Continuous Flumazenil: Perpetuating the Problem
ABSTRACT & COMMENTARY
Source: Chern C, et al. Continuous flumazenil infusion in preventing complications arising from severe benzodiazepine poisoning. Am J Emerg Med 1998;16:238-241.
Benzodiazepines are frequently taken in overdose, either as sole agents or in combination with other drugs, yet fatality and life-threatening complications are rare. The typical patient with benzodiazepine overdose presents with central nervous system depression ranging from sedation to deep coma, without any reliable change in vital signs or physical findings. When respiratory depression is present, it almost always indicates the presence of another toxin.
Flumazenil, a competitive benzodiazepine receptor antagonist, has proven to be safe and effective in reversing conscious sedation following short procedures such as endoscopy and cardioversion. It is, therefore, natural to consider this agent for reversal of benzodiazepine-induced sedation following intentional overdose. However, this concept has been extensively debated based on need and safety concerns.1 Since the incidence of complications from benzodiazepine overdose is so small, and the use of reversal agents does not change the length of stay, the need to chemically arouse patients is poorly justified. Furthermore, tolerant patients can develop life-threatening manifestations of benzodiazepine withdrawal, and patients intoxicated with tricyclic antidepressants, carbamazepine, and chloral hydrate have been noted to develop life-threatening dysrhythmias following flumazenil use.
Despite these arguments, the drug continues to be used in patients with unknown overdose. One recent article attempted to evaluate whether continuous flumazenil infusion improved the outcome of patients with benzodiazepine overdose. One hundred consecutive patients who responded to empiric flumazenil dosing were randomized to receive either a continuous infusion of flumazenil (0.5 mg/h for 5 hours) or serve as controls. Depth of coma (GCS), vital signs, and complications were observed over 24 hours.
Although patients who received the continuous infusion of flumazenil had higher GCS scores for the first 12 hours of observation, by 24 hours, the groups were identical. However, the need for intubation and the incidence of other complications were no different than the control group. On further analysis, Chern et al determined that patients who suffered complications tended to be older, had a greater incidence of underlying disease, had lower GCS scores prior to the first flumazenil bolus, and had incomplete response to flumazenil therapy.
COMMENT BY ROBERT HOFFMAN, MD
Thus Chern et al have eloquently proven the safety of benzodiazepine overdose. Since arousal from sedation had no effect on outcome, it may, therefore be concluded that outcome is determined by factors other than sedation, such as co-ingestants, prehospital events (aspiration), and other concomitant diseases and disorders. Furthermore, since flumazenil has expense and complication issues, the cost-benefit and risk-benefit analyses clearly do not favor routine use of this drug in overdose patients.
Flumazenil should never be used to reverse respiratory depression, even when it is clearly related to parenteral administration of benzodiazepines. In this setting, assisted ventilation is preferred, as flumazenil has been demonstrated to be slow and erratic. Similarly, flumazenil should not be used to determine the need for other tests such as CT scans and lumbar punctures, as benzodiazepine intoxicated patients are at risk for head trauma, and patients may take benzodiazepines in an attempt to medicate intracranial processes. This use increases risks and discourages good history taking and the performance of a thorough bedside neurologic examination, while offering little patient benefit.
Despite these limitations, there may be some role for the use of flumazenil in patients with acute overdose. While not well-defined, reversal may have the greatest use in children with ingestions of long-acting benzodiazepines. Here, the likelihood of tolerance or ingestion of other agents is small, and the emotional benefits of arousal and oral nutrition may outweigh the potential risks.
Reference
1. Hoffman RS, Goldfrank LR. JAMA 1995;274:562-569.
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