Sigh Ventilation in Patients With Trauma: The SiVent Randomized Clinical Trial.

Importance: Among patients receiving mechanical ventilation, tidal volumes with each breath are often constant or similar. This may lead to ventilator-induced lung injury by altering or depleting surfactant. The role of sigh breaths in reducing ventilator-induced lung injury among trauma patients at risk of poor outcomes is unknown. Objective: To determine whether adding sigh breaths improves clinical outcomes. Design, Setting, and Participants: A pragmatic, randomized trial of sigh breaths plus usual care conducted from 2016 to 2022 with 28-day follow-up in 15 academic trauma centers in the US. Inclusion criteria were age older than 18 years, mechanical ventilation because of trauma for less than 24 hours, 1 or more of 5 risk factors for developing acute respiratory distress syndrome, expected duration of ventilation longer than 24 hours, and predicted survival longer than 48 hours. Interventions: Sigh volumes producing plateau pressures of 35 cm H2O (or 40 cm H2O for inpatients with body mass indexes >35) delivered once every 6 minutes. Usual care was defined as the patient's physician(s) treating the patient as they wished. Main Outcomes and Measures: The primary outcome was ventilator-free days. Prespecified secondary outcomes included all-cause 28-day mortality. Results: Of 5753 patients screened, 524 were enrolled (mean [SD] age, 43.9 [19.2] years; 394 [75.2%] were male). The median ventilator-free days was 18.4 (IQR, 7.0-25.2) in patients randomized to sighs and 16.1 (IQR, 1.1-24.4) in those receiving usual care alone (P = .08). The unadjusted mean difference in ventilator-free days between groups was 1.9 days (95% CI, 0.1 to 3.6) and the prespecified adjusted mean difference was 1.4 days (95% CI, -0.2 to 3.0). For the prespecified secondary outcome, patients randomized to sighs had 28-day mortality of 11.6% (30/259) vs 17.6% (46/261) in those receiving usual care (P = .05). No differences were observed in nonfatal adverse events comparing patients with sighs (80/259 [30.9%]) vs those without (80/261 [30.7%]). Conclusions and Relevance: In a pragmatic, randomized trial among trauma patients receiving mechanical ventilation with risk factors for developing acute respiratory distress syndrome, the addition of sigh breaths did not significantly increase ventilator-free days. Prespecified secondary outcome data suggest that sighs are well-tolerated and may improve clinical outcomes. Trial Registration: ClinicalTrials.gov Identifier: NCT02582957.

Comparison of Appendectomy for Perforated Appendicitis With and Without Abscess: A National Surgical Quality Improvement Program Analysis.

BACKGROUND: Outcomes of appendectomy stratified by type of complicated appendicitis (CA) features are poorly researched, and the evidence to guide operative versus nonoperative management for CA is lacking. This study aimed to determine laparoscopic-to-open conversion risk, postoperative abscess risk, unplanned readmission risk, and length of hospital stay (LOS) associated with appendectomy in patients with perforated appendicitis without abscess (PA) and perforated appendicitis with abscess (PAWA) compared with a control cohort of nonperforated appendicitis (NPA). METHODS: The 2016-2017 National Surgical Quality Improvement Program Appendectomy-targeted database identified 12,537 (76.1%) patients with NPA, 2142 (13.0%) patients with PA, and 1799 (10.9%) patients with PAWA. Chi-squared analysis and analysis of variance were used to compare categorical and continuous variables. Binary logistic and linear regression models were used to compare risk-adjusted outcomes. RESULTS: Compared with NPA, PA and PAWA had higher rates of conversion (0.8% versus 4.9% and 6.5%, respectively; P < 0.001), postoperative abscess requiring intervention (0.6% versus 4.8% and 7.0%, respectively; P < 0.001), readmission (2.8% versus 7.7% and 7.6%, respectively; P < 0.001), and longer median LOS (1 day versus 2 days and 2 days, respectively; P < 0.001). PA and PAWA were associated with increased odds of postoperative abscess (odds ratio [OR]: 7.18, 95% confidence interval [CI]: 5.2-9.8 and OR: 9.94, 95% CI: 7.3-13.5, respectively), readmission (OR: 2.70, 95% CI: 2.1-3.3 and OR: 2.66, 95% CI: 2.2-3.3, respectively), and conversion (OR: 5.51, 95% CI: 4.0-7.5 and OR: 7.43, 95% CI: 5.5-10.1, respectively). PA was associated with an increased LOS of 1.7 days and PAWA with 1.9 days of LOS (95% CI: 1.5-1.8 and 1.7-2.1, respectively). CONCLUSIONS: Individual features of CA were independently associated with outcomes. Further research is needed to determine if surgical management is superior to nonoperative management for CA.

Beclin-1-Dependent Autophagy Protects the Heart During Sepsis.

BACKGROUND: Cardiac dysfunction is a major component of sepsis-induced multiorgan failure in critical care units. Changes in cardiac autophagy and its role during sepsis pathogenesis have not been clearly defined. Targeted autophagy-based therapeutic approaches for sepsis are not yet developed. METHODS: Beclin-1-dependent autophagy in the heart during sepsis and the potential therapeutic benefit of targeting this pathway were investigated in a mouse model of lipopolysaccharide (LPS)-induced sepsis. RESULTS: LPS induced a dose-dependent increase in autophagy at low doses, followed by a decline that was in conjunction with mammalian target of rapamycin activation at high doses. Cardiac-specific overexpression of Beclin-1 promoted autophagy, suppressed mammalian target of rapamycin signaling, improved cardiac function, and alleviated inflammation and fibrosis after LPS challenge. Haplosufficiency for beclin 1 resulted in opposite effects. Beclin-1 also protected mitochondria, reduced the release of mitochondrial danger-associated molecular patterns, and promoted mitophagy via PTEN-induced putative kinase 1-Parkin but not adaptor proteins in response to LPS. Injection of a cell-permeable Tat-Beclin-1 peptide to activate autophagy improved cardiac function, attenuated inflammation, and rescued the phenotypes caused by beclin 1 deficiency in LPS-challenged mice. CONCLUSIONS: These results suggest that Beclin-1 protects the heart during sepsis and that the targeted induction of Beclin-1 signaling may have important therapeutic potential.

Discontinuity of the Bowel Following Damage Control Operation Revisited: A Multi-institutional Study.

BACKGROUND: Discontinuity of the bowel following intestinal injury and resection is a common practice in damage control procedures for severe abdominal trauma. However, there are concerns that complete occlusion of the bowel, especially in the presence of hypotension or edema that may result in ischemic bowel changes or increase bacterial or toxin translocation. METHODS: This was a retrospective study from three Level-1 trauma centers. Included were trauma patients who required bowel resection and damage control. The study population was stratified into two groups based on the management for bowel injury: bowel discontinuity versus primary anastomosis. Outcomes included anastomotic leak, organ space infection, bowel ischemia, and mortality. RESULTS: A total of 167 cases were included. In 84 cases, continuity of the bowel was established, and in 83, the bowel was left in discontinuity. The epidemiological, admission, and intraoperative physiological characteristics, the abdominal Abbreviated Injury Scale, type of intra-abdominal injury, and transfusion requirements were similar in the two study groups. The mortality was 8.3 % in the continuity group and 16.9 % for the discontinuity group (p = 0.096). On the crude bivariate and adjusted regression analyses, there was a higher rate of bowel ischemia at the take-back operation in the discontinuity group (p = 0.003 for the crude and p = 0.034 for the adjusted). The organ space infection and anastomotic leak rate were not significantly different between the study groups. CONCLUSIONS: Discontinuity of the bowel following damage control operation is associated with a higher risk of bowel ischemia than in patients with anastomosis. Further prospective observational and randomized studies are warranted. LEVEL OF EVIDENCE: III.

Cannabis Use Has Negligible Effects Following Severe Traumatic Injury.

Nearly half of all states have legalized medical marijuana or recreational-use marijuana. As more states move toward legalization, the effects on injured patients must be evaluated. This study sought to determine effects of cannabis positivity at the time of severe injury on hospital outcomes compared with individuals negative for illicit substances and those who were users of other illicit substances. A Level I trauma center performed a retrospective chart review covering subjects over a 2-year period with toxicology performed and an Injury Severity Score (ISS) of more than 16. These individuals were divided into the negative and positive toxicology groups, further divided into the marijuana-only, other drugs-only, and mixed-use groups. Differences in presenting characteristics, hospital length of stay, intensive care unit (ICU) stays, ventilator days, and death were compared. A total of 8,441 subjects presented during the study period; 2,134 (25%) of these had toxicology performed; 843 (40%) had an ISS of more than 16, with 347 having negative tests (NEG); 70 (8.3%) substance users tested positive only for marijuana (MO), 323 (38.3%) for other drugs-only, excluding marijuana (OD), and 103 (12.2%) subjects showed positivity for mixed-use (MU). The ISS was similar for all groups. No differences were identified in Glasgow Coma Scale (GCS), ventilator days, blood administration, or ICU/hospital length of stay when comparing the MO group with the NEG group. Significant differences occurred between the OD group and the NEG/MO/MU groups for GCS, ICU length of stay, and hospital charges. Cannabis users suffering from severe injury demonstrated no detrimental outcomes in this study compared with nondrug users.

Adult obese mice suffer from chronic secondary brain injury after mild TBI.

BACKGROUND: A traumatic brain injury (TBI) event is a devastating injury to the brain that may result in heightened inflammation, neurodegeneration, and subsequent cognitive and mood deficits. TBI victims with co-morbidities such as heart disease, diabetes, or obesity may be more vulnerable to the secondary brain injury that follows the initial insult. Compared to lean individuals, obese subjects tend to have worse clinical outcomes and higher mortality rates after trauma. METHODS: To elucidate whether obesity predisposes individuals to worse outcomes after TBI, we subjected adult lean and obese male/female mice to a mild TBI. The injury was administered using a controlled skull impact (CSI) device. Lean or obese 6-month-old C57 BL/6 mice were subjected once to a mild TBI. Additionally, at day 30 after injury, both the lean and obese mice were tested for increased anxiety using the open field test. RESULTS: At day 30 after TBI, compared to the lean mice, we found heightened microglial (MG) activation in the cerebral cortex, corpus callosum, and hypothalamus. Another compelling finding was that, compared to the non-injured obese male control mice, the obese TBI mice had a decrease in the rate of weight gain and serum corticosterone levels at day 30 after injury. Additionally, the injured obese mice displayed higher levels of anxiety as determined by a significant decrease in time spent in the non-peripheral zones in the open field test. In contrast to the obese males, the obese female mice did not exhibit increases in the number of active MG in the brain, changes in weight gain/corticosterone levels, or increased anxiety at day 30 after TBI. CONCLUSIONS: The data presented here suggests that obese mice have worse outcomes compared to lean mice after mild TBI. Also, the obese males have worse outcomes than the injured female mice. This data may explain the sequela of chronic secondary brain injury in obese adults after a single mild TBI. Also, this report may help shape how the overweight/obese populations are monitored over the days and months following a TBI.

Genomic responses in mouse models poorly mimic human inflammatory diseases.

A cornerstone of modern biomedical research is the use of mouse models to explore basic pathophysiological mechanisms, evaluate new therapeutic approaches, and make go or no-go decisions to carry new drug candidates forward into clinical trials. Systematic studies evaluating how well murine models mimic human inflammatory diseases are nonexistent. Here, we show that, although acute inflammatory stresses from different etiologies result in highly similar genomic responses in humans, the responses in corresponding mouse models correlate poorly with the human conditions and also, one another. Among genes changed significantly in humans, the murine orthologs are close to random in matching their human counterparts (e.g., R(2) between 0.0 and 0.1). In addition to improvements in the current animal model systems, our study supports higher priority for translational medical research to focus on the more complex human conditions rather than relying on mouse models to study human inflammatory diseases.

Early prediction of outcome after severe traumatic brain injury: a simple and practical model.

BACKGROUND: Traumatic brain injury (TBI) is a heterogeneous syndrome with a broad range of outcome. We developed a simple model for long-term outcome prognostication after severe TBI. METHODS: Secondary data analysis of a large multicenter randomized trial. Patients were grouped according to 6-month extended Glasgow outcome scale (eGOS): poor-outcome (eGOS ≤ 4; severe disability or death) and acceptable outcome (eGOS > 4; no or moderate disability). A prediction decision tree was built using binary recursive partitioning to predict poor or acceptable 6-month outcome. Comparison to two previously published and validated models was made. RESULTS: The decision tree included the predictors of head Abbreviated Injury Scale (AIS) severity, the Marshall computed tomography score, and pupillary reactivity. All patients with a head AIS severity of 5 were predicted to have a poor outcome. In patients with head AIS severity < 5, the model predicted an acceptable outcome for (1) those with Marshall score of 1, and (2) those with Marshall score above 1 but with reactive pupils at admission. The decision tree had a sensitivity of 72.3 % (95 % CI: 66.4-77.6 %) and specificity of 62.5 % (95 % CI: 54.9-69.6 %). The proportion correctly classified for the comparison models was similar to our model. Our model was more apt at correctly classifying those with poor outcome but more likely to misclassify those with acceptable outcome than the comparison models. CONCLUSION: Predicting long-term outcome early after TBI remains challenging and inexact. This model could be useful for research and quality improvement studies to provide an early assessment of injury severity, but is not sufficiently accurate to guide decision-making in the clinical setting.

Detailed description of all deaths in both the shock and traumatic brain injury hypertonic saline trials of the Resuscitation Outcomes Consortium.

OBJECTIVE: To identify causes and timing of mortality in trauma patients to determine targets for future studies. BACKGROUND: In trials conducted by the Resuscitation Outcomes Consortium in patients with traumatic hypovolemic shock (shock) or traumatic brain injury (TBI), hypertonic saline failed to improve survival. Selecting appropriate candidates is challenging. METHODS: Retrospective review of patients enrolled in multicenter, randomized trials performed from 2006 to 2009. Inclusion criteria were as follows: injured patients, age 15 years or more with hypovolemic shock [systolic blood pressure (SBP) ≤ 70 mm Hg or SBP 71-90 mm Hg with heart rate ≥ 108) or severe TBI [Glasgow Coma Score (GCS) ≤ 8]. Initial fluid administered was 250 mL of either 7.5% saline with 6% dextran 70, 7.5% saline or 0.9% saline. RESULTS: A total of 2061 subjects were enrolled (809 shock, 1252 TBI) and 571 (27.7%) died. Survivors were younger than nonsurvivors [30 (interquartile range 23) vs 42 (34)] and had a higher GCS, though similar hemodynamics. Most deaths occurred despite ongoing resuscitation. Forty-six percent of deaths in the TBI cohort were within 24 hours, compared with 82% in the shock cohort and 72% in the cohort with both shock and TBI. Median time to death was 29 hours in the TBI cohort, 2 hours in the shock cohort, and 4 hours in patients with both. Sepsis and multiple organ dysfunction accounted for 2% of deaths. CONCLUSIONS: Most deaths from trauma with shock or TBI occur within 24 hours from hypovolemic shock or TBI. Novel resuscitation strategies should focus on early deaths, though prevention may have a greater impact.

Pretrauma center red blood cell transfusion is associated with reduced mortality and coagulopathy in severely injured patients with blunt trauma.

OBJECTIVE: To evaluate the association of pretrauma center (PTC) red blood cell (RBC) transfusion with outcomes in severely injured patients. BACKGROUND: Hemorrhage remains a major driver of mortality. Little evidence exists supporting PTC interventions to mitigate this. METHODS: Blunt injured patients in shock arriving at a trauma center within 2 hours of injury were included from the Glue Grant database. Subjects were dichotomized by PTC RBC transfusion. Outcomes included 24-hour mortality, 30-day mortality, and trauma-induced coagulopathy [(TIC), admission international normalized ratio >1.5]. Cox regression and logistic regression determined the association of PTC RBC transfusion with outcomes. To address baseline differences, propensity score matching was used. RESULTS: Of 1415 subjects, 50 received PTC RBC transfusion. Demographics and injury severity score were similar. The PTC RBC group received 1.3 units of RBCs (median), and 52% were scene transports. PTC RBC transfusion was associated with a 95% reduction in odds of 24-hour mortality [odds ratio (OR) = 0.05; 95% confidence interval (CI), 0.01-0.48; P < 0.01], 64% reduction in the risk of 30-day mortality [hazard ratio = 0.36; 95% CI, 0.15-0.83; P = 0.02], and 88% reduction in odds of TIC (OR = 0.12; 95% CI, 0.02-0.79; P = 0.03). The matched cohort included 113 subjects (31% PTC RBC group). Baseline characteristics were similar. PTC RBC transfusion was associated with a 98% reduction in odds of 24-hour mortality (OR = 0.02; 95% CI, 0.01-0.69; P = 0.04), 88% reduction in the risk of 30-day mortality (hazard ratio = 0.12; 95% CI, 0.03-0.61; P = 0.01), and 99% reduction in odds of TIC (OR = 0.01; 95% CI, 0.01-0.95; P = 0.05). CONCLUSIONS: PTC RBC administration was associated with a lower risk of 24-hour mortality, 30-day mortality, and TIC in severely injured patients with blunt trauma, warranting further prospective study.

Transfusion of cryopreserved packed red blood cells is safe and effective after trauma: a prospective randomized trial.

OBJECTIVES: To determine the safety and efficacy of cryopreserved packed red blood cell (CPRBC) transfusion in trauma patients. BACKGROUND: Liquid packed red blood cells (LPRBCs) have an abbreviated shelf-life and worsening storage lesion with age. CPRBCs are frozen 2 to 6 days after donation, stored up to 10 years, and are available for 14 days after thawing and washing. CPRBCs can be utilized in diverse settings, but the effect on clinical outcomes is unknown. METHODS: We performed a prospective, randomized, double-blind study at 5 level 1 trauma centers. Stable trauma patients requiring transfusion were randomized to young LPRBCs (≤14 storage days), old LPRBCs (>14 storage days), or CPRBCs. Tissue oxygenation (StO2), biochemical and inflammatory mediators were measured, and clinical outcomes were determined. RESULTS: Two hundred fifty-six patients with well-matched injury severity and demographics (P > 0.2) were randomized (84 young, 86 old, and 86 CPRBCs). Pretransfusion and final hematocrits were similar (P > 0.68). Patients in all groups received the same number of units postrandomization (2 [1-4]; P > 0.05). There was no difference in the change in tissue oxygenation between groups. CPRBCs contained less α2-macrogobulin, haptoglobin, C-reactive protein, and serum amyloid P (P < 0.001). Organ failure, infection rate, and mortality did not differ between groups (P > 0.2). CONCLUSIONS: Transfusion of CPRBCs is as safe and effective as transfusion of young and old LPRBCs and provides a mechanism to deliver PRBCs in a wide variety of settings.

Revisiting the "Golden Hour": An Evaluation of Out-of-Hospital Time in Shock and Traumatic Brain Injury.

STUDY OBJECTIVE: We evaluate patients with shock and traumatic brain injury who were previously enrolled in an out-of-hospital clinical trial to test the association between out-of-hospital time and outcome. METHODS: This was a secondary analysis of patients with shock and traumatic brain injury who were aged 15 years or older and enrolled in a Resuscitation Outcomes Consortium out-of-hospital clinical trial by 81 emergency medical services agencies transporting to 46 Level I and II trauma centers in 11 sites (May 2006 through May 2009). Inclusion criteria were systolic blood pressure less than or equal to 70 mm Hg or systolic blood pressure 71 to 90 mm Hg with pulse rate greater than or equal to 108 beats/min (shock cohort) and Glasgow Coma Scale score less than or equal to 8 (traumatic brain injury cohort); patients meeting both criteria were placed in the shock cohort. Primary outcomes were 28-day mortality (shock cohort) and 6-month Glasgow Outcome Scale-Extended score less than or equal to 4 (traumatic brain injury cohort). RESULTS: There were 778 patients in the shock cohort (26% 28-day mortality) and 1,239 patients in the traumatic brain injury cohort (53% 6-month Glasgow Outcome Scale-Extended score ≤4). Out-of-hospital time greater than 60 minutes was not associated with worse outcomes after accounting for important confounders in the shock cohort (adjusted odds ratio [aOR] 1.42; 95% confidence interval [CI] 0.77 to 2.62) or traumatic brain injury cohort (aOR 0.77; 95% CI 0.51 to 1.15). However, shock patients requiring early critical hospital resources and arriving after 60 minutes had higher 28-day mortality (aOR 2.37; 95% CI 1.05 to 5.37); this finding was not observed among a similar traumatic brain injury subgroup. CONCLUSION: Among out-of-hospital trauma patients meeting physiologic criteria for shock and traumatic brain injury, there was no association between time and outcome. However, the subgroup of shock patients requiring early critical resources and arriving after 60 minutes had higher mortality.

A Comparison of Invasive Airway Management and Rates of Pneumonia in Prehospital and Hospital Settings.

INTRODUCTION: Infection is a major cause of morbidity and mortality in trauma. Infection in trauma is poorly understood. The impact of prehospital invasive airway management (IAM) on the incidence of pneumonia and health services utilization is unknown. We hypothesized that trauma patients exposed to prehospital IAM will suffer higher rates of pneumonia compared to no IAM or exposure to IAM performed in the hospital. We hypothesized that patients who develop pneumonia subsequent to prehospital IAM will have longer intensive care unit (ICU) and hospital length of stay (LOS) compared to patients who acquired pneumonia after IAM performed in the hospital. METHODS: This is an observational cohort study of data previously collected for the Resuscitation Outcomes Consortium hypertonic resuscitation randomized trial. Patients were included if traumatic injury resulted in shock, traumatic brain injury, or both. Patients were excluded if they died 24 hours after injury, or pneumonia data were missing. Adjusted and unadjusted logistic regression was used to calculate the odds ratio of pneumonia if exposed in the prehospital setting compared to no exposure or exposure in the hospital. RESULTS: Of 2,222 patients enrolled in the hypertonic resuscitation trial, 1,676 patients met enrollment criteria for this study. Four and a half percent of patients suffered pneumonia. IAM in the prehospital setting resulted in 6.8-fold increase (C.I. 2.0, 23.0, p = 0.003) in the adjusted odds of developing pneumonia compared to not being intubated, while in-hospital intubation resulted in 4.8-fold increase (C.I. 1.4, 16.6, p = 0.01), which was not statistically significantly different to the odds ratio of prehospital IAM. There were no statistically significant increases in health services utilization resulting from pneumonia incurred after IAM. CONCLUSION: Exposure to IAM in prehospital and hospital settings results in an increase in pneumonia, but there does not appear to be a link between the source of pneumonia and an increase in ICU or hospital LOS.

Increased trauma center volume is associated with improved survival after severe injury: results of a Resuscitation Outcomes Consortium study.

OBJECTIVE: To investigate the relationship between trauma center volume and outcome. BACKGROUND: The Resuscitation Outcomes Consortium is a network of 11 centers and 60 hospitals conducting emergency care research. For many procedures, high-volume centers demonstrate superior outcomes versus low-volume centers. This remains controversial for trauma center outcomes. METHODS: This study was a secondary analysis of prospectively collected data from the Resuscitation Outcomes Consortium multicenter out-of-hospital Hypertonic Saline Trial in patients with Glasgow Coma Scale score of 8 or less (traumatic brain injury) or systolic blood pressure of 90 or less and pulse of 110 or more (shock). Regression analyses evaluated associations between trauma volume and the following outcomes: 24-hour mortality, 28-day mortality, ventilator-free days, Multiple Organ Dysfunction Scale incidence, worst Multiple Organ Dysfunction Scale score, and poor 6-month Glasgow Outcome Scale-Extended score. RESULTS: A total of 2070 patients were evaluated: 1251 in the traumatic brain injury cohort and 819 in the shock cohort. Overall, 24-hour and 28-day mortality was 16% and 25%, respectively. For every increase of 500 trauma center admissions, there was a 7% decreased odds of 24-hour and 28-day mortality for all patients. As trauma center volume increased, nonorgan dysfunction complications increased, ventilator-free days increased, and worst Multiple Organ Dysfunction Scale score decreased. The associations with higher trauma center volume were similar for the traumatic brain injury cohort, including better neurologic outcomes at 6 months, but not for the shock cohort. CONCLUSIONS: Increased trauma center volume was associated with increased survival, more ventilator-free days, and less severe organ failure. Trauma system planning and implementation should avoid unnecessary duplication of services.

Prehospital use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a reduced incidence of trauma-induced coagulopathy.

OBJECTIVE: To determine whether prehospital nonsteroidal anti-inflammatory drug (NSAID) use may lead to a reduced incidence of trauma-induced coagulopathy (TIC) in severely injured patients. BACKGROUND: TIC is present in up to a quarter of severely injured trauma patients and is linked to worse outcomes after injury. Evidence linking TIC to inflammation has emerged; however, the mechanism behind this association is still under investigation. NSAIDs are commonly used anti-inflammatory drugs, but their effects on TIC and outcomes after injury are largely unexplored. METHODS: We performed a secondary analysis of the Inflammation and the Host Response to Injury Large Scale Collaborative Program (Glue Grant) data set. Prehospital medications and comorbidities were analyzed by logistic regression analysis for association with TIC as defined by laboratory (international normalized ratio >1.5) or clinical (transfusion >2 units of fresh frozen plasma or >1 pack of platelets in 6 hours) parameters. RESULTS: Prehospital NSIAD use was independently associated with a 72% lower risk of TIC and was the only medication among 15 analyzed to retain significance in the model. Stepwise logistic regression also demonstrated that preadmission use of NSAIDs was independently associated with a 66% lower risk of clinically significant coagulopathy. These findings were independent of comorbid conditions linked to NSAID use. CONCLUSIONS: NSAID use before admission for severe injury is associated with a reduced incidence of TIC. These findings provide further evidence to a potential leak between TIC and inflammation.

Estrogen-provided cardiac protection following burn trauma is mediated through a reduction in mitochondria-derived DAMPs.

Mitochondria-derived danger-associated molecular patterns (DAMPs) play important roles in sterile inflammation after acute injuries. This study was designed to test the hypothesis that 17ß-estradiol protects the heart via suppressing myocardial mitochondrial DAMPs after burn injury using an animal model. Sprague-Dawley rats were given a third-degree scald burn comprising 40% total body surface area (TBSA). 17ß-Estradiol, 0.5 mg/kg, or control vehicle was administered subcutaneously 15 min following burn. The heart was harvested 24 h postburn. Estradiol showed significant inhibition on the productivity of H2O2 and oxidation of lipid molecules in the mitochondria. Estradiol increased mitochondrial antioxidant defense via enhancing the activities and expression of superoxide dismutase (SOD) and glutathione peroxidase (GPx). Estradiol also protected mitochondrial respiratory function and structural integrity. In parallel, estradiol remarkably decreased burn-induced release of mitochondrial cytochrome c and mitochondrial DNA (mtDNA) into cytoplasm. Further, estradiol inhibited myocardial apoptosis, shown by its suppression on DNA laddering and downregulation of caspase 1 and caspase 3. Estradiol's anti-inflammatory effect was demonstrated by reduction in systemic and cardiac cytokines (TNF-α, IL-1ß, and IL-6), decrease in NF-κB activation, and attenuation of the expression of inflammasome component ASC in the heart of burned rats. Estradiol-provided cardiac protection was shown by reduction in myocardial injury marker troponin-I, amendment of heart morphology, and improvement of cardiac contractility after burn injury. Together, these data suggest that postburn administration of 17ß-estradiol protects the heart via an effective control over the generation of mitochondrial DAMPs (mtROS, cytochrome c, and mtDNA) that incite cardiac apoptosis and inflammation.

Early GFAP and UCH-L1 point-of-care biomarker measurements for the prediction of traumatic brain injury and progression in patients with polytrauma and hemorrhagic shock.

OBJECTIVE: Traumatic brain injury (TBI) and hemorrhage are responsible for the largest proportion of all trauma-related deaths. In polytrauma patients at risk of hemorrhage and TBI, the diagnosis, prognosis, and management of TBI remain poorly characterized. The authors sought to characterize the predictive capabilities of glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase L1 (UCH-L1) measurements in patients with hemorrhagic shock with and without concomitant TBI. METHODS: The authors performed a secondary analysis on serial blood samples derived from a prospective observational cohort study that focused on comparing early whole-blood and component resuscitation. A convenience sample of patients was used in which samples were collected at three time points and the presence of TBI or no TBI via CT imaging was documented. GFAP and UCH-L1 measurements were performed on plasma samples using the i-STAT Alinity point-of-care platform. Using classification tree recursive partitioning, the authors determined the measurement cut points for each biomarker to maximize the abilities for predicting the diagnosis of TBI, Rotterdam CT imaging scores, and 6-month Glasgow Outcome Scale-Extended (GOSE) scores. RESULTS: Biomarker comparisons demonstrated that GFAP and UCH-L1 measurements were associated with the presence of TBI at all time points. Classification tree analyses demonstrated that a GFAP level > 286 pg/ml for the sample taken upon the patient's arrival had an area under the receiver operating characteristic curve of 0.77 for predicting the presence of TBI. The classification tree results demonstrated that a cut point of 3094 pg/ml for the arrival GFAP measurement was the most predictive for an elevated Rotterdam score on the initial and second CT scans and for TBI progression between scans. No significant associations between any of the most predictive cut points for UCH-L1 and Rotterdam CT scores or TBI progression were found. The predictive capabilities of UCH-L1 were limited by the range allowed by the point-of-care platform. Arrival GFAP cut points remained strong independent predictors after controlling for all potential polytrauma confounders, including injury characteristics, shock severity, and resuscitation. CONCLUSIONS: Early measurements of GFAP and UCH-L1 on a point-of-care device are significantly associated with CT-diagnosed TBI in patients with polytrauma and shock. Early elevated GFAP measurements are associated with worse head CT scan Rotterdam scores, TBI progression, and worse GOSE scores, and these associations are independent of other injury attributes, shock severity, and early resuscitation characteristics.

17ß-Estradiol reappropriates mass lost to the hypermetabolic state in thermally injured rats.

BACKGROUND: The hypermetabolic response to severe thermal injury is unlike any physiologic response seen in medicine. While some parallels can be drawn to shock and sepsis states, this response is typified by its intensity and duration. Our group has been interested in the myriad effects of estrogens after injury, specifically the ability of estrogens to reduce inflammatory responses. Given this, and the known link between severe inflammation and the hypermetabolic response, we examined the effects of a single dose of 17ß estradiol administered after a severe thermal injury in rats. METHODS: Twelve male Sprague-Dawley rats were subject to either a sham burn or a 40% total body surface area burn, followed by fluid resuscitation. Burned animals were divided into a vehicle and treatment group, with injections given 15 min after the injury. Animals were monitored for a period of 45 d, with markers of hypermetabolism (weight, fecal output, food intake, and serum insulin and glucose) measured daily. RESULTS: We identified a significant difference in daily measured weights between the burned groups. We observed a sparing of body mass during the acute phase lasting 2 wk after the injury and an improved recovery phase during the remainder of the study. Glucose and insulin levels during the first week of the study did not differ between the treatment groups. CONCLUSION: Estrogen may have a role in preserving body mass after severe thermal injury. Further studies are required to determine if this spared body mass composition.

Analysis of factorial time-course microarrays with application to a clinical study of burn injury.

Time-course microarray experiments are capable of capturing dynamic gene expression profiles. It is important to study how these dynamic profiles depend on the multiple factors that characterize the experimental condition under which the time course is observed. Analytic methods are needed to simultaneously handle the time course and factorial structure in the data. We developed a method to evaluate factor effects by pooling information across the time course while accounting for multiple testing and nonnormality of the microarray data. The method effectively extracts gene-specific response features and models their dependency on the experimental factors. Both longitudinal and cross-sectional time-course data can be handled by our approach. The method was used to analyze the impact of age on the temporal gene response to burn injury in a large-scale clinical study. Our analysis reveals that 21% of the genes responsive to burn are age-specific, among which expressions of mitochondria and immunoglobulin genes are differentially perturbed in pediatric and adult patients by burn injury. These new findings in the body's response to burn injury between children and adults support further investigations of therapeutic options targeting specific age groups. The methodology proposed here has been implemented in R package "TANOVA" and submitted to the Comprehensive R Archive Network at http://www.r-project.org/. It is also available for download at http://gluegrant1.stanford.edu/TANOVA/.

Predictors of failed primary abdominal closure in the trauma patient with an open abdomen.

BACKGROUND: We sought to characterize risk factors for failed closure after damage-control laparotomy and to examine the impact of two broad categories of open abdomen-management technique on rates of fascial approximation. METHODS: We retrospectively reviewed (January 2006-December 2008) all trauma patients with an open abdomen after damage-control laparotomy. Patients with definitive abdominal closure before discharge were classified as successful closure (SC) and those discharged with a planned ventral hernia were classified as failed closure (FC). Univariate stepwise logistical analyses were conducted to identify covariates related to resuscitation volumes and injury severity that were associated with FC. Surgical techniques were dichotomized as fascial based or vacuum based and compared with chi square. RESULTS: Sixty-two subjects met final eligibility (SC 44, FC 18). SC and FC were similar, with the exception of, respectively, initial base excess (-8.0 ± 4.2 vs -11.4 ± 4.9; P = 0.009), injury severity score (ISS; 29.0 ± 15.2 vs 20.6 ± 12.1; P = 0.04), and frequency of penetrating injury (47.7% vs 77.8%; P = 0.03). Stepwise regression showed significant associations between failed closure and increasing Penetrating Abdominal Trauma Index (odds ratio [OR] 1.06, 95% confidence interval [CI] 1.01-1.11), worsening base excess on arrival (OR 0.79, 95% CI 0.66-0.93), and lower ISS (OR 0.94, 95% CI 0.89-1.00). Fascial-based versus vacuum-based management techniques had no effect on closure rates. CONCLUSIONS: Volume of blood transfused, crystalloid given, and open abdomen management technique were not related to closure rates; however, worsened base excess on arrival, penetrating trauma, higher Penetrating Abdominal Trauma Index, and a lower ISS were associated with FC. The latter was true despite an association also being found between FC and lower ISS scores, reflecting the propensity of ISS to underestimate injury burden after penetrating injury.