DELIRIUMDEPRESSION, DEMENTIA

Disclosure

1. What delirium is

2. Why we care about delirium in geriatric oncology

3. Causes and mechanisms of delirium

4. How delirium can be diagnosed

5. How delirium can be differentiated from dementia, depression, psychosis

6. How to treat delirium

Delirium

• Definition

– reduced ability to focus, sustain, or shift

attention

– change in cognition or the development of a

perceptual disturbance

– Acute onset (hours to days)

– Fluctuations

– Identifiable cause

• Hyperactive– Patient is hyperactive, agitated, not cooperative, combative

– Rapid speech, irritability, restlessness– Patient shows high resistance to care

Clinical Subtypes

• Hypoactive

– lethargy, apathy

– Inability to focus when awake

– Lack of appetite

– Slowed speech

– Decreased alertness

– Absence of care request

• Mixed

Shift between hyperactive and hypoactive states

In 12 studies the prevalence of delirium subtypes has varied widelya metanalysis of these studies suggests the following figures:

Prevalence (%) Range(%)

hypoactive 48 15-71

hyperactive 24 13-46

mixed 36 11-55

Clinical Subtypes

• Overall incidence among hospitalized geriatric patients (over 65) up to 56%

• 15-53% post surgery geriatric patients • 50% post hip fracture geriatric patients• 70-80% geriatric patients in ICU • 60% nursing home residents at least once during their stay

• Up to 30% hospitalized geriatric patients with cancer• Up to 44% of advanced cancer patients at the time of admission to an acute care hospital or palliative care unit

• Over 85% cancer patients in the days and hours before death

EPIDEMIOLOGY

• Mortality rate in hospitalized patients 22-76%

• One year mortality rate is 35-40%• Prolongs hospital course• Increased cost of care in hospital• Increased likelihood of disposition to nursing home, functional decline and loss of independence

CONSEQUENCES

– Delirium is not diagnosed in up to 70% of cases– Symptoms are mistakenly attributed to age, dementia or other mental disorders.

– It is common, serious, costly, under-recognisedand often fatal

– 164 billions per year in US, 182 billions per year in Europe:

Hospital costs (> $11 billion/year US)

Post-hospital costs (including rehospitalization, emergency department visits, institutionalization, rehabilitation, formal home care services (>$153 billion/year US)

DELIRIUM: WHY SHOULD WE CARE ?

• Strong association with underlying dementia

• Frequently, patient may never return to baseline or take months to over a year to do so

• Delirium is often the sole manifestation of serious underlying disease

More reasons to care

A multifactorial syndrome that arises from an interrelationship between:

• Predisposing factors� a patient’s underlying vulnerability

AND

• Precipitating factors� noxious insults

ETHIOLOGY

Precipitating factors

/insults

Predisposing factors

/vulnerability

High vulnerability

Low vulnerability

dementia

severe

illness

advanced

cancer

social

support

high self

efficacy

sleep

deprivation

Major

surgery

ICU stay

medications

High noxious insults

low noxious insults

• Age • Male gender• Neurosensorialimpairment

• Dementia• Depression • Brain diseases (including cancer, stroke)

• Major surgery

• Advanced cancer• Functional impairment

• Dehydration• Alcohol, drug abuse• Hip fracture• Polypharmacy

Predisposing factors

• Medications

• Bedrest

• Indwelling bladder catheters

• Physical restraints

• Organ failure

• Uncontrolled pain

• Fluid/electrolyte abnormalities

• Infections

• Medical illnesses

• Urinary retention and fecal impaction

• ETOH/drug withdrawal

• Environmental influences

Precipitating factors

D Drugs, Drugs and toxins, tooE Eyes, earsL Low O2 states (MI, ARDS, PE, CHF, COPD,

stroke, shock)

I InfectionR Retention (of urine or stool). RestraintsI IctalU Underhydration, UndernutritionM Metabolic (hypo/hyper glycemia, calcemia, uremia,

liver failure, thyroid disorders)

Cause

Medicationsaccount for 30% of all cases

• Medications with psychoactive effects: – 3.9-fold increased risk

– 2 or more meds: 4.5-fold

• Sedative-hypnotics: 3.0 to 11.7-fold

• Narcotics: 2.5 to 2.7-fold

• Anticholinergic drugs: 4.5 to 11.7-fold

• Risk of delirium increases as number of meds prescribed rises

DELIRIUM

Cancer byproducts,

proinflammatory cytokines

Medications, opioids,

corticosteroids, others

Side effects of radiation,

chemotherapy

Other medical

conditions e.g.

nutritional deficiencies,

anemia, other

hypoxemia

infections

Endocrine

e.g.hypoglicemia,

hypothyroidism

Paraneoplastic syndromes

Organ failure (hepatic, renal,

cardiac

Electrolyte imbalance

e.g. hypercalcemia,

hyponatremia,

hypernatremia,

hypomagnesemia

Intracranial disease

e.g. primary and metastatic

brain tumor, leptomeningeal

disease, stroke

Factors contributing to delirium in cancer patients

Maldonado J. Am J Geriatr Psych 2013

• Involves– Neurotransmission

– Inflammation

– Chronic/acute stress

Pathophysiology

• Neurotransmission– Cholinergic deficiency

• Anticholinergics can precipitate delirium

• Serum anticholinergic activity increased in those with delirium

• Cholinesterase inhibitors can reverse this effect

– Dopaminergic excess

– Neuropeptides, endorphins, serotonin, NE, GABA , histamine, may play a role.

A schematic diagram showing how various risk factors can affect acetylcholine and dopamine levels, leading to delirium.

Benjamin D. Robertson, and Timothy J. Robertson J Bone Joint Surg Am 2006;88:2060-2068

©2006 by The Journal of Bone and Joint Surgery, Inc.

Dopamine

Acetylcholine

RETICULAR ACTIVATING SYSTEM (RAS)

INFLAMMATION

• Cytokines– Interleukins and interferons, often elevated in Delirium, have known strong CNS effects

– Increased blood brain barrier permeability

– Primary role – sepsis, bypass surgeries, dialysis, cancers

• Chronic/Acute stress– Untreated pain / analgesia are strong risk factors

– Elevated cortisol associated with delirium

– Sympathetic system activation

– Hypothalamic pituitary adrenal axis hyperactivity

Diagnosis

• History (previous mental status, medications)

• Physical exam, lab test, other test to identify medical cause (infections, hydration status, other).

• Mental status exam: inattention, decreased level of consciousness, disordered speech, disorganizedthinking

30

Delirium: Physical Exam

Examine for signs of: � Hypoxia� Volume depletion/overload� Cardiovascular injury� Metabolic encephalopathy � Alcohol withdrawal� Hypo- or hyperthermia� New onset incontinence� Urinary retention or fecal impaction

31

Delirium: Diagnostic Tests

Choice based on history and physical findings Baseline laboratory studies:• Urinalysis• Basic or Comprehensive Metabolic Panel• Blood work: CBC, Thyroid function test

Further diagnostic testing (based on exam):• Head CT• EKG • Chest X-Ray

32

• When difficult to

differentiate delirium

from acute psychotic

state

Electroencephalography

The electroencephalogram reveals:

Diffuse slowing in most cases of delirium

Fast activity in cases of delirium related to drug withdrawal

Normal patterns in patients with acute functional psychosis

Delirium: Diagnostic Tests

Delirium Assessment Tools

Diagnostic interview instruments:

- Confusion Assessment Method (CAM)

- Delirium Symptom Interview (DS)

Delirium Rating Scales:

- Delirium rating scale (DRS)

- Confusion Rating Scale (CRS)

- Memorial Delirium Assessment Scale (MDAS)

Cognitive status screening tools:

- Mini Mental State Examination (MMSE)

- Short portable mental status questionnaire (SPMSQ)

Delirium

Rating

Scale

Mini Mental State

Examination (MMSE)

Folstein 1975

Recognize KEY symptoms• Disturbance in attention and consciousness • Cognitive changes

– Attention – poor– loss of mental clarity

• Patient “isn’t acting right”– Disordered speech– Disorganized thought– Acute memory loss– Disorientation

• Acute/subacute onset• Perceptual disturbances (delusions, hallucinations)• Fluctuating course throughout a day

39

Differentiating Delirium from Dementia

• Chronic cognitive impairment seen in dementia typically:

– Occurs gradually over time

– Persists greater than one month

– Starts with memory impairment

– Is irreversible

• Most older adults with dementia are alert and able to maintain attention in the early stages of dementia

• Dementia with Lewy Bodies includes fluctuating cognition and visual hallucinations

– 2.5 fold increased risk of delirium in dementia patients

– 25-31% of delirious patients have underlying dementia

– DSD has been associated with worse recovery and higher mortality compared to dementia or delirium

Delirium superimposed on dementia(DSD)

42

Differentiating Delirium from Depression

• Depression may also present acutely with deficits in ability to sustain attention.

• Depression may present similar to hypo- or hyper-active delirium; therefore, it is important to screen for depression in older adults who present with a mixed picture (previous medical history, mood status assessment).

• Severe cognitive and psychotic symptoms are rare in mild depression.

Keys to Effective Management

• Find and treat the underlying disease(s) and contributing factors– Comprehensive history and physical

– Including neurological and mental status exams

– Choose lab tests and imaging studies based on the above

– Review medication list

Nonpharmacologic Measures First

• Presence of family members

• Interpersonal contact and reorientation

• Provide visual and hearing aids

• Remove indwelling devices: i.e. Foley catheters

• Mobilize patient

• A quiet environment with low-level lighting

• Uninterrupted sleep

Pharmacologic Management

• Use drugs only if absolutely necessary• First line agent: haloperidol (IV, IM, or PO)

– For mild delirium: • Oral dose: 0.25-0.5 mg• IV/IM dose: 0.125-0.25 mg

– For severe delirium: 0.5-1 mg IV/IM repeated q30 min until calm

• Patient will likely need 2-5 mg total as a loading dose

– Maintenance dose: 50% of loading dose divided BID

• May use olanzapine and risperidone (Lonergan E et al. Cochrane Database Syst Rev. 2007 Apr 18; (2): CD05594)

Fig.8

Dopaminergic Pathways

haloperidol Clozapine

Olanzapine Risperidone

Alpha 1

D1

D2

D4

5-HT2A

5-HT2C

H1

M1

J Pharmacol Exp Ther 1996;277:968;J Clin Pharmacol 1999;39:1S;Psychopharmacology 1993;112:S60;Am J Psychiatry 1997;154:782.

Antipsychotic receptor profiles

Conventional antipsychotic side effects

Anticholinergic

• Dry Mouth

• Constipation

• Cardiovascular (Othostatichypotentions, QT interval)

Antihistaminic

• Sedation, Weight Gain

Dopamine Blockade:

• ExtrapyramidalSide Effects

• Hyperprolctinemia• NeurolepticMalignant Syndrome

Metabolic Syndrome, Hyperglycemia,HyperlipidemiaWeight GainQT Interval Prolongation, Torsade des Pointes(ECG should be monitored daily during delirium treatment)Consider interactions with other agents thatprolong QTEPS dose dependentIncreased risk of stroke and death

Atypical antipsychotic side effects

Pharmacologic Management

• second line agent: BDZ( e.g. lorazepam)

– Reserve for: • Sedation

• Alcohol/drug withdrawal syndrome

• Parkisnon’s disease

SSRI for hypoactive delirium

Cholinesterase inhibitors, anticonvulsants, antihistamines, clonidine have not beenassessed in delirium

DELIRIUM PREVENTION

RISK FACTOR INTERVENTION

Cognitive impairment Orientation protocol, cognitively

stimulating activities 3x/day

Sleep deprivation Nonpharmacologic protocol, noise

reduction, schedule adjustments

Immobility Ambulation or active ROM

exercises; minimize equipment

Visual impairment Glasses or magnifying lens, adaptive equipment

Hearing impairment Portable amplifying devices, earwax disimpaction

Dehydration Early recognition and volume repletion

AVOID RESTRAINTS AT ALL COSTS:Measure of LAST(!!!) resort

Take Home Points

• Delirium is common among elderly patients with advanced cancer

• It is a multifactorial syndrome: predisposing vulnerability and precipitating insults

• Prevention should be the goal

• If delirium occurs, treat the underlying causes

• Always try non-pharmacologic approaches

• Use low dose antipsychotics in severe cases