flumazenil

Take Home Points

  • Flumazenil is indicated for the reversal of benzodiazepine overdose
  • The risk of seizure following the administration of flumazenil in the literature is very low in appropriately selected patients
  • Adult patients should receive doses of 0.2 mg every 1-2 minutes until arousable
  • Flumazenil associated seizures require treatment with alternative agents such as barbiturate

Benzodiazepine Overdose

Benzodiazepines are sedative-hypnotic drugs that cause central nervous system and respiratory depression. Intoxications with benzodiazepines are generally well-tolerated but can cause prolonged coma. Overall the complication rate with benzodiazepine overdose is low1. Most patients requiring intubation after benzodiazepine overdose have ingested multiple sedating substances. However, some patients with large benzodiazepine ingestions may benefit from flumazenil administration to avoid intubation.

In 2019, there were 58,430 total benzodiazepine exposures reported to US poison centers. Of those involving only benzodiazepines, 731 (1.25 %) patients experienced a major outcome and 11 (0.01 %) died.2

Flumazenil

Flumazenil is a benzodiazepine receptor antagonist FDA approved in 1992 for reversal of benzodiazepine overdose and postoperative sedation from benzodiazepine anesthetics. Flumazenil is a 1,4-benzodiazepine derivative that has a high affinity for the benzodiazepine binding site on the GABA receptor. It is a competitive antagonist at these receptors and reverses the effects of benzodiazepines. Reversal effects are typically seen within 1-2 minutes with a peak effect at 6-10 minutes3. Wakefulness may be transient and re-sedation can be observed due to its short clinical effect, however, this may be mitigated with the use of a continuous infusion.

Safety Considerations

The package insert of flumazenil contains a black box warning stating that the drug is associated with the occurrence of seizures, and states that providers should individualize the dosage and be prepared to manage seizures. Patients who may be at risk for seizures are those who have also ingested a proconvulsant medication (i.e. tricyclic antidepressants, bupropion, etc.), those with benzodiazepine dependence, and those who have a benzodiazepine prescribed for seizure disorder. 

Retrospective reviews conducted through the California Poison Control System from 1998 – 2008 looking at both pediatric and adult patients evaluated the safety of flumazenil use in benzodiazepine ingestions4,5. Of the observed adult patients, 13 patients (1.4%) experienced seizures and 32% of patients were also exposed to a proconvulsant. In their review of pediatric patients, only 1 patient was reported to have a seizure, and the medical toxicologist consulted on the case determined that the seizure was unrelated to the administration of flumazenil.

Although poison centers have an abundant database of toxicologic cases, reporting to poison centers is voluntary and does not capture all cases of overdoses and toxicity. In a review of 43 cases of flumazenil-related seizures reported to FDA, 42% occurred in patients who had also ingested tricyclic antidepressants6. An urban ED at a tertiary level I trauma center conducted a retrospective observational review of patients from 2007 to 2013 who were administered flumazenil for known or suspected benzodiazepine overdose7. A total of 49 patients were included in their study, and about 30% reported a co-ingestion of a proconvulsant medication. Patients were treated with doses of flumazenil ranging from 0.1-0.4 mg. No patients experienced seizures. In a retrospective review of ICU patients, 35 patients presenting with coma treated with flumazenil were sorted into low and high-risk groups8. The low-risk group were uncomplicated benzodiazepine exposures while the high-risk group included those with long-term benzodiazepine use, seizures, and antidepressant ingestion. In the high-risk group, 16% of patients had a seizure following flumazenil administration.

Dosing & Goals of Therapy

Guidance for the use of flumazenil can be taken from the literature. This includes avoiding administration of the drug in patients with co-ingestion of a proconvulsant medication, such as tricyclic antidepressants, cocaine, methylxanthines, isoniazid, propoxyphene, monoamine oxidase inhibitors, and bupropion or in patients with signs of a concurrent stimulant toxicity including hyperreflexia, mydriasis, and tachycardia.

Adults: 0.2 mg IV over 15 seconds, may be repeated every 1 to 2 minutes until the patient is arousable and protecting their airway.

Children: 0.01 mg/kg (maximum 0.2 mg), may be repeated if no response in 2-3 minutes, total dose not to exceed 1 mg or 0.05 mg/kg.

If seizures were to occur following the administration of flumazenil, understand that benzodiazepines will not work to abort seizures. Be prepared to utilize other agents such as phenobarbital. Patients may require intubation and sedation with propofol.

Conclusion

Common teaching is to avoid flumazenil in benzodiazepine ingestions because the risks significantly outweigh the benefits. However, in the literature, there have been minimal reports of seizures, and risk factors have been identified, primarily co-ingestion of a proconvulsant medication. Flumazenil should be considered in pediatric ingestions with respiratory insufficiency and acute adult overdose with respiratory insufficiency if no other proconvulsant medications are co-ingested.

References:

  1. Höjer J, Baehrendtz S. The effect of flumazenil (Ro 15-1788) in the management of self-induced benzodiazepine poisoning. A double-blind controlled study. Acta Med Scand. 1988;224(4):357-65. doi: 10.1111/j.0954-6820.1988.tb19595.x. PMID: 3142220.
  2. Gummin DD, Mowry JB, Beuhler MC, Spyker DA, Brooks DE, Dibert KW, Rivers LJ, Pham NPT, Ryan ML. 2019 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 37th Annual Report. Clin Toxicol (Phila). 2020 Dec;58(12):1360-1541. doi: 10.1080/15563650.2020.1834219. PMID: 33305966.
  3. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc.
  4. Kreshak AA, Tomaszewski CA, Clark RF, Cantrell FL. Flumazenil administration in poisoned pediatric patients. Pediatr Emerg Care. 2012 May;28(5):448-50. doi: 10.1097/PEC.0b013e3182531d0d. PMID: 22531190.
  5. Kreshak AA, Cantrell FL, Clark RF, Tomaszewski CA. A poison center's ten-year experience with flumazenil administration to acutely poisoned adults. J Emerg Med. 2012 Oct;43(4):677-82. doi: 10.1016/j.jemermed.2012.01.059. Epub 2012 Jul 4. PMID: 22766408.
  6. Spivey WH. Flumazenil and seizures: analysis of 43 cases. Clin Ther. 1992 Mar-Apr;14(2):292-305. PMID: 1611650.
  7. Nguyen TT, Troendle M, Cumpston K, Rose SR, Wills BK. Lack of adverse effects from flumazenil administration: an ED observational study. Am J Emerg Med. 2015 Nov;33(11):1677-9. doi: 10.1016/j.ajem.2015.07.031. Epub 2015 Jul 21. PMID: 26324010.
  8. Gueye PN, Hoffman JR, Taboulet P, Vicaut E, Baud FJ. Empiric use of flumazenil in comatose patients: limited applicability of criteria to define low risk. Ann Emerg Med. 1996 Jun;27(6):730-5. doi: 10.1016/s0196-0644(96)70191-9. PMID: 8644960.

Authors: Katie Dwyer, PharmD, PGY2 Emergency Medicine Pharmacy Resident, University of Utah & Michael Moss, MD, Medical Director, Utah Poison Control Center

 

 

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