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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.<\/jats:p>","DOI":"10.3390\/metabo16070516","type":"journal-article","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T01:01:28Z","timestamp":1784768488000},"page":"516","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Metabolomic Signatures of Biotrauma Associated with Mortality in ICU Patients Requiring Invasive Mechanical Ventilation and ECMO"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0741-2211","authenticated-orcid":false,"given":"Tiago A. H.","family":"Fonseca","sequence":"first","affiliation":[{"name":"NMS\u2014NOVA Medical School, FCM\u2014Faculdade de Ci\u00eancias M\u00e9dicas, Universidade NOVA de Lisboa, Campo dos M\u00e1rtires da P\u00e1tria 130, 1169-056 Lisbon, Portugal"},{"name":"ISEL\u2014Instituto Superior de Engenharia de Lisboa, Instituto Polit\u00e9cnico de Lisboa, Rua Conselheiro Em\u00eddio Navarro 1, 1959-007 Lisbon, Portugal"},{"name":"CHRC\u2014Comprehensive Health Research Centre, Universidade NOVA de Lisboa, 1150-082 Lisbon, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristiana P.","family":"Von Rekowski","sequence":"additional","affiliation":[{"name":"NMS\u2014NOVA Medical School, FCM\u2014Faculdade de Ci\u00eancias M\u00e9dicas, Universidade NOVA de Lisboa, Campo dos M\u00e1rtires da P\u00e1tria 130, 1169-056 Lisbon, Portugal"},{"name":"ISEL\u2014Instituto Superior de Engenharia de Lisboa, Instituto Polit\u00e9cnico de Lisboa, Rua Conselheiro Em\u00eddio Navarro 1, 1959-007 Lisbon, Portugal"},{"name":"CHRC\u2014Comprehensive Health Research Centre, Universidade NOVA de Lisboa, 1150-082 Lisbon, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9369-6486","authenticated-orcid":false,"given":"R\u00faben","family":"Ara\u00fajo","sequence":"additional","affiliation":[{"name":"NMS\u2014NOVA Medical School, FCM\u2014Faculdade de Ci\u00eancias M\u00e9dicas, Universidade NOVA de Lisboa, Campo dos M\u00e1rtires da P\u00e1tria 130, 1169-056 Lisbon, Portugal"},{"name":"ISEL\u2014Instituto Superior de Engenharia de Lisboa, Instituto Polit\u00e9cnico de Lisboa, Rua Conselheiro Em\u00eddio Navarro 1, 1959-007 Lisbon, Portugal"},{"name":"CHRC\u2014Comprehensive Health Research Centre, Universidade NOVA de Lisboa, 1150-082 Lisbon, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4828-4738","authenticated-orcid":false,"given":"Gon\u00e7alo C.","family":"Justino","sequence":"additional","affiliation":[{"name":"Centro de Qu\u00edmica Estrutural\u2014Institute of Molecular Sciences, Instituto Superior T\u00e9cnico, Universidade de Lisboa, Av. Rovisco Pais 1, 1049-001 Lisbon, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3068-4920","authenticated-orcid":false,"given":"M. Concei\u00e7\u00e3o","family":"Oliveira","sequence":"additional","affiliation":[{"name":"Centro de Qu\u00edmica Estrutural\u2014Institute of Molecular Sciences, Instituto Superior T\u00e9cnico, Universidade de Lisboa, Av. Rovisco Pais 1, 1049-001 Lisbon, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu\u00eds","family":"Bento","sequence":"additional","affiliation":[{"name":"CHRC\u2014Comprehensive Health Research Centre, NMS\u2014NOVA Medical School, FCM\u2014Faculdade de Ci\u00eancias M\u00e9dicas, Universidade NOVA de Lisboa, 1169-056 Lisbon, Portugal"},{"name":"Intensive Care Department, ULS S\u00e3o Jos\u00e9\u2014Unidade Local de Sa\u00fade S\u00e3o Jos\u00e9, Rua Jos\u00e9 Ant\u00f3nio Serrano, 1150-199 Lisbon, Portugal"},{"name":"CCAL\u2014Centro Cl\u00ednico Acad\u00e9mico de Lisboa, 1649-028 Lisbon, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5264-9755","authenticated-orcid":false,"given":"Cec\u00edlia R. 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