Effects of gamma-Aminobutyric Acid Type A Receptor Modulation by Flumazenil on Emergence from General Anesthesia

• Type of Material: Article
• Authors: Seyed A. Safavynia, Emory University; Glenda Keating, Emory University; Iris Speigel, Emory University; Jonathan A. Fidler, Emory University; Matthias Kreuzer, Emory University; David Rye, Emory University; Andrew Jenkins, Emory University; Paul Garcia, Emory University
• Language: English
• Date: 2016-07-01
• Publisher: LIPPINCOTT WILLIAMS & WILKINS
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: Copyright © 2016, the American Society of Anesthesiologists, Inc.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1097/ALN.0000000000001134
• Title of Journal or Parent Work: ANESTHESIOLOGY
• Volume: 125
• Issue: 1
• Start Page: 147
• End Page: 158
• Grant/Funding Information: This work was supported from Departmental Resources, the James S. McDonnell Foundation (220020346 to PSG), and a VA Career Development Award (BX001677 to PSG).
• Keywords: Anesthesiology; ELECTROENCEPHALOGRAM; ISOFLURANE ANESTHESIA; PROPOFOL; GABA(A) RECEPTORS; Science & Technology; Life Sciences & Biomedicine; METHYLPHENIDATE; EYE-MOVEMENT SLEEP; UNPREMEDICATED PATIENTS; RECOVERY; RO 15-1788; VOLATILE ANESTHETICS
• Research Categories: Health Sciences, Medicine and Surgery

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 (GABAAR). As the GABAAR mediates the clinical effects of many common general anesthetics, the authors hypothesized that negative GABAAR 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 GABAAR 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 GABAAR (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 GABAARs play in mediating consciousness and provide mechanistic links between emergence from anesthesia and arousal.