High Dimensional Proteomics Identifies Organ Injury Patterns Associated with Outcomes in Human Trauma

INTRODUCTION: Severe traumatic injury with shock can lead to direct and indirect organ injury, however, tissue-specific biomarkers are limited in clinical panels. We utilized proteomic and metabolomic databases to identify organ injury patterns after severe injury in humans.

METHODS: Plasma samples (times 0-, 24-, and 72-hours [h] after arrival to trauma center) from injured patients enrolled in two randomized prehospital trials were subjected to multiplexed proteomics (SomaLogic Inc.). Patients were categorized by outcome: Non-resolvers (died >72 h or required ≥7 days of critical care), Resolvers (survived to 30-days and required <7 days of critical care), and low injury severity score (ISS) controls. Established tissue-specific biomarkers were identified through a literature review and cross-referenced with tissue-specificity from the Human Protein Atlas. Untargeted plasma metabolomics (Metabolon Inc.), inflammatory mediators, and endothelial damage markers were correlated with injury biomarkers. Kruskal-Wallis/Mann-Whitney-U tests with false discovery rate correction assessed differences in biomarker expression across outcome groups (significance; P-value <0.1).

RESULTS: Of 142 patients, 78 were Non-resolvers (median ISS = 30), 34 Resolvers (median ISS = 22), and 30 low ISS controls (median ISS = 1). A broad release of tissue-specific damage markers was observed at admission; this was greater in Non-resolvers. By 72 h, 9 cardiac, 3 liver, 8 neurologic, and 3 pulmonary proteins remained significantly elevated in Non-resolvers compared to Resolvers. Cardiac damage biomarkers showed the greatest elevations at 72 h in Non-resolvers and had significant positive correlations with pro-inflammatory mediators and endothelial damage markers. Non-resolvers had lower concentrations of fatty acid metabolites compared to Resolvers, particularly acyl carnitines and cholines.

CONCLUSIONS: We identified an immediate release of tissue-specific biomarkers with sustained elevation in the liver, pulmonary, neurologic, and especially cardiac injury biomarkers in patients with complex clinical courses after severe injury. The persistent myocardial injury in Non-resolvers may be due to a combination of factors including metabolic stress, inflammation, and endotheliopathy.

STUDY TYPE: Level III, Prognostic/Epidemiological.