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Three Part Question

In [a patient with suspected benzodiazepine and mixed drug overdose] does [administration of flumazenil cause improvement in consciousness level] and [does it cause clinically significant adverse effects]

Clinical Scenario

Young lady has presented with overdose to the emergency department. She is drowsy at presentation and is suspected to have a mixed overdose of medications. Her urine toxicology screen is positive for benzodiazepines.

Search Strategy

Medline using ovid interface and Pubmed
{exp [benzodiazepine] and [mixed drug overdose] and [flumazenil]}

42 papers were found

Search Outcome

42 papers were found out of which 37 were found irrelevant to all three study questions

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Adeline Su-Yin Ngo, Charles Rabind Anthony, Miny Samuel, Evelyn Wong, R. Ponampalam , 5 September 2006. Singapore	Adults and children in emergency department and intensive care with a low GCS and suspected drug overdose	Systematic review of randomized control trials	Improvement in consciousness level within 5 minutes of intervention	Flumazenil was found to reverse coma of suspected drug poisoning with a relative benefit of 4.45 (95% CI 2.65-7.45)	No uniformity in flumazenil dosage used Lack of uniformity in reporting GCS Total sample size of pooled sample could be insufficient to demonstrate risks
			Any major side effects (death, seizure, collapse and arrhythmia)	There was no statistical difference in major side effects between flumazenil and a placebo.
R Fantozzi, L Caramelli, M Barattini, P Bott, F Ledda, F moronic, S Peruzzi, AM Zorn, PF Mannaioni 1988	12 Comatosed patients with benzodiazepine overdose and 10 with mixed overdose	Prospective interventional study	Reversal of coma in patients with suspected benzodiapine and mixed drug overdoses	Drug Ro 15-1788 led to reversal of coma in patients with grade 1 coma	Small sample size was too small Lack of randomization or blinding
E.Gellerm P. Crome, M.D. Schaller, B Marchant, M Ectors, G. ScolloLavizzari 1991	Case reports of mixed drug overdoses from 4 countries between 1982-1986	Case series	Epidemiology of mixed drug overdoses with particular reference to overdoses with benzodiazepine and tricyclic antidepressants	flumazenil should not replace appropriate primary care
				flumazenil treatment is initiated
				hypoxemia, airway obstruction, severe hypotension and/or significant arrhythmias must be corrected before
				flumazenil should be used with caution in patients with a known history of seizure disorder before treatment and TCA overdose
				flumazenil should not be administered by inexperienced persons
Gregory P Haverkos Raymond P. DiSalvo Thomas E. Imhoff 1994	1 patient with mixed overdose of benzodiazepine and tricyclic antidepressants	Case report		Caution must be exercised when administering flumazenil to patients with risk factors	Low level of evidence.
				If flumazenil causes seizures, the patient would require subsequently high doses of benzodiazepines
William H. Spivey 1992	43 patients who developed seizures after administration of flumazenil	Case series	Analysis of 43 cases of seizures with flumazenil recorded to date	Seizures though not a direct effect of flumazenil could be related to reversal of benzodiazepine effect. Certain identifiable groups with high risk of seizure activity should be administered flumazenil with caution.

Comment(s)

Flumazenil has been found to improve the Glasgow coma score in patients with mixed overdose and there has been no significant difference in adverse effects between flumazenil and placebo. However, there have been several case reports demonstrating seizures in certain high risk groups which include patients with seizure disorder, tricyclic antidepressants overdose. Further studies are needed to evaluate if flumazenil would reduce interventions in emergency departments

Editor Comment

JB

Clinical Bottom Line

Flumazenil can be used in patients with suspected benzodiazepine and mixed drug overdose though the clinical significance of the drug is questionable. It should be used with caution in high risk groups (seizure disorder and tricyclic antidepressants overdose) and they can be suspected by QRS prolongation, acidosis and history. In these cases it might be safer to symptomatically treat the patients rather than fully reversing the effects of benzodiazepines.

References

1. 3. Adeline Su-Yin Ngo, Charles Rabind Anthony, Miny Samuel, Evelyn Wong, R. Ponampalam Should a benzodiazepine antagonist be used in unconscious patients presenting to the emergency department? Resuscitation 2007;74(1):27-37.
2. R Fantozzi, L Caramelli, M Barattini, P Bott, F Ledda, F moronic, S Peruzzi, AM Zorn, PF Mannaioni. Clinical experiences with Ro 15-1788 (Anexate) in benzodiazepine and mixed-drug overdoses Resuscitation 1988:16:S79-S82.
3. 5. E.Geller, P. Crome, M.D. Schaller, B Marchant, M Ectors, G. ScolloLavizzari. Risks and Benefits of Therapy with Flumazenil (Anexate) in Mixed Drug Intoxications. Eur Neurol 1991;31:241-250.
4. Gregory P. Haverkos, Raymond P. DiSalvo, Thomas E. Imhoff. Fatal Seizures after Flumazenil Administration in a Patient with Mixed Overdose The Annals of Pharmacotherapy 1994;28(12):1347-1349
5. Spivey. Flumazenil and seizures: analysis of 43 cases. Clin Ther 1992;14:292-305.