Delirium

6th Annual Current Concepts in Brain Injury Rehabilitation
Delirium and Post-Delirium Encephalopathy

Gerald Nora, MD, PhD
Delirium and Post-Delirium

Encephalopathy
6th Annual Current Concepts in Brain Injury
Rehabilitation
Gerald J. Nora MD, PhD

November 7, 2015
Disclosures
Nothing to disclose
1
Goals of this talk

1. Distinguish the characteristics of both acute delirium and
also post-delirium encephalopathy.
2. Describe similarities and differences between the

mechanisms of traumatic brain injury and delirium.
3. Identify pharmacologic and non-pharmacologic

interventions for prevention and treatment of delirium.
4. Identify potential pharmacologic and non-pharmacologic

interventions for patients with post-delirium
encephalopathy.
Outline
• Delirium 101
• Post-delirium Encephalopathy
• Mechanisms of Brain Injury in Delirium
• Future Directions
• Potential Interventions
2
Scope of the Talk

The focus of this talk is on systemic and environmental
causes of delirium.
TBI, CVA, PRES, Meningitis, Seizures are excluded.
Perioperative delirium is excluded.
Delirium 101
3
Definition of Delirium
I. Disturbance of consciousness: reduced focus or attention.
2. Cognitive change: memory, language, orientation, or

perception.
3. Acute onset and fluctuating course.
Hyperactive: overt hallucinosis, psychomotor agitation

Hypoactive: seemingly well-behaved, more common
DSM-IV (TR);
Albrecht et al., 2015
Historical Perspective
Called “phrenitis” by Hippocrates
1959 review characterized delirium as “brain failure”
Multiple terms and etiologies frustrated early research
Morandi et al., 2008; Engel and Roman, 1959
4
Epidemiology
Incidence: 11-14% in general medicine patients.
Mortality risk increased ~1.4-2.0 fold (or greater in ICU).
Length of stay: increased by 5-10 days.
Cost: $38-152 Billion dollars in the USA annually.
Inouye et al., 2014; Ely et al., 2004; Maldonado, 2013
Post Delirium
Encephalopathy
5
Post-delirium Cognitive Deficits
Increased dependence in functional activities.
~50% of survivors with complaints of memory deficits;

>70% in ARDS. Hopkins and Jackson, 2006
BRAIN-ICU Study
Tracked 893 ICU

patients.
Tracked ICAM
assessments in
ICU.
3- and 12-month
neuropsych
battery.
Pandharipande et al., 2013
6
Delirium: “Time is Brain”
Pandharipande et al., 2013
Proposed Characteristics of PDE
Deficits in executive function and memory.
Chronic as opposed to fluctuating course.
Attention is stable.
Potentially some overlap with post-concussive symptoms.
Alternative term used is “Post-ICU Syndrome”.
7
Mechanisms of Delirium and PDE
Iacobone et al, 2009
Cerebral Malperfusion
8
Cerebral Perfusion: A Delicate

Balance
Original Lassen Model Modern Data
Tzeng and Ainslie, 2014; Tan, 2012; Lucas et al.,

2010
Cerebral Perfusion: Deficits in Concussion
92 mTBI patient prospective study.
SPECT within 72 hours of injury.
SPECT abnormal in 63% of patients.
Correlated with LOC, PTA, and PCS.
Gowda et al., 2006; Yuh et al, 2014
9
Delirium and Malperfusion

sPECT abnormalities in
11 of 22 delirious older
patients.
Plurality of patients septic.
Normalized perfusion with

resolution of delirium.
About 10 case series and

reports with supporting
data.
Fong et al., 2006; Alsop et al, 2006
Delirium and Malperfusion Key

Points
Some striking correlations with the TBI literature.
Limited but suggestive data on perfusion abnormalities

even in non-septic patients with delirium.
10
Neuroinflammation
Inflammation and Amyloid in CTE
Repetitive TBI mouse model

shows increased deposition of
amyloid over time.
Inflammation and neurotoxicity

associated with tau-deposition in
CTE.
Meehan et al., 2015; Uryu et al, 2002
11
Inflammation and Amyloidogenesis in

Delirium
S100B associated with astrocyte
activation in brain.
CSF IL-6 and Serum IL-8 and IL-10

correlated with delirium.
Alteration of amyloid metabolism

in delirium.
Van Munster et al., 2004; Khan et al.,

2011; Maldonado, 2013
Microglia activation in delirium
Retrospective case control post-

mortems of 9 delirious patients
and six age-matched controls.
Van Munster et al., 2011
12
Microglia activation in delirium
Van Munster et al., 2011
Statins May Modify Course of Delirium

Prospective cohort study of
763 patients in ICU
588 developed delirium

defined by CAM-ICU.
257 used statins pre-

admission.
197 used statins in ICU.
Early benefit with early statin

use in sepsis.
Morandi et al., 2014
13
Key Points
Correlation of delirium and neuroinflammation.
Suggests how delirium can cause, not just unmask dementia.
Further work on amyloid and tau pathology would be useful.
Neurotransmitter Imbalance
14
Frontal Lobes and Dopamine in

Delirium
Orbifrontal cortex modulates
aggression in non-human
primates.
Acetylcholine-dopamine
imbalance exists in delirium.
Restraints, noxious stimuli

provoke imbalance.
Fong et al., 2009; Nelson and Trainor, 2007
Antipsychotics and Delirium:

Dopamine Excess (?)
Randomized controlled trials show less severe
delirium for atypical and typical antipsychotics.
One perioperative study showed prophylactic

benefit in an RCT.
Must differentiate between hyperactive and

hypoactive delirium!
Wang et al., 2012; Fong et al., 2009
15
Delirium and Acetylcholine Deficiency
Elevated serum cholinesterase is associated with

delirium.
Anticholinergic drugs are classic causes of delirium
Nicotine withdrawal associated with delirium.
Donepezil in hip fracture patients had no benefit in

small RCT.
Overshott et al., 2008; Hessler et al, 2014
Benzodiazepines in Delirium
Imbalance of GABAnergic
activity can lead to
paradoxical agitation.
Associated with executive

dysfunction in BRAIN-ICU
Study.
Burst supression in ICU
predicts
subsequent delirium.
Fong et al., 2009; Pandharipande et al, 2006, 2013;
Brown et al., 2011
16
Every time you give a benzodiazepine

to a delirious patient, God kills a puppy.
Every time you give a benzodiazepine

to a delirious patient, God kills a puppy.
Please, think of the puppies.

H/T Dr. Camiolo-Reddy
17
Post-Delirium Encephalopathy
Brain Atrophy after ARDS
15 ARDS patients vs.

age- and sex-matched
controls.
Did not assess delirium

but post-dc cognition
Hopkins et al., 2006
followed.
18
Hypothesis: Acetylcholine and

Microglia Activation
Acetylcholine has
an anti-
inflammatory effect
on microglia.
Van Gool et al., 2010
Hypothesis: Acetylcholine and

Microglia Activation
Inadequate
acetylcholine leads
to uncontrolled
microglia
activation.
Microglia lead to
acetylcholinergic
neuron death.
Van Gool et al., 2010
19
Delirium
Neurotransmitter
Inflammation
imbalance
Sepsis Iatrogenic
SIRS Stimuli
Amyloid Circadian
Metabolic
dysfunction
Malperfusion
Oxidative stress
Nutrition/lytes
Delirium and Evolution to PDE
Neurotransmitter
Inflammation
imbalance
Sepsis Iatrogenic
SIRS Neuron death Stimuli
Amyloid Circadian
Metabolic
dysfunction
Malperfusion
Oxidative stress
Nutrition/lytes
20
Open Questions
Is PDE a new “miserable minority”?
Neurophysiology of delirium subtypes.
The role of discharge medications in PDE.
Amyloid and tau pathology in post-delirium patients.
Tracking chronic neuroinflammation.
So Now What?
Clinical Implications
Assessment of post-ICU patients’ return to former activities
and cognitive screening.
Consider neuropsychological evaluation if patient struggling

>3-6 months.
Clean up medications.
Assess sleep, PTSD/depression.
Address physical activity.
21
So Now What?
Pharmacology
Less is probably more, especially with senior citizens.
Poor evidence for donepezil/rivastigmine acutely, none for

PDE.
Could consider medication if a younger patient is out of

delirium with cognitive deficits.
Acknowledgements
Cara Camiolo-Reddy, MD
Julie Lanphere, DO
22
Bibliography
1. Engel, G. L. & Romano, J. Delirium, a syndrome of cerebral insufficiency. The Journal of
neuropsychiatry and clinical neurosciences 16, 526–538 (2004).
2. Morandi, A, Pandharipande, P & Trabucchi, M. Understanding international differences in
terminology for delirium and other types of acute brain dysfunction in critically ill patients. Intensive care
… (2008). doi:10.1007/s00134-008-1177-6
3. Inouye, S., Westendorp, R. & Saczynski, J. Delirium in elderly people. Lancet 383, 911–22 (2014).
4. Ely, E. W. et al. Delirium as a predictor of mortality in mechanically ventilated patients in the
intensive care unit. JAMA 291, 1753–62 (2004).
5. Maldonado, J. Neuropathogenesis of delirium: review of current etiologic theories and common
pathways. The American journal of geriatric psychiatry : official journal of the American Association for
Geriatric Psychiatry 21, 1190–222 (2013).
6. Albrecht, JS, Marcantonio, ER & Roffey, DM. Stability of Postoperative Delirium Psychomotor
Subtypes in Individuals with Hip Fracture. Journal of the … (2015). doi:10.1111/jgs.13334
7. Hopkins, RO, Gale, SD & Weaver, LK. Brain atrophy and cognitive impairment in survivors of acute
respiratory distress syndrome. Brain Injury (2006). doi:10.1080/02699050500488199
8. Pandharipande, P. et al. Long-term cognitive impairment after critical illness. The New England
journal of medicine 369, 1306–16 (2013).
9. Iacobone, E, Bailly-Salin, J & Polito, A. Sepsis-associated encephalopathy and its differential
diagnosis. Critical care … (2009). doi:10.1097/CCM.0b013e3181b6ed58
10. Tzeng, Y.-C. & Ainslie, P. Blood pressure regulation IX: cerebral autoregulation under blood pressure
challenges. European Journal of Applied Physiology (2013). doi:10.1007/s00421-013-2667-y
11. Lucas, S. et al. Influence of changes in blood pressure on cerebral perfusion and oxygenation.
Hypertension 55, 698–705 (2010).
Bibliography
12. Tan, C. Defining the characteristic relationship between arterial pressure and cerebral flow. Journal
of Applied Physiology 113, 11941200 (2012).
13. Gowda, N. K. et al. Technetium Tc-99m ethyl cysteinate dimer brain single-photon emission CT in
mild traumatic brain injury: a prospective study. AJNR Am J Neuroradiol 27, 447–51 (2006).
14. Yuh, E., Manley, G. & Hawryluk, G. Imaging Concussion: A Review. Neurosurgery 75, S50 (2014).
15. Fong, T. et al. Cerebral perfusion changes in older delirious patients using 99mTc HMPAO SPECT. The
journals of gerontology. Series A, Biological sciences and medical sciences 61, 1294–9 (2006).
16. Meehan, W., Mannix, R., Zafonte, R. & Pascual-Leone, A. Chronic traumatic encephalopathy and
athletes. Neurology (2015). doi:10.1212/WNL.0000000000001893
17. Uryu, K, Laurer, H, McIntosh, T & Praticò, D. Repetitive mild brain trauma accelerates Aβ
deposition, lipid peroxidation, and cognitive impairment in a transgenic mouse model of Alzheimer
amyloidosis. The Journal of … (2002). at <http://www.jneurosci.org/content/22/2/446.short>
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BMC Neurology 9, 21 (2009).
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the American Geriatrics Society 59, S256–S261 (2011).
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Rejuvenation … (2011). doi:10.1089/rej.2011.1185
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Study. Critical Care Medicine 0, (2014).
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(2007).
23
Bibliography
24. Wang, D.-X. et al. Haloperidol prophylaxis decreases delirium incidence in elderly patients after
noncardiac surgery: A randomized controlled trial*. Critical Care Medicine 40, 731 (2012).
25. Overshott, R, Karim, S & Burns, A. Cholinesterase inhibitors for delirium. The Cochrane Library
(2008). doi:10.1002/14651858.CD005317.pub2
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neuroscience analysis. Annual review of neuroscience 34, 601–28 (2011).
27. Van Gool, W. A., van de Beek, D. & Eikelenboom, P. Systemic infection and delirium: when cytokines
and acetylcholine collide. Lancet 375, 773–5 (2010).
28. Alsop, D. et al. The role of neuroimaging in elucidating delirium pathophysiology. The journals of
gerontology. Series A, Biological sciences and medical sciences 61, 1287–93 (2006).
29. Hessler, J. et al. Smoking increases the risk of delirium for older inpatients: a prospective
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<http://www.sciencedirect.com/science/article/pii/S0163834315000535>
24

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6th Annual Current Concepts in Brain Injury Rehabilitation

Delirium and Post-Delirium Encephalopathy

Delirium and Post-Delirium

Gerald J. Nora MD, PhD

Goals of this talk

2. Describe similarities and differences between the

3. Identify pharmacologic and non-pharmacologic

4. Identify potential pharmacologic and non-pharmacologic

• Mechanisms of Brain Injury in Delirium

Scope of the Talk

TBI, CVA, PRES, Meningitis, Seizures are excluded.

Perioperative delirium is excluded.

I. Disturbance of consciousness: reduced focus or attention.

2. Cognitive change: memory, language, orientation, or

3. Acute onset and fluctuating course.

Hyperactive: overt hallucinosis, psychomotor agitation

Called “phrenitis” by Hippocrates

1959 review characterized delirium as “brain failure”

Multiple terms and etiologies frustrated early research

Morandi et al., 2008; Engel and Roman, 1959

Incidence: 11-14% in general medicine patients.

Mortality risk increased ~1.4-2.0 fold (or greater in ICU).

Length of stay: increased by 5-10 days.

Cost: $38-152 Billion dollars in the USA annually.

Inouye et al., 2014; Ely et al., 2004; Maldonado, 2013

Post-delirium Cognitive Deficits

Increased dependence in functional activities.

~50% of survivors with complaints of memory deficits;

Tracked 893 ICU

Pandharipande et al., 2013

Delirium: “Time is Brain”

Pandharipande et al., 2013

Proposed Characteristics of PDE

Deficits in executive function and memory.

Chronic as opposed to fluctuating course.

Potentially some overlap with post-concussive symptoms.

Alternative term used is “Post-ICU Syndrome”.

Mechanisms of Delirium and PDE

Iacobone et al, 2009

Cerebral Perfusion: A Delicate

Original Lassen Model Modern Data

Tzeng and Ainslie, 2014; Tan, 2012; Lucas et al.,

Cerebral Perfusion: Deficits in Concussion

92 mTBI patient prospective study.

SPECT within 72 hours of injury.

SPECT abnormal in 63% of patients.

Correlated with LOC, PTA, and PCS.

Gowda et al., 2006; Yuh et al, 2014

Delirium and Malperfusion

Plurality of patients septic.

Normalized perfusion with

About 10 case series and

Delirium and Malperfusion Key

Some striking correlations with the TBI literature.

Limited but suggestive data on perfusion abnormalities

Inflammation and Amyloid in CTE

Repetitive TBI mouse model

Inflammation and neurotoxicity

Meehan et al., 2015; Uryu et al, 2002

Inflammation and Amyloidogenesis in

CSF IL-6 and Serum IL-8 and IL-10

Alteration of amyloid metabolism

Van Munster et al., 2004; Khan et al.,

Microglia activation in delirium