Delirium and Post-Delirium Encephalopathy Gerald Nora, MD, PhD

6th Annual Current Concepts in Brain Injury Rehabilitation

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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

Delirium and Post-Delirium Encephalopathy Gerald Nora, MD, PhD

6th Annual Current Concepts in Brain Injury Rehabilitation

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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.

Goals of this talk

Outline • Delirium 101

• Post-delirium Encephalopathy

• Mechanisms of Brain Injury in Delirium

• Future Directions • Potential Interventions

Delirium and Post-Delirium Encephalopathy Gerald Nora, MD, PhD

6th Annual Current Concepts in Brain Injury Rehabilitation

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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

Delirium and Post-Delirium Encephalopathy Gerald Nora, MD, PhD

6th Annual Current Concepts in Brain Injury Rehabilitation

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Definition of Delirium

DSM-IV (TR); Albrecht et al., 2015

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

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

Delirium and Post-Delirium Encephalopathy Gerald Nora, MD, PhD

6th Annual Current Concepts in Brain Injury Rehabilitation

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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

Delirium and Post-Delirium Encephalopathy Gerald Nora, MD, PhD

6th Annual Current Concepts in Brain Injury Rehabilitation

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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

Delirium and Post-Delirium Encephalopathy Gerald Nora, MD, PhD

6th Annual Current Concepts in Brain Injury Rehabilitation

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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”.

Delirium and Post-Delirium Encephalopathy Gerald Nora, MD, PhD

6th Annual Current Concepts in Brain Injury Rehabilitation

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Mechanisms of Delirium and PDE

Iacobone et al, 2009

Cerebral Malperfusion

Delirium and Post-Delirium Encephalopathy Gerald Nora, MD, PhD

6th Annual Current Concepts in Brain Injury Rehabilitation

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Tzeng and Ainslie, 2014; Tan, 2012; Lucas et al., 2010

Cerebral Perfusion: A Delicate Balance

Original Lassen Model Modern Data

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

Cerebral Perfusion: Deficits in Concussion

Delirium and Post-Delirium Encephalopathy Gerald Nora, MD, PhD

6th Annual Current Concepts in Brain Injury Rehabilitation

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Fong et al., 2006; Alsop et al, 2006

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.

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.

Delirium and Post-Delirium Encephalopathy Gerald Nora, MD, PhD

6th Annual Current Concepts in Brain Injury Rehabilitation

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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

Delirium and Post-Delirium Encephalopathy Gerald Nora, MD, PhD

6th Annual Current Concepts in Brain Injury Rehabilitation

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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

Inflammation and Amyloidogenesis in Delirium

Microglia activation in delirium

Van Munster et al., 2011

Retrospective case control post-mortems of 9 delirious patients and six age-matched controls.

Delirium and Post-Delirium Encephalopathy Gerald Nora, MD, PhD

6th Annual Current Concepts in Brain Injury Rehabilitation

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Microglia activation in delirium

Van Munster et al., 2011

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.

Statins May Modify Course of Delirium

Morandi et al., 2014

Delirium and Post-Delirium Encephalopathy Gerald Nora, MD, PhD

6th Annual Current Concepts in Brain Injury Rehabilitation

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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

Delirium and Post-Delirium Encephalopathy Gerald Nora, MD, PhD

6th Annual Current Concepts in Brain Injury Rehabilitation

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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

Delirium and Post-Delirium Encephalopathy Gerald Nora, MD, PhD

6th Annual Current Concepts in Brain Injury Rehabilitation

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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.

Fong et al., 2009; Pandharipande et al, 2006, 2013; Brown et al., 2011

Burst supression in ICU predicts subsequent delirium.

Delirium and Post-Delirium Encephalopathy Gerald Nora, MD, PhD

6th Annual Current Concepts in Brain Injury Rehabilitation

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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

Delirium and Post-Delirium Encephalopathy Gerald Nora, MD, PhD

6th Annual Current Concepts in Brain Injury Rehabilitation

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Post-Delirium Encephalopathy

15 ARDS patients vs. age- and sex-matched controls. Did not assess delirium but post-dc cognition followed.

Brain Atrophy after ARDS

Hopkins et al., 2006

Delirium and Post-Delirium Encephalopathy Gerald Nora, MD, PhD

6th Annual Current Concepts in Brain Injury Rehabilitation

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Van Gool et al., 2010

Hypothesis: Acetylcholine and Microglia Activation

Acetylcholine has an anti-inflammatory effect on microglia.

Inadequate acetylcholine leads to uncontrolled microglia activation. Microglia lead to acetylcholinergic neuron death.

Van Gool et al., 2010

Hypothesis: Acetylcholine and Microglia Activation

Delirium and Post-Delirium Encephalopathy Gerald Nora, MD, PhD

6th Annual Current Concepts in Brain Injury Rehabilitation

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Metabolic dysfunction

Delirium

Inflammation Neurotransmitter

imbalance

Sepsis SIRS Amyloid

Iatrogenic Stimuli Circadian

Malperfusion Oxidative stress Nutrition/lytes

Metabolic dysfunction

Delirium and Evolution to PDE

Inflammation Neurotransmitter

imbalance

Sepsis SIRS Amyloid

Iatrogenic Stimuli Circadian

Malperfusion Oxidative stress Nutrition/lytes

Neuron death

Delirium and Post-Delirium Encephalopathy Gerald Nora, MD, PhD

6th Annual Current Concepts in Brain Injury Rehabilitation

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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.

Open Questions

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.

Delirium and Post-Delirium Encephalopathy Gerald Nora, MD, PhD

6th Annual Current Concepts in Brain Injury Rehabilitation

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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

Delirium and Post-Delirium Encephalopathy Gerald Nora, MD, PhD

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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> 18. Munster, B. et al. Markers of cerebral damage during delirium in elderly patients with hip fracture. BMC Neurology 9, 21 (2009). 19. Khan, B., Zawahiri, M., Campbell, N. & Boustani, M. Biomarkers for Delirium—A Review. Journal of the American Geriatrics Society 59, S256–S261 (2011). 20. Van Munster, BC & Aronica, E. Neuroinflammation in delirium: a postmortem case-control study. Rejuvenation … (2011). doi:10.1089/rej.2011.1185 21. Morandi, A. et al. Statins and Delirium During Critical Illness: A Multicenter, Prospective Cohort Study. Critical Care Medicine 0, (2014). 22. Fong, T., Tulebaev, S. & Inouye, S. Delirium in elderly adults: diagnosis, prevention and treatment. Nature reviews. Neurology 5, 210–20 (2009). 23. Nelson, R. & Trainor, B. Neural mechanisms of aggression. Nature Reviews Neuroscience 8, 536–546 (2007).

Bibliography

Delirium and Post-Delirium Encephalopathy Gerald Nora, MD, PhD

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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 26. Brown, E., Purdon, P. & Dort, C. General anesthesia and altered states of arousal: a systems 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 population-based study. General hospital psychiatry (2015). at <http://www.sciencedirect.com/science/article/pii/S0163834315000535>

Bibliography