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 still had a statistically and clinically

Outcomes for 301 patients given emergency intramuscular sedation with midazolam or haloperidol-promethazine mix because of on 30 September 2021 by guest. Protected copyright. agitation and dangerous behaviour. Values are number (percentage) of patients unless stated otherwise

Haloperidol-promethazine Patient outcomes Midazolam (n=151) (n=150) Relative risk (CI)* Difference in % risk (CI)* By 20 minutes after injection Tranquil or asleep 134 (89) 101 (67) 1.32 (1.16 to 1.49) 22 (12 to 30) Asleep 93 (62) 43 (29) 2.15 (1.48 to 3.11) 33 (19 to 47) Serious adverse effect 1 (1) 1 (1) Unknown 1 (1) 2 (1) By 40 minutes after injection Tranquil or asleep 141 (93) 124 (83) 1.13 (1.01 to 1.26) 10 (1 to 20) Asleep 118 (78) 69 (46) 1.70 (1.32 to 2.19) 32 (18 to 46) Unknown 1 (1) 2 (1) By 60 minutes after injection Tranquil or asleep 141 (93) 131 (87) 1.07 (0.97 to 1.18) 6 (−3to15) Asleep 120 (79) 83 (55) 1.44 (1.16 to 1.78) 24 (11 to 38) Unknown 1 (1) 2 (1) By 120 minutes after injection Tranquil or asleep 144 (95) 138 (92) 1.04 (0.96 to 1.12) 3 (−4to11) Asleep 125 (83) 95 (63) 1.31 (1.08 to 1.57) 20 (7 to 32) No additional tranquillising drugs 149 (99) 143 (95) 1.04 (0.98 to 1.09) 4 (−2to8) Not needing restraints 118 (78) 110 (73) 1.07 (0.90 to 1.26) 5 (−8to18) Unknown 1 (1) 2 (1) *99% confidence intervals, except for primary outcome (tranquil or asleep by 20 minutes), which is 95%.

BMJ VOLUME 327 27 SEPTEMBER 2003 bmj.com 709 Papers BMJ: first published as 10.1136/bmj.327.7417.708 on 25 September 2003. Downloaded from significant 13% relative advantage. By an hour, about What is already known on this topic 90% of both groups were tranquil or asleep. Twice as many of the patients given midazolam Emergency tranquillisation of violent mentally ill were asleep by 20 minutes as were those given people is sometimes necessary haloperidol-promethazine. This difference remained statistically and clinically significant up to two hours Guidelines differ on which drugs to use, and the after injection. Midazolam rapidly sedated patients and evidence is limited and unconvincing kept most sedated for up to two hours. The What this study adds haloperidol-promethazine mix tranquillised and sedated patients, but with a slower onset of action. This large pragmatic randomised study in Rio de Two severe adverse events were reported, one in Janeiro compared midazolam with a mixture of each group and both within the first 20 minutes after haloperidol plus promethazine drug administration. One aggressive woman who had epilepsy was given haloperidol (5 mg) plus promethaz- By 20 minutes after injection, midazolam ine (50 mg) and had a grande mal seizure 15 minutes tranquillised 89% of people compared with 67% after injection. With benzodiazepines, she settled and tranquillised by haloperidol-promethazine recovered swiftly. A man with alcohol induced, and perhaps also cocaine induced, aggression was given Serious adverse effects for both treatments were midazolam (15 mg). His respiratory rate fell immedi- rare, but resources to deal with them should be ately, and he became cyanotic; by 15 minutes his respi- considered in the choice of the treatment ratory rate was 32 breaths/minute. He recovered fully after being given flumazenil 0.25 mg intravenously. Additional tranquillising drugs were rarely needed other settings, but the resources available for managing in the first two hours, and no difference between the adverse effects should be considered. groups was apparent. Restraints were used for 73 Few of the patients required additional drugs in the people, with no statistically significant difference first two hours after treatment, but a fifth of patients between the groups, though the fact that 5% fewer were restrained during this period. In Rio de Janeiro it people in the midazolam group needed restraints by is more common to put patients who are still not tran- two hours may be considered clinically significant. quillised in restraints rather than giving them more 7 During the first 24 hours, 74 people had another drugs. significant episode of aggression. Although there was Strengths and limitations of study no statistically significant difference between the two Trials evaluating the management of aggressive or vio- treatments, 6% more of the patients given midazolam lent people are rare and usually small. TREC is large in experienced a second episode of aggression. comparison, with a completeness of data collection not Most of the patients accepted oral medication, and seen even in short duration randomised trials for psy-

giving a benzodiazepine did not seem to affect patients’ choses. The pragmatic design, rare in mental health http://www.bmj.com/ total load of antipsychotic drugs in the first 24 hours. trials, simplified rather than complicated everyday The mean doses in chlorpromazine equivalents during practice. This strategy increased the chance of selecting the first 24 hours were 368 mg (SD 283, median 333) a sample of patients representative of those who for the midazolam group, and 355 mg (SD 267, usually attend the emergency rooms. median 333) for the haloperidol-promethazine group This study evaluated the open giving of the two (two sided permutation test P = 0.67). treatments. Blinding of outcome was never envisaged, After two weeks, 73 (48%) of the patients who had and the experienced healthcare professionals who been given midazolam were discharged, compared participated could accurately tell if and when a person on 30 September 2021 by guest. Protected copyright. with 69 (46%) of those given haloperidol- was asleep or tranquil. promethazine (relative risk 1.05 (0.77 to 1.44)). Conclusions Both treatments worked, but midazolam was clearly more effective than haloperidol-promethazine in Discussion terms of rapid sedation. Serious adverse effects for This study evaluated the effect of two widely available both treatments were rare, and should never threaten and inexpensive drug treatments for emergency life. Health professionals might prefer to use tranquillisation of aggressive or agitated patients with midazolam in circumstances where rapid sedation is mental illness. Relatively low doses of both treatments necessary and after which good observation is possible. were rapidly effective. However, about a third more Where good observation is impossible, or rapid people given midazolam were tranquil or asleep by 20 sedation not paramount, the haloperidol- minutes compared with those given haloperidol- promethazine mix might be preferred. promethazine. One in five people remained disturbed The success of this trial is due to the work, skill, and enthusiasm for 40-60 minutes longer if given haloperidol- of 37 doctors and 96 nurses and clerks from the psychiatric hos- promethazine rather than midazolam. Tranquillisation pitals of Rio de Janeiro—Instituto Phillipe Pinel, Hospital to sleep was more common with midazolam than with Municipal Jurandyr Manfredini, and Instituto Municipal de haloperidol-promethazine. Use of the benzodiazepine Assistência à Saúde Nise da Silveira. We thank Lelia Duley and Gill Rizzello for help with the final manuscript. had no apparent consequences for long term care. The members of the TREC Collaborative Group are: Gisele Huf Both drug regimens seemed reasonably safe. The (Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil); results of this study are applicable to general Evandro S F Coutinho (Fundação Osvaldo Cruz, Rio de emergency rooms and inpatients in psychiatric and Janeiro); Clive E Adams (University of Leeds, Leeds); Raul V S

710 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 Borges, Marco A V Ferreira, Francisco J F Silva, André J C R the mentally ill in Rio de Janeiro). TREC was also approved by Pereira, Francisca M Abreu, Simone M Lugão (Instituto Munici- the National Council of Ethics in Research. pal Philippe Pinel, Rio de Janeiro); Marcelo P C P Santos, Marcio Gewandsznajder, Valéria R P Mercadante (Hospital 1 McAllister-Williams RH, Ferrier IN. Rapid tranquillisation: time for a Municipal Jurandyr Manfredini, Rio de Janeiro); Walmor Lange reappraisal of options for parenteral therapy. Br J Psychiatry Jr, Carla L Dias (Instituto Municipal de Assistência à Saúde Nise 2002;180:485-9. da Silveira, Rio de Janeiro). The members of the TREC Steering 2 Kaplan HI, Sadock BJ, Grebb JA. Kaplan and Sadock’s synopsis of psychiatry. 7th ed. Baltimore: Williams and Wilkins, 1994. Committee and Data Monitoring Committee are listed on 3 Expert Consensus Guideline Group. Treatment of schizophrenia 1999. bmj.com. The expert consensus guideline series. J Clin Psychiatry 1999;60(suppl Contributors: See bmj.com 11):3-80. 4 Wing JK, Marriott S, Palmer C, Thomas V. The management of imminent Funding: No participating centre directly received funds for violence: clinical practice guidelines to support mental health services. London: involvement in TREC. GH undertook TREC as part of her work Royal College of Psychiatrists, 1998. (Occasional paper OP41.) funded by the Ministry of Health, Brazil. TREC was jointly 5 Cunnane JG. Drug management of disturbed behaviour by psychiatrists. funded by Fundação Osvaldo Cruz, the Cochrane Schizophre- Psychiatr Bull 1994;18:138-9. 6 Binder RL, McNiel DE. Emergency psychiatry: contemporary practices in nia Group, the British Council, CAPES (Coordenação de Aper- managing acutely violent patients in 20 psychiatric emergency rooms. feiçoamento de Pessoal de Nível Superior), and FAPERJ Psychiatr Serv 1999;50:1553-4. (Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro). 7 Huf G, da Silva Freire Coutinho E, Fagundes HM Jr, Oliveira ES, Lopez JR, All salary funding was intramural. Drugs used in the trial were Gewandszajder M, et al. Current practices in managing acutely disturbed patients at three hospitals in Rio de Janeiro-Brazil: a prevalence study. BMC supplied by the local government through Secretaria Municipal Psychiatry 2002;2:4. www.biomedcentral.com/1471-244X/2/4 de Saúde do Rio de Janeiro. A computer was given by the 8 Dorevitch A, Katz N, Zemishlany Z, Aizenberg D, Weizman A. Intramus- Resource Centre for Randomised Controlled Trials cular flunitrazepam versus intramuscular haloperidol in the emergency (www.rcrt.ox.ac.uk/). treatment of aggressive psychotic behavior. Am J Psychiatry 1999;156:142-4. Competing interests: None declared. 9 World Health Organization. The WHO model list of essential drugs Ethical approval: TREC was approved by ethics committees (EDL 1999). www.who.int/medicines/organization/par/edl/infedlmain. from Escola Nacional de Saúde Pública Fundação Oswaldo shtml (accessed 3 Apr 2002). 10 Huf G, Coutinho ES, Adams CE. TREC-Rio trial: a randomised control- Cruz, Instituto Phillipe Pinel, and Hospital Municipal Jurandyr led trial for rapid tranquillisation for agitated patients in emergency psy- Manfredini, Instituto Municipal de Assistência à Saúde Nise da chiatric rooms [ISRCTN44153243]. BMC Psychiatry 2002;2:11. Silveira and by the members of the Consumer Advocate Group www.biomedcentral.com/1471-244X/2/11 of Rio de Janeiro (SOSINTRA—Society of family and friends of (Accepted 10 July 2003)

Drug points

Fatal lactic acidosis associated with tenofovir Tenofovir is being increasingly used even though its Division of safety is not certain.2 Because of its low affinity for Infectious Diseases,

Pablo Rivas, Jorge Polo, Miguel de Górgolas, Manuel L Fundación Jiménez http://www.bmj.com/ Fernández-Guerrero mitochondrial DNA polymerase , tenofovir may be less Díaz, Universidad Recently introduced, tenofovir disoproxil is the first toxic to mitochondria than nucleoside analogues and less Autónoma de 34 Madrid, Avda Reyes nucleotide analogue for treating HIV-1 infection.1 We likely to cause hyperlacticacidaemia. But we believe that tenofovir was central to the onset of hyperlacticacidaemia Católicos 2, 28040, report a fatal case of lactic acidosis during treatment with Madrid, Spain tenofovir. because the woman died soon after taking the drug. Pablo Rivas A 45 year old woman presented with vomiting, The woman had taken stavudine and didanosine with- medical doctor abdominal pain, and obtundation. She was HIV positive out side effects. Tenofovir may have directly caused lactic Jorge Polo and had been recently treated with a combination of dida- acidosis or may have affected the toxicity of the other medical doctor nosine, stavudine, and nevirapine and had chronic hepati- drugs. Taking tenofovir and didanosine together can Miguel de Górgolas on 30 September 2021 by guest. Protected copyright. medical doctor tis C. Because concentrations of liver enzymes had increase didanosine concentrations by 60%, leading to hyperlacticacidaemia.5 Patients who take tenofovir and Manuel L increased eight weeks before admission, nevirapine was Fernández-Guerrero stopped; concentrations then returned to initial values. didanosine should be closely monitored. Doses of didano- medical doctor Admitting doctors prescribed enteric coated didanosine sine should allow for simultaneous use of tenofovir. Correspondence to: (250 mg a day), stavudine (30 mg twice a day), and tenofo- P Rivas vir (300 mg a day). Funding: None. pablorivasg@ Three days before admission she had developed vom- Competing interests: None declared. hotmail.com iting, abdominal pain, and then confusion and obtunda- tion. On admission she was jaundiced and disoriented, BMJ 2003;327:711 1 FDA approves Viread for HIV-1 infection. FDA Consum 2002;36:5. and we felt tender hepatomegaly. Laboratory values were 2 Cheng A, Barriere S, Coackley DF, Chen SS, Wulfsohn M, Toole JJ. Safety serum aspartate aminotransferase 2.35
kat/l (normal profile of Tenofovir DF in antiretroviral treatment-experienced patients range 0.18-0.58
kat/l), serum alanine aminotransferase from randomized, double-blind, placebo-controlled clinical trials. 14th International AIDS Conference, Barcelona, July 2002. (Abstract No 2.68 (0.08-0.72)
kat/l, total bilirubin 215.46 (1.71-22.23) TuPeB4460.)
mol/l, amylase 9.35 (0-1.67)
kat/l, lipase 57.58 3 Birkus G, Hitchcock MJ, Cihlar T.Assessment of mitochondrial toxicity in (1.9-4.77)
kat/l, international normalised ratio for human cells treated with tenofovir: comparison with other nucleoside co reverse transcriptase inhibitors. Antimicrob Agents Chemother 2002;46:716- prothrombin time 2.12, blood pH 7.24, P 2 2.38 23. (4.66-5.99) kPa, sodium bicarbonate 11.4 (22-26) mmol/l, 4 Kakuda TN. Pharmacology of nucleoside and nucleotide reverse and lactic acid 16.38 (0.6-1.7) mmol/l. Computed tomog- transcriptase inhibitor-induced mitochondrial toxicity. Clin Ther raphy showed fatty infiltration of the liver and slight 2000;22:685-708. 5 Kearney BP, Damle B, Plummer A, Sayre J, Zhang X, Ryan K, et al. Teno- enlargement of pancreas. fovir DF (TDF) and Didanosine EC (ddI EC): investigation of We discontinued antiretrovirals and gave her bicarbo- pharmacokinetic (PK) drug-drug and drug-food interactions. 14th Inter- nate, vitamin K, thiamin, and riboflavin. Unfortunately, national AIDS Conference, Barcelona, July 2002. (Abstract No LbPeB9026.) lactic acidosis worsened; she developed severe bleeding and died 36 hours later. (Accepted 4 June 2003)

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