Pain, Agitation/Sedation, Delirium, Immobility, Sleep Disruption, and Neuromuscular Blockade

Initial dose range for ICU delirium: 50 mg one to three times daily. Consider lower starting doses

for older adult patients because of sedating effects. The Devlin study initiated 50 mg every 12

hours and titrated to a maximum dose of 200 mg every 12 hours.

Adverse effects (early onset): Sedation, orthostatic hypotension, extrapyramidal symptoms, QTc

prolongation

Olanzapine (Zyprexa): Available in oral, orally disintegrating, and intramuscular (immediate and

extended release) dosage forms. Intramuscular administration may result in plasma concentrations

5 times those of oral administration. The immediate release intramuscular formulation can also be

administered intravenously. The U.S. Food and Drug Administration (FDA) warns that the use of

intramuscular olanzapine has resulted in unexplained deaths; use of intramuscular olanzapine with

benzodiazepines may result in significant oxygen desaturation.

Pharmacokinetics: Metabolized by glucuronidation and CYP 1A2, 2D6 oxidation. Clearance is

significantly increased (around 40%) in smokers and decreased in females (around 30%). Many

drug interactions, CYP1A2 (major) and CYP2D6 (minor) substrates. Weak inhibitor of several

CYP isoenzymes. Peak plasma concentrations for oral: About 6 hours.

Suggested starting dose for ICU delirium: 5 mg orally once daily

Adverse effects (early onset): Drowsiness, extrapyramidal symptoms, neuromuscular weakness,

serotonin syndrome. High doses may cause cardiac arrhythmias, cardiopulmonary arrest, and

extreme sedation to coma-like states.

Risperidone (Risperdal): Available in oral and oral dispersible tablets (M-tabs) and intramuscular

injection dosage forms

Pharmacokinetics: Hepatically metabolized to active metabolites, renally cleared. Many drug

interactions, CYP2D6 (major) and CYP3A4 (minor) substrates and P-glycoprotein. Peak plasma

concentrations for oral about 1 hour.

Suggested starting dose for ICU delirium: 0.25–0.5 mg once or twice daily

Adverse effects (early onset): Cardiac arrhythmias, anticholinergic effects, extrapyramidal

symptoms

Ziprasidone (Geodon): Studied in a multicenter, randomized, placebo-controlled pilot trial of

mechanically ventilated patients to test the hypothesis that antipsychotics would improve days alive

without delirium or coma in the ICU (MIND trial). Medical and surgical adult ICU patients (n=101)

from six tertiary-care centers in the United States on mechanical ventilation who had an abnormal level

of consciousness or were receiving analgesia/sedative medications were randomly assigned to receive

haloperidol, ziprasidone, or placebo every 6 hours for up to 14 days during a 21-day study. During the

study, no difference was found in median days alive without delirium or coma between the haloperidol

(14 days), ziprasidone (15 days), and placebo (12.5 days) groups, p=0.66. The study also found no

Med 2010;38:428-37).

Ziprasidone is available in oral and intramuscular dosage forms.

Pharmacokinetics: Hepatic by glutathione and aldehyde oxidase. Minor substrates of CYP 1A2,

3A4. Peak plasma concentrations for oral about 6 hours; intramuscular about 1 hour.

Suggested starting dose for ICU delirium: 20 mg twice daily (oral)

hypotension