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The Edge: The Overstated Dangers of Droperidol
The Edge is a new monthly column from FlightBridgeED that features top EMS medical directors sharing current trends in critical care and prehospital medicine. In this installment FlightBridgeED Chief Medical Director Jeffrey Jarvis, MD, reviews droperidol.
Have you ever used droperidol? If you answered yes, congratulations: You’re old. If you answered, “What’s droperidol?” you’ve been deprived of an amazing drug. More important, your patients have been deprived of a safe and effective therapy.
This drug has been unavailable for the last decade or so but has recently become available again. Because it may soon appear in an ambulance near you, it’s worth reviewing what happened to it and why.
Before and After
Droperidol (Inapsine) is a first-generation antipsychotic in the butyrophenone class, similar to haloperidol. It is FDA-approved for treatment of postoperative nausea and vomiting at or below 2.5 mg IV or IM. Droperidol has been used extensively off-label around the world at doses up to 0.25 mg/kg for over 40 years for a variety of indications, including nausea, vomiting, migraines, and agitation.
In the “before” times, life was good. Droperidol was used effectively and frequently.1 One review of 74 peer-reviewed trials with more than 13,000 patients who received droperidol found no cases of ventricular arrhythmia or sudden cardiac death.2
Then a bad thing happened:3 In December 2001 the FDA issued a “black box warning”—an alert of potentially serious adverse reactions with a drug, in this case “reports of deaths associated with QT prolongation and torsades de pointes in patients treated with doses of droperidol above, within, and even below the approved range.” It recommended ECG monitoring before administration of droperidol and for 2–4 hours after, as well as avoiding it altogether for anyone with prolonged QT on their ECG.
After that life was not as good. Many hospital formularies and EMS agencies removed droperidol. Other medications were substituted, even if they weren’t as effective. Examples include ondansetron for nausea; haloperidol, midazolam, or ketamine for agitation; and metoclopramide or prochlorperazine for migraines. Sadly some of these medications, including ondansetron and haloperidol, also are associated with QT prolongation or have other black box warnings. Since the rapid drop-off in droperidol use, it actually became unavailable because of back order.
Early in 2019, though, a supplier started manufacturing it again, and this spring I was finally able to get a supply of droperidol back at my EMS agencies. So…should we use it? What should we make of the FDA’s black box warning? Is the risk overstated?
A Review of the Evidence
First let’s look at the potential issue: The FDA warning is primarily concerned with QT prolongation and torsades. Multiple articles have described the evidence used to justify this warning.3–6 They are based on 271 reports between November 1997 and December 2001 from the FDA’s MedWatch system. This is a system where anyone can report adverse events. No attempt is made to verify these reports.
On review of these reports, there were many duplicates and even triplicates, meaning the same case was reported multiple times by different people and counted as unique patients. After removing these duplicates there were 93 unique deaths. Many of these were reported from sources in Europe, where droperidol is used differently, at higher doses and in oral preparations for daily use. Fifty-two of these deaths involved doses greater than 10 mg, some in the 50–100-mg range. Twenty-two had no dose listed at all. For comparison, the typical dose of droperidol for vomiting is 2.5 mg, and the highest dose is 10 mg for violent agitation.
Most interesting, 71 adverse events and 55 deaths were all reported on the same day from Janssen Pharmaceuticals. Janssen was the European distributor for droperidol and the U.S. distributor for risperidone, a drug that competed in the U.S. with droperidol. The average time from occurrence to that report was over seven years. The actual link to droperidol was difficult to determine; many patients had multiple comorbid conditions or coingestions.
So it is probably an understatement to say there is skepticism about the degree to which the FDA may have overstated the dangers of droperidol. Again, much of its justification was based on case reports. So what does the literature say?
Hennepin Healthcare’s Jon Cole, MD, and colleagues published a retrospective observational study this year that reflected their experience with droperidol in the “before” times.7 They did a chart review of patients who presented to their urban emergency department between 1997 and 2001. They included anyone who received at least one dose of IV droperidol for any reason and had an ECG. They reported on the QTc (corrected) interval and calculated the incidence of torsades. There were 16,546 patients who received over 18,000 doses of droperidol. They broke these patients into two groups based on their acuity: noncritical and critical. Of the 15,374 noncritical patients, 16% had ECGs, and of the 1,172 critical patients, 35% had ECGs. They found no differences in the QTc intervals in ECGs obtained before and after droperidol in either group.
They also used a different technique (QT nomogram) to identify those at risk for torsades because of QT prolongation. They found 5% before administration and 4% after. Finally, they found only one case of torsades. This one patient was a cocaine “stuffer” who experienced torsades over 11 hours after being given a single dose of droperidol for agitation. Since the half-life of droperidol is around two hours, it is unlikely this was caused by droperidol. But assuming it was, this translated to an incidence of torsades from droperidol of 1/16,546, or 0.006%.
Australian docs Leonie Calver and Geoffrey Isbister reported on patients receiving droperidol as part of a prospective observational study in Australian emergency departments.8 This study was unique because they were able to obtain high-quality continuous 12-lead ECGs on patients who got droperidol for acute agitation. And they didn’t get small doses, either: Their protocol was 10 mg IM every 10 minutes. Their primary outcome was the proportion of patients with an abnormal QTc. They included 43 patients: 29 of them got a single 10-mg dose, 11 got a total of 20 mg, three got 30 mg, and three got 40 mg.
Of those 43 patients, only four had abnormal QTcs. Interestingly, they saw no dose response relationship: None of the patients with prolonged QT received 30 or 40 mg. Also, three of the four had normal QT intervals until many hours after droperidol administration, suggesting the prolongation may not have been from the droperidol. Most important, there were no cases of torsades despite close and continuous monitoring.
One of the strongest pieces of evidence supporting the use of droperidol comes from the DORM study (Droperidol vs. Midazolam for Violence and Acute Behavioral Disturbance).9 This was another study by Isbister and Calver. They randomized 91 patients with acute, undifferentiated agitation to receive either droperidol 10 mg IM, midazolam 10 mg IM, or a combination of droperidol 5 mg IM plus midazolam 5 mg IM.
Their primary outcome was the duration of violent behavior, defined as the length of time security staff were required (something that likely overestimates the time to behavioral control). They found no significant differences between the groups, but they did find a need for more sedation and more adverse events with midazolam.
Conclusion
So, we have a drug that effectively became unavailable after decades of safe use because of poor-quality case reports of adverse events. Since the FDA black box warning, literature has again confirmed the very low incidence of QT prolongation and the more clinically relevant torsades. This would strongly suggest using droperidol at the doses typically used in the U.S. is safe and effective.
My two EMS agencies used droperidol often when it was available. We had good success with it. I even left it in our protocols for several years after it became unobtainable, just in hopes the EMS supply gods would favor us with its return. Now that we can get it again, I’m putting it back in our protocols for several indications:
- Nausea/vomiting refractory to ondansetron: 2.5 mg IV/IM every 10 minutes as needed;
- Migraine: 2.5 mg IV/IM repeated once at 1.25 mg;
- Agitation/psychosis: 5 mg IM repeated once at 2.5 mg;
- Violent agitation: 10 mg IM, repeated once at 5 mg.
We will obtain a 12-lead ECG as soon as safely possible for doses above 2.5 mg. I’ll leave alternative treatments in place but hope we will use less metoclopramide, haloperidol, and ketamine. My main hope now is that droperidol remains available.
References
1. White PF. Droperidol: a cost-effective antiemetic for over thirty years. Anesth Analg, 2002; 95: 789–90.
2. Henzi I, Sondereggeer J, Tramer MR. Efficacy, dose-response, and adverse effects of droperidol for prevention of post-operative nausea and vomiting. Can J Anaesth, 2000; 47: 537–51.
3. Horowitz BZ, Bizovie K, Moreno R. Droperidol—Behind the Black Box Warning. Acad Emerg Med, 2002; 9: 615–8.
4. Kao LW, Kirk MA, Evers SJ, Rosenfeld SH. Droperidol, QT prolongation, and sudden death: What is the evidence. Ann Emerg Med, 2003; 41: 546–58.
5. Newman DH. Training the Mind, and the Food and Drug Administration, on Droperidol. Ann Emerg Med, 2015; 66: 243–5.
6. van Zwieten K, Mullins ME, Jang T. Droperidol and the black box warning. Ann Emerg Med, 2004; 43: 139–40.
7. Cole J, Lee S, Martel M, Smith S, Biros M, Miner J. The Incidence of QT Prolongation and Torsades des Pointes in Patients Receiving Droperidol in an Urban Emergency Department. West J Emerg Med, 2020 Jul; 21(4): 728–36.
8. Calver L, Isbister GK. High dose droperidol and QT prolongation: analysis of continuous 12‐lead recordings. Brit J Clin Pharm, 2014; 77: 880–6.
9. Isbister GK, Calver LA, Page CB, Stokes B, Bryant JL, Downes MA. Randomized controlled trial of intramuscular droperidol versus midazolam for violence and acute behavioral disturbance: the DORM study. Ann Emerg Med, 2010; 56: 392–401 e1.
Jeffrey L. Jarvis, MD, MS, EMT-P, FACEP, FAEMS, is the chief medical director for FlightBridgeED and cohost of the FlightBridgeED EMS Lighthouse Project podcast.
