PERSISTENT METABOLOMIC ALTERATIONS CHARACTERIZE CHRONIC CRITICAL ILLNESS AFTER SEVERE TRAUMA.

BACKGROUND Following trauma, persistent inflammation, immunosuppression, and catabolism may characterize delayed recovery or failure to recover. Understanding the metabolic response associated with these adverse outcomes may facilitate earlier identification and intervention. We characterized the metabolic profiles of trauma victims who died or developed chronic critical illness (CCI), and hypothesized that differences would be evident within one-week post-injury. METHODS Venous blood samples from trauma victims with shock who survived at least seven days were analyzed using mass spectrometry. Subjects who died or developed CCI (ICU LOS ≥ 14 days with persistent organ dysfunction) were compared to subjects who recovered rapidly (ICU LOS ≤ 7 days), and uninjured controls. We used Partial Least Squares Discriminant Analysis (PLS-DA), t-tests, linear mixed effects regression, and pathway enrichment analyses to make broad comparisons and identify differences in metabolite concentrations and pathways. RESULTS We identified 27 patients who died or developed CCI, and 33 who recovered rapidly. Subjects were predominantly male (65%) with a median age of 53 years and injury severity score of 36. Healthy controls (n=48) had similar age and sex distributions. Overall, from the 163 metabolites detected in the samples, 56 metabolites and 21 pathways differed between injury outcome groups, and PLS-DA models distinguished injury outcome groups as early as 1-day post-injury. Differences were observed in tryptophan, phenylalanine, and tyrosine metabolism; metabolites associated with oxidative stress via methionine metabolism; inflammatory mediators including kynurenine, arachidonate, and glucuronic acid; and products of the gut microbiome including indole-3-propionate. CONCLUSIONS The metabolic profiles in subjects who ultimately die or develop CCI differ from those who have recovered. In particular, we have identified differences in markers of inflammation, oxidative stress, amino acid metabolism and alterations in the gut microbiome. Targeted metabolomics has the potential to identify important metabolic changes post-injury to improve early diagnosis and targeted intervention. LEVEL OF EVIDENCE Prognostic/Epidemiologic Level III.