The effect of flumazenil on midazolam-induced depression of the ventilatory response to hypoxia during isohypercarbia

Abstract

Background: 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. Methods: 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 Sp(O2) decreased to 70%. V̇(E) 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. Results: After midazolam, the slope of the hypoxic ventilatory response curve (V̇(E) vs. Sp(O2)) decreased to 0.59 ± 0.05 (x̄ ± SE) times its premidazolam baseline; likewise, at Sp(O2) = 90%, minute ventilation (V̇(E)90) 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). V̇(E)90 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). Conclusions: 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.