Washington University Emergency Medicine Journal Club- October 2020
During a remarkably slow overnight EM-5 shift, EMS wheels in a 23-year-old male with bizarre behavior. Per report, family stated the patient has a history of schizophrenia and has not had his Invega shot in 6 months. He has been more agitated recently, pacing the house all night, threatening family members, and claiming the government is trying to read his thoughts.
While calm and cooperative with the paramedics, the patient becomes immediately agitated once he is brought into the sally port, claiming you and the nurses are going to try to kill him. The patient is restrained by public safety and given “the usual,” a cocktail consisting of 5 mg of haldol and 2 mg of lorazepam IM. Ten minutes later the patient is in one of the seclusion rooms, banging his head against the door. He requires redosing of meds and is placed on a stretcher in locked limb restraints.
Once he is properly sedated, you begin discussing acute agitation management with your attending. The attending remarks that she used to give droperidol for these emergencies during her training and how sad it was when droperidol was pulled from use in the U.S. You are aware that EMS often gives ketamine for agitated delirium, but since droperidol is back on the formulary and in plentiful supply, you wonder how it stacks up against our current standard of haloperidol/lorazepam and whether it would be effective more quickly. While you wait for the next patient to arrive, you begin to perform a literature search to see what the evidence says…
Population: Adult patients in the ED with behavioral disturbance of any etiology requiring chemical sedation
Intervention: Droperidol administration (IV or IM)
Comparison: Haloperidol administration (IV or IM)
Outcome: Time to adequate sedation, failed sedation/need for rescue sedation, ED length of stay, respiratory depression, QT prolongation, Torsades de Pointes
A PubMed search was conducted using the terms “droperidol AND (agitation OR “agitated delirium”)” (https://tinyurl.com/yxl5pkv2) resulting in 102 citations. Of these, 4 were chosen for inclusion.
Article 1: Calver L, Drinkwater V, Gupta R, Page CB, Isbister GK. Droperidol v. haloperidol for sedation of aggressive behaviour in acute mental health: randomised controlled trial. Br J Psychiatry. 2015 Mar;206(3):223-8. Answer Key.
Article 2:Klein LR, Driver BE, Horton G, Scharber S, Martel ML, Cole JB. Rescue Sedation When Treating Acute Agitation in the Emergency Department With Intramuscular Antipsychotics. J Emerg Med. 2019 May;56(5):484-490. Answer Key.
Article 3: Calver L, Page CB, Downes MA, Chan B, Kinnear F, Wheatley L, Spain D, Isbister GK. The Safety and Effectiveness of Droperidol for Sedation of Acute Behavioral Disturbance in the Emergency Department. Ann Emerg Med. 2015 Sep;66(3):230-238.e1. Answer Key.
Acute agitation is a common occurrence in the emergency department setting, where it is most often due to acute psychosis or intoxication with alcohol or other illicit substances. Patients with agitated delirium are at risk for several adverse outcomes, including rhabdomyolysis, cardiac dysrhythmia, hyperthermia, and asphyxiation. The risks associated with agitation in the ED include not only harm to the patient, but the potential for harm to ED staff. In a recent poll from the American College of Emergency Physicians (ACEP), nearly half of respondents reported that they had been physically assaulted at work, and over two-thirds reported witnessing an assault. To prevent harm to both the patient and staff, the goals of management in agitation and excited delirium are primarily aimed at deescalation.
While verbal deescalation is recommended as a first-line modality, it is often unsuccessful and physical restraint and chemical sedation become necessary. In these cases, antipsychotic agents are often used as first-line agents. Specifically, the butyrophenones (haloperidol and droperidol) are often chosen given their selective antagonism of the dopamine-2 (D2) receptor and relatively low side-effect profile when compared with phenothiazines (such as chlorpromazine). Droperidol was previously issued a black-box warning by the FDA given concerns about prolongation of the QTc interval and risk of developing torsades de pointes (TdP). Combined with recent drug shortages, this warning has led to a decline in droperidol use, with many clinicians favoring haloperidol instead for agitation in the ED. We sought to review the evidence specifically comparing droperidol and haloperidol for management of agitation, looking at both onset of action and risk of adverse effects.
A randomized, controlled trial comparing IM haloperidol and IM droperidol was conducted in Australia between 2011 and 2013. Over 200 patients with acute behavioral disturbance admitted to their psychiatric intensive care unit were randomized to receive 10 mg of intramuscular (IM) haloperidol or droperidol, and were then monitored for level of agitation based on a novel Sedation Assessment Tool (SAT). Patients who received haloperidol had a statistically insignificant shorter median time to adequate sedation (20 minutes, IQR 15-30 vs. 25 minutes, IQR 15-30). Adequate sedation was achieved within 2 hours in 92% of patients in both groups, with 13% of haloperidol patients requiring additional sedative agent compared to 5% in the droperidol group. The risk of adverse effects was low in both groups, with no cardiac dysrhythmias reported. While this study demonstrated essentially equal effectiveness between IM haloperidol and IM droperidol, the results are at risk of selection bias as over half of eligible patients were not included.
We identified one additional randomized controlled trial, conducted at Wake Forest Medical Center in the early 1990s. Patients in the ED with agitation requiring physical restraint (n = 68) were randomized to receive 5 mg of haloperidol or droperidol, which could be given either IM or intravenous (IV) at clinician discretion. Combativeness was then assessed on a novel 5-point scale at 15, 30, and 60 minutes after drug administration. Patients could be given an additional rescue sedative agent at 30 minutes, but were then excluded from 60-minute analysis if this was required. The authors report a significantly more rapid response to IM droperidol compared to IM haloperidol (p = 0.03) at 10 minutes (combativeness score 2.11 vs. 3.00, p = 0.004), 15 minutes (3.11 vs. 4.00, p = 0.010) and 30 minutes (3.75 vs. 4.43, p = 0.010), with no difference in combativeness scores at 5 minutes. There was no significant difference in combativeness scores between the groups receiving IV medication. While this study did demonstrate significant reductions in combativeness with IM droperidol at 30 minutes, this was a small study whose results may not be replicated with larger samples. In addition, the authors did not look at adverse outcomes, specifically prolonged QT and TdP.
Given the specific concerns regarding cardio-toxicity with droperidol administration, we reviewed one article looking specifically at the frequency of QT prolongation and TdP after droperidol administration for acute agitation. Patients presenting to the EDs of 6 Australian hospitals between 2009 and 2013 were eligible for enrollment. Patients with agitation who were not willing to take oral medications were given 10 mg of droperidol, IV or IM, and were then monitored via cardiac monitor and SAT scores. While ECGs were not routinely performed on these patients, they were included in the final analysis if performed within 2 hours of droperidol administration. Out of 1403 patients with complete data, just over 1000 had ECGs performed. Of these, 13 had an abnormal QT duration (1.3%, 95% CI 0.7% to 2.3%). Excluding two patients with a preexisting prolonged QT on ECG performed prior to droperidol administration and two patients receiving medications known to prolong the QT interval, there were 6 cases of new QT prolongation without another cause identified (0.6%, 95% CI 0.2% to 1.4%). There were no cases of TdP.
The final article reviewed was a retrospective, observational study conducted at Hennepin County Medical Center. Patients receiving IM droperidol, olanzapine, or haloperidol for an encounter with “Altered Mental Status” as the chief complaint were included and assessed for the need for rescue sedation within one hour of initial medication administration. With nearly 16000 encounters included, the authors found a higher need for rescue sedation among patients receiving haloperidol 18% (95% CI 17-20%) compared with those receiving droperidol 11% (95% CI 10-12%) or olanzapine 11% (95% CI 10-12%). Adverse events were rare (0.2-0.4%) and there were no cases of TdP or other cardiac dysrhythmias.
While there is no overwhelming evidence that droperidol is superior to haloperidol for management of acute agitation in the ED, there is some suggestion that it may work a few minutes faster and may require less rescue sedation. More importantly, the previous safety concerns appear to be unfounded, as the incidence of prolonged QT was around 0.6% with no reported cases of TdP in any study. While none of these studies followed patients beyond the initial management, it seems unlikely that TdP would occur more than a few hours after droperidol administration. The emergency physician should feel safe using this agent in the armamentarium for acute agitation, and may consider its use ahead of haloperidol given the possible faster onset of action.