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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., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

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.

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, R 2  = 0.397, Q 2  = 0.058) and urine metabolic profiles ( p < 0.001, R 2  = 0.419, Q 2  = 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, R 2  = 0.631, Q 2  = 0.246) or urine ( p =0.065, R 2  = 0.602, Q 2  = -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.

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.

Context: The characterization of the urinary metabolome may yield biomarkers indicative of pancreatitis., Objectives: We establish a non-invasive technique to compare urinary metabolic profiles in patients with acute and chronic pancreatitis to healthy controls., Methods: Urine was obtained from healthy controls (HC, n=5), inpatients with mild acute pancreatitis (AP, n=5), and outpatients with chronic pancreatitis (CP, n=5). Proton nuclear magnetic resonance spectra were obtained for each sample. Metabolites were identified and quantified in each spectrum; resulting concentrations were normalized to account for differences in dilution among samples. Kruskal-Wallis test, post-hoc Mann-Whitney U tests, and principal component analysis were performed to identify metabolites that discriminate healthy controls, acute pancreatitis, and chronic pancreatitis., Results: Sixty metabolites were identified and quantified; five were found to differ significantly (P&lt;0.05) among the three groups. Of these, citrate and adenosine remained significant after validation by random permutation. Principal component analysis demonstrated that healthy control urine samples can be differentiated from patients with chronic pancreatitis or acute pancreatitis; chronic pancreatitis patients could not be distinguished from acute pancreatitis patients., Conclusions: This metabolomic investigation demonstrates that this non-invasive technique offers insight into the metabolic states of pancreatitis. Although the identified metabolites cannot conclusively be defined as biomarkers of disease, future studies will validate our findings in larger patient cohorts.

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.

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 < 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. [ABSTRACT FROM AUTHOR]

Abstract: 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 107 S 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 log10 S 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. [Copyright &y& Elsevier]

Highlights: [•] Bovine serum albumin can be used as a molecular sensor to simplify complex samples. [•] The assay is rapid, robust, and enhances the ability to categorize complex biological fluids. [•] Biological fluids such as wine and urine can be separated into appropriate groups. [•] First demonstration of shock markers at a clinically relevant time point from urine. [ABSTRACT FROM AUTHOR]