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Background The hypercoagulable state associated with pancreatic adenocarcinoma (PDA) results in increased risk of venous thromboembolism, leading to substantial morbidity and mortality. Recently, neutrophil extracellular traps (NETs), whereby activated neutrophils release their intracellular contents containing DNA, histones, tissue factor, high mobility group box 1 (HMGB1) and other components have been implicated in PDA and in cancer-associated thrombosis. Methods Utilizing an orthotopic murine PDA model in C57/Bl6 mice and patient correlative samples, we studied the role of NETs in PDA hypercoagulability and targeted this pathway through treatment with the NET inhibitor chloroquine. PAD4 and RAGE knockout mice, deficient in NET formation, were used to study the role of NETs in platelet aggregation, release of tissue factor and hypercoagulability. Platelet aggregation was assessed using collagen-activated impedance aggregometry. Levels of circulating tissue factor, the initiator of extrinsic coagulation, were measured using ELISA. Thromboelastograms (TEGs) were performed to assess hypercoagulability and changes associated with treatment. Correlative data and samples from a randomized clinical trial of preoperative gemcitabine/nab-paclitaxel with and without hydroxychloroquine were studied and the impact of treatment on venous thromboembolism (VTE) rate was evaluated. Results The addition of NETs to whole blood stimulated platelet activation and aggregation. DNA and the receptor for advanced glycation end products (RAGE) were necessary for induction of NET associated platelet aggregation. PAD4 knockout tumor-burdened mice, unable to form NETs, had decreased aggregation and decreased circulating tissue factor. The NET inhibitor chloroquine reduces platelet aggregation, reduces circulating tissue factor and decreases hypercoagulability on TEG. Review of correlative data from patients treated on a randomized protocol of preoperative chemotherapy with and without hydroxychloroquine demonstrated a reduction in peri-operative VTE rate from 30 to 9.1% with hydroxychloroquine that neared statistical significance ( p  = 0.053) despite the trial not being designed to study VTE. Conclusion NETs promote hypercoagulability in murine PDA through stimulation of platelets and release of tissue factor. Chloroquine inhibits NETs and diminishes hypercoagulability. These findings support clinical study of chloroquine to lower rates of venous thromboembolism in patients with cancer. Trial registration This study reports correlative data from two clinical trials that registered with clinicaltrials.gov, NCT01128296 (May 21, 2010) and NCT01978184 (November 7, 2013).

Severe injury is known to cause a systemic cytokine storm that is associated with adverse outcomes. However, a comprehensive assessment of the time-dependent changes in circulating levels of a broad spectrum of protein immune mediators and soluble immune mediator receptors in severely injured trauma patients remains uncharacterized. To address this knowledge gap, we defined the temporal and outcome-based patterns of 184 known immune mediators and soluble cytokine receptors in the circulation of severely injured patients. Proteomics (aptamer-based assay, SomaLogic, Inc) was performed on plasma samples drawn at 0, 24, and 72 hours (h) from time of admission from 150 trauma patients, a representative subset from the Prehospital Plasma during Air Medical Transport in Trauma Patients at Risk for Hemorrhagic Shock (PAMPer) trial. Patients were categorized into outcome groups including Early Non-Survivors (died within 72 h; ENS; n=38), Non-Resolvers (died after 72 h or required ≥7 days of intensive care; NR; n=78), and Resolvers (survivors that required < 7 days of intensive care; R; n=34), with low Injury Severity Score (ISS) patients from the Tranexamic Acid During Prehospital Transport in Patients at Risk for Hemorrhage After Injury (STAAMP) trial as controls. The major findings include an extensive release of immune mediators and cytokine receptors at time 0h that is more pronounced in ENS and NR patients. There was a selective subset of mediators elevated at 24 and 72 h to a greater degree in NR patients, including multiple cytokines and chemokines not previously described in trauma patients. These findings were validated in a quantitative fashion using mesoscale discovery immunoassays (MSD) from an external validation cohort (VC) of samples from 58 trauma patients matched for R and NR status. This comprehensive longitudinal description of immune mediator patterns associated with trauma outcomes provides a new level of characterization of the immune response that follows severe injury.

Injury mechanism is an important consideration when conducting clinical trials in trauma. Mechanisms of injury may be associated with differences in mortality risk and immune response to injury, impacting the potential success of the trial. We sought to characterize clinical and endothelial cell damage marker differences across blunt and penetrating injured patients enrolled in three large, prehospital randomized trials which focused on hemorrhagic shock. In this secondary analysis, patients with systolic blood pressure < 70 or systolic blood pressure < 90 and heart rate > 108 were included. In addition, patients with both blunt and penetrating injuries were excluded. The primary outcome was 30-day mortality. Mortality was characterized using Kaplan–Meier and Cox proportional-hazards models. Generalized linear models were used to compare biomarkers. Chi squared tests and Wilcoxon rank-sum were used to compare secondary outcomes. We characterized data of 696 enrolled patients that met all secondary analysis inclusion criteria. Blunt injured patients had significantly greater 24-h (18.6% vs. 10.7%, log rank p  = 0.048) and 30-day mortality rates (29.7% vs. 14.0%, log rank p  = 0.001) relative to penetrating injured patients with a different time course. After adjusting for confounders, blunt mechanism of injury was independently predictive of mortality at 30-days (HR 1.84, 95% CI 1.06–3.20, p  = 0.029), but not 24-h (HR 1.65, 95% CI 0.86–3.18, p  = 0.133). Elevated admission levels of endothelial cell damage markers, VEGF, syndecan-1, TM, S100A10, suPAR and HcDNA were associated with blunt mechanism of injury. Although there was no difference in multiple organ failure (MOF) rates across injury mechanism (48.4% vs. 42.98%, p  = 0.275), blunt injured patients had higher Denver MOF score ( p  < 0.01). The significant increase in 30-day mortality and endothelial cell damage markers in blunt injury relative to penetrating injured patients highlights the importance of considering mechanism of injury within the inclusion and exclusion criteria of future clinical trials.

Trauma resuscitation practices have continued to improve with new advances targeting prehospital interventions. The critical care burden associated with severely injured patients at risk of hemorrhage has been poorly characterized. We aim to describe the individual and additive effects of multiorgan failure (MOF) and nosocomial infection (NI) on delayed mortality and resource utilization. A secondary analysis of harmonized data from two large prehospital randomized controlled trials (Prehospital Air Medical Plasma (PAMPer) Trial and Study of Tranexamic Acid during Air and Ground Medical Prehospital Transport (STAAMP) Trial) was conducted. Only those patients who survived beyond the first 24 hours post-injury and spent at least one day in the ICU were included. Patients were stratified by development of MOF only, NI only, both, or neither and diagnosis of early (≤ 3 days) versus late MOF (> 3 days). Risk factors of NI and MOF, time course of these ICU complications, associated mortality, and hospital resource utilization were evaluated. Of the 869 patients who were enrolled in PAMPer and STAAMP and who met study criteria, 27.4% developed MOF only (n = 238), 10.9% developed NI only (n = 95), and 15.3% were diagnosed with both MOF and NI (n = 133). Patients developing NI and/or MOF compared to those who had an uncomplicated ICU course had greater injury severity, lower GCS, and greater shock indexes. Early MOF occurred in isolation, while late MOF more often followed NI. MOF was associated with 65% higher independent risk of 30-day mortality when adjusting for cofounders (OR 1.65; 95% CI 1.04–2.6; p  = 0.03), however NI did not significantly affect odds of mortality. NI was individually associated with longer mechanical ventilation, ICU stay, hospital stay, and rehabilitation requirements, and the addition of MOF further increased the burden of inpatient and post-discharge care. MOF and NI remain common complications for those who survive traumatic injury. MOF is a robust independent predictor of mortality following injury in this cohort, and NI is associated with higher resource utilization. Timing of these ICU complications may reveal differences in pathophysiology and offer targets for continued advancements in treatment.

Immune dysfunction is an important factor driving mortality and adverse outcomes after trauma but remains poorly understood, especially at the cellular level. To deconvolute the trauma-induced immune response, we applied single-cell RNA sequencing to circulating and bone marrow mononuclear cells in injured mice and circulating mononuclear cells in trauma patients. In mice, the greatest changes in gene expression were seen in monocytes across both compartments. After systemic injury, the gene expression pattern of monocytes markedly deviated from steady state with corresponding changes in critical transcription factors, which can be traced back to myeloid progenitors. These changes were largely recapitulated in the human single-cell analysis. We generalized the major changes in human CD14 + monocytes into 6 signatures, which further defined 2 trauma patient subtypes (SG1 vs. SG2) identified in the whole-blood leukocyte transcriptome in the initial 12 hours after injury. Compared with SG2, SG1 patients exhibited delayed recovery, more severe organ dysfunction, and a higher incidence of infection and noninfectious complications. The 2 patient subtypes were also recapitulated in burn and sepsis patients, revealing a shared pattern of immune response across critical illness. Our data will be broadly useful to further explore the immune response to inflammatory diseases and critical illness.

Background The staged laparotomy in the operative management of emergency general surgery (EGS) patients is an extension of trauma surgeons operating on this population. Indications for its application, however, are not well defined, and are currently based on the lethal triad used in physiologically-decompensated trauma patients. This study sought to determine the acute indications for the staged, rapid source control laparotomy (RSCL) in EGS patients. Methods All EGS patients undergoing emergent staged RSCL and non-RSCL over 3 years were studied. Demographics, physiologic parameters, perioperative variables, outcomes, and survival were compared. Logistic regression models determined the influence of physiologic parameters on mortality and postoperative complications. EGS-RSCL indications were defined. Results 215 EGS patients underwent emergent laparotomy; 53 (25 %) were staged RSCL. In the 53 patients who underwent a staged RSCL based on the lethal triad, adjusted multivariable regression analysis shows that when used alone, no component of the lethal triad independently improved survival. Staged RSCL may decrease mortality in patients with preoperative severe sepsis / septic shock, and an elevated lactate (≥3); acidosis (pH ≤ 7.25); elderly (≥70); male gender; and multiple comorbidities (≥3). Of the 162 non-RSCL emergent laparotomies, 27 (17 %) required unplanned re-explorations; of these, 17 (63 %) had sepsis preoperatively and 9 (33 %) died. Conclusions The acute physiologic indicators that help guide operative decisions in trauma may not confer a similar survival advantage in EGS. To replace the lethal triad, criteria for application of the staged RSCL in EGS need to be defined. Based on these results, the indications should include severe sepsis / septic shock, lactate, acidosis, gender, age, and pre-existing comorbidities. When correctly applied, the staged RSCL may help to improve survival in decompensated EGS patients.

BackgroundThe use of low titer group O whole blood (LTOWB) for resuscitation of patients with traumatic hemorrhage is becoming increasingly common. Practices regarding the administration of RhD-positive LTOWB to childbearing age females (CBAFs) vary between institutions due to concerns about RhD alloimmunization. This study examined practices related to LTOWB transfusion as they pertain to age and sex.MethodsThis was a secondary analysis of the Shock, Whole blood, and Assessment of TBI (traumatic brain injury) trial, a prospective, multicenter observational cohort study where outcomes following LTOWB transfusion were analyzed at seven level 1 trauma centers between 2018 and 2021, as well as a survey on transfusion practices at these centers conducted in 2023. The proportion of patients who received LTOWB or components was examined over the course of the study and grouped by age and sex, and the RhD group of injured CBAFs was documented.ResultsA total of 1046 patients were evaluated: 130 females aged <50 years (CBAFs), 77 females aged ≥50 years; 661 males aged <50 years, and 178 males aged ≥50 years. Among them, 26.2% of CBAFs received RhD-positive LTOWB, whereas 57.1%–66.3% of other sex/age groups received LTOWB. The proportion of CBAFs who received LTOWB increased significantly throughout the 4 years of this study. Except for older women in years 2 and 4, CBAFs were significantly less likely to receive LTOWB than all other groups for the study period and individual years. Among the 33 CBAFs who received LTOWB and for whom an RhD type was available, 4/33 (12.1%) were RhD-negative, while 9/95 (9.5%) CBAFs who received component therapy were RhD-negative. RhD blood product selection practices varied considerably between institutions.ConclusionsMany institutions transfused LTOWB to CBAFs. Policies regarding RhD product selection varied. Of the total cohort, the proportion of RhD-negative CBAFs who received LTOWB increased over time but remained lower than all other groups.Level of evidence3.

Background Optimizing resuscitation to reduce inflammation and organ dysfunction following human trauma-associated hemorrhagic shock is a major clinical hurdle. This is limited by the short duration of pre-clinical studies and the sparsity of early data in the clinical setting. Methods We sought to bridge this gap by linking preclinical data in a porcine model with clinical data from patients from the Prospective, Observational, Multicenter, Major Trauma Transfusion (PROMMTT) study via a three-compartment ordinary differential equation model of inflammation and coagulation. Results The mathematical model accurately predicts physiologic, inflammatory, and laboratory measures in both the porcine model and patients, as well as the outcome and time of death in the PROMMTT cohort. Model simulation suggests that resuscitation with plasma and red blood cells outperformed resuscitation with crystalloid or plasma alone, and that earlier plasma resuscitation reduced injury severity and increased survival time. Conclusions This workflow may serve as a translational bridge from pre-clinical to clinical studies in trauma-associated hemorrhagic shock and other complex disease settings. Plain language summary Research to improve survival in patients with severe bleeding after major trauma presents many challenges. Here, we created a computer model to simulate the effects of severe bleeding. We refined this model using data from existing animal studies to ensure our simulations were accurate. We also used patient data to further refine the simulations to accurately predict which patients would live and which would not. We studied the effects of different treatment protocols on these simulated patients and show that treatment with plasma (the fluid portion of blood that helps form blood clots) and red blood cells jointly, gave better results than treatment with intravenous fluid or plasma alone. Early treatment with plasma reduced injury severity and increased survival time. This modelling approach may improve our ability to evaluate new treatments for trauma-associated bleeding and other acute conditions. Cannon et al. integrate large animal and human experimental results to develop and validate a mechanistic model of acute hemorrhagic shock. This model, in turn, can be used to evaluate therapeutic interventions for severely injured patients.

BackgroundTranexamic acid (TXA) has been hypothesized to mitigate coagulopathy in patients after traumatic injury. Despite previous prehospital clinical trials demonstrating a TXA survival benefit, none have demonstrated correlated changes in thromboelastography (TEG) parameters. We sought to analyze if missing TEG data contributed to this paucity of findings.MethodsWe performed a secondary analysis of the Study of Tranexamic Acid During Air Medical and Ground Prehospital Transport Trial. We compared patients that received TEG (YES-TEG) and patients unable to be sampled (NO-TEG) to analyze subgroups in which to investigate TEG differences. TEG parameter differences across TXA intervention arms were assessed within subgroups disproportionately present in the NO-TEG relative to the YES-TEG cohort. Generalized linear models controlling for potential confounders were applied to findings with p<0.10 on univariate analysis.ResultsNO-TEG patients had lower prehospital systolic blood pressure (SBP) (100 (78, 140) vs 125 (88, 147), p<0.01), lower prehospital Glascow Coma Score (14 (3, 15) vs 15 (12, 15), p<0.01), greater rates of prehospital intubation (39.4% vs 24.4%, p<0.01) and greater mortality at 30 days (36.4% vs 6.8%, p<0.01). NO-TEG patients had a greater international normalized ratio relative to the YES-TEG subgroup (1.2 (1.1, 1.5) vs 1.1 (1.0, 1.2), p=0.04). Within a severe prehospital shock cohort (SBP<70), TXA was associated with a significant decrease in clot lysis at 30 min on multivariate analysis (β=−27.6, 95% CI (−51.3 to –3.9), p=0.02).ConclusionsMissing data, due to the logistical challenges of sampling certain severely injured patients, may be associated with a lack of TEG parameter changes on TXA administration in the primary analysis. Previous demonstration of TXA’s survival benefit in patients with severe prehospital shock in tandem with the current findings supports the notion that TXA acts at least partially by improving clot integrity.Level of evidenceLevel II.

BackgroundOperative mortality for high-grade liver injury (HGLI) remains 42% to 66%, with near-universal mortality after retrohepatic caval injury. The objective of this study was to evaluate mortality and complications of operative and nonoperative management (OM and NOM) of HGLI at our institution, characterized by a trauma surgery–liver surgery collaborative approach to trauma care.MethodsThis was an observational cohort study of adult patients (age ≥16) with HGLI (The American Association for Surgery of Trauma (AAST) grades IV and V) admitted to an urban level I trauma center from January 2010 to November 2021. Data were obtained from the electronic medical record and state trauma registry. Patients were categorized by management strategy: immediate OM or planned NOM. The primary outcome was 30-day mortality.ResultsOur institution treated 179 patients with HGLI (78% blunt, 22% penetrating); 122 grade IV (68%) and 57 grade V (32%) injuries. All abdominal gunshot wounds and 49% of blunt injuries underwent initial OM; 51% of blunt injuries were managed initially by NOM. Procedures at the initial operation included hepatorrhaphy±packing (66.4%), nonanatomic resection (5.6%), segmentectomy (9.3%), and hepatic lobectomy (7.5%). Thirty-day mortality in the OM group was substantially lower than prior reports (23.4%). Operative mortality attributable to the liver injury was 15.7%. 19.4% of patients failed NOM with one death (1.4%).ConclusionWe report an operative mortality of 23.4% for HGLI in a trauma care system characterized by a collaborative approach by trauma surgeons and liver surgeons.Level of evidenceIII