Metabolomic signatures prior to in-hospital cardiac arrest: insights into potential therapeutic targets.

Plasma metabolomic alterations occurring up to 48 h before in-hospital cardiac arrest (IHCA) and their associations with return of spontaneous circulation (ROSC) and in-hospital mortality (IHM) were evaluated in this exploratory case-control study. Adults with IHCA at a tertiary university hospital were identified, and archived serum samples collected within 48 h before the event were analyzed. For the ROSC analysis, patients with ROSC were matched to non-ROSC patients, while for the IHM analysis, patients with IHM were matched to survivors according to age, sex, initial IHCA rhythm, interval between sample collection and cardiac arrest, and major comorbidities. Untargeted metabolomic profiling was performed, and data was analyzed using complementary multivariate and univariate approaches. Candidate metabolites were further evaluated through qualitative assessment of their distribution across groups. Six metabolites initially differed between groups; however, after this refinement step, only two remained consistently associated with clinically relevant outcomes. Lower circulating tryptophan concentrations were associated with IHM, whereas higher levels of 2-methylbutyryl-L-carnitine were associated with failure to achieve ROSC and increased IHM. Pathway enrichment analysis suggested disruptions in mitochondrial energy metabolism, particularly within the tricarboxylic acid cycle, as well as alterations in amino acid-related pathways, including tryptophan, histidine, and alanine-aspartate-glutamate metabolism. These findings indicate that detectable metabolic disturbances are present up to 48 h before IHCA and are associated with clinical outcomes. As all patients in this study experienced IHCA, these results should be interpreted as differences between outcome groups rather than predictors of IHCA occurrence. Within this context, the findings support the concept that IHCA may represent the culmination of a progressive metabolic deterioration rather than an abrupt event, highlighting a potential window for earlier risk stratification and future investigation of preventive strategies.