THE EFFECT OF FLUMAZENIL ON MIDAZOLAM-INDUCED DEPRESSION OF THE VENTILATORY RESPONSE TO HYPOXIA DURING ISOHYPERCARBIA

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%, V(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 midazotam, the slope of the hypoxic ventilatory response curve (V(E) vs Sp(O2) decreased to 0.59 +/- 0.05 (xBAR +/- SE) times its premidazolam baseline; likewise, at Sp(O2) = 90%, minute ventilation (V(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). V(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.