Department of Psychiatry, Christian Medical College, Vellore, India
Cochrane Schizophrenia Group and Academic Unit of Psychiatry and Behavioural Sciences, University of Leeds, UK
Department of Psychiatry, Christian Medical College, Vellore, India
Medical Documentation Programme, University of Ulm, Germany
Department of Psychiatry, Christian Medical College, Vellore, India
Correspondence: Dr Jacob Alexander, Department of Psychiatry, Christian Medical College, Vellore 632002, Tamil Nadu, India. Tel: 91 416 2262603, ext. 4259; fax: 91 416 2261632; e-mail: dralexander_in{at}yahoo.com
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ABSTRACT |
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Aims To compare interventions commonly used for controlling agitation or violence in people with serious psychiatric disorders.
Method We randomised 200 people to receive intramuscular lorazepam (4 mg) or intramuscular haloperidol (10 mg) plus promethazine (2550 mg mix).
Results At blinded assessments 4 h later (99.5% follow-up), equal numbers in both groups (96%) were tranquil or asleep. However, 76% given the haloperidolpromethazine mix were asleep compared with 45% of those allocated lorazepam (RR=2.29,95% CI 1.593.39; NNT=3.2,95% CI 2.35.4). The haloperidolpromethazine mix produced a faster onset of tranquillisation/sedation and more clinical improvement over the first 2 h. Neither intervention differed significantly in the need for additional intervention or physical restraints, numbers absconding, or adverse effects.
Conclusions Both interventions are effective for controlling violent/agitated behaviour. If speed of sedation is required, the haloperidolpromethazine combination has advantages over lorazepam.
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INTRODUCTION |
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METHOD |
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Patient selection
Consecutive patients were assessed and were eligible for trial entry if the
attending physician felt that intramuscular sedation was clearly indicated
because of agitation, aggression or violent behaviour, and if the physician
did not feel that either one of the interventions posed an additional risk for
the patient. In keeping with prevailing clinical practice in this country,
consent was obtained from a responsible relative if patients refused, or
lacked capacity to consent to treatment by virtue of severe mental illness.
For this trial relatives were fully informed and their written consent
obtained; patients without a responsible relative were excluded. This trial
compared two low-risk interventions in common use, the relative benefits of
which are unknown. The institutional research and ethics committee approved
the trial design, the consent procedure and the form used.
Sample size
From the existing literature, with tranquillisation of 73% of people given
benzodiazepines and 57% given typical antipsychotics
(Battaglia et al,
1997; Joy et al,
2003), with a power of 80% at 95% confidence intervals and an
expected precision of 20%, the minimum sample size required was 90 people per
arm.
Randomisation and interventions
Eligible patients were randomised to receive either intramuscular
haloperidol (10 mg) and promethazine (25 or 50 mg) mixed in the same syringe,
or intramuscular lorazepam (4 mg). All doses were at the discretion of the
attending doctor, although the recommended dose was 10 mg haloperidol plus 50
mg promethazine, or 4 mg lorazepam. These doses were arrived at by prevailing
clinical practice and a pilot study that showed that at least 4 mg lorazepam
was required to achieve a similar degree of tranquillisation as the
haloperidolpromethazine mix.
Randomisation was according to a computer-generated random numbers list in varying sized blocks of less than 10 prepared by the UK collaborator. This collaborator worked with a member of the TRECIndia team who had no clinical responsibilities in conducting the trial. The team member and a pharmacist prepared consecutively numbered opaque cardboard boxes, identical in appearance and weight, on the outside of which was a form with questions to be completed by the attending doctor while blind to the contents of the box. The boxes contained haloperidol (5 mg x 2 ampoules) plus promethazine (50 mg x 1 ampoules) or lorazepam (4 mg x 1 ampoule), as determined by the randomisation list, one disposable syringe and needle and study follow-up forms. All those involved clinically in the study had no indication of what medicines were in the boxes until they were opened.
Procedure
Once eligibility of a patient was ensured, the next consecutive box was
taken from the emergency cupboard and this constituted randomisation. The duty
doctor recorded the severity of the episode and the initial diagnosis on the
form stuck to the outside of the sealed intervention pack. The box was then
opened and the intervention administered. The patient was then followed up at
15, 30, 60 and 120 min by the treatment team and at 240 min and at 2 weeks by
the study coordinators. Data were also obtained from the case notes as well as
from interviews with relatives and the treatment team.
Blinding
The study was blind until the point of treatment assignment, which
minimised selection bias. After assignment, rating for the first 2 h was not
blind as the management team had to know the prescribed medications. In any
event, TRECIndia evaluated real-world interventions that are not given
blind. The study coordinators, however, who were blind to interventions given,
undertook ratings at 240 min. At this time, they also guessed the allocated
intervention, to assess their blinding.
Outcomes
Patients were rated at each assessment point on whether they were tranquil
or asleep; in addition, the time of onset of tranquillisation and sleep were
noted. Participants were considered to be tranquil when they were calm and not
exhibiting agitated, aggressive or dangerous behaviour. They were considered
to be asleep if, on inspection, they appeared to be sound asleep and were not
aroused by ambient disturbances; the depth of this apparent slumber was not
assessed further. They were also rated on the Clinical Global Impression
Severity (CGIS) scale at entry, and the CGIImprovement
(CGII) scale (Guy,
1976) with respect to aggression and violence, the
SimpsonAngus extrapyramidal side-effects rating scale
(Simpson & Angus, 1970)
and the Barnes Akathisia Scale (Barnes,
1989) at each assessment point; any other clinically important
adverse effect, especially dystonia, was also noted. These assessments were
conducted only on participants who were awake, as extrapyramidal symptoms are
usually not apparent during sleep or, in the case of dystonia or akathisia,
are likely to prevent sleep. Other outcomes within the first 4 h were the use
of additional medication for control of agitated or aggressive behaviour, the
use of physical restraints, the need for further medical attention and numbers
absconding. Participants were also followed up 2 weeks later to check for
adverse effects or adverse outcomes and compliance with oral medication. The
primary outcome was tranquil or asleep by 4 h.
Data analyses
We used double data entry and analysed data using the Statistical Package
for Social Sciences (SPSS) version 9.0 for Windows. We assessed the adequacy
of randomisation by comparing participants' baseline socio-demographic and
clinical characteristics. We compared proportions tranquillised, asleep,
improved (CGI much and very much improved, stipulated in the trial protocol),
requiring restraints, requiring the doctor to be recalled and requiring
additional sedation, all using the chi-squared test, with a continuity
correction, or Fisher's exact test, as appropriate. We calculated relative
risks and an absolute measure, the number-needed-to-treat (NNT), and their 95%
confidence intervals (Altman,
1998) using intention-to-treat analysis. We also used repeated
measures analysis of variance to compare mean CGII scores between
groups across various time points, with being asleep at the follow-up points
entered as a covariate. We used the MannWhitney U-test to
compare mean times to tranquillisation and sedation in the two groups, as the
data did not have a normal distribution. The kappa statistic was used to
evaluate agreement between the blinded guesses of the coordinators regarding
treatment allocation.
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RESULTS |
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All patients allocated to the lorazepam arm received 4 mg of the drug and everyone randomised to haloperidolpromethazine received 10 mg of haloperidol combined with 50 mg (96/100) or 25 mg (4/100) promethazine.
Most patients were male, were diagnosed to have mania (ICD10; World Health Organization, 1992) and were rated as markedly or severely ill (Table 1). Nineteen patients with severe depression with agitation, psychotic or suicidal behaviour were judged to require parenteral medication to prevent harm to themselves or others. Groups were evenly balanced on the numbers on psychotropic medication, mean age and CGI mean scores.
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The study coordinators accurately guessed allocation for 58% of those given lorazepam and 33% of those given the antipsychoticantihistamine combination (k0.68).
Equal numbers of people (96%) were tranquil or asleep by 4 h. The combination treatment, however, resulted in more people being tranquil/asleep by 15 min, 30 min, 1 h and 2 h (Table 2). Haloperidol plus promethazine was also superior to lorazepam in inducing sleep. The 40% difference in favour of the antipsychoticantihistamine mix at 15 min increased to 47% by 30 min but receded to 31% by 4 h. That the combination treatment produced faster onset of tranquillisation/sedation was additionally evident when mean time to onset of tranquillisation/sleep and mean time to sleep were compared (Table 3). Four people given lorazepam were never tranquil, compared with one allocated to the haloperidolpromethazine mix. Twenty-three people given lorazepam failed to sleep at all during the 4-h follow-up compared with only eight in the combination group.
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The haloperidolpromethazine combination also resulted in greater numbers of people being rated as clinically improved (Table 2). Compared with lorazepam, the 31% difference at 15 min in favour of the antipsychoticantihistamine combination receded to 14% at 2 h. By 4 h there was no difference in CGI scores between the two interventions.
The mean scores on the CGII scale over the 4 h of follow-up were entered into repeat measures analysis of variance (Table 4). The CGI scores showed significant differences over time as well as between groups. When being asleep was entered as a covariate to control for differential sedative effects between drugs on clinical improvement ratings, CGI scores continued to show differences over time, but the differences in CGI scores between drugs administered was not significant.
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Despite the superiority of the antipsychoticantihistamine combination in producing sedation, the two interventions did not differ in proportions of people requiring restraint, exhibiting further episodes of agitation or violence and needing additional medication, or in requiring the duty doctor to be recalled (Table 2), nor were there differences for the outcomes of admitted or discharged after 4 h, and lost to follow-up over 4 h and 2 weeks. No differences were evident between interventions in those with different clinical diagnoses, or with respect to age or gender (data available on request). None of those given the combination reported any adverse effects, whereas one person given lorazepam, who had a history of bronchial asthma, complained of moderate worsening of respiratory difficulty and another reported nausea and dizziness following the administration of the benzodiazepine. Two people given lorazepam scored 10 and 18 on the SimpsonAngus scale for extrapyramidal side-effects before the intervention, with no change in scores post-intervention. No other patient scored above zero on the extrapyramidal or akathisia scales before or after the intervention. No patient developed dystonia.
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DISCUSSION |
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Management of agitation and violence in emergency settings: lack of consensus
Drugs commonly used to manage agitation and violence in emergency
situations world-wide include antipsychotics, benzodiazepines and
antipsychotic and benzodiazepine combinations
(Allen, 2002; McAllister-Williams & Ferrier,
2002). More recent strategies include longer-acting drugs such as
zuclopenthixol acetate (Coutinho et
al, 2000) and rapidly acting intra-muscular formulations of
the atypical antipsychotics olanzapine
(Jones et al, 2001) and ziprasidone (Brook et al,
2000).
The recommendations of guidelines for the management of psychiatric emergencies (Royal College of Psychiatrists, 1998; Expert Consensus Guideline Group, 1999) are not evidence-based (Allen, 2002), or are they followed uniformly (Pilowsky et al, 1992; Cunnane, 1994; Binder & McNeil, 1999; Huf et al, 2002a). Evidence from randomised trials and systematic reviews is limited and does not indicate the superiority of zuclopenthixol acetate over conventional antipsychotics (Fenton et al, 2003), or the commonly used combination of haloperidol and benzodiazepines over haloperidol alone (Battaglia et al, 1997). There is a suggestion that benzodiazepines are superior to typical antipsychotics (Battaglia et al, 1997; Allen, 2002) and that haloperidol is superior to placebo (Joy et al, 2003).
Management of violence in middle- and low-income countries
The management of aggressive or violent psychiatric patients in India
includes talking down techniques, physical restraint and
seclusion, as well as the use of medication. The initial minutes and hours are
crucial and drugs that rapidly render people tranquil and/or sedated without
producing distressing or dangerous adverse effects are desirable. In
low-income countries such as India, the high cost of zuclopenthixol acetate
precludes its widespread use; intramuscular atypical antipsychotics are not
available and are likely to be prohibitively expensive.
TRECIndia and TRECRio
TRECIndia, the largest and only study for this comparison,
randomised violent or agitated patients likely to be seen in everyday clinical
practice. It compared two inexpensive, commonly used interventions for
clinically relevant outcomes and lost data on only one person (0.5%) for the
primary outcome and on 18 people for the 2-week follow-up (9%). Although both
interventions are effective for controlling agitated or violent behaviour,
with over 75% in each group tranquil/asleep within 15 min of administration
and 96% in each group tranquil/asleep by 4 h, 10 mg of intramuscular
haloperidol combined with 2550 mg promethazine is superior to 4 mg
intramuscular lorazepam in the speed of onset of sleep and thereby clinical
improvement. If lorazepam is used alone a significant proportion of people
remain awake for longer, potentially exposing everyone to danger.
TRECIndia did not find, however, that the reduced ability of lorazepam
to sedate compared with the combination was accompanied by a greater need for
subsequent intervention or harm to the patient or others.
TRECRio (Huf et al, 2002a,b; TREC Collaborative Group, 2003) randomised 301 people over 6 months to receive either a haloperidolpromethazine mix or intramuscular midazolam. Though midazolam is available in India, it is five-times as expensive as the haloperidol and promethazine mix and is not in common use in psychiatry.
Midazolam consistently induced more rapid tranquillisation and sedation than the haloperidolpromethazine mix. However, the combination treatment in TRECRio was less tranquillising/sedating than in TRECIndia (Table 5). Similar numbers of people in both trials were male, markedly ill and psychotic. In TRECIndia, however, everyone allocated combination treatment received 10 mg haloperidol. In the TRECRio haloperidolpromethazine arm, 77/148 (52%) were given 5 mg haloperidol and 71/148 (48%) were given 10 mg. Most people allocated to the combination treatment in both studies were given 50 mg promethazine. Subgroup analysis of the two different doses of haloperidol in TRECRio, however, did not suggest differences in numbers tranquil/asleep (Evandro Coutinho, personal communication, 2003). However, evaluation of whether the dose of haloperidol matters will require a direct comparison with an adequately large sample.
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TRECIndia did not compare haloperidol alone with a haloperidollorazepam combination, but adding promethazine to haloperidol could be superior to adding lorazepam for promoting tranquillisation and sedation and superior to haloperidol alone for preventing extrapyramidal adverse effects such as acute dystonia or akathisia (Salzman et al, 1991; Battaglia et al, 1997; Brook et al, 2000). No serious adverse effects, particularly those related to the extrapyramidal system, were reported for either treatment, although the moderate worsening of respiratory difficulty reported with lorazepam is in keeping with the known association of benzodiazepines with respiratory depression.
About 15% of people in this trial were physically restrained and less than 10% were given additional medication over the 4 h. This common practice in India and Brazil (Huf et al, 2002a) of physically restraining disruptive patients after administration of a parenteral drug as opposed to administering additional medication requires evaluation.
The two treatment regimens evaluated in this study are inexpensive, effective and available worldwide. Where rapid sedation is needed a combination of intramuscular haloperidol and promethazine is superior to intramuscular lorazepam.
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Clinical Implications and Limitations |
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LIMITATIONS
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ACKNOWLEDGMENTS |
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Received for publication June 30, 2003. Revision received November 26, 2003. Accepted for publication December 15, 2003.
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