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

Esther W Chan, Kim S J Lao, Lam Lam, Sik-Hon Tsui, Chun-Tat Lui, Chi-Pang Wong, Colin A Graham, Chi-Hung Cheng, Tong-Shun Chung, Hiu-Fung Lam, Soo-Moi Ting, Jonathan C Knott, David M Taylor, David C M Kong, Ling-Pong Leung, Ian C K Wong, Esther W Chan, Kim S J Lao, Lam Lam, Sik-Hon Tsui, Chun-Tat Lui, Chi-Pang Wong, Colin A Graham, Chi-Hung Cheng, Tong-Shun Chung, Hiu-Fung Lam, Soo-Moi Ting, Jonathan C Knott, David M Taylor, David C M Kong, Ling-Pong Leung, Ian C K Wong

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.

Conflict of interest statement

All authors declare that no other support has been received from any organisation for the submitted work; no other financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted study. Outside the submitted work, EWC has received honorarium from the Hospital Authority, research grants from Narcotics Division of the Security Bureau of HKSAR, National Health and Medical Research Council (NHMRC, Australia), National Natural Science Foundation of China (NSFC), Research Fund Secretariat of the Food and Health Bureau (HMRF, HKSAR), Research Grants Council (RGC, HKSAR), Wellcome Trust; Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Janssen, Pfizer, RGA and Takeda outside the submitted work.. KSJL reports personal fees from MSD China, outside the submitted work. ICKW received grants from the Research Grants Council (RGC, Hong Kong), Innovative Medicines Initiative (IMI), Shire, Janssen-Cilag, Eli-Lily, Pfizer, Bayer, European Union FP7 program. ICKW is a member of the National Institute for Health and Clinical Excellence (NICE) ADHD Guideline Group, the British Association for Psychopharmacology ADHD guideline group, and advisor to Shire.

© 2021 The Authors.

Figures

Fig. 1
Fig. 1
Flow Diagram of Patient Inclusion (Modified CONSORT Diagram) a, including other exclusion criteria, patients’ preference, profound risk of adverse event, and multiple exclusion reasons; b, the age of these 3 patients was unknown at recruitment, two patients were found to be over 75 years old, one below 18 years old after treatment; c. two patients were unconscious during the length of stay at Emergency Department and not accompanied by any representative; d, one dose of study drug was discarded due to contamination; e, one dose of study drug was given intravenously; f, allocation of two patients was unblinded due to protocol violation (intravenous route; n = 1) and for informing of the procedural sedation for endoscopy after transfer (5 mg given in Emergency Department; n = 1); g, allocation of three patients was unblinded due to adverse event (n = 2) and for informing of further sedation (10 mg given in Emergency Department; n = 1).
Fig. 2
Fig. 2
Proportion of Patients Adequately Sedated by Time in Kaplan-Meier Curve No included patient was censored during observation. p-values derived by using asymptotic log-rank two-sample test for comparison of midazolam vs olanzapine, midazolam vs haloperidol, and haloperidol vs olanzapine were 0.03, 0.002 and 0.78, respectively.

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Source: PubMed

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