title: Absence of agonist effects of high-dose flumazenil on ventilation and psychometric performance in human volunteers.
abstract: 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 sessions: 1) 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.
authors.affiliation: Department of Anaesthesiology, University Hospital of Geneva, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Forster
authors.forename: G
authors.initials: G
authors.lastname: Crettenand
authors.forename: C E
authors.initials: CE
authors.lastname: Klopfenstein
authors.forename: D R
authors.initials: DR
authors.lastname: Morel
mesh_terms: D000328:Adult; D003864:Depression, Chemical; D004311:Double-Blind Method; D005442:Flumazenil / Q000008:administration & dosage*; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008874:Midazolam / Q000008:administration & dosage; D011597:Psychomotor Performance / Q000187:drug effects* / Q000502:physiology; D012016:Reference Values; D012119:Respiration / Q000187:drug effects* / Q000502:physiology
chemical_list: D005442:Flumazenil; D008874:Midazolam