FLUMAZENIL ANTAGONISM OF MIDAZOLAM-INDUCED VENTILATORY DEPRESSION

Flumazenil, a benzodiazepine antagonist, reliably reverses midazolam-induced sedation; however, its effect on respiratory depression has not been established completely. Twelve healthy volunteers received sufficient midazolam (0.13 +/- 0.01 mg.kg-1 mean +/- SE) to render them unresponsive to verbal command; they then received flumazenil 1.0 mg or placebo (flumazenil vehicle) in a randomized, double-blind fashion. Ventilatory drive was measured before and after administration of midazolam, as well as 3, 30,60, and 120 min after administration of flumazenil or placebo. Seven to 30 days later, the study was repeated, with subjects receiving placebo or flumazenil (whichever they had not received during their first trial). Midazolam caused significant decreases in the slope of the CO2 response (-29 +/- 5%; P < 0.005); minute ventilation (V(E)) at end-tidal CO2 tension (PET(CO2)) = 46 mmHg (-28 +/- 4%; P < 0.001), and tidal volume at PET(CO2) = 46 mmhg (-44 +/- 4%; P < 0.005). Three minutes after intravenous administration of flumazenil 1.0 mg, V(E)46 and tidal volume increased to 108 +/- 6%, and 105 +/- 6%, respectively, of their premidazolam values; at the same time after administration of placebo, V(E)46 and tidal volume remained significantly depressed (between groups, P < 0.005 for each variable). Thirty minutes later, these variables did not differ between groups, probably because the effects of flumazenil and midazolam were diminishing. Neither flumazenil nor placebo affected the slope of the CO2 response, which remained significantly (P < 0.05) less than premidazolam values for 2 h after both treatments, this variable never differed between groups. By virtue of its ability to reverse some components of midazolam-induced ventilatory depression, flumazenil may help improve resting ventilation in patients who have received midazolam.