1. Delirium: The Next Proposed “Never Event.”
Is This Realistic?
Pratik Pandharipande, MD, MSCI
Department of Anesthesiology/Critical Care
Vanderbilt University School of Medicine, Nashville, TN
VA TN Valley Health Care System

2. Disclosure
Research Grant - Hospira Inc
Honorarium - Hospira Inc
FAER Grant
VPSD Award
VA Career Development Award

3. Delirium: A never event? Maybe
not 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

4. 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)
70
60 P-value for trend shift at
Number of Articles
year 2000 = 0.002
50
40
30
20
10
0
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
Year
Morandi et al ICM 2008;34:1907-1915

5. Delirium: A brain organ dysfunction
Morandi et al ICM 2008;34:1907-1915

6. 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
Roberts B. Aust Crit Care. 2005;18:6,8-9.
Ely EW. ICM. 2001;27:1892-1900. Thomason J. Crit Care. 2005;9:375-381.
Ely EW. JAMA. 2001;286,2703-2710. Ely EW. CCM. 2004;32:106-112.
Pandharipande. J Trauma. 2008;65:34-41. Peterson. JAGS. 2006;54:479-484.
Ely EW. CCM. 2001;29:1370-1379. Ouimet S. ICM. 2007;33:66-73.
Pandharipande. ICM. 2007;33:1726-1731. Spronk P. Neth J Med.2009;67:296-300
Lat I. CCM.2009;37:1898-1905 Slooter A. CCM.2009. 37 (6):1881-1885, 2009

7. 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.

8. Delirium and Long-Term Cognitive
60
Outcomes
Cognitive Function at 12 Months
P=.005
50
(Predicted Mean T-score)
40
30
20
10
0
0 5 10 15 20
Days of ICU Delirium
Girard TD, et al. ATS 2009

9. Delirium duration and Mortality
Pisani M. Am. J. Respir. Crit.
Care Med. Sept 2009
(epub)

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

11. Subsyndromal Delirium and
Clinical Outcomes
No Clinical
Delirium Subsyndromal Delirium 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.

12. Pathogenesis of Delirium
•Inflammation
•Neurotransmitters
•Tryptophan metabolites

13. Risk Factors for Delirium
• Aging • Psychoactive medications
• Baseline dementia • Sleep deprivation
• Psychiatric disorders
• Underlying illness
– Inflammation
– Coagulation
• Metabolic disturbances Inouye. JAMA. 1996;275:852-857.
Dubois. Intens Care Med. 2001;27:1297-1304.
• Hypoxemia Inouye. NEJM. 1999;340:669-676.
Jacobi. Crit Care Med. 2002;30:119-141.
• Genetic predisposition (?) 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

14. Lorazepam and Delirium
100
90
Delirium Risk
80
70
60
50
No drug 0 -1 1 -2 2 -3 3 -4 4+ Log scale
0 - 2.7 2.7 -7.4 7.4 -20 20 -55 55+ Original scale
Lorazepam Dose (mg)
Pandharipande PP, et al. Anesthesiology. 2006;104:21-26.

15. Midazolam and Fentanyl (?) as
Risk Factors for Delirium
Midazolam Fentanyl
100 100
Users Users
Non-Users Non-Users
80 80
% Days Delirious
% Days Delirious
P=.014 P=.007
P=.031
60 60
P=.936
40 40
20 20
0 0
Surgical Trauma Surgical Trauma
Daily Midazolam Use (Exc. Coma Days) Daily Fentanyl Use (Exc. Coma Days)
Pandharipande, et al. J Trauma. 2008;65:34-41.

16. Risk factors of Delirium in Burn ICU patients
Benzodiazepines
1.0
Odds of delirium
0.8
0.6
0.4
0.2
0.0
0 50 100 150 200
Benzodiazepines in previous 24 hours (midazolam equivalents)
Opiates
Odds of delirium
1.0
0.8
0.6
0.4
0.2
0.0
0 2000 4000 6000 8000
Opiates in previous 24 hours (fentanyl equivalents)
Pandharipande, Agarwal, Cotton et al. ASA 2009

17. What should we do to “try and
make delirium a never event?”
• 1. Monitoring
• 2. Non pharmacolgical interventions
• 3. Reduction in deliriogenic medications
• 4. Pharmacological interventions
– Dexmedetomidine
– Antipsychotics

18. BRAIN ROAD MAP on ROUNDS
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?)

19. Confusion Assessment Method
(CAM-ICU)
1. Acute onset of mental status changes
or a fluctuating course
and
2. Inattention
and
3. Altered level of 4. Disorganized thinking
or
consciousness
= Delirium
Ely EW, et al. Crit Care Med. 2001;29:1370-1379.
Ely EW, et al. JAMA. 2001;286:2703-2710.

20. 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.

21. Multicomponent preventive protocols
Study design Incidence of delirium Duration of Severity of
Delirium Delirium
Inouye Prospective 9.9% intervention No benefit No benefit
matching 15% control
Marcantonio RCT 32% intervention 50% No benefit No benefit
control
Milisen Prospective No benefit 1 day intervention Lower CAM
sequential 4 days control score
design
Lundstrom Clinical Trial No benefit 30.2% intervention Not
59.7% control evaluated
Vidan Prospective 11.7% intervention No benefit No benefit
cohort trial 18.5% control
Inouye S.K,1999 NEJM:669-676
Lundstrom M, 2005 JAGS:622-628
Marcantonio E.R, 2001 JAGS:516-522
Vidan M.T, 2009 JAGS E Pub
Milisen K, 2001 JAGS:523-532

22. Early Mobilization Protocol in
Mechanically Ventilated Patients
Schweickert et al, Lancet 2009;373:1874-82

23. Daily Wake-Up + Early Mobility
Intervention Control
Outcome (n=49) (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.

24. Have a Plan:
Sedation Protocols and Targeted Sedation

25. Sedation Protocols: The Evidence
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

26. Less is More:
Daily Interruption of Sedatives and
Wake-Up and Breathe

27. Benzodiazepines
70
Usual Care + SBT
Daily Dose of Benzodiazepines
60
SBT + SAT
50
40
30
20
10
0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
Study Day

28. 6000
Opiates
Usual Care + SBT
SBT + SAT
Daily Dose of Opiates
4000
2000
0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
Study Day

29. Avoid Benzodiazepines:
Alternative Sedatives

30. MENDS Trial
Double-blind, Randomized, Controlled
MICU/SICU patients
ventilated and sedated
Control Intervention
lorazepam (GABA) dexmedetomidine (α2)
± fentanyl ± fentanyl
Vanderbilt University Medical Center and Washington Hospital Center
Pandharipande PP, et al. JAMA. 2007;298:2644-2653.

31. Risk of Developing Delirium
Pandharipande PP, et al. unpublished data

32. Brain Dysfunction
P=.01 P=.09 P=.001
12
10
8
6
4
2
Dexmedetomidine
0 Lorazepam
Delirium/Coma-Free Days Delirium-Free Days Coma-Free Days
Pandharipande PP, et al. JAMA. 2007;298:2644-2653.

33. Prevalence of Delirium
54% DEX vs 76.6% MDZ, P<.001
Riker et al. JAMA 2009

34. 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.

35. Resolution of Delirium and Coma
100
Patients Without Delirium or Coma (%)
80
60
40
Haloperidol (n=35)
Ziprasidone (n=32)
20 Placebo (n=36)
0
1 5 10 15 20
Day
Girard TD, et al. Am J Respir Crit Care Med. 2008;177:A817.

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