Breath Analysis of Propofol and Associated Metabolic Signatures: A Pilot Study Using Secondary Electrospray Ionization High-Resolution Mass Spectrometry

Background: Propofol is a widely used anesthetic for total intravenous anesthesia (TIVA). Though generally safe, rare but serious complications can occur in vulnerable groups, such as critically ill patients and children. Clinicians often rely on surrogate measures (e.g., predicted effect‐site concentrations or bispectral index), yet more direct indicators of anesthetic exposure and metabolic stress would be valuable. We hypothesized that pharmacometabolomics via breath analysis could yield real‐time insights into propofol concentrations as well as accompanying metabolic responses to surgery. Methods: In this pilot, 10 pediatric patients (median age 5.9 years; interquartile range 4.3–6.6) undergoing propofol anesthesia contributed 47 breath samples (10 pre‐induction, 37 post‐induction) and 37 blood samples. All samples were analyzed by high‐resolution mass spectrometry. Linear mixed‐effects models examined associations between exhaled compounds and serum propofol concentrations while accounting for repeated measures in individual patients. Volcano plots were used to identify differential changes in metabolites following propofol induction. Results: Propofol, its metabolites, and endogenous metabolites were readily detected in exhaled breath, demonstrating strong correlations with serum propofol concentrations (R² ≥ 0.65; adjusted p < 0.001). Differential analysis showed significant upregulation of endogenous fatty aldehydes (log₂[post/pre] ≥ 1; adjusted p ≤ 0.05), suggestive of lipid peroxidation and oxidative stress. Exogenous compounds, including benzene and phenols, were also observed, reflecting propofol metabolism in vivo. Conclusions: This pilot study highlights a robust breath–serum relationship for propofol and reveals surgery‐associated shifts in metabolic pathways, including evidence of oxidative stress. These findings underscore the feasibility of exhaled‐breath pharmacometabolomics for individualized anesthetic care. Further validation in larger cohorts is warranted to confirm clinical utility and to determine whether real‐time breath analysis could ultimately serve as a useful adjunct for guiding anesthetic management and monitoring perioperative metabolic responses.