Intravenous amino acid supplementation reduces 28-d mortality in sepsis: a retrospective cohort study from Medical Information Mart for Intensive Care-IV database and Mendelian randomisation analysis

Sepsis-related deaths remain prevalent in intensive care settings, with metabolic dysregulation as a key contributor. Although amino acid supplementation has shown promise, its clinical effectiveness in sepsis is unclear. This study evaluated the impact of intravenous amino acid administration on 28-d mortality in intensive care unit (ICU) sepsis patients using retrospective cohort analysis and Mendelian randomisation (MR). We analysed data from the Medical Information Mart for Intensive Care-IV database, matching 726 patients (363 per group) using propensity scores. The association between amino acid supplementation and mortality was assessed using logistic regression, Cox regression and targeted maximum likelihood estimation (TMLE). Two-sample MR was used to explore causal links between twenty common amino acids and sepsis mortality. In the cohort analysis, amino acid supplementation was consistently associated with significantly reduced 28-d mortality across all analytical methods (logistic regression: OR = 0·48, <i>P</i> < 0·01; Cox regression: HR = 0·48, <i>P</i> < 0·01; TMLE: average treatment effect = -0·102, <i>P</i> < 0·01). In contrast, the MR analysis did not find a significant causal association for any single amino acid after correction for multiple comparisons; although glycine showed a nominal protective signal, it did not remain significant after false discovery rate correction. This dual-method study demonstrates a strong association between compound amino acid infusions and reduced mortality in sepsis but did not identify any single amino acid as a robust causal mediator. These findings suggest the benefit may arise from a synergistic effect, highlighting the need for randomised controlled trials to validate these observational results and optimise nutritional strategies.