A Rising Tide Lifts All Boats: Increased Ventilation May Be Involved in Accelerated Recovery from Isoflurane Anesthesia after Flumazenil Administration

Recently, Safavynia et al.¹  demonstrated that flumazenil administration upon cessation of isoflurane anesthesia hastens the reappearance of the wake-like electroencephalographic activity in rats that is suggestive of accelerated emergence. They also demonstrated that flumazenil can inhibit enhancement of isoflurane-induced γ-aminobutyric acid (GABA) receptor—mediated activity in preparations of cultured human cells.¹  Hence, the authors are inclined to think that the observed speedier recovery is a direct consequence of flumazenil antagonism of GABA receptors in the brain that results in faster restoration of cortical activity. They exclude the possibility of improved lung ventilation after flumazenil administration as a potential cause for accelerated emergence based solely on similar respiratory rates observed in their pilot studies in control and flumazenil-treated groups, which, in our view, is not sufficient. By examining only a respiratory rate, the authors leave out another critical determinant of minute ventilation, tidal volume, which can be modulated positively by flumazenil.

In this regard, enhancement of function of GABA receptor type A (GABA_A) in brainstem respiratory neurons has a primary role in the respiratory depression caused by all volatile and most intravenous anesthetics.²  Under general anesthesia or non–rapid eye movement sleep, the excitatory input from the retrotrapezoid nucleus to the respiratory centers of the pontomedullary region is critical for breathing automaticity.³  Retrotrapezoid nucleus inactivation under anesthesia inhibits breathing markedly primarily via a decrease in tidal volume. In rats, local microdialytic application of the GABA_A receptor agonist muscimol decreases tidal volume and minute ventilation significantly,⁴  whereas application of the GABA_A receptor antagonist bicuculline increases them.⁵  In cats, potentiation of GABA_A receptors at the ventral surface of the medulla reduces tidal volume and arterial pressure, and these cardiorespiratory-depressant effects can be counteracted by flumazenil or bicuculline.⁶  In humans, flumazenil reverses the reduction in tidal volume and minute ventilation caused by midazolam effectively.^7–9  The fact that Safavynia et al.¹  have shown that flumazenil can counteract isoflurane-mediated enhancement of function of GABA_A receptors makes it very likely that its administration at cessation of isoflurane delivery could have resulted in improved ventilation and faster elimination of isoflurane through the lungs, thereby hastening postanesthetic recovery. Therefore, to exclude the possibility of improved ventilation as a reason for faster emergence after flumazenil administration, a more detailed look into cardiorespiratory parameters accompanied by blood gases analyses is required.

Additionally (and perhaps more importantly), to demonstrate unequivocally the ability of any candidate drug (including flumazenil) to reverse anesthesia, it should be administered during continuous administration of an anesthetic (and not at cessation of delivery of anesthetic gas as undertaken by the authors), and its ability to restore the righting reflex under these conditions must be demonstrated clearly. Such a protocol was introduced originally (and is used actively) by Chemali et al.,¹⁰  Solt et al.,¹¹  and Taylor et al.¹²  Without demonstrating the ability of flumazenil to restore the righting reflex during maintenance of the minimal concentration of isoflurane required for loss of consciousness, flumazenil cannot be called an “isoflurane-reversal agent” in the strict sense of the phrase. Simultaneously, demonstration of reappearance of the wake-like electroencephalographic activity after flumazenil administration during continuous administration of isoflurane would provide supportive (though not essential) evidence indicating the ability of flumazenil to reverse isoflurane anesthesia, and thus could be omitted if positioning of the electroencephalographic recording cable presented a problem for the authors.¹ 

The ability of flumazenil to reverse isoflurane anesthesia must be demonstrated, and the exact mechanism underlying a wake-promoting effect of flumazenil may prove to be different from that suggested by Safavynia et al.¹  Nevertheless, these factors in no way depreciate the practical importance of their findings, suggesting that flumazenil may become a valuable addition to the anesthesiologist’s armamentarium to facilitate postanesthetic recovery.

The authors declare no competing interests.