Intramuscular midazolam, olanzapine, or haloperidol for the management of acute agitation: A multi-centre, double-blind, randomised clinical trial

Abstract

Background The safety and effectiveness of intramuscular olanzapine or haloperidol compared to midazolam as the initial pharmacological treatment for acute agitation in emergency departments (EDs) has not been evaluated. Methods A pragmatic, randomised, double-blind, active-controlled trial was conducted from December 2014 to September 2019, in six Hong Kong EDs. Patients (aged 18–75 years) with undifferentiated acute agitation requiring parenteral sedation were randomised to 5 mg intramuscular midazolam ( n = 56), olanzapine ( n = 54), or haloperidol ( n = 57). Primary outcomes were time to adequate sedation and proportion of patients who achieved adequate sedation at each follow-up interval. Sedation levels were measured on a 6-level validated scale (ClinicalTrials.gov Identifier: NCT02380118). Findings Of 206 patients randomised, 167 (mean age, 42 years; 98 [58·7%] male) were analysed. Median time to sedation for IM midazolam, olanzapine, and haloperidol was 8·5 (IQR 8·0), 11·5 (IQR 30·0), and 23·0 (IQR 21·0) min, respectively. At 60 min, similar proportions of patients were adequately sedated (98%, 87%, and 97%). There were statistically significant differences for time to sedation with midazolam compared to olanzapine ( p = 0·03) and haloperidol ( p = 0·002). Adverse event rates were similar across the three arms. Dystonia ( n = 1) and cardiac arrest ( n = 1) were reported in the haloperidol group. Interpretation Midazolam resulted in faster sedation in patients with undifferentiated agitation in the emergency setting compared to olanzapine and haloperidol. Midazolam and olanzapine are preferred over haloperidol's slower time to sedation and potential for cardiovascular and extrapyramidal side effects. Funding Research Grants Council, Hong Kong.

Antipsychotic Drugs or Benzodiazepines for Rapid Tranquilization in Mental Health Facilities or Emergency Department Settings

“…Thirteen relevant reports were identified: 5 SRs, [13][14][15][16][17] 3 RCTs, [18][19][20] 4 observational studies, [21][22][23][24] and 1 clinical practice guideline. 1 Two of the 5 SRs had broader inclusion criteria than the present review.…”

“…All 3 RCTs directly compared 2 or more therapies. [18][19][20] Two RCTs involved a single study centre 19,20 and 1 involved multiple centres within Hong Kong. 18 All 4 observational studies compared 2 or more therapies.…”

“…[18][19][20] Two RCTs involved a single study centre 19,20 and 1 involved multiple centres within Hong Kong. 18 All 4 observational studies compared 2 or more therapies. [21][22][23][24] Three were prospective comparative studies, 21,23,24 while 1 was a retrospective chart review.…”

“…15 Lead authors of 2 SRs were from Italy. 16,17 Among the RCTs, 1 each was from China, 18 Lebanon, 19 and the US. 20 Three observational studies were from the US [21][22][23] and 1 was from Mexico.…”

“…13 The 3 RCTs enrolled somewhat different patient populations. Age of patients enrolled ranged from 18 to 75 years, 18 18 to 65 years, 19 or 18 years and older with no upper limit. 20 Two trials took place in the emergency department 18,20 and 1 in a psychiatric hospital.…”