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

Drug

CYP Substrate

(major)

Usual

Starting Dose

Significant Adverse Effectsb

Formulations

Haloperidol

3A4, 2D6

1–2 mg older adults;

2–4 mg if history of

psychiatric disorders

Anticholinergic: *

Sedation: *

EPS: **

NMS: *

Olanzapine

1A2

5 mg

Anticholinergic: **

Sedation: **

EPS: *

NMS: *

Neuromuscular weakness

PO, disintegrating

tablet, IV, IM

Quetiapine

3A4

12.5–25 mg

Anticholinergic: **

Sedation: **

NMS: *

Orthostatic hypotension: **

PO

Risperidone

2D6

0.5–1 mg

Anticholinergic: *

Sedation *

EPS: **

NMS: *

Orthostatic hypotension: **

Cardiac conduction abnormalities

PO, disintegrating

tablet

Ziprasidone

1A2 (minor)

3A4 (minor)

20 mg PO;

10 mg IM

Anticholinergic: *

Sedation: *

EPS: *

NMS: *

Oral,

IM

NOTE: * = lower risk; ** = medium-higher risk

aNot all medications listed are FDA label approved for use in delirium; not all are recommended by SCCM for the treatment of delirium in the ICU.

bAdverse effects other than QTc prolongation. Documented QTc prolongation incidence: IV haloperidol = ziprasidone > risperidone > olanzapine = quetiapine.

EPS = extrapyramidal symptoms; IM = intramuscular(ly); IV = intravenous(ly); NMS = neuroleptic malignant syndrome; PO = oral(ly)

Haloperidol (Haldol): Available in oral, intravenous, and intramuscular injection dosage forms

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

CYP3A4 and 2D6 substrate. Peak plasma concentrations for oral about 6 hours for oral and 20

minutes for intramuscular.

Suggested starting dose for ICU delirium: 2–5 mg as needed

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

of scheduled quetiapine with placebo for the treatment of delirium in ICU patients during a 10-day

liver disease, those with alcohol withdrawal, those with a QTc greater than 500, and those receiving

concomitant QTc-prolonging agents. This small pilot study (n=36), in which the placebo group was

administered as-needed intravenous haloperidol, found that quetiapine was associated with a shorter time

to first resolution of delirium, reduced duration of delirium, and less agitation than placebo. Mortality

and ICU length of stay were not different from placebo.

Pharmacokinetics: Hepatically metabolized to one active and two inactive metabolites. Metabolites

renally cleared. Many drug interactions, CYP3A4 (major) and CYP2D6 (minor) substrates. Peak

plasma concentrations for oral about 1½ hours (immediate release).