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Background: Sleep and circadian disruption (SCD) is common and severe in the ICU. On the basis of rigorous evidence in non-ICU populations and emerging evidence in ICU populations, SCD is likely to have a profound negative impact on patient outcomes. Thus, it is urgent that we establish research priorities to advance understanding of ICU SCD. Methods: We convened a multidisciplinary group with relevant expertise to participate in an American Thoracic Society Workshop. Workshop objectives included identifying ICU SCD subtopics of interest, key knowledge gaps, and research priorities. Members attended remote sessions from March to November 2021. Recorded presentations were prepared and viewed by members before Workshop sessions. Workshop discussion focused on key gaps and related research priorities. The priorities listed herein were selected on the basis of rank as established by a series of anonymous surveys. Results: We identified the following research priorities: establish an ICU SCD definition, further develop rigorous and feasible ICU SCD measures, test associations between ICU SCD domains and outcomes, promote the inclusion of mechanistic and patient-centered outcomes within large clinical studies, leverage implementation science strategies to maximize intervention fidelity and sustainability, and collaborate among investigators to harmonize methods and promote multisite investigation. Conclusions: ICU SCD is a complex and compelling potential target for improving ICU outcomes. Given the influence on all other research priorities, further development of rigorous, feasible ICU SCD measurement is a key next step in advancing the field.

Thrombotic complications after total pancreatectomy with islet autotransplantation (TPIAT) are common. However, the systemic changes to coagulation in the perioperative period have not been well studied. Our objective was to evaluate the derangements in coagulation in the perioperative period for this procedure.This was a prospective observational study of patients undergoing elective TPIAT for chronic pancreatitis. Multiple methods of evaluating coagulation, including 2 viscoelastic assays and standard laboratory assays were obtained at defined intraoperative and postoperative intervals.Fifteen patients were enrolled. Laboratory values demonstrated initial intraoperative hypercoagulability before significant systemic anticoagulation after islet infusion with heparin. Hypercoagulability is again seen at postoperative days 3 and 7. Subgroup analysis did not identify any major coagulation parameters associated with portal vein thrombosis formation.Apart from the immediate period after islet cell and heparin infusion, patients undergoing TPIAT are generally hypercoagulable leading to a high rate of thrombotic complications. Portal vein thrombosis development had minimal association with systemic derangements in coagulation as it is likely driven by localized inflammation at the time of islet cell infusion. This study may provide the groundwork for future studies to identify improvements in thrombotic complications.

There is a lack of consensus regarding the optimal nutritional support for trauma patients. We hypothesize that early postinjury metabolic support focusing on adequate protein would modify the metabolic signature and alter the inflammatory environment for critically ill trauma patients.We conducted a prospective randomized controlled pilot trial for adult patients admitted to the surgical intensive care unit following traumatic injury. Patients were randomized to receive early metabolic support (EMS) (peripheral amino acid infusions) or standard of care (enteral nutrition as soon as feasible). Routine laboratory assessments, nitrogen balance, cytokines, and metabolomic analyses were assessed at baseline and day 5 after intervention.A total of 42 trauma patients were randomized into well-balanced groups with similar age (32 years), Injury Severity Score (25), and body mass index (27.4 kg/m2). Early metabolic support provided significantly more protein (1.43 g/kg vs. 0.35 g/kg; p0.0001) and more calories (12.6 kcal/kg vs. 7.5 g/kg; p = 0.0012) over the first 5 days as compared with the standard of care. Early metabolic support modified protein catabolism and synthesis as demonstrated by a larger median negative nitrogen balance (-16.3 g vs. -5.3 g; p = 0.03) and a unique metabolomic profile at day 5. The biochemical profile of patients who received EMS was defined by greater declines in circulating levels of stress hormone precursors and increased levels of amino acids. The inflammatory response following EMS resulted in a greater decrease in interleukin-1B (p = 0.02) and increase in soluble interleukin-6 receptor (p = 0.01) between baseline and day 5 as compared with the standard of care. The EMS group had a decreased length of stay (15 vs. 22 days) and decreased surgical intensive care unit length of stay (8 vs. 9 days); however, this disappeared after adjustment for Injury Severity Score in this small population.Early metabolic support with amino acid is safe, modifies metabolism, and may downregulate the inflammatory state associated with significant trauma, warranting a larger trial to assess for improved outcomes.Therapeutic/Care Management; Level II.

BACKGROUND: Preoperative optimization is increasingly emphasized for high-risk surgical patients. One critical component of this includes preoperative advanced care planning to promote goal-concordant care. We aimed to define a subset of patients that might benefit from preoperative palliative care consult for advanced care planning. MATERIALS AND METHODS: We examined adult patients admitted from January 2016 to December 2018 to a university health system for elective surgery. Multivariate logistic regression was used to identify variables associated with death within one year, and presence of palliative care consult preoperatively. Chi-square analysis evaluated the impact of a palliative care consult on advanced care planning variables. RESULTS: Of the 29,132 inpatient elective procedures performed, there was a 2.0% mortality rate at 6 months and 3.5% at one year. Those who died were more likely to be older, male, underweight (BMI

The cosinor model, in which a cosine curve is fitted to periodic data within a regression model, is a frequently used method for describing patterns of cyclical activity such as circadian rhythms. For circadian variables of interest (e.g., melatonin and heart rate) that do not take on negative values, the assumption of normally distributed residuals required by the general linear model, which is most commonly used for cosinor analysis, may not be appropriate. Alternatively, a generalized linear model with the gamma distribution (GZLM-gamma) is specifically defined to accommodate non-negative outcomes. Herein, we demonstrate the improved fit and gains of efficiency in detection of circadian rhythm afforded by using the GZLM-gamma in cosinor models of heart rate, actigraphic activity, and urinary 6-sulfatoxymelatonin. Notably, this improved detection of circadian rhythm allows retention of additional patients for downstream analyses, further improving study power.

OBJECTIVE Gastrointestinal bleeding (GIB) is an uncommon complication after abdominal surgery. Given the unique risks in the total pancreatectomy with islet autotransplant (TPIAT) population, we aimed to describe this population's incidence of postoperative GIB. METHODS Prospectively collected data on patients who underwent a TPIAT from 2001 to 2018 at the University of Minnesota were reviewed for postoperative GIB. Each GIB patient was matched to a control patient and compared for medical, medication, and social history and for clinical outcomes. RESULTS Sixty-eight patients developed a GIB (12.4%) at median time after surgery of 17 months. Etiologies included the following: anastomotic ulcer (35%), Clostridium difficile (4%), gastric or duodenal ulcers (9%), esophagitis/gastritis (10%), hemorrhoids (3%), inflammatory bowel disease (4%), Mallory-Weiss tears (1%), and unknown (29%). During diagnostic workup, 87% had an endoscopic procedure and 3% underwent imaging. Seven patients required an operation (10%), 1 required an open embolization (1%), and 13 required endoscopic treatments (19%). Patients with a GIB were more likely to die (15% vs 5%, P = 0.055). CONCLUSIONS Twelve percent of patients developed a GIB after TPIAT. One third of those had an undefined etiology despite endoscopy. The need for intervention was high (30%).

OBJECTIVES This study aimed to quantify the prevalence of venous thromboembolic (VTE) events in patients with pancreatitis requiring hospitalization and its impact on outcomes. METHODS Adult patients admitted from 2011 to 2018 for pancreatitis were identified. Every admission for pancreatitis in the first year after diagnosis was evaluated for a VTE (pulmonary embolism, deep vein thrombosis, or mesenteric vessel thrombosis) within 30 days of discharge. Characteristics of patients who developed a thromboembolic event were compared with those who did not. RESULTS There were 4613 patients with pancreatitis identified, 301 of whom developed a VTE (6.5%). Patients who developed a VTE were more likely to be male (P < 0.01), older (P = 0.03), and have an underlying coagulopathy (P < 0.01). Those with VTEs were more likely to die (27% vs 13%, P < 0.01), have more readmissions for pancreatitis (1.7 vs 1.3, P < 0.01), longer length of stay (16 vs 5.5 days, P < 0.01), and be discharged to acute or long-term rehabilitation rather than home (P < 0.01). CONCLUSIONS Acute pancreatitis requiring hospitalization is associated with high risk of VTE in the first year after diagnosis. Thromboembolic disease is associated with worse morbidity and mortality.

Supplemental Digital Content is available in the text., Severe acute respiratory distress syndrome (ARDS) unresponsive to conventional intensive care unit (ICU) management is an accepted indication for venovenous extracorporeal membrane oxygenation (V-V ECMO) support. The frequency with which patients with coronavirus disease 2019 (COVID-19) pneumonia are selected for V-V ECMO has not been described. This was a cohort study including all patients placed on either V-V ECMO or venoarteriovenous ECMO at the four adult ECMO Centers of Excellence. Primary outcomes evaluated were survival to decannulation from the ECMO circuit, survival to discharge, and 60-day survival. Secondary outcomes were hospital length of stay (LOS), ICU LOS, length of ECMO cannulation, and length of intubation. During the study period, which corresponded to the first surge in COVID-19 hospitalizations in Minnesota, 35 patients with ARDS were selected for V-V ECMO support out of 1,849 adult ICU patients with COVID-19 infection in the state (1.9% incidence; 95% CI, 1.3–2.6%). This represents 46 (95% CI, 34–61) expected V-V ECMO patients per 100,000 confirmed positive cases of COVID-19. Twenty-six of the 35 patients (74.3%) supported with V-V ECMO survived to 60-day post-ECMO decannulation. Recent studies have demonstrated ongoing success rescuing patients with severe ARDS in COVID-19 infection. Our data add to the support of ECMO and the consideration for encouraging cooperation among regional ECMO centers to ensure access to this highest level of care. Finally, by evaluating all the patients of a single region, we estimate overall need for this resource intensive intervention based on the overall number of COVID-19 cases and ICU admissions.

Early in the SARS-CoV-2 pandemic, the M Health Fairview Hospital System established dedicated hospitals for establishing cohorts and caring for patients with COVID-19, yet the association between treatment at COVID-19-dedicated hospitals and mortality and complications is not known.To analyze the mortality rate and complications associated with treatment at the COVID-19-dedicated hospitals.This retrospective cohort study evaluated data prospectively collected from March 1, 2020, through June 30, 2021, from 11 hospitals in Minnesota, including 2 hospitals created solely to care for patients with COVID-19. Data obtained included demographic characteristics, treatments, and outcomes of interest for all patients with a confirmed COVID-19 infection admitted to this hospital system during the study period.Patients were grouped based on whether they received treatment from 1 of the 2 COVID-19-dedicated hospitals compared with the remainder of the hospitals within the hospital system.Multivariate analyses, including risk-adjusted logistic regression and propensity score matching, were performed to evaluate the primary outcome of in-hospital mortality and secondary outcomes, including complications and use of COVID-specific therapeutics.There were 5504 patients with COVID-19 admitted during the study period (median age, 62.5 [IQR, 45.0-75.6] years; 2854 women [51.9%]). Of these, 2077 patients (37.7%) (median age, 63.4 [IQR, 50.7-76.1] years; 1080 men [52.0%]) were treated at 1 of the 2 COVID-19-dedicated hospitals compared with 3427 (62.3%; median age, 62.0 [40.0-75.1] years; 1857 women (54.2%) treated at other hospitals. The mortality rate was 11.6% (n = 241) at the dedicated hospitals compared with 8.0% (n = 274) at the other hospitals (P .001). However, risk-adjusted in-hospital mortality was significantly lower for patients in the COVID-19-dedicated hospitals in both the unmatched group (n = 2077; odds ratio [OR], 0.75; 95% CI, 0.59-0.95) and the propensity score-matched group (n = 1317; OR, 0.78; 95% CI, 0.58-0.99). The rate of overall complications in the propensity score-matched group was significantly lower (OR, 0.81; 95% CI, 0.66-0.99) and the use of COVID-19-specific therapeutics including deep vein thrombosis prophylaxis (83.9% vs 56.9%; P .001), high-dose corticosteroids (56.1% vs 22.2%; P .001), remdesivir (61.5% vs 44.5%; P .001), and tocilizumab (7.9% vs 2.0; P .001) was significantly higher.In this cohort study, COVID-19-dedicated hospitals had multiple benefits, including providing high-volume repetitive treatment and isolating patients with the infection. This experience suggests improved in-hospital mortality for patients treated at dedicated hospitals owing to improved processes of care and supports the use of establishing cohorts for future pandemics.

Background: Venovenous extracorporeal membrane oxygenation (VV-ECMO) for select adults with severe acute respiratory distress syndrome (ARDS) cause by coronavirus disease 2019 (COVID-19) infection is a guideline-supported therapy with associated hospital survival of 62%-74%, similar to expected survival with VV-ECMO for other indications. However, ECMO is a resource-heavy intervention, and these patients often require long ECMO runs and prolonged intensive care unit (ICU) care. Identifying factors associated with mortality in VV-ECMO patients with COVID-19 infection can inform the evaluation of ECMO candidates as well as prognostication for those patients on prolonged VV-ECMO. Patients and Methods: This was a retrospective cohort study that included all patients who received either VV- or venoarteriovenous (VAV)-ECMO at one of four ECMO Centers of Excellence in the state of Minnesota between March 1, 2020 and November 1, 2020. The primary outcome was 60-day survival. Secondary outcomes were hospital complications, infectious complications, and complications from ECMO. Results: There were 46 patients who met criteria during this study period and 30 survived to 60-day follow-up (65.2%). Prior to cannulation, older patient age (55.5 in non-survivors vs. 49.1 years in survivors; p = 0.03), lower P/F ratio (62.1 vs. 76.2; p = 0.04), and higher sequential organ failure assessment (SOFA) score (8.1 vs. 6.6; p = 0.02) were identified as risk factors for mortality. After ECMO cannulation, increased mortality was associated with increased number of antibiotic days (25.9 vs. 14.5; p = 0.04), increased number of transfusions (23.9 vs. 9.9; p = 0.03), elevated white blood cell (WBC) count at post-ECMO days one through three, elevated D-dimer at post-ECMO day 21-27, and decreased platelet count from post-ECMO days 14 and onward using univariable analysis. Conclusions: Multiple markers of infection including leukocytosis, thrombocytopenia, and increased antibiotic days are associated with increased mortality in patients placed on VV-ECMO for COVID-19 infection and subsequent ARDS. Knowledge of these factors may assist with determining appropriate candidates for this limited resource as well as direct goals of care in prolonged ECMO courses.

Introduction Age and sex affect outcomes from trauma. Older patients tend to be under-triaged, consume more healthcare resources, and experience worse outcomes relative to younger patients. Sex has also been associated with different outcomes, with women experiencing better outcomes than men. While baseline metabolism differs with both age and sex, no study has examined how these differences affect the response to trauma. We used high-throughput metabolomics to assess metabolic differences associated with blunt trauma according to age and sex. Methods Metabolic profiles were constructed using nuclear magnetic resonance spectroscopy for trauma patients age 21–40 years (n = 20, 55% male) and >65 years (n = 22, 41% male) from plasma samples obtained on Day 1 and Day 3 of each patient’s hospital stay. These were compared to profiles constructed from plasma obtained from healthy controls of the same age (21–40: n = 23, 61% male; 65+: n = 26, 50% male). Differences in metabolic profiles were assessed with partial least squares discriminant analysis. Results Trauma elicits an overwhelming global stress response that includes more subtle differences in metabolism related to age and gender. Significant differences due to normal aging were also identified. Many of the metabolites measured were present in similar levels in healthy controls age 65+ as they were in trauma patients of all ages. Sex-based differences in metabolism were observed in younger trauma patients on Day 3 but not in older patients. Conclusions Differences in energy metabolism and oxidative stress were implicated in the response to trauma in all patients. Older trauma patients may enter the trauma state with pre-existing oxidative stress and energy deficits that complicate recovery. Sex-based differences in recovery from trauma support the large body of work demonstrating the role of sex in recovery from trauma.

BackgroundTraditionally, patient risk scoring is done by evaluating vital signs and clinical severity scores with clinical intuition. Urinary biomarkers can add objectivity to these models to make risk prediction more accurate. We used metabolomics to identify prognostic urinary biomarkers of mortality or need for renal replacement therapy (RRT). Additionally, we assessed acute kidney injury (AKI) diagnosis, injury severity score (ISS), and AKI stage.MethodsUrine samples (n = 82) from a previous study of combat casualties were evaluated using proton nuclear magnetic resonance (1H-NMR) spectroscopy. Chenomx software was used to identify and quantify urinary metabolites. Metabolite concentrations were normalized by urine output, autoscaled, and log-transformed. Partial least squares discriminant analysis (PLS-DA) and statistical analysis were performed. Receiver operating characteristic (ROC) curves were used to assess prognostic utility of biomarkers for mortality and RRT.ResultsEighty-four (84) metabolites were identified and quantified in each urine sample. Of these, 11 were identified as drugs or drug metabolites and excluded. The PLS-DA models for ISS and AKI diagnosis did not have acceptable model statistics. Therefore, only mortality/RRT and AKI stage were analyzed further. Of 73 analyzed metabolites, 9 were significantly associated with mortality/RRT (p p p p ConclusionsWe identified urinary metabolites associated with AKI stage and the primary outcome of mortality or need for RRT. Lactate, 1-methylnicotinamide, and glycine may be used as a panel of predictive biomarkers for mortality and RRT. 1-Methylnicotinamide is a novel biomarker associated with adverse outcomes. Additional studies are necessary to determine how these metabolites can be utilized in clinically-relevant risk prediction models.

BackgroundThere is limited understanding of heterogeneity in outcomes across hospitalized patients with coronavirus disease 2019 (COVID-19). Identification of distinct clinical phenotypes may facilitate tailored therapy and improve outcomes.ObjectiveIdentify specific clinical phenotypes across COVID-19 patients and compare admission characteristics and outcomes.Design, Settings, and ParticipantsRetrospective analysis of 1,022 COVID-19 patient admissions from 14 Midwest U.S. hospitals between March 7, 2020 and August 25, 2020.MethodsEnsemble clustering was performed on a set of 33 vitals and labs variables collected within 72 hours of admission. K-means based consensus clustering was used to identify three clinical phenotypes. Principal component analysis was performed on the average covariance matrix of all imputed datasets to visualize clustering and variable relationships. Multinomial regression models were fit to further compare patient comorbidities across phenotype classification. Multivariable models were fit to estimate the association between phenotype and in-hospital complications and clinical outcomes.Main outcomes and measuresPhenotype classification (I, II, III), patient characteristics associated with phenotype assignment, in-hospital complications, and clinical outcomes including ICU admission, need for mechanical ventilation, hospital length of stay, and mortality.ResultsThe database included 1,022 patients requiring hospital admission with COVID-19 (median age, 62.1 [IQR: 45.9-75.8] years; 481 [48.6%] male, 412 [40.3%] required ICU admission, 437 [46.7%] were white). Three clinical phenotypes were identified (I, II, III); 236 [23.1%] patients had phenotype I, 613 [60%] patients had phenotype II, and 173 [16.9%] patients had phenotype III.When grouping comorbidities by organ system, patients with respiratory comorbidities were most commonly characterized by phenotype III (p=0.002), while patients with hematologic (pConclusionIn this retrospective analysis of patients with COVID-19, three clinical phenotypes were identified. Future research is urgently needed to determine the utility of these phenotypes in clinical practice and trial design.

Background: Synchronized circadian rhythms play a key role in coordinating physiologic health. Desynchronized circadian rhythms may predispose individuals to disease or be indicative of underlying disease. Intensive care unit (ICU) patients likely experience desynchronized circadian rhythms due to disruptive environmental conditions in the ICU and underlying pathophysiology. This observational pilot study was undertaken to determine if 24-h rhythms are altered in ICU patients relative to healthy controls by profiling 24-h rhythms in vital signs and plasma metabolites. Methods: We monitored daily rhythms in 5 healthy controls and 5 ICU patients for 24 h. Heart rate and blood pressure were measured every 30 min, temperature was measured every hour, and blood was sampled for mass spectrometry-based plasma metabolomics every 4 h. Bedside sound levels were measured every minute. Twenty-four hours rhythms were evaluated in vitals and putatively identified plasma metabolites individually and in each group using the cosinor method. Results: ICU patient rooms were significantly louder than healthy controls' rooms and average noise levels were above EPA recommendations. Healthy controls generally had significant 24-h rhythms individually and as a group. While a few ICU patients had significant 24-h rhythms in isolated variables, no significant rhythms were identified in ICU patients as a group, except in cortisol. This indicates a lack of coherence in phases and amplitudes among ICU patients. Finally, principal component analysis of metabolic profiles showed surprising patterns in plasma sample clustering. Each ICU patient's samples were clearly discernable in individual clusters, separate from a single cluster of healthy controls. Conclusions: In this pilot study, ICU patients' 24-h rhythms show significant desynchronization compared to healthy controls. Clustering of plasma metabolic profiles suggests that metabolomics could be used to track individual patients' clinical courses longitudinally. Our results show global disordering of metabolism and the circadian system in ICU patients which should be characterized further in order to determine implications for patient care.

BackgroundSynchronized circadian rhythms play a key role in coordinating physiologic health. Desynchronized circadian rhythms may predispose individuals to disease or be indicative of underlying disease. Intensive care unit (ICU) patients likely experience desynchronized circadian rhythms due to disruptive environmental conditions in the ICU and underlying pathophysiology. This observational pilot study was undertaken to determine if circadian rhythms are altered in ICU patients relative to healthy controls by profiling circadian rhythms in vital signs and plasma metabolites.MethodsWe monitored circadian rhythms in 5 healthy controls and 5 ICU patients for 24 hours. Heart rate and blood pressure were measured every 30 minutes, temperature was measured every hour, and blood was sampled for mass spectrometry-based plasma metabolomics every 4 hours. Bedside sound levels were measured every minute. Circadian rhythms were evaluated in vitals and plasma metabolites individually and in each group using the cosinor method.ResultsICU patient rooms were significantly louder than healthy controls’ rooms and average noise levels were above EPA recommendations. Healthy controls generally had significant circadian rhythms individually and as a group. While a few ICU patients had significant circadian rhythms in isolated variables, no significant rhythms were identified in ICU patients as a group, except in cortisol. This indicates a lack of coherence in circadian phases and amplitudes among ICU patients. Finally, principal component analysis of metabolic profiles showed surprising patterns in plasma sample clustering. Each ICU patient’s samples were clearly discernable in individual clusters, separate from a single cluster of healthy controls.ConclusionsICU patients’ circadian rhythms show significant desynchronization compared to healthy controls. Clustering of plasma metabolic profiles suggests that metabolomics could be used to track individual patients’ clinical courses longitudinally. Our results show global disordering of metabolism and the circadian system in ICU patients which should be characterized further in order to determine implications for patient care.

The quality of prehospital care impacts patient outcomes. Military efforts have focused on training revision and the creation of high-fidelity simulation models to address potentially survivable injuries. We sought to investigate the applicability of models emphasizing hemorrhage control and airway management to a civilian population.Prehospital health care providers (PHPs) undergoing their annual training were enrolled. A trauma scenario was simulated with two modules: hemorrhage control and airway management. Experienced raters used a validated tool to assess performance. Pearson correlation, logistic regression, and χ tests were used for analysis.Ninety-five PHPs participated with a mean experience of 15.9 ± 8.3 years, and 7.4% reported past military training. The PHPs' overall execution rate of the six hemorrhage control measures varied from 38.9% to 88.4%. The median blood loss was 1,700 mL (interquartile range, 1,043-2,000), and the mean global rater score was 25.0 ± 7.4 (scale, 5-40). There was a significant relationship between PHP profession and past military experience to their consideration of blood transfusion and tranexamic acid. An inverse relationship between blood loss and global rater score was found (r = -0.59, n = 88, p = 1.93 × 10). After simulated direct laryngoscope failure in the airway module, 58% of PHPs selected video laryngoscopy over placement of a supraglottic airway. Eighty-six percent of participants achieved bilateral chest rise in the manikin regardless of management method. Participants reported improved comfort with skills after simulation.Our data reveal marginal performance in hemorrhage control regardless of the PHP's prior experience. The majority of PHPs were able to secure an advanced airway if direct laryngoscope was unavailable with a predisposition for video laryngoscopy over supraglottic airway. Our findings support the need for continued training for PHPs highlighting hemorrhage control maneuvers and increased familiarity with airway management options. Improved participant confidence posttraining gives credence to simulation training.Prognostic/epidemiological study, level III.

IntroductionAlthough there are multiple studies regarding the management and outcomes of colonic injuries incurred in combat, the literature is limited with regard to small bowel injuries. This study seeks to provide the largest reported review of the characteristics of combat-associated small bowel injuries.Materials and MethodsThe Department of Defense Trauma Registry was queried for U.S. Armed Forces members who sustained hollow viscus injuries in the years 2007–2012 during Operations Enduring Freedom, Iraqi Freedom, and New Dawn. Concomitant injuries, procedures, and complications were delineated. Fisher’s exact test was used to analyze the relationship of bowel injury pattern to rates of repeat laparotomy, fecal diversion, and complications.ResultsOne hundred seventy-one service members had small bowel injuries. The mean age was 25.8 ± 6.6 yr with a mean injury severity score of 27.9 ± 12.4. The majority of injuries were penetrating (94.2%, n = 161) as a result of explosive devices (61.4%, n = 105). The median blood transfusion requirement in the first 24 h was 6.0 units (interquartile range 1.0–17.3 units). The most frequent concomitant injuries were large bowel (64.3%, n = 110), pelvic fracture (35.7%, n = 61), and perineal (26.3%, n = 45). Fifty patients (29.2%) had a colostomy, and nine patients (5.3%) had an ileostomy; 62.6% (n = 107) of soldiers underwent more than one laparotomy. The mortality rate was 1.8% (n = 3). The most common complications were pneumonia (15.2%, n = 26), deep vein thrombosis (14.6%, n = 25), and wound infection (14.6%, n = 25). The need for repeat laparotomy and fecal diversion was found to be significantly associated with injury pattern (p = 0.00052 and p < 0.0001, respectively).ConclusionWe found that two-thirds of service members with small bowel injuries also had a large bowel injury. One-third of the patients required diversion and two-thirds had more than one laparotomy. The pattern of bowel injury significantly affected the need for repeat laparotomy and fecal diversion.

Introduction: Venovenous extracorporeal membrane oxygenation (V-V ECMO) improves survival in patients with ARDS from COVID-19 pneumonia. Due to equipment shortages throughout the pandemic, systems for allocation have been proposed, but not tested. In this study, we evaluate 3 systems of allocation for V-V ECMO in both pre-COVID-19 and COVID-19 patients with ARDS. Methods: We retrospectively evaluated 3 systems of ECMO allocation (MN, MDH, and OHI) across 4 ECMO Centers of Excellence. Logistic regression was used to assess the relationship between the scores and in-hospital and 30-day mortality. Cut points for priority groups were evaluated by maximizing the sum of sensitivity and specificity. Results: Of 124 patients, 38% were treated for COVID-19 ARDS. The median age was 48 years and 73% were male. The in-hospital mortality rate was 38% and increased to 42% at 30 days. For each additional point in the MN score, the odds ratio for mortality was 1.13 (p = 0.02) for in-hospital and 1.15 (p = 0.015) at 30 days. OHI and MDH scores were not significant for in-hospital or 30-day mortality. COVID-19 status did not change the findings significantly. For the MN score, a threshold between the low and medium priority groups was found to be 7 and the threshold between medium and high priority groups was found to be 9 (p = 0.05) (Fig. 1). Conclusions: Higher MN score is associated with increased mortality. Proposed priority groups can be used to identify patients that would more greatly benefit from V-V ECMO allocation in times of increasing scarcity. [Formula presented]

Treatment of hypoglycemia in children is currently based on plasma glucose measurements. This approach may not ensure neuroprotection since plasma glucose does not reflect the dynamic state of cerebral energy metabolism. To determine whether cerebral metabolic changes during hypoglycemia could be better characterized using plasma metabolomic analysis, insulin-induced acute hypoglycemia was induced in 4-week-old rats. Brain tissue and concurrent plasma samples were collected from hypoglycemic (N = 7) and control (N = 7) rats after focused microwave fixation to prevent post-mortem metabolic changes. The concentration of 29 metabolites in brain and 34 metabolites in plasma were determined using 1H NMR spectroscopy at 700 MHz and examined using partial least squares-discriminant analysis. The sensitivity of plasma glucose for detecting cerebral energy failure was assessed by determining its relationship to brain phosphocreatine. The brain and plasma metabolite profiles of the hypoglycemia group were distinct from the control group (brain: R2 = 0.92, Q2 = 0.31; plasma: R2 = 0.95, Q2 = 0.74). Concentration differences in glucose, ketone bodies and amino acids were responsible for the intergroup separation. There was 45% concordance between the brain and plasma metabolite profiles. Brain phosphocreatine correlated with brain glucose (control group: R2 = 0.86; hypoglycemia group: R2 = 0.59; p

Objectives To determine the rate of portal vein thrombosis (PVT) based on pharmacologic prophylaxis protocol and the impact of PVT on islet graft function after total pancreatectomy with islet autotransplantation (TPIAT). Methods We compared the incidence of PVT, postsurgical bleeding, and thrombotic complications in patients undergoing TPIAT between 2001 and 2018 at the University of Minnesota who received either unfractionated heparin (UFH) or enoxaparin for postoperative PVT prophylaxis. Six-month and 1-year graft function was compared between patients who developed PVT and those who did not. Results Twelve patients (6.6%) developed a PVT, which resolved by 6 months after TPIAT in 10 patients. There was no statistically significant difference in PVT rate between patients who received UFH or enoxaparin for prophylaxis (P = 0.54). Patients who received enoxaparin developed other thrombotic complications more often (6% vs 0%, P = 0.02). Islet graft function did not differ in patients who developed PVT versus those who did not. Conclusions There was no difference between enoxaparin or UFH prophylaxis in preventing PVT, but there may be a higher incidence of other thrombotic complications with enoxaparin. In the setting of routine screening and anticoagulation therapy, PVT is a self-limited process.

Burn injury initiates a hypermetabolic response leading to muscle catabolism and organ dysfunction but has not been well-characterized by high-throughput metabolomics. We examined changes in metabolism over the first 72 h post-burn using proton nuclear magnetic resonance (1H-NMR) spectroscopy and serum from a porcine model of severe burn injury. We sought to quantify the changes in metabolism that occur over time in response to severe burn and smoke inhalation in this preliminary study. Fifteen pigs received 40% total body surface area (TBSA) burns with additional pine bark smoke inhalation. Arterial blood was drawn at baseline (pre-burn) and every 24 h until 72 h post-injury or death. The aqueous portion of each serum sample was analyzed using 1H-NMR spectroscopy and metabolite concentrations were used for principal component analysis (PCA). Thirty-eight metabolites were quantified in 39 samples. Of these, 31 showed significant concentration changes over time (p &lt, 0.05). PCA revealed clustering of samples by time point on a 2D scores plot. The first 48 h post-burn were characterized by high concentrations of histamine, alanine, phenylalanine, and tyrosine. Later timepoints were characterized by rising concentrations of 2-hydroxybutyrate, 3-hydroxybutyrate, acetoacetate, and isovalerate. No significant differences in metabolism related to mortality were observed. Our work highlights the accumulation of organic acids resulting from fatty acid catabolism and oxidative stress. Further studies will be required to relate accumulation of the four organic carboxylates identified in this analysis to outcomes from burn injury.

Hemorrhagic shock is the leading cause of preventable death after trauma. Hibernation-based treatment approaches have been of increasing interest for various biomedical applications. Owing to apparent similarities in tissue perfusion and metabolic activity between severe blood loss and the hibernating state, hibernation-based approaches have also emerged for the treatment of hemorrhagic shock. Research has shown that hibernators are protected from shock-induced injury and inflammation. Utilizing the adaptive mechanisms that prevent injury in these animals may help alleviate the detrimental effects of hemorrhagic shock in non-hibernating species. This review describes hibernation-based preclinical and clinical approaches for the treatment of severe blood loss. Treatments include the delta opioid receptor agonist D-Ala-Leu-enkephalin (DADLE), the gasotransmitter hydrogen sulfide, combinations of adenosine, lidocaine, and magnesium (ALM) or D-beta-hydroxybutyrate and melatonin (BHB/M), and therapeutic hypothermia. While we focus on hemorrhagic shock, many of the described treatments may be used in other situations of hypoxia or ischemia/reperfusion injury.

We aimed to investigate whether metabolomic analysis can discriminate acute respiratory failure due to COPD exacerbation from respiratory failure due to heart failure and pneumonia. Since COPD exacerbation is often overdiagnosed, we focused on those COPD exacerbations that were severe enough to require noninvasive mechanical ventilation. We enrolled stable COPD subjects and patients with acute respiratory failure requiring noninvasive mechanical ventilation due to COPD, heart failure, and pneumonia. We excluded subjects with history of both COPD and heart failure and patients with obstructive sleep apnea and obstructive lung disease other than COPD. We performed metabolomics analysis using NMR. We constructed partial least squares discriminant analysis (PLS-DA) models to distinguish metabolic profiles. Serum (p=0.001, R2 = 0.397, Q2 = 0.058) and urine metabolic profiles (p<0.001, R2 = 0.419, Q2 = 0.142) were significantly different between the four diagnosis groups by PLS-DA. After excluding stable COPD patients, the metabolomes of the various respiratory failure groups did not cluster separately in serum (p=0.2, R2 = 0.631, Q2 = 0.246) or urine (p=0.065, R2 = 0.602, Q2 = −0.134). However, several metabolites in the serum were reduced in patients with COPD exacerbation and pneumonia. We did not find a metabolic profile unique to COPD exacerbation, but we were able to clearly and reliably distinguish stable COPD patients from patients with respiratory failure in both serum and urine.

The potential for using serum albumin (SA) as a broadly applicable molecular sensor was explored in an effort to develop a method for rapid analysis of complex metabolite samples. SA is a protein present at high concentration in blood, which transports a diverse set of compounds including fatty acids, hormones, and drugs. The effectiveness of the bovine ortholog (BSA) as a molecular sensor was tested by analyzing the pool of small molecules bound to the protein after a brief incubation with complex fluids of biological origin. As an initial test, three varietals of red wine were readily distinguished. Further analysis using four varietals of white wine also showed clear separation. In a second analysis using urine, animals in hemorrhagic shock were separated from a group of comparably treated controls. A time course analysis showed that recovery from injury could also be followed using the assay. This finding is significant as there currently is no method or biomarker for predicting the onset of shock. Comparison of samples was based on liquid chromatography mass spectrometry (LCMS) analysis of compounds selectively bound by BSA. Analysis of the samples after protein selection revealed a significant reduction in complexity and clear separation of groups by Principle Component Analysis (PCA). These results show the potential for using cargo-carrying proteins as molecular sensors for screening complex samples without the need for prior knowledge of sample composition or concentration and may streamline elucidation of biomarkers.

Hemorrhagic shock with injury results in alterations of the metabolic state of an organism, which contribute to organ dysfunction and death. Previous investigations have explored the effects of carbohydrate prefeed in murine models but few in clinically relevant large animal models. We performed carbohydrate prefeed in pigs undergoing simulated polytrauma and hemorrhagic shock with resuscitation to determine if carbohydrate prefeeding if the metabolic response to shock is dependent on fed state. Sixty-four Yorkshire pigs were divided into two experimental groups: fasted (32) and prefed (32). Experimental animals were subjected to a standardized hemorrhagic shock protocol, including pulmonary contusion and liver crush injury. To determine molecular alterations in response to trauma as a result of prefeeding, liver biopsies were obtained at set timepoints throughout the procedure. Fifty-one metabolites were profiled for each sample via proton nuclear magnetic resonance spectroscopy (1H NMR). Partial-Least Squared Discriminant Analysis (PLS-DA) was used to examine clustering of the data with respect to fed state. Cross-validated models separated the fed from fasted animals. Metabolites contributing to the separation have known relationships to alternate carbon energy sources, amino acid metabolism, oxidative stress response, and membrane maintenance. In conclusion, metabolomic techniques allowed identification of an alternate response to shock and resuscitation, dependent upon fed state, through the use of metabolomics.

Background Many infections involve bacterial biofilms that are notoriously antibiotic resistant. Unfortunately, the mechanism for this resistance is unclear. We tested the effect of oxygen concentration on development of Staphylococcus aureus biofilms, and on the ability of gentamicin and vancomycin to inhibit biofilm development. Materials and methods To mimic catheter-associated biofilms, silastic coupons were inoculated with 107S aureus and incubated either aerobically (∼21% O2) or anaerobically (10% CO2, 5% H2, 85% N2) for 16 h at 37°C with varying concentrations of gentamicin and vancomycin. Viable colony-forming units were quantified from sonicated biofilms, and the crystal violet assay quantified biofilm biomass. Metabolomic profiles probed biochemical differences between aerobic and anaerobic biofilms. Results Control biofilms (no antibiotic) cultivated aerobically contained 8.1–8.6 log10S aureus. Anaerobiasis inhibited biofilm development, quantified by viable bacterial numbers and biomass (P < 0.05). Bactericidal concentrations of gentamicin inhibited biofilm development in normoxia but not anoxia, likely because bacterial uptake of gentamicin is oxygen dependent. The inhibitory effect of vancomycin was more uniform aerobically and anaerobically, although at high bactericidal concentrations, vancomycin effectiveness was decreased under anoxia. There were notable differences in the metabolomic profiles of biofilms cultivated under normoxia versus anoxia. Conclusions Compared with aerobic incubation, anaerobiasis resulted in decreased biofilm development, and metabolomics is a promising tool to identify key compounds involved in biofilm formation. The effectiveness of a specific antibiotic depended on its mode of action, as well as on the oxygen concentration in the environment.

Background Previous studies have indicated that hemorrhagic shock and injury cause significant early changes in metabolism. Recently, global changes in metabolism have been described using metabolomics in animal models and civilian trauma. We evaluated metabolic changes associated with combat injury to identify early biomarkers and aid in triage. Methods Plasma obtained at emergency department presentation and intervals thereafter from patients injured during combat operations in Iraq (n = 78) were compared with healthy control subjects (n = 40). Using proton Nuclear Magnetic Resonance (NMR), water-soluble metabolites were detected and quantified. Resulting metabolic profiles were analyzed with partial least squares discriminant analysis, Receiver Operating Characteristic (ROC), and cluster analyses to identify features of combat injury and mortality. Results Significant alterations to metabolism resulted from traumatic injury. Metabolic profiles of injured patients differed from those of healthy controls, driven by increased 5-aminolevulinate and hypoxanthine that persisted through 24 hours. Among combat-injured patients, increased succinate and malonate best discriminated between those who survived from those who did not. Higher levels of succinate and hypoxanthine were associated with increased injury severity. ROC analysis showed that these metabolites had equivalent or superior performance to lactate in distinguishing the presence of trauma, injury severity, and mortality. Conclusion Combat injury is associated with several changes at the metabolic level compared with healthy individuals. Novel potential biomarkers of mortality (succinate, malonate), injury severity (succinate, hypoxanthine), and the presence of trauma (hypoxanthine, 5-aminolevulinate) perform as well as or better than the common clinical standard, lactate. Level of evidence Prognostic study, level III.

Hemorrhagic shock, a result of extensive blood loss, is a dominant factor in battlefield morbidity and mortality. Early rodent studies in hemorrhagic shock reported carbohydrate feeding prior to the induction of hemorrhagic shock decreased mortality. When repeated in our laboratory with a porcine model, carbohydrate pre-feed resulted in a 60% increase in death rate following hemorrhagic shock with trauma when compared to fasted animals (15/32 or 47% vs. 9/32 or 28%). In an attempt to explain the unexpected death rate for pre-fed animals, we further investigated the metabolic profiles of pre-fed non-survivors (n = 15) across 4 compartments (liver, muscle, serum, and urine) at specific time intervals (pre-shock, shock, and resuscitation) and compared them to pre-fed survivors (n = 17). As hypothesized, pre-fed pigs that died as a result of hemorrhage and trauma showed differences in their metabolic and physiologic profiles at all time intervals and in all compartments when compared to pre-fed survivors. Our data suggest that, although all animals were subjected to the same shock and trauma protocol, non-survivors exhibited altered carbohydrate processing as early as the pre-shock sampling point. This was evident in (for example) the higher levels of ATP and markers of greater anabolic activity in the muscle at the pre-shock time point. Based on the metabolic findings, we propose two mechanisms that connect pre-fed status to a higher death rate: (1) animals that die are more susceptible to opening of the mitochondrial permeability transition pore, a major factor in ischemia/reperfusion injury; and (2) loss of fasting-associated survival mechanisms in pre-fed animals.

We report on four radio-detected cosmic-ray (CR) or CR-like events observed with the Antarctic Impulsive Transient Antenna (ANITA), a NASA-sponsored long-duration balloon payload. Two of the four were previously identified as stratospheric CR air showers during the ANITA-I flight. A third stratospheric CR was detected during the ANITA-II flight. Here we report on characteristics these three unusual CR events, which develop nearly horizontally, 20-30~km above the surface of the Earth. In addition, we report on a fourth steeply upward-pointing ANITA-I CR-like radio event which has characteristics consistent with a primary that emerged from the surface of the ice. This suggests a possible $\tau$-lepton decay as the origin of this event, but such an interpretation would require significant suppression of the Standard Model ${\tau}$-neutrino cross section., Comment: 5pp,4 figures, referees' comments addressed, this version accepted to Phys. Rev. Letters. Supplemental PDF material available; see source files

BACKGROUND: Early recognition and intervention in hemorrhagic shock is essential to improved outcomes. However, the lack of robust diagnostic tools readily available to identify patients in the field inhibits the ability to provide timely intervention. Therefore, the development of a reliable prognostic indicator, such as a serum biomarker or a metabolic profile, has significant potential to improve far-forward trauma care. In this study, we used metabolomics as a tool to identify a metabolic state associated with the hemorrhagic shock and outcome in our porcine model of multiple injuries, shock, and resuscitation. METHODS: Proton nuclear magnetic resonance spectroscopy was used to evaluate serum metabolites from 23 animals that underwent multiple injuries, controlled hemorrhage, and 20 hours of a standard resuscitation protocol. Serum samples were collected from the animals at baseline (before hemorrhage), at shock (after 45 minutes of shock), and at 8 hours of full resuscitation. RESULTS: We were able to demonstrate shifts in the metabolome throughout different time points and construct a metabolic profile associated with mortality using partial least squares discriminate analysis. The metabolites most responsible for the classification of hemorrhagic shock in our model serve as markers for ischemia, changes in energy production, and cellular damage. Hemorrhagic shock was characterized by marked increases in tricarboxylic acid cycle intermediates, glycolytic-gluconeogenic by-products, purine-pyrimidine catabolism, and fatty acid oxidation. CONCLUSION: The results of this study demonstrate the potential for metabolomics as a tool to classify the metabolic flux, to identify relevant biochemical pathways, and to identify clinically useful biomarkers.

Hemorrhagic shock, often a result of traumatic injury, is a condition of reduced perfusion that results in diminished delivery of oxygen to tissues. The disruption in oxygen delivery induced by both ischemia (diminished oxygen delivery) and reperfusion (restoration of oxygen delivery) has profound consequences for cellular metabolism and the maintenance of homeostasis. The pathophysiologic state associated with traumatic injury and hemorrhagic shock was studied with a scale-invariant metabolic network. Urinary metabolic profiles were constructed from NMR spectra of urine samples collected at set timepoints in a porcine model of hemorrhagic shock that included a pulmonary contusion, a liver crush injury, and a 35 % controlled bleed. The network was constructed from these metabolic profiles. A partial least squares discriminant analysis (PLS-DA) model that discriminates by experimental timepoint was also constructed. Comparisons of the network (functional relationships among metabolites) and PLS-DA model (observable relationships to experimental time course) revealed complementary information. First, ischemia/reperfusion injury and evidence of cell death due to hemorrhage was associated with early resuscitation timepoints. Second, evidence of increased protein catabolism and traumatic injury was associated with late resuscitation timepoints. These results are concordant with generally accepted views of the metabolic progression of shock.

Background Despite ongoing advances in treatment, thousands of patients still die annually from complications due to hemorrhagic shock, a condition causing dramatic physiologic and metabolic changes as cells switch to anaerobic metabolism in response to oxygen deprivation. As the shift from aerobic to anaerobic metabolism occurs in the peripheral tissues during shock, the liver must increase production of endogenous glucose as well as process excess lactate produced in the periphery. This places the liver at the center of metabolic regulation in the body during hemorrhagic shock. Therefore, we hypothesized that liver tissue from pigs during an in vivo model of hemorrhagic shock ( n = 6) would reflect resultant metabolic changes. Materials and Methods The in vivo model of shock consisted of 45 min of shock followed by 8 h of hypotensive resuscitation (80 mmHg) and subsequent normotensive resuscitation (90 mmHg) ending 48 h after the shock period. Control groups of pigs ( n = 3) (1) shock with no resuscitation, and (2) only anesthesia and instrumentation, also were included. Metabolic changes within the liver after shock and during resuscitation were investigated using both proton ( 1 H) and phosphorous ( 31 P) nuclear magnetic resonance (NMR) spectroscopy. Results Concentrations of glycerylphosphorylcholine (GPC) and glycerylphosphorylethanolamine (GPE) were significantly lower at 8 h after shock, with recovery to baseline by 23 and 48 h after shock. Uridine diphosphate-glucose (UDP-glucose), and phosphoenolpyruvate (PEP) were elevated 23 h after shock. Conclusions These results indicate that 1 H and 31 P NMR spectroscopy can be used to identify differences in liver metabolites in an in vivo model of hemorrhagic shock, indicating that metabolomic analysis can be used to elucidate biochemical events occurring during this complex disease process.

Radiowave detection of the Cherenkov radiation produced by neutrino-ice collisions requires an understanding of the radiofrequency (RF) response of cold polar ice. We herein report on a series of radioglaciological measurements performed approximately 10 km north of Taylor Dome Station, Antarctica from December 6, 2006–December 16, 2006. Using RF signals broadcast from: (a) an englacial discone, submerged to a depth of 100 m and broadcasting to a surface dual-polarization horn receiver, and (b) a dual-polarization horn antenna on the surface transmitting signals which reflect off the underlying bed and back up to the surface receiver, we have made time-domain estimates of both the real (index-of-refraction “ n ”) and imaginary (attenuation length “ L atten ”) components of the complex ice dielectric constant. We have also measured the uniformity of ice response along two orthogonal axes in the horizontal plane. We observe an apparent wavespeed asymmetry of order 0.1% between two orthogonal linear polarizations projected into the horizontal plane, consistent with some previous measurements, but somewhat lower than others.

Background Treatment with oral carbohydrate prior to trauma and hemorrhage confers a survival benefit in small animal models. The impact of fed states on survival in traumatically injured humans is unknown. This work uses regulatory networks to examine the effect of carbohydrate pre-feeding on metabolic response to polytrauma and hemorrhagic shock in a clinically-relevant large animal model. Methods Male Yorkshire pigs were fasted overnight (n = 64). Pre-fed animals (n = 32) received an oral bolus of Karo\textregistered\syrup before sedation. All animals underwent a standardized trauma, hemorrhage, and resuscitation protocol. Serum samples were obtained at set timepoints. Proton NMR was used to identify and quantify serum metabolites. Metabolic regulatory networks were constructed from metabolite concentrations and rates of change in those concentrations to identify controlled nodes and controlling nodes of the network. Results Oral carbohydrate pre-treatment was not associated with survival benefit. Six metabolites were identified as controlled nodes in both groups: adenosine, cytidine, glycerol, hypoxanthine, lactate, and uridine. Distinct groups of controlling nodes were associated with controlled nodes; however, the composition of these groups depended on feeding status. Conclusions A common metabolic output, typically associated with injury and hypoxia, results from trauma and hemorrhagic shock. However, this output is directed by different metabolic inputs depending upon the feeding status of the subject. Nodes of the network that are related to mortality can potentially be manipulated for therapeutic effect; however, these nodes differ depending upon feeding status. Electronic supplementary material The online version of this article (doi:10.1186/s12873-015-0038-1) contains supplementary material, which is available to authorized users.

Electrical communication between cardiomyocytes can be perturbed during arrhythmia, but these perturbations are not captured by conventional electrocardiographic metrics. We developed a theoretical framework to quantify electrical communication using information theory metrics in 2-dimensional cell lattice models of cardiac excitation propagation. The time series generated by each cell was coarse-grained to 1 when excited or 0 when resting. The Shannon entropy for each cell was calculated from the time series during four clinically important heart rhythms: normal heartbeat, anatomical reentry, spiral reentry, and multiple reentry. We also used mutual information to perform spatial profiling of communication during these cardiac arrhythmias. We found that information sharing between cells was spatially heterogeneous. In addition, cardiac arrhythmia significantly impacted information sharing within the heart. Entropy localized the path of the drifting core of spiral reentry, which could be an optimal target of therapeutic ablation. We conclude that information theory metrics can quantitatively assess electrical communication among cardiomyocytes. The traditional concept of the heart as a functional syncytium sharing electrical information cannot predict altered entropy and information sharing during complex arrhythmia. Information theory metrics may find clinical application in the identification of rhythm-specific treatments which are currently unmet by traditional electrocardiographic techniques., 26 pages (including Appendix), 6 figures, 8 videos (not uploaded due to size limitation)

INTRODUCTION Hemorrhagic shock and injury lead to dramatic changes in metabolic demands and continue to be a leading cause of death. We hypothesized that altering the preinjury metabolic state with a carbohydrate load prior to injury would affect subsequent metabolic responses to injury and lead to improved survival. METHODS Sixty-four pigs were randomized to fasted (F) or carbohydrate prefeeding (CPF) groups and fasted 12 h prior to experiment. The CPF pigs received an oral carbohydrate load 1 h prior to anesthesia. All pigs underwent a standardized injury/hemorrhagic shock protocol. Physiologic parameters and laboratory values were obtained at set time points. RESULTS Carbohydrate prefeeding did not convey a survival benefit; instead, CPF animals had greater mortality rates (47% vs. 28%; P = 0.153; log-rank [Mantel-Cox]). Carbohydrate prefeeding animals also had higher rates of acute lung injury (odds ratio, 4.23; 95% confidence interval, 1.1-16.3) and altered oxygen utilization. Prior to shock and throughout resuscitation, CPF animals had significantly higher serum glucose levels than did the F animals. CONCLUSIONS Carbohydrate prefeeding did not provide a survival benefit to swine subjected to hemorrhagic shock and polytrauma. Carbohydrate prefeeding led to significantly different metabolic profile than in fasted animals, and prefeeding led to a greater incidence of lung injury, increased multiorgan dysfunction, and altered oxygen utilization.

Hemorrhagic shock is a leading cause of trauma-related mortality in both civilian and military settings. Resuscitation often results in reperfusion injury and survivors are susceptible to developing multiple organ failure (MOF). The impact of fed state on the overall response to shock and resuscitation has been explored in some murine models but few clinically relevant large animal models. We have previously used metabolomics to establish that the fed state results in a different metabolic response in the porcine liver following hemorrhagic shock and resuscitation. In this study, we used our clinically relevant model of hemorrhagic shock and polytrauma and the Illumina HiSeq platform to determine if the liver transcriptomic response is also altered with respect to fed state. Functional analysis of the response to shock and resuscitation confirmed several typical responses including carbohydrate metabolism, cytokine inflammation, decreased cholesterol synthesis, and apoptosis. Our findings also suggest that the fasting state, relative to a carbohydrate prefed state, displays decreased carbohydrate metabolism, increased cytoskeleton reorganization and decreased inflammation in response to hemorrhagic shock and reperfusion. Evidence suggests that this is a consequence of a shrunken, catabolic state of the liver cells which provides an anti-inflammatory condition that partially mitigates hepatocellar damage.

Background: Patients admitted to the intensive care unit with alcohol use disorders have increased morbidity and mortality. The purpose of this study was to determine how chronic alcohol ingestion alters the host response to sepsis in mice. Methods: Mice were randomized to receive either alcohol or water for 12 weeks and then subjected to cecal ligation and puncture. Mice were sacrificed 24 hours post-operatively or followed seven days for survival. Results: Septic alcohol-fed mice had a significantly higher mortality than septic water-fed mice (74% vs. 41%, p=0.01). This was associated with worsened gut integrity in alcohol-fed mice with elevated intestinal epithelial apoptosis, decreased crypt proliferation and shortened villus length. Further, alcohol-fed mice had higher intestinal permeability with decreased ZO-1 and occludin protein expression in the intestinal tight junction. The frequency of splenic and bone marrow CD4+ T cells was similar between groups; however, splenic CD4+ T cells in septic alcohol-fed mice had a marked increase in both TNF and IFN-c production following ex vivo stimulation. Neither the frequency nor function of CD8+ T cells differed between alcoholfed and water-fed septic mice. NK cells were decreased in both the spleen and bone marrow of alcohol-fed septic mice. Pulmonary myeloperoxidase levels and BAL levels of G-CSF and TFG-b were higher in alcohol-fed mice. Pancreatic metabolomics demonstrated increased acetate, adenosine, xanthine, acetoacetate, 3-hydroxybutyrate and betaine in alcohol-fed mice and decreased cytidine, uracil, fumarate, creatine phosphate, creatine, and choline. Serum and peritoneal cytokines were generally similar between alcohol-fed and water-fed mice, and there were no differences in bacteremia, lung wet to dry weight, or pulmonary, liver or splenic histology. Conclusions: When subjected to the same septic insult, mice with chronic alcohol ingestion have increased mortality. Alterations in intestinal integrity, the host immune response, and pancreatic metabolomics may help explain this differential response.