• Kuei-Pin Chung, Yi-Hsuan Chen, Yi-Jung Chen, Jung-Yien Chien, Han-Chun Kuo, Yen-Tsung Huang, Sheng-Yuan Ruan, Yu-Li Lin, Yen-Fu Chen, Li-Ta Keng, Lu-Cheng Kuo, Shih-Chi Ku, Ching-Hua Kuo, Chong-Jen Yu, and TAiwan CollaboraTive Intensive Care Study group(TACTICS).
• Department of Laboratory Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
• Shock. 2025 Jan 14.

ObjectiveRecent studies have proposed that Krebs cycle metabolites may serve as potential biomarkers for prognosis in sepsis. However, whether these metabolites are associated with disease severity and can be applied to improve the effectiveness of current prognosis assessment in sepsis remains unclear and is explored in this study.MethodsThis prospective multicenter cohort study was conducted in medical intensive care units (ICUs). From December 2019 to September 2022, consecutive patients admitted to medical ICUs for sepsis were screened and recruited. Plasma samples were obtained for measurements of cytokines and Krebs cycle metabolites, including citrate/isocitrate, cis-aconitate, alpha-ketoglutarate, succinate, fumarate and malate.ResultsIn total, 97 patients admitted for sepsis were enrolled in the study. The 28-day mortality rate was 17.5%, and non-survivors exhibited significantly increased plasma lactate levels and Sequential Organ Failure Assessment (SOFA) scores. Plasma levels of Krebs cycle metabolites were significantly correlated with both plasma lactate and interleukin-6 levels. Except for citrate/isocitrate, all Krebs cycle metabolites were significantly elevated in patients with acute kidney injury. Multivariate Cox proportional hazard models, adjusted for plasma lactate levels and SOFA scores, revealed that plasma levels of alpha-ketoglutarate (adjusted hazard ratio [HR]: 2.404, P = 0.002), fumarate (adjusted HR: 1.904, P = 0.001) and malate (adjusted HR: 1.327, P = 0.019) were associated with increased risk of 28-day mortality.ConclusionsStudy findings indicate that Krebs cycle metabolites, particularly alpha-ketoglutarate, fumarate, and malate, when applied with SOFA score, might enhance prognostic assessment in patients with sepsis.Copyright © 2025 by the Shock Society.

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