Electroencephalogram Signatures of Agitation Induced by Sevoflurane and Its Association With Genetic Polymorphisms

Abstract

Background: Volatile anesthetic-induced agitation, also called paradoxical excitation, is not uncommon during anesthesia induction. Clinically, patients with agitation may lead to self-injury or disrupt the operative position, increasing the incidence of perioperative adverse events. The study was designed to investigate clinical features of sevoflurane-induced agitation and examined whether any gene polymorphisms can potentially be used to predict agitation.Methods: One hundred seventy-six patients underwent anesthesia induction with sevoflurane were included in this study. Frontal electroencephalogram (EEG), electromyography (EMG), and hemodynamics were recorded continuously during anesthesia induction. DNA samples were genotyped using the Illumina Infinium Asian Screening Array and the SNaPshot technology. Genetic association was analyzed by genome-wide association study. Logistic regression analysis was used to determine the role of variables in the prediction of agitation.Results: Twenty-five (14.2%) patients experienced agitation. The depth of anesthesia index (Ai index) (p < 0.001), EMG (p < 0.001), heart rate (HR) (p < 0.001), and mean arterial pressure (MAP) (p < 0.001) rapidly increased during the agitation. EEG exhibited a shift toward high frequencies with spikes during agitation. The fast waves (alpha and beta) were more pronounced and the slow rhythms (delta) were less prominent during the occurrence of agitation. Moreover, three SNPs in the methionine synthase reductase (MTRR) gene were correlated to the susceptibility to agitation (p < 5.0 × 10−6). Carrying rs1801394 A > G (odds ratio 3.50, 95% CI 1.43–9.45) and/or rs2307116 G > A (3.31, 1.36–8.95) predicted a higher risk of agitation.Discussion: This study suggests that the agitation/paradoxical excitation induced by sevoflurane is characterized as increases in Ai index, EMG, HR and MAP, and the high frequency with spikes in EEG. Moreover, our results provide preliminary evidence for MTRR genetic polymorphisms, involving folate metabolism function, may be related to the susceptibility to agitation.Clinical Trial Number and Registry URL: ChiCTR1900026218; http://www.chictr.org.cn/showproj.aspx?proj=40655.

Study of the Association of Single Nucleotide Polymorphisms in Candidate Genes With Sevoflurane

“…Moreover, a study has proven that sevoflurane disrupts folate metabolism and impedes neuronal transportation and communication, leading to demyelination of the juvenile brain 31 . A recent study by our research team also showed that MTRR gene polymorphisms may be associated with agitation susceptibility during sevoflurane anesthesia induction 20 . However, no study has yet reported the relationship between the MTRR gene and susceptibility to sevoflurane.…”

“…But lower Ai values are more likely to be associated with higher levels of sedation, even in individuals. Therefore, Ai can serve as a good guide for clinicians to titrate sevoflurane for the individuals 20,21 . Altogether, it must certainly be admitted that Ai is not the gold standard for sedation evaluation.…”

“…Moreover, the cytochrome P450 (CYP) family (eg, CYP2E1 , CYP2A6 , and CYP2B6 ), glutathione S‐transferase‐p (GSTP), uridine diphospho‐glucuronosyltransferase (UGT), and ATP‐binding cassette are postulated to be involved in sevoflurane pharmacokinetics 1,18,19 . And a recent study from our research team also suggested that methionine synthase reductase (MTRR) genetic polymorphisms may be related to the susceptibility to agitation induced by sevoflurane 20 …”

“…1,18,19 And a recent study from our research team also suggested that methionine synthase reductase (MTRR) genetic polymorphisms may be related to the susceptibility to agitation induced by sevoflurane. 20 However, the association between the variants in the above-mentioned genes and the individual differences in sevoflurane remains unknown. Thus, the purpose of this study was to explore whether genetic polymorphisms in pharmacokinetic and pharmacodynamic pathways explained the individual differences in sevoflurane susceptibility.…”

Fractal Properties of Heart Rate Dynamics: A New Biomarker for Anesthesia—Biphasic Changes in General Anesthesia and Decrease in Spinal Anesthesia

“…A biphasic reaction during induction of propofol anesthesia was also observed in spectral EEG analyses [ 41 , 42 ], i.e., a paradox excitation of EEG alpha and beta power even if unconsciousness was observed. Interestingly, nonlinear EEG methods do not follow a biphasic course but adequately reflect the hypnotic state [ 43 ].…”