2. OUTLINE OF THE TALK
• Definitions
– types/prevalence/importance
– risk factors/pathoetiology of delirium
risk factors/pathoetiology of delirium
• What can we do to prevent delirium:
a. Monitoring
p g
b. Non pharmacolgical interventions
c. Reduction in deliriogenic medications
• Use of Protocols and less is more
Use of Protocols and “less is more”
d. Pharmacological interventions
a. Antipsychotics
a Antips chotics
b. Dexmedetomidine
3. Definition of Delirium
Definition of Delirium
• derived from Latin:
derived from Latin:
– de “away from”
– lira “ furrow in field”
– ium (Latin for singular)
(Latin for singular)
4. Delirium
• Delirium is
li i i
(1) fluctuation/change in mental status
fluctuation/change in mental status
(2) inattention
either/or
(3) disorganized thinking
disorganized thinking
(4) altered level of consciousness
( )
DSM IV and CAM‐ICU
6. Delirium Subtypes
yp
• Hyperactive delirium ‐
agitation, restlessness, pulling catheters or tubes,
agitation restlessness pulling catheters or tubes
hitting, biting, and emotional lability. (At risk for self‐
extubation and subsequent reintubation)
q )
• Hypoactive delirium –
yp
withdrawal, flat affect, apathy, lethargy and perhaps
even unresponsiveness; often unrecognized due to
these “quiet” symptoms; (At risk for aspiration,
h “ i ” ( i kf i i
pulmonary embolism, decubitus ulcers, and other
complications related to immobility)
complications related to immobility)
• Mixed ‐ combination
Mixed
7. Delirium versus Cognitive Impairment
D li i C iti I i t
• Delirium • Cognitive impairment
– rapid onset – variable to insidious onset
– fluctuation – not fluctuating
not fluctuating
– clouded consciousness – no clouding of
– Inattention, disorganized consciousness
thought – many domains impaired
– not chronic – persistent/chronic (?)
Gordon SM, Intensive Care Med 30:1997‐2008, 2004
Jackson JC, Intensive Care Med 30:2009‐2016, 2004
8. Prevalence of ICU Delirium
Prevalence of ICU Delirium
• Occurs in up to 80% MICU/SICU MVpatients
• 20 50% of lower severity ICU patients develop
20‐50% of lower severity ICU patients develop
• Hypoactive or mixed forms most common
• 65‐70% goes undiagnosed if routine monitoring is
p
not implemented
Roberts B. Aust
Roberts B Aust Crit Care 2005;18:6 8‐9
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.
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
9. “Invisible” Organ Dysfunction
“I i ibl ” O D f ti
• Delirium is not routinely monitored in the ICU 1
• Validated tools – ICU‐DSC 2 or CAM‐ICU 3‐4
• “ICU Psychosis” traditionally an expected outcome
• In non ICU settings, delirium has been associated with
In non‐ICU settings delirium has been associated with
prolonged stay, institutionalization, and death 5‐7
1 Ely EW CCM 2004;32:106‐112 4 Ely EW CCM 2001;29,1370‐79
5 Inouye, Am J Med 1999;106:565‐573
2 Bergeron, ICM 2001;27:859‐64
g , ; 6 Lawlor, Arch Intern Med 2000;160:786‐794
3 Ely EW JAMA 2001;286,2703‐2710 7 McCusker, Arch Intern Med 2002;162:457‐463
10. ICU Delirium ‐ i li ti
ICU D li i implications
• 3 times higher risk of death by 6 months
3 i hi h i k f d h b 6 h
• $15k to $25k higher hospital costs
• Estimated national $4 to $16 billion associated costs
• 5 fewer ventilator free days (days alive and off vent),
adjusted P=0.03
• 9 times higher incidence of cognitive impairment at
hospital discharge, adj. P=0.002
• Using similar methodology (CAM‐ICU, etc) a
Taiwanese cohort found similar mortality data
Ely EW et al, JAMA 2004;291‐1753‐1762
y , ;
Milbrandt E et al, Crit Care Med 2004;32:955‐962
Lin et al, Crit Care Med 2004;32:2254‐59
12. Risk factors you can t control
Risk factors you can’t control
Age Severity of Ilness
S i f l
Each year increase risk in 2% Each point increase risk in 6%
Pandharipande P et all. Lorazepan is an independent risk factor for transitioning to
delirium in ICU patients, Anesthesiology, 2006; 104:21‐26
16. Hipoxemia, metabolic Systemic Inflamation
derangements
Drugs
Global impairment of Activation of primed
cerebral metabolism microglia
Neurotransmitter
Decreased synthesis imbalance, disruption
disruption
and release of of synaptic Increased cytokines
neurotransmitters communication levels in the brain
delirium
deliri m
17. What should we do to prevent
What should we do to prevent
delirium in ICU patients?
p
1. Monitoring
2. Non pharmacolgical interventions
2. Non pharmacolgical interventions
3. Reduction in deliriogenic medications
4. Pharmacological interventions
Dexmedetomidine
Antipsychotics
18. Two Step Approach to Assessing
Consciousness
Step 1 Level:
Arousal/Sedation Assessment (RASS, SAS)
(If pt opens eyes to voice then proceed to Step 2)
(f i h d )
Step 2 Content:
Delirium Assessment (CAM‐ICU)
19. Confusion Assessment Method
CAM‐ICU
1. Acute onset of mental status changes
1 A t t f t l t t h
or a fluctuating course
and
2. Inattention
2 I i
and
and
3. Disorganized or 4. Altered level of
Thinking consciousness
= Delirium
Ely, E.W., et al. JAMA; 286, 2703‐2710, 2001. Ely, E.W., et al. Crit Care Med; 29, 1370‐1379, 2001.
20. ICU Delirium Screening Checklist
8 items based on DSM criteria
8 items based on DSM criteria
Normal = 0, 1‐3 = subsyndromal delirium, ≥ 4 = delirium
1. Altered level of consciousness 1
2. Inattention 1
3. Disorientation 1
4. Hallucinations
4 Hallucinations 0
5. Psychomotor agitation or retardation 1
6. Inappropriate speech 0
p/ y
7. Sleep/wake cycle disturbances 1
8. Symptom fluctuation 1
Total score (0‐8)
Total score (0 8) 6/8
Bergeron, et al. ICM. 2001; 27:859
21. What should we do to prevent
What should we do to prevent
delirium in ICU patients?
p
1. Monitoring
2. Non pharmacolgical interventions
2. Non pharmacolgical interventions
3. Reduction in deliriogenic medications
4. Pharmacological interventions
Dexmedetomidine
Antipsychotics
22. Daily Wake‐Up + Early Mobility
Outcome Intervention Control P
(n=49) (n=50)
Funcionally independent at discharge (nnt=4) 29 (59%) 19 (35%) .02
ICU delirium (days) 2 (0‐6) 4 (2‐7) .03
Time in ICU with delirium (%) 33% (0‐58) 57% (33‐69) .02
Hospital delirium (days) 2 (0‐6) 4 (2‐8) .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 – 23.8) .05
Lenght of stay in ICU (days) 5.9 (4.5‐13.2) 7.9 (6.1‐12.9) .08
LOS hospital (days) 13.5 (8‐23.1) 12.9 (8.9‐19.8) .93
Hospital Mortality 9 (18%) 14 (25%) .53
Schweickert WD – Early physical and occupational therapy in MV, critically ill patients, a RCT, Lancet 2009
23. Environmental factor
E i t lf t
• Extremes in sensory experience (eg. Hypothermia)
• Deficits in vision or hearing
f h
• Immobility or decreased activity
y y
• Social isolation
• Novel environment
• Stress
24. A “bundle” for delirium prevention?
bu d e o de u p e e t o
• Family support (all levels, kids, childrens)
y pp
• Allow family at bedside, 24 h/day
•Oi
Orientation improvements
i i
– Daylights
– Wall clocks
• Hearing aid
Hearing aid
• Glasses
• Sleep...
25. Sleep deprivation and delirium
l d dd l
Sleep Deprivation Delirium
D li i
• Daytime sleepiness
D ti l i • Lethargy
h
• Lethargy • Agitation
• Irritability • Confusion
• Confusion • Inattention
• Poor short term memory
Poor short‐term memory
• Sympathetic stimulation
• Sympathetic stimulation
• Anger and Frustration
g • Emotional liability
• Restlessness • Restlessness
• Anxiety • Hallucinations
26. Sleep P t l
Sl Protocol
• Design behavioral protocol to reduce sleep disturbance
• Noise reduction at night
• Light reduction at night (cover eyes)
• Modify timing of patient/staff intervention at night
y g p / g
• Avoid unnecssary analgesia and sedation
• Ear plugs
Ear plugs
• Pharmacology (melatonin, sedatives)
• Back massage, relaxation, music therapy
Back massage relaxation music therapy
• Record hours of sleep and discuss during round
27. What should we do to prevent
What should we do to prevent
delirium in ICU patients?
p
1. Monitoring
2. Non pharmacolgical interventions
2. Non pharmacolgical interventions
3. Reduction in deliriogenic medications
‐ sedation protocols and “less is more”
4. Pharmacological interventions
4 Pharmacological interventions
Dexmedetomidine
Antipsychotics
h
28. Sedation Protocols: The Evidence
Sedation Protocols: The Evidence
Trial RCT Outcome(s) improved by Protocol
Brook AD, CCM 1999 Yes Ventilator days, ICU and HO LOS, need for tracheostomy
Kress JP, O’Connor NEJM 2000 Yes Ventilator days, ICU LOS
Brattebo G, BMJ 2000
G, BMJ 2000 No Ventilator days
Ventilator days
Chanques G, CCM 2006 No Ventilator days, pain/agitation, infections
Quenot JP, CCM 2007 No Ventilator days, extubation sucess, VAP
Arias‐Rivera S, CCM 2008
, No Extubation sucess
Girart TD, Lancet 2008 (ABC) Yes Ventilator days, HO LOS, survival (nnt=7)
Robinson BR, J Trauma 2008 No Ventilator days, HO LOS
29. What should we do to prevent
What should we do to prevent
delirium in ICU patients?
p
1. Monitoring
2. Non pharmacolgical interventions
2. Non pharmacolgical interventions
3. Reduction in deliriogenic medications
‐ sedation protocols and “less is more”
4. Pharmacological interventions
4 Pharmacological interventions
Antipsychotics
Dexmedetomidine
d d
30. Risperidone and Delirium
Risperidone and Delirium
• Double‐blind randomized trial
Double blind randomized trial
• Single dose (1 mg) of risperidone administered after
cardiac surgery
di
• Reduced the incidence of postoperative delirium
p p
– 11.1% (intervention) vs. 31.7% (placebo), P=.009
– RR=0 35 95% CI=0 16 0 77
RR=0.35, 95% CI=0.16‐0.77
Prakanrattana, et al. Anaesth Intensive Care. 2007;35:714‐719
33. Dexmedetomidine x Haloperidol
Randomised, open label, parallel‐groups pilot trial
, p ,p g p p
• 20 ventilated patients with agitated delirium
• Randomized to haloperidol 0.5‐2mg/hr or
dexmedetomidine 0.2‐0.7 μg/kg/hr
• Dexmedetomidine shorter hours to extubation
Dexmedetomidine shorter hours to extubation
42 (IQR 23.2‐117.8) vs 20 (IQR 7.3‐24), p=0.016
• Dexmedetomidine decreased ICU length of stay
6.5 (IQR 4 9) vs 1.5 (IQR 1 3) days, p=0.004
6 5 (IQR 4‐9) vs 1 5 (IQR 1‐3) days p=0 004
Reade MC. Critical Care 2009, 13:R75
34. Dexmedetomidine x Haloperidol
Randomised, open label, parallel‐groups pilot trial
, p ,p g p p
• 20 ventilated patients with agitated delirium
• Randomized to haloperidol 0.5‐2mg/hr or
dexmedetomidine 0.2‐0.7 μg/kg/hr
• Dexmedetomidine shorter hours to extubation
Dexmedetomidine shorter hours to extubation
42 (IQR 23.2‐117.8) vs 20 (IQR 7.3‐24), p=0.016
• Dexmedetomidine decreased ICU length of stay
6.5 (IQR 4 9) vs 1.5 (IQR 1 3) days, p=0.004
6 5 (IQR 4‐9) vs 1 5 (IQR 1‐3) days p=0 004
Reade MC. Critical Care 2009, 13:R75
35. MENDS Study
MICU/SICU Ventilated on Sedatives
V til t d S d ti
Informed Consent
Control Intervention
Lorazepam (GABA)
L Dexmedetomidine ( 2)
D d idi (α2)
+/- Fentanyl +/- Fentanyl
Pandharipande et al JAMA. 2007 Dec 12;298(22):2644-53
36. Brain Dysfunction
p .01
p=.01 p .09
p=.09 p .001
p=.001
12
10
8
6
4
2
Dexmedetomidine
Lorazepam
0
Delirium/Coma‐Free Days Delirium‐Free Days Coma‐Free Days
Pandharipande PP, et al. JAMA 2007;298:2644‐53
37. SEDCOM Trial
MICU Patients
Ventilated & Sedated
Control Intervention
Midazolam (GABA) Dexmedetomidine (α2)
± Fentanyl ± Fentanyl
Riker R. et all JAMA 2009 301, 5:489
ik ll
38. Daily Incidence of Delirium
54% DEX vs 76.6% MDZ, p<0.001
Dexmedetomidine Midazolam †
80
75.7
*
70
ents with Delirium
m
60 * 54,6
* P < 0.05
50 † P < 0.001
*
40
*
Percen of Patie
30
*
20
*
nt
10
0
Baseline 1 2 3 4 5 6 7 8 Total
Treatment Day
39. Daily Delirium ‐ CAM‐ICU Negative at Baseline
Dexmedetomidine Midazolam
†
60
55,3
um_
50
rcent of Subjects with Deliriu
* P < 0.05
† P < 0.001
40 *
33.3
33 3
w
30
20
10
Per
0
Baseline 1 2 3 4 5 6 7 8 Total
Treatment Day
40. Daily Delirium CAM ICU Positive at Baseline
Daily Delirium ‐ CAM‐ICU Positive at Baseline
†
Dexmedetomidine Midazolam
100 94,6
90 *
atients wit Delirium
m
80
* * P < 0.05 69,7
70
† P < 0.001
P < 0.001
th
60
*
50
*
rcent of Pa
40
30
*
*
Perc
20
10
0
Baseline 1 2 3 4 5 6 7 8 Total
41. SEDCOM Results
Dexmedetomidine Midazolam
Outcome P
n=244 n=122
Time sedation target
Ti d ti t t 77.3 (%)
77 3 (%) 75.1
75 1 .18
18
Delirium prevalence
p 132 (54%)
( ) 93 (76%)%
( ) <0,001
Delirium free‐days 2.5 1.7 .002
Time to extubation 3,7 days 5.6 days .01
ICU LOS
ICU LOS 5,9
59 7,6
76 .24
24
42. Summary of MENDS & SEDCOM
Summary of MENDS & SEDCOM
• Two multicenter, double blind RCTs of
Two multicenter, double blind RCTs of
benzodiazepines vs dexmedetomidine (GABA vs. Alpha 2
agonists) in high severity medical and surgical ICU
agonists) in high severity medical and surgical ICU
patients:
– R d d i id
Reduced incidence and duration of delirium/coma
d d ti f d li i /
– Significant or trend towards shorter time to extubation and
ICU length of stay
– Other very interesting hypothesis generating findings such
Other very interesting hypothesis generating findings such
as reduced infection rates and improved survival in severe
sepsis
p
43. Conclusions
• Delirium is a frequent disease in the ICU and
Delirium is a frequent disease in the ICU and
associated with poor outcomes.
• Delirious is under‐recognized, can be monitored and
rapidly identified.
rapidly identified.
• New approaches to manage and prevent delirium
are emerging every day.
i d
• Dexmedetomidine has a place in this new strategies.
p g
44. Conclusions (6 points for DEX)
( p )
1. GABA‐agonists increase delirium
g
2. Dexmedetomidine improves outcomes compared to
GABA‐agonists
GABA agonists
3. Dexmedetomidine reduces incidence of delirium
4. Dexmedetomidine facilitates clearing of delirium
5. Dexmedetomidine saves money compared to
5 Dexmedetomidine saves money compared to
GABAagonists
6. Dexmedetomidine may be better than haloperidol
