Flumazenil expedites recovery from sevoflurane/remifentanil anaesthesia when administered to healthy unpremedicated patients

Karakosta, Agathi; Andreotti, B.; Chapsa, Chara; Pouliou, A.; Anastasiou, Emmanouil

doi:10.1097/eja.0b013e3283398ef9

Cited by 20 publications

(28 citation statements)

References 29 publications

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“…Our results are consistent with clinical studies that suggest flumazenil can reverse anesthesia even in the absence of benzodiazepines 35 . However, Schwieger and Szlam found that flumazenil had no effect on the anesthetic requirements of dogs undergoing inhaled anesthesia 51 and other studies show that flumazenil can potentiate the sedative qualities of propofol in patients undergoing minor surgery 9 .…”

Section: Discussionsupporting

confidence: 91%

“…The results from pharmacologic experiments of flumazenil on the GABA A receptor suggest that although antagonism of the GABA A receptor is possible with flumazenil, partial agonism can also be exhibited, consistent with the pharmacological profile of a competitive antagonist with weak intrinsic agonist activity. These in vitro findings might help explain some of the variability in emergence characteristics previously shown with flumazenil administration in humans 8,34,35 .…”

Section: Discussionmentioning

confidence: 53%

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

et al. 2016

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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.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 53%

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

et al. 2016

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“…Flumazenil, a benzodiazepine receptor antagonist, effectively reverses benzodiazepine-induced CNS depression via competitive inhibition at the GABA-A receptor-binding site [2][3][4][5][6][7][8]. Flumazenil has been beneficial for expediting patient recovery from anesthesia [9][10][11] and was previously studied in 519 patients at our center; of which, 15 were diagnosed with alcohol withdrawal [12].…”

Section: Introductionmentioning

confidence: 99%

Safety and Efficacy of Flumazenil for Reversal of Iatrogenic Benzodiazepine-Associated Delirium Toxicity During Treatment of Alcohol Withdrawal, a Retrospective Review at One Center

et al. 2014

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“…Different from the study where the injection was performed 30 minutes before the end of the anesthesia, there was a study in which flumazenil was injected just before the end of the operation to investigate the effect on recovery, but only the time taken to the appearance of the recovery parameters was measured, without measuring the BIS value [6]. Since BIS decreases in a dose-dependent manner with respect to various anesthetics such as propofol, sevoflurane, and midazolam among others, it allows for measurement of the depth of anesthesia with these anesthetics [24], and is useful for measuring the degree of awareness after general anesthesia [25].…”

Section: Discussionmentioning

confidence: 99%

“…For this reason, flumazenil is used for the purpose of antagonism in general anesthesia when a benzodiazepine is used [4], but recently, a few studies have been performed testing the effect of flumazenil on recovery from general anesthesia in which no benzodiazepines were used. For example, there have been reports demonstrating a positive effect of flumazenil injection on recovery from general anesthesia that did not include benzodiazepine medication [5,6]. Additionally, a few studies have reported on the effect of inhalation anesthetics, including sevoflurane, on the GABA-A receptor [7-9].…”

Section: Introductionmentioning

confidence: 99%

Effect of flumazenil on recovery from anesthesia and the bispectral index after sevoflurane/fentanyl general anesthesia in unpremedicated patients

Kim

Lee

Kim

et al. 2012

Korean J Anesthesiol

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BackgroundBenzodiazepines have a hypnotic/sedative effect through the inhibitory action of γ-aminobutyric acid type A receptor. Flumazenil antagonizes these effects via competitive inhibition, so it has been used to reverse the effect of benzodiazepines. Recently, flumazenil has been reported to expedite recovery from propofol/remifentanil and sevoflurane/remifentanil anesthesia without benzodiazepines. Endogenous benzodiazepine ligands (endozepines) were isolated in several tissues of individuals who had not received benzodiazepines.MethodsForty-five healthy unpremedicated patients were randomly allocated to either flumazenil or a control groups. Each patient received either a single dose of 0.3 mg of flumazenil (n = 24) or placebo (n = 21). After drug administration, various recovery parameters and bispectral index (BIS) values in the flumazenil and control groups were compared.ResultsMean time to spontaneous respiration, eye opening on verbal command, hand squeezing on verbal command, extubation and time to date of birth recollection were significantly shorter in the flumazenil group than in the control group (P = 0.004, 0.007, 0.005, 0.042, and 0.016, respectively). The BIS value was significantly higher in flumazenil group than in the control group beginning 6 min after flumazenil administration.ConclusionsAdministration of a single dose of 0.3 mg of flumazenil to healthy, unpremedicated patients at the end of sevoflurane/fentanyl anesthesia without benzodiazepines resulted in earlier emergence from anesthesia and an increase in the BIS value. This may indicate that flumazenil could have an antagonistic effect on sevoflurane or an analeptic effect through endozepine-dependent mechanisms.

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Flumazenil expedites recovery from sevoflurane/remifentanil anaesthesia when administered to healthy unpremedicated patients

Cited by 20 publications

References 29 publications

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

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

Safety and Efficacy of Flumazenil for Reversal of Iatrogenic Benzodiazepine-Associated Delirium Toxicity During Treatment of Alcohol Withdrawal, a Retrospective Review at One Center

Effect of flumazenil on recovery from anesthesia and the bispectral index after sevoflurane/fentanyl general anesthesia in unpremedicated patients

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