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Barbic D, et al. "Rapid Agitation Control With Ketamine in the Emergency Department: A Blinded, Randomized Controlled Trial". Annals of Emergency Medicine. 2021. 78(6):788-795.
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Clinical Question

In agitated patients that present to the Emergency Department with a RASS score of at least +3 or greater, does ketamine calm them faster than a fixed dose combination of midazolam plus haloperidol.

Bottom Line

Ketamine calmed agitated patients in the Emergency department faster than the combination of a benzodiazepine and haloperidol but it is unknown the duration of effect.

Major Points

Walking a difficult balance, calming an agitated patient can be a challenging experience to calm them sufficiently that they no longer pose a safety risk to themselves or the staffs attempting to provide care, but not overly sedating them for a prolonged period. Common use of benzodiazepine and antipsychotics have been common place for this purpose but both classes carry significant risk of adverse effects and long duration of sedation. Use of ketamine[1] at different doses[2] has been an attractive option and has started being used in some health systems for some time.[3] In this single centre, parallel-arm, blinded randomized control trial, they compared patients to receive ketamine 5mg/kg intramuscularly (n=39) to midazolam 5mg + haloperidol 5mg as a single intramuscular injection (n=40). They found that the combination midazolam+haloperidol was significantly slower than ketamine [14.7 minutes vs. 5.8minutes (difference 8.8, 95% CI 3-14.5)] for time to adequate sedation. They also found that more midazolam+haloperidol required rescue medications (15% vs 13%) and more serious adverse events occurred in the ketamine arm (5% vs 12.5%.) Due to the SARS CoV-2 global pandemic and a moratorium on research activities, this trial did not reach their proposed sample size. With it we may have drawn a better picture of the adverse events. There was also an imbalance in sex in each arm and the levels of agitation at baseline. This trial also only tracked the patients for 30 minutes so we cannot comment on the duration of effect past that point.


As of March 2022, no guidelines have been published that reflect the results of this trial.


  • Single-centre, parallel-arm, blinded, randomize controlled trial
  • N=80
    • Ketamine (n=39)
    • Midazolam+haloperidol (n=40)
  • Setting: Tertiary care centre in Vancouver, Canada
  • Enrollment: June 30, 2018 to March 13, 2020
  • Analysis: Per Protocol
  • Primary Outcome: time to adequate sedation


Inclusion Criteria

  • 19 to 60 years old
  • severe psychomotor agitation [Richmond Agitation Score (RASS) greater or equal to +3]

Exclusion Criteria

  • previously enrolled
  • in police custody
  • suspected or known pregnancy or breastfeeding
  • known hypersensitivity/intolerance/allergy to study medication
  • History of CVA

Baseline Characteristics

Ketamine Group displayed

  • Demographics: median age 35 years, Female 15%, arrival with paramedics 69%, arrival with police 88%
  • Initial RASS +3 36%, +4 64%
  • Median physiologic parameters: pulse 104, respiratory rate 20, systolic blood pressure 135, temperature 37.2 degrees centigrade


  • ketamine 5mg/kg intramuscularly
  • midazolam 5mg + haloperidol 5mg as a single intramuscular injection


Comparisons are midazolam+haloperidol vs. ketamine.

Primary Outcomes

Median time to sedation (minutes)
14.7 vs. 5.8 (difference 8.8, 95% CI 3-14.5)
unadjusted (HR 2.39, 95% CI 1.46 to 3.90)
adjusted (HR 2.43, 95% CI 1.43 to 4.12)

Secondary Outcomes

Patients requiring rescue medications
15% vs. 13%

Adverse Events

Serious adverse drug reaction
5% vs. 12.5%
Apnea (<5 Minutes)
2.5% vs. 5%
Supplemental O2
2.5% vs. 2.5%
Laryngospasm (Treated with jaw thrust)
0 vs. 2.5%
0 vs. 2.5%


  • single urban centre
  • did not reach sample size (due to pandemic restrictions)
  • imbalance of sex in arms (male 85% ketamine, 50% comparator)
  • imbalance of initial agitation level between arms
  • only followed patients for 30 minutes, unclear duration of effect and requirement of rescue medications


  • peer-reviewed funding from the Vancouver Coastal Health and Providence Health Care Research Institutes
  • Canadian Association of Emergency Physicians

Further Reading