Antipsychotics have been the medication of choice in the treatment of delirium. Evidence for their efficacy has come from numerous case reports and uncontrolled trials (63, 64). A series of controlled trials also showed that antipsychotic medications can be used to treat agitation and psychotic symptoms in medically ill and geriatric patient populations (65–69). However, most of these trials were not conducted with patients who had clearly or consistently defined delirium; in some studies, agitation and disorientation were the sole criteria and symptom assessments ranged from questionnaires to simple identification without symptom descriptions.

A randomized, double-blind, comparison trial by Breitbart et al. (70) identified delirium by using standardized clinical measures, and it demonstrated the clinical superiority of antipsychotic medications over benzodiazepines in delirium treatment. The Delirium Rating Scale, Mini-Mental State examination, and DSM-III-R were used to make the diagnosis in 244 hospitalized AIDS patients. The subjects were randomly assigned to one of three medications: chlorpromazine, haloperidol, and lorazepam. There were statistically significant decreases in scores on the Delirium Rating Scale after 2 days in the haloperidol and chlorpromazine groups but not in the lorazepam group (the mean decreases in scores were 8.0, 8.5, and 1.0, respectively). The improvement in delirium symptoms observed among those treated with antipsychotic medications occurred quickly, usually before the initiation of interventions directed at the medical etiologies of the delirium.

Droperidol, a butyrophenone with a rapid onset of action and relatively short half-life that is more sedating than haloperidol, has also been found to be an effective treatment for hospitalized patients with agitation, although not necessarily delirium (71). Results of two double-blind clinical trials comparing droperidol to haloperidol suggest that a more rapid response may be obtained with droperidol. Resnick and Burton (72) reported that 30 minutes after intramuscular injections, 81% of patients initially treated with 5 mg of haloperidol required a second injection, compared to only 36% of patients initially given 5 mg of droperidol. Thomas and colleagues (69), comparing 5 mg i.m. of droperidol to 5 mg i.m. of haloperidol, found significantly decreased combativeness among the droperidol treatment group after 10, 15, and 30 minutes. There has been very little study of the newer antipsychotic medications (risperidone, olanzapine, and quetiapine) in the treatment of delirium. Although there have been several case reports of use of risperidone for patients with delirium (61, 62, 73, 74), there have been no published clinical trials of any of the new antipsychotic medications for patients with delirium.

Phenothiazines can be associated with sedation, anticholinergic effects, and α‐adrenergic blocking effects that can cause hypotension; each of these side effects may complicate delirium. Butyrophenones, particularly haloperidol and droperidol, are considered the safest and most effective antipsychotics for delirium. Haloperidol, a high-potency dopamine-blocking agent with few or no anticholinergic side effects, minimal cardiovascular side effects, and no active metabolites, has generally been considered the antipsychotic medication of first choice in the treatment of delirium. High-potency antipsychotic medications also cause less sedation than the phenothiazines and therefore are less likely to exacerbate delirium. Although droperidol may have the advantages of a more rapid onset of action and a shorter half-life than haloperidol, droperidol is associated with greater sedation and hypotensive effects (75).

The use of antipsychotic medications can be associated with neurological side effects, including the development of extrapyramidal side effects, tardive dyskinesia, and neuroleptic malignant syndrome. However, there is some evidence to suggest that extrapyramidal side effects may be less severe when antipsychotic medications are administered intravenously (76). One case series involved 10 consecutive general medical inpatients receiving doses of oral or intravenous haloperidol at approximately 10 mg/day. Four patients were given intravenous medication, and six were given oral doses. Although delirium was not identified as the reason for treatment, five patients met diagnostic criteria by description. There was no significant difference in the incidence of akathisia, but the group receiving intravenous medication experienced less severe extrapyramidal symptoms. Neither method of administration resulted in acute dystonic reactions or changes in blood pressure or pulse rate (76).

Haloperidol used in the treatment of delirium has been found in some instances to lengthen the QT interval, which can lead to torsades de pointes, a form of polymorphic ventricular tachycardia that can degenerate to ventricular fibrillation and sudden death. Estimates of the incidence of torsades de pointes among patients with delirium treated with intravenous haloperidol have ranged from four out of 1,100 patients (77) to eight out of 223 patients (78). Although development of this serious event has been associated with higher intravenous doses (>35 mg/day) of haloperidol, it is important to note that torsades de pointes has also been reported with low-dose intravenous haloperidol and oral haloperidol as well (78, 79). Droperidol has also been associated with lengthening of the QT interval, and it may also be associated with torsades de pointes and sudden death.

Other side effects of antipsychotic medication use can rarely include lowering of the seizure threshold, galactorrhea, elevations in liver enzyme levels, inhibition of leukopoiesis, neuroleptic malignant syndrome, and withdrawal movement disorders.

Although different antipsychotic medications can be given orally, intramuscularly, or intravenously, in emergency situations or when there is lack of oral access, intravenous administration may be most effective. In addition, as described in the preceding section on side effects, there is some evidence that antipsychotic medications may cause less severe extrapyramidal side effects when administered intravenously (76). Intravenous administration of haloperidol has not yet received approval by the Food and Drug Administration (FDA).

There have been few studies to determine the optimal doses of antipsychotic medications in the treatment of delirium. On the basis of doses used in several studies, starting haloperidol in the range of 1–2 mg every 2–4 hours as needed has been suggested (80). Low doses, for example as low as 0.25–0.50 mg of haloperidol every 4 hours as needed, have been suggested for elderly patients (81). On the other hand, severely agitated patients may require titration to higher doses. Bolus intravenous haloperidol doses exceeding 50 mg with total daily doses up to 500 mg have been reported, and they were associated with minimal effects on heart rate, respiratory rate, blood pressure, and pulmonary artery pressure and minimal extrapyramidal side effects (82, 83).

Several studies (75, 84) have examined the use of continuous intravenous infusions of haloperidol or droperidol among agitated medically ill patients who have required multiple bolus intravenous injections of antipsychotic medications. The results indicate that this means of administration can be safe and may help avoid some of the complications associated with repeated bolus dosing (e.g., hypotension). The authors of one study (84) recommended continuous infusion of haloperidol for patients who required more than eight 10-mg haloperidol boluses in 24 hours or more than 10 mg/hour for more than 5 consecutive hours. They suggested initiating haloperidol with a bolus dose of 10 mg followed by continuous infusion at 5–10 mg/hour.

Because antipsychotic medications used in the treatment of delirium have occasionally been found to lengthen the QT interval, possibly leading to torsades de pointes, ventricular fibrillation, and sudden death, recommendations for medication management include a baseline ECG with special attention paid to the length of the QTc interval. A prolongation of the QTc interval to greater than 450 msec or to greater than 25% over that in previous ECGs may warrant telemetry, a cardiology consultation, and dose reduction or discontinuation (85, 86). It has also been recommended that serum levels of magnesium and potassium be monitored in critically ill patients, especially those whose baseline QTc interval is 440 msec or longer, those who are receiving other drugs that increase the QT interval, or those who have electrolyte disturbances (87).