Flumazenil: Efficacy and Ethics
ABSTRACT & COMMENTARY
Source: Chudnofsky CR, et al. Safety and efficacy of flumazenil in reversing conscious sedation in the emergency department. Acad Emerg Med 1997;4:944-950.
The purpose of this study was to evaluate the safety and efficacy of reversing conscious sedation induced by a fentanyl and midazolam combination in ED patients undergoing short and painful procedures. The study design was multicenter, randomized, parallel, double-blinded, and placebo-controlled. Sedation and reversal were evaluated using an alertness scale administered at several time intervals. Patients were given a single dose of fentanyl and titrated doses of midazolam. Physician and patient satisfaction with the sedation and reversal medications were evaluated as well.
Patients receiving flumanzenil returned to baseline levels of alertness roughly 14 minutes sooner than those receiving placebo. However, those patients did not leave the ED any faster than the placebo group. Patients were satisfied with both regimens but did not show a preference for either placebo or flumazenil, and the same was true of physicians. Chudnofsky and associates conclude that flumanzenil is safe and efficacious in reversing midazolam-induced sedation in ED patients given fentanyl and midazolam to facilitate performance of short and painful procedures.
COMMENT BY GLENN C. FREAS, MD, JD
In accompanying editorials, two respected academicians in our specialty argue respectively that flumazenil is neither safe1 nor efficacious.2 This study and the editorials highlight both the clinical and ethical issues surrounding the use and marketing of flumazenil.
Flumazenil reverses benzodiazepine-induced sedation by binding to GABA receptors in the CNS. Its makers touted it as the naloxone of the 1990s. It is contraindicated in patients with cyclic antidepressant toxicity, patients with a known or suspected history of chronic benzodiazepine use, and patients with seizure disorders. Its use in poisoned patients appears to be relatively restricted, as most patients with benzodiazepine toxicity have a relatively benign course, and, if they do not, it is because of more serious concurrent drug toxicity. Goldfrank eloquently argues that the use of flumazenil is so limited and its potential drawbacks so significant, that it may be unethical to promote its use as a toxicologic antidote at all.1 Taking his skepticism about flumazenil research a step further, this study appears to be an effort to find some use for a drug that is running out of indications.
This study found a modest increase in rate of return to level of alertness in those patients receiving fentanyl and midazolam for conscious sedation. Because it is standard practice to observe patients for at least an hour after conscious sedation, Chudnofsky et al were unable to show that their statistically significant results had any clinical significance (i.e., an earlier discharge from the ED). It should be noted that the alertness scale that was used in the study (the main outcome measure) was developed for the purpose of this study and has not been validated in any other published studies. Another interesting point about the study design (and perhaps more concerning) is that participating physicians were encouraged to induce deep sedation with midazolam. A corollary is that repeat doses of analgesia excluded patients from the study population. Interestingly, and perhaps by no coincidence, only two patients were removed from the study because of extra doses of analgesia. I am troubled from an ethical standpoint about both of these points. Why was deep sedation encouraged? Although the initial dose of fentanyl was certainly therapeutic, was adequate analgesia withheld from any patients because of the preference for more midazolam? Coupled with Goldfrank’s concerns about flumazenil research, these points cannot be ignored.
Todd persuasively argues that the patient and physician satisfaction components of this study are faulty.2 The study lacked the power to detect differences in patient satisfaction with flumazenil, and the tools used to measure patient and physician satisfaction are prone to error.
My take on this literature is that flumazenil has little, if any, use in the setting of reversing conscious sedation. My experience with the short-acting agents we use is that patients are awake and ready to go within an hour. By the time prescriptions are written, the chart is completed, transportation arrangements are made, and any other details are taken care of, the patients are back to baseline. I have yet to use the drug in an overdose setting. In short, flumazenil is a drug with limited indications and use.
References
1. Goldfrank LR. Flumazenil: A pharmacologic antidote with limited medical toxicology utility, or . . . an antidote in search of an overdose? Acad Emerg Med 1997;4:935-936. Editorial.
2. Todd KH. A significant difference is one that makes a difference. Acad Emerg Med 1997;4:936-937. Editorial.
In the study by Chudnofsky et al, flumazenil was demonstrated to:
a. be an excellent drug in the management of patients with unknown poisoning.
b. lead to a faster discharge from the ED in patients who received it to reverse conscious sedation.
c. be safe when used in the setting of chronic benzodiazepine use.
d. return patients to baseline alertness faster than those who received placebo to reverse conscious sedation.
e. provide excellent conscious sedation for use in the ED in short, painful procedures.
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