A talk by Pratik Pandharipande at the 2017 meeting of the Scandinavian Society of Anaestesiology and Intensive Care Medicine. All of the conference content can be found here: https://scanfoam.org/ssai2017/ Developed in collaboration between scanFOAM, SSAI and SFAI.

1. Pratik Pandharipande, MD, MSCI
Professor of Anesthesiology and Surgery
Vanderbilt University School of Medicine
VA TN Valley Health Care System
ICU Delirium-Critical Factors and
Liberation Bundles

2. Disclosure
• Research grant from Hospira (now Pfizer) Inc in
collaboration with NIH
• Salary support
– Vanderbilt Physician Scientist Award (2003-2005)
– Foundation of Anesthesia Education and Research
(2005-2007)
– VA Career Development Award (2008-2011)
– R01 NHLBI (HL111111) (2012-present)

3. Morandi A, et al. Intensive Care Med. 2008;34:1907-1915.
Delirium and Coma

4. 1. Delirium is Very Prevalent
1. Post-acute-Rehabilitation settings: 16-23%
2. General Medical services: 9-42%
3. Orthopedics: 5-65%
4. Cardiac surgery: 32-50%
5. ICU: 60-80% of ventilated patients; 20-50% of lower severity
of illness
6. PICU: 30-50%; higher rates in younger children/those on MV
Kalisvaart K.J, 2006 JAGS;54:817-822
Marcantonio E.R, 2001JAGS;49:516-522
Williams-Russo P, 1992 JAGS;40:759-767
Klugkist M, 2008 Anesthetist;57:464-474
Sandeberg O, 1999 JAGS;47:1300-06
O’Keefe ST, 1996 AgeAgeing;25:317-321
Ely EW, ICM 2001;27:1892-900
Ely EW, JAMA 2001;286,2703-2710
Inouye S.K,1999 NEJM:669-676
Rockwood K, 1994 JAGS;42:252-6
Rudolph J.L, 2006 JAGS;54:937-941
Gustafson Y, 1988 JAGS;36:525-530
Francis J, 1990 JAMA;263:1097-101
Levkoff S, 1992 Arch Int Med;152:334-40
McNicoll L, JAGS 2003;51:591-98
Ely EW, CCM 2001;29,1370-79
Pandharipande, ICM 2007;33(10):1726-31
Ryan DJ, 2013 BMJ Open 2013;3:1-9

5. 2. Delirium = Acute End Organ Dysfunction
Urine Output/Cr ----------------------->
MAP ------------------------------------>
PaO2 / FiO2 -------------------------->
Delirium ----------------------------->

6. 3. Delirium is Associated with Worse
Outcomes
• $15k to $25k higher hospital costs
• Longer hospital stays
• Higher risk of death
• Prolonged cognitive and psychological
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.

7. Delirium Duration and Mortality
Pisani M. Am J Respir Crit
Care Med. 2009 Dec
1;180(11):1092-7.

8. ©rustyrhodesviaFlickr©rustyrhodesviaFlickr
30-50%
Cognitively Impaired
Wolters Intensive Care Med 2013; 39: 376
Jackson AJRCCM 2010; 182: 183
Girard Crit Care Med 2010; 38: 1513
Newman et al.
McDonald et al.

9. 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

10. 50
60
70
80
90
100
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+
DeliriumRisk
Pandharipande PP, et al. Anesthesiology. 2006;104:21-26.
Lorazepam and Delirium

12. AA Assessing and Treating Pain
BB Both Awakening and Breathing trials
CC Coordination and Choice of
Sedation
DD Delirium management
EE Exercise & mobility
FF Family involvement

13. AA
•Assessing and Managing PainAssessing and Managing Pain

14. Behavioral Pain Scale (BPS)
Payen JF, et al. Crit Care Med. 2001;29(12):2258-2263.
Item Description Score
Facial expression
Relaxed 1
Partially tightened (eg, brow lowering) 2
Fully tightened (eg, eyelid closing) 3
Grimacing 4
Upper limbs
No movement 1
Partially bent 2
Fully bent with finger flexion 3
Permanently retracted 4
Compliance with
ventilation
Tolerating movement 1
Coughing but tolerating ventilation for most of
the time
2
Fighting ventilator 3
Unable to control ventilation 4

15. Prn morphine at 2.5- 5 mg for comfort
Physician consult if patient seemed uncomfortable
Prn haloperidol for delirium
If still uncomfortable propofol infusion for 6 hours
Transitioned to back to prn morphine
3 such cycles allowed; if failed propofol infusion with DIS
A Protocol of no sedation/analgo-sedation
for mechanically ventilated patients
Strom et al. Lancet 2010; 375:475-80

16. Control group on “Sedation”
Sedation with propofol to achieve Ramsay
score of 3-4
Morphine prn for pain
Daily interruption of sedation; restart at half dose
After 48 hours of propofol, transitioned to
midazolam titrated to Ramsay 3-4 with daily
interruption of sedation
Strom et al. Lancet 2010; 375:475-80

17. Strom et al. Lancet 2010; 375:475-80
Study Outcomes

18. BB
•Awakening and BreathingAwakening and Breathing

19. The ABC Trial
(Both groups get patient targeted sedation)
O U T C O M E S
d e lir iu m , L O S , 1 2 - m o N P S t e s t in g , Q O L
S p o n t a n e o u s B r e a t h i n g T r i a l ( S B T )
v e n tila t o r o ff
s a f e ly m o n it o r e d
O U T C O M E S
d e lir iu m , L O S , 1 2 - m o N P S t e s t in g , Q O L
S p o n t a n e o u s B r e a t h i n g T r i a l ( S B T )
v e n tila t o r o ff
s a f e ly m o n it o r e d
S p o n t a n e o u s A w a k e n i n g T r i a l ( S A T )
t u r n s e d a t io n / n a rc o t ic s o ff
m o n it o r s a f e ly
M e d ic a l I C U o n V e n t ila t o r
S u r ro g a t e I n f o r m e d C o n s e n t
ControlControl InterventionIntervention

20. Successful Extubation
00
DaysDays
77
00
2020
4040
6060
8080
100100
PatientsSuccessfullyExtubated(%)PatientsSuccessfullyExtubated(%)
1414 2121 2828
SAT + SBT (n=167)SAT + SBT (n=167)
SBT (n=168)SBT (n=168)
Mean ventilator-free days, 14.7 versus 11.6 daysMean ventilator-free days, 14.7 versus 11.6 days
95% CI for the difference, 0.7 to 5.6 days;95% CI for the difference, 0.7 to 5.6 days; PP=.02=.02
Girard TD, et al.Girard TD, et al. LancetLancet. 2008;371:126-134.. 2008;371:126-134.
• Reduction in
duration of
coma but not
delirium

21. Improved 1-Year Survival in ABC TrialPatientsAlive(%)PatientsAlive(%)
00
00
2020
4040
6060
8080
100100
6060 120120 180180 240240 300300 360360
DaysDays
SBT (n=168)SBT (n=168)
SAT+SBT (n=167)SAT+SBT (n=167)
Hazard Ratio=0.68 (0.50-0.92),Hazard Ratio=0.68 (0.50-0.92), PP=.01=.01
Girard TD, et al.Girard TD, et al. LancetLancet. 2008;371:126-134.. 2008;371:126-134.

22. CC
•Choice of sedation (after analgesia)Choice of sedation (after analgesia)

23. Propofol-Based Sedation
Randomized Controlled Trial
University of North Carolina and University of Chicago Hospitals
MICU patients
ventilated and sedated
Control
lorazepam
via intermittent bolus,
Ramsay 2-3 targeted,
daily interruption
Intervention
propofol
via continuous infusion,
Ramsay 2-3 targeted,
daily interruption
Carson SS, et al. Crit Care Med. 2006;34:1326-1332.

24. Outcome
Lorazepam
(n=64)
Propofol
(n=68) P-Value
Ventilator days
All patients 8.4 [4.6-14.7] 5.8 [3.5-10.3] .04
Survivors 9.0 [5.3-16.8] 4.4 [3.0-8.7] .006
ICU length of stay, days
Survivors 12.7 [7.8-19.1] 8.6 [5.0-14.7] .05
Hospital mortality 38 37 .82
Outcomes with Propofol-based sedation
Carson SS, et al. Crit Care Med. 2006;34:1326-1332.

25. Dexmedetomidine-based sedation
MENDS double blind RCT
•Doses of Dexmedetomidine up to 1.5 mcg/kg.hr
** Duration of Dexmedetomidine infusion up to 5 days or 120
hours
MICU/SICU patients
ventilated and sedated
Control
lorazepam (GABA)
± fentanyl
Intervention
dexmedetomidine (α2)
± fentanyl
Pandharipande PP, et al. JAMA. 2007;298:2644-2653.

26. Risk of Developing Delirium
Pandharipande PP, et al. Critical Care March 2010 (epub)

27. Prevalence of Delirium (SEDCOM)
54% DEX vs 76.6% MDZ, P<.001
Riker RR, et al. JAMA. 2009;301:489-499.

28. Dexmedetomidine – Extubation
P=.01
0
20
40
60
80
100
PatientsMechanicallyVentilated(%)
Days
0 2 4 6 8
Dexmedetomidine
Midazolam
Riker RR, et al. JAMA. 2009;301:489-499.

29. DD
•Delirium assessment and managementDelirium assessment and management

30. MIND: Resolution of Delirium and Coma
Girard TD, et al.Girard TD, et al. CCM . Feb 2010; 38 (2)CCM . Feb 2010; 38 (2)..
11 55 1010 1515 2020
DayDay
PatientsWithoutDeliriumorComa(%)PatientsWithoutDeliriumorComa(%)
00
2020
4040
6060
8080
100100
Haloperidol (n=35)Haloperidol (n=35)
Ziprasidone (n=32)Ziprasidone (n=32)
Placebo (n=36)Placebo (n=36)
Trauma ICU
SICU
MICU

31. Devlin, et al.Devlin, et al. CCM . Feb 2010; 38 (2)CCM . Feb 2010; 38 (2)..
Quetiapine in DeliriumQuetiapine in Delirium

32. EE
•Early mobilityEarly mobility

33. Daily Wake-Up + Early Mobility
Outcome
Intervention
(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.

34. Milestones Achieved Safely ~3
days earlier (p<0.001)
1. Standing
2. Marching
3. Walking
4. Transferring
Schweickert et al, Lancet 2009;373:1874-82Schweickert et al, Lancet 2009;373:1874-82

35. ICU Survivorship:
“The defining challenge of critical
care in the 21st
century”
Family
Hobbies
Work
Iwashyna Annals of Int Med 2010; 153:204-5FF