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Three Part Question

In [patients with suspected overdose] is [a single dose of flumazenil] indicated to [safely diagnose benzodiazepine ingestion] ?

Clinical Scenario

An unresponsive young adult is brough to the emergency department. No history is available. Neurological examination reveals no focal abnormality and pupils are mid-size and reactive. Blood glucose is normal. You suspect an overdose and wonder whether flumazenil should be given to ascertain whether benzodiazepines are involved.

Search Strategy

Medline 1966-01/00 using the OVID interface.
[({exp flumazenil OR flumazenil.mp} AND {exp overdoses OR overdoses.mp OR exp poisoning OR poisoning.mp}) AND {exp diagnosis OR exp diagnosis, differential OR diagnosis.mp OR diagnos$.mp}] LIMIT to human AND english.

Search Outcome

45 papers found of which 39 were irrelevant or of insufficient quality. The remaining 6 papers are shown in the table.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Hojer J and Baehrendtz S. 1988. Sweden.	52 ICU patients with suspected drug overdose. Flumazenil vs placebo.	PRCT	Glasgow Coma Scale score	Significantly improved
			Side effect rate	No difference
Ritz R, et al. 1990. Switzerland.	23 ICU patients with suspected drug overdose. Flumazenil vs placebo.	PRCT	Conscious level	Significant improvement	7 overdoses were iatrogenic.
			Side effect rate	No significant side effects
Hojer J and Baehrendtz S. 1990. Sweden.	105 unconscious adults in whom a benzodiazepine overdose could not be excluded. Flumazenil vs placebo.	PRCT	Conscious level	Significant improvement
			Blood gas analysis	Significant improvement
			Side effect rate	No difference
Chern TL, et al. 1993. Taiwan.	61 adults with altered mental status in whom a benzodiazepine overdose could not be excluded.	Diagnostic test study	Benzodiazepine OD	Sensitivity 100% Specificity 42%	Gold standard (urinary assay for benzodiazepines) only possible in 44 cases.
Gueye PN, et al. 1996. USA.	35 adults admitted to ICU with suspected OD.	Retrospective survey.	Full wakening	7 cases	Retrospective.
			Partial wakening	6 cases
			Seizures	5 cases
Barnett R, et al. 1999. Canada.	43 adults with suspected OD and GCS < 13 (patients with known tricyclic antidepressant overdose were excluded). Flumazenil vs placebo.	PRCT	Glasgow Coma Scale score	Significantly improved

Comment(s)

All the studies are small. Most are PRCTs investigating the use of flumazenil in the management of benzodiazepine overdose. These show that flumazenil improves conscious level in patients who have taken overdoses. Significant adverse reactions occurred including fitting and transient increases in conscious level. The single diagnostic study gives some idea of the clinical utility of the test.

Clinical Bottom Line

The sensitivity of a single dose of flumazenil is high enough to allow failure to respond to be used as a SnNout for benzodiazepine overdose. The specificity is too low to allow it to be used to rule-in. The possibility of mixed overdose is a relative contraindication to using flumazenil.

References

1. Hojer J and 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.
2. Ritz R, Zuber M, Elsasser S, Scollo-Lavizzari G. Use of flumazenil in intoxicated patients with coma. A double-blind placebo-controlled study in ICU. Int Care Med 1990;16(4):242-7.
3. Hojer J, Baehrendtz S, Matell G, Gustafsson LL. Diagnostic utility of flumazenil in coma with suspected poisoning: a double blind, randomised controlled study. Br Med J 1990;301(6764):1308-11.
4. Chern TL, Hu SC, Lee CH Deng JF. Diagnostic and therapeutic utility of flumazenil in comatose patients with drug overdose. Am J Emerg Med 1993;11(2):122-4.
5. 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;27(6):730-5.
6. Barnett R, Grace M, Boothe P et al. Flumazenil in drug overdose: randomized placebo controlled study to assess cost effectiveness. Crit Care Med 1999;27(1):78-81.