Agitation or Assault Risk Requiring Parenteral Treatment
The need for emergency treatment typically occurs when the patient first arrives at the hospital, but may arise at any time during the course of the inpatient stay. The first step is always to provide structure, reduce stimulation, and attempt to verbally reassure and calm the troubled individual. Evaluation of the medical and psychiatric differential diagnosis of the acutely psychotic and agitated patient is important but often difficult or impossible when unknown patients first present in the emergency room. Therefore, most emergency room directors medicate first if necessary, and proceed with the diagnostic workup when the patient is less agitated.(1) A more thorough evaluation is usually done at the time the patient reaches the inpatient unit.(2)
For the patient who presents with agitation, excitement, or aggression that failed to respond to psychosocial interventions and who requires rapid parenteral treatment, the approach that appears to work most rapidly is a combination of an intramuscular (i.m.) conventional antipsychotic and a benzodiazepine. Two controlled studies involving 167 patients have found that this is statistically and clinically superior to either treatment alone.(3,4) Also, a random survey of 20 medical directors of psychiatric emergency rooms found that the majority currently favor combination neuroleptic/benzodiazepine treatment for acutely violent patients.(1) The most commonly used regimen is 2 to 5 mg of haloperidol combined in the same syringe with 2 mg of lorazepam, given intramuscularly every 0.5 to 1.0 hour, up to three doses.(4-6) Extrapyramidal side effects are apparently infrequent with this combination (2 of 32 patients [6%]; (3) 0 of 33 patients [0%] (4)), so prophylactic antiparkinsonian therapy is usually unnecessary.
A consensus of expert opinion indicates that it is reasonable to use a benzodiazepine even if there is a history of substance abuse or dependence.(7) The benzodiazepine should be tapered and discontinued prior to discharge. Paradoxical excitement occurs occasionally,(9) although this appears to be rare.25 No clear risk factors for paradoxical excitement have been identified,(10) but it has been speculated that patients with a history of chronic, well-suppressed anger could be disinhibited by benzodiazepines.(11) There is also a small risk of respiratory depression with high or repeated doses of benzodiazepines especially if other sedatives such as alcohol are present or if the patient has a pulmonary condition.
Other neuroleptics available in i.m. form which are occasionally used instead of haloperidol are fluphenazine HCl, loxapine, and perphenazine. Chlorpromazine should be avoided due to greater risk of hypotension.(6) Thiothixene injection has been discontinued.
Droperidol, a neuroleptic used most often to induce anesthesia, also can be used to treat the acutely agitated psychotic patient.(12) Five out of 20 of the emergency room medical directors surveyed prefer droperidol monotherapy over haloperidol/lorazepam.(1) One double-blind, randomized prospective study comparing i.m. droperidol with i.m. haloperidol on 47 patients found that droperidol worked faster.(13) At 10, 15, and 30 minutes, droperidol produced about one point greater improvement in a five point combativeness scale. These differences were statistically significant at p=.006, p=.01, and p=.04, respectively. By 60 minutes, the haloperidol caught up and both were working well. Droperidol also has the advantage of a shorter duration of action compared with haloperidol (a half-life of 2.2 hours vs. more than 10 hours)(12) but it may be somewhat more likely than haloperidol to lower blood pressure when given i.m. (4 of 26 patients vs. 2 of 21; difference not significant).(13) The usual dose of droperidol is 5 mg i.m. or 2.5 to 5 mg intravenously. Extrapyramidal side effects (EPS) occur rarely.(12) One study found droperidol to be superior to lorazepam for agitated patients with cocaine toxicity.(14)
However, a new Box Warning is out on droperidol, as of Dec. 4, 2001. There have been reports of deaths from QT prolongation and torsades de pointes arrhythmias in patients treated with high, medium, and even low doses. The QTc problems appear dose related, but some of the cases occurred in patients with no known risk factors for QT prolongation. If droperidol is to be used (and it should only be used if other reasonable options have failed), the FDA now recommends a pre-treatment EKG, and if the interval is 440 msec or more for males, or 450 msec for females it should not be used. EKG monitoring should continue through treatment and for 2-3 hours afterwards. There is a long list of high risk situations including CHF, bradycardia, use of a diuretic, cardiac hypertrophy, low K+, low Mg+. This would appear to make use of droperidol impractical to use for acute behavior control in most patients with schizophrenia.
Even though haloperidol plus lorazepam combination treatment appears more effective, some experts prefer monotherapy with lorazepam.(1) The advantage of this is that it might enable the patient to avoid any exposure to a conventional neuroleptic. The usual lorazepam dose is 1-3 mg i.m. hourly for up to three doses, until behavioral control is achieved.(5) This is followed by an oral new generation ("atypical") antipsychotic when the patient becomes cooperative.
Monotherapy with a parenteral benzodiazepine appears equivalent to monotherapy with a parenteral neuroleptic: this was demonstrated in two controlled, short term (30-60 minute) studies.(15-16) Both studies involved inpatients who were taking oral antipsychotic drugs, and sometimes other drugs, but had an aggressive or assaultive outburst. In a third smaller study involving 16 patients with manic symptoms, of whom only 5 were diagnosed with schizophrenia, three injections of haloperidol 5 or 10 mg or clonazepam 1 or 2 mg. were given every half hour.(17) This double-blind, random assignment study found that haloperidol was significantly more effective than clonazapam on manic symptoms at one hour, although the effects were roughly the same by two hours. This study suggested that clonazepam may have a slower onset of action compared to other benzodiazepines. However, the apparent differences in benzodiazepine effects could also be related to the different diagnoses of patients in these three studies.
In all these studies, the neuroleptic produces much more EPS than the benzodiazepine. The rate of significant EPS ranges from 20 to 50% even with low dose i.m. treatment.(3,16,18) Thus, if a neuroleptic is used alone, prophylactic antiparkinsonian therapy is reasonable, particularly for high-risk patients such as males younger than age 35 and patients with a history of previous dystonic reactions.(19) Anticholinergic prophylaxis can reduce the rate of dystonia from oral high potency neuroleptics by 5- to 8-fold.(20)
Summary of Recommendations:
1. The combination of haloperidol and lorazepam i.m. seems to have the most support from evidence and expert opinion for acute parenteral treatment of agitated or combative patients with schizophrenia. (HIGH confidence)
2. Second in terms of evidence and support from some experts was monotherapy with droperidol. (MODERATE confidence) However, because of QTc prolongation, a new FDA Box Warning (12/4/01) now requires that this option be "...reserved for use in the treatment of patients who fail to show an acceptable response to other adequate treatments, either because of insufficient effectiveness or the inability to achieve an effective dose due to intolerable adverse effects."
3. Another good option is monotherapy with lorazepam (MODERATE confidence) Studies indicate parenteral benzodiazepines such as lorazepam are at least as effective as high potency neuroleptics when each is used alone.
4. Neuroleptics alone are least desirable due to the high risk of EPS, although this can probably be minimized with prophylactic antiparkinsonians. (Educated Guess level of confidence)
Olanzapine,(21) risperidone and ziprasidone(22) have parenteral forms undergoing clinical trials, and they may eventually replace haloperidol as the standard medications for this indication. Another promising antipsychotic with a parenteral in the pipeline is aripiprazole.
Recommendation #12
