Introduction

Agitation is defined as excessive verbal or motor activity that can present as verbally abusive behavior, assault, threatening conduct, and physical destructiveness.¹ Agitation is a common presentation in the emergency department and poses a hazard to staff, property, and the patient. Common etiologies for agitation in the acute setting include alcohol intoxication, illicit substance use, psychiatric conditions, or trauma responses; however, agitation can arise from various other patient-specific factors.² Owing to the risk for staff members, other patients, hospital property, and the patient themselves, it is vital to manage agitation effectively and safely.

A poll from August 2022 published by the American College of Emergency Physicians stated that 55% of emergency physicians reported being personally assaulted by a patient, and 79% reported witnessing an assault on another staff member, which is a marked increase from the 47% and 71% incidence of each event, respectively, in 2018.³ Due to these concerns, it is imperative to promptly and safely manage a patient exhibiting acute agitation to maintain a safe environment and ensure that the patient receives appropriate treatment for the condition that they are seeking medical attention for. The approach to managing acute agitation in the emergency department routinely includes verbal de-escalation techniques, pharmacologic agents, and physical restraints as a last resort, depending upon the severity.⁴ Antipsychotic medications, such as droperidol and haloperidol, are commonly administered for agitation management.

Antipsychotics have historically been used for their sedative properties in addition to their primary indication for the treatment of psychiatric conditions. Droperidol and haloperidol are both first-generation antipsychotics within the butyrophenone class that elicit their responses through dopamine-2 receptor antagonism and have a congruent safety profile. Some commonly reported drug class adverse effects are QTc prolongation, extrapyramidal symptoms, such as akathisia and dystonia, and sedation.⁵ While all antipsychotics have the potential to induce QTc prolongation and arrhythmias, droperidol specifically carries a boxed warning that haloperidol does not. This is believed to have influenced the decrease in the use of droperidol in the past and likely led to the favoring of haloperidol in practice.⁶ However, since the designation of the boxed warning in 2001, new literature has been published that suggests the incidence of QTc prolongation with droperidol is likely overestimated.^7-9

While the pharmacologic profiles of both agents are similar, their pharmacokinetic properties differ and may influence their effects. Droperidol levels after an intramuscular dose will peak within 30 minutes, with the onset of action occurring between 3 and 10 minutes after administration and a duration generally lasting for 2 to 4 hours.⁵ In contrast, intramuscular haloperidol exhibits a peak concentration within 20 minutes, with the onset of action occurring 15 minutes after administration and effects generally lasting for 2 hours when used for sedation.^6,7

Because of the reemergence of droperidol use, this study aims to expand the literature by directly comparing the use of these 2 agents in the setting of acute agitation management.

Methods

Results

Baseline Characteristics

A total of 210 patients were included in the study, and 95% power was met. Baseline characteristics were mostly comparable between the droperidol and haloperidol arms, as summarized in Table 1. Both arms had similar incidences of preexisting psychiatric diagnoses, with minor differences in the incidence of bipolar disorder and schizophrenia that were acceptable. The droperidol arm had a higher percentage of patients diagnosed with bipolar disorder (13.34%) compared with haloperidol (8.57%). The haloperidol arm had a higher percentage of those diagnosed with schizophrenia (30.47%) compared with droperidol (25.71%). Alcohol, benzodiazepines, and cannabis were among the most common psychoactive substances leading to intoxication across the entire patient population, but the percentages did differ between each arm. These differences are further summarized in Table 1.

TABLE 1Baseline characteristics for droperidol and haloperidol arms

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Secondary Endpoints

The overall proportion of patients requiring any additional doses was lower in the droperidol arm than in the haloperidol arm, with 57% and 79% of each arm requiring additional doses, respectively. The droperidol mean first dose was 5.5 mg, while the haloperidol mean first dose was 6.9 mg. There were zero documented cases of EPS, and there was no observed QTc prolongation in either arm. The mean post-dose QTc was 451 ms in the droperidol arm and 449 ms in the haloperidol arm. However, only 14 medical records in the droperidol arm and 22 in the haloperidol arm had EKG documentation available. A summary of both the primary and secondary endpoints is available in Table 2.

TABLE 2Summary of primary and secondary endpoint results

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Discussion

The results of this study demonstrated that droperidol may provide some advantageous properties over haloperidol in the management of acute agitation. The results indicated that the droperidol arm required a lower number of subsequent antipsychotic or benzodiazepine doses within 4 hours of the initial dose. The droperidol arm also reflected a lower overall proportion of patients requiring any additional as-needed doses after the initial dose, and patients in this arm were administered a lower first dose in milligrams compared with the haloperidol arm. While the results of the primary endpoint were statistically significant, there may be a lack of clinical significance due to the minor practical difference between 0.75 and 1.1 additional doses. The secondary endpoints regarding effectiveness may translate more significantly into clinical practice, however. The droperidol arm, resulting in a lower proportion of patients requiring additional as-needed doses and a lower mean initial dose, demonstrates that less medication was required in general for agitation management compared to haloperidol. This finding is beneficial not only to the clinicians caring for the patient regarding prompt treatment and performance of assessments, but also to the patient themselves because repeated dosing can expose a patient to adverse drug effects, especially with concurrent usage of agents in other drug classes.

Several limitations were present in this study. The study population was confined to that of the included emergency department locations, which only included the demographic of patients within the Southern New Jersey area, and, therefore, limits the external validity of the results. Additionally, formulary limitations and prevailing provider drug selection preferences may have influenced the results due to the retrospective nature of this study design. There were also multiple confounders while in the emergency department, such as concomitant medication use, severity of agitation, substance intoxication, and preexisting psychiatric conditions, all of which may affect a patient’s response to droperidol or haloperidol. While the most prevalent substances were alcohol, benzodiazepines, and cannabis in each arm, there was also an observed presence of patients under the influence of amphetamines and cocaine in each arm, which could have increased the severity of agitation due to stimulatory effects.

Additionally, the higher prevalence of psychoactive intoxication in the haloperidol arm may have introduced an additional confounder to this study. Another limitation of this study was the inability to compare agitation severity between arms, as this was a retrospective chart review, and these data were not available to collect. There was also a lack of data for the safety secondary endpoints. EKG documentation was only available for 14 and 22 patients in the droperidol and haloperidol arms, respectively. While the available EKG results did not reflect QTc prolongation for either arm, the small sample size prevents the generalizability of these findings. Finally, the ability to collect data on the incidence of EPS depended solely on the presence of nursing documentation or the administration of benztropine and was therefore limited. While there was no documented incidence of this adverse event in either arm based on these parameters, it cannot be definitively determined that it did not occur due to the administration of either agent.

Conclusion

Droperidol use for acute agitation within the emergency department resulted in a reduced number of required additional as-needed doses of antipsychotics or benzodiazepines within 4 hours of the initial dose, an overall lower proportion of patients requiring any additional doses of these agents, and a lower mean initial dose in milligrams compared with haloperidol. The results of this study suggest that droperidol is a viable option for agitation management. Larger studies are needed to increase the applicability of these results to a patient population other than those included in this study and over a longer timeframe; however, the results of this retrospective study serve as insight into the application of droperidol use for acute agitation and may help to provide clinicians with real-world data on its effectiveness and safety in comparison to a more commonly used agent such as haloperidol.