Ketamine provides the highest safety profile among sedatives for procedural sedation and analgesia in the pediatric emergency setting. However, it can cause vomiting and recovery agitation. No studies have examined epigenetic factors, such as microRNAs, for predicting the occurrence of these adverse events. Neuronal‐derived extracellular vesicle microRNA profiles were studied to predict the occurrence of ketamine‐induced vomiting and recovery agitation in children. For this aim, a single‐center prospective pharmacoepigenetic study was performed and 50 children who underwent procedural sedation with intravenous ketamine as the only sedative drug were enrolled between October 2019 and November 2022. MiRNA profiling in plasma neural‐derived extracellular vesicles was analyzed through next‐generation sequencing and measured before treatment with ketamine. Twenty‐two patients experienced vomiting or recovery agitation. Among the 16 differentially expressed microRNAs, the upregulated miR‐15a‐5p and miR‐484 targeted genes related to N‐methyl‐D‐aspartate (NMDA) receptor activity, including glutamate ionotropic receptor NMDA type subunit 2A (GRIN2A). Preliminary data confirmed lower GRIN2A levels in patients who developed these events. Downregulated miR‐126‐3p and miR‐24‐3p targeted AMPA receptor‐associated genes. Functional analyses of gene targets revealed the enrichment of glutamatergic and neurotrophins signaling. Recovery agitation was associated with this network. Vomiting was related to dopaminergic and cholinergic systems. Three miRNAs (miR‐18a‐3p, miR‐484, and miR‐548az‐5p) were identified as predictive biomarkers (AUC 0.814; 95% CI: 0.632–0.956) for ketamine‐induced vomiting and recovery agitation. MicroRNA profiles can predict the development of ketamine‐induced vomiting or recovery agitation in children. This study contributes to the understanding of the mechanisms underlying ketamine‐induced adverse events.
