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; 27:1892-1900Pandharipande J Trauma 2008;65:34-41Ouimet ICM 2007;33:66-73.Lat CCM 2009;37:1898-1905

Sequelae of Delirium

During the ICU or Hospital stay

Post hospital discharge

5 fewer ventilator free days

3x greater re-intubation rate

~10 additional days in hospital

$15-25K higher hospital costs

Mortality

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;32:2254-59Ely 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 1999Jacobi CCM 2002;30:119-141Patel CCM 2009;37:825-832Wang 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;46:302-316Dubois 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;0:1-7Dubois Int Care Med 2001;27:1297-1304Pisani 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, p0.007)]

TICU [OR (2.45 (1.09,5.52, p0.936]

Most consistent & significant predictor of transitioning into delirium

Agents with significant anticholinergic effects

Atropine

Antidepressants – amitriptyline, clomipramine, doxepin, phenelzineparoxetine

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):21-26Han Arch Intern Med 2001;161:1099-1105

SLEAP RCT

Mehta ESICM 2012

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