Effects of γ-Aminobutyric Acid Type A Receptor Modulation by Flumazenil on Emergence from General Anesthesia. (July 2016)

• Record Type: Journal Article
• Authors: Safavynia, Seyed A.; Keating, Glenda; Speigel, Iris; Fidler, Jonathan A.; Kreuzer, Matthias; Rye, David B.; Jenkins, Andrew; García, Paul S.
• Is Part Of: Anesthesiology. Volume 125:Number 1(2016)
• Publication Date: 2016-07
• Subjects: Anesthesiology -- Periodicals; Anesthetics -- Periodicals; Anesthesia -- Periodicals; 617.9605
• DOI: 10.1097/ALN.0000000000001134
• Languages: English
• ISSNs: 0003-3022

Abstract

Abstract : Background: Transitions into conscious states are partially mediated by inactivation of sleep networks and activation of arousal networks. Pharmacologic hastening of emergence from general anesthesia has largely focused on activating subcortical monoaminergic networks, with little attention on antagonizing the γ-aminobutyric acid type A receptor (GABAA R). As the GABAA R mediates the clinical effects of many common general anesthetics, the authors hypothesized that negative GABAA R modulators would hasten emergence, possibly via cortical networks involved in sleep. Methods: The authors investigated the capacity of the benzodiazepine rescue agent, flumazenil, which had been recently shown to promote wakefulness in hypersomnia patients, to alter emergence. Using an in vivo rodent model and an in vitro GABAA R heterologous expression system, they measured flumazenil's effects on behavioral, neurophysiologic, and electrophysiologic correlates of emergence from isoflurane anesthesia. Results: Animals administered intravenous flumazenil (0.4 mg/kg, n = 8) exhibited hastened emergence compared to saline-treated animals (n = 8) at cessation of isoflurane anesthesia. Wake-like electroencephalographic patterns occurred sooner and exhibited more high-frequency electroencephalography power after flumazenil administration (median latency ± median absolute deviation: 290 ± 34 s) compared to saline administration (473 ± 186 s; P = 0.042). Moreover, in flumazenil-treated animals, there was a decreased impact on postanesthesia sleep. In vitro experiments in human embryonic kidney-293T cells demonstrated that flumazenil inhibited isoflurane-mediated GABA current enhancement (n = 34 cells, 88.7 ± 2.42% potentiation at 3 μM). Moreover, flumazenil exhibited weak agonist activity on the GABAA R (n = 10 cells, 10.3 ± 3.96% peak GABA EC20 current at 1 μM). Conclusions: Flumazenil can modulate emergence from isoflurane anesthesia. The authors highlight the complex role GABAA Rs play in mediating consciousness and provide mechanistic links between emergence from anesthesia and arousal. Abstract : Flumazenil had a modest effect on accelerating emergence from isoflurane anesthesia. Prolongation of sleep time in the first day after isoflurane anesthesia was significantly reduced by flumazenil. The data suggest that inhibition of γ-aminobutyric acid type A receptors can not only hasten emergence but can mitigate postanesthesia sleep disturbances.