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A Randomised Trial of Midazolam Versus Haloperidol

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A Randomised Trial of Midazolam Versus Haloperidol Papers BMJ: first published as 10.1136/bmj.327.7417.708 on 25 September 2003. Downloaded from Rapid tranquillisation for agitated patients in emergency psychiatric rooms: a randomised trial of midazolam versus This is an abridged version; the full haloperidol plus promethazine version is on bmj.com TREC Collaborative Group Correspondence to: Abstract In Rio de Janeiro a relatively low dose mixture of G Huf, haloperidol, a typical neuroleptic, plus promethazine, Universidade Objective To compare two widely used drug Federal do Rio de an antihistamine with sedative and anticholinergic Janeiro, Núcleo de treatments for people with aggression or agitation properties, is used for 80% of severe psychiatric emer- Estudos de Saúde due to mental illness. Coletiva, Av. gencies, and a benzodiazepine is a second choice, both Design Pragmatic, randomised clinical trial. 78 Brigadeiro treatments given intramuscularly. Of the two rapidly Trompowsky s/n, Setting Three psychiatric emergency rooms in Rio de acting benzodiazepines, midazolam and lorazepam, Edifício Hospital Janeiro, Brazil. Universitário 5 only midazolam is available in Brazil as lorazepam is andar, ala sul - Ilha Subjects 301 aggressive or agitated people. unstable at high temperatures. Haloperidol, prometh- do Fundão, Rio de Interventions Open treatment with intramuscular azine, and midazolam are on Rio’s list of essential Janeiro, Brazil, midazolam or intramuscular haloperidol plus 21941-590, Caixa drugs, and haloperidol and promethazine are on the Postal 68037 promethazine. World Health Organization’s model list of essential gisele@ensp. Main outcome measures Patients tranquil or sedated 9 fiocruz.br drugs. at 20 minutes. Secondary outcomes: patients tranquil Although new, atypical antipsychotic drugs may or asleep by 40, 60, and 120 minutes; restrained or BMJ 2003;327:708–11 become available for use in psychiatric emergencies. given extra drugs within 2 hours; severe adverse These drugs are expensive and unlikely to affect the events; another episode of agitation or aggression; care of most people in need of emergency tranquillisa- needing extra visits from doctor during first 24 hours; tion living in low or middle income countries. overall antipsychotic load in first 24 hours; and not discharged by two weeks. Results 151 patients were randomised to midazolam, Methods and 150 to haloperidol-promethazine mix. Follow up for the primary outcome was available for 298 (99%): TREC (tranquilização rápida-ensaio clínico [rapid 134/151 (89%) of patients given midazolam were tranquillisation-clinical trial])was a randomised con- tranquil or asleep after 20 minutes compared with trolled trial performed in three public psychiatric hos- 101/150 (67%) of those given haloperidol plus pitals in the city of Rio de Janeiro, Brazil.10 These promethazine (relative risk 1.32 (95% confidence hospitals cover about 3.5 million people. We designed http://www.bmj.com/ interval 1.16 to 1.49)). By 40 minutes, midazolam still TREC not to interfere with the routine care of people had a statistically and clinically significant 13% relative in the participating centres, so eligibility criteria were advantage (1.13 (1.01 to 1.26)). After 1 hour, about simple and data collection limited to the minimum. 90% of both groups were tranquil or asleep. One important adverse event occurred in each group: a Selection of patients patient given midazolam had transient respiratory Patients were eligible for trial entry if the treating doc- depression, and one given haloperidol-promethazine tor considered that they needed acute intramuscular had a grande mal seizure. sedation because of agitation and dangerous behav- on 30 September 2021 by guest. Protected copyright. Conclusions Both treatments were effective. iour and if the doctor was uncertain which treatment to Midazolam was more rapidly sedating than use. Patients were ineligible if the clinician believed that haloperidol-promethazine, reducing the time people one treatment represented an additional risk for the are exposed to aggression. Adverse effects and patient. resources to deal with them should be considered in the choice of the treatment. Intervention and randomisation We compared the standard treatment, haloperidol plus promethazine (drawn into the same syringe), with Introduction midazolam, both given by intramuscular injection. Doses were at the treating doctors’ discretion. We made Agitated or violent behaviour among patients is flumazenil, a benzodiazepine antagonist, available at particularly prevalent in emergency psychiatric serv- each centre for use in the event of midazolam toxicity. ices (10%),1 where most incidents are secondary to The drugs were randomly packed into identical severe illnesses such as schizophrenia or substance cardboard boxes, sealed firmly with tape, and consecu- misuse.2 Any drugs used to calm such patients should tively numbered. They contained either one ampoule work safely and swiftly. Guidelines differ on which of midazolam 15 mg or two ampoules of haloperidol drugs to use,34 as do surveys of clinicians’ preferred 5 mg plus one of promethazine 50 mg, along with a drug treatments,56 although the broad class of older syringe, needle, swabs, and a follow up form. Members of the generation antipsychotics and benzodiazepines are Verification of order of allocated treatment was moni- TREC Collaborative 17 10 Group are listed at often used. Given the limited and unconvincing tored throughout the study. If a patient met the eligi- the end of the evidence in this subject, variations in guidance and bility criteria, the treating clinician took the next article practice are understandable. consecutive box. 708 BMJ VOLUME 327 27 SEPTEMBER 2003 bmj.com Papers BMJ: first published as 10.1136/bmj.327.7417.708 on 25 September 2003. Downloaded from Outcomes number needed to treat (with 95% confidence The primary outcome of interest for emergency intervals) for primary and secondary outcomes. tranquillisation was “tranquillised or asleep by 20 min- 7 utes,” chosen by an earlier survey. Patients were Results considered tranquillised when they were calm and peaceful—that is, neither agitated nor restless, and not Between June and December 2001, 301 patients were showing threatening verbal behaviour or physical randomised to treatment, 95% between 8 am and mid- aggression against objects, other people, or themselves. night, and 16% at the weekend. For the primary Secondary outcomes were patients asleep by 20 outcome, data were available for 298 (99%) people. minutes; tranquil or asleep by 40, 60, and 120 minutes; Patients in the two treatment groups had similar physically restrained or given additional drugs within baseline characteristics and estimated severity of agita- two hours; severe adverse events; having another tion, suggesting that randomisation was successful. The episode of agitation or aggression; needing extra visits experienced staff estimated most patients to be from the treating doctor during the subsequent 24 markedly disturbed as a result of psychosis. The hours; overall antipsychotic load in the first 24 hours; patients’ demographic and diagnostic characteristics and still in hospital after two weeks. As this study was were as expected from the characteristics of the client designed not to burden routine practice, we were population who receive emergency psychiatric inter- restricted to the information reliably recorded in vention in the three hospitals in Rio de Janeiro. medical notes, such as those adverse effects considered The time from injection to tranquillisation or sleep dangerous. was checked by independent observers for 24 (8%) of the patients. For 22 of these patients there was full Procedures agreement. The two discrepancies resulted from an Before opening a TREC box, and while still blind to the observer’s estimate being 10 minutes greater than that allocated treatment, a participating doctor completed of the attending nurse, and from a tranquillised patient the form printed on its top. This constituted trial entry. being roused to become aggressive again by another This form recorded the doctor’s estimate of the sever- patient. ity and cause of the episode of agitation or Of the 148 patients given haloperidol- 10 aggression. The box was then opened, the treatment promethazine mix, 77 were given 5 mg of haloperidol given, and the outcomes assessed every 20 minutes for and 71 were given 10 mg, while 147 were given 50 mg the first hour by the attending nurse. Other data were of promethazine and one was given 25 mg. Of the 150 extracted from the patient’s notes. patients given midazolam, 124 were given 15 mg and The accuracy of assessment of primary outcome 26 were given 7.5 mg. was checked by other staff not involved in the manage- ment of the emergency. Blind to the allocated Outcomes treatment, and unknown to the clinicians looking after The table shows the outcomes for the two treatments. the patient, they timed the period between injection By 20 minutes after injection, 32% more of the patients http://www.bmj.com/ and tranquillisation or sleep for 10% of patients. given midazolam were tranquil or asleep compared with those given haloperidol-promethazine (number Statistical analysis needed to treat for one extra patient to be We assessed randomisation by comparing socio- tranquillised = 5 (95% confidence interval 3 to 8)). By demographic and clinical characteristics between the 40 minutes, although most patients were tranquil or two treatment groups and calculated relative risks and asleep, midazolam
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