The use of flumazenil in the management of acute drug poisoning — a review

Abstract

The popularity and widespread availability of benzodiazepines (BZD) has led to their frequent abuse in intentional drug poisoning. Although mortality from pure BZD overdose is usually small, in elderly, debilitated patients, or when BZD are combined with other CNS depressant drugs, morbidity increases significantly and outcome may be fatal. Drug overdose is therefore a medical emergency necessitating close observation and support of vital functions. Recently, the specific BZD antagonist flumazenil (Anexate) has become clinically available and much experience in its usefulness has accumulated. The present review summarizes a total of 30 studies and reports published to date, involving approximately 760 intoxicated patients. Flumazenil was evaluated both in prehospital use as well as in emergency rooms or in intensive care units. The age of patients ranged from 4-90 years and doses of flumazenil varied between 0.3-10 mg, approximately 1 mg being the most frequently used. All patients intoxicated with only BZD returned to full consciousness within minutes after the injection of flumazenil. When a mixture of BZD and other CNS depressants was abused, a range of effects was observed. This varied from no change to a return to full orientation, depending on the contribution of the BZD to the state of unconsciousness. Re-sedation occurred in about 65% of flumazenil treated patients, usually within 0.5-3 h after the first dose, the shorter interval being associated with mixed-drug poisoning. Repeated doses of the antagonist (0.2-2 mg), sometimes followed by continuous infusion (0.1-0.5 mg/h), were effective in maintaining patients fully oriented.(ABSTRACT TRUNCATED AT 250 WORDS)

Flumazenil improves cognitive and neuromotor emergence and attenuates shivering after halothane-, enflurane- and isoflurane-based anesthesia

“…A coded ampoule containing either 1.0 mg flumazenil (Hoffmann La Roche, Basle, Switzerland) or an equal volume (10 mL) of saline was administered at a rate of 2 mL·10 sec -1 when the patient began to awaken. We had shown previously, 13,16 that 1 mg flumazenil was better than 0.5 but of equal efficacy to 1.5 mg. Moreover, 1 mg flumazenil is well reported as being the most frequent maximal dose used to reverse BZD effects in humans.…”

“…23 Only few case reports have described unexplained antagonistic effects of flumazenil in cases of barbiturates-induced central nervous system depression. 16,24 In-vivo and in-vitro studies have concluded that barbiturates and BZD act at two distinct and separate sites of the GABA receptor complex. 25 Also, even if barbiturates might modulate GABA action to produce a pro-inhibitory effect, this would only occur when BZD are present at the binding site.…”

Benzodiazepine receptor antagonist (flumazenil) does not affect sleep-related breathing disorders

“…The dose of flumazenil used in the present study was derived from existing results of pharmacological and toxicological studies of the drug [17,34]. Several authors have reported that patients with pure benzodiazepines overdose require <1 mg flumazenil to fully reverse benzodiazepine-induced coma [35,36].…”

“…On the first or second study night, patients were randomly assigned to receive flumazenil or placebo (0.9% NaCl) in a cross-over, patientblinded design. The total amount of 2 mg flumazenil or placebo (20 ml 0.9% NaCl) was injected between 01:00 and 01:30 h. The mode of injection followed that described previously [17]: i.v. bolus of 0.3 mg flumazenil followed by 0.1 mg·min -1 .…”

Risks and Benefits of Therapy with Flumazenil (Anexate®) in Mixed Drug Intoxications

“…A review [ 11] of the published literature where flumazenil had been used to treat drug ODs revealed that, up to the end of 1989, 758 patients (double-blind studies = 387 patients, open-label administration/individual case [ 12]. Patients were allocated to one of two groups to receive either flumazenil or placebo in double-blind design.…”