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

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.

Association of electroencephalogram trajectories during emergence from anaesthesia with delirium in the postanaesthesia care unit: an early sign of postoperative complications

“…Recent interest in anaesthesia reversal agents represents a potentially promising clinical research strategy. 37,60…”

Paradoxical Emergence

“…39 Although general anesthetics are powerful and effective tools to reversibly modulate levels of consciousness, prolonged or abnormal recovery from general anesthesia can have significant consequences. 40–42 Although anesthesiologists have pharmacological tools to antagonize specific drugs acting at specific receptors (e.g., benzodiazepines), 43 only recently has research focused on reversing anesthetic effects by promoting arousal systems. 1–3,12,4–6,8 This has been typically accomplished by either pharmacological manipulation using catecholamine reuptake inhibitors, 3,12 dopamine agonists, 4 central nervous system stimulants, 13 and nicotine, 1,3,12,4,6 or by electrical stimulation of specific brain regions such as the ventral tegmental area 5 or parabrachial nucleus.…”

Infrared pupillometry helps to detect and predict delirium in the post-anesthesia care unit

“…Another point to be considered in future studies would be the investigation of appropriate treatment strategies for PACU-D. Recent interest in anesthesia reversal agents represents a potentially promising clinical research strategy [50,51].…”