delerium, dementia and insomnia 14 th feb 2006. delerium delirium - “to go out of the furrow”
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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