The Safety and Effectiveness of Droperidol for Sedation of Acute Behavioral Disturbance in the Emergency Department

doi:10.1016/j.annemergmed.2015.03.016

Annals of Emergency Medicine

Volume 66, Issue 3, September 2015, Pages 230-238.e1

https://doi.org/10.1016/j.annemergmed.2015.03.016 Get rights and content

Study objective

We investigate the safety and effectiveness of droperidol for sedation of acute behavioral disturbance in the emergency department (ED).

Methods

This was a prospective observational study in 6 EDs (August 2009 to April 2013). Adult patients requiring parenteral sedation for acute behavioral disturbance received droperidol 10 mg. If this did not sedate the patient within 15 minutes, further sedation was allowed but droperidol 10 mg was recommended as part of a sedation protocol. The primary outcome was the proportion of patients with an abnormal QT interval, defined by the at-risk line on the QT nomogram. Secondary outcomes were effectiveness determined by the time to sedation measured on the Sedation Assessment Tool, use of additional sedation, adverse events, and injury to staff or patients.

Results

There were 1,009 patients with an ECG performed within 2 hours of droperidol administration, with a median dose of 10 mg (interquartile range [IQR]10 to 17.5 mg). Thirteen of the 1,009 patients had an abnormal QT (1.3%; 95% confidence interval 0.7% to 2.3%), but 7 of these had another cause attributed for prolonged QT (methadone, escitalopram, amiodarone, or preexisting). In 1,403 patients sedated with a median total dose of droperidol of 10 mg (IQR 10 to 20 mg), the median time to sedation was 20 minutes (IQR 10 to 30 minutes) and 97% were sedated within 120 minutes. Additional sedation was required for 435 patients (31.0%; 95% confidence interval 28.6% to 33.5%). Adverse events occurred in 70 patients (5%) and oversedation without complications in 109 (8%), the latter more common for patients receiving benzodiazepines as additional sedation (16/109 [15%]). There were no cases of torsades de pointes. Injuries occurred in 34 staff members and 4 patients.

Conclusion

The study supports the use of high-dose droperidol as a safe sedating agent for patients with acute behavioral disturbance in the ED. There is no evidence of increased risk for QT prolongation with the doses used in this study.

Introduction

Acute behavioral disturbance is a regular occurrence in emergency departments (EDs) worldwide, and it is disruptive and often dangerous for staff and patients. There are numerous causes of acute behavioral disturbance in the ED, the most common being drug and alcohol intoxication, mental illness, and deliberate self-harm.¹ The goal in the management of patients with acute behavioral disturbance is to ensure safety for the patient, staff, and other patients. When verbal de-escalation fails and oral medication is refused or ineffective, parenteral medication is the only option to sedate the patient to enable safe assessment, diagnosis, and treatment. All parenteral medication used for rapid sedation carries inherent risk, and there is little consensus on which drug is optimal. The ideal drug would have a rapid onset and offset, and a low adverse event profile.² Benzodiazepines and antipsychotics, as single agents or in combination, have been the 2 major drug groups used for sedating patients with acute behavioral disturbance. The lack of consensus has led to vastly differing clinical practice, with potentially dangerous cumulative doses being administered and high adverse event rates.³

Editor’s Capsule Summary

What is already known on this topic

Although previously popular, the emergency department (ED) administration of droperidol substantially waned after the Food and Drug Administration issued a controversial black box warning in 2001 about potential QT prolongation.

What question this study addressed

Does high-dose droperidol cause QT prolongation or torsades de pointes?

What this study adds to our knowledge

In this observational study of 1,009 ED adults receiving a median of 10 mg of droperidol for acute behavioral disturbance, QT prolongation was observed in just 1.3%, of whom half had other reasons for such prolongation. There were no cases of torsades de pointes or other serious adverse events.

How this is relevant to clinical practice

Droperidol is safe even with the high doses used in this study.

Droperidol is a sedating first-generation antipsychotic that has been used to safely treat acute behavioral disturbance for decades.4, 5 A controversial decision was made by the Food and Drug Administration to publish a black box warning for droperidol⁶ in December 2001 because of reported cases of QT prolongation and torsades de pointes. The black box warning has led to a marked reduction in the use of droperidol around the world despite a systematic review⁷ and increasing evidence that the risk of QT prolongation with droperidol is minimal.4, 8 A number of more recent studies have demonstrated that droperidol is at least as effective as benzodiazepines in sedating patients with acute behavioral disturbance and is potentially safer.8, 9

This study aimed to investigate the frequency of QT prolongation and torsades de pointes in patients administered high-dose (10 mg or more) droperidol in the ED for acute behavioral disturbance. In addition, it aimed to investigate the frequency of other adverse events and the effectiveness of droperidol for sedation.

Section snippets

Study Design and Setting

This was a prospective multicenter observational study of patients administered droperidol for sedation of acute behavioral disturbance in the ED, including the recording of an ECG within 2 hours of drug administration. The study was undertaken in 6 large regional and metropolitan EDs between August 2009 and March 2013. The hospitals ranged in size and case mix and included those in large cities, as well as large urban regional hospitals. Ethics approval was obtained from the Hunter New England

Results

There were 1,781 patient presentations reported to the investigators from the 6 EDs for acute behavioral disturbance between August 2009 and March 2014, with a median of 164 per hospital (52 to 928). There were 1,403 of 1,781 presentations with a complete set of data collected, including when droperidol was the initial drug given and there was a completed acute behavioral disturbance chart and a time to sedation recorded. There were no cases of torsades de pointes in these excluded patients. In

Limitations

A limitation of the study was the difficulty obtaining ECGs at the same time for every patient, and many ECGs could not be done within the 2-hour timeframe of administration of droperidol. Patients were either uncooperative or staff were reluctant to disturb them once they were settled. However, more than 1,000 ECGs were conducted within 2 hours of droperidol administration, and this is when the peak effects of droperidol are likely to occur. Despite the large number of ECGs, the study

Discussion

This study has shown that an abnormal QT interval is rare in a large cohort of patients given high-dose droperidol. In addition, there were no cases of torsades de pointes in the larger cohort of 1,403 patients, suggesting that the risk of torsades de pointes is less than 0.3% according to the size of the cohort. In addition, the study showed that droperidol was effective for sedation, with almost all patients being sedated within 120 minutes and less than a third requiring 2 or more doses.

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Cited by (71)

Droperidol Use in the Emergency Department: A Clinical Review
2023, Journal of Emergency Medicine
Droperidol is a butyrophenone, with antiemetic, sedative, anxiolytic, and analgesic properties. Although droperidol was once widely used in both emergency and perioperative settings, use of the medication declined rapidly after a 2001 U.S. Food and Drug Administration (FDA) boxed warning called the medication's safety into question.
The purpose of this clinical review was to provide evidence-based answers to questions about droperidol's safety and to examine its efficacy in its various clinical indications.
Droperidol is an effective sedative, anxiolytic, analgesic, and antiemetic medication. As a sedative, when compared with haloperidol, droperidol has faster onset, as well as greater efficacy, in patients experiencing acute psychosis, with no increase in adverse events. As an antiemetic, droperidol has been found to have equal or greater efficacy in reducing nausea and vomiting than ondansetron and metoclopramide, with similar adverse effects and the added effect of reducing the need for rescue analgesia in these patients. As an analgesic, droperidol is effective for migraines and has opioid-sparing effects when used to treat abdominal pain. Droperidol is a particularly useful adjunct in patients who are opioid-tolerant, whose pain is often difficulty to manage adequately.
Droperidol seems to be effective and safe, despite the boxed warning issued by the FDA. Droperidol is a powerful antiemetic, sedative, anxiolytic, antimigraine, and adjuvant to opioid analgesia and does not require routine screening with electrocardiography when used in low doses in otherwise healthy patients before administration in the emergency department.
Management of Pain and Agitation in Trauma
2023, Emergency Medicine Clinics of North America
Prospective real-time evaluation of the QTc interval variation after low-dose droperidol among emergency department patients
2022, American Journal of Emergency Medicine
To assess the QTc interval variation after low-dose droperidol in a population of undifferentiated, stable, and non-agitated patients receiving droperidol in the emergency department.
Prospective cohort study of patients aged ≥12 years of age who received low-dose droperidol (≤ 2.5 mg) for indications other than acute behavioral disturbances. QTc intervals were monitored in real-time during pre-specified observation periods in the ED. Primary outcome was variation of QTc interval after droperidol administration, defined as the maximum delta (change) of QTc interval. Other outcomes included proportion of patients with a QTc ≥ 500 ms after droperidol, delta ≥ +60 ms, and incidence of clinical adverse events. Patients were monitored up to 30 min after IV bolus and up to 46 min after infusion.
A total of 68 patients were included (mean age 42.1 years, 66.2% females). The median dose of droperidol was 1.875 mg (range 0.625 mg, 2.5 mg) and 94.1% received droperidol for headache management. Most patients received droperidol as a 2-min bolus (n = 41, 60.3%). The mean maximum delta of QTc interval after droperidol across all 68 patients was +29.9 ms (SD 15). A total of 12 patients (17.6%) experienced a QTc interval ≥ 500 ms during the observation period after droperidol, and 3 patients (4.4%) had a delta QTc ≥ +60 ms. There were no serious arrhythmias, such as TdP, or deaths among the 68 participants in this study (0/68). However, 13.2% (n = 9) had at least one non-serious adverse event including restlessness and/or anxiety.
The QTc interval slightly increased after droperidol administration, but these prolongations were brief, mostly below 500 msec and did not lead to serious arrhythmias. The yield of continuous cardiac monitoring in patients receiving low doses of droperidol is likely low.
Rapid tranquilization of the agitated patient in the emergency department: A systematic review and network meta-analysis
2022, American Journal of Emergency Medicine
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).
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.
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.
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.
A Prospective Study of Intramuscular Droperidol or Olanzapine for Acute Agitation in the Emergency Department: A Natural Experiment Owing to Drug Shortages
2021, Annals of Emergency Medicine
Intramuscular medications are commonly used to treat agitation in the emergency department (ED). The purpose of this study is to compare intramuscular droperidol and olanzapine for treating agitation.
This was a prospective observational study of ED patients receiving intramuscular droperidol or olanzapine for acute agitation. The treating physician determined the medication and dose; however, over time drug shortages made either olanzapine (July to September 2019) or droperidol (November 2019 to March 2020) unavailable, creating a natural experiment. The primary outcome was time to adequate sedation, assessed by the Altered Mental Status Scale (AMSS), defined as time to AMSS score less than or equal to 0.
We analyzed 1,257 patients (median age 42 years; 73% men); 538 received droperidol (median dose 5 mg) and 719 received olanzapine (median dose 10 mg). The majority of patients (1,086; 86%) had agitation owing to alcohol intoxication. Time to adequate sedation was 16 minutes (interquartile range 10 to 30 minutes) for droperidol and 17.5 minutes (interquartile range 10 to 30 minutes) for olanzapine (absolute difference –0.7 minutes; 95% confidence interval –2.1 to 0.5 minutes). Adjusted Cox proportional hazard model analysis revealed no difference between groups in time to sedation (hazard ratio for adequate sedation for droperidol compared with olanzapine 1.12; 95% confidence interval 1.00 to 1.25). Patients receiving olanzapine were more likely to receive additional medications for sedation (droperidol 17%; olanzapine 24%; absolute difference –8% [95% confidence interval –12% to –3%]). We observed no difference between drugs regarding adverse effects except for extrapyramidal adverse effects, which were more common with droperidol (n=6; 1%) than olanzapine (n=1; 0.1%).
We found no difference in time to adequate sedation between intramuscular droperidol and olanzapine.
Intramuscular medication for treatment of agitation in the emergency department: A systematic review of controlled trials
2021, American Journal of Emergency Medicine
Severely agitated patients in the emergency department (ED) are often sedated with intramuscularly-administered medications. The evidence base underlying particular medication choices is surprisingly sparse, as existing reviews either have methodological limitations or have included data collected outside of emergent settings.
The objective of this review was to examine all controlled trials in emergent settings that have used standardized scales to measure the effectiveness of intramuscular medication for the treatment of acute agitation.
This review was registered in Prospero as CRD42018105745. PubMed, International Pharmaceutical Abstracts, Web of Science, PsycINFO, and clinicaltrials.gov were searched for prospective controlled trials investigating intramuscular antipsychotics for agitation. Articles were assessed for bias across five domains using the revised Cochrane Risk of Bias Tool.
Eight studies were eligible for inclusion in the systematic review, none of which had a low risk of bias. Five studies had a moderate risk of bias with heterogenous designs, populations, and treatments. These studies seemed to suggest that second generation antipsychotics (SGAs) likely reduce agitation as effectively as first generation antipsychotics (FGAs) plus an adjunctive medication with similar or lower risk of side effects.
Existing trials on the use of intramuscular antipsychotics in the ED/psychiatric ED setting were small, heterogenous, and at a moderate or high risk of bias. Given the clinical importance of this topic, further prospective investigations are desperately needed but are currently unfeasible under Food and Drug Administration Exception From Informed Consent regulations.

View all citing articles on Scopus

: Please see page 231 for the Editor’s Capsule Summary of this article.

: Supervising editor: Steven M. Green, MD

: Author contributions: GKI and LC designed the study. LC and CBP enlisted the additional sites. LC supervised the study and entered the data. CBP, MAD, BC, FK, LW, and DS recruited or supervised recruitment of patients and data collection. GKI performed a data audit and analyzed the data. LC wrote the first draft and all authors contributed to the final article. GKI takes responsibility for the paper as a whole.

: Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article as per ICMJE conflict of interest guidelines (see www.icmje.org). The authors have stated that no such relationships exist and provided the following details: Dr. Isbister is supported by NHMRC Senior Research Fellowship 1061041. The study was funded in part by NSW Health Drug and Alcohol Research Grants Program 2010.

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View full text

Pain management and sedation/original researchThe Safety and Effectiveness of Droperidol for Sedation of Acute Behavioral Disturbance in the Emergency Department

Study objective

Methods

Results

Conclusion

Introduction

Editor’s Capsule Summary

Section snippets

Study Design and Setting

Results

Limitations

Discussion

Ann Emerg Med

Ann Emerg Med

Ann Emerg Med

Ann Emerg Med

Ann Emerg Med

J Emerg Med

Structured team approach to the agitated patient in the emergency department

Emerg Med Australas

A prospective study of high dose sedation for rapid tranquilisation of acute behavioural disturbance in an acute mental health unit

BMC Psychiatry

A retrospective review of the use and safety of droperidol in a large, high-risk, inner-city emergency department patient population

Acad Emerg Med

Pain management and sedation/original research
The Safety and Effectiveness of Droperidol for Sedation of Acute Behavioral Disturbance in the Emergency Department