Randomized Clinical Trial Comparing Intravenous Midazolam and Droperidol for Sedation of the Acutely Agitated Patient in the Emergency Department

doi:10.1016/j.annemergmed.2005.07.003

Annals of Emergency Medicine

Volume 47, Issue 1, January 2006, Pages 61-67

https://doi.org/10.1016/j.annemergmed.2005.07.003 Get rights and content

Study objective

We compare intravenous midazolam and droperidol for the onset of sedation of acutely agitated patients in the emergency department (ED).

Methods

This was a double-blind, randomized, clinical trial set in the ED of a university teaching hospital. Subjects were adults, acutely agitated because of mental illness, intoxication, or both, who received midazolam or droperidol, 5 mg intravenously, every 5 minutes until sedated. We analyzed time to sedation using survival analysis, median times to sedation, and proportions sedated at 5 and 10 minutes.

Results

Seventy-four patients received midazolam; 79 patients, droperidol. Survival analysis showed no difference in time to sedation (hazard ratio 0.86; 95% confidence interval [CI] 0.61 to 1.23), P=.42. Median time to sedation was 6.5 minutes for midazolam (median dose 5 mg) and 8 minutes for droperidol (median dose 10 mg), P=.075 (effect size 1.5 minutes; 95% CI 0 to 4 minutes). At 5 minutes, 33 of 74 (44.6%) patients from the midazolam group were adequately sedated compared with 13 of 79 (16.5%) patients from the droperidol group, a difference of 28.1% (95% CI 12.9% to 43.4%; P<.001). By 10 minutes, 41 of 74 (55.4%) from the midazolam group were sedated compared to 42 of 79 (53.2%) from droperidol, a difference of 2.2% (95% CI −14.9% to 19.3%; P=.91). Eleven adverse events occurred in the midazolam group and 10 in the droperidol group. Three patients required active airway management (3 patients with assisted ventilation and 1 patient intubated); all received midazolam.

Conclusion

There is no difference in onset of adequate sedation of agitated patients using midazolam or droperidol. Patients sedated with midazolam may have an increased need for active airway management.

Introduction

The management of acutely agitated patients, whether because of psychiatric illness or drug or alcohol intoxication, results in a disproportionate use of emergency department (ED) resources. A number of techniques are used to placate such patients, including setting limits, clear explanations of procedures, and chemical and physical restraint. Restraints are used only when individuals are at risk of harming themselves or those around them, including staff and other patients, and is required in 0.3% to 2% of all ED presentations.1, 2

Reviews of Australasian, United Kingdom, and US restraint practices indicate that the drugs used for restraint in the ED are neuroleptics and short-acting benzodiazepines.1, 3, 4 The majority of acute sedation studies has examined the management of acute agitation in psychiatric wards or ICUs. These settings often require long sedation times, often measured in hours, and either lack applicability to the general ED population or lack the power to exclude differences between agents.5, 6, 7, 8

Benzodiazepines are effective sedatives, with midazolam and diazepam (but not lorazepam) available parenterally in Australasia, and are used frequently as first-line agents.¹ Alternatives include the neuroleptics; droperidol has been shown to be more effective as a sedative compared with haloperidol.7, 9 For rapid tranquillization requiring intravenous administration, midazolam and droperidol have gained ascendancy in Australasian EDs.1, 2

The decision to sedate an acutely agitated patient requires a rapid response to prevent harm. Because of the complex issues surrounding the treatment of these individuals, the best available evidence-based therapy should be used in their treatment.

Midazolam and droperidol have not been compared for treatment of acutely agitated patients. The aim of this study is to compare these agents with respect to time to adequate sedation, the need for subsequent sedation within 60 minutes, and adverse event rates. We hypothesized that there would be no difference between the drugs with respect to these outcomes.

Section snippets

Study Design and Setting

The study was a double-blind, randomized, clinical trial of intravenous midazolam versus droperidol conducted in the ED of a large Australian metropolitan university hospital with approximately 50,000 attendances annually.

Selection of Participants

Patients were eligible for enrollment if they were aged 18 to 65 years (inclusive) and exhibited marked agitation that required chemical restraint as deemed by a consultant (attending) emergency physician or a senior accredited resident of the Australasian College for

Characteristics of Study Subjects

One hundred seventy patients were enrolled by study-pack allocation. Of these, 17 packs were lost so that data on 153 patients were available for analysis (Figure 1). Table 1 shows patient characteristics; there were no significant differences between the patients in each arm of the trial. A number of patients sedated before their full details became available were subsequently found to be outside the age inclusion criteria (18 to 65 years). Six patients in the midazolam arm were aged 15, 17,

Limitations

A number of limitations in this study have been identified.

Selection bias may have occurred if physicians failed to enroll patients for whom they had a particular preference in terms of pharmacologic management. It was difficult to determine the number of eligible patients not enrolled. In our department, it is likely to be low because midazolam and droperidol are the preferred sedation agents and used interchangeably on an ad hoc basis; it is uncommon for a particular preference for either

Discussion

We believe this to be the first blinded, randomized, clinical study comparing midazolam and droperidol for rapid sedation of agitated patients in a general ED. There was no difference in the time to sedation; however, more patients were sedated in the first 5 minutes when midazolam was used.

The TREC collaborative group¹⁴ (Rio) and Nobay et al¹⁵ found midazolam results in a shorter time to sedation than a neuroleptic. However, those studies used intramuscular haloperidol, and haloperidol has

References (19)

J. Battaglia et al.
Haloperidol, lorazepam, or both for psychotic agitation? a multicenter, prospective, double-blind, emergency department study
Am J Emerg Med
(1997)
H. Thomas et al.
Droperidol versus haloperidol for chemical restraint of agitated and combative patients
Ann Emerg Med
(1992)
J.R. Richards et al.
Chemical restraint for the agitated patient in the emergency department: lorazepam versus droperidol
J Emerg Med
(1998)
L.W. Kao et al.
Droperidol, QT prolongation, and sudden death: what is the evidence?
Ann Emerg Med
(2003)
M.E. Cannon et al.
Restraint practices in Australasian emergency departments
Aust N Z J Psychiatry
(2001)
J.C. Knott et al.
Unarmed threats in the emergency department
Emerg Med Aust
(2005)
M.H. Allen
Managing the agitated psychotic patient: a reappraisal of the evidence
J Clin Psychiatry
(2000)
R.H. McAllister-Williams et al.
Rapid tranquillisation: time for a reappraisal of options for parenteral therapy
Br J Psychiatry
(2002)
C. Salzman et al.
Parenteral lorazepam versus parenteral haloperidol for the control of psychotic disruptive behavior
J Clin Psychiatry
(1991)

There are more references available in the full text version of this article.

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This was a retrospective observational study conducted at an urban, academic ED. The primary endpoint was time from the first dose of study medication to restraint removal. Safety endpoints included incidence of bradycardia (heart rate < 60 bpm), hypotension (systolic blood pressure < 90 mmHg), hypoxia (oxygen saturation < 90% or need for respiratory support), and incidence of intubation for ongoing agitation or respiratory failure.
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Supervising editor: Steven M. Green, MD

Author contributions: JK was principal investigator. JK, DT, and DC were responsible for initial study design. JK conducted the study and collected the data. JK, DT, and DC conducted data analysis and manuscript preparation. JK was principally responsible for the statistical analysis of the data. JK takes responsibility for the paper as a whole.

Funding and support: This study was supported by a postgraduate scholarship from the National Health and Medicine Research Council and a research grant from the Australasian College for Emergency Medicine (Morson Taylor Award).

Presented at the 8th International Conference for Emergency Medicine, June 2004, Cairns, Queensland, Australia.

Reprints not available from the authors.

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Original ResearchRandomized Clinical Trial Comparing Intravenous Midazolam and Droperidol for Sedation of the Acutely Agitated Patient in the Emergency Department

Study objective

Methods

Results

Conclusion

Introduction

Section snippets

Study Design and Setting

Selection of Participants

Characteristics of Study Subjects

Limitations

Discussion

Am J Emerg Med

Ann Emerg Med

J Emerg Med

Ann Emerg Med

Restraint practices in Australasian emergency departments

Aust N Z J Psychiatry

Unarmed threats in the emergency department

Emerg Med Aust

Managing the agitated psychotic patient: a reappraisal of the evidence

J Clin Psychiatry

Rapid tranquillisation: time for a reappraisal of options for parenteral therapy

Br J Psychiatry

Parenteral lorazepam versus parenteral haloperidol for the control of psychotic disruptive behavior

J Clin Psychiatry

Original Research
Randomized Clinical Trial Comparing Intravenous Midazolam and Droperidol for Sedation of the Acutely Agitated Patient in the Emergency Department