Delirium in cancer
palliative care
Augusto Caraceni
Chief of Palliative Care, Pain Therapy
Rehabilitation
Fondazione IRCCS National Cancer Institute
Milan, Italy
In the beginning
• 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
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
• “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 sleepwake cycle”
Lipowski Z.J. Delirium: acute confusional states OUP 1990
Delirium 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
Consciousness (awareness of self and environment) as a filter
controlling the quality and quantity of stimuli reaching consciousness
taste
smell
touch
sound
sight
Environment
pain
Body
breathing
body position sense
memories
Unconscious
hopes
hunger
fears
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
Consciousness 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 sleep
• Cholinergic n.
(opioids)
Cortex
• Noradrenergic n.
(Clonidine)
Thalamus
• Histaminergic n.
(prometazine)
• Dopaminergic n.
(haloperidol)
• Serotonergic n.
(ssri)
• Gabaergic
(Benzodiazepine
propofol)
Pathological states of consciousness
Clinical condition
Wakefulness
Awareness
Coma
Absent
Absent
Vegetative state
Present
Absent
Abnormal
Abnormal
Delirium
Epidemiology of delirium comparing oncology with palliative
care 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)
From Caraceni & Simonetti The Lancet Oncology In Press
85
Differential diagnosis
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
Prodromal symptoms and signs
Insomnia
Concentration difficulties
Vivid dreams , nightmeres
Agitation
Difficulties in marshalling
own thought
Irritability
Unusual behaviours
Distractability
Behaviour changes
Ipersensitivity to sounds,
lights
Hypo hyperactivity
Anxiety/depression
Clinical 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
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 delirium
• In the MMSE 4 items
over 20 are sufficient
to screen for delirium
–
–
–
–
Orientation to year
Orientation to date
backward spelling
copy design
Fayers PM et al J Pain
Sympt Manage 2005; 30:
41-50
• NUDESC
–
–
–
–
–
Disorientation
Behaviour
Communication
Illusion Hallucination
Psychomotor
Gaudreau et al. The nursing
delirium screening scale J Pain
Sympt Manage 2005; 29: 368-375
Delirium scales
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
DRS and DRS-revised-98 (Trzepacz et al 1988, 2001)
Memorial delirium assessment scale (Breitbart et al 1997)
Confusional state evaluation (Robertson et al 1997)
Cognitive test for delirium (ICU) (Hart et al 1996)
Delirium Index (Mc Cusker et al 1998)
Delirium writing test (Aakerlund and Rosenberg 1994)
Communication capacity scale and Agitation distress scale
(Morita et al 2001) (Morita JPSM, 2003; 26: 827-834)
Delirium assessment scale (O’Keefe et al 1994)
Intensive care delirium screening checklist (Dubois et al
2001)
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
DELIRIUM
RATING
SCALE
Hallucinations type
0-3
Delusions
0-3
Psychomotor behavior
0-3
Trzepacz P Psych Res 1987
Cognitive status
0-4
J Neuropsychiatry Clin
Neurosci 2001 13: 229-242
Physical disorder
0-2
Sleep wake cycle dist.
0-4
Lability of mood
0-3
Variability of symptoms 0-4
max 32
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.
0-3
Max 30
MEMORIAL
DELIRIUM
ASSESSMENT
SCALE
Breitbart et al JPSM, 1997
Writing abnormalities
Macleod &
Whitehead
Palliative
Medicine
1997; 11:
127
Perseveration
Tremors
Writing abormalities
Causes of delirium in cancer patients
Structural
Brain metastases
Meningeal metastases
Non cancer related (vascular, infectious)
Non structural
Metabolic encephalopathy
Systemic Infectio
Hematologic disorders (DIC)
Nutritional
Toxicity of chemotherapy or radiation therapy
Toxicity of other drugs
Paraneoplastic neurologic syndromes
Alcohol and drug withdrawal
Seizures
• 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 patients
1
2
4
3
5
Screening of causes
Toxic
drug screening and history
Sepsis
Temperature, coltures,
leucocyte, PCR
Glucose oxydative
metabolism
blood gases
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-etiology
• Multiple factors are almost always
identified
• Drug toxicity and concurrent or
predisponsing factors (the soil concept)
Risk 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 model
• Risk factors
–
–
–
–
Vision impairment
Severity of illness
Cognitive impairment
BUN/creatinine ratio
Inouye and Charpentier JAMA 1996
• Precipitating factors
–
–
–
–
–
Physical restrains
Malnutrition
> 3 medications
Bladder catheter
Any iatrogenic event
DELIRIUM
INCIDENT FACTORS:
Toxic , Metabolic , Brain lesion
PREDISPOSING FACTORS:
Cognitive Failure, Age , Dementia , Brain lesion
Multifactor model with baseline vulnerability and
precipitating factors
High vulnerability
Low vulnerability
Inouye and Chapentier JAMA 1996
Noxious insult
Less noxious insult
Precipitating factors in 40 reversible episodes
Factor
Prob. Poss. Total
•
•
•
•
•
•
•
•
•
35
5
18
10
2
3
12
5
4
3
13
8
2
2
0
1
6
1
38
98
28
126
Opioids
Psy. Drugs
8
Dehydration
Nonresp. Infection
Alcohol withdrawal
Intracranial cause
Hypoxia
Metabolic
Hematologic
Totals
Lawlor et al Arch Int Med 2000
26
12
4
3
13
11
5
Precipitating 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 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 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
palliative care programmes A, B and C identify three different
prognostic groups according to the PaP score
1
- - - = delirious
___ = not delirious
SURVIVAL %
0,8
0,6
A
0,4
B
0,2
C
0
0
30
60
Caraceni et al Cancer 1999
90
DAYS
120
150
180