OBJECTIVES: To assess the efficacy, usefulness, safety, and dosages of 
flumazenil required when flumazenil is used in the diagnosis of 
benzodiazepine-induced coma (vs. other drug-induced coma), and to reverse or 
prevent the recurrence of unconsciousness.
DESIGN: A two-phase study: a controlled, randomized, double-blind study followed 
by a prospective, open study.
SETTING: An 800-bed, teaching, university-affiliated hospital.
PATIENTS: Unconscious patients (n = 110) suspected of benzodiazepine overdose, 
graded 2 to 4 on the Matthew and Lawson coma scale, were treated with 
flumazenil, the specific benzodiazepine receptor antagonist. The first 31 
patients were studied in a double-blind fashion, while the rest of the patients 
were given flumazenil according to an open protocol. INTERVENTIONS; All patients 
received supplemental oxygen; endotracheal intubation was performed, and 
synchronized intermittent mandatory ventilation was initiated whenever it was 
deemed necessary. A peripheral intravenous cannula was inserted, as were 
indwelling arterial and urinary bladder catheters. Blood pressure, 
electrocardiogram, respiratory rate, end-tidal CO2, and core temperature were 
continuously monitored. The first 31 double-blind patients received either 
intravenous flumazenil (to a maximum of 1 mg) or saline, while the rest of the 
patients were given flumazenil until either regaining consciousness or a maximum 
of 2.5 mg was injected. Patients remaining unconscious among double-blind 
patients or those patients relapsing into coma after the first dose were later 
treated in the open phase of the study. Treatment continued by boluses or 
infusion as long as efficacious.
MEASUREMENTS AND MAIN RESULTS: Fourteen of 17 double-blind, flumazenil-treated 
patients woke after a mean of 0.8 +/- 0.3 (SD) mg vs. one of 14 placebo patients 
(p < .001). Seventy-five percent of the aggregated controlled and uncontrolled 
patients awoke from coma scores of 3.1 +/- 0.6 to 0.4 +/- 0.5 (p < .01) after 
the injection of 0.7 +/- 0.3 mg of flumazenil. These patients had high 
benzodiazepine serum blood concentrations. Twenty-five percent of the patients 
did not regain consciousness. These patients had very high serum concentrations 
of nonbenzodiazepine drugs. Sixty percent of the responders who had primarily 
ingested benzodiazepines remained awake for 72 +/- 37 mins after flumazenil 
administration; 40% relapsed into coma after 18 +/- 7 mins and various central 
nervous system depressant drugs were detected in their blood in addition to 
benzodiazepines. Seventy-one percent of the patients had ingested tricyclic 
antidepressants. Seventy-eight percent of the responders were continually and 
efficaciously treated for < or = 8 days. Fourteen (25%) of the intubated 
patients were extubated safely while 12 patients, who had shown increased 
respiratory insufficiency, resumed satisfactory respiration after flumazenil 
injection. Five cases of transient increase in blood pressure and heart rate 
were encountered. There were 27 mildly unpleasant "waking" episodes, such as 
anxiety, restlessness, and aggression, but no patient had benzodiazepine 
withdrawal signs, convulsions, or dysrhythmia, most noticeably absent in 
tricyclic antidepressant-intoxicated patients.
CONCLUSIONS: Flumazenil is a valid diagnostic tool for distinguishing pure 
benzodiazepine from mixed-drug intoxication or nondrug-induced coma. Flumazenil 
is effective in preventing recurrence of benzodiazepine-induced coma. 
Respiratory insufficiency is reversed after its administration. Flumazenil is 
safe when administered cautiously, even in patients with coma caused by a mixed 
overdose of benzodiazepine plus tricyclic antidepressants.