAIDs) for acute posttraumatic analgesia is increasing in popularity as an alternative to opioids despite reservations regarding its potential impact on the development of acute kidney injury (AKI). We hypothesized that early NSAID administration for analgesia would be associated with worsened renal function in severely injured trauma patients. Methods A retrospective cohort study of severely injured adult (≥16 years) patients admitted to the intensive care unit with ≥1 rib fracture between 2010 and 2017 was performed. The early NSAID group was defined by receipt of one or more doses of NSAID within the first 48 hours of hospitalization. Acute kidney injury diagnosis and staging were defined by the Kidney Disease Improving Global Outcomes Guidelines. The primary outcome was a composite measure of two outcomes within the first week of hospitalization: (1) AKI progression (increase in AKI stage from arrival) or (2) death. Secondary outcomes included AKI progression, AKI improvement, AKI duration, and mortality. Inverse propensity of treatment weights were generated using clinically sound covariates suspected to be associated with the decision to give early NSAIDs and the primary or secondary outcomes. Multivariable analyses were performed adjusting for inverse propensity of treatment weights, covariates, and length of stay. Results Of 2,340 patients, 268 (11%) were administered early NSAIDs. When compared with the control group, patients who received early NSAIDs were less severely injured. Renal outcomes were worse in the control group. Standardized mean differences were minimal after weighting. On multivariable analysis, administration of early NSAIDs was not associated with worsened renal outcomes or increased mortality. Conclusion Although only 11% of patients received early NSAIDs after trauma for analgesia, early NSAID exposure was not associated with increased AKI progression, decreased AKI improvement, prolonged duration, or increased mortality. Given the lack of evidence showing harm, early NSAIDs for analgesia may be underused for severely injured patients. Level of evidence Prognostic, level III, Therapeutic, level IV.

INTRODUCTION: traumatic brain injury (TBI) is associated with secondary injury to the central nervous system (CNS) via inflammatory mechanisms. The combination of polytrauma and TBI (TBI) further exacerbates the inflammatory response to injury, however combined injury phenomena has not been thoroughly studied. In this study, we examined the inflammatory differences between patients with TBI versus patients with polytrauma but no TBI (polytrauma). We hypothesize that patients with TBI have a heightened early inflammatory response compared to polytrauma. METHODS: We conducted a single center retrospective study of a cohort of patients with polytrauma who were enrolled in the PROPPR study. These patients had blood samples prospectively collected at eight time points in the first 3 days of admission. Using radiological data to determine TBI, our polytrauma cohort was dichotomized into TBI (n=30) or polytrauma (n=54). Inflammatory biomarkers were measured using ELISA. Data across time were compared for TBI vs. polytrauma groups using Wilcoxon rank sum test. Network analysis techniques were used to systematically characterize the inflammatory responses at admission. RESULTS: Patients with TBI (51.6%) had a higher 30-day mortality compared to polytrauma (16.9%) (p-value

Background Acute kidney injury (AKI) after trauma is associated with poor outcomes. According to current guidelines, a diagnosis of AKI should be made based on an increase in serum creatinine from a reference value. However, a true reference is often unknown in patients presenting with traumatic injury. The aim of this study was to determine the optimal reference creatinine estimate for post-traumatic AKI diagnosis and staging. The optimal reference estimate was defined by a high incidence, strong prognostic ability, and incrementality at each stage. Study Design This was a cohort study of adult trauma patients (older than 16 years) requiring ICU admission between 2009 and 2018 (n = 8,026) at a single Level I trauma center. AKI was determined using the following 4 reference creatinine estimates: Modified Diet of Renal Diseases (MDRD), Trauma MDRD, admission creatinine, and the first-day creatinine nadir. Inclusivity was assessed by incidence of AKI diagnosed with different reference creatinine estimates; prognostic ability was assessed by multivariable modified Poisson regression; and incrementality was assessed by correlation of mortality risk by AKI stage. Results There was a wide range of AKI incidence, from 21% when using admission creatinine to 76% using the Trauma MDRD. The MDRD reference creatinine estimate resulted in an AKI incidence of 41% and a diagnosis that was both prognostic of mortality and incremental with each AKI stage. All other reference estimates resulted in AKI diagnoses that were either not prognostic or not incremental. Conclusions Reference creatinine estimate determines the clinical importance of AKI diagnoses. In this study, the MDRD reference resulted in optimal AKI diagnoses.

Prior work established that exercise alleviates muscle function loss in a clinically relevant rodent model mimicking the clinical sequelae of severely burned patients. On the basis of these data, we posit that pharmacologic treatment with insulin combined with exercise further mitigates loss of muscle function following severe burn with immobilization. Twenty‐four Sprague–Dawley rats were assessed and trained to complete a climbing exercise. All rats followed a standardized protocol to mimic severe burn patients (40% total body surface area scald burn); all rats were immediately placed into a hindlimb unloading apparatus to simulate bedrest. The rats were then randomly assigned to four treatment groups: saline vehicle injection without exercise (VEH/NEX), insulin (5 U/kg) injection without exercise (INS/NEX), saline vehicle with daily exercise (VEH/EX), and insulin with daily exercise (INS/EX). The animals were assessed for 14 days following injury. The groups were compared for multiple variables. Isometric tetanic (Po) and twitch (Pt) forces were significantly elevated in the plantaris and soleus muscles of the INS/EX rats (P

BACKGROUND: Thrombelastography (TEG) fibrinolysis shutdown after trauma is associated with increased mortality due to hypercoagulability-associated organ failure. However, a lack of mechanistic data has precluded the development of novel interventions to treat shutdown. OBJECTIVES: To define the pathophysiology of TEG shutdown in severely injured, bleeding patients through secondary analysis of the PROPPR trial. METHODS: Fibrinolysis was characterized in PROPPR subjects using admission TEG lysis at 30 minutes (LY30) or plasmin-antiplasmin (PAP) levels. LY30 categories were low (< 0.9%), moderate (0.9-2.9%), or high (≥ 3%). PAP was classified as low (20,000 μg/L). Demographics, outcomes, admission TEG values, platelet count and function, standard coagulation tests and coagulation proteins were compared. RESULTS: 547 patients had TEG data and 549 patients had PAP data available. Low LY30 was associated with reduced platelet count and aggregation, poorer TEG clot formation, prolonged clotting times, and reduced fibrinogen and alpha2 antiplasmin. Compared to moderate PAP, low PAP subjects had similar platelet parameters, TEG values, fibrinogen, and alpha2 antiplasmin, but reduced tPA, and elevated PAI-1. D-Dimer values increased as PAP increased, however patients with low LY30 had elevated D-Dimer compared to moderate LY30 patients. Most low LY30 deaths were due to TBI (45%) and hemorrhage (42%) versus one of each cause (TBI, hemorrhage, MOF) in low PAP patients. CONCLUSIONS: Low TEG LY30 does not reflect shutdown of enzymatic fibrinolysis with hypercoagulability, but rather a coagulopathic state of moderate fibrinolysis with fibrinogen consumption and platelet dysfunction that is associated with poor outcomes.

OBJECTIVE: Investigate and confirm the association between sympathoadrenal activation, endotheliopathy and poor outcome in trauma patients.BACKGROUND: The association between sympathoadrenal activation, endotheliopathy, and poor outcome in trauma has only been demonstrated in smaller patient cohorts and animal models but needs confirmation in a large independent patient cohort.METHODS: Prospective observational study of 424 trauma patients admitted to a level 1 Trauma Center. Admission plasma levels of catecholamines (adrenaline, noradrenaline) and biomarkers reflecting endothelial damage (syndecan-1, thrombomodulin, and sE-selectin) were measured and demography, injury type and severity, physiology, treatment, and mortality up till 28 days were recorded.RESULTS: Patients had a median ISS of 17 with 72% suffering from blunt injury. Adrenaline and noradrenaline correlated with syndecan-1 (r = 0.38, PCONCLUSIONS: We confirmed that sympathoadrenal activation was strongly and independently associated with endothelial glycocalyx and cell damage (ie, endotheliopathy) and furthermore that sympathoadrenal activation and endotheliopathy were independent predictors of mortality in trauma patients.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/4.0.

Background In an earlier study, we reported the successful reduction in the use of damage control laparotomy (DCL); however, no change in the relative frequencies of specific indications was observed. In this study, we aimed to use machine learning to help identify the changes in surgical decision making that occurred. Study Design Adult patients undergoing emergent trauma laparotomy were included: pre-quality improvement (QI): January 1, 2011 to October 31, 2013 and post-QI: November 1, 2013 to June 30, 2016. Using 72 variables before or during emergent laparotomy, random forest algorithms predicting DCL before and after a QI intervention were created. The main end point of the algorithms was the strength of individual factor significance in predicting the use of DCL, calculated by determining the mean decrease in accuracy (MDA) in the model if that variable was removed. Results In the pre-QI group, 24 of 72 factors significantly predicted DCL, the strongest being bowel resection (mean MDA 16) and operating room RBC transfusions (mean MDA 15). The remaining variables were spread along the continuum of care from injury to emergent laparotomy end. In the post-QI group, 12 of 72 factors significantly predicted DCL, the strongest being last operating room lactate (mean MDA 12) and operating room RBC transfusions (mean MDA 14). In addition to having 12 fewer significant factors predictive of DCL, the predictive factors in the post-QI group were mainly intraoperative factors. Conclusions A machine learning analysis provided novel insights into the changes in decision making achieved by a successful QI intervention and should be considered an adjunct to understanding successful pre- and post-intervention QI studies. The analysis suggested a shift toward using mostly intraoperative factors to determine the use of DCL.

Background Previously, a model to predict massive transfusion protocol (MTP) (activation) was derived using a single-institution data set. The PRospective, Observational, Multicenter, Major Trauma Transfusion database was used to externally validate this model's ability to predict both MTP activation and massive transfusion (MT) administration using multiple MT definitions. Methods The app model was used to calculate the predicted probability of MTP activation or MT delivery. The five definitions of MT used were: (1) 10 units packed red blood cells (PRBCs) in 24 hours, (2) Resuscitation Intensity score ≥ 4, (3) critical administration threshold, (4) 4 units PRBCs in 4 hours; and (5) 6 units PRBCs in 6 hours. Receiver operating curves were plotted to compare the predicted probability of MT with observed outcomes. Results Of 1,245 patients in the data set, 297 (24%) met definition 1, 570 (47%) met definition 2, 364 (33%) met definition 3, 599 met definition 4 (49.1%), and 395 met definition 5 (32.4%). Regardless of the outcome (MTP activation or MT administration), the predictive ability of the app model was consistent: when predicting activation of the MTP, the area under the curve for the model was 0.694 and when predicting MT administration, the area under the curve ranged from 0.695 to 0.711. Conclusion Regardless of the definition of MT used, the app model demonstrates moderate ability to predict the need for MT in an external, homogenous population. Importantly, the app allows the model to be iteratively recalibrated ("machine learning") and thus could improve its predictive capability as additional data are accrued. Level of evidence Diagnostic test study/Prognostic study, level III.

Platelet contraction provides a minimally invasive source for physiologic information. In this article, we describe a device that directly measures the kinetics of platelet contraction. Whole blood is injected between acrylic plates and an adherent clot forms. The bottom plate is fixed, and the top plate is attached to a wire cantilever. Platelet contraction drives deflection of the wire cantilever which is captured by a camera. Force generated by the clot with time is derived using beam equations. Force derivations were verified using a microelectromechanical (MEMS) force sensor. Kinetics of clot contraction were defined, including maximum contraction force (FMAX), lift-off time (TLIFTOFF), and contraction rate (CR). Metrics were compared with optical aggregometry and thromboelastography. FMAX correlates with optical aggregometry maximal amplitude with a Spearman's rho of 0.7904 and p = 0.0195 and thromboelastography maximal amplitude with a Spearman's rho of 0.8857 and p = 0.0188. Lift-off time correlates with optical aggregometry lag time with a Spearman's rho of 0.9048 and p = 0.002. This preliminary study demonstrates the repeatability of a useful platelet contraction device and its correlation with thromboelastography and optical aggregometry, the gold standard platelet function test.

Introduction Damage control laparotomy (DCL) for trauma is thought to be associated with increased abdominal complications. The purpose of this study is to determine the effect of DCL on abdominal complications by comparing two groups of trauma patients: DCL patients who were prospectively adjudicated to potentially being closed at the primary laparotomy (potential DEF or pDEF) and those who underwent definitive laparotomy (DEF). Methods The pDEF group was matched to DEF patients according to mechanism of injury, abdominal injury severity, operating room transfusions, and performance of a colon resection. The primary outcome was major abdominal complications (MAC), a composite variable. Results No statistically significant difference in the primary outcome, major abdominal complications, were seen (pDEF 19% versus DEF 56%, p = 0.066). The pDEF group was more likely to have a fascial dehiscence (38% versus 0%, p = 0.018), and to be re-opened after fascial closure (38% versus 0%, p = 0.018). Conclusion Damage control laparotomy was associated with clinically but not statistically significant increase in rates of MAC. Increased numbers of patients to analyze in this fashion is needed.

The objectives of this review are to assess the current state of hypertonic saline as a prehospital resuscitation fluid in hypotensive trauma patients, particularly after the 3 major Resuscitation Outcomes Consortium trauma trials in the US and Canada were halted due to futility. Hemorrhage and traumatic brain injury are the leading causes of death in both military and civilian populations. Prehospital fluid resuscitation remains controversial in civilian trauma, but small-volume resuscitation with hypertonic fluids is of utility in military scenarios with prolonged or delayed evacuation times. A large body of pre-clinical and clinical literature has accumulated over the past 30 years on the hemodynamic and, most recently, the anti-inflammatory properties of hypertonic saline, alone or with dextran-70. This review assesses the current state of hypertonic fluid resuscitation in the aftermath of the failed Resuscitation Outcomes Consortium trials.

Sepsis from bacteremia occurs in 250,000 cases annually in the United States, has a mortality rate as high as 60%, and is associated with a poorer prognosis than localized infection. Because of these high figures, empiric antibiotic administration for patients with systemic inflammatory response syndrome (SIRS) and suspected infection is the second most common indication for antibiotic administration in intensive care units (ICU)s. However, overuse of empiric antibiotics contributes to the development of opportunistic infections, antibiotic resistance, and the increase in multi-drug-resistant bacterial strains. The current method of diagnosing and ruling out bacteremia is via blood culture (BC) and Gram stain (GS) analysis.Conventional and molecular methods for diagnosing bacteremia were reviewed and compared. The clinical implications, use, and current clinical trials of polymerase chain reaction (PCR)-based methods to detect bacterial pathogens in the blood stream were detailed.BC/GS has several disadvantages. These include: some bacteria do not grow in culture media; others do not GS appropriately; and cultures can require up to 5 d to guide or discontinue antibiotic treatment. PCR-based methods can be potentially applied to detect rapidly, accurately, and directly microbes in human blood samples.Compared with the conventional BC/GS, particular advantages to molecular methods (specifically, PCR-based methods) include faster results, leading to possible improved antibiotic stewardship when bacteremia is not present.

Victims of trauma often develop impaired blood clot formation (coagulopathy) that contributes to bleeding and mortality. Fibrin polymerization is one critical component of clot formation that can be impacted by post-translational oxidative modifications of fibrinogen after exposure to oxidants. In vitro evidence suggests that Aα-C domain methionine sulfoxide formation, in particular, can induce conformational changes that prevent lateral aggregation of fibrin protofibrils during polymerization. We used mass spectrometry of plasma from trauma patients to find that fibrinogen Aα-C domain methionine sulfoxide content was selectively-increased in patients with coagulopathy vs. those without coagulopathy. This evidence supports a novel linkage between oxidative stress, coagulopathy, and bleeding after injury.

Background The endothelial glycocalyx layer (EGL) is a key regulator of vascular permeability, cell adhesion, and inflammation. The EGL is primarily composed of syndecan-1, hyaluronic acid (HA), heparan sulfate (HS) and chondroitin sulfate (CS). While many studies have observed increased shedding of syndecan-1 during hemorrhagic shock, little is known about the shedding of other EGL components, and their effects on altered permeability and coagulation. We characterized shedding of all four primary components of the EGL, as well as the plasma’s effect on permeability and thrombin generation in a cohort of trauma patients. Methods Plasma samples were collected from 5 healthy consented volunteers and 22 severely injured trauma patients upon admission to the emergency department. ELISA assays were performed to quantify shed HA, HS, CS and syndecan-1 in plasma. A colloid osmometer and Electric Cell-substrate Impedance Sensing (ECIS) system were used to measure plasma colloid osmotic pressure (COP) and cell permeability, respectively. Thrombin generation was measured using a calibrated automated thrombogram (CAT). Initial vital signs, routine laboratory values, and injury severity scores (ISS) were recorded. Non-parametric statistical tests were used to compare differences between groups. Results We observed increased shedding of all four proteins in trauma patient plasma compared to healthy controls: 31.7 vs. 21.2 U/L of CS, 175.8 vs. 121.9 ng/ml of HS, 946.7 vs. 618.6 ng/ml of HA and 245.8 vs. 31.6 ng/ml of syndecan-1 (all p

Early recognition and treatment of trauma patients requiring massive transfusion (MT) has been shown to reduce mortality. While many risk factors predicting MT have been demonstrated, there is no universally accepted method or algorithm to identify these patients. We hypothesised that even among experienced trauma surgeons, the clinical gestalt of identifying patients who will require MT is unreliable.Transfusion and mortality outcomes after trauma were observed at 10 U.S. Level-1 trauma centres in patients who survived ≥ 30 min after admission and received ≥ 1 unit of RBC within 6h of arrival. Subjects who received ≥ 10 units within 24h of admission were classified as MT patients. Trauma surgeons were asked the clinical gestalt question "Is the patient likely to be massively transfused?" 10 min after the patients arrival. The performance of clinical gestalt to predict MT was assessed using chi-square tests and ROC analysis to compare gestalt to previously described scoring systems.Of the 1245 patients enrolled, 966 met inclusion criteria and 221 (23%) patients received MT. 415 (43%) were predicted to have a MT and 551(57%) were predicted to not have MT. Patients predicted to have MT were younger, more often sustained penetrating trauma, had higher ISS scores, higher heart rates, and lower systolic blood pressures (all p0.05). Gestalt sensitivity was 65.6% and specificity was 63.8%. PPV and NPV were 34.9% and 86.2% respectively.Data from this large multicenter trial demonstrates that predicting the need for MT continues to be a challenge. Because of the increased mortality associated with delayed therapy, a more reliable algorithm is needed to identify and treat these severely injured patients earlier.

Background Collider bias, or stratifying data by a covariate consequence rather than cause (confounder) of treatment and outcome, plagues randomised and observational trauma research. Of the seven trials of prehospital hypertonic saline in dextran (HSD) that have been evaluated in systematic reviews, none found an overall between-group difference in survival, but four reported significant subgroup effects. We hypothesised that an avoidable type of collider bias often introduced inadvertently into trauma comparative effectiveness research could explain the incongruous findings. Methods The two most recent HSD trials, a single-site pilot and a multi-site pivotal study, provided data for a secondary analysis to more closely examine the potential for collider bias. The two trials had followed the a priori statistical analysis plan to subgroup patients by a post-randomisation covariate and well-established surrogate for bleeding severity, massive transfusion (MT), ≥10 unit of red blood cells within 24 h of admission. Despite favourable HSD effects in the MT subgroup, opposite effects in the non-transfused subgroup halted the pivotal trial early. In addition to analyzing the data from the two trials, we constructed causal diagrams and performed a meta-analysis of the results from all seven trials to assess the extent to which collider bias could explain null overall effects with subgroup heterogeneity. Results As in previous trials, HSD induced significantly greater increases in systolic blood pressure (SBP) from prehospital to admission than control crystalloid ( p = 0.003). Proportionately more HSD than control decedents accrued in the non-transfused subgroup, but with paradoxically longer survival. Despite different study populations and a span of over 20 years across the seven trials, the reported mortality effects were consistently null, summary RR = 0.99 ( p = 0.864, homogeneity p = 0.709). Conclusions HSD delayed blood transfusion by modifying standard triggers like SBP with no detectable effect on survival. The reported heterogeneous HSD effects in subgroups can be explained by collider bias that trauma researchers can avoid by improved covariate selection and data capture strategies.

Trauma-induced coagulopathy following severe injury is associated with increased bleeding and mortality. Injury may result in alteration of cellular phenotypes and release of cell-derived microparticles (MP). Circulating MPs are procoagulant and support thrombin generation (TG) and clotting. We evaluated MP and TG phenotypes in severely injured patients at admission, in relation to coagulopathy and bleeding.As part of the Prospective Observational Multicenter Major Trauma Transfusion (PROMMTT) study, research blood samples were obtained from 180 trauma patients requiring transfusions at 5 participating centers. Twenty five healthy controls and 40 minimally injured patients were analyzed for comparisons. Laboratory criteria for coagulopathy was activated partial thromboplastin time (APTT) ≥ 35 sec. Samples were analyzed by Calibrated Automated Thrombogram to assess TG, and by flow cytometry for MP phenotypes [platelet (PMP), erythrocyte (RMP), leukocyte (LMP), endothelial (EMP), tissue factor (TFMP), and Annexin V positive (AVMP)].21.7% of patients were coagulopathic with the median (IQR) APTT of 44 sec (37, 53), and an Injury Severity Score of 26 (17, 35). Compared to controls, patients had elevated EMP, RMP, LMP, and TFMP (all p0.001), and enhanced TG (p0.0001). However, coagulopathic PROMMTT patients had significantly lower PMP, TFMP, and TG, higher substantial bleeding, and higher mortality compared to non-coagulopathic patients (all p0.001).Cellular activation and enhanced TG are predominant after trauma and independent of injury severity. Coagulopathy was associated with lower thrombin peak and rate compared to non-coagulopathic patients, while lower levels of TF-bearing PMPs were associated with substantial bleeding.

The impact of do-not-resuscitate (DNR) orders has not been systematically evaluated in acute trauma research. We determined the frequency, timing, and impact on mortality-based effect estimates for patients with DNR orders in the Prospective Observational Multicenter Major Trauma Transfusion (PROMMTT) study.Trauma patients surviving at least 30 minutes and transfused one or greater unit of red blood cell within 6 hours of admission (n = 1,245) from 10 Level 1 centers were enrolled. We report descriptive statistics and results from survival analysis to compare the association of blood product transfusion ratios with outcome defined as mortality and as a composite, DNR, and death.DNRs were reported for 95 patients (7.6%), with 94 in-hospital deaths. There were 172 deaths without DNRs. Of 90 known DNR order times, the median was 53 hours (interquartile range, 9-186 hours) after admission; the median DNR-to-death time was 10 hours (2-32 hours). DNRs were for comfort measures only (43%), no cardiopulmonary resuscitation (40%), and no intubation or cardiopulmonary resuscitation (16%). Compared with the 116 non-DNR deaths that occurred after the earliest DNR order (2 hours), the DNR decedents were significantly older with a less severe base deficit, fewer red blood cell and plasma transfusions, and a later median time of death (98 [21-230] hours vs. 17 [4-91] hours). In multivariable Cox models that accounted for time-varying blood product ratios, the associations were consistent, regardless of whether outcome was defined as mortality or the composite.DNR orders were instituted after the 24-hour period of highest mortality risk and more often in older patients not in severe shock. Findings from the primary PROMMTT analyses of the impact of blood product ratios on survival did not materially change when the original mortality outcome was redefined as a composite of DNR or death. DNR orders are potentially an important mediating variable that should be systematically evaluated in trauma research.

Background In the PRospective Observational Multicenter Major Trauma Transfusion (PROMMTT) study, waiver of consent was used because previous literature reported low response rates and subsequent bias. The goal of this article was to examine the rationale and tradeoffs of using waiver of consent in PROMMTT. Methods PROMMTT enrolled trauma patients receiving at least 1 U of red blood cells within 6 hours after admission at 10 US Level 1 trauma centers. Local institutional review boards (IRBs) from all sites approved the study. Site 8 was required by their IRB to attempt consent but was allowed to retain data on patients unable to be consented. Results Of 121 subjects enrolled at Site 8, 55 consents were obtained (46%), and no patient or legally authorized representative refused to give consent. Of the patients, 36 (30%) died, and 6 (5%) were discharged before consent could be attempted. Consent was attempted but not possible among 24 patients (20%). Of the 10 clinical sites, 6 of the local IRBs approved collection of residual blood samples, 1 had previous approval to collect timed blood samples under a separate protocol, and 3 reported that their local IRBs would not approve collection of residual blood under a waiver of consent. Conclusion Waiver of consent was used in PROMMTT because of the potential adverse impact of consent refusals; however, there were no refusals. If the IRB for Site 8 had required withdrawal of patients unable to consent and destruction of their data, a serious bias would likely have been introduced. Other tradeoffs included a reduction in sites participating in residual blood collection and a smaller than expected amount of residual blood collected among sites operating under a waiver of consent. Noninterventional emergency research studies should consider these potential tradeoffs carefully before deciding whether waiver of consent would best achieve the goals of a study.