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We hypothesized that plasma metabolomics could identify ECMO-mode-specific metabolic shifts and biomarkers preceding ABI. Methods: Untargeted plasma metabolomics was performed in 70 participants across two centers: 30 healthy controls, 17 critically ill controls, and 23 ECMO patients [14 venovenous (VV) and 9 venoarterial (VA)]. Plasma was collected within 24 h and 7 days after cannulation. Fold-change analyses and partial least squares discriminant analysis were used to define metabolic differences and identify metabolites associated with subsequent ABI. Results: ABI occurred in seven ECMO patients, including five venoarterial and two venovenous ECMO patients. ECMO support was associated with broad alterations in circulating lipid metabolism, including changes in sphingomyelins, lysophospholipids, and monoacylglycerols. PLS-DA demonstrated metabolomic separation between ECMO patients and controls. Among ECMO patients, three structurally related glycerophospholipids\u2014GPI (18:0\/18:2), GPC (16:0\/18:2), and GPE (16:0\/18:2)\u2014were significantly decreased before ABI diagnosis. ABI was also associated with broader reductions in phosphatidylethanolamines, phosphatidylinositols, lysophospholipids, and polyunsaturated fatty acids. Conclusions: Early reductions in membrane-associated phospholipids were associated with subsequent ABI during ECMO support, suggesting that alterations in circulating lipid homeostasis may identify neurological vulnerability before clinical or radiographic recognition of injury. Plasma metabolomics may provide a complementary approach for early neurological risk stratification and support future biomarker development.<\/jats:p>","DOI":"10.3390\/cells15171593","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T16:28:22Z","timestamp":1788280102000},"page":"1593","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Early Metabolomic Changes During Extracorporeal Membrane Oxygenation Are Associated with Subsequent Acute Brain Injury"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2287-3684","authenticated-orcid":false,"given":"Bosco Seong Kyu","family":"Yang","sequence":"first","affiliation":[{"name":"Division of Neurocritical Care, Department of Neurosurgery, McGovern School of Medicine, University of Texas Health Science Center, Houston, TX 77030, 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D.","family":"McCullough","sequence":"additional","affiliation":[{"name":"Department of Neurology, McGovern School of Medicine, University of Texas Health Science Center, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"resources","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-4083-8143","authenticated-orcid":false,"given":"Kha","family":"Dinh","sequence":"additional","affiliation":[{"name":"Divisions of Pulmonary, Critical Care, and Sleep Medicine, McGovern Medical School, the University of Texas Health Science Center at Houston, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"resources","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Bindu","family":"Akkanti","sequence":"additional","affiliation":[{"name":"Divisions of Pulmonary, Critical Care, and Sleep Medicine, McGovern Medical School, the 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