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DELIRIUM

Etiology

Patho-physiology

assessment

Principles of management

Dr.Manjunadh.M., MBBS.,MD(Psy),Asst Prof, Department of Psychiatry, Mount Zion Medical College, Adoor

PREVIEW Case vignette

History

Aetiology and Clinical Features

Patho-physiology

Differential diagnosis

Assessment

Management

Conclusion

CASE VIGNETTE

Mr. K is a 71 year old gentleman with history of asthma, BPH and HTN admitted to surgery 3 days ago for bilateral lower extremity cellulites. At the time of admission he was cooperative and oriented but over the past 24 hours has become occasionally confused, agitated, uncooperative and somnolent. He appears to be talking to someone in his room when no one is there. His current meds include: lisinopril, naproxen, cimetadine, albuterol/ipratroprium inhaler, levofloxacin, oxygen via nasal canula

Contd..He has no known psych history, drinks 1-2 glasses of wine/night

When you speak to him he is difficult to rouse and falls asleep several times. He struggles to maintain focus on questions and is unable to perform the mental status exam. He believes he is at home and that you are his cousin.

Questions:

What are the causes of delirium in this patient?

What are the factors associated in this patient for occurrence of delirium?

What would be the ideal management plan in this patient?

WHAT IS DELIRIUM..? de (away from, out of) + Lira (the earth thrown up between two furrows) means out of tract

Important aspect in Consultation-Liaison Psychiatry

Definition

Delirium is a transient organic mental syndrome of acute onset , characterized by global impairment of cognitive functions, a reduced level of consciousness, attentional abnormalities, increased or decreased psychomotor activity and a disordered sleep wake cycle.Lipowski (1990)

HISTORY

Hippocrates

Erasinus, who lived near the Canal of Bootes, was seized with fever after supper; passed the night in an agitated state. During the first day quiet, but in pain at night. On the second, symptoms all exacerbated; at night [mad]. On the third, was in a painful condition; great incoherence. On the fourth, in a most uncomfortable state; had no sound sleep at night, but dreaming and talking; then all the appearances worse, of a formidable and alarming character; fear, impatience. On the morning of the fifth, was composed, and quite coherent, but long before noon was furiously mad, so that he could not constrain himself; extremities cold, and somewhat livid; urine without sediment; died about sunset

(Contd..)

spectrum of mental disorders ranging from general insanity to acute transient states of mental disturbance, including phrenitis, lethargus, hysteria, melancholia, and maniaCelsus

Phrenitis and lethargus as acute manifestations of disease

Cappadocia 16th century : Philip Barrough : Clarified the concept Ambroise Pare

17th century : Thomas Willis : Delirium as Specific set of symptoms

Thomas Willis

(Contd..)18th century : Erasmus Darwin : Compared with Dream state John Hunter : A cessation of consciousnessJames Sims: Alienation of the mind

19th century : Sutton : Coined the term Delirium

20th century : George Engel and John Romano : Reduction in metabolic activity in the brain with use of EEGsLipowski : Monograph

DarwinEngleRomano

NOSOLOGYAcute confusional stateHepatic encephalopathyAcute mental status changeOrganic brain syndromeAltered mental statusToxic or metabolic EncephalopathyBrain failureICU Psychosis

Evaluation of the concept :DSM IIIDelirium as official TermDSM III RClassified as organic brain syndromeICD 9Classified under transient organic psychotic condition

ICD-10 Impairment of consciousness and attention , with reduced ability to direct focus and sustain attention

Global disturbance of cognition

Psycho motor disturbance

Disturbance of sleep wake cycle

Emotional disturbances

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DSM V

INCIDENCE AND PREVALENCEIt occurs in 35 -80 % of critically ill hospitalized patients

Recognition rates of delirium are 12 -43 % and inadequately treated in up to 80 % of patients who exhibit it (Berney et al 2007)

Complicates the hospital stays of 20 % of patients who are 65 years of age or older (Inouye SK et al. 2006)

Delirium was common among older patients undergoing cardiac surgery, around 54.5% (Nima et al. 2013)

Incidence ranges 50.1% to 52.2% after noncardiac surgery (Dasgupta et al. 2006)

Delirium occurs in 60-87 % of ICU patients,15-60 % of nursing home patients, and14-56 % of hospital inpatients

Delirium occurs in 15 - 53 % of older patients postoperativelyKamholz et al. 2010

Prevalence is estimated to be between 11% and 42% for elderly patients on medical wards and close to 50% in patients with hip fractures (Neerland BE et al 2013)

Delirium is observed in up to one-third of patients admitted with an acute stroke (Shi et al. 2012)

Khurana et al.(1999) showed that overall rate of delirium was 27% in which prevalent delirium was 19% and incident delirium was 8% in a sample of 100 patients.

ETIOLOGYComplex interaction of the patient, predisposing and precipitating and protective factors

More susceptible patients may require minimal insult

Less susceptible patients will require more substantial insults

Often multifactorial

INTERACTION OF THE FACTORS

PrecipitatingfactorsPredisposingfactorsProtective factors

Protective factorsPredisposingfactorsPrecipitatingfactors

PRECIPITATING FACTORS Surgery or multiple (diagnostic) procedures

Drugs: sedative hypnotics, benzodiazepines, opioids, anticholinergic drugs, treatment with multiple drugs, alcohol or drug withdrawal

Intercurrent illness: infections, iatrogenic complications, severe acute illness, metabolic derangements, fever /hypothermia, shock, hypoxia, anaemia dehydration, low serum albumin and poor nutrition

Admission to ICU

Primary neurological disease: stroke, intracranial haemorrhage and meningitis

Pain

Use of physical restraints

Use of urinary catheters

Prolonged sleep deprivation

PREDISPOSING FACTORS

Baseline cognitive impairment2.5 fold increased risk of delirium in dementia patients25-31% of delirious patients have underlying dementia

Medical co morbidities:Any medical illness

Visual impairment

Hearing impairment

Functional impairment

Depression

Advanced age

Male gender

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PROTECTIVE FACTORSGood neuro-cognitive Reserve

Educational attainment and leisure activity

Regular physical exercise-Strongest (Wilson et al. 2003)

An association between greater lifetime participation in complex mental activities and less hippocampal atrophy has been demonstrated suggesting some neuronal reserve (Yang et al. 2008)It is an active process by which a brain disorder is met with greater efficiency (Johns RN et al.2010)

CAUSESI WATCH DEATH!!

ICU AND DELIRIUM (Maldonado et al.2008)

Environmental factorsIntrinsic factorsStressPainFearNoiseLight ExposureTherapeutic and diagnostic monitoringDisruption in melatonin secretionDisturbance in 24hr circadian pattern + sleep fragmentation Prolongation of mechanical ventilation Impaired immune function Alteration in metabolic parameters

DeliriumNeuro-cognitive deficits

OTHER ETIOLOGIESSubstance intoxication (PCP, Heroin, alcohol, nitrous oxide, amphetamine and derivatives , Flunitrazepam, GHB and marijuana)

Substance Withdrawal Induced Delirium

Alcohol withdrawal Delirium Tremens BZD withdrawal Opiate withdrawal

Post operative delirium

CLINICAL FEATURES

Neurological Symptoms Dysphagia as seen after a CVA Tremor Asterixis (hepatic encephalopathy, hypoxia, uraemia) Poor coordination Gait apraxia frontal release signs (grasp, suck) Choreiform movements Seizures Babinskis sign DysarthriaOTHER TERMINOLOGIES Occupational Delirium

Carphologia

PATHO-PHYSIOLOGY

Neuro-transmittersDrugsInflammatory conditionsCortisolOxidative impairment

Delirium

NEUROTRANSMITTERS Ach IN DELIRIUMAnaesthetic agents cerebral oxidative metabolism

Volume of Ach producing cellsNAD:NADH ratioAch synthesis Ach

DeliriumImmobilisationHypoxiaAgePsycho-active RxAnti-Ach treatment

Cholinergic deficiency in delirium causes disruption in REM sleep, attention, arousal and memory

Administration of anti-cholinergics produce clinical delirium with typical EEG changes (Marcantonio et al. 2006)

Cholinesterase inhibitors have been found to reduce symptoms of delirium in some studies (Gleason et al. 2003)

An excess of dopaminergic neurotransmitters has also been cited as a mechanism of delirium and is most likely related to the role they play in regulating the release of acetylcholine (Trzepacz and van der Mast 2002)

DA in Delirium O2 availability to brain tissue

ATPase pump failureNa+ InfluxCa+ InfluxK+ Out fluxCell swellingAnoxic Depolarization+Activation of Catabolic enzymes Breakdown in ATP dependent transportTyrosine HydroxylaseOxidative Phosphorylation in Brain MitochondriaATP production

DA Toxic metabolites Activity of O2 Dependent COMT DA

Delirium

(Contd..)The number of D1 and D2 receptors decreases with age, which could increase the likelihood of delirium in elderly individuals

Intoxication with dopaminergic substances such as levodopa may trigger hyperactive delirium (Trzepacz PT et al.2000)

Increase in the level of dopamine may cause symptoms of the hyperactive type of delirium, including hallucinations and delusions (Maldonado JR et al.2008)

Suboptimal levels of dopamine can also cause atrophy of the midbrain and prefrontal cortex (Meyer-Lindenberg A et al. 2005)

GABA AND GLUTAMATE IN DELIRIUMGABA and glutamate have both been implicated in the development of delirium (Morandi A et al. 2008)

Glutamate is metabolized into GABA, which is an inhibitory neurotransmitter

In hepatic encephalopathy, there is increased ammonia levels, which is the precursor of GABA

Benzodiazepine and alcohol withdrawal are associated with reduced GABA activity which can cause delirium (Gunther ML et al. 2008)

SEROTONIN IN DELIRIUMSerotonin is the most abundant neurotransmitter in the brainstem; its synthesis and release depends on its precursor tryptophan (Pridmore et al.2009)

Alcohol withdrawal, L DOPA-induced delirium and postoperative delirium have been associated with decreases in tryptophan (Morandi et al. 2010)

Cerebral serotonin is increased in hepatic encephalopathy, septic delirium, and in the serotonin syndrome

INFLAMMATORY PROCESS IN DELIRIUM

ProstaglandinsCytokinesCircumventricular OrgansProstaglandinsCytokinesAfferent signals from periphery (e.g.. Vagus nerve)ProstaglandinsCytokinesPathogen-associated molecular patternsEndothelial cells and perivascular macrophages at blood-brain barrier

Neuro-behaviour DisturbancesBBB disruptionCytokines: IL-1, TNF , IL-6Inflammatory cytokines

Patients with delirium were more likely to have IL-6 and IL-8 levels above the limit of detection compared with patients who did not have delirium (Rooij et al.2007)

Increased CRP can stimulate the formation of reactive oxygen species, which cause disruption of BBB and causes delirium (Burkhart et al.2010)

(contd..)

Elevated blood levels of the beta subunit of S100 protein (S100 B), a marker of glial injury can be considered as evidence of increased BBB permeability (Maldonado JR et al.2008)

The ageing process appears to serve as a priming stimulus for microglia, and with secondary stimulation by peripheral signals communicating inflammation, these primed microglia release excessive quantities of pro-inflammatory cytokine (Dilger et al.2008)

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OXIDATIVE IMPAIRMENTDecrease in the oxygen supply to the brain causes inadequate oxidative metabolism, which leads to cerebral dysfunction

Extrinsic factors, such as cardiac disease, intra operative hypotension, intrinsic lung disease and anaemia lead to decreased oxygen exchange (Maldonado JR et al.2008)

Delirium was more frequently precipitated by impaired oxidative metabolism, but was not linked to illness severity (Seaman et al 2009)

CORTISOL IN DELIRIUMStress Sympathetic activityCortisolOther stress hormonesHippo-campusCell deathAtrophyMitochondrial dysfunctionHippocampal and limbic pathway DysfunctionMemoryMood

Delirium

DRUGS AND DELIRIUMMedication use contributes to delirium in more than 40% of cases (Inouye 2004;Inouye and Charpentier 2006)

Use of psychoactive medication results in a 4-fold increased risk of delirium, whereas the use of two or more psychoactive medications is associated with a 5-fold increased risk (Inouye and Charpentier 2006)

Some drugs also produce a potent neurotoxin metabolite, which may cause delirium (Gunther ML et al. 2008)

Physiologic changes associated with aging may increase the development of drug-induced delirium; anti-cholinergic toxicity and poly pharmacy are very common in elderly people (Mayer et al. 2010)

Drugs that may contribute to the presence of delirium include those with anticholinergic properties, tranquilizers, analgesics, and narcotics (Iglseder B et al. 2010)

GlucocorticoidsCushing's SyndromeSurgeryStrokeCortisolExcess

Tryptophan depletionPhenylalanine elevationSerotoninDeficiencySurgical Illness /Medical Illness

Hepatic failureAlcohol withdrawalGlutamateActivation

BenzodiazepinesHepatic FailureGABAActivation

Benzodiazepine andAlcohol WithdrawalReducedGABA Activity

Medications/Medical IllnessSurgical IllnessCholinergicInhibition

MedicationsAlcohol withdrawalCholinergicactivation

MedicationsStrokeDopamineActivation

MedicationsSubstance withdrawalSerotoninActivation

CytokineExcess

Summary of Patho-physiology

PAEDIATRIC DELIRIUMChildhood delirium has a different course and clinical profile than adults and geriatric patients (leentjens et al. 2009)

The clinical manifestations between children and adults might differ, which may be due to their young age and developmental changes (Schieveld et al. 2005)

PD shows a more distinct course with a more acute onset, less circadian variety in symptoms and less sleep-wake cycle disturbances, as compared to adults (Turkel et al. 2003)

Treatment of PD consists of two components: psychosocial(restoring orientation and comfort) and pharmacological (antipsychotic) management (Schieveld et al. 2005)

ASSESSMENT OF DELIRIUMConfusion Assessment Method (CAM) (Inouye et al. 1990)

Delirium Rating Scale (DRS)

Intensive Care Delirium Screening Checklist (ICDSC)

Memorial Delirium Assessment Scale (MDAS)

NEECHAM

Delirium Symptom Interview (DSI)

Clock drawing Test

RECOGNISING DELIRIUM

History:Sleep-wake cycle, nutrition, substance use etc.

Blood IxS.ElectrolyteS.GlucoseC.B.C.S.Creatinine

Urine examination :Culture/sensitivity and microscopyEEG

VitalsHydration

Medication reviewMSENeuro-imagingChest X-rayOther:TFT, Drug screen, Toxicological analysis, Lumbar puncture, Vit B12 and folate, HIV and Syphilis serology

Physical examination

ECG

DIFFERENTIAL DIAGNOSISClinical featuresDeliriumDementiaDepressionOnsetSudden/AbruptInsidious/slowRecentCourseFluctuating, shortChronicVariableLevel of consciousnessFluctuates (usually reduced)Clear (except in end stage)ClearAttentionImpairedInitially normalGenerally normalSpeechIncoherent and disorganised ramblingOrdered- many have difficulties in finding wordsNormal-themes of Hopelessness and Helplessness

Psychiatric IllnessDepressionMania

Non-convulsive status epilepticusEspecially in ICU

Wernickes aphasia

Occipital lesions(cortical lesions and confabulations)

Bifrontal lesions (tumors or trauma)

PREVENTION OF DELIRIUM 3 types of prevention strategies

Multicomponent approaches to reduce the risk factors

Difficult for a single person to implement and often led by teams of physicians, nurse, care givers and others

It can be prevented or at least moderated by addressing modifiable risk factors

PrimarySecondaryTertiary

Yale Delirium Prevention TrialRISK FACTORINTERVENTIONCognitive impairmentOrientation protocol, cognitively stimulating activities 3x/daySleep deprivationNon-pharmacologic protocol, noise reduction, schedule adjustmentsImmobilityAmbulation or active ROM exercises; minimize equipmentVisual impairmentGlasses or magnifying lens, adaptive equipmentHearing impairmentPortable amplifying devices, earwax disimpactionDehydrationEarly recognition and volume repletion

Mobilization: 1 day a patient is left un mobilized in their bed adds on 3 days of hospital stay.

PHARMACOLOGICAL PREVENTIONA randomised placebo-controlled trial using low dose haloperidol in elderly hip-surgery patients at risk of delirium showed that although there was no difference in the incidence of delirium, the severity and duration of delirium, and length of hospital stay was reduced (Cochrane review 2007)

One RCT compared quetiapine with placebo among patients already receiving haloperidol found faster resolution of delirium symptoms among patients treated with quetiapine (Torres et al. 2003)

Peri-operative, low-dose, short-term administration of haloperidol or risperidone may reduce the incidence of delirium among elderly cardiac and gastrointestinal (GI) surgical patients who require ICU support (Devlin et al. 2012)

PRINCIPLES OF MANAGEMENT Determine the cause and treat it

Avoid exacerbation

Provide supportive care

Manage the behaviour by pharmacological and non-pharmacological methods

Restoration of cognitive and self care functions

Psycho-education of the family members

MANAGEMENT STRATEGIES & PRECAUTIONS Avoid poly-pharmacy

Attempt to restore sleep integrity

Minimise the use of antipsychotics and sedatives

Titrate the dose, maintenance of the dose and later taper it according to the course of symptoms

Monitor the condition by using assessment tools

Find the cause of delirium and repeat the necessary investigations until then

NON PHARMACOLOGICAL MANAGEMENTRemove unnecessary intrusions (indwelling urinary catheters, IV lines etc.)

Avoid interrupting sleep (unnecessary monitoring during sleep)

Sensory Aids (hearing aids, glasses)

Family support to reduce fear and anxiety in the patient

Early mobilization, avoid restraints

Provide reorientation (view of clock, calendars, familiar objects)

Adequate lighting and temperature

Use of restrain only when.

Increase risk of falls, injury, & deliriumUse only in emergency, for as short a duration as possible with frequent re-evaluations

Pain relief

Relaxation techniques

PHARMACOLOGICAL MANAGEMENTNICE GUIDELINESReserved for patients with severe agitation or behavioural disturbance who are at risk of interrupting essential medical care and risk of causing harm to themselves or others (Tropea et al 2008)

1st choice-Haloperidol Oral Dose : 0.25-0.5 mg Very agitated patients : Bolus dose of 5-10mg IV/IM Less anticholinergic activity HPL+ atypical antipsychotic use has increased to 5-40% in recent years (Conn et al. 2001)

Olanzapine Orally or sublingually initial dose 1.252.5 mg then adjusted, depending on response, to 1.2520 mg per day

Amisulpride : 50800 mg/day. Dose is flexible according to clinicians experience

Quetiapine : 50 300 mg /day dosage flexible Most commonly used drug in treatment of delirium in india (Prasad et al. 2009 )

TREATMENT OF SPECIFIC CAUSES Anti-cholinergic Intoxication :Physical agitation and visual hallucinationsPhysostigmine- Drug of choice

Wernickes Encephalopathy : Thiamine supplementation IV or IM

Substance Intoxication : Cessation of the substance BZD- Flumazenil (Hepatic encephalopathy??)Opioid- Naloxone

Substance Withdrawal :

Aim is to reduce severity of withdrawal, preventing delirium and reducing the incidence of the seizuresBZD-1st line

Terminally ill patients :

Not all causes are reversible and realistic treatment expectations should be set after discussion with patient and care givers

IMPACT AND OUCOME OF THE DELIRIUM

OUTCOME OF DELIRIUMProlonged hospital stay (on average 8 days longer) (McCusker et al. 2003)

Increased mortality whilst in hospital (up to 75%), in the months following discharge (40%- 1 year mortality) (Siddiqi N et al. 2006)

Increased risk of developing complications such as hospital acquired infection; pressure ulcers, incontinence and falls (despite the use of restraints)

Poor physical and cognitive recovery at 6 and 12 months (Andrew MK et 2005)

Increased risk of placement in a residential home (Rockwood K et al. 1993)

Increased risk of developing dementia(40%) even in patients with no cognitive impairment at baseline (Neerland et al.2013)

Functional impairment

Pt with Suspected deliriumCriteria to diagnose delirium

DeliriumNo deliriumHypoactive :Rx with Haloperidol or atypical APHyperactive Or MixedMx with HPL or Atypical APAssess Patient for reversible causesLab testsReview medication and change if necessaryHydrationEnvironmental assessmentPsycho-education of the family membersReassess and continue Pharmacological and non pharmacological Mx

RecoveryNo further action butContinue observationReassess

CONCLUSIONDelirium is a critical illness and a serious complication of hospitalization and also associated with high morbidity and mortality

It is potentially preventable and treatable, but poor understanding of its patho-physiology and the complexities that occur in the brain during delirium have limited the development of successful treatment

Recognizing delirium and treating the underlying medical cause are the first steps in the management of this potentially fatal syndrome

Non pharmacological management is the more important aspect of the management

Pharmacological management is reserved for patients with severe agitation or behavioural disturbance who are at risk of interrupting essential medical care and risk of causing harm

Antipsychotic medications are useful in the management of symptoms of delirium. Haloperidol is used most frequently.

Benzodiazepines are useful in cases of alcohol or benzodiazepine withdrawal only

Ive seen a dying eyeRun round and round a room

In search of something, as it seemed,Then cloudier become;

And then, obscure with fog,And then be soldered down,

Without disclosing what it be,Twere blessed to have seen-Anonymous

Thank you..!!!

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