1. Delirium in cancer palliative care
Augusto Caraceni Chief of Palliative Care, Pain Therapy Rehabilitation
Fondazione IRCCS National Cancer Institute Milan, Italy

2. 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 ” Oxford University Press 2002

3. 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

4. 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

5. 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

6. 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
memories
Body
Unconscious
breathing
hopes
body position sense
fears
hunger
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) : ,

7. 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
A fundamental aspect of this integrative function is taken by attention that can be viewed as the gateway to awareness by selectin stimuli, experiernces and actions that can be preset to consciousness at a given time
- Attention and arousal neurophysiological mechanisms are linked and dependent

8. Pathogenesis, the ascending reticular activating system Moruzzi and Magoun 1949
Reproduced from Magoun 1952

9. Conscious states = wakefulness and sleep
Cholinergic n. (opioids)
Noradrenergic n. (Clonidine)
Histaminergic n. (prometazine)
Dopaminergic n. (haloperidol)
Serotonergic n (ssri)
Gabaergic (Benzodiazepine propofol)
Cortex
Thalamus
In more modern terms we know that a numeber of neurotrasmitters can be found in the same structures and have a role in regulating sleep and wakefulness under normal condition
Please note that these neuronal pathways are at the same time the target of toxic effects due to poisoning or disease and the target of pharmacological interventions aimed at different therapeutic outcomes

10. Pathological states of consciousness
Clinical condition
Wakefulness
Awareness
Coma
Absent
Vegetative state
Present
Delirium
Abnormal
From the recognition of anatomical, neurophysiologica and neurochemical mechanisms derives the fact that the conditions fund in human diseases has to find an explanation
By concentrating artificially on only two major clinical aspects we can see that vigilance (the activated state of wakefulness) and awareness can be differentially affected and manifest as specific clinical conditions

11. Epidemiology of delirium comparing oncology with palliative care with elderly populations
Authors
Prevalence
Incidence
≥ 70
Francis (1990)
16.0
06.0
≥ 65
Levfkoff (1992)
10.5
31.3
Inouye (1993)
25.0
Inouye (1996)
18.0
Oncology
Ljubisavjevic (2003)
Gaudreau (2005)
16.5
Hospice
Minagawa (1999)
28.0
PC Unit
Lawlor(2000)
42.0
45.0
Homecare
Caraceni(2000) -
Dying patient
Massie et al.(1983) 85
From Caraceni & Simonetti The Lancet Oncology In Press

12. Differential diagnosis
Clinical Aspect
DELIRIUM
DEMENZA
ACUTE PSYCHOSIS
onset
acute
insidious
24 hour course
fluctuating
stable
Level of consciousness
reduced
spared
Attention
abnormal
Initially spared
Can be abnormal
Cognitive functions
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
Absent
EEG
abnormal*
normal

13. Prodromal 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

14. Clinical assessment Assessement of the level of consciousness
Assessment of cognitive functions
Hallucinations
Delusions
Incoherent thought
Written and spoken language
Neurologic signs

15. 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

16. 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
NUDESC
Disorientation
Behaviour
Communication
Illusion Hallucination
Psychomotor
And indeed this reasearch conducted with very careful statistical analysis in a sample of more than 500 patients shows that the items of the MMSE examination that is so popular for assessing cognitive functions also in PC patients that are needed to screen for delirium are indeed only 4 pointing again at temporal orientatuìion and at at other performces which might be well influenced by change in attention and arousal
The ability to develop instruments finally accuarate to identify this and other affections of cosnciousness needs to be rooted onsome theory and than validated into practice One recent example could regad the Nursing Delrium SCreening Scale that has been recently published
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:

17. Delirium scales 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: )
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

18. Perceptual disturbances 0-3 Hallucinations type 0-3 Delusions 0-3
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 max 32
DELIRIUM RATING SCALE
Trzepacz P Psych Res 1987
J Neuropsychiatry Clin Neurosci :

19. 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 Max 30
MEMORIAL DELIRIUM ASSESSMENT SCALE
Breitbart et al JPSM, 1997

20. Writing abnormalities
Macleod & Whitehead
Palliative Medicine 1997; 11: 127
Tremors
Perseveration

21. Writing abormalities

22. 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

23. Seizures
It is possible that seizures present with clinical features which overlap with delirium

24. Delirium EEG slowing
Non convulsive status epilepticus

25. Structural causes of delirium in cancer patients1 2 3 4 5

26. Screening of causes Toxic 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

27. Pathogenesis-etiology
Multiple factors are almost always identified
Drug toxicity and concurrent or predisponsing factors (the soil concept)

28. 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

29. A multifactor model Risk factors Precipitating 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

30. DELIRIUM Toxic , Metabolic , Brain lesion
INCIDENT FACTORS:
Toxic , Metabolic , Brain lesion
PREDISPOSING FACTORS:
Cognitive Failure, Age , Dementia , Brain lesion
DELIRIUM

31. Multifactor model with baseline vulnerability and precipitating factors
High vulnerability
Noxious insult
Less noxious insult
Low vulnerability
Inouye and Chapentier JAMA 1996

32. Precipitating factors in 40 reversible episodes
Factor Prob. Poss. Total
Opioids
Psy. Drugs
Dehydration
Nonresp. Infection
Alcohol withdrawal 2 2 4
Intracranial cause 3 0 3
Hypoxia
Metabolic
Hematologic
Totals
Lawlor et al Arch Int Med 2000

33. Precipitating factors and reversibility in PC
Type of factor Reversed Non rev. Hazard r. (95 C.I.)
Psychoactive d. 38 (95%) 15 (48%) (1.5-29)
Dehydration 26 (65%) 8 (26%) (.7-3.2)
Hypoxia 11 (28%) 22 (71%) (.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

34. Delirium reversibility in hospice
Total 121 Cases
reversible irreversible
33 (27%) 88 (73%)
survival 39+/ /- 10
organ failure
attention
vigilance
Leonard et al Pall Med 2008; 22 :

35. 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)

36. 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 30 60 90
120
150
180
DAYS
0,2
0,4
0,6
0,8 1 C B A
SURVIVAL %
- - = delirious
___ = not delirious
Caraceni et al Cancer 1999