Pratik Pandharipande, MD, MSCIDepartment of Anesthesiology/Critical Care

Vanderbilt University School of Medicine, Nashville, TNVA TN Valley Health Care System

Delirium: The Next Proposed “Never Event.”Is This Realistic?

Disclosure

Research Grant - Hospira Inc

Honorarium - Hospira Inc

FAER Grant

VPSD Award

VA Career Development Award

Delirium: A never event? Maybenot yet……BUT

• Delirium proposed by CMS as a “Never Event”

• “Never Events” are errors in medical care that are clearly identifiable, preventable, and serious in consequences and indicate a problem in the safety of a healthcare facility.

• The proposal has given delirium publicity

• Increased interest and research in this topic

Histogram showing the number of English articles detected when searching for Delirium and ICU as MeSH or Text Words by year from 1990 through 2007.

Articles on Delirium in ICU (MeSH or Text headings in English)

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PP--value for trend shift at value for trend shift at year 2000 = 0.002 year 2000 = 0.002

Morandi et al ICM 2008;34:1907-1915

Delirium: A brain organ dysfunction

Morandi et al ICM 2008;34:1907-1915

Prevalence of ICU Delirium

• Occurs in up to 80% MICU/SICU/TICU ventilated patients develop delirium

• 20-50% of lower severity ICU patients develop delirium

• Hypoactive or mixed forms most common

• 65-70% goes undiagnosed if routine monitoring is not implemented

Ely EW. ICM. 2001;27:1892-1900.Ely EW. JAMA. 2001;286,2703-2710.Pandharipande. J Trauma. 2008;65:34-41.Ely EW. CCM. 2001;29:1370-1379.Pandharipande. ICM. 2007;33:1726-1731.Lat I. CCM.2009;37:1898-1905

Roberts B. Aust Crit Care. 2005;18:6,8-9.Thomason J. Crit Care. 2005;9:375-381.

Ely EW. CCM. 2004;32:106-112.Peterson. JAGS. 2006;54:479-484.

Ouimet S. ICM. 2007;33:66-73.Spronk P. Neth J Med.2009;67:296-300

Slooter A. CCM.2009. 37 (6):1881-1885, 2009

Key Points: ICU Delirium

• $15k to $25k higher hospital costs

• Longer hospital stays

• 3 times higher risk of death by 6 months

• Prolonged neuropsychological dysfunction

Milbrandt E, et al. Crit Care Med. 2004;32:955-962.Ely EW, et al. JAMA. 2004;291:1753-1762.

Ouimet S. ICM. 2007;33:66-73.Lin, et al. Crit Care Med. 2004;32:2254-2259.

Girard TD, et al. ATS 2009

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Days of ICU Delirium

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nitiv

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P=.005

Delirium and Long-Term CognitiveOutcomes

Delirium duration and Mortality

Pisani M. Am. J. Respir. Crit.

Care Med. Sept 2009(epub)

Subsyndromal Delirium

Patients who present some symptoms of delirium, but do not fulfill all criteria for delirium.

Subsyndromal Delirium andClinical Outcomes

No Delirium Subsyndromal

ClinicalDelirium P-Value

ICU Mortality 2.4% 10.6% 15.9% <.001

ICU LOS 2.5 (2.1) 5.2 (4.9) 10.8 (11.3) <.001

Mean (SD) when applicable

Ouimet S. Int Care Med. 2007;33:1007-1013.

Pathogenesis of Delirium

•Inflammation•Neurotransmitters•Tryptophan metabolites

Risk Factors for Delirium

• Aging

• Baseline dementia

• Psychiatric disorders

• Underlying illness

– Inflammation

– Coagulation

• Metabolic disturbances

• Hypoxemia

• Genetic predisposition (?)

• Psychoactive medications

• Sleep deprivation

Inouye. JAMA. 1996;275:852-857.Dubois. Intens Care Med. 2001;27:1297-1304.

Inouye. NEJM. 1999;340:669-676.Jacobi. Crit Care Med. 2002;30:119-141.

Milbrandt. Crit Care Med. 2005;33:226-229.Ouimet S. Int Care Med. 2007;33:66-73

Pisani M. Crit Care Med. 2009 Jan;37(1):354-5

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No drug

Lorazepam Dose (mg)

Log scale

Original scale

0 -1 1 -2 2 -3 3 -4 4+

0 -2.7 2.7 -7.4 7.4 -20 20 -55 55+

Del

irium

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Pandharipande PP, et al. Anesthesiology. 2006;104:21-26.

Lorazepam and Delirium

Surgical Trauma

Users

Non-Users

Midazolam

Daily Midazolam Use (Exc. Coma Days)

% D

ays

Del

iriou

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P=.014P=.031

Surgical Trauma

UsersNon-Users

Fentanyl

Daily Fentanyl Use (Exc. Coma Days)

% D

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iriou

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P=.007

P=.936

Midazolam and Fentanyl (?) asRisk Factors for Delirium

Pandharipande, et al. J Trauma. 2008;65:34-41.

Benzodiazepines in previous 24 hours (midazolam equivalents)

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Risk factors of Delirium in Burn ICU patientsRisk factors of Delirium in Burn ICU patients

Pandharipande, Agarwal, Cotton et al. ASA 2009

What should we do to “try andmake delirium a never event?”

• 1. Monitoring

• 2. Non pharmacolgical interventions

• 3. Reduction in deliriogenic medications

• 4. Pharmacological interventions– Dexmedetomidine

– Antipsychotics

1. Target RASS/ (where going?)

(or any valid scale)

2. Actual RASS (where now?)

3. CAM-ICU/ICDSC (content ?)

4. Drugs/toxins/metabolic (how got here?)

BRAIN ROAD MAP on ROUNDS

Confusion Assessment Method(CAM-ICU)

1. Acute onset of mental status changes or a fluctuating course

and

2. Inattention

and

or3. Altered level of consciousness

4. Disorganized thinking

= DeliriumEly EW, et al. Crit Care Med. 2001;29:1370-1379.

Ely EW, et al. JAMA. 2001;286:2703-2710.

Intensive Care Delirium Screening Checklist

1. Altered level of consciousness

2. Inattention

3. Disorientation

4. Hallucinations

5. Psychomotor agitation or retardation

6. Inappropriate speech

7. Sleep/wake cycle disturbances

8. Symptom fluctuation

Bergeron, et al. ICM. 2001;27:859-864.

Multicomponent preventive protocols

Inouye S.K,1999 NEJM:669-676Marcantonio E.R, 2001 JAGS:516-522Milisen K, 2001 JAGS:523-532

Study design Incidence of delirium Duration of

Delirium

Severity of

Delirium

Inouye Prospective matching

9.9% intervention 15% control

No benefit No benefit

Marcantonio RCT 32% intervention 50% control

No benefit No benefit

Milisen Prospective sequential design

No benefit 1 day intervention 4 days control

Lower CAM score

Lundstrom Clinical Trial No benefit 30.2% intervention 59.7% control

Not evaluated

Vidan Prospective cohort trial

11.7% intervention18.5% control

No benefit No benefit

Lundstrom M, 2005 JAGS:622-628Vidan M.T, 2009 JAGS E Pub

Early Mobilization Protocol in Mechanically Ventilated Patients

Schweickert et al, Lancet 2009;373:1874-82

Daily Wake-Up + Early Mobility

OutcomeIntervention

(n=49)Control(n=50) P

Functionally independent at discharge 29 (59%) 19 (35%) .02

ICU delirium (days) 2.0 (0.0-6.0) 4.0 (2.0-7.0) .03

Time in ICU with delirium (%) 33% (0-58) 57% (33-69) .02

Hospital delirium (days) 2.0 (0.0-6.0) 4.0 (2.0-8.0) .02

Hospital days with delirium (%) 28% (26) 41% (27) .01

Barthel Index score at discharge 75 (7.5-95) 55 (0-85) .05

ICU-acquired paresis at discharge 15 (31%) 27 (49%) .09

Ventilator-free days 23.5 (7.4-25.6) 21.1 (0.0-23.8) .05

Length of stay in ICU (days) 5.9 (4.5-13.2) 7.9 (6.1-12.9) .08

Length of stay in hospital (days) 13.5 (8.0-23.1) 12.9 (8.9-19.8) .93

Hospital mortality 9 (18%) 14 (25%) .53

Schweickert WD, et al. Lancet. 2009;373:1874-1882.

Have a Plan:Sedation Protocols and Targeted Sedation

Trial RCT Outcome(s) Improved by Protocol

Brook et al.1999 Yes Ventilator days, ICU LOS

Kress et al. 2000 Yes Ventilator days, ICU LOS

Brattebo et al. 2002 No Ventilator days

de Lemos et al. 2005 Yes Ventilator days, ICU LOS

De Jonghe et al. 2005 No Ventilator days, time to awaken

Chanques et al. 2006 No Ventilator days, pain/agitation, infection

Quenot et al. 2007 No Ventilator days, extubation success, VAP

Arias-Rivera et al. 2008 No Extubation success

Bucknall et al. 2008 Yes None

Girard et al. 2008 Yes Ventilator days, hospital LOS, survival

Robinson et al. 2008 No Ventilator days, hospital LOS

Tobar et al. 2008 Yes Oversedation rate

Sedation Protocols: The Evidence

Less is More:Daily Interruption of Sedatives and

Wake-Up and Breathe

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Avoid Benzodiazepines:Alternative Sedatives

MENDS TrialDouble-blind, Randomized, Controlled

Vanderbilt University Medical Center and Washington Hospital Center

MICU/SICU patientsventilated and sedated

Controllorazepam (GABA)

± fentanyl

Interventiondexmedetomidine (α2)

± fentanyl

Pandharipande PP, et al. JAMA. 2007;298:2644-2653.

Risk of Developing Delirium

Pandharipande PP, et al. unpublished data

Delirium/Coma-Free Days

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12P=.01

Delirium-Free Days

P=.09 P=.001

Coma-Free Days

Dexmedetomidine

Lorazepam

Brain DysfunctionBrain Dysfunction

Pandharipande PP, et al. JAMA. 2007;298:2644-2653.

Prevalence of Delirium

54% DEX vs 76.6% MDZ, P<.001

Riker et al. JAMA 2009

Risperidone and Delirium

• Double-blind randomized trial (DBRT)

• Single dose (1 mg) of risperidone administered after cardiac surgery

• Reduced the incidence of postoperative delirium

– 11.1% vs.31.7%, P=.009

– RR=0.35, 95% CI=0.16-0.77

Prakanrattana, et al. Anaesth Intensive Care. 2007;35:714-719.

Resolution of Delirium and Coma

Girard TD, et al. Am J Respir Crit Care Med. 2008;177:A817.

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Haloperidol (n=35)Ziprasidone (n=32)Placebo (n=36)

Are we making any progress?• Growing awareness about delirium and associated

outcomes

• Better monitoring instruments for health care providers at bedside

• Identification of potential mechanisms and risk factors

• Non pharmacological interventions have shown promise in non-ICU cohorts and in ICU cohorts (early mobilization)

• Reducing benzodiazepine exposure with alternative sedation paradigms, especially dexmedetomidine has shown improvements in delirium rates and duration