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University of Massachusetts, Worcester, MA
To the Editor:
In their consideration of the cases on which the FDA warning on droperidol was based, Habib and Gan (1) used 1.25 mg as the threshold dose and reported 10 cases in which droperidol supposedly caused a severe adverse cardiac event. In my earlier article on the same subject (2), I used 10 mg as the threshold dose and described in detail the 19 cases in the FDA database alleging severe droperidol-induced cardiac toxicity. Even when the more liberal threshold of 10 mg is used, there is an alternate and more plausible explanation for the etiology of each of the described events.
There is no doubt that droperidol at larger doses can cause severe arrhythmias. In fact, if you are acutely psychotic, present to the emergency department of a European hospital, are given droperidol at doses of 25–100 mg, and are subsequently not monitored, you have cause for real worry. Many such cases are found within the FDA database and such cases are certainly what worried FDA officials. Conversely, droperidol given at the usual antiemetic doses is safe. A statement made by Hill et al. in 2000 (3) should still guide us today irrespective of what FDA might think about droperidol: "The use of 1.25 mg droperidol intravenously was associated with greater effectiveness, lower costs, and similar patient satisfaction compared with 0.625 mg droperidol intravenously and 4 mg ondansetron intrave- nously." There should thus be a threshold dose, e.g., 5 or 10 mg, beyond which the stipulations of the black-box warning would apply.
I believe our specialty has been too complacent in accepting FDA’s decision to not include a threshold dose in the black-box warning. In my article (2), I concluded by recommending that FDA "establish an independent ‘blue ribbon’ panel of anesthesiology and pharmacology experts to review independently the safety data on droperidol." If enough members of our specialty write FDA (and perhaps our Congressional representatives as well), FDA might conceivably be convinced to act on our collective requests.
References
Department of Anesthesiology, Duke University Medical Center, Durham, NC
In Response:
Thank you for the opportunity to respond to the comments of Dr. Chang et al and Dr. Dershwitz regarding our article (1).
We appreciate the position of the FDA as a regulatory agency and its concern regarding possible QTc prolongation and torsades de pointes following the administration of small-dose droperidol for PONV prophylaxis. We also agree that there are many confounding factors in the perioperative period. For instance, the following drugs, which are routinely used in anesthesia, are known to prolong the QTc interval: thiopentone, isoflurane, sevoflurane, succinyl-choline, neostigmine, atropine, and glycopyrrolate (2–6). Cardiac arrhythmias and QTc prolongation have also been reported following administration of the 5-HT3 receptor antagonists (ondansetron, dolasetron, and granisetron) (7). However, despite this fact and despite a number of case reports of life-threatening arrhythmias and myocardial ischemia following the administration of these agents (8–10), they continue to be used in everyday practice with no black box warning attached to them and without a need to perform a pretreatment 12-lead ECG or posttreatment 3 hours ECG monitoring.
There is no doubt that droperidol causes a dose-dependent prolongation of the QT interval. However, the evidence suggests that this effect is likely to be of significance following large doses of droperidol. Indeed, all the references quoted by Dr. Chang and colleagues as evidence of QT prolongation with droperidol involved large doses (0.1–0.25 mg/kg) of this drug (11–14). There is no evidence that small doses of droperidol (
1.25 mg) are associated with significant QT segment prolongation. Indeed, the volunteer FDA-sponsored study quoted by Dr. Chang, failed to show a difference between droperidol 0.625 mg and placebo regarding the effect on QTc. The 1.25 mg dose was not used in that study. It is important to note, however, that this study involved only eight subjects and was terminated prematurely (15).
In this era of evidence-based medicine and cost-effective medical practice, practitioners have to weigh the benefits and side effects profile of a given drug, based on the available information. We believe that there is very good evidence regarding the efficacy, safety, and cost-effectiveness of small-dose droperidol ( 1.25 mg) for PONV prophylaxis (16–19). Putting a black box warning on this drug deprives our patients the benefits of a very effective antiemetic agent and goes against the provision of cost-effective medical care. In agreement with Dr. Dershwitz, we urge the FDA to convene an independent expert panel to review this important issue.
References
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