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

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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 (V̇E 46 and VT 46, 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 (V̇E58). Midazolam reduced V̇E46, VT46, and V̇E58, 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 V̇E 46 and VT 46 within 5 min. The reduction in V̇E58, however, was reversed less consistently. Flumazenil's effect on V̇E 46 and VT 46 lasted at least 30 min after 1 mg and at least 60 min after 3 mg, paralleling the effect of these doses on hypnosis. After 10 mg, however, V̇E 46 and VT 46 declined to placebo and midazolam control values by 120 min, whereas reversal of sedation lasted 154 ± 30 min. Midazolam plasma concentrations were similar among groups and constant throughout the study. Plasma flumazenil concentrations 5 min after administration were 10.4 ± 3.4, 37.8 ± 7.0, and 113 ± 22.7 ng/mL in the three dose groups, respectively. In the 10-mg dose group, plasma concentrations at 150 min (14.2 ± 3.6 ng/mL) were still greater than the 5-min concentrations in the 1-mg group, even though both hypnosis and ventilatory depression had returned. This could indicate the development of acute tolerance to flumazenil's effects. In this study, flumazenil 1.0 mg intravenously (IV) was sufficient to achieve full reversal of midazolam's effects on hypnosis and ventilation. Larger doses produced full acute effects and achieved longer durations but produced results consistent with the development of acute tolerance. The results at the 10-mg dose suggested discordance between the duration of hypnosis and ventilatory depression reversal.

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