DELIRIUM

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.

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”

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”

  [Museu Nacional Arqueológico de Nápoles]

[Gustav Doré]

El sueño de la razon produce monstrous

The sleep of reason produces monsters

Plate 43 from Los Caprichos, 1799

Francisco Goya

[British Museum]

Charles Dickens: The Pickwick Papers (1837) 

[Robert Seymour]

• Victor Hugo: “La Mort de Balzac” (1850)

[Musée d'Orsay]

[American Antiquarian Society]

“congestionof the brain”

October 1849

Self-portrait after the Spanish

Flu, 1919

Edvard Munch

[National Gallery,Oslo]

[‘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

[Will Munny:] I seen 'em, Ned, I seen the angel of death, he's gotsnake 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 tellmy kids, none of the things I done, hear me?

[Ned Nolan:] All right, Will.

Unforgiven

1992 film directed by Clint Eastwood

Incidence and Prevalence:

● Prevalence at hospital admissionranges 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 patientspresenting to ERs and complicates hospital stays forat least 20% of the 12.5 million patients 65 and olderwho are hospitalized annually.

[Institute of Arts / Minneapolis]

Incidence and Prevalence (cont.):

● It occurs in up to 53% of older patientspost-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 theend of life.

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.

► 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).

Consequences (cont.):

[The New York Times][Neurogenetics (1998) 1:223-228][Alois Alzheimer, 1911]

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)

Features Delirium Dementia

Onset Acute Insidious

Course Fluctuating Progressive

Duration Days to weeks Months to years

Consciousness Altered Clear

Attention Impaired Normal, except in severe dementia

Psychomotor changes

Increased or decreased

Often normal

Reversibility Usually Rarely

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)

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

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]

Pathophysiology:

Poorly understood.

Multifactorial.

Generalized disruption of higher cortical functions.

≈Disruption of cerebral perfusion

Neurotransmission

Inflammation

Stress≈

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 instudy patients with delirium.

Journal of Gerontology: MEDICAL SCIENCES2006, Vol. 61A, No. 12, 1294-1299

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

Neurotransmission:

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.

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.

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.

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.

Inflammation:

IL-1, IL-2, IL-6, TNF-α and other cytokinesmay contribute to delirium by increasing permeability of the blood-brain barrier

and by altering neurotransmission.

[Institute for Molecular Psychiatry / Bonn][J Clin Oncol 21:25x-265s, 2003]

Stress:

Chronic stress activates thesympathetic nervous system and the

hypothalamic-pituitary-adrenocortical axis.

Hypercortisolism has deleterious effectson hippocampal serotonin 5-HT1A receptors.

[Henri Huet]

Natural History:

Although acute in onset,delirium is not always transient.

It is now recognized that in some casesdelirium 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).

[overlap/continuum]

persistent delirium ↔ reversible dementia

Neuroanatomic changes in imaging studiesof delirium patients.

Measurable long-term cognitive impairments following delirium.

Neuron injury leading to chronic cognitive and behavioral changes (dementia).

Natural History (cont.):

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.

Prevention and Management:

Identify and address predisposing andprecipitating factors

Supportive care:[reorientation; sleep; mobilization;

vision; hearing; hydration]

Non-pharmacologic approaches

Pharmacotherapy

[AP]

[Vanity Fair]

[The New York Times]

[N Engl J Med 2005;352:1112-20]

Libby Zion(1965-1984)

[Etsy / molecularmuse]

Pharmacologic classes of

deliriants:

AnticholinergicsTropanes:

atropinehyoscyaminescopolamine

Antihistaminesdiphenhydramine

(Benadryl)dimenhydrinate

(Dramamine) [Royal College of Physicians]

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.