The Effects of Large-Dose Flumazenil on Midazolam-Induced Ventilatory Depression

Abstract

Flumazenil, a benzodiazepine antagonist, clearly reverses midazolam-induced sedation; reversal of ventilatory depression has not been as well demonstrated. Thirty-two subjects completed this randomized, double-blind, placebo-controlled study investigating the dose-response relationship and duration of flumazenil's effects on ventilatory depression and hypnosis induced by a continuous midazolam infusion. A computer-controlled infusion of midazolam was used to titrate the predicted midazolam plasma concentration to a level at which subjects were unresponsive to verbal commands and then to maintain that concentration. Measurements of ventilation and hypnosis were repeated at predetermined intervals: before midazolam administration, before test drug (flumazenil [1, 3, or 10 mg] or placebo), and 5, 30, 60, 120, and 180 min after test drug administration. Ventilation and tidal volume were measured during an isocapnic hyperoxia clamp at a PETCO2 of 46 mm Hg (VE46 and VT46, respectively). A pseudo-rebreathing technique was used to measure the hypercapnic ventilatory response (HCVR) slope and ventilation intercept at a PETCO2 of 58 mm Hg (VE58). Midazolam reduced VE46, VT46, and VE58, as well as hypnosis scores, in all test drug groups. The reduction in HCVR slope, however, was significant only when all 32 subjects were considered in aggregate. All three doses of flumazenil reversed hypnosis and also reversed the reduction in VE46 and VT46 within 5 min. The reduction in VE58, however, was reversed less consistently. Flumazenil's effect on VE46 and VT46 lasted at least 30 min after 1 mg and at least 60 min after 3 mg, paralleling the effect of these doses on hypnosis.(ABSTRACT TRUNCATED AT 250 WORDS)