Metabolomic Signatures of Biotrauma Associated with Mortality in ICU Patients Requiring Invasive Mechanical Ventilation and ECMO

Background: Biotrauma from invasive mechanical ventilation (IMV) and extracorporeal membrane oxygenation (ECMO) drives systemic inflammation, metabolic dysregulation, and organ dysfunction in critically ill patients. Therefore, this study aimed to identify clinical and metabolomic features associated with ICU mortality in patients receiving IMV or ECMO, as these remain incompletely characterized. Methods: The retrospective analysis included 30 ICU patients on IMV and 22 on ECMO. Metabolomic and proteomic profiling were performed using ultra-high-performance liquid chromatography coupled with high-resolution mass spectrometry (UHPLC-HRMS), and serum spectral analysis by Fourier-transform infrared spectroscopy (FTIRS). Significant variables were incorporated into multivariate logistic regression models, ranked by AIC, AUC, and statistical significance. Model performance was evaluated using stratified 5-fold cross-validation. Final models were adjusted for relevant demographic and clinical covariates. Results: The IMV cohort showed discriminatory FTIRS wavenumbers across all preprocessings, and 155 metabolites plus 14 proteins were significantly altered, with unadjusted models achieving mean AUCs above 0.9. The ECMO cohort showed discriminatory FTIRS wavenumbers in one preprocessing, and 15 metabolites plus 3 proteins were highlighted. FTIRS, metabolomic, and proteomic models reached mean AUCs of 0.967, 0.867, and 0.783, respectively, with lower stability during cross-validation. Adjustment for demographic and clinical covariates reduced model robustness. Conclusions: Stronger and more reproducible molecular signatures related to ICU mortality were observed in the IMV cohort, whereas the ECMO cohort showed reduced model stability, likely reflecting increased biological heterogeneity and small sample size. These findings support the utility of integrated omics for characterizing critical illness and outcome stratification, while reinforcing the need for validation in larger and independent cohorts.