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Ketamine vs Midazolam-Haloperidol for Acute Agitation

September 24, 2021

Written by Sam Parnell

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Use of intramuscular ketamine for patients with severe agitation resulted in significantly shorter time to sedation compared to a combination of intramuscular midazolam and haloperidol (5.8 vs 14.7 minutes).

Why does this matter?
Severe psychomotor agitation is a life-threatening condition that requires rapid treatment to ensure both patient and staff safety as well as the ability to evaluate, monitor, and treat underlying pathology or associated injuries. Pharmacologic treatment of severe agitation is usually achieved with monotherapy (as we discussed yesterday) or combination therapy, with medications such as benzodiazepines, antipsychotics, and occasionally anticholinergic agents like diphenhydramine or benztropine (i.e., the classic “B52” approach). However, these medications are associated with significant risks, including respiratory depression, QT prolongation, extrapyramidal symptoms, and neuroleptic malignant syndrome. Furthermore, onset of action can be prolonged, especially for intramuscular (IM) administration. Ketamine is another medication that has been studied for treatment of agitated and violent patients and has the advantages of rapid dissociation, preservation of respiratory drive, and a favorable cardiovascular profile. So how does ketamine stack up compared to the frequently used combination of midazolam and haloperidol?

Good night, sleep tight, don’t let the patient bite…
This was a blinded, randomized controlled trial at a single site ED in Vancouver, Canada from June 30, 2018 to March 13, 2020. A total of 80 adult patients with severe agitation were included. Unfortunately, the study was ended early due to COVID-19 mandated restrictions, and the targeted sample size was not reached. Patients were randomized to receive either ketamine (5mg/kg IM) or a combination of midazolam/haloperidol (5mg/5mg IM). Onset of action, level of sedation, and adverse events were compared between the two groups.

Median time to sedation was significantly shorter in the ketamine group compared to the midazolam/haloperidol group (5.8 minutes vs 14.7 minutes). At every time interval studied, a greater proportion of patients receiving ketamine were adequately sedated. The use of rescue medications was similar (ketamine 13% vs midazolam/haloperidol 15%). However, more patients in the ketamine arm experienced serious adverse events compared to the midazolam/haloperidol arm (12.5% vs 5%). Adverse events included apnea, hypoxia, laryngospasm, and dystonia. One patient in the ketamine group experienced laryngospasm that resolved with airway repositioning, but no patients required intubation or ICU admission. This difference in adverse events did not reach statistical significance, and the authors concluded they did not have an adequate sample size to assess for potential differences in safety.

In conclusion, it appears that ketamine allows for more rapid chemical sedation and control of agitation compared to a combination of midazolam and haloperidol. However, there was concern for more adverse events with ketamine, and all these patients require close monitoring to reduce the risk of potential complications.

Rapid Agitation Control With Ketamine in the Emergency Department: A Blinded, Randomized Controlled Trial. Ann Emerg Med. 2021 Aug 2;S0196-0644(21)00433-9. doi: 10.1016/j.annemergmed.2021.05.023. Online ahead of print.

2 thoughts on “Ketamine vs Midazolam-Haloperidol for Acute Agitation

  • The adverse effects could be related to the high dose of ketamine (5 mg/kg). In our practice we use 1 mg/Kg IM in agitates patients, with good results and low adverse effects.

  • I agree with Juan Pablo Gonzalez. The Ketamine seems pretty high dose compared to the somewhat standard dose of 5 mg MDZ + 5 mg Aloperidol. Could this be the reason why they saw much more sedation (and more adverse events) in the Ketamine branch?

What are your thoughts?