Etiology, Patho-physiology, assessment and Principles of management of Delirium.

1. DELIRIUM

2. PREVIEW
 Case vignette
 History
 Aetiology and Clinical Features
 Patho-physiology
 Differential diagnosis
 Assessment
 Management
 Conclusion

3. 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

4. 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:
1. What are the causes of delirium in this patient?
2. What are the factors associated in this patient for
occurrence of delirium?

5. 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 Lipowski (1990)

6. 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

7. (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
Thomas Willis

8. (Contd..)
 18th century :
 Erasmus Darwin : Compared with Dream state
 John Hunter : A cessation of consciousness
 James 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 EEGs
 Lipowski : Monograph
Darwin
Engle
Romano

9. NOSOLOGY
Acute confusional state Hepatic encephalopathy
Acute mental status change Organic brain syndrome
Altered mental status Toxic or metabolic
Encephalopathy
Brain failure ICU Psychosis
• Evaluation of the
concept :
DSM III Delirium as official Term
DSM III R Classified as organic brain syndrome
ICD 9 Classified under transient organic psychotic
condition

10. ICD-10
A. Impairment of consciousness and attention , with
reduced ability to direct focus and sustain attention
B. Global disturbance of cognition
C. Psycho motor disturbance
D. Disturbance of sleep wake cycle
E. Emotional disturbances

11. DSM V

12. INCIDENCE AND PREVALENCE
 It 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)

13.  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
postoperatively
In
Patien
t
10%
Nursin
g
Home
30%
ICU
60%
Kamholz et al. 2010

14.  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.

15. ETIOLOGY
 Complex 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

16. INTERACTION OF THE FACTORS
Precipitating
factors
Predisposing
factors
Protective
factors
Protective
factors
Predisposing
factors
Precipitating
factors

17. PRECIPITATING FACTORS
1) Surgery or multiple (diagnostic)
procedures
2) Drugs: sedative hypnotics,
benzodiazepines, opioids,
anticholinergic drugs, treatment
with multiple drugs, alcohol or
drug withdrawal
3) Intercurrent illness: infections,
iatrogenic complications, severe
acute illness, metabolic
derangements, fever
/hypothermia, shock, hypoxia,
anaemia dehydration, low
serum albumin and poor
4) Admission to ICU
5) Primary neurological
disease: stroke, intracranial
haemorrhage and
meningitis
6) Pain
7) Use of physical restraints
8) Use of urinary catheters
9) Prolonged sleep
deprivation

18. PREDISPOSING FACTORS
 Baseline cognitive
impairment
2.5 fold increased risk
of delirium in dementia
patients
25-31% of delirious
patients have
underlying dementia
 Medical co morbidities:
Any medical illness
 Visual impairment
 Hearing impairment
 Functional impairment
 Depression
 Advanced age
 Male gender

19. PROTECTIVE FACTORS
 Good 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
It is an active process by which a brain disorder is
met with greater efficiency
(Johns RN et al.2010)

20. CAUSES
I WATCH DEATH…!!

21. ICU AND DELIRIUM (Maldonado et
al.2008)
Environment
al factors
Intrinsic
factors
Stres
s
Pain FearNoiseLight
Exposu
re
Therapeutic
and diagnostic
monitoring
Disruptio
n in
melatoni
n
secretio
n
Disturbance in
24hr circadian
pattern + sleep
fragmentation
• Prolongation of
mechanical
ventilation
• Impaired immune
function
• Alteration in
metabolic
parameters
Delirium
Neuro-cognitive
deficits

22. OTHER ETIOLOGIES
 Substance 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

23. CLINICAL FEATURES
• Hyperactive(25%):Restlessness, heightened startle,
hypervigilance and increased alertness
• Hypoactive (50%):lethargic and mute initially perceived
as depressed or demented states
• Mixed (25%)
Arousal
• Inability to discriminate sensory stimuli and to integrate
current perceptions with past experiences
• Obsessed with irrelevant stimuli and misinterpret objects in
their environment
• Auditory and visual Hallucination
Perception
• Nonsensical rambling and incoherent speech or sometimes
completely mute
• Impairment of primary and secondary memory
• Remote memory may be preserved
Language
and
cognition

24. • Fluctuating course of disorientation
• Orientation to time is most commonly impaired
and to person is usually preserved
• Disorientation to self- significant impairment
Orientation
• Rapid fluctuation in mood
• Fear-Most common and lead to increased
vigilance and an unwillingness to sleep
• Apathy and Euphoria
Mood
• Day- hyper-somnolent and night-combative and
restless
• Fragmented sleep and vivid nightmares
• sleep phobia
Sleep and
wakefulness

25. 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
√ Babinski’s sign
√ Dysarthria
OTHER TERMINOLOGIES
• Occupational Delirium
• Carphologia

26. PATHO-PHYSIOLOGY
Neuro-
transmitte
rs
Drugs
Inflammato
ry
conditions
Cortisol
Oxidative
impairme
nt
Delirium

27. NEUROTRANSMITTERS
Ach IN DELIRIUM
Anaesth
etic
agents
cerebral
oxidative
metabolism
Volume of Ach
producing cells
NAD:NADH
ratio
Ach synthesis
Ach
Delirium
Immobili
sation
Hypoxia
Age
Psycho-
active Rx
Anti-Ach
treatmen
t

28.  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

29. DA in Delirium
O2 availability
to brain tissue
ATPase
pump failure
Na+ Influx
Ca+ Influx
K+ Out
flux
Cell
swelling
Anoxic
Depolarizati
on
+
Activation of
Catabolic
enzymes
Breakdow
n in ATP
dependent
transport
Tyrosine
Hydroxylase
Oxidative
Phosphorylation
in Brain
Mitochondria
ATP
productio
n
DA Toxic
metabolites
Activity
of O2
Depende
nt COMTDA
Delirium

30. (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)

31. GABA AND GLUTAMATE IN
DELIRIUM
 GABA 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

32. SEROTONIN IN DELIRIUM
 Serotonin 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)

33. INFLAMMATORY PROCESS IN
DELIRIUM
Prostaglandi
ns
Cytokines
Circumventricular
Organs
Prostaglandi
ns
Cytokines
Afferent signals from
periphery (e.g.. Vagus
nerve)
Prostaglandi
ns
Cytokines
Pathogen-associated
molecular patterns
Endothelial cells and
perivascular macrophages
at blood-brain barrier
Neuro-behaviour
Disturbances
BBB disruption
Cytokines: IL-β1, TNF α, IL-6
Inflammatory cytokines

34.  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)

35. (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

36. OXIDATIVE IMPAIRMENT
 Decrease 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

37. CORTISOL IN DELIRIUM
Stress
Sympathetic
activity Cortis
ol
Other
stress
hormon
es
Hippo-
campu
s
•Cell death
•Atrophy
•Mitochondrial
dysfunction
Hippocampal
and limbic
pathway
Dysfunction
Memory
Mood
Delirium

38. DRUGS AND DELIRIUM
 Medication 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

39.  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)

41. Glucocorticoids
Cushing's Syndrome
Surgery
Stroke
Cortisol
Excess
Tryptophan depletion
Phenylalanine elevation
Serotonin
Deficiency
Surgical Illness /Medical Illness
Hepatic failure
Alcohol withdrawal
Glutamate
Activation
Benzodiazepines
Hepatic Failure
GABA
Activation
Benzodiazepine and
Alcohol Withdrawal
Reduced
GABA Activity
Medications/Medical Illness
Surgical Illness
Cholinergic
Inhibition
Medications
Alcohol withdrawal
Cholinergic
activation
Medications
Stroke
Dopamine
Activation
Medications
Substance withdrawal
Serotonin
Activation
Cytokine
Excess
Summary of Patho-physiology

42. PAEDIATRIC DELIRIUM
 Childhood 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)

43. ASSESSMENT OF DELIRIUM
 Confusion 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

44. RECOGNISING DELIRIUM •History:
Sleep-wake
cycle,
nutrition,
substance
use etc.
•Blood Ix
S.Electrolyt
e
S.Glucose
C.B.C.
S.Creatinin
e
•Urine examination :
Culture/sensitivity
and microscopy
•EEG
Vitals
Hydratio
n
Medicati
on
review
MSENeuro-
imaging
Chest X-ray
Other:
TFT, Drug screen,
Toxicological analysis,
Lumbar puncture, Vit B12
and folate, HIV and
Physical
examinati
on
ECG

45. DIFFERENTIAL DIAGNOSIS
Clinical
features
Delirium Dementia Depression
Onset Sudden/Abrup
t
Insidious/slow Recent
Course Fluctuating,
short
Chronic Variable
Level of
consciousn
ess
Fluctuates
(usually
reduced)
Clear
(except in
end stage)
Clear
Attention Impaired Initially
normal
Generally
normal
Speech Incoherent
and
Ordered-
many have
Normal-
themes of

46.  Psychiatric Illness
Depression
Mania
 Non-convulsive status epilepticus
Especially in ICU
 Wernicke’s aphasia
 Occipital lesions(cortical lesions and confabulations)
 Bifrontal lesions (tumors or trauma)

47. 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
Primary
Secondary
Tertiary

48. Yale Delirium Prevention Trial
RISK FACTOR INTERVENTION
Cognitive impairment Orientation protocol,
cognitively stimulating
activities 3x/day
Sleep deprivation Non-pharmacologic protocol,
noise reduction, schedule
adjustments
Immobility Ambulation or active ROM
exercises; minimize equipment
Visual impairment Glasses or magnifying lens,
adaptive equipment
Hearing impairment Portable amplifying devices,
earwax disimpaction
Dehydration Early recognition and volume

49. PHARMACOLOGICAL
PREVENTION
 A 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

51. PRINCIPLES OF MANAGEMENT
1) Determine the cause and treat it
2) Avoid exacerbation
3) Provide supportive care
4) Manage the behaviour by pharmacological and
non-pharmacological methods
5) Restoration of cognitive and self care functions
6) Psycho-education of the family members

52. 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

53. NON PHARMACOLOGICAL
MANAGEMENT
 Remove 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

54.  Provide reorientation (view of clock, calendars,
familiar objects)
 Adequate lighting and temperature
 Use of restrain only when….
 Increase risk of falls, injury, & delirium
 Use only in emergency, for as short a duration as
possible with frequent re-evaluations
 Pain relief
 Relaxation techniques

55. PHARMACOLOGICAL MANAGEMENT
NICE GUIDELINES
 Reserved 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

56.  Olanzapine Orally or sublingually initial dose 1.25–
2.5 mg then adjusted, depending on response, to
1.25–20 mg per day
 Amisulpride : 50–800 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 )

57. TREATMENT OF SPECIFIC CAUSES
Anti-cholinergic Intoxication :
 Physical agitation and visual hallucinations
 Physostigmine- Drug of choice
 Wernicke’s Encephalopathy :
 Thiamine supplementation IV or IM
 Substance Intoxication :
 Cessation of the substance
 BZD- Flumazenil (Hepatic encephalopathy??)
 Opioid- Naloxone

58. Substance Withdrawal :
 Aim is to reduce severity of withdrawal, preventing
delirium and reducing the incidence of the seizures
 BZD-1st line
 Terminally ill patients :
 Not all causes are reversible and realistic treatment
expectations should be set after discussion with
patient and care givers

59. IMPACT AND OUCOME OF THE
DELIRIUM

60. OUTCOME OF DELIRIUM
 Prolonged 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,

61.  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)

62. Pt with Suspected
delirium
Criteria to diagnose
delirium
Delirium No delirium
Hypoactive :
Rx with
Haloperidol or
atypical AP
Hyperactive
Or Mixed
Mx with
HPL or
Atypical
AP Assess Patient for reversible causes
•Lab tests
•Review medication and change if
necessary
•Hydration
•Environmental assessment
Psycho-education of the family members
Reassess and continue Pharmacological and non pharmacologicaRecovery
No further action bu
Continue observatio
Reassess

63. CONCLUSION
 Delirium 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

64.  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