Delirium in cancer palliative care

Delirium in cancer Delirium in cancer palliative carepalliative care

Augusto Caraceni Chief of Palliative Care, Pain Therapy

Rehabilitation

Fondazione IRCCS National Cancer Institute Milan, Italy

• 29 April 1965 to Dr RobertTwycross“.... I hope we will continue to reduce this figure

when we have St Christopher’s and when we learn more about the relief of mental suf fering and confusion, which as you see remain the big problem”

• 16 August 1976 To Prof. Exton Smith

“…the confusion which many patients experience …we agreed that, all too often, this is and remains somewhat of a mistery”

David Clark: “Cicely Saunders Founder of the Hospice movement selected letters 1959-1999” Oxford University Press 2002

In the beginning

A problem of definition ?A problem of definition ?

• Ippocrates frenitis• Celsus (25 b.C – 50 a.C.) and then Areteus

from Cappadocia delirium• Greiner 1817 Verdunkelung des Bewusstseins

(Obnubilation of consciousness)• Chaslin 1895 La confusion mental primitive• Lipowski 1990

Lipowski and the modern concept Lipowski and the modern concept

• “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 Z.J. Delirium: acute confusional states OUP 1990

Delirium DSM IV diagnostic criteriaDelirium DSM IV diagnostic criteria

• Disturbance of consciousness (i.e reduced clarity of awareness of the environment) with reduced ability to focus, sustain and shift attention

• Change in cognition or the development of perceptual disturbances

• Develops in hours to days and fluctuates• Is caused by the direct physiological consequence

of a general medical condition

Diagnostic and statistical manual of mental disorders (DSM) IV – TR APA 2000

Environment

Body Unconscious

Consciousness (awareness of self and environment) as a filter controlling the quality and quantity of stimuli reaching consciousness

sound

sight

body position sense

breathing

hunger

memories

hopes

touch

From Averil Stedeford in: Bates TD (Ed) Contemporary Palliation of Difficult Symptoms Balliere’s and Tindall, London 1987, Br J Hosp Med 1978; 20 (6) : 694-698, 703-704

fears

pain

tastesmell

Consciousness and attentionConsciousness and attention

• We are always conscious of something. The ability of the brain to have different levels of awareness of stimuli and experience is dependent on attention which can be viewed as the gateway to awareness

Pathogenesis, the ascending reticular activating system Moruzzi and Magoun 1949

Reproduced from Magoun 1952

Conscious states = wakefulness and sleepConscious states = wakefulness and sleep• Cholinergic n.

(opioids)

• Noradrenergic n. (Clonidine)

• Histaminergic n. (prometazine)

• Dopaminergic n. (haloperidol)

• Serotonergic n. (ssri)

• Gabaergic (Benzodiazepine propofol)

Thalamus

Cortex

Pathological states of consciousnessPathological states of consciousness

Clinical condition Wakefulness Awareness

Coma Absent Absent

Vegetative state Present Absent

Delirium Abnormal Abnormal

Epidemiology of delirium comparing oncology with palliative Epidemiology of delirium comparing oncology with palliative care with elderly populationscare with elderly populations

Population Authors Prevalence Incidence

≥ 70 Francis (1990) 16.0 06.0

≥ 65 Levfkoff (1992) 10.5 31.3

≥ 70 Inouye (1993) 25.0

≥ 70 Inouye (1996) 18.0

Oncology Ljubisavjevic (2003) 18.0

Oncology Gaudreau (2005) 16.5

Hospice Minagawa (1999) 28.0

PC Unit Lawlor(2000) 42.0 45.0

Homecare Caraceni(2000) 28.0 -

Dying patient Massie et al.(1983) 85

From Caraceni & Simonetti The Lancet Oncology In Press

Clinical Aspect DELIRIUM DEMENZA ACUTE PSYCHOSIS

onset acute insidious acute

24 hour course fluctuating stable stable

Level of consciousness

reduced spared spared

Attention abnormal Initially spared Can be abnormal

Cognitive functions abnormal abnormal Can be compromised

Hallucinations Often visual Usually absent Usually auditory

Delusions Poorly organized impersistent

Often absent Complex and persistent

Psychomotor activity Increased, reduced, mixed, fluctuating

Normal Variable with bizzarre behaviour

Involuntary movements

asterixis, myoclonus or tremors

Usually absent Absent

EEG abnormal* abnormal* normal

Differential diagnosis

Prodromal symptoms and signsProdromal symptoms and signs

Insomnia

Vivid dreams , nightmeres

Agitation

Irritability

Distractability

Ipersensitivity to sounds, lights

Anxiety/depression

Concentration difficulties

Difficulties in marshalling own thought

Unusual behaviours

Behaviour changes

Hypo hyperactivity

Clinical assessmentClinical assessment• Assessement of the level of consciousness• Assessment of cognitive functions

– Hallucinations– Delusions– Incoherent thought– Written and spoken language

• Neurologic signs

Should specific delirium scales be used Should specific delirium scales be used routinely in palliative care?routinely in palliative care?

• Diagnostic instruments– CAM (Confusion Assessment Method)

Inouye et al Ann Int Medicine 1999, Ryan et al Pall Med 2009)– Delirium symptom interview

(Albert et al , J Geriatr Psych Neurol 1992)– Nursing delirium screening scale

(Gaudreau et al J Pain Sympt Manage 2005)

• Descriptive, assessing severity, specific– DRS , MDAS

• Non specific of delirium but assessing cognitive functions in general– MMSE

Screening for deliriumScreening for delirium

• In the MMSE 4 items over 20 are sufficient to screen for delirium– Orientation to year– Orientation to date– backward spelling– copy design

• NUDESC– Disorientation– Behaviour– Communication– Illusion Hallucination– Psychomotor

Fayers PM et al J Pain Sympt Manage 2005; 30: 41-50

Gaudreau et al. The nursing delirium screening scale J Pain Sympt Manage 2005; 29: 368-375

Delirium scalesDelirium scales1. DRS and DRS-revised-98 (Trzepacz et al 1988, 2001)2. Memorial delirium assessment scale (Breitbart et al 1997)3. Confusional state evaluation (Robertson et al 1997)4. Cognitive test for delirium (ICU) (Hart et al 1996)5. Delirium Index (Mc Cusker et al 1998)6. Delirium writing test (Aakerlund and Rosenberg 1994)7. Communication capacity scale and Agitation distress scale

(Morita et al 2001) (Morita JPSM, 2003; 26: 827-834)8. Delirium assessment scale (O’Keefe et al 1994)9. Intensive care delirium screening checklist (Dubois et al

2001)10. Delirium severity scale (Bettin et al 1998)

From: Caraceni A and Grassi L, Delirium acute confusional states in palliative medicine OUP 2003

Temporal onset 0-3

Perceptual disturbances 0-3

Hallucinations type 0-3

Delusions 0-3

Psychomotor behavior 0-3

Cognitive status 0-4

Physical disorder 0-2

Sleep wake cycle dist. 0-4

Lability of mood 0-3

Variability of symptoms 0-4 max 32

DELIRIUMRATING SCALE

Trzepacz P Psych Res 1987

J Neuropsychiatry Clin Neurosci 2001 13: 229-242

Level of consciousness 0-3

Disorientation 0-3

Short term memory 0-3

Digit span 0-3

Attention 0-3

Thought 0-3

Perceptual disturbances 0-3

Delusions 0-3

Psychomotor activity 0-3

Sleep-wake cycle dist. 0-3Max 30

MEMORIAL DELIRIUM ASSESSMENTSCALE

Breitbart et al JPSM, 1997

Writing abnormalitiesWriting abnormalities

Tremors

Perseveration

Macleod & Whitehead

Palliative Medicine 1997; 11: 127

Writing abormalitiesWriting abormalities

Causes of delirium in cancer patientsCauses of delirium in cancer patients

StructuralBrain metastases Meningeal metastases Non cancer related (vascular, infectious)

Non structuralMetabolic encephalopathySystemic InfectioHematologic disorders (DIC)NutritionalToxicity of chemotherapy or radiation therapyToxicity of other drugs

Paraneoplastic neurologic syndromes

Alcohol and drug withdrawal

SeizuresSeizures

• It is possible that seizures present with clinical features which overlap with delirium

Delirium EEG slowing

Non convulsive status epilepticus

Structural causes of delirium in cancer patientsStructural causes of delirium in cancer patients

1 2 3

4 5

Screening of causesScreening of causesToxic drug screening and history

Sepsis Temperature, coltures, leucocyte, PCR

Glucose oxydative blood gases metabolism

Electrolytes Na, K, Mg, Ca, Cl

Renal function Uremia, Creatinine cl.

Liver function Ammonio

Cofactor deficiency B1, B12

Tyroid (endocrine) T3, T4, TSH, others ?

Epilepsy EEG

Paraneoplastic syndrome Specific autoantiboides

Pathogenesis-etiologyPathogenesis-etiology

• Multiple factors are almost always identified

• Drug toxicity and concurrent or predisponsing factors (the soil concept)

Risk factors in cancer patients at multivariate analysisRisk factors in cancer patients at multivariate analysis

• Age• Previous cognitive failure• Severity of associated

illness• Functional impairment• Renal function• Metabolic abnormalities• Low albumin

• Bone metastases

• Liver metastases

• History of delirium

• Metastasis to CNS

• Opiods

• Benzodiazepines

• Fever infection

Caraceni & Simonetti Lancet Oncology IN PRESS

A multifactor modelA multifactor model

• Risk factors– Vision impairment– Severity of illness– Cognitive impairment– BUN/creatinine ratio

• Precipitating factors– Physical restrains– Malnutrition– > 3 medications– Bladder catheter– Any iatrogenic event

Inouye and Charpentier JAMA 1996

INCIDENT FACTORS:Toxic , Metabolic , Brain lesion

PREDISPOSING FACTORS: Cognitive Failure, Age , Dementia , Brain lesion

DELIRIUM

Multifactor model with baseline vulnerability and Multifactor model with baseline vulnerability and precipitating factorsprecipitating factors

High vulnerability

Low vulnerability

Noxious insult

Less noxious insult

Inouye and Chapentier JAMA 1996

Precipitating factors in 40 reversible episodesPrecipitating factors in 40 reversible episodes

Factor Prob. Poss. Total

• Opioids 35 3 38• Psy. Drugs 8 5 13• Dehydration 18 8 26• Nonresp. Infection 10 2 12• Alcohol withdrawal 2 2 4• Intracranial cause 3 0 3• Hypoxia 12 1 13• Metabolic 5 6 11• Hematologic 4 1 5

Totals 98 28 126

Lawlor et al Arch Int Med 2000

Precipitating factors and reversibility in PCPrecipitating factors and reversibility in PC

Type of factor Reversed Non rev. Hazard r. (95 C.I.)

Psychoactive d. 38 (95%) 15 (48%) 6.65 (1.5-29)

Dehydration 26 (65%) 8 (26%) 1.5 (.7-3.2)

Hypoxia 11 (28%) 22 (71%) 0.32 (.15-.7)

Miscellaneous 7 (18%) 7 (23%)

Nonresp. Infection 10 (25%) 8 (26%)

Metabolic 10 (25%) 18 (58%)

Hematologic 5 (13%) 7 (23%)

Lawlor P. et al 2000 Arch Int Med

Delirium reversibility in hospiceDelirium reversibility in hospice

Total 121 Cases

reversible irreversible

33 (27%) 88 (73%)

survival 39+/- 69 16 +/- 10

organ failure ++ +

attention ++ +

vigilance ++ +

Leonard et al Pall Med 2008; 22 : 848-854

Delirium and prognosisDelirium and prognosis• Delirium is independently associated with

reduced survival at 12 month (McCusker 2002)

• In advanced cancer patients it is independently associated with worse prognosis to 30 days (Caraceni et al Cancer 2000)

– PaP score (Maltoni et al JPSM 1999)

• Il 50% of delirium episodes in PC are reversible (Lawlor Arch Int Med 2001)

Impact of delrium on survival curves after the beginning of Impact of delrium on survival curves after the beginning of palliative care programmes A, B and C identify three different palliative care programmes A, B and C identify three different

prognostic groups according to the PaP scoreprognostic groups according to the PaP score

0 30 60 90 120 150 180

DAYS

0

0,2

0,4

0,6

0,8

1

C

B

ASURVIVAL %

Caraceni et al Cancer 1999

- - - = delirious

___ = not delirious