Delirium

Butyrophenone (phenylbutylpiperidine) antipsychotic, potent D2 antagonist. Derivative of meperidine (a phenylpiperidine analgesic) and closely related to droperidol. Can be given intravenously or intramuscularly. Relatively little sedation. QTc prolongation (and torsade de pointes followed by fatal ventricular arrhythmias) is problematic – there is a Black Box Warning for IV (but not oral or IM) haloperidol. High incidence of extrapyramidal effects

Although atypical agents are thought to have less QTc prolongation, a recent retrospective analysis found a 2-fold risk for sudden cardiac death among both typical and atypical antipsychotic users (as compared to non users) [Ray WA, Chung CP, Murray KT, et al. Atypical antipsychotic drugs and the risk of sudden cardiac death. N Engl J Med, 2009, 360:225–235 [PMID: 19144938]]. Mean increase in QTc 4.7s, lower than most anti-psychotics, although it important to note that only haloperidol (and droperidol) have been definitively linked to torsades [Huffman JC, Stern TA. Prim Care Companion J Clin Psychiatry 5: 278, 2003]. Retrospective analysis has shown a mortality benefit when using haloperidol in critically ill patients [Milbrandt EB et al. Crit Care Med 33: 226, 2005]

First-line treatment for delirium according to the SCCM Guidelines [Jacobi J et al. Crit Care Med 30: 119, 2002]

Start at 2 to 5 mg every 6 to 12 hours (maximum effect at 20 mg/day)

Atypical Agents

Risperidone

A benzisoxazole-derivative antipsychotic agent and chemically unrelated to other antipsychotic agents. Mechanism of action not completely worked out but likely involves antagonism of central type 2 serotonergic (5-HT2) receptors and central dopamine D2 receptors (also an α2-antagonist). Available in tablet form or as a solution. Peak in 1 hour. Hepatic metabolism. Mild sedation only

Start with 1 mg q 12h. Renal adjustment required. Binds to the IKr channel and can prolong the QTc interval [Glassman AH, Bigger JT Jr. Am J Psychiatry 158: 1774, 2001] leading to a mean increase in QTc 10 [Huffman JC, Stern TA. Prim Care Companion J Clin Psychiatry 5: 278, 2003] to 12 seconds. Notably, although this is significantly higher than haloperidol, there is no convincing evidence that risperidone has ever caused torsades or sudden death [Glassman AH, Bigger JT Jr. Am J Psychiatry 158: 1774, 2001]

Pricing: Risperdal 1MG Tablets (JANSSEN): $6.33 each ($12.66/day, AHFS Drug Information, 2011)

Aripiprazole

Can be given intramuscularly, also available as a solution. Relatively little sedation.

Quetiapine

A dibenzothiazepine-derivative antipsychotic agent. Mechanism of action related to antagonism at serotonin type 1 and type 2 receptors as well as dopamine (D1, D2) receptors. Also blocks α1 (orthostatic hypotension), α2, and H1 (sedating) receptors. Available in tablet form only. Peaks in 1.5 hours. Hepatic metabolism. Moderately sedating [Miller DD. Prim Care Companion J Clin Psychiatry 6 (Suppl 2): 3, 2004]

Start with 25 mg PO q12h. Binds to the IKr channel and can prolong the QTc interval (mean increase in QTc 14.5s [Huffman JC, Stern TA. Prim Care Companion J Clin Psychiatry 5: 278, 2003]), but it is not clear that it can cause torsade de pointes or ventricular fibrillation [Glassman AH, Bigger JT Jr. Am J Psychiatry 158: 1774, 2001]

Pricing: SEROquel 25MG Tablets (ASTRAZENECA): $3.53 each ($7.06/day, AHFS Drug Information, 2011)

Olanzapine[edit]

Tablet form only. Peaks in 6 hours. Start with 2.5 mg PO qhs. Moderately sedating [Miller DD. Prim Care Companion J Clin Psychiatry 6 (Suppl 2): 3, 2004]

Binds to the IKr channel and can prolong the QTc interval (mean increase in QTc 6.4s [Huffman JC, Stern TA. Prim Care Companion J Clin Psychiatry 5: 278, 2003]), but it is not clear that it can cause torsade de pointes or ventricular fibrillation [Glassman AH, Bigger JT Jr. Am J Psychiatry 158: 1774, 2001]

Pricing: ZyPREXA 2.5MG Tablets (LILLY): $10.90 each ($10.90/day, AHFS Drug Information, 2011)

Dexmedetomidine[edit]

Both the Maximizing Efficacy of Targeted Sedation and Reducing Neurological Dysfunction (MENDS) [Pandharipande PP et al. JAMA 298: 2644, 2007] and the Safety and Efficacy of Dexmedetomidine Compared to Midazolam (SEDCOM) [Riker R et al. JAMA 301: 489, 2009] studies suggest that dexmedetomidine may decrease delirium when compared to benzodiazepines. A retrospective analysis of data from two phase III multicenter, randomized, double-blind trials (MIDEX and PRODEX) suggested that dexmedetomidine was not inferior to midazolam and propofol and as compared to midazolam reduced the duration of mechanical ventilation [Jakob et al.].