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



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.



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).



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.
From the Neuroanesthesia Laboratory, Atlanta VA Medical Center/Emory University, Atlanta, Georgia (S.A.S., G.K., I.S., J.A.F., M.K., P.S.G.); Department of Anesthesiology, Weill Cornell Medical College, New York, New York (S.A.S.); Department of Anesthesiology (S.A.S., G.K., J.A.F., M.K., A.J., P.S.G.), Neuroscience Program (I.S., D.B.R., A.J., P.S.G.), and Department of Neurology (G.K., D.B.R.), Emory University, Atlanta, Georgia.
Seyed A
SA
Safavynia
Glenda
G
Keating
Iris
I
Speigel
Jonathan A
JA
Fidler
Matthias
M
Kreuzer
David B
DB
Rye
Andrew
A
Jenkins
Paul S
PS
García
D061605:Administration, Intravenous; D000762:Anesthesia Recovery Period; D000769:Anesthesia, Inhalation; D018685:Anesthetics, Inhalation / Q000494:pharmacology; D000818:Animals; D001143:Arousal / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D004569:Electroencephalography / Q000187:drug effects; D004576:Electromyography / Q000187:drug effects; D005442:Flumazenil / Q000008:administration & dosage / Q000494:pharmacology*; D018757:GABA Modulators / Q000008:administration & dosage / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D007530:Isoflurane / Q000494:pharmacology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000096:biosynthesis / Q000187:drug effects* / Q000235:genetics; D012890:Sleep / Q000187:drug effects
D018685:Anesthetics, Inhalation; D018757:GABA Modulators; D011963:Receptors, GABA-A; D005442:Flumazenil; D007530:Isoflurane