Rethinking B52

Acute agitation is a common presentation in the emergency department. Since the 1980s, medications used to manage agitation in the ED include first-generation antipsychotics (FGAs) such as haloperidol and droperidol.¹

One common pharmacological practice has been to administer a drug cocktail known as a B52, named for "B" Benadryl, "5" mg haloperidol, and "2" mg of lorazepam, but the cocktail since evolved to simply "52," consisting of 50 mg of an anticholinergic (either haloperidol or droperidol) plus 2 mg of a benzodiazepine.² A 2022 study designed to compare the efficacy of B52 vs. 52 concluded that both combinations infrequently required repeat agitation medication, while the B52 combination resulted in more oxygen desaturation, hypotension, physical restraint use, and longer length of stay.³ Other controlled studies to examine this protocol have been limited, with inconclusive results, likely due to the complexity of the evidence. These studies have compared various combinations of medications, different doses, and different routes of administration.

Absent a compelling body of research, sedating medication continues to be directed by inherited or local practice protocol rather than by evidence, with too many sites persisting with the use of haloperidol and other FGAs.^1,4

Recent literature has focused on the management of agitation in specific populations, novel pharmacologic agents, and a reconsideration of previously utilized medications (eg, B52, haloperidol, and droperidol).^1,5 Newer and equally potent pharmaceutical agents and treatment protocols with better side effect profiles that reduce the risk for oversedation, dystonic reactions, and QT prolongation are available. Best practice guidelines have recommended these approaches over the traditional reliance on the B52 cocktail, haloperidol, and droperidol.^1,5 In a 2013 Cochrane Review of 25 haloperidol studies, the authors put forth this recommendation: "Haloperidol is a potent antipsychotic drug with a high propensity to cause adverse effects....when available, clinicians may wish to prescribe an alternative antipsychotic with less likelihood of adverse effects such as Parkinsonism, akathisia, and acute dystonias."¹

Concerns about droperidol with regards to QTc interval prolongation and subsequent risk of developing torsades de pointes led to a 2001 FDA Black Box Warning calling into question its widespread use.⁶

Multiple studies published since the FDA warning have confirmed the safety and efficacy of low-dose droperidol for the treatment of nausea, vomiting, migraine headaches, and agitation in the ED.^6,7 Droperidol at 2.5 mg IV was found to be superior to prochlorperazine at 10 mg IV for migraine control, with doses of up to 8.25 mg IM found to be superior to placebo for migraines without inducing any QT prolongation. Higher doses (greater than or equal to 10 mg) of droperidol have been used safely, with no evidence for risk for QT prolongation, for acute undifferentiated agitation in ED patients.^6,8 A 2015 study of 1009 patients supported the use of high-dose droperidol for the treatment of acute behavioral disturbance in the ED with no evidence of increased QT prolongation.⁸ The ACEP 2021 policy statement on the basis of numerous randomized controlled trials, prospective observational studies, and a systematic review from 2018 confirmed the safety and efficacy of droperidol for acute psychosis-induced agitation. An intramuscular dose of up to 10 mg of droperidol appears to be as safe and possibly more effective than other medications used for acute agitation. There were no reports of increased cardiac or respiratory events in any of the droperidol trials. It was concluded that droperidol provides effective treatment for acute agitation in the ED.⁶

The FDA has agreed that the current literature does not support the mandate of electrocardiogram prior to administration of droperidol or telemetry monitoring for doses <2.5 mg IV. Additionally, there should be no restrictions for use of higher doses of droperidol in the ED, provided cardiac monitoring is available soon after IV administration for high-risk patients. For agitated psychosis based on the extensive literature supporting the safety of droperidol, ACEP recommends the continued use of droperidol, at even higher doses, starting at 5–10 mg IM or IV, and up to 20 mg, regardless of initial monitoring capability or EKG. It is further recommended that the FDA black box warning be revised to reflect current data regarding the safety and efficacy of droperidol.⁶

Now considered a safe and effective treatment for acute agitation in the ED, droperidol has been studied for its efficacy and safety when compared to haloperidol. A randomized, controlled trial conducted in Australia comparing IM haloperidol and IM droperidol showed the risk for adverse effects was low in both groups, with no cardiac dysrhythmias reported.⁹ Another study comparing IM haloperidol and IM droperidol found that IM droperidol decreased combativeness significantly compared with IM haloperidol at 10, 15, and 30 minutes. There was no significant difference between the two drugs when given IV.¹⁰

Informed by the results of current literature regarding the efficacy and safety of droperidol, further efforts to move forward have been advanced by revised clinical policy from ACEP aiming to clarify the often indirect evidence and seeking to guide clinicians in choosing the most effective parenteral agents for patients with severe agitation.^4,6 The clinical policy gives a Level B recommendation to the use of a combination of droperidol and midazolam (or another atypical antipsychotic plus midazolam) for "rapid and efficacious treatment of severe agitation.” The combination of droperidol and midazolam appears to result in rapid sedation, requires fewer additional medications, and has a favorable safety profile in agitated ED patients. A randomized study found that droperidol (5 mg IV) plus midazolam (5 mg IV) resulted in a higher proportion of patients adequately sedated at 10 minutes compared with droperidol (10 mg IV) or olanzapine (10 mg IV) alone. Similarly, another randomized study found that a combination of droperidol (5 mg IV) with midazolam or olanzapine (5 mg IV) resulted in quicker time to adequate sedation than IV midazolam alone. Both droperidol and olanzapine appear to work more quickly than haloperidol. A 2018 study found more patients were adequately sedated at 15 minutes with 5 mg of IM midazolam compared with haloperidol, 5 mg, haloperidol 10 mg, and ziprasidone 20 mg.^4,6      

ACEP policy recommendations provide a Level C consensus recommendation for the use of ketamine (commonly used in procedural sedation and induction setting), as a novel therapy for analgesia and severe agitation and delirium in the ED, in critical circumstances, "in situations where the safety of the patient, bystanders, or staff is a concern."^6,12 Ketamine is a highly dissociative sedative that provides effective low-dose analgesia, procedural sedation, and general sedation.¹² Rapid dissociation, favorable cardiovascular stability, and preservation of respiratory drive suggests that ketamine may be an option for the safe control of agitated and violent ED patients.¹² Studies examining the safety of ketamine used for pain and agitation in the ED have described the efficacy and safety for pain with dosing regimens of 0.1–0.3 mg/kg, (IV), and for dissociative sedation ketamine, dosing is defined as 3–5 mg/kg, (IM). IM ketamine provided significantly shorter time to adequate sedation than a combination of IM midazolam and haloperidol;¹³ and when used for dissociative sedation for severe agitation, ketamine led to less endotracheal intubation than reported in the prehospital literature.¹² Currently, ACEP recommends the use of ketamine, at a dose of 3 to 5 mg/kg (IM), achieving sedation in 2-10 minutes with a single dose in situations where patient and staff safety is the overarching concern. It is critical, however, to be cognizant of and prepared for the potential for serious adverse effects including respiratory depression and laryngospasm.^4,6,12,13      

Safer and more efficacious protocols for the management of acute agitation in the ED have also been advanced by the American Association for Emergency Psychiatry's (AAEP) 2012 Project BETA, tasked to set forth best practice guidelines for the evaluation and management of agitation.⁵

In the decade that followed, those guidelines have been expanded with new recommendations, summarized in Table 1.

Table 1. AAEP Guidelines for ED Management of Acute Agitation

Summary

Despite the assumption that B52 combination therapy is commonly used in the ED, there is little research to support its efficacious use.² Concerns about the risk of oversedation, variable patient response, and potential side effects (extrapyramidal symptoms, anticholinergic effects, dependency, and paradoxical reactions) have inhibited the widespread use of the B52 or 52 cocktails in the ED.

Alternative pharmacological management protocols endorsed and promulgated by best practice guidelines have been found to be safer and more efficacious in the management of severe agitation than many first-generation antipsychotics (FGAs) for the emergency management of delirium, agitation due to alcohol intoxication, agitation due to a known psychiatric disorder, and undifferentiated presentations with prominent psychotic symptoms. Second-generation antipsychotics (SGAs), such as olanzapine, ziprasidone, and risperidone, are often favored over FGAs such as haloperidol and droperidol. Both classes have similar efficacy in managing agitation, but many FGAs pose a greater risk for adverse events/effects on patient health.^1,5

References

1. Zeller S. Haloperidol in the Emergency Department Setting. Psychiatry Advisor. October 10, 2016.
2. Wilson MP, Minassian A, Bahramzi M, Campillo A, Vilke GM. Despite expert recommendations, second-generation antipsychotics are not often prescribed in the emergency department. J Emerg Med. 2014 Jun;46(6):808-13. doi: 10.1016/j.jemermed.2014.01.017. Epub 2014 Mar 20. PMID: 24656982.
3. Jeffers T, Darling B, Edwards C, Vadiei N. Efficacy of Combination Haloperidol, Lorazepam, and Diphenhydramine vs. Combination Haloperidol and Lorazepam in the Treatment of Acute Agitation: A Multicenter Retrospective Cohort Study. J Emerg Med. 2022;62(4):516-523.
4. Westafer L. Which Sedatives Are Best for Managing Severe Agitation in the Emergency Department? ACEP Now. 2023;42(12).
5. Curry A, Malas N, Mroczkowske M, Hong V, Nordstrom K, Terrell C. Updates in the Assessment and Management of Agitation. Focus. 2023;21(1).
6. ACEP Policy Statement. Use of Droperidol in the Emergency Department. American College of Emergency Physicians. Published January 2021.
7. Gaw CM, Cabrera D, Bellolio F, Mattson AE, Lohse CM, Jeffery MM. Effectiveness and Safety of Droperidol in a United States Emergency Department. Am J Emerg Med. 2020;38(7):1310-1314. 
8. Calver LA, Page CB, Downes MA, Chan B, Wheatley L, Kinnear F, Spain D, Isbister GK. The Safety and Effectiveness of Droperidol for Sedation of Acute Behavioral Disturbance in the Emergency Department. Ann Emerg Med. 2015;66(3)230-238.
9. Calver LA, Stokes B, Isbister GK. Sedation Assessment Tool to Score Acute Behavioral Disturbance in the Emergency Department. Emerg Med Australas. 2011;23(6):732-740.
10. Thomas H, Schwartz E, Petrilli R. Droperidol versus Haloperidol for Chemical Restraint of Agitated and Combative Patients. Ann Emerg Med. 1992;21(4):407-413.
11. Mo H, Campbell MJ, Fertei BS, Lam SW, Wells EJ, Casserly E, Meidon SW. Ketamine Safety and Use in the Emergency Department for Pain and Agitation/Delirium: A Health System Experience. West J Emerg Med. 2020;21(2):272-281.
12. Barbic D, Andolfatto G, Grunau B, Scheuermeyer FX, Macewan B, Qian H, Wong H, Barbic SP, Honer WG. Rapid Agitation Control with Ketamine in the Emergency Department: A Blinded, Randomized Controlled Trial. Ann Emerg Med. 2021;78(6):788-795.