High-mobility group box 1 (HMGB1) is a late mediator of the systemic inflammation associated with sepsis. Recently, HMGB1 has been shown in animals to be a mediator of hemorrhage-induced organ dysfunction. However, the time course of plasma HMGB1 elevations after trauma in humans remains to be elucidated. Consequently, we hypothesized that mechanical trauma in humans would result in early significant elevations of plasma HMGB1. Trauma patients at risk for multiple organ failure (ISS ≥15) were identified for inclusion (n = 23), and postinjury plasma samples were assayed for HMGB1 by enzyme-linked immunosorbent assay. Comparison of postinjury HMGB1 levels with markers for patient outcome (age, injury severity score, units of red blood cell (RBC) transfused per first 24 h, and base deficit) was performed. To investigate whether postinjury transfusion contributes to elevations of circulating HMGB1, levels were determined in both leuko-reduced and non–leuko-reduced packed RBCs. Plasma HMGB1 was elevated more than 30-fold above healthy controls within 1 h of injury (median, 57.76 vs. 1.77 ng/mL; P < 0.003), peaked from 2 to 6 h postinjury (median, 526.18 ng/mL; P < 0.01 vs. control), and remained elevated above control through 136 h. No clear relationship was evident between postinjury HMGB1 levels and markers for patient outcome. High-mobility group box 1 levels increase with duration of RBC storage, although concentrations did not account for postinjury plasma levels. Leuko-reduced attenuated HMGB1 levels in packed RBCs by approximately 55% (P < 0.01). Plasma HMGB1 is significantly increased within 1 h of trauma in humans with marked elevations occurring from 2 to 6 h postinjury. These results suggest that, in contrast to sepsis, HMGB1 release is an early event after traumatic injury in humans. Thus, HMGB1 may be integral to the early inflammatory response to trauma and is a potential target for future therapeutics.

Introduction: Historically, hemorrhage has been attributed as the leading cause (40%) of early death. However, a rigorous, real-time classification of the cause of death (COD) has not been performed. This study sought to prospectively adjudicate and classify COD to determine the epidemiology of trauma mortality. Methods: 18 trauma centers prospectively enrolled all adult trauma patients at the time of death during 12/2015-8/2017. Immediately following death, attending providers adjudicated the primary and contributing secondary COD using standardized definitions. Data were confirmed by autopsies, if performed. Results: 1536 patients were enrolled with a median age of 55 (IQR 32-75). 74.5% were male. Penetrating mechanism (n=412) patients were younger (32 vs 64, p<0.0001) and more likely male (86.7% vs. 69.9%, p<0.0001). Falls were the most common mechanism of injury (26.6%), with GSWs second (24.3%). The most common overall primary COD was TBI (45%), followed by exsanguination (23%). TBI was non-survivable in 82.2% of cases. Blunt patients were more likely to have TBI (47.8% vs. 37.4%, p<0.0001) and penetrating patients exsanguination (51.7% vs 12.5%, p<0.0001) as the primary COD. Exsanguination was the predominant prehospital (44.7%) and early COD (39.1%) with TBI most common later. Penetrating mechanism patients died earlier with 80.1% on day 0 (vs. 38.5%, p<0.0001). Most deaths were deemed disease related (69.3%), rather than by limitation of further aggressive care (30.7%). Hemorrhage was a contributing cause to 38.8% of deaths that occurred due to withdrawal of care. Conclusions: Exsanguination remains the predominant early primary COD with TBI accounting for most deaths at later time points. Timing and primary COD vary significantly by mechanism. Contemporaneous adjudication of COD is essential to elucidate the true understanding of patient outcome, center performance, and future research.

BACKGROUND Severe trauma is associated with massive alterations in metabolism. Thus far, investigations have relied upon traditional bio-analytical approaches including calorimetry or nuclear magnetic resonance. However, recent strides in the field of mass spectrometry (MS)-based metabolomics present enhanced analytic opportunities to characterize a wide range of metabolites in the critical care setting. METHODS MS-based metabolomics analyses were performed on plasma samples from severely injured patients trauma-activation field blood (TAFB) and plasma samples obtained during emergency department thoracotomy (EDT). These were compared against the metabolic profiles of healthy controls. RESULTS Few significant alterations were observed between TAFB and EDT patients. On the other hand, we identified trauma-dependent metabolic signatures which support a state of hypercatabolism, driven by sugar consumption, lipolysis and fatty acid utilization, accumulation of ketone bodies, proteolysis and nucleoside breakdown which provides carbon and nitrogen sources to compensate for trauma-induced energy consumption and negative nitrogen balance. Unexpectedly, metabolites of bacterial origin (including tricarballylate and citramalate) were detected in plasma from trauma patients. CONCLUSIONS In the future, the correlation between metabolomics adaptation and recovery outcomes could be studied by MS-based approaches and this work can provide a method for assessing the efficacy of alternative resuscitation strategies.