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.

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.

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.

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.

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.

Whole Blood Resuscitation and Association with Survival in Injured Patients with an Elevated Probability of Mortality.

BACKGROUND: Low-titer group O whole blood (LTOWB) resuscitation is becoming common in both military and civilian settings and may represent the ideal resuscitation intervention. We sought to characterize the safety and efficacy of LTOWB resuscitation relative to blood component resuscitation. STUDY DESIGN: A prospective, multicenter, observational cohort study was performed using 7 trauma centers. Injured patients at risk of massive transfusion who required both blood transfusion and hemorrhage control procedures were enrolled. The primary outcome was 4-hour mortality. Secondary outcomes included 24-hour and 28-day mortality, achievement of hemostasis, death from exsanguination, and the incidence of unexpected survivors. RESULTS: A total of 1,051 patients in hemorrhagic shock met all enrollment criteria. The cohort was severely injured with >70% of patients requiring massive transfusion. After propensity adjustment, no significant 4-hour mortality difference across LTOWB and component patients was found (relative risk [RR] 0.90, 95% CI 0.59 to 1.39, p = 0.64). Similarly, no adjusted mortality differences were demonstrated at 24 hours or 28 days for the enrolled cohort. When patients with an elevated prehospital probability of mortality were analyzed, LTOWB resuscitation was independently associated with a 48% lower risk of 4-hour mortality (relative risk [RR] 0.52, 95% CI 0.32 to 0.87, p = 0.01) and a 30% lower risk of 28-day mortality (RR 0.70, 95% CI 0.51 to 0.96, p = 0.03). CONCLUSIONS: Early LTOWB resuscitation is safe but not independently associated with survival for the overall enrolled population. When patients were selected with an elevated probability of mortality based on prehospital injury characteristics, LTOWB was independently associated with a lower risk of mortality starting at 4 hours after arrival through 28 days after injury.

Benchmarking outcomes in the critically injured trauma patient and the effect of implementing standard operating procedures.

OBJECTIVE: To determine and compare outcomes with accepted benchmarks in trauma care at 7 academic level I trauma centers in which patients were treated on the basis of a series of standard operating procedures (SOPs). BACKGROUND: Injury remains the leading cause of death for those younger than 45 years. This study describes the baseline patient characteristics and well-defined outcomes of persons hospitalized in the United States for severe blunt trauma. METHODS: We followed 1637 trauma patients from 2003 to 2009 up to 28 hospital days using SOPs developed at the onset of the study. An extensive database on patient and injury characteristics, clinical treatment, and outcomes was created. These data were compared with existing trauma benchmarks. RESULTS: The study patients were critically injured and were in shock. SOP compliance improved 10% to 40% during the study period. Multiple organ failure and mortality rates were 34.8% and 16.7%, respectively. Time to recovery, defined as the time until the patient was free of organ failure for at least 2 consecutive days, was developed as a new outcome measure. There was a reduction in mortality rate in the cohort during the study that cannot be explained by changes in the patient population. CONCLUSIONS: This study provides the current benchmark and the overall positive effect of implementing SOPs for severely injured patients. Over the course of the study, there were improvements in morbidity and mortality rates and increasing compliance with SOPs. Mortality was surprisingly low, given the degree of injury, and improved over the duration of the study, which correlated with improved SOP compliance.

Specific inhibition of mitochondrial oxidative stress suppresses inflammation and improves cardiac function in a rat pneumonia-related sepsis model.

Using a mitochondria-targeted vitamin E (Mito-Vit-E) in a rat pneumonia-related sepsis model, we examined the role of mitochondrial reactive oxygen species in sepsis-mediated myocardial inflammation and subsequent cardiac contractile dysfunction. Sepsis was produced in adult male Sprague-Dawley rats via intratracheal injection of S. pneumonia (4 × 10(6) colony formation units per rat). A single dose of Mito-Vit-E, vitamin E, or control vehicle, at 21.5 µmol/kg, was administered 30 min postinoculation. Blood was collected, and heart tissue was harvested at various time points. Mito-Vit-E in vivo distribution was confirmed by mass spectrometry. In cardiac mitochondria, Mito-Vit-E improved total antioxidant capacity and suppressed H(2)O(2) generation, whereas vitamin E offered little effect. In cytosol, both antioxidants decreased H(2)O(2) levels, but only vitamin E strengthened antioxidant capacity. Mito-Vit-E protected mitochondrial structure and function in the heart during sepsis, demonstrated by reduction in lipid and protein oxidation, preservation of mitochondrial membrane integrity, and recovery of respiratory function. While both Mito-Vit-E and vitamin E suppressed sepsis-induced peripheral and myocardial production of proinflammatory cytokines (tumor necrosis factor-α, interleukin-1ß, and interleukin-6), Mito-Vit-E exhibited significantly higher efficacy (P < 0.05). Stronger anti-inflammatory action of Mito-Vit-E was further shown by its near-complete inhibition of sepsis-induced myeloperoxidase accumulation in myocardium, suggesting its effect on neutrophil infiltration. Echocardiography analysis indicated that Mito-Vit-E ameliorated cardiac contractility of sepsis animals, shown by improved fractional shortening and ejection fraction. Together, our data suggest that targeted scavenging of mitochondrial reactive oxygen species protects mitochondrial function, attenuates tissue-level inflammation, and improves whole organ activities in the heart during sepsis.

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.

Value in acute care surgery, Part 1: Methods of quantifying cost.

BACKGROUND: With health care expenditures continuing to increase rapidly, the need to understand and provide value has become more important than ever. In order to determine the value of care, the ability to accurately measure cost is essential. The acute care surgeon leader is an integral part of driving improvement by engaging in value increasing discussions. Different approaches to quantifying cost exist depending on the purpose of the analysis and available resources. Cost analysis methods range from detailed microcosting and time-driven activity-based costing to less complex gross and expenditure-based approaches. An overview of these methods and a practical approach to costing based on the needs of the acute care surgeon leader is presented.

Value in acute care surgery, part 2: Defining and measuring quality outcomes.

ABSTRACT: The prior article in this series delved into measuring cost in acute care surgery, and this subsequent work explains in detail how quality is measured. Specifically, objective quality is based on outcome measures, both from administrative and clinical registry databases from a multitude of sources. Risk stratification is key in comparing similar populations across diseases and procedures. Importantly, a move toward focusing on subjective outcomes like patient-reported outcomes measures and financial well-being are vital to evolving surgical quality measures for the 21st century.