Do benzos, opioids, or strong anticholinergics cause delirium? Lisa Burry

Delirium in the ICU Occurs in up to 85% of MICU/SICU MV patients 20-50% of lower severity ICU patients develop delirium Hypoactive or mixed forms most common 65-70% undiagnosed if routine monitoring not implemented <5% of Canadian ICUs routinely monitor for delirium Ely ICM 2001; 27:1892-1900 Pandharipande J Trauma 2008;65:34-41 Ouimet ICM 2007;33:66-73. Lat CCM 2009;37:1898-1905

Sequelae of Delirium During the ICU or Hospital stay 5 fewer ventilator free days 3x greater re-intubation rate ~10 additional days in hospital $15-25K higher hospital costs Mortality Post hospital discharge Mortality 9x higher incidence of cognitive impairment Transfer to chronic care facility Functional status @ 6 months Milbrandt CCM 2004;32:955-62 Lin CCM 2004;32:2254-59 Ely JAMA 2004;291:1753-62

Delirium Treatment Am Psychiatric Association (1999) Antipsychotic medications are often the pharmacologic treatment of choice (grade I = recommended with substantial clinical confidence) Some clinicians choose to use atypical antipsychotics SCCM (2002) Haloperidol is the preferred agent for the treatment of delirium in critically ill patients (grade C recommendations) Use of antipsychotics is common practice in ICUs (25-40%) Lack of substantial evidence treatment improves clinical outcomes plus significant adverse effects associated with antipsychotics, energies should focus on prevention Trzepacz APA 1999 Jacobi CCM 2002;30:119-141 Patel CCM 2009;37:825-832 Wang NEJM 2005

18767 studies reporting on medications and delirium 136 medications listed as potential causes Estimated 40% of delirium cases are caused by medications Numerous limitations in study design (e.g. size, definition of drug exposure).

Prevention protocols non ICU patients

Opioids Conflicting data! Evidence from 2 moderate quality multivariate analyses support association of increased delirium risk in medical-surgical patients Dubois et al: Morphine all doses OR 6.0-9.2 & Epidural OR 3.5 (1.20-10.39) Recent no sedation study (opioid offered without sedation) found this strategy to be associated with increased agitated delirium (n = 140 pt; 20% vs. 7%; p=0 0400) Inverse dose-response relationship in patients recovering from hip fracture < 10 mg morphine RR 25.2, 95% CI 1.3-493.3 10-30 mg morphine RR 4.4, 95% CI 0.3 68.6 Clegg Age and Ageing 2010;0:1-7 Gaudreau Psychosomatics 2005;46:302-316 Dubois Int Care Med 2001;27:1297-1304 Strom Lancet 2010;375:475-480

Opioids - Surgical & Trauma ICU patients N = 100; 70% had delirium Figure illustrates the proportion of time that pts were delirious while receiving the drug vs. those not exposed Exposed to fentanyl: SICU [OR 3.99 (1.47,10.85)] vs TICU [OR 1.03 (0.47, 2.25)] Exposed to morphine: SICU [OR 0.37(0.13-1.08)] vs TICU [OR 0.22(0.06-0.82)] caution low # of patients included

Benzodiazepines In a mixed ICU Dubois et al (n = 216) found lorazepam doses > 1.8 mg/day was linked to delirium OR 3.3 (1.31-8.04) by univariate analysis; multivariate not significant In mixed ICUs Van Rompaey et al (n = 523) found OR 2.89 (1.44-5.69) Higher doses during a 24 hr period associated with increased risk compared to lower doses OR 3.3 (1.0-11.0) vs. 2.6 (0.8-9.1) In a MICU Pisani et al (n = 304 > 60 years) found exposure to benzodiazepine or opioid to be associated with increased duration of delirium [RR 1.64 (1.27-2.10)] Clegg Age and Ageing 2010;0:1-7 Dubois Int Care Med 2001;27:1297-1304 Pisani Crit Care Med 2009;37:177-183

Midazolam - Surgical-Trauma ICU patients 100 surgical-trauma ICU patients Exposed to midazolam: SICU [OR ( 3.22 (1.27-8.20, p 0.007)] TICU [OR (2.45 (1.09,5.52, p 0.936] Most consistent & significant predictor of transitioning into delirium

Agents with significant anticholinergic effects Atropine Antidepressants amitriptyline, clomipramine, doxepin, phenelzine paroxetine Antipsychotics chlorpromazine, clozapine, olanzapine, thioridazine Anti-allergy diphenhydramine, hydroxyzine Antiemetics dimenhydrinate, promethazine, scopolamine Belladona alkaloids Parkinsonism amatadine, benztropine, biperidine, trihexyphenidyl

Strong Anticholinergics Pisani et al: N = 304 MICU; > 60 years Evaluated impact of drugs on the duration of delirium Administration of anticholinergic to 32% of patients Anticholinergics were not associated with increased duration of delirium Pandharipande et al: N = 198 MICU patients 32% (63) were administered anticholinergics; 83% (n = 52) experienced delirium Administration of anticholinergic was not associated in univariate or multivariable analysis with delirium Pandharipande Anesthesiology 2006;104(1):21-26 Han Arch Intern Med 2001;161:1099-1105

SLEAP RCT Mehta ESICM 2012

Work in progress A prospective evaluation of the association between psychoactive medications and delirium in critically ill adults 535 mixed ICU patients from 6 sites admitted at least 24 hr Daily delirium assessment with ICDSC until discharge Pre-enrollment drug exposure, cigarettes, illicit drugs and ethanol use Captured daily drug exposure, use of sedation strategies, physical restraint use, catheters, lab values, environmental factors, mobilization, clinical outcomes Enrollment closed June 27, 2012

Summary Delirium is common in the ICU & associated with poor outcomes Medications are an important consideration for patients with or at risk of delirium Whether or not sufficient evidence that these medications cause delirium there are significant other benefits from reducing sedative doses (e.g. duration of MV) Further clarification of the risk of delirium following exposure to medications is important for changing prescribing practices including further evaluation of dose relationships, impact of drug titration strategies (e.g. DSI), & polypharmacy