Acute Brain Dysfunction in the Critically Ill Patient:

Data from recent delirium studies

Pratik Pandharipande, MD, MSCIAnesthesiology/ Critical Care

Vanderbilt University, Nashville, TN

…The biggest problem is that “doctors are focused only on the organs that got patients into the hospital, ignoring newly acquired brain problems…”

Delirium• Disturbance of consciousness• Rapid onset• Fluctuating course• Inattention• Impaired ability to receive, process, store and

recall information• Perceptual disturbances- illusions,

hallucinations

Prevalence of ICU Delirium • 60-80% MICU/SICU/TICU ventilated patients develop

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

delirium• Hypoactive or mixed forms most common • Majority goes undiagnosed if routine monitoring is not

implemented

Ely EW, ICM 2001;27:1892-900Ely EW, JAMA 2001;286,2703-2710Pandharipande J Trauma 2008;65(1):34-41 Ely EW, CCM 2001;29,1370-79Pandharipande, ICM 2007;33(10):1726-31

Roberts B, Aust Crit Care. 2005;18(1):6, 8-9 Thomason J, Crit Care. 2005;9(4):375-81 Ely EW CCM 2004;32:106-112Peterson JAGS 2006;54(3):479-84Ouimet S, ICM 2007;33(1):66-73

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;291-1753-1762Ouimet S, ICM 2007;33(1):66-73Lin et al, Crit Care Med 2004;32:2254-59

Long-term cognitive impairment (LTCI) after ICU survival

• 10 cohorts (~500 pts) and the largest with neuropsychological testing was 74 patients

• Summary: ~2 out of 3 ICU survivors leave the ICU with long-term cognitive impairment that equates to mild/moderate dementia (sometimes severe)

• Deficits tend to be diffuse and occur in domains including memory, attention/concentration, language, executive functioning

Rothenhausler, Gen Hosp Psych 2001;23:90-96Hopkins, AJRCCM 1999;160:50-56Jackson, Crit Care Med 2003;31;1226-34Hopkins, JINS 2004; 10:1005-1017Hopkins, AJRCCM 2005; 171:340-347

Marquis, AJRCCM 2000;161:A383 (Curtis)Al Saidi, AJRCCM 2003:167:A737 (Herridge) Sukantarat, Anaesthesia 2005;60:847-853Suchyta, AJRCCM 2004; 169:A18Christie, AJRCCM 2004; 169:A781

0

10

20

30

40

50

60

0 5 10 15 20

Days of ICU Delirium

Cog

nitiv

e F

unct

ion

at 1

2 m

onth

s(p

redi

cte

d m

ean

T-s

core

)

Girard TD, et al. 2008, unpublished dataGirard TD, et al. 2008, unpublished data

p=.005

Delirium and Long-Term Cognitive OutcomesDelirium and Long-Term Cognitive Outcomes

Delirium risk factors

Risk Factors, Prevention, and Treatment

• Aging• Baseline dementia• Psychiatric disorders• Underlying illness

– Inflammation

– Coagulation

• Metabolic Disturbances• Hypoxemia• Genetic Predisposition (?)

• Psychoactive Medications• Sleep Deprivation

Inouye, JAMA 1996;275:852-57Dubois, Intens Care Med 2001;27:1297-1304Inouye, NEJM 1999;340:669-676Jacobi, Crit Care Med 2002;30:119-141Milbrandt, Crit Care Med. 2005;33:226-9Ouimet S. Int Care Med 2007;33:66-73

Probability of transitioning from normal to delirium after lorazepam

Lorazepam Dose (mg)

Delirium Risk

Pandharipande et al. Pandharipande et al. Anesthesiology 2006: Anesthesiology 2006: 124:21-6124:21-6

OR 1.2 (1.1-1.4), P=0.003

Surgical Trauma

Users

Non-Users

Midazolam

Daily Midazolam Use (Exc. Coma Days)

% D

ays

De

lirio

us

02

04

06

08

01

00

p=0.014p=0.031

Surgical Trauma

Users

Non-Users

Fentanyl

Daily Fentanyl Use (Exc. Coma Days)

% D

ays

De

lirio

us

02

04

06

08

01

00

p=0.007

p=0.936

Midazolam and fentanyl as risk factors for delirium

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

Sedatives/analgesics in delirium

Pandharipande et al. unpublished dataPandharipande et al. unpublished data

Delirium in surgical ICU patients

• 134 surgical and trauma adult patients requiring mechanical ventilation

• 63% developed delirium • Delirium was associated with more MV days (9.1

vs. 4.9 days, p < 0.01), longer ICU stay (12.2 vs. 7.4 days, p < 0.01), longer hospital stay (20.6 vs. 14.7 days, p < 0.01).

• Greater cumulative lorazepam dose (p = 0.012), and higher cumulative fentanyl dose (p = 0.035) were administered in the delirium group.

Lat I. Crit Care Med. April 2009 (epub)

0

5

10

15

20

25

Discharge One-Year Two-Years

% N

eu

roco

gn

itiv

e S

eq

uela

e

ICU RecallNo Recall

ARDS Patients

Larson MJ. JINS 2007;13:595-605

Psychological outcomes

• Pts with delusional but not factual recall of ICU experience at 2 weeks scored highly for PTSD related symptoms and panic attacks at 8 weeks (p = 0.023 and 0.014 respectively).

Jones C et al. Crit Care Med 2001; 29: 573

How do we prevent/ treat delirium ?

1. Prevention protocols

2. Changing sedation paradigms

-Reducing exposure

-Changing medications

3. Antipsychotics

Prevention protocols

• Reorientation, continuity of care givers

• Improving sleep architecture

• Reducing exposure to deliriogenic medications

• Cognitive stimulation

• Role of geriatrician visits or trained personnel in neuropsychological disorders

Inouye et al. NEJM 1999; 9(340):669-676

Reduce exposure to sedatives and analgesics

Protocol and target based sedation and analgesia

Daily awakening trials

Mascia et al. CCM 2000; 28: 2300-2306Mascia et al. CCM 2000; 28: 2300-2306Brook et al. CCM 1999; 27: 2609-2615Brook et al. CCM 1999; 27: 2609-2615Kress et al. NEJM 2000; 342: 1471-1477Kress et al. NEJM 2000; 342: 1471-1477Brattebo et al. BMJ 2002; 324: 1386-1389Brattebo et al. BMJ 2002; 324: 1386-1389

The ABC Trial(both groups get patient targeted sedation)

O U TC O M ESd e lirium , LO S , 1 2 -m o N P S tes tin g , Q O L

S p o ntan eo u s B rea th ing T ria l (S B T)ve n tila to r o ff

sa fe ly m o n ito red

O U TC O M ESd e lirium , LO S , 1 2 -m o N P S tes tin g , Q O L

S p o ntan eo u s B rea th ing T ria l (S B T)ve n tila to r o ff

sa fe ly m o n ito red

S p on taneo us A w aken ing T ria l (SA T)tu rn se d a tio n /n a rco tics o ff

m o n ito r sa fe ly

M e d ica l IC U o n V en tila to rS u rro g a te In fo rm e d C o nse ntControl Intervention

Study Day

Da

ily D

os

e o

f B

en

zod

iaze

pin

es

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

010

2030

4050

6070

BenzodiazepinesBenzodiazepines

Usual Care+SBTSBT+SAT

Study Day

Da

ily D

os

e o

f O

pia

tes

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

0

2000

4000

6000

Usual Care+SBTSBT+SAT

OpiatesOpiates

SBT- CONTROL

SAT+SBT- INTERVENTION

Treatment group

No YesSepsis

0

10

20

Day

s o

f D

elir

ium

p=.74

Delirium duration in septic patients in ABC studyDelirium duration in septic patients in ABC study

Girard et al. Personal communication

p=.02

Pa

tie

nts

Aliv

e (

%)

00

20

40

60

80

100

60 120 180 240 300 360

Days

Usual Care+SBT (n=168)

SAT+SBT (n=167)

One-Year SurvivalOne-Year Survival

p=.01NNT=7

Girard TD, et al. Lancet 2008;371:126-34Girard TD, et al. Lancet 2008;371:126-34

Hospital Discharge

3-Month Follow-Up

12-Month Follow-Up

1.86 (1.04, 3.34)

2.01 (1.09, 3.71)

2.23 (1.13, 4.41)

0.04

0.02

0.02

Time of Cognitive Assessment Odds Ratio (95% CI) P-value

0 1 2 3 4

Favors Control Favors Intervention

Long-Term Cognitive Outcomes

Jackson JC, et al. 2008, in submission

Changing sedation paradigms

MENDS

SEDCOM

MENDS StudyDouble blind randomized controlled trial

C o n tro lL o ra ze p a m (G A B A )

+ /- F en ta n yl

In te rve n tionD e xm e d eto m id in e (2 )

+ /- F en ta n yl

M IC U /S IC U V en tila ted o n S e da tivesIn fo rm ed C o n se n t

Vanderbilt University Medical Center and Washington Hospital CenterVanderbilt University Medical Center and Washington Hospital Center

Pandharipande P et al. JAMA Dec 2007Pandharipande P et al. JAMA Dec 2007

Delirium/Coma-Free Days

02

46

810

12

p=.01

Delirium-Free Days

p=.09 p=.001

Coma-Free Days

DexmedetomidineLorazepam

Brain DysfunctionBrain Dysfunction

Pandharipande PP, et al. JAMA 2007;298:2644-53

Risk of developing delirium

Septic subgroup analysis

MENDS: Patients Outcomes in Septic subgroupOutcome variable Lorazepam Dexmedetomidine P value

(N=20) (N=19)

Brain Dysfunction Delirium and coma free days 1.5 (1,4) 8 (4,10) 0.002

Delirium free days 7.5 (4, 8) 10 (8, 11) 0.007

Coma free days 7 (1,9) 10 (9, 12) <0.003

Prevalence of delirium 70% 79% 0.52

Prevalence of coma 95% 68% <0.03

Efficacy of sedationDays at Physician RASS goal 35% (0,60) 67% (35,85) 0.016

Pandharipande et al. Critical Care 2008, 12(Suppl 2):P275

28-Day Survival, Sepsis Patients28-Day Survival, Sepsis Patients

0 7 14 21 28

020

4060

8010

0

Days

Pat

ient

s A

live

(%)

Dexmedetomidine

Lorazepam

Pandharipande et al. Critical Care 2008, 12(Suppl 2):P275

HR 0.3 (0.1- 0.9). P=0.04

Data on antipsychotics and delirium in the ICU

Olanzapine vs. haloperidol: treating delirium in a critical care setting

Mean daily delirium scores

Day

5 4 3 2 1

Mean score

8.0

7.5

7.0

6.5

6.0

5.5

5.0

4.5

4.0

Group

Haloperidol

Olanzapine

Skrobik et al, ICM 2004;30:444-49

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=0.009– RR=0.35, 95% CI=0.16-0.77)

Prakanrattana et al. Anaesth Intensive Care 2007 Oct;35(5):714-9.

MIND Multicenter Double Blind RCT

MV Surgical, MV Surgical, Medical and Medical and Trauma ICU Trauma ICU

patientspatients

PO haloperidolPO haloperidol PO ziprasidonePO ziprasidone PlaceboPlacebo

Girard T, Pandharipande P et al. in reviewGirard T, Pandharipande P et al. in review

Delirium rates in MIND

Girard T, Pandharipande P et al. in reviewGirard T, Pandharipande P et al. in review

Conclusion– Delirium occurs in majority of mechanically ventilated

patients and is associated with worse outcomes – Easy to diagnose in ICU with new validated instruments– Sedatives and analgesics may be modifiable risks factors– Avoiding benzodiazepines/ using alpha2 agonists may

reduce delirium– No difference between typical and atypical antipsychotics

in delirium management in ICU patients (risperidone in 1 study)

– Prevention protocols with emphasis on restoring sleep may help