Article Identification

• Title: Rapid tranquillisation for agitated patients in emergency psychiatric rooms: a randomised trial of midazolam versus haloperidol plus promethazine
• Citation: TREC Collaborative Group. BMJ. 2003;327(7417):708.
• DOI/PMID: 10.1136/bmj.327.7417.708

Quick Reference Summary

• In this pragmatic, randomized clinical trial of 301 agitated or aggressive adults, 89% of those treated with intramuscular midazolam were tranquil or sedated at 20 minutes (vs 67% with haloperidol plus promethazine [RR 1.32, 95% CI 1.16 to 1.49]; p < 0.05).
• By 40 minutes, a clinically significant difference persisted in favor of midazolam (13% advantage), though rates converged by 60 minutes. Adverse events occurred in both groups (one case of respiratory depression in the midazolam arm and one seizure in the haloperidol-promethazine arm).

Core Clinical Question

In adults presenting to psychiatric emergency rooms with severe agitation or aggression, does intramuscular midazolam compared with intramuscular haloperidol plus promethazine more rapidly achieve safe and effective sedation?

Background

• Agitation or aggression occurs in up to 10% of psychiatric emergency presentations, often requiring rapid tranquillisation to ensure safety for both staff and patients.
• Prior data have suggested that typical antipsychotics (such as haloperidol) and benzodiazepines (such as midazolam or lorazepam) are commonly used, but evidence on which agent or combination is most effective and safe is limited.
• Current standard of care: Many clinicians worldwide use a combination of a typical antipsychotic with an antihistamine (e.g., haloperidol plus promethazine) or a benzodiazepine. In Brazil, haloperidol plus promethazine intramuscular injection is the usual front-line treatment; midazolam is second-line.
• Knowledge gaps: Limited comparative data exist regarding the speed of sedation and adverse events of these regimens, leaving clinicians without clear evidence-based guidelines.
• Study rationale: To identify which regimen—midazolam alone or haloperidol plus promethazine—provides more rapid tranquillisation and acceptable safety in real-world psychiatric emergency settings.

Methods Summary

• Study Design: Pragmatic, randomized, open-label clinical trial (TREC) in three psychiatric emergency rooms in Rio de Janeiro, Brazil.
• Setting and Time Period: Conducted in routine care conditions; exact dates not specified.
• Population Characteristics: 301 adults (≥18 years) presenting with acute agitation or aggressive behavior secondary to mental illness.
• Exclusion Criteria: Exclude those with known contraindications to study drugs or significant clinical instability (e.g., compromised airway).
• Intervention: Midazolam (intramuscular) dosed per local protocols.
• Control: Haloperidol plus promethazine (intramuscular) dosed per local protocols.
• Primary Outcome: Proportion of patients tranquil or sedated at 20 minutes.
• Secondary Outcomes: Tranquil or asleep at 40, 60, 120 minutes; Need for restraints or additional medication; Adverse events (e.g., respiratory depression, seizures); Requirement for further medical interventions or sedation over 24 hours; Discharge status by two weeks.
• Statistical Analysis: Rate ratios and 95% CIs calculated for primary outcome.

Detailed Results

• Participant Flow & Demographics: 151 randomized to midazolam, 150 to haloperidol-promethazine. Primary outcome data were available for 298 of 301 participants (99% follow-up).
• Primary Outcome: Midazolam: 134/151 (89%) tranquil or sedated at 20 min; Haloperidol-Promethazine: 101/150 (67%); Relative Risk: 1.32 (95% CI 1.16 to 1.49); p < 0.05
• By 40 Minutes: 13% advantage for midazolam persists; RR 1.13 (95% CI 1.01 to 1.26).
• By 60 and 120 Minutes: Sedation rates converge (~90% sedated in both groups at 60 minutes).
• Adverse Events: One case respiratory depression (midazolam), one seizure (haloperidol-promethazine).

Results Tables

Note: Exact numerical values for some entries are based on depicted results, such as relative risk.

Authors' Conclusions

• Midazolam provided more rapid sedation than haloperidol-promethazine in the first 20–40 minutes, potentially reducing the immediate risk to staff and patients.
• Both regimens were generally effective for sedation by 60 minutes, with rare but important adverse events requiring monitoring.
• Clinical implications: Balance rapid sedation (midazolam) with risk of respiratory depression versus slightly delayed sedation (haloperidol-promethazine) with potential for seizure or extrapyramidal complications.
• Future research: Larger trials to expand on safety profiles and evaluate other drug regimens.

Critical Analysis

A. Strengths

• Randomization minimized selection bias.
• Pragmatic design enhances real-world applicability.
• 99% follow-up rate improves reliability of completion data.

B. Limitations

• Open-label design may introduce performance and detection biases.
• Potential selection bias based on patient's likelihood of receiving one regimen.
• Limited generalizability due to setting, population, and dosing protocol differences.

Literature Context

A. Previous Studies and Meta-Analyses

• Baldacara et al. showed midazolam combinations can facilitate rapid tranquillisation but pose agitation control challenges long-term.
• Mantovani et al. indicated midazolam combinations provide strong agitation control but risk extrapyramidal symptoms with promethazine.

B. Methodological Quality

• The TREC trial provides foundational evidence, though later studies introduced double-blind designs and addressed additional drug arms.
• Findings align with fast onset of benzodiazepines seen in other trials.

Clinical Application

• Midazolam supports faster control of acutely agitated patients in psychiatric emergency rooms, crucial when aggression needs immediate reduction.
• Practitioners should consider potential respiratory risks with benzodiazepines versus seizure or extrapyramidal risks with antipsychotic combinations.

How To Use This Info In Practice

Clinicians may choose midazolam when rapid sedation is essential, monitoring respiratory status, against haloperidol plus promethazine, mindful of extrapyramidal or seizure risk.