Metabolomics after trauma in experimental models- a systematic review

BACKGROUND: Hemorrhagic shock (HS) is a major risk factor for mortality and complications after severe trauma. Yet, complex mechanisms on a cellular and physiological level are still not fully understood, Metabolomics offers a powerful tool to unravel these complex biochemical alterations following HS and trauma (T). However, no systematic synthesis of metabolomic findings in in standardized translational animal models of HS and HS + T exists to date. OBJECTIVES: To systematically review and compare metabolomic alterations in animal models of isolated hemorrhagic shock and hemorrhagic shock with trauma, highlighting key metabolic pathways and their modulation by resuscitation strategies. METHODS: We performed a systematic review on Pubmed and EMBASE to identify relevant metabolomic changes measured in with mass spectrometry in translational animal models following HS and HS + T. Studies were categorized into two groups in regard to our main objective: Isolated HS and HS + T. Key metabolite changes were extracted and analyzed qualitatively across seven major metabolic domains: energy, amino acids, purines, arginine/urea cycle, lipids, sulfur/creatine, and redox balance. RESULTS: Overall, 25 studies were included in our analysis. HS and HS + T both exhibited consistent changes in lactate (↑), succinate (↑), glutamine (↑), and acylcarnitines (↑), indicating hypoxia-driven glycolysis, mitochondrial dysfunction, and enhanced proteolysis. HS + T models displayed more pronounced alterations in branched-chain amino acids, purine catabolites (urate, inosine), and markers of oxidative stress. ATP depletion and glutathione imbalance were common, particularly in the trauma group. Plasma resuscitation partially corrected several abnormalities, especially in redox, purine, and glutamine pathways, compared to saline. CONCLUSIONS: Metabolic responses to hemorrhagic shock are reproducible across animal models and are amplified by the presence of trauma. Trauma accentuates proteolysis, oxidative stress, and nucleotide turnover. Plasma-based resuscitation appears superior to crystalloid in correcting these derangements. These findings support the exploration of targeted metabolic therapies and advocate for metabolomics-informed resuscitation strategies in trauma care.