The Effect of Flumazenil on Midazolam-induced Depression of the Ventilatory Response to Hypoxia during Isohypercarbia

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Abstract
While flumazenil reverses benzodiazepine-induced sedation, its ability to antagonize the ventilatory depressant effects of benzodiazepines has not been fully established. A randomized, double-blind study was conducted to determine whether flumazenil effectively reverses midazolam-induced depression of the hypoxic ventilatory response. Twelve healthy male volunteers received intravenous midazolam 0.12 +/- 0.01 mg.kg-1 followed by either flumazenil 1.0 mg or placebo. Hypoxic ventilatory response was measured using an isocapnic rebreathing technique: as Spo2 decreased to 70% VE and tidal volume were continuously recorded. Hypoxic response determinations were performed before and after midazolam, as well as 3, 30, 60, 120, and 180 min after flumazenil or placebo. After midazolam, the slope of the hypoxic ventilatory response curve (VE vs. SpO2) decreased to 0.59 +/- 0.05 (means +/- SE) times its premidazolam baseline; likewise, at Spo2 = 90%, minute ventilation (VE90) and tidal volume (TV90) decreased to 0.70 +/- 0.04 and 0.62 +/- 0.03 times baseline, respectively. Three minutes after flumazenil, the slope increased to 1.10 +/- 0.13 times baseline (P < 0.05 vs. postmidazolam), while following placebo, it was only 0.81 +/- 0.09 times baseline (P = NS vs. postmidazolam, P < 0.05 between treatments). VE90 and TV90, after flumazenil, increased to 1.45 +/- 0.15 and 1.27 +/- 0.09 times baseline, respectively (P < 0.05 vs. postmidazolam); these increases were significantly greater than the corresponding changes observed after placebo (P < 0.05 between treatments). It was concluded that, after sedation with midazolam, flumazenil causes a greater increase in hypoxic ventilatory response during isohypercarbic conditions than does placebo, and may, therefore, be useful in the treatment of midazolam-induced ventilatory depression.

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