In this episode I’ll discuss the use of flumazenil.
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Shout out to “Pharmacy Ashkan” for suggesting this topic and sending many of the references that are linked in this episode.
Flumazenil is a competitive benzodiazepine receptor inhibitor. It is classified as an antidote to benzodiazepines.
Indications
The approved indications for flumazenil are:
– Reversal of conscious sedation and general anesthesia
– Suspected benzodiazepine overdose
The usual dose is 0.2 mg over 15-30 seconds, repeated every minute if needed. The onset of action is 1-2 minutes and the effect lasts for about 1 hour.
Controversy in benzodiazepine overdose
Many providers insist on not using flumazenil in benzodiazepine overdose scenarios due to the risk of precipitating acute benzodiazepine withdrawal and seizures.
This risk was described in case reports in the early 1990’s.
A 39-year-old woman who overdosed on benzodiazepines and tricyclic antidepressants was treated with flumazenil. The patient developed refractory seizures. Lorazepam, phenytoin, and phenobarbital were administered; however, seizures persisted for 4 hours, resulting in rhabdomyolysis, acute renal failure, severe brain damage, and death.
Another set of authors reported the occurrence of a generalized tonic-clonic seizure in a pediatric patient following the administration of flumazenil.
A review of 43 seizures reported with flumazenil identified that almost half of the cases involved co-ingestion of a pro-convulsant agent (such as a tricyclic antidepressant).
In addition to these human case reports, rat and dog data suggest the increased risk of seizure when flumazenil is given.
Is the seizure risk overblown?
In the present decade, some slightly more robust data has been presented suggesting the risk of seizure from flumazenil in benzodiazepine toxicity may be overstated.
A single center retrospective observational study of 23 adult patients administered flumazenil for known or suspected benzodiazepine overdose in the ED, revealed that no patient experienced a seizure.
A poison center published 10 years of data on flumazenil administration in acutely poisoned adults. Out of 904 patients, there were 13 patients with seizures and 1 death following flumazenil administration. 8 of the 13 patients who seized had also taken pro-convulsant medications.
Given this more recent data, it seems unlikely that flumazenil would be harmful when given to overdose patients, and that patients with pro-convulsant co-ingestion might be the only group to be concerned about.
What is flumazenil good for?
While it may be true that flumazenil is relatively safe, I am not impressed with the benefit that it is likely to offer benzodiazepine overdose patients.
Firstly, in the 10 year study by the poison center, only half of the patients who received flumazenil woke up afterwards.
Secondly, flumazenil might not reverse the respiratory depressive effects of benzodiazepines! A 1993 article concluded:
When benzodiazepine-induced respiratory depression was evident, the ability of flumazenil to reverse it was inconsistent and short-lived.
Benzodiazepine toxicity is easily treated with supportive care, so to use an antidote that doesn’t consistently work is not appealing to me, no matter how small the risk of seizure may be. If I’m going to use flumazenil in benzodiazepine toxicity, I want there to be a significant diagnostic value. Perhaps avoiding a lumbar puncture or other invasive procedure would make it worthwhile.
Summary
To summarize my opinion: In toxicology scenarios, flumazenil has little to no therapeutic value. Lack of benefit rather than risk of harm is my reason for almost never using flumazenil.
Other uses for flumazenil
There are a couple off-label considerations for flumazenil use:
A single center toxicology unit described using flumazenil to diagnose benzodiazepine delirium during the treatment of alcohol withdrawal syndrome.
Many published articles suggest that flumazenil may have some effect in clearing hepatic encephalopathy.
If you like this post, check out my book – A Pharmacist’s Guide to Inpatient Medical Emergencies: How to respond to code blue, rapid response calls, and other medical emergencies.
Excellent job and thanks again Joe! My good friend and colleague Chris Ho (Emergency Dept. MD) and I have extensively reviewed the flumazenil data and have subsequently used quite a bit of it in real world practice over the past several years. Thus l feel that based on the low risk of seizure with sole BZD ingestion the following are examples of cases when the use of Flumazenil would be warranted:
1. Symptomatic peds patient status post accidental BZD ingestion.
2. Post procedure. Grampa gets too much versed and is now over-sedated; flumazenil is then given to prevent fall or aspiration risk.
3. Now this one will not be reported in any article even though it happens in ‘real world’ scenarios across the nation. Pt is holding up a bed in a busy ED with a full lobby. Pt has ingested an overdose of BZD although not quite enough to need intubation. Cmax of ingested BZD has passed and we are monitoring the pt waiting for drug to clear. Psych eval is needed prior to discharge but pt unable to be evaluated. Flumazenil is given for Psych to clear patient, info to be obtained, then pt is safely discharged home with family. Again drug Cmax has passed and given the relatively large therapeutic index of BZDs when ingested without ETOH, pt can safely be discharged thereby opening up an ED Bed.
4. Diagnostic purposes (as you stated above).
Thank you Ash! I really appreciate you sending me the idea for the episode…keep ’em coming!!!
Joe