Re-evaluating the Use of High Sensitivity Troponin to Diagnose Blunt Cardiac Injury.

INTRODUCTION: Blunt cardiac injury (BCI) can be challenging diagnostically, and if misdiagnosed, can lead to life-threatening complications. Our institution previously evaluated BCI screening with troponin and electrocardiogram (EKG) during a transition from troponin I to high sensitivity troponin (hsTnI), a more sensitive troponin I assay. The previous study found an hsTnI of 76 ng/L had the highest capability of accurately diagnosing a clinically significant BCI. The aim of this study was to determine the efficacy of the newly implemented protocol. METHODS: Patients diagnosed with a sternal fracture from March 2022 to April 2023 at our urban level-1 trauma center were retrospectively reviewed for EKG findings, hsTnI trend, echocardiogram changes, and clinical outcomes. The BCI cohort and non-BCI cohort ordinal measures were compared using Wilcoxon's two-tailed rank sum test and categorical measures were compared with Fisher's exact test. Youden indices were used to evaluate hsTnI sensitivity and specificity. RESULTS: Sternal fractures were identified in 206 patients, of which 183 underwent BCI screening. Of those screened, 103 underwent echocardiogram, 28 were diagnosed with clinically significant BCIs, and 15 received intervention. The peak hsTnI threshold of 76 ng/L was found to have a Youden index of 0.31. Rather, the Youden index was highest at 0.50 at 40 ng/L (sensitivity 0.79 and specificity 0.71) for clinically significant BCI. CONCLUSIONS: Screening patients with sternal fractures for BCI using hsTnI and EKG remains effective. To optimize the hsTnI threshold, this study determined the hsTnI threshold should be lowered to 40 ng/L. Further improvements to the institutional protocol may be derived from multicenter analysis.

The Bitter and the Sweet: Relationship of Lactate, Glucose, and Mortality After Severe Blunt Trauma.

BACKGROUND: Hyperglycemia is associated with mortality after trauma; however, few studies have simultaneously investigated the association of depth of shock and acute hyperglycemia. We evaluated lactate, as a surrogate measure for depth of shock, and glucose levels on mortality following severe blunt trauma. We hypothesize that measurements of both lactate and glucose are associated with mortality when considered simultaneously. METHODS: This is a retrospective cohort study at a single academic trauma center. Inclusion criteria are age 18-89 years, blunt trauma, injury severity score (ISS) ≥15, and transferred from the scene of injury. All serum blood glucose and lactate values were analyzed within the first 24 hours of admission. Multiple metrics of glucose and lactate were calculated: first glucose (Glucadm) and lactate (Lacadm) at hospital admission, mean 24-hour after hospital admission glucose (Gluc24-hMean) and lactate (Lac24-hMean), maximum 24-hour after hospital admission glucose (Gluc24-hMax) and lactate (Lac24-hMax), and time-weighted 24-hour after hospital admission glucose (Gluc24-hTW) and lactate (Lac24-hTW). Primary outcome was in-hospital mortality. Multivariable logistic regression modeling assessed the odds ratio (OR) of mortality, after adjusting for confounding variables. RESULTS: A total of 1439 trauma patients were included. When metrics of both glucose and lactate were analyzed, after adjusting for age, ISS, and admission shock index, only lactate remained significantly associated with mortality: Lacadm (OR, 1.28; 95% confidence interval [CI], 1.13-1.44); Lac24-hMean (OR, 1.86; 95% CI, 1.52-2.28); Lac24-hMax (OR, 1.39; 95% CI, 1.23-1.56); and Lac24-hTW (OR, 1.86; 95% CI, 1.53-2.26). CONCLUSIONS: Lactate is associated with mortality in severely injured blunt trauma patients, after adjusting for injury severity, age, and shock index. However, we did not find evidence for an association of glucose with mortality after adjusting for lactate.

Impact of Injury Severity on the Inflammatory State and Severe Anemia.

BACKGROUND: Severe traumatic injury is a major cause of morbidity and mortality. Our goal was to analyze blunt traumatic injury by injury severity score (ISS) and compare with elective hip repair, as a transient injury, and healthy control with the hypothesis that more severe injury would lead to an increase in neuroendocrine activation, systemic inflammation, and worse anemia. MATERIALS AND METHODS: A prospective observational cohort study was performed at a level 1 trauma center, comparing blunt trauma patients (n = 37), elective hip replacement patients (n = 26), and healthy controls (n = 8). Bone marrow and plasma were assessed for hyperadrenergic state, erythropoiesis, and systemic inflammation. Trauma patient's ISS ranged from 4 to 41 and were broken down into quartiles for analysis. The ISS quartiles were 4-13, 14-20, 21-26, and 27-41. RESULTS: Plasma norepinephrine, interleukin-6, tumor necrosis factor-alpha, and hepcidin increased progressively as ISS increased. Hemoglobin significantly decreased as ISS increased and packed red blood cell (pRBC) transfusion increased as ISS increased. Elective hip replacement patients had an appropriate increase in the bone marrow expression of erythropoietin and the erythropoietin receptor, which was absent in all trauma patient groups. CONCLUSIONS: Increased neuroendocrine activation, systemic inflammation, and anemia correlated with worsening injury severity, lower age, and increased pRBC transfusions. Elective hip replacement patients have only minimal systemic inflammation with an appropriate bone marrow response to anemia. This study demonstrates a link between injury severity, neuroendocrine activation, systemic inflammation, and the bone marrow response to anemia.

Elevations in Circulating sST2 Levels Are Associated With In-Hospital Mortality and Adverse Clinical Outcomes After Blunt Trauma.

BACKGROUND: Soluble suppression of tumorigenicity 2 (sST2), a decoy receptor for interleukin (IL)-33, has emerged as a novel biomarker in various disease processes. Recent studies have elucidated the role of the sST2/IL-33 complex in modulating the balance of Th1/Th2 immune responses after tissue stress. However, the role of sST2 as a biomarker after traumatic injury remains unclear. To address this, we evaluated serum sST2 correlations with mortality and in-hospital adverse outcomes as endpoints in blunt trauma patients. METHODS: We retrospectively analyzed clinical and biobank data of 493 blunt trauma victims 472 survivors (mean age: 48.4 ± 0.87; injury severity score [ISS]: 19.6 ± 0.48) and 19 nonsurvivors (mean age: 58.8 ± 4.5; ISS: 23.3 ± 2.1) admitted to the intensive care unit. Given the confounding impact of age on the inflammatory response, we derived a propensity-matched survivor subgroup (n = 19; mean age: 59 ± 3; ISS: 23.4 ± 2) using an IBM SPSS case-control matching algorithm. Serial blood samples were obtained from all patients (3 samples within the first 24 h and then once daily from day [D] 1 to D5 after injury). sST2 and twenty-nine inflammatory biomarkers were assayed using enzyme-linked immunosorbent assay and Luminex, respectively. Two-way analysis of variance on ranks was used to compare groups (P < 0.05). Spearman rank correlation was performed to determine the association of circulating sST2 levels with biomarker levels and in-hospital clinical outcomes. RESULTS: Circulating sST2 levels of the nonsurvivor cohort were statistically significantly elevated at 12 h after injury and remained elevated up to D5 when compared either to the overall 472 survivor cohort or a matched 19 survivor subcohort. Admission sST2 levels obtained from the first blood draw after injury in the survivor cohort correlated positively with admission base deficit (correlation coefficient [CC] = 0.1; P = 0.02), international normalized ratio (CC = 0.1, P = 0.03), ISS (CC = 0.1, P = 0.008), and the average Marshall multiple organ dysfunction score between D2 and D5 (CC = 0.1, P = 0.04). Correlations with ISS revealed a positive correlation of ISS with plasma sST2 levels across the mild ISS (CC = 0.47, P < 0.001), moderate ISS (CC = 0.58, P < 0.001), and severe ISS groups (CC = 0.63, P < 0.001). Analysis of biomarker correlations in the matched survivor group over the initial 24 h after injury showed that sST2 correlates strongly and positively with IL-4 (CC = 0.65, P = 0.002), IL-5 (CC = 0.57, P = 0.01), IL-21 (CC = 0.52, P = 0.02), IL-2 (CC = 0.51, P = 0.02), soluble IL-2 receptor-α (CC = 0.5, P = 0.02), IL-13 (CC = 0.49, P = 0.02), and IL-17A (CC = 0.48, P = 0.03). This was not seen in the matched nonsurvivor group. sST2/IL-33 ratios were significantly elevated in nonsurvivors and patients with severe injury based on ISS ≥ 25. CONCLUSIONS: Elevations in serum sST2 levels are associated with poor clinical trajectories and mortality after blunt trauma. High sST2 coupled with low IL-33 associates with severe injury, mortality, and worse clinical outcomes. These findings suggest that sST2 could serve as an early prognostic biomarker in trauma patients and that sustained elevations of sST2 could contribute to a detrimental suppression of IL-33 bioavailability in patients with high injury severity.

Deceleration, Acceleration, and Impacts Are Strong Contributors to Muscle Damage in Professional Australian Football.

Gastin, PB, Hunkin, SL, Fahrner, B, and Robertson, S. Deceleration, acceleration, and impacts are strong contributors to muscle damage in professional Australian football. J Strength Cond Res 33(12): 3374-3383, 2019-The purpose of this study was to investigate the relationships between serum creatine kinase [CK], an indirect marker of muscle damage, and specific indices of match load in elite Australian football. Twenty-six professional players were assessed during a competitive Australian Football League (AFL) season. [CK] was collected 24-36 hours before match and 34-40 hours after match during 8 in-season rounds. An athlete-tracking technology was used to quantify match load. Generalized estimating equations and random forest models were constructed to determine the extent to which match-load indices and pre-match [CK] explained post-match [CK]. There was a 129 ± 152% increase in [CK] in response to AFL competition. Generalized estimating equations found that number of impacts >3g (p = 0.004) and game time (p = 0.016) were most strongly associated with post-match [CK]. Random forest, with considerably lower errors (130 vs. 316 U·L), found deceleration, acceleration, impacts >3g, and sprint distance to be the strongest predictors. Pre-match [CK] accounted for 11% of post-match [CK], and considerable interindividual and intraindividual variability existed in the data. Creatine kinase, an indicator of muscle damage, was considerably elevated as a result of AFL competition. Parametric and machine-learning analysis techniques found several indices of physical load associated with muscle damage during competition, with impacts >3g and high-intensity running variables as the strongest predictors. [CK] may be used as a global measure of muscle damage in field team sports such as AF, yet with some caution given cost, invasiveness, and inherent variability. Quantifying physical load and the responses to that load can guide athlete management decision-making and is best undertaken within a suite of practical, sport-specific measures, where data are interpreted individually and with an understanding of the limitations.

Does Lactate Affect the Association of Early Hyperglycemia and Multiple Organ Failure in Severely Injured Blunt Trauma Patients?

BACKGROUND: Early hyperglycemia is associated with multiple organ failure (MOF) after traumatic injury; however, few studies have considered the contribution of depth of clinical shock. We hypothesize that when considered simultaneously, glucose and lactate are associated with MOF in severely injured blunt trauma patients. METHODS: We performed a retrospective investigation at a single tertiary care trauma center. Inclusion criteria were patient age ≥18 years, injury severity score (ISS) >15, blunt mechanism of injury, and an intensive care unit length of stay >48 hours. Patients with a history of diabetes or who did not survive the initial 48 hours were excluded. Demographics, injury severity, and physiologic data were recorded. Blood glucose and lactate values were collected from admission through the initial 24 hours of hospitalization. Multiple metrics of glucose and lactate were calculated: the first glucose (Glucadm, mg/dL) and lactate (Lacadm, mmol/L) at hospital admission, the mean initial 24-hour glucose (Gluc24hMean, mg/dL) and lactate (Lac24hMean, mmol/L), and the time-weighted initial 24-hour glucose (Gluc24hTW) and lactate (Lac24hTW). These metrics were divided into quartiles. The primary outcome was MOF. Separate Cox proportional hazard models were generated to assess the association of each individual glucose and lactate metric on MOF, after controlling for ISS, admission shock index, and disposition to the operating room after hospital admission. We assessed the interaction between glucose and lactate metrics in the multivariable models. Results are reported as hazard ratios (HRs) for an increase in the quartile level of glucose and lactate measurements, with 95% confidence intervals (CIs). RESULTS: A total of 507 severely injured blunt trauma patients were evaluated. MOF occurred in 46 of 507 (9.1%) patients and was associated with a greater median ISS (33.5, interquartile range [IQR]: 22-41 vs 27, IQR: 21-34; P < .001) and a greater median admission shock index (0.82, IQR: 0.68-1.1 vs 0.73, IQR: 0.60-0.91; P = .02). Patients who were transferred to the operating room after the initial trauma resuscitation were also more likely to develop MOF (20 of 119, 14.4% vs 26 of 369, 7.1%; P = .01). Three separate Cox proportional regression models demonstrated the following HR for an increase in the individual glucose metric quartile and MOF, while controlling for confounding variables: Glucadm HR: 1.35, 95% CI, 1.02-1.80; Gluc24hMean HR: 1.63, 95% CI, 1.14-2.32; Gluc24hTW HR: 1.14, 95% CI, 0.86-1.50. Three separate Cox proportional hazards models also demonstrated the following HR for each individual lactate metric quartile while controlling for the same confounders, with MOF again representing the dependent variable: Lacadm HR: 1.94, 95% CI, 1.38-2.96; Lac24hMean HR: 1.68, 95% CI, 1.22-2.31; Lac24hTW HR: 1.49, 95% CI, 1.10-2.02. When metrics of both glucose and lactate were entered into the same model only lactate remained significantly associated with MOF: Lacadm HR: 1.86, 95% CI, 1.29-2.69, Lac24hMean HR: 1.54, 95% CI, 1.11-2.12, and Lac24hTW HR: 1.48, 95% CI, 1.08-2.01. There was no significant interaction between lactate and glucose variables in relation to the primary outcome. CONCLUSIONS: When glucose and lactate are considered simultaneously, only lactate remained significantly associated with MOF in severely injured blunt trauma patients.

Thromboelastogram does not detect pre-injury anticoagulation in acute trauma patients.

PURPOSE: Thromboelastography (TEG) has been recommended to characterize post-traumatic coagulopathy, yet no study has evaluated the impact of pre-injury anticoagulation (AC) on TEG variables. We hypothesized patients on pre-injury AC have a greater incidence of coagulopathy on TEG compared to those without AC. METHODS: This retrospective chart review evaluated all trauma patients admitted to an urban, level one trauma center from February 2011 to September 2014 who received a TEG within the first 24h. Patients were classified as receiving pre-injury AC or no AC if their documented medications prior to admission included warfarin, dabigatran, or anti-Xa (aXa) inhibitors (apixaban or rivaroxaban). The presence of coagulopathy on TEG or conventional assays was defined by exceeding local laboratory reference standards. RESULTS: A total of 54 patients were included (AC, n=27 [warfarin n=13, dabigatran n=6, aXa inhibitor n=8] vs. no AC, n=27). Baseline characteristics were similar between groups, including age (72±13years vs. 72±15; p=0.85), male gender (70% vs. 74%; p=0.76) and blunt mechanism of injury (100% vs. 100%; p=1). There was no difference in the number of patients determined to have coagulopathy on TEG (no AC 11% vs. AC 15%; p=0.99). Conventional tests, including the international normalized ratio (INR) and activated partial thromboplastin time (aPTT), identified coagulopathy in a high proportion of anti-coagulated patients (no AC 22% vs. AC 85%; p<0.01). CONCLUSION: TEG has limited clinical utility to evaluate the presence of pre-injury AC. Traditional markers of drug induced coagulopathy should guide reversal decisions.

Re-evaluation of liver transaminase cutoff for CT after pediatric blunt abdominal trauma.

PURPOSE: Current guidelines for computed tomography (CT) after blunt trauma were developed to capture all intra-abdominal injuries (IAI). We hypothesize that current AST/ALT guidelines are too low leading to unnecessary CT scans for children after blunt abdominal trauma (BAT). METHODS: Patients who received CT of the abdomen after blunt trauma at our Level I Pediatric Trauma Center were stratified into a high risk (HR) (liver/spleen/kidney grade ≥III, hollow viscous, or pancreatic injuries) and low risk (LR) (liver/kidney/spleen injuries grade ≤II, or no IAI) groups. RESULTS: 247 patients were included. Of the 18 patients in the HR group, two required surgery (splenectomy and sigmoidectomy). Transfusion was required in 30% of grade III and 50% of grade IV injuries. Eleven (5%) patients in LR group were transfused for indications other than IAI, and none were explored surgically. Both AST (r = 0.44, p < 0.001) and ALT (r = 0.43, p < 0.001) correlated with grade of liver injury. Using an increased threshold of AST/ALT, 400/200 had a negative predictive value of 96% in predicting the presence of HR liver injuries. CONCLUSION: The current cutoff of liver enzymes leads to over-identification of LR injuries. Consideration should be given to an approach that aims to utilize CT in pediatric BAT that identifies clinically HR injury.

Temporal Patterns of Circulating Inflammation Biomarker Networks Differentiate Susceptibility to Nosocomial Infection Following Blunt Trauma in Humans.

BACKGROUND: Severe traumatic injury can lead to immune dysfunction that renders trauma patients susceptible to nosocomial infections (NI) and prolonged intensive care unit (ICU) stays. We hypothesized that early circulating biomarker patterns following trauma would correlate with sustained immune dysregulation associated with NI and remote organ failure. METHODS: In a cohort of 472 blunt trauma survivors studied over an 8-year period, 127 patients (27%) were diagnosed with NI versus 345 trauma patients without NI. To perform a pairwise, case-control study with 1:1 matching, 44 of the NI patients were compared with 44 no-NI trauma patients selected by matching patient demographics and injury characteristics. Plasma obtained upon admission and over time were assayed for 26 inflammatory mediators and analyzed for the presence of dynamic networks. RESULTS: Significant differences in ICU length of stay (LOS), hospital LOS, and days on mechanical ventilation were observed in the NI patients versus no-NI patients. Although NI was not detected until day 7, multiple mediators were significantly elevated within the first 24 hours in patients who developed NI. Circulating inflammation biomarkers exhibited 4 distinct dynamic patterns, of which 2 clearly distinguish patients destined to develop NI from those who did not. Mediator network connectivity analysis revealed a higher, coordinated degree of activation of both innate and lymphoid pathways in the NI patients over the initial 24 hours. CONCLUSIONS: These studies implicate unique dynamic immune responses, reflected in circulating biomarkers that differentiate patients prone to persistent critical illness and infections following injury, independent of mechanism of injury, injury severity, age, or sex.

A comparison of initial lactate and initial base deficit as predictors of mortality after severe blunt trauma.

BACKGROUND: After injury, base deficit (BD) and lactate are common measures of shock. Lactate directly measures anaerobic byproducts, whereas BD is calculated and multifactorial. Although recent studies suggest superiority for lactate in predicting mortality, most were small or analyzed populations with heterogeneous injury severity. Our objective was to compare initial BD with lactate as predictors of inhospital mortality in a large cohort of blunt trauma patients all presenting with hemorrhagic shock. MATERIALS AND METHODS: The Glue Grant multicenter prospective cohort database was queried; demographic, injury, and physiologic parameters were compiled. Survivors, early deaths (≤24 h), and late deaths were compared. Profound shock (lactate ≥ 4 mmol/L) and severe traumatic brain injury subgroups were identified a priori. Chi-square, t-test, and analysis of variance were used as appropriate for analysis. Multivariable logistic regression and area under the receiver operating characteristic curve analysis assessed survival predictors. P < 0.05 was significant. RESULTS: A total of 1829 patients met inclusion; 289 (15.8%) died. Both BD and lactate were higher for nonsurvivors (P < 0.00001). After multivariable regression, both lactate (odds ratio [OR] 1.17; 95% confidence interval [CI]: 1.12-1.23; P < 0.00001) and BD (OR 1.04; 95% CI: 1.01-1.07; P < 0.005) predicted overall mortality. However, when excluding early deaths (n = 77), only lactate (OR 1.12 95% CI: 1.06-1.19; P < 0.0001) remained predictive but not BD (OR 1.00 95% CI: 0.97-1.04; P = 0.89). For the shock subgroup, (n = 915), results were similar with lactate, but not BD, predicting both early and late deaths. Findings also appear independent of traumatic brain injury severity. CONCLUSIONS: After severe blunt trauma, initial lactate better predicts inhospital mortality than initial BD. Initial BD does not predict mortality for patients who survive >24 h.

Hemostatic Therapy Using Tranexamic Acid and Coagulation Factor Concentrates in a Model of Traumatic Liver Injury.

BACKGROUND: The potential clinical benefits of targeted therapy with coagulation factor concentrates (e.g., fibrinogen) and antifibrinolytic agents (e.g., tranexamic acid [TXA]) for the treatment of trauma-induced coagulopathy are increasingly recognized. We hypothesized that human fibrinogen concentrate (FC) and prothrombin complex concentrate (PCC), administered as combined therapy with TXA, would provide additive effects for reducing blood loss in an animal trauma model. METHODS: Thirty-six pigs were subjected to 2 consecutive blunt liver injuries, resulting in severe hemorrhagic shock and coagulopathy. Intervention comprised saline (control group); TXA (15 mg kg, TXA group); TXA and FC (90 mg kg, TXA-FC); or TXA, FC, and PCC (20 U kg, TXA-FC-PCC). Blood loss, thromboelastometry (ROTEM), measures of thrombin generation, platelet activation, and global coagulation variables were monitored for 4 hours. Tissue sections were examined to determine the occurrence of thromboembolic events. RESULTS: Total blood loss was similar in the TXA-FC and TXA-FC-PCC groups (mean ± SD: 1012 ± 86 mL and 1037 ± 118 mL, respectively; P = 1.000). These values were both lower (P < 0.001) than the TXA group (1579 ± 306 mL). Blood loss in all 3 intervention groups was lower (P < 0.001) than in the control group (2376 ± 478 mL). After trauma and resuscitation, but before study intervention, plasma fibrinogen levels were severely depleted (median for the whole study population: 66 mg dL; interquartile range: 51-108 mg dL) and clot strength was decreased (EXTEM whole-blood maximum clot firmness [MCF]: 53 ± 5 mm). Compared with controls, TXA inhibited fibrinolysis and stabilized MCF and clotting time. The addition of FC restored and stabilized hemostasis to a greater extent than TXA alone; the addition of PCC had no statistically significant impact on blood loss, clot strength (MCF), or clotting time, but it increased thrombin generation. There were no significant differences among the study groups regarding platelet activation. No thrombi or microthrombi were observed in any group at necropsy. CONCLUSIONS: The early use of TXA and FC reduced blood loss and improved coagulation measurements in a porcine model of blunt liver injury and hemorrhagic shock. FC, administered in addition to TXA, was highly effective in reducing blood loss. The lack of statistically significant reduction in blood loss when PCC was added to TXA and FC may be attributable to the absence of thrombin generation impairment in this model.

Elevated Admission Base Deficit Is Associated with a Complex Dynamic Network of Systemic Inflammation Which Drives Clinical Trajectories in Blunt Trauma Patients.

We hypothesized that elevated base deficit (BD) ≥ 4 mEq/L upon admission could be associated with an altered inflammatory response, which in turn may impact differential clinical trajectories. Using clinical and biobank data from 472 blunt trauma survivors, 154 patients were identified after excluding patients who received prehospital IV fluids or had alcohol intoxication. From this subcohort, 84 patients had a BD ≥ 4 mEq/L and 70 patients with BD < 4 mEq/L. Three samples within the first 24 h were obtained from all patients and then daily up to day 7 after injury. Twenty-two cytokines and chemokines were assayed using Luminex™ and were analyzed using two-way ANOVA and dynamic network analysis (DyNA). Multiple mediators of the innate and lymphoid immune responses in the BD ≥ 4 group were elevated differentially upon admission and up to 16 h after injury. DyNA revealed a higher, sustained degree of interconnectivity of the inflammatory response in the BD ≥ 4 patients during the initial 16 h after injury. These results suggest that elevated admission BD is associated with differential immune/inflammatory pathways, which subsequently could predispose patients to follow a complicated clinical course.

Genetic variants of microRNA sequences and susceptibility to sepsis in patients with major blunt trauma.

OBJECTIVE: The objective of this study was to conduct a systematic survey of common precursor microRNA (pre-miRNA) single nucleotide polymorphisms (SNPs) and evaluate their clinical relevance in patients with major blunt trauma. BACKGROUND: Recent evidence indicates that small noncoding RNA molecules known as miRNAs can function as important negative gene regulators and are implicated in the pathogenesis of various diseases. METHODS: We conducted a 2-stage study to examine the impact of 9 selected SNPs with potential functional significance on the susceptibility to sepsis of 1268 trauma patients (1 screening cohort, n = 666) and 2 independent validated cohorts (n = 286 and n = 316, respectively) in China. RESULTS: Among the 9 selected SNPs with potential functional significance, only 1 (miR-608 rs4919510) was found to be strongly associated with a higher risk of developing sepsis and multiple organ dysfunction in all 3 independent study cohorts. An even stronger association was observed for the rs4919510 polymorphism when combining these 3 study cohorts together. In addition, the rs4919510 polymorphism showed a significant correlation with a higher production of proinflammatory cytokines and a lower production of anti-inflammatory cytokines. In vitro experiments further indicated that the G→C variant of this polymorphism could significantly increase the expression of mature miR-608. CONCLUSIONS: Our results indicate that the rs4919510G/C SNP in hsa-mir-608 may be a prognostic biomarker for sepsis in patients with major trauma. Further characterization of miRNA SNPs may open new avenues for studying sepsis and developing novel therapeutic approaches.

An International Normalized Ratio-Based Definition of Acute Traumatic Coagulopathy Is Associated With Mortality, Venous Thromboembolism, and Multiple Organ Failure After Injury.

OBJECTIVES: Acute traumatic coagulopathy is associated with adverse outcomes including death. Previous studies examining acute traumatic coagulopathy's relation with mortality are limited by inconsistent criteria for syndrome diagnosis, inadequate control of confounding, and single-center designs. In this study, we validated the admission international normalized ratio as an independent risk factor for death and other adverse outcomes after trauma and compared two common international normalized ratio-based definitions for acute traumatic coagulopathy. DESIGN: Multicenter prospective observational study. SETTING: Nine level I trauma centers in the United States. PATIENTS: A total of 1,031 blunt trauma patients with hemorrhagic shock. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: International normalized ratio exhibited a positive adjusted association with all-cause in-hospital mortality, hemorrhagic shock-associated in-hospital mortality, venous thromboembolism, and multiple organ failure. Acute traumatic coagulopathy affected 50% of subjects if defined as an international normalized ratio greater than 1.2 and 21% of subjects if defined by international normalized ratio greater than 1.5. After adjustment for potential confounders, acute traumatic coagulopathy defined as an international normalized ratio greater than 1.5 was significantly associated with all-cause death (odds ratio [OR], 1.88; p < 0.001), hemorrhagic shock-associated death (OR, 2.44; p = 0.001), venous thromboembolism (OR, 1.73; p < 0.001), and multiple organ failure (OR, 1.38; p = 0.02). Acute traumatic coagulopathy defined as an international normalized ratio greater than 1.2 was not associated with an increased risk for the studied outcomes. CONCLUSIONS: Elevated international normalized ratio on hospital admission is a risk factor for mortality and morbidity after severe trauma. Our results confirm this association in a prospectively assembled multicenter cohort of severely injured patients. Defining acute traumatic coagulopathy by using an international normalized ratio greater than 1.5 but not an international normalized ratio greater than 1.2 identified a clinically meaningful subset of trauma patients who, adjusting for confounding factors, experienced more adverse outcomes. Targeting future therapies for acute traumatic coagulopathy to patients with an international normalized ratio greater than 1.5 may yield greater returns than using a lower international normalized ratio threshold.

A new aortic injury score predicts early rupture more accurately than clinical assessment.

OBJECTIVE: The optimal timing for repair of a high-grade blunt thoracic aortic injury (BTAI) is uncertain. Delayed repair is common and associated with improved outcomes, but some lesions may rupture during observation. To determine optimal patient selection for appropriate management, we developed a pilot clinical risk score to evaluate aortic stability and predict rupture. METHODS: Patients presenting in stable condition with Society for Vascular Surgery grade III or IV BTAI diagnosed on computed tomography (CT) were retrospectively reviewed. To determine clinical and radiographic factors associated with aortic rupture, patients progressing to aortic rupture (defined by contrast extravasation on CT or on operative or autopsy findings) were compared with those who had no intervention ≤48 hours of admission. A model targeting 100% sensitivity for rupture was generated and internally validated by bootstrap analysis. Clinical utility was tested by comparison with clinical assessment by surgeons experienced in BTAI management who were provided with CT images and clinical data but were blinded to outcome. RESULTS: The derivation cohort included 18 patients whose aorta ruptured and 31 with stable BTAI. There was no difference in age, gender, injury mechanism, nonchest injury severity, blood pressure, or Glasgow Coma Scale on admission between patient groups. As dichotomous factors, admission lactate >4 mM, posterior mediastinal hematoma >10 mm, and lesion/normal aortic diameter ratio >1.4 on the admission CT were independently associated with aortic rupture. The model had an area under the receiver operator curve of .97, and in the presence of any two factors, was 100% sensitive and 84% specific for predicting aortic rupture. No aortic lesions ruptured in patients with fewer than two factors. In contrast, clinical assessment had lower accuracy (65% vs 90% total accuracy, P < .01). CONCLUSIONS: This novel risk score can be applied on admission using clinically relevant factors that incorporate patient physiology, size of the aortic lesion, and extent of the mediastinal hematoma. The model reliably identifies and distinguishes patients with high-grade BTAI who are at risk for early rupture from those with stable lesions. Although preliminary, because it is more accurate than clinical assessment alone, the score may improve patient selection for emergency or delayed intervention.

Plasma levels of high mobility group box 1 increase in patients with posttraumatic stress disorder after severe blunt chest trauma: a prospective cohort study.

BACKGROUND: High-mobility group box 1 (HMGB1), a key late mediator of systemic inflammation, is a potentially useful biomarker for predicting outcome in patients with severe blunt chest trauma. The purpose of this study was to define the relationship between plasma levels of HMGB1 and posttraumatic stress disorder (PTSD) in patients with severe blunt chest trauma. METHODS: All patients with severe blunt chest trauma (abbreviated injury score ≥3) who were admitted to traumatic surgery department and ultimately survived to follow-up at 6 mo were eligible for the study. HMGB1 was sampled every other day from day 1-day 7 after admission, and plasma concentrations of HMGB1 were measured by a quantitative enzyme-linked immunosorbent assay test. Multivariate regression analysis was used to define the independent contribution of possible risk factors selected by univariate analysis. RESULTS: PTSD was identified in 43 patients including acute PTSD (n = 21), chronic PTSD (n = 18), and delayed-onset PTSD (n = 4) after 6-mo follow-up, in whom significant higher plasma levels of HMGB1 on days three, five, and seven after blunt chest trauma were noted compared with those seen in patients without PTSD (n = 10). Multivariate logistic analysis showed that transfusion, injury severity score, and HMGB1 levels at day 7 were the valuable risk factors for PTSD. CONCLUSIONS: In blunt chest trauma, plasma HMGB1 levels were significantly higher in patients with PTSD compared with patients with non-PTSD. Our data indicate that patients with high plasma levels of HMGB1 may be more prone to develop PTSD including acute and chronic PTSD.

Changes in coagulation in standard laboratory tests and ROTEM in trauma patients between on-scene and arrival in the emergency department.

BACKGROUND: When trauma patients arrive in the emergency department (ED), coagulopathy frequently is present. The time course, however, in which this coagulopathy develops is poorly understood. No study has fully evaluated the coagulation status, including thromboelastometry on-scene and at hospital arrival. We hypothesized that measured coagulation variables might change when measured at the scene of injury and upon arrival to the ED. METHODS: We performed a prospective, single-center, observational study investigating coagulation status in 50 trauma patients on-scene and at arrival in the ED. Measurements included arterial blood gases, ROTEM®, protein S100, protein C activity, protein S, Quick value, international normalized ratio, activated partial thromboplastin time, D-dimer, coagulation factor V (FV), coagulation factor XIII (FXIII), fibrinogen, hemoglobin, hematocrit, platelets, and volume and blood products being administered during the first 24 hours. RESULTS: Significant changes between on-scene and the ED were observed for the following values: partial venous oxygen pressure increased and sodium, glucose, and lactate decreased. For EXTEM, INTEM, and APTEM, clotting time and clot formation time increased significantly, whereas maximal clot firmness and angle α decreased significantly (all P ≤ 0.004). For FIBTEM, clotting time increased significantly and maximal clot firmness decreased significantly. In the laboratory, significant reductions in hemoglobin, hematocrit, platelets, activated partial thromboplastin time, fibrinogen, FV, FXIII, protein C activity, protein S, and protein S100 were observed (all P ≤ 0.001). CONCLUSIONS: Although most all laboratory and rotational thromboelastometry coagulation tests worsened over time when measured on-scene and in the ED, monitoring coagulation at the scene of trauma does not provide clinically important information in a majority of trauma patients. One hour after injury, significant activation and consumption of fibrinogen, FV, FXIII, protein C activity, and protein S were observed.

Predictors of hypofibrinogenemia in blunt trauma patients on admission.

PURPOSE: Massive bleeding usually leads to critically low levels of clotting factors, including fibrinogen. Although reduced fibrinogen levels correlate with increased mortality, predictors of hypofibrinogenemia have remained poorly understood. We investigated whether findings available on admission can be used as predictors of hypofibrinogenemia. METHODS: We retrospectively reviewed serum fibrinogen levels tested on arrival in 290 blunt trauma patients transported to a level I trauma center during a 3-year period. The primary outcome was prehospital predictors for hypofibrinogenemia. Covariates included age, sex, prehospital fluid therapy, prehospital anatomical and physiological scores, time from injury, base excess, and lactate on arrival. All variables with values of p < 0.10 in univariate analysis were included in a multivariate logistic regression model. The relationships between the variables and the 7-day mortality rate were evaluated in a Cox proportional hazards model. RESULTS: Patient's age [odds ratio (OR): 0.97, p < 0.001], Triage Revised Trauma Score (T-RTS) (OR: 0.81, p = 0.003), and prehospital fluid therapy (OR: 2.54, p = 0.01) were detected as independent predictors for hypofibrinogenemia in multivariate logistic regression analysis. Serum fibrinogen level [hazard ratio (HR): 0.99, p = 0.01] and T-RTS (HR: 0.77, p < 0.01) were associated with the 7-day mortality rate. CONCLUSION: T-RTS is considered to play an important role in predicting hypofibrinogenemia and 7-day mortality in blunt trauma patients.

Inducible protein-10, a potential driver of neurally controlled interleukin-10 and morbidity in human blunt trauma.

OBJECTIVE: Blunt trauma and traumatic spinal cord injury induce systemic inflammation that contributes to morbidity. Dysregulated neural control of systemic inflammation postinjury is likely exaggerated in patients with traumatic spinal cord injury. We used in silico methods to discern dynamic inflammatory networks that could distinguish systemic inflammation in traumatic spinal cord injury from blunt trauma. DESIGN: Retrospective study. SETTINGS: Tertiary care institution. PATIENTS: Twenty-one severely injured thoracocervical traumatic spinal cord injury patients and matched 21 severely injured blunt trauma patients without spinal cord injury. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Serial blood samples were obtained from days 1 to 14 postinjury. Twenty-four plasma inflammatory mediators were quantified. Statistical significance between the two groups was determined by two-way analysis of variance. Dynamic Bayesian network inference was used to suggest dynamic connectivity and central inflammatory mediators. Circulating interleukin-10 was significantly elevated in thoracocervical traumatic spinal cord injury group versus non-spinal cord injury group, whereas interleukin-1ß, soluble interleukin-2 receptor-α, interleukin-4, interleukin-5, interleukin-7, interleukin-13, interleukin-17, macrophage inflammatory protein 1α and 1ß, granulocyte-macrophage colony-stimulating factor, and interferon-γ were significantly reduced in traumatic spinal cord injury group versus non-spinal cord injury group. Dynamic Bayesian network suggested that post-spinal cord injury interleukin-10 is driven by inducible protein-10, whereas monocyte chemotactic protein-1 was central in non-spinal cord injury dynamic networks. In a separate validation cohorts of 356 patients without spinal cord injury and 85 traumatic spinal cord injury patients, individuals with plasma inducible protein-10 levels more than or equal to 730 pg/mL had significantly prolonged hospital and ICU stay and days on mechanical ventilator versus patients with plasma inducible protein-10 level less than 730 pg/mL. CONCLUSION: This is the first study to compare the dynamic systemic inflammatory responses of traumatic spinal cord injury patients versus patients without spinal cord injury, suggesting a key role for inducible protein-10 in driving systemic interleukin-10 and morbidity and highlighting the potential utility of in silico tools to identify key inflammatory drivers.