Text version
How common is QT prolongation on droperidol—and more importantly, how often does that lead to torsades? The FDA issued a QT warning for droperidol in 2001. In the intervening years, have we come up with another treatment with clearly better benefit–risk ratios? If so, what is it?
Hi! Jim Phelps here for the Psychopharmacology Institute. The authors of a new network meta-analysis, Dr. Ian DeSouza and colleagues, all work in emergency departments, and they ask, what’s the best agent or combination for safe and rapid tranquilization? There have been some randomized trials, but very few are head-to-head comparisons. So, enter network meta-analysis. You’ll remember that this is a mathematical technique that allows us to make comparisons, albeit with caution, between agents that have never been studied head to head.
The authors found 11 studies of suitable precision, with 27 different arms between them. For example, a study might compare haloperidol with lorazepam or lorazepam alone. Another study might compare ziprasidone with placebo. Each of those arms is compared in this study with all the rest. Comparisons were possible between 11 agents. There is haloperidol and haloperidol with lorazepam, as well as midazolam alone and in combination with haloperidol or droperidol. There are fewer data on olanzapine alone and a few studies have ketamine as well.
So, what works the best? For effectiveness, the top 2 agents are intramuscular droperidol and ketamine. In this analysis, the combination of droperidol and midazolam was not more effective than droperidol alone. Remember that these are not true head-to-head randomized trials. Rather, they’re comparisons of trials, so patients may have differed. Acuity may have differed. Timing of administration may have differed. So, we can’t conclude, at least not firmly, that adding midazolam to droperidol adds no value.
On the risk side, I found this meta-analysis somewhat difficult to interpret. I jumped to a quick search for current information regarding QT prolongation with droperidol, and that suggests why. Incidence rates are all over the place. There’s a paper on 1,000 patients, of whom only 1.3% had prolongation and no cases of torsades. Additionally, there’s a pharmacy review suggesting that at doses for agitation, nearly all patients experienced prolongation, although torsades is recognized as rare. At a minimum, it’s clear that QT prolongation is dose related.
Also helpful are statements from the American Academy of Emergency Physicians in 2015 and the American College of Emergency Physicians in 2021, which both conclude that droperidol for agitation is superior to alternatives for efficacy and acceptably safe.
What did the authors of the network meta-analysis conclude? For efficacy, droperidol and intramuscular ketamine are the top candidates, but both carry a risk. Whereas droperidol carries the risk of QT prolongation, ketamine can cause enough sedation to require intubation for respiratory support.
In summary, this meta-analysis might be useful if your team is inclined to hark back to our practices before the 2001 FDA warning about droperidol. It’s not without risks, but neither are the alternatives. Of course, all of these risks must be compared with the risks posed by agitation itself to the patient, the medical team, and the care of other patients in the emergency department.
For more information, if you work in the ED or an inpatient unit, you’ll want to be familiar with Project BETA, where BETA stands for Best Practices in the Evaluation and Treatment of Agitation, published in 2020. It presents conclusions on a full range of practices and procedures, not just medications, and is linked here at the Psychopharmacology Institute.
Abstract
Background: Safe and effective tranquilization of the acutely agitated patient is challenging, and head-to-head comparisons of medications are limited. We aimed to identify the most optimal agent(s) for rapid tranquilization of the severely agitated patient in the emergency department (ED).
Methods: The protocol for systematic review was registered (PROSPERO; CRD42020212534). We searched MEDLINE, Embase, PsycINFO, and Cochrane Database/CENTRAL from inception to June 2, 2021. We limited studies to randomized controlled trials that enrolled adult ED patients with severe agitation and compared drugs for rapid tranquilization. Predetermined outcomes were: 1) Adequate sedation within 30 min (effectiveness), 2) Immediate, serious adverse event – cardiac arrest, ventricular tachydysrhythmia, endotracheal intubation, laryngospasm, hypoxemia, hypotension (safety), and 3) Time to adequate sedation (effect onset). We extracted data according to PRISMA-NMA and appraised trials using Cochrane RoB 2 tool. We performed Bayesian network meta-analysis (NMA) using a Markov Chain Monte Carlo method with random-effects model and vague prior distribution to calculate odds ratios with 95% credible intervals for dichotomous outcomes and frequentist NMA to calculate mean differences with 95% confidence intervals for continuous outcomes. We assessed confidence in results using CINeMA. We used surface under the cumulative ranking (SUCRA) curves to rank agent(s) for each outcome.
Results: Eleven studies provided data for effectiveness (1142 patients) and safety (1147 patients). Data was insufficient for effect onset. The NMA found that ketamine (SUCRA = 93.0%) is most likely to have superior effectiveness; droperidol-midazolam (SUCRA = 78.8%) is most likely to be safest. There are concerns with study quality and imprecision. Quality of the point estimates varied for effectiveness but mostly rated “very low” for safety.
Conclusions: Available evidence suggests that ketamine and droperidol have intermediate effectiveness for rapid tranquilization of the severely agitated patient in the ED. There is insufficient evidence to definitively determine which agent(s) may be safest or fastest-acting. Further, direct-comparison study of ketamine and droperidol is recommended.
Keywords: Agitation; Delirium; Network meta-analysis; Sedation; Tranquilization.
Download PDF and other files
Reference
deSouza, I. S., Thode Jr, H. C., Shrestha, P., Allen, R., Koos, J., & Singer, A. J. (2022). Rapid tranquilization of the agitated patient in the emergency department: A systematic review and network meta-analysis. The American Journal of Emergency Medicine, 51, 363-373.
Related References
- American College of Emergency Physicians. Policy Statement: Use of droperidol in the emergency department, 2021. https://www.acep.org/globalassets/new-pdfs/policy-statements/use-of-droperidol-in-the-emergency-department.pdf
- Roppolo, L. P., Morris, D. W., Khan, F., Downs, R., Metzger, J., Carder, T., … & Wilson, M. P. (2020). Improving the management of acutely agitated patients in the emergency department through implementation of Project BETA (Best Practices in the Evaluation and Treatment of Agitation). Journal of the American College of Emergency Physicians Open, 1(5), 898-907.
