Analysis of the Plasma Metabolome after Trauma, Novel Circulating Sphingolipid Signatures, and In-Hospital Outcomes

Abstract

BACKGROUND: Trauma is the leading cause of death and disability for individuals under age 55. Many severely injured trauma patients experience complicated clinical courses despite appropriate initial therapy. We sought to identify novel circulating metabolomic signatures associated with clinical outcomes following trauma. STUDY DESIGN: Untargeted metabolomics and circulating plasma immune mediator analysis was performed on plasma collected during 3 post-injury time periods (<6 hours [h], 6 he24h, day 2eday 5) in critically ill trauma patients enrolled between April 2004 and May 2013 at UPMC Presbyterian Hospital in Pittsburgh, PA. Inclusion criteria were age 18 years, blunt mechanism, ICU admission, and expected survival 24 h. Exclusion criteria were isolated head injury, spinal cord injury, and pregnancy. Exploratory endpoints included length of stay (overall and ICU), ventilator requirements, nosocomial infection, and Marshall organ dysfunction (MOD) score. The top 50 metabolites were isolated using repeated measures ANOVA and multivariate empirical Bayesian analysis for further study. RESULTS:Eighty-six patients were included for analysis. Sphingolipids were enriched significantly (chisquare, p < 10 -6 ) among the top 50 metabolites. Clustering of sphingolipid patterns identified 3 patient subclasses: nonresponders (no time-dependent change in sphingolipids, n ¼ 41), sphingosine/sphinganine-enhanced (n ¼ 24), and glycosphingolipid-enhanced (n ¼ 21). Compared with the sphingolipid-enhanced subclasses, nonresponders had longer mean length of stay, more ventilator days, higher MOD scores, and higher circulating levels of proinflammatory immune mediators IL-6, IL-8, IL-10, MCP1/CCL2, IP10/CXCL10, and MIG/CXCL9 (all p < 0.05), despite similar Injury Severity Scores (p ¼ 0.12). CONCLUSIONS: Metabolomic analysis identified broad alterations in circulating plasma sphingolipids after blunt trauma. Circulating sphingolipid signatures and their association with both clinical outcomes and circulating inflammatory mediators suggest a possible link between sphingolipid metabolism and the immune response to trauma.

Multi-omic analysis in injured humans: Patterns align with outcomes and treatment responses

“…The clinical data, EC, cytokines, and lipidomic data for PAMPer and all three layers for TD2 have been previously published. 21 , 22 , 23 , 24 Here, we provide an overview of the metabolomic and proteomic findings for the PAMPer cohort. Untargeted plasma metabolomics was performed on 17 non-fasting healthy controls (HCs) and 194 trauma patients at 0, 24, and 72 h after arrival to the hospital.…”

Circulating Metabolomic Analysis following Cecal Ligation and Puncture in Young and Aged Mice Reveals Age‐Associated Temporal Shifts in Nicotinamide and Histidine/Histamine Metabolic Pathways

“…As these small molecules represent the end result of layered epigenomic, transcriptomic, and proteomic regulation, metabolite profiles provide an integrative view of complex biological systems. In humans, studies utilizing metabolomic methods to help delineate age-associated patterns and patient subgroups in sepsis [11], pneumonia [12], and trauma [13] have proven to be of significant value in highlighting potentially novel avenues for both basic research and potential intervention. However, human studies remain costly and time-consuming, and murine models remain a mainstay for evaluation of central metabolic pathways following insult.…”

Integration of Metabolomic and Clinical Data Improves the Prediction of Intensive Care Unit Length of Stay Following Major Traumatic Injury

“…Our current understanding of the metabolic response to traumatic injury is based almost entirely upon the results of studies that have analysed serum samples acquired from patients at either a single post-injury time-point [20][21][22]24,43] or at multiple timepoints during the acute injury phase (days 1-7) [23,25,26,28,44,45]. Thus, via the analysis of blood samples obtained in the acute (days 0-4), intermediate (days [5][6][7][8][9][10][11][12][13][14] and late (days 15-112) post-injury phases, our study has provided novel insights into both the kinetics of the metabolic response to injury as well as the long-term metabolomic profiles of major trauma patients.…”

“…For example, disturbances in amino acid and fatty acid metabolism have been reported in TBI patients who experience post-traumatic cognitive impairments [21], whilst significantly increased concentrations of glucose and glutamate were measured in serum samples obtained at the time of hospital admission from non-survivors of severe trauma [20]. More recently, in a cohort of eighty-six blunt trauma patients, Cyr et al found that at days 2-5 post-injury, a plasma metabolome enriched in sphingolipids was associated with several improved clinical outcomes, which included a shorter ICU LOS [28]. However, the study did not address whether metabolomic profiles in the immediate post-injury phase could be used to predict which patients would experience an extended LOS in ICU.…”