Associations of Fatty Liver Disease With Recovery After Traumatic Injury.

INTRODUCTION: Fatty liver disease (FLD) is associated with systemic inflammation, metabolic disease, and socioeconomic risk factors for poor health outcomes. Little is known on how adults with FLD recover from traumatic injury. METHODS: We studied adults admitted to the intensive care unit of a level 1 trauma center (2016-2020), excluding severe head injury/cirrhosis (N = 510). We measured the liver-spleen attenuation difference in Hounsfield units (HUL-S) using virtual noncontrast computerized tomography scans: none (HUL-S>1), mild (-10≤HUL-S<1), moderate/severe (HUL-S < -10). We used Cox models to examine the "hazard" of recovery from systemic inflammatory response (SIRS score 2 or higher) organ dysfunction, defined as sequential organ failure assessment score 2 or higher, and lactate clearance (<2 mmol/L) in relation to FLD. RESULTS: Fifty-one participants had mild and 29 had moderate/severe FLD. The association of FLD with recovery from SIRS differed according to whether an individual had shock on admission (hazard ratio [HR] = 0.76; 95% confidence interval [CI] 0.55-1.05 with shock; HR = 1.81; 95% CI 1.43-2.28 without shock). Compared to patients with no FLD, the hazard of lactate clearance was similar for mild FLD (HR = 1.04; 95% CI 0.63-1.70) and lower for moderate/severe FLD (HR = 0.40; 95% CI 0.18-0.89). CONCLUSIONS: FLD is common among injured adults. Associations of FLD with outcomes after shock and critical illness warrant further study.

HLA-A Locus is Associated With Sepsis and Septic Shock After Traumatic Injury.

OBJECTIVE: Determine whether variation in the HLA region is associated with the development of post-traumatic sepsis and septic shock. BACKGROUND: Sepsis-related deaths remain a major source of mortality after traumatic injury. Genetic characteristics may contribute to susceptibility to adverse outcomes including sepsis and septic shock. Recent advances in next-generation sequencing technology now allow comprehensive genotyping of the HLA region. METHODS: White adult trauma patients requiring more than 2 days of mechanical ventilation underwent HLA genotyping, and were followed for the development of sepsis and septic shock. Odds ratios (OR) for the associations between our outcomes and HLA variants were estimated, a correction for multiple comparisons was applied, and significant variants were included in regression models adjusting for potential confounders. RESULTS: A total of 1184 patients were included. Patients were severely injured (median injury severity score 33); 33% developed sepsis, 6% septic shock, and in-hospital mortality was 14%. An amino acid variant (156Q) within the HLA-A peptide-binding groove was associated with greater odds of sepsis [OR 1.50, (1.18-1.89)]. HLA-A∗02:01 was associated with lower odds of septic shock [OR 0.52, (0.32-0.82)]. These associations remained significant after adjusting for potential confounders. CONCLUSIONS: This is the first study to apply next-generation sequencing techniques to evaluate associations between immunogenetic factors and post-traumatic sepsis and septic shock. Associations with class I HLA variants are novel as they implicate adaptive immunity in post-traumatic sepsis. These findings are a step towards developing a panel of genetic markers assessing risk of infection-related complications as we move towards more personalized medicine.

Duration of Respiratory Failure After Trauma Is Not Associated With Increased Long-Term Mortality.

OBJECTIVES: Although 1-year survival in medically critically ill patients with prolonged mechanical ventilation is less than 50%, the relationship between respiratory failure after trauma and 1-year mortality is unknown. We hypothesize that respiratory failure duration in trauma patients is associated with decreased 1-year survival. DESIGN: Retrospective cohort of trauma patients. SETTING: Single center, level 1 trauma center. PATIENTS: Trauma patients admitted from 2011 to 2014; respiratory failure is defined as mechanical ventilation greater than or equal to 48 hours, excluded head Abbreviated Injury Score greater than or equal to 4. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Mortality was calculated from the Washington state death registry. Cohort was divided into short (≤ 14 d) and long (> 14 d) ventilation groups. We compared survival with a Cox proportional hazard model and generated a receiver operator characteristic to describe the respiratory failure and mortality relationship. Data are presented as medians with interquartile ranges and hazard ratios with 95% CIs. We identified 1,503 patients with respiratory failure; median age was 51 years (33-65 yr) and Injury Severity Score was 19 (11-29). Median respiratory failure duration was 3 days (2-6 d) with 10% of patients in the long respiratory failure group. Cohort mortality at 1 year was 16%, and there was no difference in mortality between short and long duration of respiratory failure. Predictions for 1-year mortality based on respiratory failure duration demonstrated an area under the receiver operator characteristic curve of 0.57. We determined that respiratory failure patients greater than or equal to 75 years had an increased hazard of death at 1 year, hazard ratio, 6.7 (4.9-9.1), but that within age cohorts, respiratory failure duration did not influence 1-year mortality. CONCLUSIONS: Duration of mechanical ventilation in the critically injured is not associated with 1-year mortality. Duration of ventilation following injury should not be used to predict long-term survival.

Outcomes in necrotizing soft tissue infections treated with therapeutic plasma exchange.

BACKGROUND: Treatment of necrotizing soft tissue infections (NSTIs) includes prompt surgical debridement and antibiotics, but despite standard care, the morbidity and mortality remain high. Since therapeutic plasma exchange (TPE) has been considered for treatment of severe sepsis, this study evaluates the efficacy of TPE for patients with NSTI. STUDY DESIGN AND METHODS: This is a retrospective study of patients with diagnosis of NSTI who received treatment with and without TPE over an 11-year period. The primary outcome was in-hospital mortality. RESULTS: Fifty-two patients with NSTI treated with TPE (TPE group) and 125 patients with NSTI not treated with TPE (non-TPE group) were assessed. Nineteen (36.5%) patients died in the TPE group, and 35 (28%) patients died in the non-TPE group. Within the TPE group, there was significant improvement in white blood cell (WBC) count and sodium levels 7 days after TPE treatment, but no improvement in creatinine. Inverse probability weighting based on propensity scores was used to compare survival in the TPE and non-TPE groups and demonstrated that TPE was associated with an increased odds of death (odds ratio, 2.8). A second analysis matched for six variables yielded 31 pairs and demonstrated no significant difference in mortality or length of stay. CONCLUSIONS: This study describes the largest series of patients with NSTIs treated with TPE and showed no evidence of clinical benefit. Further carefully designed studies with meaningful clinical endpoints would prove useful in assessing reproducibility and determining if there is a role for TPE in other forms of severe sepsis.

Acute kidney injury subphenotypes based on creatinine trajectory identifies patients at increased risk of death.

BACKGROUND: Acute kidney injury (AKI) is common among intensive care unit (ICU) patients. AKI is highly heterogeneous, with variable links to poor outcomes. Current approaches to classify AKI severity and identify patients at highest risk for poor outcomes focus on the maximum change in serum creatinine (SCr) values. However, these scores are hampered by the need for a reliable baseline SCr value and the absence of a component differentiating transient from persistent rises in SCr. We hypothesized that identification of resolving or nonresolving AKI subphenotypes based on the early trajectory of SCr values in the ICU would better differentiate patients at risk of hospital mortality. METHODS: We performed a secondary analysis of two prospective studies of ICU patients admitted to a trauma ICU (group 1; n = 1914) or general medical-surgical ICUs (group 2; n = 1867). In group 1, we tested definitions for resolving and nonresolving AKI subphenotypes and selected the definitions resulting in subphenotypes with the greatest separation in risk of death relative to non-AKI controls. We applied this definition to group 2 and tested whether the subphenotypes were independently associated with hospital mortality after adjustment for AKI severity. RESULTS: AKI occurred in 46% and 69% of patients in groups 1 and 2, respectively. In group 1, a resolving AKI subphenotype (defined as a decrease in SCr of 0.3 mg/dl or 25% from maximum in the first 72 h of study enrollment) was associated with a low risk of death. A nonresolving AKI subphenotype (defined as all AKI cases not meeting the "resolving" definition) was associated with a high risk of death. In group 2, the resolving AKI subphenotype was not associated with increased mortality (relative risk [RR] 0.86, 95% CI 0.63-1.17), whereas the nonresolving AKI subphenotype was associated with higher mortality (RR 1.68, 95% CI 1.15-2.44) even after adjustment for AKI severity stage. CONCLUSIONS: The trajectory of SCr levels identifies AKI subphenotypes with different risks for death, even among AKI cases of similar severity. These AKI subphenotypes might better define the patients at risk for poor outcomes who might benefit from novel interventions.

Traumatic injury, early gene expression, and gram-negative bacteremia.

OBJECTIVES: Bacteremic trauma victims have a higher risk of death than their nonbacteremic counterparts. The role that altered immunity plays in the development of bacteremia is unknown. Using an existing dataset, we sought to determine if differences in early postinjury immune-related gene expression are associated with subsequent Gram-negative bacteremia. DESIGN: Retrospective cohort study, a secondary analysis of the Glue Grant database. SETTING: Seven level I trauma centers across the United State. SUBJECTS: Severely injured blunt trauma patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Total leukocyte gene expression was compared between the subjects in whom Gram-negative bacteremia developed and those in whom it did not develop. We observed that Gram-negative bacteremia was an independent risk factor for death (odds ratio, 1.86; p = 0.015). We then compared gene expression at 12 and 96 hours after injury in 10 subjects in whom subsequently Gram-negative bacteremia developed matched to 26 subjects in whom it did not develop. At 12 hours, expression of 64 probes differed more than or equal to 1.5-fold; none represented genes related to innate or adaptive immunity. By 96 hours, 102 probes were differentially expressed with 20 representing 15 innate or adaptive immunity genes, including down-regulation of IL1B and up-regulation of IL1R2, reflecting suppression of innate immunity in Gram-negative bacteremia subjects. We also observed down-regulation of adaptive immune genes in the Gram-negative bacteremia subjects. CONCLUSIONS: By 96 hours after injury, there are differences in leukocyte gene expression associated with the development of Gram-negative bacteremia, reflecting suppression of both innate and adaptive immunity. Gram-negative bacteremia after trauma is, in part, consequence of host immunity failure and may not be completely preventable by standard infection-control techniques.

IL1RN coding variant is associated with lower risk of acute respiratory distress syndrome and increased plasma IL-1 receptor antagonist.

RATIONALE: Acute respiratory distress syndrome (ARDS) behaves as a complex genetic trait, yet knowledge of genetic susceptibility factors remains incomplete. OBJECTIVES: To identify genetic risk variants for ARDS using large scale genotyping. METHODS: A multistage genetic association study was conducted of three critically ill populations phenotyped for ARDS. Stage I, a trauma cohort study (n = 224), was genotyped with a 50K gene-centric single-nucleotide polymorphism (SNP) array. We tested SNPs associated with ARDS at P < 5 × 10(-4) for replication in stage II, a trauma case-control population (n = 778). SNPs replicating their association in stage II (P < 0.005) were tested in a stage III nested case-control population of mixed subjects in the intensive care unit (n = 2,063). Logistic regression was used to adjust for potential clinical confounders. We performed ELISA to test for an association between ARDS-associated genotype and plasma protein levels. MEASUREMENTS AND MAIN RESULTS: A total of 12 SNPs met the stage I threshold for an association with ARDS. rs315952 in the IL1RN gene encoding IL-1 receptor antagonist (IL1RA) replicated its association with reduced ARDS risk in stages II (P < 0.004) and III (P < 0.02), and was robust to clinical adjustment (combined odds ratio = 0.81; P = 4.2 × 10(-5)). Plasma IL1RA level was associated with rs315952C in a subset of critically ill subjects. The effect of rs315952 was independent from the tandem repeat variant in IL1RN. CONCLUSIONS: The IL1RN SNP rs315952C is associated with decreased risk of ARDS in three populations with heterogeneous ARDS risk factors, and with increased plasma IL1RA response. IL1RA may attenuate ARDS risk.

Early Fluid Is Less Fluid: Comparing Early Versus Late ICU Resuscitation in Severely Injured Trauma Patients.

OBJECTIVES: The temporal trends of crystalloid resuscitation in severely injured trauma patients after ICU admission are not well characterized. We hypothesized early crystalloid resuscitation was associated with less volume and better outcomes than delaying crystalloid. DESIGN: Retrospective, observational. SETTING: High-volume level 1 academic trauma center. PATIENTS: Adult trauma patients admitted to the ICU with emergency department serum lactate greater than or equal to 4 mmol/dL, elevated lactate (≥ 2 mmol/L) at ICU admission, and normal lactate by 48 hours. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: For the 333 subjects, we analyzed patient and injury characteristics and the first 48 hours of ICU course. Receipt of greater than or equal to 500 mL/hr of crystalloid in the first 6 hours of ICU admission was used to distinguish early vs. late resuscitation. Outcomes included ICU length of stay (LOS), ventilator days, and acute kidney injury (AKI). Unadjusted and multivariable regression methods were used to compare early resuscitation vs. late resuscitation. Compared with the early resuscitation group, the late resuscitation group received more volume by 48 hours (5.5 vs. 4.1 L; p ≤ 0.001), had longer ICU LOS (9 vs. 5 d; p ≤ 0.001), more ventilator days (5 vs. 2 d; p ≤ 0.001), and higher occurrence rate of AKI (38% vs. 11%; p ≤ 0.001). On multivariable regression, late resuscitation remained associated with longer ICU LOS and ventilator days and higher odds of AKI. CONCLUSIONS: Delaying resuscitation is associated with both higher volumes of crystalloid by 48 hours and worse outcomes compared with early resuscitation. Judicious crystalloid given early in ICU admission could improve outcomes in the severely injured.

Predicting high-intensity resuscitation needs in injured patients in the post-hemostasis phase of care following intervention.

BACKGROUND: Best resuscitation practices in the posthemostasis phase of care are poorly defined; this phase of care is characterized by a range of physiologic derangements and multiple therapeutic modalities used to address them. Using a cohort of injured patients who required an immediate intervention in the operating room or angiography suite following arrival to the emergency department, we sought to define high-intensity resuscitation (HIR) in this posthemostasis phase of care; we hypothesized that those who would require HIR could be identified, using only data available at intensive care unit (ICU) admission. METHODS: Clinical data were extracted for consecutive injured patients (2016-2019) admitted to the ICU following an immediate procedure in the operating room or angiography suite. High-intensity resuscitation thresholds were defined as the top decile of blood product (≥3 units) and/or crystalloid (≥4 L) use in the initial 12 hours of ICU care and/or vasoactive medication use between ICU hours 2 and 12. The primary outcome, HIR, was a composite of any of these modalities. Predictive modeling of HIR was performed using logistic regression with predictor variables selected using Least Absolute Shrinkage and Selection Operator (LASSO) estimation. Model was trained using 70% of the cohort and tested on the remaining 30%; model predictive ability was evaluated using area under receiver operator curves. RESULTS: Six hundred five patients were included. Patients were 79% male, young (median age, 39 years), severely injured (median Injury Severity Score, 26), and an approximately 3:2 ratio of blunt to penetrating mechanisms of injury. A total of 215 (36%) required HIR. Predictors selected by LASSO included: shock index, lactate, base deficit, hematocrit, and INR. The area under receiver operator curve for the LASSO-derived HIR prediction model was 0.82. CONCLUSION: Intensive care unit admission data can identify subsequent HIR in the posthemostasis phase of care. Use of this model may facilitate triage, nursing ratio determination, and resource allocation. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level IV.

Distinct and replicable genetic risk factors for acute respiratory distress syndrome of pulmonary or extrapulmonary origin.

BACKGROUND: The role of genetics in the development of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) from direct or indirect lung injury has not been specifically investigated. The aim of this study was to identify genetic variants contributing to ALI/ARDS from pulmonary or extrapulmonary causes. METHODS: We conducted a multistage genetic association study. We first performed a large-scale genotyping (50K ITMAT-Broad_CARe Chip) in 1717 critically ill Caucasian patients with either pulmonary or extrapulmonary injury, to identify single nucleotide polymorphisms (SNPs) associated with the development of ARDS from direct or indirect insults to the lung. Identified SNPs (p≤0.0005) were validated in two separated populations (Stage II), with trauma (Population I; n=765) and pneumonia/pulmonary sepsis (Population II; n=838), as causes for ALI/ARDS. Genetic variants replicating their association with trauma related-ALI in Stage II were validated in a second trauma-associated ALI population (n=224, Stage III). RESULTS: In Stage I, non-overlapping SNPs were significantly associated with ARDS from direct/indirect lung injury, respectively. The association between rs1190286 (POPDC3) and reduced risk of ARDS from pulmonary injury was validated in Stage II (p<0.003). SNP rs324420 (FAAH) was consistently associated with increased risk of ARDS from extrapulmonary causes in two independent ALI-trauma populations (p<0.006, Stage II; p<0.05, Stage III). Meta-analysis confirmed these associations. CONCLUSIONS: Different genetic variants may influence ARDS susceptibility depending on direct versus indirect insults. Functional SNPs in POPDC3 and FAAH genes may be driving the association with direct and indirect ALI/ARDS, respectively.

Defining Posttraumatic Sepsis for Population-Level Research.

Importance: Multiple classification methods are used to identify sepsis from existing data. In the trauma population, it is unknown how administrative methods compare with clinical criteria for sepsis classification. Objectives: To characterize the agreement between 3 approaches to sepsis classification among critically ill patients with trauma and compare the sepsis-associated risk of adverse outcomes when each method was used to define sepsis. Design, Setting, and Participants: This retrospective cohort study used data collected between January 1, 2012, and December 31, 2020, from patients aged 16 years or older with traumatic injury, admitted to the intensive care unit of a single-institution level 1 trauma center and requiring invasive mechanical ventilation for at least 3 days. Statistical analysis was conducted from August 1, 2021, to March 31, 2022. Exposure: Hospital-acquired sepsis, as classified by 3 methods: a novel automated clinical method based on data from the electronic health record, the National Trauma Data Bank (NTDB), and explicit and implicit medical billing codes. Main Outcomes and Measures: The primary outcomes were chronic critical illness and in-hospital mortality. Secondary outcomes included number of days in an intensive care unit, number of days receiving mechanical ventilation, discharge to a skilled nursing or long-term care facility, and discharge to home without assistance. Results: Of 3194 patients meeting inclusion criteria, the median age was 49 years (IQR, 31-64 years), 2380 (74%) were male, and 2826 (88%) sustained severe blunt injury (median Injury Severity Score, 29 [IQR, 21-38]). Sepsis was identified in 747 patients (23%) meeting automated clinical criteria, 118 (4%) meeting NTDB criteria, and 529 (17%) using medical billing codes. The Light κ value for 3-way agreement was 0.16 (95% CI, 0.14-0.19). The adjusted relative risk of chronic critical illness was 9.9 (95% CI, 8.0-12.3) for sepsis identified by automated clinical criteria, 5.0 (95% CI, 3.4-7.3) for sepsis identified by the NTDB, and 4.5 (95% CI, 3.6-5.6) for sepsis identified using medical billing codes. The adjusted relative risk for in-hospital mortality was 1.3 (95% CI, 1.0-1.6) for sepsis identified by automated clinical criteria, 2.7 (95% CI, 1.7-4.3) for sepsis identified by the NTDB, and 1.0 (95% CI, 0.7-1.2) for sepsis identified using medical billing codes. Conclusions and Relevance: In this cohort study of critically ill patients with trauma, administrative methods misclassified sepsis and underestimated the incidence and severity of sepsis compared with an automated clinical method using data from the electronic health record. This study suggests that an automated approach to sepsis classification consistent with Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) clinical criteria is feasible and may improve existing approaches to health services and population-based research in this population.

Early Fluid is Less Fluid: Comparing Early Versus Late Resuscitation in Severely Injured Trauma Patients.

Background: We aimed to characterize the temporal trends of crystalloid resuscitation in severely injured trauma patients after intensive care unit (ICU) admission. Using 500 mL/hr of crystalloid in the first 6 hours of ICU admission to distinguish early versus late resuscitation, we hypothesized early resuscitation was associated with less volume by 48 hours and better outcomes compared with late resuscitation. Methods: We performed a retrospective review of the trauma registry of a high-volume level 1 academic trauma center to examine adult trauma patients admitted to the ICU (2016-2019) with: with initial serum lactate ≥ 4 mmol/dL, elevated lactate (≥ 2 mmol/L) at ICU admission, and lactate normalization within 48 hours. We analyzed patient and injury characteristics, and the first 48 hours of ICU course. The primary outcome was ICU length of stay (LOS); secondary outcomes included ventilator days, acute kidney injury (AKI), and in-hospital death. We compared subjects who received early resuscitation to those received late resuscitation using unadjusted methods and multivariable regression models. Results: We analyzed 333 subjects. The late resuscitation group received less volume over the first 24 hours, but surpassed the early group by 48 hours (5.5 vs 4.1L, p ≤ 0.001). The late group had longer ICU LOS (9 vs 5 days, p ≤ 0.001) and ventilator days (5 vs 2 days, p ≤ 0.001), and higher incidence of AKI (38% vs 11%, p ≤ 0.001). On multivariable regression, late resuscitation remained associated with longer ICU LOS and ventilator days, and higher odds of AKI after adjusting for important confounders. Conclusions: After hemostasis, crystalloid can play an important role in restoration of organ perfusion. Delaying resuscitation is associated with both receipt of higher volumes of crystalloid by 48 hours and worse outcomes compared to early resuscitation. Judicious crystalloid given early in ICU admission could improve outcomes in the severely injured.

PREHOSPITAL CRYSTALLOID RESUSCITATION: PRACTICE VARIATION AND ASSOCIATIONS WITH CLINICAL OUTCOMES.

ABSTRACT: Introduction: Although resuscitation guidelines for injured patients favor blood products, crystalloid resuscitation remains a mainstay in prehospital care. Our understanding of contemporary prehospital crystalloid (PHC) practices and their relationship with clinical outcomes is limited. Methods: The Pragmatic, Randomized Optimal Platelet and Plasma Ratios trial data set was used for this investigation. We sought to identify factors associated with PHC volume variation and hypothesized that higher PHC volume is associated with worse coagulopathy and a higher risk of acute respiratory distress syndrome (ARDS) but a lower risk of acute kidney injury (AKI). Subjects were divided into groups that received <1,000 mL PHC (PHC<1,000) and ≥1,000 mL PHC (PHC≥1,000); initial laboratory values and outcomes (ARDS and AKI risk) were summarized with medians and interquartile ranges or percentages and compared using Wilcoxon rank-sum tests and chi-square tests. The primary outcome was ARDS risk. Multivariable regression was used to characterize the association of each 500 mL aliquot of PHC with initial laboratory values and clinical outcomes. Results: PHC volume among study subjects (n = 680) varied (median, 0.3 L; interquartile range, 0-0.9 L) with weak associations demonstrated among prehospital hemodynamics, intubation, Glasgow Coma Score, and Injury Severity Score (0.008 ≤ R2 ≤ 0.09); prehospital time and enrollment site explained more variation in PHC volume with R2 values of 0.2 and 0.54, respectively. Compared with PHC<1,000, PHC≥1,000 had higher INR, PT, PTT, and base deficit and lower hematocrit and platelets. The proportion of ARDS in the PHC≥1,000 group was higher than PHC<1,000 (21% vs. 12%, P < 0.01), whereas the rate of AKI was similar between groups (23% vs. 23%, P = 0.9). In regression analyses, each 500 mL of PHC was associated with increased INR and PTT, and decreased hematocrit and platelet count (P < 0.05). Each 500 mL of PHC was associated with increased ARDS risk and decreased AKI risk (P < 0.05). Conclusion: PHC administration correlates poorly with prehospital hemodynamics and injury characteristics. Increased PHC volume is associated with greater anemia, coagulopathy, and increased risk of ARDS, although it may be protective against AKI.

Association of Trauma Molecular Endotypes With Differential Response to Transfusion Resuscitation Strategies.

Importance: It is not clear which severely injured patients with hemorrhagic shock may benefit most from a 1:1:1 vs 1:1:2 (plasma:platelets:red blood cells) resuscitation strategy. Identification of trauma molecular endotypes may reveal subgroups of patients with differential treatment response to various resuscitation strategies. Objective: To derive trauma endotypes (TEs) from molecular data and determine whether these endotypes are associated with mortality and differential treatment response to 1:1:1 vs 1:1:2 resuscitation strategies. Design, Setting, and Participants: This was a secondary analysis of the Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) randomized clinical trial. The study cohort included individuals with severe injury from 12 North American trauma centers. The cohort was taken from the participants in the PROPPR trial who had complete plasma biomarker data available. Study data were analyzed on August 2, 2021, to October 25, 2022. Exposures: TEs identified by K-means clustering of plasma biomarkers collected at hospital arrival. Main Outcomes and Measures: An association between TEs and 30-day mortality was tested using multivariable relative risk (RR) regression adjusting for age, sex, trauma center, mechanism of injury, and injury severity score (ISS). Differential treatment response to transfusion strategy was assessed using an RR regression model for 30-day mortality by incorporating an interaction term for the product of endotype and treatment group adjusting for age, sex, trauma center, mechanism of injury, and ISS. Results: A total of 478 participants (median [IQR] age, 34.5 [25-51] years; 384 male [80%]) of the 680 participants in the PROPPR trial were included in this study analysis. A 2-class model that had optimal performance in K-means clustering was found. TE-1 (n = 270) was characterized by higher plasma concentrations of inflammatory biomarkers (eg, interleukin 8 and tumor necrosis factor α) and significantly higher 30-day mortality compared with TE-2 (n = 208). There was a significant interaction between treatment arm and TE for 30-day mortality. Mortality in TE-1 was 28.6% with 1:1:2 treatment vs 32.6% with 1:1:1 treatment, whereas mortality in TE-2 was 24.5% with 1:1:2 treatment vs 7.3% with 1:1:1 treatment (P for interaction = .001). Conclusions and Relevance: Results of this secondary analysis suggest that endotypes derived from plasma biomarkers in trauma patients at hospital arrival were associated with a differential response to 1:1:1 vs 1:1:2 resuscitation strategies in trauma patients with severe injury. These findings support the concept of molecular heterogeneity in critically ill trauma populations and have implications for tailoring therapy for patients at high risk for adverse outcomes.

A genome-wide in vitro bacterial-infection screen reveals human variation in the host response associated with inflammatory disease.

Recent progress in cataloguing common genetic variation has made possible genome-wide studies that are beginning to elucidate the causes and consequences of our genetic differences. Approaches that provide a mechanistic understanding of how genetic variants function to alter disease susceptibility and why they were substrates of natural selection would complement other approaches to human-genome analysis. Here we use a novel cell-based screen of bacterial infection to identify human variation in Salmonella-induced cell death. A loss-of-function allele of CARD8, a reported inhibitor of the proinflammatory protease caspase-1, was associated with increased cell death in vitro (p = 0.013). The validity of this association was demonstrated through overexpression of alternative alleles and RNA interference in cells of varying genotype. Comparison of mammalian CARD8 orthologs and examination of variation among different human populations suggest that the increase in infectious-disease burden associated with larger animal groups (i.e., herds and colonies), and possibly human population expansion, may have naturally selected for loss of CARD8. We also find that the loss-of-function CARD8 allele shows a modest association with an increased risk of systemic inflammatory response syndrome in a small study (p = 0.05). Therefore, a by-product of the selected benefit of loss of CARD8 could be increased inflammatory diseases. These results demonstrate the utility of genome-wide cell-based association screens with microbes in the identification of naturally selected variants that can impact human health.

The changing pattern and implications of multiple organ failure after blunt injury with hemorrhagic shock.

OBJECTIVES: To describe the incidence of postinjury multiple organ failure and its relationship to nosocomial infection and mortality in trauma centers using evidence-based standard operating procedures. DESIGN: Prospective cohort study wherein standard operating procedures were developed and implemented to optimize postinjury care. SETTING: Seven U.S. level I trauma centers. PATIENTS: Severely injured patients (older than age 16 yrs) with a blunt mechanism, systolic hypotension (<90 mm Hg), and/or base deficit (≥6 mEq/L), need for blood transfusion within the first 12 hrs, and an abbreviated injury score ≥2 excluding brain injury were eligible for inclusion. MEASUREMENTS AND MAIN RESULTS: One thousand two patients were enrolled and 916 met inclusion criteria. Daily markers of organ dysfunction were prospectively recorded for all patients while receiving intensive care. Overall, 29% of patients had multiple organ failure develop. Development of multiple organ failure was early (median time, 2 days), short-lived, and predicted an increased incidence of nosocomial infection, whereas persistence of multiple organ failure predicted mortality. However, surprisingly, nosocomial infection did not increase subsequent multiple organ failure and there was no evidence of a "second-hit"-induced late-onset multiple organ failure. CONCLUSIONS: Multiple organ failure remains common after severe injury. Contrary to current paradigms, the onset is only early, and not bimodal, nor is it associated with a "second-hit"-induced late onset. Multiple organ failure is associated with subsequent nosocomial infection and increased mortality. Standard operating procedure-driven interventions may be associated with a decrease in late multiple organ failure and morbidity.

ANGPT2 genetic variant is associated with trauma-associated acute lung injury and altered plasma angiopoietin-2 isoform ratio.

RATIONALE: Acute lung injury (ALI) acts as a complex genetic trait, yet its genetic risk factors remain incompletely understood. Large-scale genotyping has not previously been reported for ALI. OBJECTIVES: To identify ALI risk variants after major trauma using a large-scale candidate gene approach. METHODS: We performed a two-stage genetic association study. We derived findings in an African American cohort (n = 222) using a cardiopulmonary disease-centric 50K single nucleotide polymorphism (SNP) array. Genotype and haplotype distributions were compared between subjects with ALI and without ALI, with adjustment for clinical factors. Top performing SNPs (P < 10(-4)) were tested in a multicenter European American trauma-associated ALI case-control population (n = 600 ALI; n = 2,266 population-based control subjects) for replication. The ALI-associated genomic region was sequenced, analyzed for in silico prediction of function, and plasma was assayed by ELISA and immunoblot. MEASUREMENTS AND MAIN RESULTS: Five SNPs demonstrated a significant association with ALI after adjustment for covariates in Stage I. Two SNPs in ANGPT2 (rs1868554 and rs2442598) replicated their significant association with ALI in Stage II. rs1868554 was robust to multiple comparison correction: odds ratio 1.22 (1.06-1.40), P = 0.0047. Resequencing identified predicted novel splice sites in linkage disequilibrium with rs1868554, and immunoblots showed higher proportion of variant angiopoietin-2 (ANG2) isoform associated with rs1868554T (0.81 vs. 0.48; P = 0.038). CONCLUSIONS: An ANGPT2 region is associated with both ALI and variation in plasma angiopoietin-2 isoforms. Characterization of the variant isoform and its genetic regulation may yield important insights about ALI pathogenesis and susceptibility.

Detection and localization of peripheral vascular bleeding using Doppler ultrasound.

BACKGROUND: Hemorrhage from wounds in the extremities is the leading cause of preventable death on the battlefield. To successfully treat these injuries, the exact source of bleeding must be localized. OBJECTIVE: The purpose of this study was to determine the feasibility of using Doppler ultrasound to precisely detect and localize peripheral vascular bleeding. METHODS: Injuries were produced in common femoral arteries (diameter of ∼5 mm) of 28 pigs in vivo. Single puncture injuries were produced using 6 French (F) (n = 10), 9 F (n = 22), and 12 F (n = 12) catheters. In addition, multiple punctures were made (using 6 F and 9 F catheters) in eight common femoral arteries to simulate bleeding from multiple injuries. Finally, laceration injuries were produced using a scalpel in 10 femoral vessels. RESULTS: In color Doppler images, bleeding was observed as a turbulent jet flow originating from the injury site in the vessel. This jet flow had checkered red-blue color pattern at the bleeding site, as opposed to a uniform color pattern in an intact artery. Peak systolic velocity at the injury site, measured using pulsed Doppler, was elevated to up to 152.0 ± 81.6 cm/s, as compared to 78.8 ± 17.5 cm/s in normal arteries. Further, end diastolic velocity increased from 6.1 ± 4.9 cm/s before the injury to up to 59.1 ± 33.1 cm/s after the injury. Resistance index was significantly lower (0.6 for 9 F and 12 F punctures, and 0.8 for 6 F punctures) at the bleeding site in injured arteries as compared to the resistance index of intact arteries (of 0.9). CONCLUSION: Our results showed a characteristic change in the systolic and diastolic velocities, as well as resistance indices at the injury site in peripheral arteries. These findings may serve as groundwork for development of automated bleeding detection and localization methods, and facilitate various hemorrhage control treatments.

Acute intensive care unit resuscitation of severely injured trauma patients: Do we need a new strategy?

BACKGROUND: Unlike recent advances in blood product resuscitation, intravenous crystalloid (IVF) use after intensive care unit (ICU) admission in hemorrhagic shock has received less attention and current recommendations are based on limited evidence. To address this knowledge gap, we aimed to determine associations between IVF administration during acute ICU resuscitation and outcomes. We hypothesized that larger IVF volumes are associated with worse outcomes. METHODS: We linked our trauma registry with electronic health record data (2012-2015) to identify adults with an initial lactate level of ≥4 mmol/L and documented lactate normalization (≤2 mmol/L), excluding those with isolated head Abbreviated Injury Scale score ≥3. We focused on the period from ICU admission to lactate normalization, analyzing duration, volume of IVF, and proportion of volume as 1-L boluses. We used linear regression to determine associations with ICU length of stay and duration of mechanical ventilation in survivors, and logistic regression to identify associations with acute kidney injury and home discharge while adjusting for important covariates. RESULTS: We included 337 subjects. Median time to lactate normalization was 15 hours (interquartile range, 7-25 hours), and median IVF volume was 3.7 L (interquartile range, 1.5-6.4 L). The fourfold difference between the upper and lower quartiles of both duration and volume remained after stratifying by injury severity. Hourly volumes tapered over time but persistently aggregated at 0.5 and 1 L, with 167 subjects receiving at least one 0.5-L bolus for 6 hours after ICU admission. Administration of larger volumes was associated with longer ICU length of stay and duration of mechanical ventilation, as well as acute kidney injury. CONCLUSION: There is substantial variation in volume administered during acute ICU resuscitation, both absolutely and temporally, despite accounting for injury severity. Administration of larger volumes during acute ICU resuscitation is associated with worse outcomes. There is an opportunity to improve outcomes by further investigating and standardizing this important phase of care. LEVEL OF EVIDENCE: Therapeutic/care management, level IV.

Persistent metabolomic alterations characterize chronic critical illness after severe trauma.

BACKGROUND: Following trauma, persistent inflammation, immunosuppression, and catabolism may characterize delayed recovery or failure to recover. Understanding the metabolic response associated with these adverse outcomes may facilitate earlier identification and intervention. We characterized the metabolic profiles of trauma victims who died or developed chronic critical illness (CCI) and hypothesized that differences would be evident within 1-week postinjury. METHODS: Venous blood samples from trauma victims with shock who survived at least 7 days were analyzed using mass spectrometry. Subjects who died or developed CCI (intensive care unit length of stay of ≥14 days with persistent organ dysfunction) were compared with subjects who recovered rapidly (intensive care unit length of stay, ≤7 days) and uninjured controls. We used partial least squares discriminant analysis, t tests, linear mixed effects regression, and pathway enrichment analyses to make broad comparisons and identify differences in metabolite concentrations and pathways. RESULTS: We identified 27 patients who died or developed CCI and 33 who recovered rapidly. Subjects were predominantly male (65%) with a median age of 53 years and Injury Severity Score of 36. Healthy controls (n = 48) had similar age and sex distributions. Overall, from the 163 metabolites detected in the samples, 56 metabolites and 21 pathways differed between injury outcome groups, and partial least squares discriminant analysis models distinguished injury outcome groups as early as 1-day postinjury. Differences were observed in tryptophan, phenylalanine, and tyrosine metabolism; metabolites associated with oxidative stress via methionine metabolism; inflammatory mediators including kynurenine, arachidonate, and glucuronic acid; and products of the gut microbiome including indole-3-propionate. CONCLUSIONS: The metabolic profiles in subjects who ultimately die or develop CCI differ from those who have recovered. In particular, we have identified differences in markers of inflammation, oxidative stress, amino acid metabolism, and alterations in the gut microbiome. Targeted metabolomics has the potential to identify important metabolic changes postinjury to improve early diagnosis and targeted intervention. LEVEL OF EVIDENCE: Prognostic/epidemiologic, level III.