The mechanism of action, pharmacokinetics, and use of flumazenil in 
benzodiazepine overdose, as well as in the management of other disease states, 
are reviewed. Flumazenil interacts at the central benzodiazepine receptor to 
antagonize or reverse the behavioral, neurologic, and electrophysiologic effects 
of benzodiazepine agonists and inverse agonists. Flumazenil has been studied for 
a variety of indications, including as an antidote to benzodiazepine overdose 
and for awakening of comatose patients, reversal of sedation after surgery and 
in critically ill patients, and management of hepatic encephalopathy. It 
improves the level of consciousness in patients with benzodiazepine overdose; 
however, resedation may occur within one to two hours after administration, so 
repeated doses or a continuous infusion may be required to maintain therapeutic 
efficacy. It appears to be effective in reversing sedation induced by midazolam 
or diazepam, and case reports suggest that it is useful in awakening comatose 
patients, although its clinical utility is questionable. Flumazenil has proved 
useful in reversing conscious sedation in critically ill patients, although 
response may be dose dependent. Animal models indicate that flumazenil is of 
some benefit in hepatic encephalopathy, but until well-designed clinical trials 
are conducted, hepatic encephalopathy must be considered an investigational 
indication for flumazenil. Adverse reactions include CNS manifestations, 
resedation, cardiovascular effects, seizures, and alterations in intracranial 
pressure and cerebral perfusion pressure. Hepatic dysfunction results in a 
substantial change in the pharmacokinetic profile of flumazenil; therefore, 
dosage adjustment may be necessary in patients with hepatic dysfunction or in 
those receiving medications that alter flumazenil metabolism. Flumazenil has 
been shown to reverse sedation caused by intoxication with benzodiazepines alone 
or benzodiazepines in combination with other agents, but it should not be used 
when cyclic antidepressant intoxication is suspected. It may be beneficial after 
surgery when benzodiazepines have been used as part of anesthesia and after a 
diagnostic or surgical procedure when assessment of CNS function is necessary.