Article Identification

• Article title: Rapid tranquillisation in psychiatric emergency settings in India: pragmatic randomised controlled trial of intramuscular olanzapine versus intramuscular haloperidol plus promethazine
• Citation: Raveendran NS, Tharyan P, Alexander J, Elliot C, Adams CE, TREC-India II Collaborative Group. BMJ. 2007; approximately.
• DOI/PMID: DOI: 10.1136/bmj.39341.608519.BE

Quick Reference Summary

• Primary Outcome: At 15 minutes, 87% of patients receiving intramuscular olanzapine were tranquil or asleep compared to 91% with haloperidol plus promethazine (relative risk 0.96, 95% CI: 0.34 to 1.47). At 240 minutes, 96% vs. 97% achieved the primary outcome (relative risk 0.99, 95% CI: 0.95 to 1.03), showing no statistically significant difference.
• Additional Findings: Patients treated with olanzapine required additional medical interventions in 43% of cases versus 21% with haloperidol plus promethazine (relative risk 2.07, 95% CI: 1.43 to 2.97, p < 0.05).

Core Clinical Question

Does intramuscular olanzapine compare to intramuscular haloperidol plus promethazine in achieving rapid tranquillisation and sedation in agitated or violent psychiatric patients within emergency settings in India?

Background

• Disease Overview: Severe mental disorders affect approximately 15 million people in India, with agitation or violent behavior presenting in about 10% of psychiatric emergency cases worldwide.
• Prior Data:
  • Previous TREC trials in India and Brazil demonstrated the efficacy and safety of haloperidol plus promethazine for rapid tranquillisation.
  • Industry-sponsored trials of olanzapine showed effectiveness but often excluded severely violent patients, limiting real-world applicability.
• Current Standard of Care: Intramuscular haloperidol plus promethazine is widely used in low and middle-income countries for managing acute agitation in psychiatric emergencies.
• Knowledge Gaps:
  • Comparative effectiveness of olanzapine versus haloperidol plus promethazine in real-world settings.
  • Long-term outcomes and need for additional interventions post-tranquillisation.
• Study Rationale: To evaluate whether intramuscular olanzapine offers similar or superior efficacy and safety compared to the established haloperidol plus promethazine combination in a pragmatic, real-life clinical setting in India.

Methods Summary

• Study design: Pragmatic, allocation-concealed, randomised controlled trial.
• Setting and time period: Emergency services of a general hospital psychiatry department in Vellore, South India, from September 2005 to July 2006.
• Population characteristics: 300 adults presenting with agitated or violent behavior due to mental illness.
• Inclusion/exclusion criteria: Included adults requiring intramuscular sedation; excluded those without a responsible relative, seizures, diabetes, alcoholic liver disease, or those managed by other methods.
• Intervention details:
  • Olanzapine group: Intramuscular olanzapine (5 mg or 10 mg).
  • Control group: Intramuscular haloperidol (5 mg or 10 mg) plus promethazine (25 mg or 50 mg).
• Control/comparison group details: Haloperidol plus promethazine combination administered as per prevailing clinical practice.
• Primary and secondary outcomes:
  • Primary: Proportion tranquil or asleep at 15 and 240 minutes.
  • Secondary: Proportion tranquil, asleep, restrained, absconding, or clinically improved at various time points; additional medical interventions; adverse effects; compliance with oral drugs at two weeks.
• Basic statistical analysis approach: Relative risks, number needed to treat (NNT), confidence intervals, repeated measures ANOVA, Mann-Whitney U test.
• Sample size calculations: 300 patients to detect a 20% difference with 80% power at a 5% significance level.
• Ethics and funding information: Approved by the institutional review board of Christian Medical College, Vellore. Funded by an intramural grant from the fluid research fund of the same institution. No declared conflicts of interest.

Results

• Participant flow and demographics: 364 patients assessed; 300 randomized (150 to each group). Follow-up data available for primary outcomes for 298 (99%). Groups were similar in age (~30 years), sex distribution (~61-65% male), diagnoses (schizophrenia, mania, depression, acute psychosis), and severity of illness.
• Primary outcome results:
  • At 15 minutes: 87% (131/150) olanzapine vs. 91% (136/150) haloperidol plus promethazine (RR 0.96, 95% CI: 0.34 to 1.47).
  • At 240 minutes: 96% (144/150) vs. 97% (145/150) (RR 0.99, 95% CI: 0.95 to 1.03).
• Secondary outcome results:
  • Additional medical interventions: 43% (65/150) olanzapine vs. 21% (31/150) haloperidol plus promethazine (RR 2.07, 95% CI: 1.43 to 2.97).
  • Adverse effects: 2% olanzapine vs. 0.6% haloperidol plus promethazine.
  • Restraints: 6% more in olanzapine group over four hours, not statistically significant.
• Subgroup analyses: Not detailed, but overall evaluation did not find significant subgroup differences.
• Adverse events/safety data: Minimal; olanzapine group had minor adverse effects like akathisia and nausea, while haloperidol plus promethazine group had transient hypotension in one patient.

Results Table

Outcome	Olanzapine Group	Haloperidol plus Promethazine Group	Difference (95% CI)	P-value
Primary Outcome Tranquil or asleep at 15 mins	131/150 (87%)	136/150 (91%)	+3.3 (-3.7 to 10.4)%	<0.05*
Tranquil or asleep at 240 mins	144/150 (96%)	145/150 (97%)	+0.67 (-3.6 to 4.9)%	<0.05*
Secondary Outcomes Additional medical interventions	65/150 (43%)	31/150 (21%)	+20.0 (10.0 to 30.0)%	<0.05
Adverse effects	3/150 (2.0%)	1/150 (0.6%)	+1.3 (-1.3 to 3.9)%	-
Absconded	5/150 (3.4%)	0	1.0 (-0.1 to 2.7)	-
Doctor called back	49/150 (33%)	23/150 (15%)	+17.3 (7.9 to 26.8)%	<0.05
Restraints after injection (240 mins)	24/150 (16%)	15/150 (10%)	+6.0 (-1.6 to 13.6)%	-

*Primary outcomes: tranquil or asleep at 15 and 240 minutes.

Authors' Conclusions

• Primary conclusions: Both intramuscular olanzapine and haloperidol plus promethazine are effective for rapid tranquillisation and sedation in agitated or violent psychiatric patients. However, haloperidol plus promethazine required fewer additional medical interventions within four hours post-intervention.
• Clinical implications: In emergency settings, especially busy and resource-limited ones, haloperidol plus promethazine may be preferred over olanzapine due to its sustained tranquillisation effect and reduced need for further interventions.
• Future research: Further studies are needed to evaluate long-term safety, effectiveness in more diverse and severely violent populations, and cost-effectiveness analyses.

Critical Analysis

A. Strengths

• Methodological strengths:
  • Central random allocation and allocation concealment minimized selection bias.
  • Pragmatic trial design enhanced external validity by mimicking routine clinical practice.
  • High follow-up rate (99% for primary outcomes) ensured data reliability.
  • Reliable blinding of outcome assessors reduced measurement bias.
  • Sufficient sample size to detect meaningful differences in primary outcomes.

B. Limitations

• Study design limitations:
  • Open-label administration post-randomization could introduce performance bias; however, primary outcomes were assessed blindly.
  • Lack of placebo control limits assessment of absolute efficacy; ethical considerations justified this choice.
• Generalizability issues:
  • Conducted in a single hospital in South India; results may differ in other geographic or cultural settings.
  • Excluded patients without a responsible relative or those managed by other methods, potentially limiting applicability to all emergency scenarios.

Literature Review

A. Positioning the Current Study in Existing Evidence

The management of acute agitation and violence in psychiatric emergency settings is critical for ensuring patient and public safety. Several studies and guidelines have sought to identify the most effective pharmacological interventions for rapid tranquillisation.

Key Previous Studies:

• TREC Trials in Brazil and India:
  • Demonstrated the efficacy and safety of haloperidol plus promethazine in managing severe agitation with minimal extrapyramidal side effects.
  • Confirmed similar findings, supporting the combined use of haloperidol and promethazine in real-world settings.
• Industry-Sponsored Olanzapine Trials:
  • Often excluded highly violent or severely disturbed patients.
  • Utilized placebo arms or narrower populations, limiting external validity and applicability to emergency scenarios.
  • Found intramuscular olanzapine effective in controlled settings but raised concerns about generalizability to real-life emergency conditions.

Recent Comparative Studies:

• Brazilian Study: Compared various protocols including olanzapine, ziprasidone, haloperidol plus promethazine, haloperidol plus midazolam, and haloperidol alone.

Guidelines and Consensus Statements:

The findings suggest that while intramuscular olanzapine is effective, the increased need for additional interventions may limit its practicality in high-demand emergency settings.

B. Comprehensive Synthesis of Findings

The current study aligns with previous TREC trials, reinforcing the effectiveness and safety of haloperidol plus promethazine for rapid tranquillisation in psychiatric emergencies.

C. Gaps and Future Directions

Despite robust findings, several gaps remain including long-term outcomes, safety profiles, and more diverse populations.

Clinical Application

• The findings suggest that in busy and resource-limited emergency psychiatric settings, intramuscular haloperidol plus promethazine remains an effective choice for rapid tranquillisation.
• Haloperidol plus promethazine should continue to be utilized as a first-line treatment, particularly in settings where sustained tranquillisation is essential to ensure safety.

How To Use This Info In Practice

Practitioners should integrate the evidence supporting haloperidol plus promethazine as a first-line option for rapid tranquillisation with current guidelines, emphasizing its effectiveness and practicality in emergency settings.