Pharmacogenetic, pharmacokinetic and epigenetic profiles in children who experience vomiting or recovery agitation during sedation with ketamine

Background: Ketamine is one of the sedatives most used in North America for procedural sedation outside the operating room in children. Vomiting and recovery agitation are the adverse events most frequently reported after ketamine administration in children. The aim of this study was to identify genetic variants associated with the development of vomiting or recovery administration after intravenous ketamine administration. Material and methods: This was a single-center prospective pharmacogenetic study performed at the tertiary level children’s hospital Institute for Maternal and Child Health IRCCS Burlo Garofolo of Trieste, Italy. Children, between 1 and 17yrs of age, performing procedural sedation with intravenous ketamine as the sole sedative agent were enrolled. Pharmacogenetic, pharmacokinetic and epigenetic analysis were predisposed. The genotyping was performed through Illumina Omni 2.5+ exome array. The search for biomarkers was performed through the analysis of the variants of 10 candidate genes, codifying for proteins responsible for the metabolism and pharmacodynamics of ketamine. A target sequencing genome-wide analysis was carried out to identify the presence of genetic variants associated with the development of adverse events but not related to the candidate genes. The plasma concentration of ketamine and norketamine were determined and pharmacokinetic parameters were determined. A pharmacogenomic approach provided neural-derived exosomal miRNA profiles for patients. The miRNA contained in neural-derived exosomes were quantified and related to the occurrence of ketamine adverse events, through a next-generation sequencing technique. Results: From September 2019 to October 2021, 106 patients were enrolled in the study. Among them, 87 patients were analyzed. The mean age was 8yrs (+/- 4.3). 55% were females, 37% were affected by chronic diseases. Arthrocentesis and bone fracture reduction were the procedures most frequently performed. A mean dose of 1.7mg/kg of intravenous ketamine was employed to perform the procedures. Thirty-one patients (35%) experienced vomiting or recovery agitation and were compared to the 56 patients (65%) without these events. Polymorphisms on GRIN2A, GRIN2B, and CYP2A6 were associated with the development of vomiting or recovery agitation. A stronger association was found with polymorphisms related to the pharmacodynamic of ketamine. Conclusion: The development of vomiting and recovery agitation after ketamine administration seems associated with specific genetic variants. These findings should be confirmed in a greater population.