Behavioral outcomes after sevoflurane-based general anesthesia in preschool children: a prospective cohort study with perioperative hydrogen sulfide–related biomarker profiling

The association between general anesthesia (GA) for surgical procedures in preschool children and subsequent neurobehavioral outcomes remains unresolved, and human biomarker data on potential biological correlates are limited. We conducted a prospective cohort study of 118 preschool children undergoing surgical procedures requiring sevoflurane-based GA and 113 unexposed peers, with 6-month behavioral and neurocognitive follow-up and perioperative profiling of hydrogen sulfide (H 2 S)-related biomarkers. Compared with unexposed children, exposed children had modestly higher parent-reported CBCL behavioral problem scores, most prominently for internalizing symptoms, whereas executive-function and cognitive-screening differences were limited. Within the exposed group, greater perioperative exposure burden, reflected by repeated anesthesia episodes, longer anesthesia duration, and higher cumulative sevoflurane dose, was associated with less favorable behavioral profiles. Serum H 2 S and cystathionine β-synthase (CBS) decreased postoperatively, whereas 3-mercaptopyruvate sulfurtransferase (3-MST) increased; lower postoperative H 2 S was associated with higher subsequent behavioral scores. Exploratory analysis of publicly available single-nucleus hippocampal data further suggested that virtual perturbation of Cbs , encoding CBS, converges on neuronal programs relevant to synaptic plasticity and excitability. These findings suggest modest behavioral differences within a real-world sevoflurane-based perioperative context, with H 2 S-related biomarkers providing exploratory biological and mechanistic context.