Delerium, Dementia Delerium, Dementia

and Insomniaand Insomnia

1414thth Feb 2006 Feb 2006

DeleriumDelerium

Delirium - “to go out of the furrow”

Acute Confusional Acute Confusional StateState 30% of elderly medical inpatients30% of elderly medical inpatients High MortalityHigh Mortality High MorbidityHigh Morbidity Longer hospital staysLonger hospital stays Predicts institutionalisationPredicts institutionalisation Often missedOften missed Poorly managedPoorly managed

Diagnosis of DeliriumDiagnosis of Delirium

Disturbance of consciousness with reduced ability to Disturbance of consciousness with reduced ability to

focus, sustain or shift attentionfocus, sustain or shift attention

Change in cognition or perceptual disturbance Change in cognition or perceptual disturbance

Short period of time (hours to days) and fluctuatesShort period of time (hours to days) and fluctuates

Caused by the direct physiological consequences of a Caused by the direct physiological consequences of a

general medical condition, substance intoxication or general medical condition, substance intoxication or

substance withdrawalsubstance withdrawal

Differential DiagnosisDifferential Diagnosis

Dementia Dementia

- AMT / MMSE cannot distinguish- AMT / MMSE cannot distinguish

- often delerium superimposed on dementia- often delerium superimposed on dementia

Psychotic illnessPsychotic illness

Delirium vs Dementia Delirium vs Dementia

Collateral historyCollateral history Acute onset, short durationAcute onset, short duration Reduced consciousnessReduced consciousness Diurnal fluctuationDiurnal fluctuation Hallucinations commonHallucinations common Physical precipitantPhysical precipitant

Risk factorsRisk factors

AgeAge DementiaDementia Severe illnessSevere illness Physical frailtyPhysical frailty Infection/dehydrationInfection/dehydration Sensory impairmentSensory impairment PolypharmacyPolypharmacy Excess alcoholExcess alcohol Psychosocial stressesPsychosocial stresses

Common CausesCommon Causes

InfectionInfection DrugsDrugs NeurologicalNeurological CardiacCardiac RespiratoryRespiratory PainPain ElectrolytesElectrolytes Endocrine/metabolicEndocrine/metabolic NutritionalNutritional Often multiple aetiologiesOften multiple aetiologies

Drug classes commonly Drug classes commonly implicated in Deliriumimplicated in Delirium

OpiatesOpiates AnticholinergicsAnticholinergics Sedative/hypnotics including withdrawalSedative/hypnotics including withdrawal Dopamine agonistsDopamine agonists AntidepressantsAntidepressants Alcohol withdrawalAlcohol withdrawal CorticosteroidsCorticosteroids LithiumLithium

Investigations - for allInvestigations - for all

FBCFBC CalciumCalcium Urea and electrolytesUrea and electrolytes LFTsLFTs GlucoseGlucose TFTsTFTs CXRCXR ECGECG Blood culturesBlood cultures UrinalysisUrinalysis

Investigations - when Investigations - when indicatedindicated

ABGABG B12 & FolateB12 & Folate Specific culturesSpecific cultures Lumbar punctureLumbar puncture CT headCT head EEGEEG

CT Brain ScanningCT Brain Scanning

Not helpful if performed routinelyNot helpful if performed routinely

Focal neurological signsFocal neurological signs

Confusion following head injuryConfusion following head injury

Confusion following a fallConfusion following a fall

Raised intracranial pressureRaised intracranial pressure

EEGEEG

Limited useLimited use

Delirium versus dementiaDelirium versus dementia

Non-convulsive status epilepticusNon-convulsive status epilepticus

Focal intracranial lesionsFocal intracranial lesions

ManagementManagement

Identify and treat the underlying causeIdentify and treat the underlying cause Evaluate response (monitor AMT)Evaluate response (monitor AMT) Optimum environmentOptimum environment Multidisciplinary teamMultidisciplinary team Avoid physical restraintsAvoid physical restraints Avoid major tranquilizers where possibleAvoid major tranquilizers where possible Control dangerous and disruptive behaviorControl dangerous and disruptive behavior

Psychotropic medicationPsychotropic medication

To prevent harm or allow evaluation and treatment To prevent harm or allow evaluation and treatment

Low-doseLow-dose haloperidol haloperidol (0.5 to 1.0 mg orally or (0.5 to 1.0 mg orally or

intramuscularly) to control agitation or psychotic symptoms intramuscularly) to control agitation or psychotic symptoms

MOA: D2 dopamine receptor antagonistMOA: D2 dopamine receptor antagonist

Low frequency of sedation and hypotension Low frequency of sedation and hypotension

Onset of action is 30 to 60 minutes after parenteral Onset of action is 30 to 60 minutes after parenteral

administration or longer with the oral route administration or longer with the oral route

s/e extrapyramidal; neuroleptic malignant syndrome s/e extrapyramidal; neuroleptic malignant syndrome

Atypical antipsychotics - Atypical antipsychotics - ↑ risk cerebrovascular disease↑ risk cerebrovascular disease

BenzodiazepinesBenzodiazepines

Benzodiazepines (eg, lorazepam 0.5 to 1.0 mg po/IM) Benzodiazepines (eg, lorazepam 0.5 to 1.0 mg po/IM)

have a more rapid onset of action (five minutes after have a more rapid onset of action (five minutes after

parenteral administration) parenteral administration)

Commonly worsen confusion and sedation Commonly worsen confusion and sedation

Drugs of choice in cases of sedative drug and alcohol Drugs of choice in cases of sedative drug and alcohol

withdrawal withdrawal

May be useful adjuncts to neuroleptics to promote May be useful adjuncts to neuroleptics to promote

light sedation and reduce extrapyramidal side effects light sedation and reduce extrapyramidal side effects

Alois Alzheimer 1864-Alois Alzheimer 1864-19151915

DementiaDementia

A general decrease in the level of A general decrease in the level of cognition, especially memorycognition, especially memory

Behavioral disturbanceBehavioral disturbance

Interference with daily function and Interference with daily function and independenceindependence

Dementia syndromes Dementia syndromes

Alzheimer's disease (AD) 60-80%Alzheimer's disease (AD) 60-80% Vascular dementia (VaD) 10-20%Vascular dementia (VaD) 10-20% Dementia with Lewy bodies (DLB) 10%Dementia with Lewy bodies (DLB) 10% Parkinson's disease with dementia (PDD) Parkinson's disease with dementia (PDD)

5%5% Fronto-temporal dementia (FTD)Fronto-temporal dementia (FTD) Reversible dementiasReversible dementias Others eg alcoholicOthers eg alcoholic

Cholinergic DeficitCholinergic Deficit

Alzheimer's Alzheimer's

disease (AD) disease (AD)

sufferers have sufferers have

reduced cerebral reduced cerebral

production of production of

choline acetyl choline acetyl

transferase & transferase &

impaired cortical impaired cortical

cholinergic cholinergic

function function

Cholinesterase Cholinesterase inhibitors inhibitors MOA: increase cholinergic transmission by inhibiting MOA: increase cholinergic transmission by inhibiting

cholinesterase at the synaptic cleft cholinesterase at the synaptic cleft

TacrineTacrine (abn LFTs), (abn LFTs), donepezildonepezil od, rivastigmine bd, and od, rivastigmine bd, and

galantamine galantamine

s/e: insomnia; nausea; diarrhoea; syncope; BP s/e: insomnia; nausea; diarrhoea; syncope; BP

changes; arrhythmiaschanges; arrhythmias

Int: anticholinergics; antipsychoticsInt: anticholinergics; antipsychotics

Evidence of EfficacyEvidence of Efficacy

13 RCTs 13 RCTs

treatment for 6 months - 1 yeartreatment for 6 months - 1 year

mild, moderate or severe dementia due to Alzheimer's mild, moderate or severe dementia due to Alzheimer's

disease disease

improvements in cognitive functionimprovements in cognitive function

-2.7 points (95%CI -3.0 to -2.3), in the midrange of the -2.7 points (95%CI -3.0 to -2.3), in the midrange of the

70 point ADAS-Cog Scale70 point ADAS-Cog Scale

↑ ↑ clinical global measuresclinical global measures

Delay disease progressionDelay disease progression

Conflicting data on cost effectivenessConflicting data on cost effectiveness

NMDA Receptor NMDA Receptor antagonistsantagonists

Excessive N-methyl-Excessive N-methyl-

D-aspartate (NMDA) D-aspartate (NMDA) receptor stimulation receptor stimulation can be induced by can be induced by ischemia and lead ischemia and lead

to excitotoxicityto excitotoxicity

Memantine Memantine

MOA: low affinity glutamate NMDA receptor antagonist MOA: low affinity glutamate NMDA receptor antagonist Ind: Moderate to severe VaD, ADInd: Moderate to severe VaD, AD small beneficial effect at six months small beneficial effect at six months 1.85 ADAS-Cog points, 95% CI 0.88 to 2.831.85 ADAS-Cog points, 95% CI 0.88 to 2.83 Agents that block pathologic stimulation of NMDA Agents that block pathologic stimulation of NMDA

receptors may protect against further damage in receptors may protect against further damage in

patients with vascular dementiapatients with vascular dementia

s/e Dizziness, agitation, delusionss/e Dizziness, agitation, delusions

AntioxidantsAntioxidants

Vitamin EVitamin E Selegiline (Selegiline (MAO-B MAO-B

inhibitor)inhibitor) Delayed nursing Delayed nursing

home placementhome placement No evidence of No evidence of

benefit on benefit on cognition cognition

Selegiline and Vitamin E: Delay in Clinical Progression of Alzheimer's Disease

Ginkgo BilobaGinkgo Biloba

Chinese herbal medicineChinese herbal medicine Contains flavoglycosides Contains flavoglycosides potent free radical scavengerspotent free radical scavengers inhibit platelet-activating factor (PAF)inhibit platelet-activating factor (PAF) May improve regional circulationMay improve regional circulation May improve cholinergic May improve cholinergic

neurotransmission neurotransmission

Ginkgo BilobaGinkgo Biloba

Ginkgo Biloba (Meta-analysis of RCTs)Ginkgo Biloba (Meta-analysis of RCTs)

Four studies with 212 subjects in each placebo and drug Four studies with 212 subjects in each placebo and drug

groups using EGb 761 120–240 mg/daygroups using EGb 761 120–240 mg/day

Results: small but significant effect of 3–6 month treatment Results: small but significant effect of 3–6 month treatment

120–240 mg of Gingko biloba extract on objective measures 120–240 mg of Gingko biloba extract on objective measures

of cognitive functionof cognitive function

Side effects: four reports of hemorrhageSide effects: four reports of hemorrhage

Caution: in patients taking anticoagulants, antiplatelets or Caution: in patients taking anticoagulants, antiplatelets or

with bleeding diathesiswith bleeding diathesis

lack of regulation, including variability in the dosing and lack of regulation, including variability in the dosing and

contents of herbal extracts contents of herbal extracts

Agents with no clear Agents with no clear benefit or evidence of benefit or evidence of harmharm

Oestrogen/testosterone Oestrogen/testosterone replacement replacement

NSAIDSNSAIDS immunization with amyloid beta immunization with amyloid beta

peptide (6% meningoencephalitis)peptide (6% meningoencephalitis)

Behavioral symptoms Behavioral symptoms

Agitation Agitation

AggressionAggression

DelusionsDelusions

HallucinationsHallucinations

wandering wandering

Behavioral symptomsBehavioral symptoms

depression and sleep disturbancesdepression and sleep disturbances

depressive pseudodementia depressive pseudodementia

concomitant medical illness concomitant medical illness

medication toxicity medication toxicity

behavioral methods behavioral methods

Treatment of Treatment of behavioral symptomsbehavioral symptoms

Non-pharmacologicalNon-pharmacological

- look for medical cause- look for medical cause eg: constipation, urinary retention, infection, drug eg: constipation, urinary retention, infection, drug

toxicity, pain, deliriumtoxicity, pain, delirium

- look for an environmental cause- look for an environmental cause eg: fear of unrecognized caregivers, trigger of the eg: fear of unrecognized caregivers, trigger of the

behavior, sensory deprivationbehavior, sensory deprivation

Treatment of Treatment of behavioral symptomsbehavioral symptoms

Antipsychotic agents Antipsychotic agents

Atypical Atypical 1.6- to 1.7 fold increase in mortality 1.6- to 1.7 fold increase in mortality

compared with placebo compared with placebo

Typical agents have problems with extrapyramidal s/eTypical agents have problems with extrapyramidal s/e

AntidepressantsAntidepressants

SSRIs preferableSSRIs preferable

Benzodiazepines worsening gait, potential paradoxical Benzodiazepines worsening gait, potential paradoxical

agitation, and possible physical dependence agitation, and possible physical dependence

InsomniaInsomnia

InsomniaInsomnia

inadequate quantity or quality of sleep inadequate quantity or quality of sleep

difficulty initiating or maintaining sleep difficulty initiating or maintaining sleep

Non-restorative sleep/impaired daytime Non-restorative sleep/impaired daytime

functioning functioning

Persistent insomnia is usually a consequence Persistent insomnia is usually a consequence

of medical, neurologic or psychiatric disease of medical, neurologic or psychiatric disease

AssessmentAssessment

Alcohol and drug historyAlcohol and drug history - central nervous system stimulants - central nervous system stimulants - withdrawal of CNS depressant drugs - withdrawal of CNS depressant drugs

Treatment of co-morbid insomnia is unlikely Treatment of co-morbid insomnia is unlikely to be successful unless the primary cause of to be successful unless the primary cause of the disturbance is diagnosed and properly the disturbance is diagnosed and properly remedied remedied

Nonpharmacologic measures in conjunction Nonpharmacologic measures in conjunction with the judicious use of hypnoticswith the judicious use of hypnotics

Who should be prescribed Who should be prescribed hypnotics?hypnotics?

Judicious use of hypnotics may be helpful when Judicious use of hypnotics may be helpful when

treating transient or short-term idiopathic or treating transient or short-term idiopathic or

psychophysiologic insomnia psychophysiologic insomnia

Short courses to alleviate acute insomnia after causal Short courses to alleviate acute insomnia after causal

factors have been establishedfactors have been established

Some patients with insomnia benefit from long term Some patients with insomnia benefit from long term

hypnotics without evidence of tolerance or abusehypnotics without evidence of tolerance or abuse

Who should not?Who should not?

Contraindicated in pregnancy Contraindicated in pregnancy

Avoid or use judiciously in patients with alcoholism or Avoid or use judiciously in patients with alcoholism or

renal, hepatic, or pulmonary disease renal, hepatic, or pulmonary disease

Avoid in patients with sleep apnea syndromeAvoid in patients with sleep apnea syndrome

Avoid concomitant alcohol ingestionAvoid concomitant alcohol ingestion

Avoid where high risk of abuse/dependenceAvoid where high risk of abuse/dependence

Avoid where altered performance may be detrimental Avoid where altered performance may be detrimental

eg driving, on-call, carers eg driving, on-call, carers

Historical agentsHistorical agents

LaudanumLaudanum Bromide 19Bromide 19thth C C Chloral hydrateChloral hydrate ClomethiazoleClomethiazole BarbituratesBarbiturates Chlordiazepoxide Chlordiazepoxide

1960s1960s

Hypnotic agentsHypnotic agents

BenzodiazepinesBenzodiazepines

Nonbenzodiazepine drugsNonbenzodiazepine drugs

Sedating antidepressants eg, amitriptyline, trazodoneSedating antidepressants eg, amitriptyline, trazodone

Antihistamines diphenhydramine Antihistamines diphenhydramine

ValerianValerian – no clear evidence of effectiveness – no clear evidence of effectiveness

Melatonin - Melatonin - large doses sold over-the-counter may be large doses sold over-the-counter may be

associated with side effects, such as hypothermia, associated with side effects, such as hypothermia,

gynecomastia, seizuresgynecomastia, seizures

Melatonin receptor agonists - unpublished trialsMelatonin receptor agonists - unpublished trials

BenzodiazepinesBenzodiazepines

Low capacity to produce fatal CNS depressionLow capacity to produce fatal CNS depression MOA: enhance effects of the inhibitory MOA: enhance effects of the inhibitory

neurotransmitter, GABA on the GABA A receptorneurotransmitter, GABA on the GABA A receptor Sedative, hypnotic, muscle relaxant, anxiolytic, Sedative, hypnotic, muscle relaxant, anxiolytic,

anticonvulsant, anterograde amnesiaanticonvulsant, anterograde amnesia Increase total sleep time but shortened time in REM Increase total sleep time but shortened time in REM

sleepsleep Most have active metabolites with long t1/2Most have active metabolites with long t1/2

Adverse effects of Adverse effects of BZDsBZDs Can get rebound insomnia on withdrawal esp with short-acting Can get rebound insomnia on withdrawal esp with short-acting

agentsagents Residual somnolence esp with long-acting agentsResidual somnolence esp with long-acting agents ToleranceTolerance Dependence and abuseDependence and abuse ↑ ↑ falls risk in elderlyfalls risk in elderly Delirium in elderlyDelirium in elderly Withdrawal – confusion, convulsions, DTsWithdrawal – confusion, convulsions, DTs Up to 3 weeks after long-acting agentUp to 3 weeks after long-acting agent Paradoxical effectsParadoxical effects Anterograde amnesiaAnterograde amnesia

Nonbenzodiazepine Nonbenzodiazepine hypnoticshypnotics

nonbenzodiazepine drugs nonbenzodiazepine drugs eg zolpidem, zaleplon, eg zolpidem, zaleplon, zopiclonezopiclone also activate the benzodiazepine also activate the benzodiazepine

receptor, although they do not receptor, although they do not have a benzodiazepine structure have a benzodiazepine structure

Nonbenzodiazepine Nonbenzodiazepine hypnoticshypnotics

at hypnotic doses less muscle at hypnotic doses less muscle relaxation or memory-disrupting relaxation or memory-disrupting effects effects

↓ ↓ tolerance and dependencetolerance and dependence Less effects on REM sleepLess effects on REM sleep Short half-life of ±2 hours and Short half-life of ±2 hours and

elimination by liver metabolism - elimination by liver metabolism - minimal sedation the next day after minimal sedation the next day after administrationadministration

AzapironesAzapirones

MOA: 5HT1A agonistsMOA: 5HT1A agonists Eg BuspironeEg Buspirone Mild to moderate anxietyMild to moderate anxiety NoNo tolerance or withdrawaltolerance or withdrawal