Violence against health-care workers caused by acutely agitated patients is an unfortunate reality for many of us.
When attempts at verbal redirection do not successfully de-escalate the situation, expedient medication administration becomes a key step to minimize the damage and maximize the safety of both the patient and hospital staff. If the agitated patient refuses an offer of oral or sublingual medication, clinicians often rely on intramuscular (IM) or intravenous (IV) administration to achieve adequate behavior control.
Many medications are available for use either individually or in combination for the acutely agitated patient. Although the classic “B-52” combination of 5 mg haloperidol, 2 mg lorazepam, and 50 mg diphenhydramine is often considered first-line therapy and has maintained longstanding popularity across emergency medicine, recent literature and specialty society policy recommendations suggest that 1 or more of these medications may not be the optimal pharmacologic choice under these high-stress, time-sensitive circumstances.
To address this, we introduce the “Fiver”: a combination of 5 mg droperidol, 5 mg midazolam, and 50 mg diphenhydramine. The name “Fiver” is meant to be a clever memory aid to quickly recall the 5 mg dosing of both the antipsychotic and benzodiazepine medications used.
Similar to the traditional B-52 cocktail, the Fiver includes 1 antipsychotic medication and 1 benzodiazepine medication, used in combination with diphenhydramine. The medication combination included in the Fiver also aligns with the droperidol-midazolam combination that received a Level B recommendation in the most recent ACEP Clinical Policy on Severe Agitation,1,2,3 with the simple addition of diphenhydramine. Droperidol may be replaced by 5 mg olanzapine based on facility availability or provider preference. Like any reliable anti-agitation cocktail, it can be either IM- or IV-administered.
Why droperidol instead of haloperidol?
Droperidol has been shown to have faster onset and greater efficacy compared to haloperidol, with no evidence of increased adverse events. A meta-analysis published by Zun et al.4 found that 5 mg IM droperidol had effect within 5-10 minutes, compared to 15-30 minutes for 5 mg olanzapine and 20-60 minutes for 5 mg haloperidol.
When you and your staff are dodging punches and trying to avoid showers of spit, these minutes matter. The observational study published by Klein et al.5 found that patients who received 5 mg IM droperidol or 5 mg IM olanzapine required fewer additional doses for agitation control in the 60 minutes following the initial dose and fewer overall doses during the ED encounter than patients who received 5 mg IM haloperidol. There were no differences in adverse events among the 3 study groups. Taylor et al. found that this clinical effect was further seen when droperidol and midazolam were administered together (as the Fiver proposes), again with no difference in adverse effects.6
Doesn’t droperidol have a black box warning?
Great question, and we are glad you asked. Droperidol developed a negative reputation when it received a black box warning for QT prolongation in 2001, but current literature has shown that droperidol has a well-established safety profile at doses of 5 mg and lower.7 In fact, the study published by Klein et al.5 included nearly 5,000 patients who received 5 mg IM droperidol for agitation control, with zero incidences of torsades de pointes, the dreaded arrhythmia associated with QT prolongation.
ACEP agrees that droperidol is safe in patients without established history of QT prolongation who receive appropriate dosing, as an updated clinical policy was published in 2021 highlighting its safety profile and recommending droperidol use in circumstances including acute agitation.8
The potential risk of QT prolongation is further minimized when olanzapine is used as the antipsychotic medication of choice.
Why midazolam instead of lorazepam?
Both are effective and either benzodiazepine can ultimately be used, but the current literature demonstrates that midazolam has a faster onset than lorazepam. Goldfrank’s Toxicologic Emergencies textbook reports the onset of IM midazolam to be 5-10 minutes compared to 20-30 minutes for IM lorazepam, and the onset of IV midazolam to be 1-2 minutes compared to 5-20 minutes for IV lorazepam.9 Again, in the context of acute agitation control, these minutes matter.
Many facilities across the United States are also facing a lorazepam shortage, making midazolam an ideal replacement both from a clinical and practical standpoint.
Why include diphenhydramine?
Classic teaching dictates that diphenhydramine reduces the risk of extrapyramidal side effects associated with antipsychotic medications such as haloperidol, and the meta-analysis performed by Mokthari et al. supports this.10 Diphenhydramine also has sedative effects due to its antagonism of the H1 histamine receptor and has been shown to improve sedation for procedures including colonoscopy11 and bronchoscopy.12
But what about ketamine?
It is true that ketamine can be rapidly administered for agitation control as well, and 5 mg/kg ketamine monotherapy is discussed in the 2023 ACEP Clinical Policy with Level C recommendations.1 However, the critical potential side effects of rapid ketamine administration include laryngospasm and emergence reaction, each of which represents added risk to either the patient or hospital staff when encountered. Neither of these side effects are known to be a potential complication of the Fiver.
For these reasons, we propose the Fiver as a modernized alternative to the B-52 for acute agitation control in the emergency department.
Disclaimer: The views expressed in this work are those of the author and do not reflect the official policy or position of the Department of the Navy, Department of Defense, or the U.S. Government.
References
- Thiessen ME, Godwin SA, Hatten BW, et al. Clinical policy: Critical issues in the evaluation and management of adult out-of-hospital or emergency department patients presenting with severe agitation. Ann Emerg Med. 2024;83(1):E1-E30.
- Thiessen ME. “ACEP’s New Clinical Policy on Severe Agitation”. ACEPNow. Published online February 12, 2024. Accessed March 06, 2024. <https://www.acepnow.com/article/aceps-new-clinical-policy-on-severe-agitation/?singlepage=1>
- Westafer L. “Which Sedatives Are Best for Managing Severe Agitation in the Emergency Department?” ACEPNow. Published online December 11, 2023. Accessed March 07, 2024. https://www.acepnow.com/article/which-sedatives-are-best-for-managing-severe-agitation-in-the-emergency-department/?singlepage=1
- Zun LS. Evidence-Based Review of Pharmacotherapy for Acute Agitation. Part 1: Onset of Efficacy. J Emerg Med. 2018 Mar;54(3):364-374. doi: 10.1016/j.jemermed.2017.10.011. Epub 2018 Feb 1. PMID: 29361326.
- 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. doi: 10.1016/j.jemermed.2018.12.036. Epub 2019 Feb 10. PMID: 30745194.N
- Taylor DM, Yap CY, Knott JC, et al. “Midazolam-droperidol, droperidol, or olanzapine for acute agitation: a randomized clinical trial”. Ann EmergMed. 2017;69(3):318-326.
- Siegel RB, Motov SM, Marcolini EG. “Droperidol Use in the Emergency Department: A Clinical Review”. J Emerg Med. 2023;64(3):289-294.
- ACEP Policy statement: Use of Droperidol in the Emergency Department. Available from the ACEP clinical policy website. Published January 2021. Accessed March 07, 2024. https://www.acep.org/patient-care/policy-statements/use-of-droperidol-in-the-emergency-department
- Horner F, Hoffman RS, Nelson LS, Howland M. Benzodiazepines. In: Nelson LS, Howland M, Lewin NA, Smith SW, Goldfrank LR, Hoffman RS. eds. Goldfrank's Toxicologic Emergencies, 11e. McGraw-Hill Education; 2019. Accessed March 19, 2024. https://accessemergencymedicine-mhmedical-com.nmcsd.idm.oclc.org/content.aspx?bookid=2569§ionid=210263172
- Mokhtari A, Yip O, et al. Prophylactic Administration of Diphenhydramine to Reduce Neuroleptic Side Effects in the Acute Care Setting: A Systematic Review and Meta-Analysis. J Emer Med 2020;60(2):165-174.
- Abrencillo R, Simoff M, et al. Diphenhydramine as an Adjunct to Conscious Sedation in Bronchoscopy. Chest 2016;150(4):980A.
- Tu RH, Grewall P, Leung JW, Suryaprasad AG, Sheykhzadeh PI, Doan C, Garcia JC, Zhang N, Prindiville T, Mann S, Trudeau W. Diphenhydramine as an adjunct to sedation for colonoscopy: a double-blind randomized, placebo-controlled study. GastrointestEndosc. 2006 Jan;63(1):87-94. doi: 10.1016/j.gie.2005.08.015. PMID: 16377322.