Developmental Stage–Dependent Neurotoxicity of Sevoflurane: Evidence from Brain Organoids

Abstract

Sevoflurane is widely used in pediatric anesthesia because it allows rapid induction and recovery, yet its use during vulnerable periods of brain development has raised concerns about long-term neurocognitive effects. Experimental data indicate that sevoflurane engages multiple interacting pathways, including mitochondrial dysfunction, oxidative and iron-dependent injury, and immune-mediated synaptic and inflammatory responses, whose net impact depends on dose, timing, and exposure duration. Human brain organoids have meanwhile emerged as human-based three-dimensional models that reproduce key aspects of cortical and midbrain development and permit clinically relevant exposure paradigms to be tested in vitro. In both cortical-like and midbrain-like organoids, sevoflurane narrows and disorganizes progenitor zones, disrupts interkinetic nuclear migration, reduces apical mitoses, and accelerates neuronal or dopaminergic differentiation, with more pronounced changes after more intense exposure. These architectural alterations are accompanied by molecular and electrophysiological signatures of mitochondrial stress, iron dysregulation, and inflammatory activation, forming multidimensional "injury fingerprints" that parallel clinical observations that single, brief anesthetics rarely cause overt global decline, whereas repeated or prolonged anesthetics are associated with subtler, domain-specific deficits. This review synthesizes current evidence on the developmental stage– dependent effects of sevoflurane and highlights how brain organoids are being used to dissect underlying cellular and molecular mechanisms. It also discusses key limitations of current organoid systems and considers how more mature, vascularized, and microglia-containing models, integrated with perioperative cohorts and targeted interventions, may eventually inform exposure-aware anesthetic planning without delaying necessary surgery. Overall, this review advances a developmental stage–aware, organoid-centered conceptual framework that integrates animal and human-based evidence to better understand and stratify the risk of sevoflurane-induced neurotoxicity.