Po

Sedation, orthostatic hypotension

Sedating effects may be helpful in patients with sleep-wake cycle disturbance

Ziprasidone

10-40 mg every 12-24 h

PO, IM

Monitor QT interval on EKG

Evidence is limited to case reports

Aripiprazole

5-30 mg every 24 h

PO*, IM

Monitor for akathisia

Evidence is limited to case reports and case series

•Risperidone, olanzapine, and aripiprazole are available in orally disintegrating tablets.

•Risperidone, olanzapine, and aripiprazole are available in orally disintegrating tablets.

severe agitation in terminally ill patients to decrease distress for the patient, family, and staff. It is important to monitor chlorpromazine's anticholinergic and hypoten-sive side effects, particularly in elderly patients (Breitbart and Alici 2008).

A systematic review of the pharmacologic therapies for delirium in the terminally ill concluded that haloperi-dol was the most suitable medication for the treatment of patients with delirium near the end of life, with chlor-promazine being an acceptable alternative (Jackson and Lipman 2006).

FDA has issued a warning against the risk of QT interval prolongation and torsades de pointes with IV haloperidol, thus monitoring QT intervals daily among medically ill patients receiving IV haloperidol has become the standard clinical practice.

► Atypical antipsychotic agents (i.e., risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole)

are increasingly used in the treatment of delirium due to lower risk of extrapyramidal adverse effects (Breitbart and Friedlander 2006).

A Cochrane review, comparing the efficacy and the incidence of adverse effects between haloperidol and atypical antipsychotics, concluded that, like haloperidol, selected newer atypical antipsychotics (risperidone, olanzapine) were effective in managing delirium. Haloperidol doses greater than 4.5 mg/day were more likely to result in increased rates ofextrapyramidal symptoms when compared with the atypical antipsychotics, but low-dose haloperidol (i.e., less than 3.5 mg/day) did not result in a greater frequency of extrapyramidal adverse effects (Lonergan et al. 2007).

The APA guidelines for the treatment of delirium recommend use of low-dose haloperidol (i.e., 1-2 mg po every 4 h as needed or 0.25-0.5 mg po every 4 h for the elderly) as the treatment of choice in cases where medications are necessary (APA 1999).

On the basis of the existing literature, ► risperidone may be used in the treatment of delirium, starting at doses ranging from 0.25 to 1 mg and titrated up as necessary with particular attention to the risk EPS, orthostatic hypotension, and sedation at higher doses. ► Olanzapine can be started between 2.5 and 5 mg nightly and titrated up with the sedation being the major limiting factor, which may be favorable in the treatment of hyperactive delirium. The current literature on the use of ► quetia-pine suggests a starting dose of 25-50 mg and a titration up to 100-200 mg a day (usually at twice-daily divided doses). Sedation and orthostatic hypotension are the main dose-limiting factors. Case reports suggest a starting dose of 10-15 mg daily for ► aripiprazole, with a maximum dose of 30 mg daily (Breitbart and Alici 2008; Breitbart and Friedlander 2006).

Despite the availability of intramuscular formulations of olanzapine, aripiprazole, and ziprasidone, none of these medications have been studied in the treatment of delirium.

Important considerations in starting treatment with any antipsychotic for delirium may include EPS risk, sedation, ► anticholinergic side effects, cardiac arrhythmias, and possible drug-drug interactions. The FDA has issued a "black box'' warning of increased risk of death associated with the use of typical and atypical antipsychotics in elderly patients with dementia-related psychoses (Breitbart and Alici 2008). A retrospective study comparing the mortality risk among elderly patients with delirium who were treated with antipsychotics to those who did not receive antipsychotics did not find an increased risk of mortality with the use of antipsychotics in this patient population (Elie et al. 2009).

Psychostimulants

Some clinicians have suggested that the hypoactive subtype of delirium may respond to ► psychostimulants such as ► methylphenidate, or combinations of antipsychotics and psychostimulants or antipsychotics and wakefulness agents such as modafinil (Breitbart and Alici 2008). However, there have been no randomized controlled trials supporting the use of psychostimulants in the treatment of delirium. The risks of precipitating agitation and exacerbating psychotic symptoms should be carefully evaluated when psychostimulants are considered in the treatment of delirium.

Cholinesterase Inhibitors

Impaired cholinergic function has been implicated as one of the final common pathways in the neuropathogenesis of delirium (Trzepacz 2006). Despite case reports of beneficial effects of ► donepezil and ► rivastigmine in the treatment of delirium, a Cochrane review concluded that there is currently no evidence from controlled trials supporting the use of ► cholinesterase inhibitors in the treatment of delirium (Breitbart and Alici 2008).

Dexmedetomidine

Dexmedetomidine, an alpha-2-adrenergic agonist, is used in the ICUs for its central sedative effects through inhibition of noradrenergic cortex activation (Riker et al. 2009). The use of dexmedetomidine in the treatment of delirium among mechanically ventilated ICU patients has been associated with an increased number of delirium-free days when compared with lorazepam-treated patients in a randomized controlled trial (Lonergan et al. 2009). Dexmedetomidine has also been associated with a lower incidence of delirium when compared with ► midazolam among ICU patients (Riker et al. 2009). However, the expense of dexmedetomidine treatment limits its routine use in ICU patients despite encouraging results with this agent.

Benzodiazepines

Benzodiazepines are commonly used in the treatment and prevention of ► alcohol-withdrawal delirium. A systematic review of the use of ► benzodiazepines in the treatment of nonalcohol-withdrawal delirium has concluded that there are no controlled trials to support the use of benzodiazepines, and a controlled trial comparing the effectiveness of lorazepam, haloperidol, and chlorproma-zine has shown increased confusion associated with the use of lorazepam among HIV-patients with delirium.

Prevention of Delirium

Several researchers have studied both pharmacologic and nonpharmacologic interventions in the prevention of delirium among older patient populations, particularly in surgical settings (Breitbart and Alici 2008). Antipsychotic medications (i.e., haloperidol) and cholinesterase inhibitors (donepezil and rivastigmine) have been studied in randomized controlled trials for their effectiveness in the prevention of postoperative delirium. Both groups of medications have failed to reduce the incidence of delirium in patients undergoing elective cardiac or joint replacement surgery (Breitbart and Alici 2008). Geriatric consultations and nonpharmacologic interventions such as a multicomponent intervention program have reported reduced number and duration of episodes of delirium among hospitalized older patients. However, a systematic review of all the existing delirium-prevention studies concluded that the current evidence on effectiveness of interventions to prevent delirium was limited (Breitbart and Alici 2008).

Conclusion

Clinicians commonly encounter delirium as a major complication of medical illness and its treatments, particularly among hospitalized patients. Proper assessment, diagnosis, and management of delirium are essential in improving quality of life and minimizing morbidity in the medically ill.

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