DELIRIUM

1. DELIRIUM

2. Background: • Delirium is a common clinical syndrome with significant morbidity and mortality. • It frequently complicates acute illness and hospital care. • It consumes massive health care resources (In 2004, $6.9 billion U.S. dollars of Medicare hospital expenditures were attributable to delirium). • It contributes to loss of independence and need for continuing care including institutionalization. • It is potentially preventable.

3. Definitions of Delirium: • Acute confusional state • Acute decline in attention and cognition • Organic brain syndrome (acute) • “ICU psychosis” • Etymology: Latin and Greek “to go off the furrow” (plowing metaphor) “straying from the rules of reason; wandering of the mind”

4. Historical Descriptions: • Genesis 32:24 • Hippocrates of Cos (c. 400 B.C.): “When sleep puts an end to delirium, it is a good symptom.” • Plutarch (c. 110 A.D.): “Alexander” [Gustav Doré] [Museu Nacional Arqueológico de Nápoles]

5. El sueño de la razon produce monstrous The sleep of reason produces monsters Plate 43 from Los Caprichos, 1799 Francisco Goya [British Museum]

6. [Robert Seymour] Charles Dickens: The Pickwick Papers (1837)

7. Victor Hugo: “La Mort de Balzac” (1850) [Musée d'Orsay]

8. “congestion of the brain” October 1849 [American Antiquarian Society]

9. Self-portrait after the Spanish Flu, 1919 Edvard Munch [National Gallery, Oslo]

10. [‘Bim’ Nolan, Male Nurse:] It’s like the doctor was just telling me: delirium is a disease of the night. Good night. The Lost Weekend, 1945 film directed by Billy Wilder

11. Unforgiven 1992 film directed by Clint Eastwood [Will Munny:] I seen 'em, Ned, I seen the angel of death, he's got snake eyes. [Ned Logan:] Who, Will, who's got snake eyes? [Will Munny:] It's the angel of death. Oh Ned, I'm scared of dying. [Ned Logan:] Easy, partner, easy. [Will Munny:] I see Claudia too. [Ned Logan:] That's good, Will, that's good you saw Claudia, ain't it? [Will Munny:] Her face was all covered with worms. Oh Ned, I'm scared, I'm dying. Don't tell nobody, don't tell my kids, none of the things I done, hear me? [Ned Nolan:] All right, Will.

12. Incidence and Prevalence: ● Prevalence at hospital admission ranges from 14 to 24%. ● It has an incidence of up to 56% of general hospital populations. ● Incidence increases with age. ● Delirium is a symptom in 10 to 30% of older patients presenting to ERs and complicates hospital stays for at least 20% of the 12.5 million patients 65 and older who are hospitalized annually. [Institute of Arts / Minneapolis]

13. Incidence and Prevalence (cont.): ● It occurs in up to 53% of older patients post-operatively. ● It occurs in 70 to 87% of patients in the ICU. ● It occurs in up to 60% of patients in nursing homes and post-acute settings. ● It occurs in up to 83% of all patients at the end of life.

14. Consequences: ► Delirium often heralds life-threatening illnesses and conditions. ► The mortality rates of hospitalized patients with delirium ranges from 22 to 76%. ► The one-year mortality rate associated with a case of delirium is 35 to 40%. ► Delirium at discharge is associated with a 2.6-fold increased risk of death or nursing home placement. ► Up to 50% of cases of delirium persistent until hospital discharge, and it is associated with rehospitalization.

15. Consequences (cont.): ► The duration of an episode of delirium can be days or months. ► Persistent or prolonged delirium has worse long-term cognitive and functional outcomes. ► The pathophysiology of delirium may lead to neuron injury and irreversible sequelae (i.e., dementia). [Neurogenetics (1998) 1:223-228] [The New York Times] [Alois Alzheimer, 1911]

16. Characteristics: ■ Acute onset ■ Fluctuating course ■ Inattention ■ Altered level of consciousness ■ Cognitive deficits ■ Disorganized thinking ■ Perceptual disturbance (illusions and hallucinations) ■ Psychomotor disturbances Hyperactive (agitation, hypervigilance, delusions) Hypoactive (lethargy) ■ Altered sleep-wake cycle ■ Emotional disturbance (fearfulness, anxiety, irritability, depression, apathy)

18. Risk Factors for Delirium: ♦ Age (65 years and older) ♦ Gender (male > female) ♦ Previous/underlying cognitive status ▪ Dementia ▪ History of delirium ▪ Affective disorders (depression) ♦ Functional status ▪ Functional dependence ▪ Immobility ▪ History of falls ♦ Sensory impairment (vision, hearing)

19. Risk Factors for Delirium (cont.): ♦ Decreased oral intake ▪ Dehydration ▪ Malnutrition ♦ Drugs ▪ Treatment with multiple psychoactive drugs ▪ Polypharmacy ▪ Alcohol abuse ♦ Coexisting medical conditions ▪ Systemic illness ▪ Multisystem dysfunction ▪ Trauma ▪ Infection ▪ Metabolic abnormalities ▪ Terminal illness

20. Precipitating Factors: ♦ Drugs (sedatives, narcotics, anticholinergics, multiple medications, alcohol withdrawal) ♦ Primary neurologic diseases (stroke, intracranial bleed, meningitis) ♦ Intercurrent illness ♦ Surgery ♦ Environmental ­ Admission to an ICU ­ Use of physical restraints ­ Use of bladder catheter ­ Multiple procedures ­ Pain; emotional distress ♦ Sleep deprivation [Wellcome Institute]

21. Pathophysiology: Poorly understood. Multifactorial. Generalized disruption of higher cortical functions. ≈ Disruption of cerebral perfusion Neurotransmission Inflammation Stress ≈

22. Disruption of cerebral perfusion: Functional neuroimaging has shown that delirious patients can experience a more than 40% reduction in overall cerebral blood flow (CBF). There were greater CBF decreases in subcortical and occipital regions as well as the brainstem. Single photon emission computed tomography (SPECT) perfusion changes in study patients with delirium. Journal of Gerontology: MEDICAL SCIENCES 2006, Vol. 61A, No. 12, 1294-1299

23. Neurotransmission: [Psychiatry (Edgemont) 2008;5(10):29–36]

24. Neurotransmission (cont.): —— Cholinergic deficiency ▪ Anticholinergic drugs can induce delirium. ▪ Serum anticholinergic activity increases in patients with delirium. ▪ Physostigmine reverses delirium associated with anticholinergic drugs. ▪ Cholinesterese inhibitors appear to give some benefits even when delirium is not drug-induced.

25. Neurotransmission (cont.): —— Dopaminergic excess ▪ Dopaminergic excess may be due to its regulatory influence on the release of acetylcholine. ▪ Dopaminergic drugs such as levodopa and buproprion can precipitate delirium. ▪ Dopamine antagonists (e.g., antipsychotic drugs) effectively treat delirium symptoms.

26. Neurotransmission (cont.): • —— Serotonergic activity • High levels of tryptophan (the precursor of serotonin) have been demonstrated in patients with septic encephalopathy. • Low levels of tryptophan have been postulated to contribute to the hypoactive form of delirium. • “serotonin syndrome” (mental status changes, autonomic hyperactivity, neuromuscular abnormalities). • The use of ondansetron, a 5-HT3-receptor antagonist, was associated with improved mental status scores in patients who had delirium following cardiac surgery.

27. Neurotransmission (cont.): —— GABAergic activity ▪ γ-Aminobutyric acid (GABA) is the primary inhibitory neurotransmitter. ▪ Drugs such as benzodiazepines and propofol have high affinity for GABAergic receptors in several key areas including the brainstem. ▪ GABA agonists cause decreases in global CNS arousal, effective neurotransmission and cerebral functional connectivity.

28. Inflammation: IL-1, IL-2, IL-6, TNF-α and other cytokines may contribute to delirium by increasing permeability of the blood-brain barrier and by altering neurotransmission. [J Clin Oncol 21:25x-265s, 2003] [Institute for Molecular Psychiatry / Bonn]

29. Stress: Chronic stress activates the sympathetic nervous system and the hypothalamic-pituitary-adrenocortical axis. Hypercortisolism has deleterious effects on hippocampal serotonin 5-HT1A receptors. [Henri Huet]

30. Natural History: Although acute in onset, delirium is not always transient. It is now recognized that in some cases delirium can take months to resolve. There is an overlap of delirium and dementia. Dementia is the leading risk factor for delirium (2/3 of cases of delirium occur in patients with dementia).

31. [overlap/continuum] persistent delirium ↔ reversible dementia Neuroanatomic changes in imaging studies of delirium patients. Measurable long-term cognitive impairments following delirium. Neuron injury leading to chronic cognitive and behavioral changes (dementia). Natural History (cont.):

32. Diagnosis: Determine the acuity of the change in mental status. Cognitive testing (MMSE). Consider occult or atypical presentation of illnesses (myocardial infarction, infection, respiratory failure). Electroencephalography (EEG) has a limited role. Neuroimaging if indicated.

33. Prevention and Management: Identify and address predisposing and precipitating factors Supportive care: [reorientation; sleep; mobilization; vision; hearing; hydration] Non-pharmacologic approaches Pharmacotherapy

34. [AP] [Vanity Fair]

35. Libby Zion (1965-1984) [The New York Times] [Etsy / molecularmuse] [N Engl J Med 2005;352:1112-20]

36. Pharmacologic classes of deliriants: Anticholinergics Tropanes: atropine hyoscyamine scopolamine Antihistamines diphenhydramine (Benadryl) dimenhydrinate (Dramamine) [Royal College of Physicians]

38. References: Boyer, Edward W., et al., Current Concepts: The Serotonin Syndrome, N Engl J Med 2005;352:1112-20. Girard, Timothy D., et al., Feasibility, efficacy, and safety of antipsychotics for intensive care unit delirium: The MIND randomized, placebo-controlled trial, Crit Care Med 2010; 38:428-437. Gunther, Max L., et al., Pathophysiology of Delirium in the Intensive Care Unit, Crit Care Clin 24 (2008) 45-65. Inouye, Sharon K., A Multicomponent Intervention to Prevent Delirium in Hospitalized Older Patients, N Engl J Med 1999;340:669-76. Inouye, Sharon K., Delirium in Older Persons, N Engl J Med 2006; 354:1157-65. Inouye, Sharon K., et al., Risk Factors for Delirium at Discharge, Arch Intern Med. 2007; 167(13):1406-1413.