Aggressive and violence behaviour is a common behaviour seen in emergency psychiatric presentations (Tardiff & Koenigsberg, 1985) with a prevalence of 3-10% due to a range of psychiatric disorders such as schizophrenia, bipolar, substance use, personality disorders, etc as well as organic disorders such as dementia although they are less frequent (Kaplan & Sadock, 1998). Guidelines (see Table XX) recommend aggressive patients to be ‘verbally tranquilised’ in order for the attending physician to accurately and safely perform a diagnostic history and physical examination. Since aggressive patients make this process difficult and potentially impossible, doctors and nurses face a dilemma and are required to work with limited knowledge. Since the psychiatric team has a responsibility of ensuring the safety of everyone, rapid and safe tranquilisation becomes an unavoidable option. Medication and physical restraints are the available options when planning to tranquilise an agitated patient. Medication can be given orally, intravenously (IV) or intramuscularly (IM). Oral and IV medications are usually not possible when the patient is lashing out aggressively. Physical restraints usually include straitjackets, seclusion room or medical restraints by use of binding patient safely to a bed using two or four points. All options have advantages and disadvantages. For example, IV medication may work faster when tranquilising an agitated patient but may also lead to cardiac and respiratory problems – not to mention extreme difficulties implementing IV needles into an aggressive patient (Atakan & Davies, 1997). IM medications are easier to administer making them more efficient in terms of implementation. However, the time onset whereby sedation is achieved is longer and unpredictable compared to IV (Kaplan & Sadock, 1998). Physical restraints have the advantage of preventing an aggressive patients from physically assaulting staff as well as self-injury. They also have the advantage of being more efficient when used in combination of drugs being delivered via IV or IM. However, the disadvantages include out of date practice (depending on country) as well as death via asphyxiation (Miles & Irvine, 1992). Hence it is imperative to find a decent management scheme that is best suited to tranquilise aggressive patients safely and rapidly to ensure the safety of both patients and the workers involved which is why randomised controlled trials have been carried out in order to attain the best suitable option.
What is a Randomised Controlled Trial?
A randomised controlled trial (RCT) or randomised controlled clinical trial is a type of study whereby participants are assigned to one of two – or more arms (different group with different intervention options) of a clinical trial (O’Gorman et al., 2013). Usually a placebo is used as one of the interventions but if there happens to be a recognised and accepted intervention option known to work, it is known as the ‘Gold Standard’ then the new intervention is used to test against the gold standard rather than a placebo. In the event whereby a gold standard intervention exists, it would be unethical to randomised to a placebo which will make an effective treatment unavailable to some of the participants. (O’Gorman et al., 2013). The main reason RCTs are conducted is that there is an uncertainty to whether a new intervention is possibly better than an existing one. The team of people that supervise, conduct and analyse the results of the trial (The trialists) start with a null hypothesis (there is no difference between the two interventions). The goal of the RCT is to either accept or reject the null hypothesis. In the event that they manage to reject the null hypothesis, they can accept the ‘alternative hypothesis’ which indicates there is a difference between the two interventions (Nelson, 2011).
Methods
TREC-Lebanon (Rapid Tranquilisation – Clinical Trial) will compare HPL (Haloperidol + Promethazine + Chlorpromazine) with Haloperidol + Promethazine mix for treatment of agitated patients in emergency psychiatric wards in Deir Salib – Lebanon’s largest and only public psychiatric hospital. TREC-Lebanon is a randomised, controlled, pragmatic and open study. Primary measure of outcome is tranquilisation at 20 minutes but effects on other measures of morbidity will also be assessed. TREC-Lebanon will involve the collaboration of as many health care professionals – clinicians and psychiatric nurses in wards whereby the trial is taking place. Because the design of the trial does not substantially complicate clinical management, and in several aspects simplifies it, the study can be large, and treatments used in everyday practice can be evaluated.
Setting
The prevalence of any mental disorder across the world is 1-2% and although 80% of people live in low or middle income countries, typical antipsychotics and/or benzodiazepines are readily available across the world as well as affordable making them accessible to people across the world. Lebanon ranks as a low to middle income country (El Laithy, Abu-Ismail, & Hamdan, 2008). However, the interventions (both medication and non-medication) as seen in the studies above, are not only available but are frequently afforded and used by the Lebanese population. Therefore, since these treatment options are readily available, it is imperative that a definitive study is undertaken to fully investigate and understand their advantages and disadvantages.
BOX
CLINCIAL JOURNEY
The TREC-Lebanon study was designed in collaboration with those working in Lebanon’s main and only public Psychiatric hospital. Most clinical trials are explanatory; they’re short, small, evaluate rigid care regimens, measure outcomes in way that are of little clinical value and are difficult to relate to everyday practice (Thornley & Adams, 1998). On the other hand, pragmatic trials evaluate care that can be used in everyday practice and measure outcomes that are of general concern (Hotopf, Churchill, & Lewis, 1999).
Size
Two main factors determine the number of people who should be recruited to in order for the trial to provide clear answers. They are the frequency of the investigated event and the size of the effect of treatment. It is important to avoid results that are erroneous. The probability of producing so called ‘false-positive’ results (Type I error – a) and ‘false negative’ findings (Type II error – B) is minimised by having adequate sample size. The aim of TREC-Lebanon is to investigate whether people do better if they get HPL or HP. The main outcome to monitor in the TREC-Lebanon trial is the proportion of patients who are tranquilised at 20 minutes in each group.
In such a stressful situation, even a small advantage for an intervention could represent a worthwhile benefit and so, TREC-Lebanon has been planned so that even a 15% difference in the proportion of tranquilised patients within the 20 minutes could be detected. TREC-Lebanon expects to involve a minimum of 90 patients at least in a 3 month period.
TABLE
Ethical and legal considerations
The Helsinki Declaration (“World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects,” 2004), the European Directive on Clinical Trials (“European Union: EUR-Lex: Community legislation in force – Document 301L0020 (Web page). 03/04/2002, ,” 2002) and the Nuffield Council documents on bioethics (“Nuffield Council: Nuffield Council on Bioethics (Web page). 03/04/2002,” 2002) state that trials in non-consenting patients are permitted on two conditions: i. no other context exists in which to answer the question; and ii. All trial participants get clear therapeutic benefit from whichever arm they’re randomised to.
Aggressive patients in a situation of psychiatric emergency are not able to give consent for their participation in a study. Drugs are usually given against the will of the patient. So, in the same way that doctors are responsible for the choice of a treatment, they take responsibility for the recruitment of a patient into the study. However, TREC-Lebanon will not involve administering an inactive compound to those who clearly need sedation/tranquillisation. Both treatments can calm the patient and there is no ‘experimental’ intervention. What is still uncertain is the speed for the onset of action, the duration of the effects and the different kinds of adverse reactions. TREC-Lebanon will answer clinical questions to help the care of these people be more informed. TREC-Lebanon will also produce widely applicable findings, so that the treatment of people beyond Lebanon should also be safer. A patient/carer information leaflet about TREC-Lebanon is available for all for whom a TREC-Lebanon box is opened. Carers will always be free to decide that their relative should not be entered. Not being involved in TREC-Lebanon will not affect the person’s standard of care.
Methods
VISIT
Table 1- follow up enrolment
Assessed for eligibility by Doctors working in TREC-Rio
Not meeting Inclusion criteria
Carers refuse to participate
Randomize
Allocate to Haloperidole+ Prometazine Allocate to Midazolam
For primary outcome – 20 minutes
For 24 hours outcome
For 14 days outcome For primary outcome – 20 minutes
For 24 hours outcome
For 14 days outcome
Analyze- intention to treat Analyze- intention to treat
Table 2- The TREC Lebanon trial
Eligible if
• Patient is needing acute intramuscular sedation because of disturbed and dangerous behaviour
• Clinician is uncertain about the benefits and risks of haloperidol plus promethazine versus HPL
Exclude if
• The Clinician believes that one treatment represents an additional risk for the patient
Trial Entry
• Treatment is allocated using opening of consecutive TREC boxes stored in the emergency drug cupboard. The box contains:
– The treatment
– One syringe, one needle, two swabs, one plaster
– TREC forms to be filled out by the attending doctor/nurse
– TREC stickers for the patient’s notes
Treatment
• Either:
– Haloperidol (2x5mg ampules) + promethazine (1x50mg ampules_
Or:
– HPL (TBA mg ampule)
• One or other supplied in the TREC box
• All doses are at the discretion of the doctor
Follow up
• All people for whom a pack is opened will be followed up by the TREC study co-ordinators
• Data will be extracted from the notes on clinical state, hospital status, sedations, use of additional medications, and adverse reactions
TREC-Lebanon is designed to fit into everyday practice
For the trialists to be able to detect important differences between the treatments, it will be necessary to treat hundreds of patients and this will only be possible if many professionals collaborate in each centre involved. The TREC-Lebanon trial is designed to not interfere with the routine care of people in participating centres. The process of randomisation is very similar to the normal procedure of beginning the treatment and the eligibility criteria are simple. Drugs will be provided in emergency sealed boxes. Data collection will be limited to the minimum necessary, and will involve little more than extraction of routine information by a person designated to spend time on the TREC-Lebanon trial. It is not envisaged that busy doctors and nurses will be spending time filling out complicated forms and all trial materials. The interventions will be supplied in a TREC-box that will be opened in the emergency situation.
Randomisation
A fundamental step in such a trial is the randomisation; the distribution of the treatments in a way that is not a function of a clinical decision, but of pure chance. Randomisation will be undertaken in Lebanon. Microsoft Excel ‘RAND’ function will be used to choose even numbered block sizes less than ten. Again using this function, the order of use of these block sizes will be randomised. Which drug regimen was represented by which number within the block was then selected, again at random. Finally a table of random numbers will be used to randomise within the blocks. Tables of TREC-box number by contents will be constructed and will be supplied to a Lebanese colleague. The tables will list the contents of the boxes in groups of ten, not disclosing the block sizes used. The Lebanese colleague, always working independently of the TREC-Rio team, will ensure that the correct drugs are in the TREC-box before it is sealed. Concealment of allocation will be ensured by not disclosing the randomly varied block sizes to the colleagues packing the boxes, the supply of tables to those colleagues that gives no suggestion that blocks are even being employed, the independence of those packing the boxes from the other researchers or the clinicians, and the identical nature of the packed boxes.
These easy-to-use boxes will be constructed of cardboard, identical and consecutively numbered. The final check to ensure that nothing has gone wrong with the randomisation will be by the principal investigator filling in a form for each block of ten opened boxes. The colleague will record which intervention was in the box and these data will be returned to the UK so that any inconsistencies can quickly become known.
TREC-Lebanon is blinded for the initial ratings only
Because the TREC-Lebanon study evaluates care in the emergency situation, it is imperative that the doctors and nurses know which intervention is being given. The study is blind only up until the time that the TREC-Lebanon trial box is opened. Therefore, it is crucial that the evaluation of the severity of a person’s disturbance and the first impression on the possible cause for the disturbed behaviour are recorded before this box is opened. Once the box is opened, doctors and nurses will have knowledge of the drug to be used. It is perfectly feasible that the knowledge that one drug has been given will influence the care beyond the actual effects of the medication. Keeping the study open is not only practical in the emergency situation, but also desirable as the evaluation of care being undertaken is as near real-world circumstances as is possible.
Interventions
Placebo controlled studies in this area are difficult to justify (see section on ethics). TREC-Lebanon will evaluate the existing care in the health services of Lebanon and this care involves the use of medication that is considered both safe and effective. Currently, this protocol includes a comparison of an intramuscular haloperidol-promethazine mix with an intramuscular rapid acting benzodiazepine, midazolam. In the future, other centers may wish to compare interventions such as a haloperidol-benzodiazepine mix with lorazepam or zuclopenthixol acetate.
The haloperideol-promethazine-Chlorpromazine mix is an obvious choice as standard treatment for TREC-Lebanon. A pragmatic randomised trial should not substantially interfere with routine practice and, in Brazil, this combination was given to 61% of patients needing sedation in the public psychiatric rooms in Rio de Janeiro [13]. It is perceived as effective, safe, and with adverse effects that are readily recognised by both medical and nursing staff. It is easy to administer by intra-muscular injection and has never been evaluated within a randomised control trial. Haloperidol and promethazine are both included in WHO’s Model List of Essential Drugs [25].
The comparison intervention in TREC-Rio is a rapidly acting intramuscular benzodiazepine. Only lorazepam and midazolam are indicated for IM use, as all other benzodiazepines are slowly and erratically absorbed by this method. Lorazepam is not available for IM use in Brazil, however, midazolam is widely used in Brazil as premedication prior to surgical procedures in general emergency rooms and its use for the management of acutely disturbed people is being reported. The use of midazolam for rapid tranquillisation in psychiatry has not been subject to rigorous evaluation within a large and well-designed randomised controlled trial.
All drugs, haloperidol, promethazine and Chlorpromazine are included in Lebanon’s list of essential drugs.
Haloperidol – risks and benefits
Haloperidol is a highly potent, widely used, neuroleptic that is indicated to help promote adequate levels of tranquillisation when administered IM. Doses used are usually 5–10 mg and its onset of action is by 60–90 minutes. The half-life of haloperidol varies between 13 and 40 hours, although effects may occur even two days after administration. Adverse effects include akathisia (manifested as restlessness) in 20% and acute dystonic reactions (rigid muscles and involuntary movements) for about 2% of patients. Neuroleptic malignant syndrome (hypothermia, rigid muscles and alteration in the level of consciousness developing 24–72 hours after administration) is an idiosyncratic serious reaction occurring in 0.02–3.2% of people (“The Royal Pharmaceutical Society of Great Britain: The British National Formulary (Web page). ,” 2001). Akathisia and acute dystonia are usually treated with the administration of antimuscarinic agents, although the optimal management of neuroleptic malignant syndrome is unclear. Despite these adverse effects, which may happen even after a single injection, haloperidol is the elected treatment, widely available and used in the emergency situations.
Promethazine – risks and benefits
Promethazine is an antihistamine combined as an IM injection with haloperidol for the management of acutely disturbed people in both Brazil and India. The rational for this combination lies in the main sedative effects of promethazine and its antimuscarinic properties. Doses are usually between 25–50 mg but, as adjunctive sedative for emergency use, may reach 100 mg IM (“The Royal Pharmaceutical Society of Great Britain: The British National Formulary (Web page). ,” 2001). The onset of action is about 1–2 hours after intramuscular administration and half-life is 5–14 hours. The main adverse reactions of promethazine are gastrointestinal disturbances, dry mouth and blurred vision. Paradoxical reactions such as CNS stimulation and extrapyramidal symptoms have also been reported. Overdose may lead to coma and convulsions, progressing to respiratory failure or possibly cardiovascular collapse.
Chlorpromazine – Risks and benefits
Chlorpromazine is in the phenothiazine family of compounds and may work by its ability to block dopaminergic receptor in limbic forebrain. Beside this action it also blocks to different degrees adrenergic, dopamine reuptake, histaminic, muscarinic and serotonergic receptors (Adams, Awad, Rathbone, Thornley, & Soares‐Weiser, 2014). It may be the antihistaminic effects that cause the sedation associated with use of chlorpromazine. Chlorpromazine is mainly indicated for schizophrenia or other psychosis, mania, short-term adjunctive management of severe anxiety, psychomotor agitation, excitement and violent or dangerously impulsive behaviour (Samara, Cao, Helfer, Davis, & Leucht, 2014)
Procedures
All trial materials, and guidelines for their use, are provided in the TREC-Rio folder supplied by the co-ordinating centre. What follows here is a brief summary of all of trial procedures.
Whenever possible, carers accompanying the disturbed person should have an opportunity to see the information leaflet (Appendix 1, see Additional file 1) before randomisation. Randomisation proceeds using a local pack system. Identical sealed treatment packs are provided.
As soon as the person enters the study, the clinician completes the trial entry form on the top of the next consecutive pack (Appendix 2, see Additional file 1). This must be completed before the treatment pack is opened. It records brief baseline details about the person and the number of the treatment pack. The treatment packs must be used in order in which they are removed, the lowest number first. Once the trial entry form has been completed the person is in the trial, even if the doctor changes his/her management and the treatment pack is not opened.
Trial packs
As soon as the person has been allocated a treatment pack, the pack is opened and the trial treatment inside given. Each pack contains:
1 × ampoule of Chlorpromazine 100mg
2 x ampoule of haloperidol 5 mg
1 x ampoule of promethazine 50 mg
1 × syringe
1 × needle
2 × swabs
1 × TREC-Lebanon follow-up form (Appendix 3, see Additional file 1)
2 × TREC-Lebanon stickers for the drug prescription form and medical notes
or
2 × ampoules of haloperidol 5 mg
1 × ampoule of promethazine 50 mg
1 × syringe
1 × needle
2 × swabs
1 × TREC-Lebanon follow-up forms (Appendix 3, see Additional file 1)
2 × TREC-Lebanon stickers for the drug prescription form and medical notes
All doses used are at the discretion of the attending clinician. Ampoules will be clearly labelled and the clinician will be in no doubt as regards the treatment being given. If the contents of a trial pack are destroyed, or unfit for use, the person should not be randomised a second time and the equivalent material should be obtained from the usual hospital supplies.
In the event of continuing aggression despite the TREC-Rio medication, ongoing emergency management would be up to the discretion of the clinicians. Another pack is not opened and the doctor is free to use any standard interventions.
Toxicity and serious unexpected events
After trial entry, clinical events are recorded, as usual, in the patients’ notes. Complications and adverse events should be managed as usual. A serious unexpected event form (Appendix 5, see Additional file 1) is provided, and will be sent to the TREC-Lebanon Co-ordinator as soon it is completed.
Outcome and follow-up
It is crucial that follow-up is complete and accurate for everyone entered into the study. As a pragmatic study, causing minimal interference with routine care, TREC will not employ any rating scale outcomes. It is likely that completion of scales would be inaccurate, and incomplete, validity and reliability would be in question, and clinical utility problematic. The main outcome of TREC-Lebanon is tranquillisation by 20 minutes. This primary outcome was requested by the nursing and medical staff of the hospital. By asking the relevant clinical staff to select the primary outcome for TREC-Lebanon we hoped to ensure maximum compliance with the trial protocol. Therefore, upon injection of the patient, a timer is started, and this rings at 20 minutes and then again at 40, 60 and 120 minutes. At each period the attending nurse rates whether the person is tranquil, asleep, has shown adverse effects or needs additional treatment (see Appendix 2, see Additional file 1). This attending nurse is not blinded. The person is considered tranquillised when they are felt to be calm and peaceful, but not asleep. They should not be agitated or restless, nor displaying threatening verbal behaviour, physical aggression against objects, self-aggression or physical aggression to other people. Blinding this rater for every participant would have added additional complexity to the study that would have made the trial much less acceptable to the emergency room staff. More importantly, it would have completely changed the emphasis of TREC-Lebanon. We are interested in evaluating the real-world practice of giving two different drug regimens in the psychiatric emergency setting. In the real world situation health care professionals know what treatment is being given. In addition, for 10% of participants an additional rater, blind to allocated treatment, will, unknown to the health professionals looking after the patient, time the period between injection and tranquillisation and / or sleep exactly. These data will be used to validate the rating of the follow up form (see Appendix 4, see Additional file 1).
Additional data are then recorded at 24 hours and finally at two weeks (see Appendix 6, see Additional file 1). All data is extracted from routine notes. If the person is transferred to another hospital, the co-ordinating centre will contact every hospital to find out further details on what happened after transfer.
Data collection, entry and analysis
All data for TREC-Rio will be collated from the TREC-box forms and routine notes of each emergency room or ward (see Appendix 6, see Additional file 1). These data will be entered by the principal investigator into especially created forms in Epi-Info v 6.0 [5].
Analysis will take place within this package and SPSS [21]. Dummy tables for this analysis are prepared before recruitment of the first patient (see Appendix 7, see Additional file 1). All analysis will be based on groups as randomly allocated; this will be an intention-to-treat analysis. For the principal comparisons statistical significance will be taken at a 5% level and for subsidiary comparisons at the 1% level, to minimise the impact of multiple comparisons. Relative risk, risk difference, number needed to treat and respective 95% confidence intervals will be estimated for tranquillisation by 20, 40 and 60 minutes.
For the continuous outcome mean difference will be assessed. As in most experiments, this study carried out a randomisation of a non random sample instead of a random sampling of a specific population. In order to be coherent with the adopted design, the statistical significance of the means difference will be evaluated by a randomisation model (not a population model), and a design-based permutation test will be used instead of an approximate test to preserve the type I error rate [3, 17]. Permutation test will be performed using StatXact 3.0 for Windows [8]. For a subgroup of 10% of patients, quality of data on time to tranquillisation will be evaluated by two independent observers. The agreement of this measurement will be assessed using Kappa statistics.
Trial organisation
The TREC-Lebanon Co-ordinating Group: The co-ordinating centre of the Lebanese arm is based at the Institute of Mental Health University of Nottingham United Kingdom. The Co-ordinating Group has overall responsibility for the design of the proposed trial and is responsible for all aspects of day to day trial administration. The Co-ordinating team is also responsible for preparing reports for the steering committee. Membership: Joseph Dib, Clive E Adams.
The TREC-Lebanon Steering Committee: The overall progress of the trial, adherence to protocol, patient safety and the consideration of new information will be monitored by a scientific and administrative steering committee. At the end of the proposed study period, the Steering Committee will consider the extension of the study, to allow the detection of other important effects. The membership of this committee is