Plasma and Urine Metabolite Panels for Early Sepsis Diagnosis and Risk Stratification in the ICU: An Integrated Review of MS-Based Metabolomics Workflow and Clinical Translation Barriers

Background: Early diagnosis and risk stratification of sepsis in the intensive care unit (ICU) remain major clinical challenges. Conventional biomarkers such as lactate, procalcitonin, and C-reactive protein lack sufficient specificity and prognostic resolution. Mass spectrometry (MS)–based metabolomics has emerged as a promising platform for identifying plasma and urine metabolite panels capable of reflecting host metabolic reprogramming during early sepsis. Methods: This review synthesizes evidence from studies published between 2000 and 2024 evaluating plasma and urine metabolite signatures for early sepsis diagnosis and ICU risk stratification. We examine MS-based workflows, analytical platforms (LC-MS, GC-MS, HRMS), statistical modeling strategies, and translational barriers. Results: Consistent alterations in amino acid metabolism (arginine, tryptophan, phenylalanine), lipid mediators (lysophosphatidylcholines, acylcarnitines), glycolytic intermediates, and TCA cycle metabolites have been reported. Several multivariate metabolite panels demonstrate AUC values >0.85 for early diagnosis and mortality prediction. However, inter-study variability, lack of external validation, preanalytical heterogeneity, and regulatory barriers limit clinical translation. Conclusions: Plasma and urine metabolite panels show strong potential for early sepsis detection and ICU risk stratification. Standardization of workflows, multicenter validation, and integration with clinical decision tools are essential for translation into routine care.