Absence of Agonist Effects of High-Dose Flumazenil on Ventilation and Psychometric Performance in Human Volunteers

Flumazenil, a specific benzodiazepine antagonist, reverses sedative and respiratory depressant effects of benzodiazepines. We determined whether a large dose of flumazenil, injected alone, induces respiratory depression or alteration of psychomotor performance. After informed consent, eight healthy volunteers participated at three different sessions1) flumazenil (0.1 mg/kg) (a dose 7–15 times the clinically recommended dose) injected intravenously over a 5-min period, followed by placebo (NaCl 0.9%); 2) flumazenil at the same dose and injection rate as in Session 1, followed by midazolam (0.1 mg/kg) injected over 5 min; and 3) placebo followed by midazolam at the same dose as above and administered over 5 min. All drug combinations were administered in a randomized and double-blind manner. Tidal volume, respiratory frequency, minute ventilation, and mean inspiratory flow were continuously measured from 15 min before until 120 min after drug injection by noninvasive on-line data acquisition methods. Psychometric performance was evaluated 15 min before the first drug and 15 min after administration of the second drug. During the placebo-midazolam session, tidal volume (−40%), minute ventilation (−25%), and inspiratory flow (−25%) were significantly (P < 0.01) decreased compared both with baseline and with the other two sessions, and psychometric performance was significantly (P < 0.01) altered; in contrast, there was no significant change in any of the measured respiratory or psychometric variables during the flumazenil-placebo or flumazenil-midazolam sessions. We conclude that flumazenil, administered at about 10 times the clinically recommended dose, has no agonist effects on resting ventilation or psychomotor performance in normal subjects.