QT prolongation with antiemetics

Review of Documented Cases:

Habib et al.

The FDA warning is based on 10 reported cases from 1997-2002 – these 10 cases were all with 1.25 mg or less, but in none of them could a definitive cause-effect relationship be described, and in five of them there were substantial confounding factors. Assuming that droperidol sales averaged 11 MM ampules per year, and that these events were truly related to droperidol, the authors estimated that the incidence of associated events was 1:150,000.

Smaller Studies

Charbit et al.

A small study compared QT prolongation with droperidol alone, ondansetron alone, and both combined. Both droperidol and ondansetron significantly prolonged QT interval as expected (droperidol>ondansetron), but when combined did not prolong QT significantly more than droperidol alone.

Chu et al.

Another small study (400 total patients, randomized, prospective, controlled) studied haloperidol plus dexamethasone on PONV versus placebo and droperidol alone in vaginal hysterectomy patients. Haloperidol plus dexamethasone produced the greatest reduction in PONV when compared to placebo, either drug alone, or droperidol alone. There was no difference in QT prolongation in the haloperidol plus dexamethasone vs. droperidol alone.

Nuttal et al.

Lastly, a retrospective study in Anesthesiology studied whether or not droperidol (low dose) administration increased the incidence of torsades during a 3 year period before and after the FDA placed the black box warning on the drug. They determined that there was no change in the incidence of torsades with the use of low dose droperidol versus none used. The incidence of torsades in droperidol exposure was found to be 1:16791, and the one incident may not have actually been due to droperidol.

5HT-3 antagonists

Known to cause QT prolongation, ex. ondansetron (Zofran), granisetron (Kytril), and dolasetron (Anzemet). These drugs have been reported to widen the QRS complex and prolong JT, QT, and PR intervals. Dolasetron (1.2-4mg/kg IV) can prolong QRS by 5-20% whereas Ondansetron has been shown to increase QT and JT intervals by an average of 2-5%. The QRS widening is likely due to blockade of sodium channels while the QT prolongation is caused by blocking potassium channels. In a study done with human myocytes, all of the drugs in this class where shown to block human cardiac Na+ channels probably by interacting with the inactivated state. This could lead to clinically relevant blockade, especially with high heart rates or depolarized/ischemic tissue, potentially leading to ventricular arrhythmias. The rank order of potency for Na+ blockade is granisetron>dolasetron>ondansetron. For blockade of the K+ channel (QT prolongation), the order of potency is ondansetron>granisetron>dolasetron.

PONV Guidelines

The Guidelines state that only moderate/high risk patients should receive PONV prophylaxis, and that these patients should receive combination therapy. Interesting, the ambulatory surgery Guidelines suggest haldol, which at 0.5-2 mg IM or IV has been shown on meta-analysis to reduce PONV with a NNT of 4-6; however, it does cause QTc prolongation as well. If not for the black box warning, the committee would have made droperidol the first choice.