Delirium - causes outside of the brain

Question 1

DEFINING DELIRIUM

i) which criteria is used?
ii) what must there be a disturbance in? (2)
iii) how quickly does it develop over? does it change or stay the same during the day?
iv) name an additional disturbance on cognition that must be seen
v) what must the disturbance be due to?

Answer 1

i) DSM 5
ii) disturbance in attention (reduced ability to direct/focus/sustain and shift attention) and in awareness (orientation to enviro)
iii) dev over a short period (hours-days) and fluctuates in severity during the course of the day (and change from baseline status)
iv) memory deficit, disorientation, language, visuospatial ability or perception
v) another medical conidition, substance intoxication or withdraw, exposure to a toxin, multiple aetiologies

Question 2

COGNITIVE DOMAINS AFFECTED IN DELIRIUM

i) name three things that occur due to global disturbance of cognition?
ii) how is conciousness and attention affected?
iii) how is circadian rhythm affected?
iv) name two things that can result from emotional dysregulation?
v) what can be used to describe the delerium phenotype? what is hypoactive delirium? what is hyperactive delerium? which is more common
vi) which feature is the critical feature?

Answer 2

i) illusions, delusions, hallucinations
ii) impaired conc and attention > reduced ability to direct focus, sustain and shift attention
iii) disturbance of sleep wake cycle
iv) irritability, fear, anger, anxietu

v) psychomotor disturbance > hypoactive = more withdrawn/low awareness (most common)
hyperactive = hyper arousal, aggresion, physically active (25%)
- can also be mixed and fluctuate between them

vi) impairment of conciousness and attention

Question 3

DELIRIUM VS DEMENTIA

i) which has an abrupt onset? which is slower?
ii) what is the rate of decline in delirium?
iii) how is attention affected in del and dementia?
iv) is the sleep wake cycle affected in dementia?
v) how is orientation impacted in del and dementia?
vi) how may someone with del behave? how about dementia?
vii) how is speech implicated in del and dementia?

Answer 3

i) del has abrupt onset and dementia is slower (or quick post stroke)
ii) fluctated rate of decline in del but dementia has a slow progressive decline
iii) impaired attention in del but often in tact in early but not in tact in late demtentia
iv) usually normal
v) impaired in del and intact in early dem but impared in late dem

vi) del = agitated, withdrawn
dem = intact behaviour early on

vii) del = incoherent, rapid, slow
dem = word finding problems

late dementia can look similar to delirium

Question 4

EPIDEMIOLOGY OF DELIRIUM

i) what % of general inpatients will have it?
ii) name three adverse outcomes it is associated with?
iii) why is it a sensitive marker for illness?
iv) what % of people may have symptoms at 6 months?

Answer 4

i) 23% of adults

ii) assoc with pressure damage (stay in bed longer), falls, aspiration pneumonia, fractures, mortality
- assoc with increased cog decline, dementia

iii) demonstrates there is an underlying vulnerability > most causes outside the brain
iv) 20% of patients

Question 5

PREDISPOSING AND PPT FACTORS

i) what are the two main predisposing factors?
ii) name four other predis factors
iii) which three medications can ppt delirium?
iv) name four other things that ppt delirium

Answer 5

i) older age and predisposing cog impariment / dementia
ii) func dependence, male, sensory impairment, depression, immobility, alcohol depedence, depression, undernutrition, prev stroke (atrophy and white matter disease - low brain reserve)
iii) hypnotics, sedatives, opiates
iv) ETOH withdraw, infection, metabolic (hyponat, hypercalc), hypxaemia, anaemia, urinary catether (things that happen in hospital)

frailty is a big predis factor

Question 6

BRAIN VULNERABILITY

i) what needs to be added to predisposing factors to get delirium?
ii) what may need to happen to a resilient individual to cause delirium?
iii) name two things that the severity of the stressor to trigger delirium decreases with

Answer 6

i) predis factors + superimposed acute stressor > delirium
ii) may need a major stress eg head injury, stroke, septic shock
iii) decreased severity of stressor needed when increased frailty or worsening cognition (linear relationship with baseline cognition and delirium risk)

the more frail/less resiliant you are > less of an insult it takes to progress to delirium

Question 7

PATHPHYSIOLOGY OF DELIRIUM

i) what is it mostly due to? how does it result in acute cognitive dysfunction?
ii) name three direct brain insults that can cause it
iii) name a peripheral stress event that may occur? name three systems activated in response to this stress event

Answer 7

i) mostly multifactorial
- interac biol pathways > disruption in NTs/neuronal networks > acute cog dysfunction

ii) hypoxia, hypoglycaemia, metabolic abnorms, stroke, drugs affecting the CNS

iii) infection/injury/insult
- activates symp NS, HPA axis (elevated cortisol), inflammatory pathways
> abnormal stress response which can ppt delirium

Question 8

NEURONAL AGEING

i) what happens to brain connectitivy as you age? which neuronal populations degenerate? (2)
ii) what happens to microglia and astrocytes?
iii) name three vascular changes that happen
iv) what do all these things lead to?

Answer 8

i) brain network activity is impaired
- degeneration of cholinergic and noradrenergic neuronal populations

ii) neuroinflammation > exaggerated pro inflam responses to secondary inflam stimuli
- astrocytes get metabolically impaired (less efficient support cells)

iii) impaired brain perfusion and vascular reactivity, disrup of plasma protein transport into the brain, inc perm of BBB
iv) all reduced physiol reserve and increase vulnerability to disruptions in energy or oxygen supply and effects of inflammatory molecules

Question 9

NEUROINFLAMMATORY HYPOTHESIS

i) name three things that can be the trigger? what does this lead to the release of?
ii) what effects do these substances have on the brain? what do they do to endothelial and microglial cells?
iii) which cells are further activated?what does this lead to?
iv) is coagulation promoted or inhibited? what may this lead to?
v) what is key for how the individual responds to these insults?

Answer 9

i) infection, trauma, surgery > local cytokine release eg IL-1, TNF
- pres of microbial products eg LPS

ii) cytokines etc activate the brain as they can cross BBB and make it more permeable
- endothelial cells and microglial cells in the brain further produce pro inflammatory molecules

iii) further activates astrocytes > recruit further inflammatory cells to the brain > affects neuronal energy production and promotes cell dysfunction
iv) promotion of coagulation > impairs cerebral autoregulation > thrombosis and ischaemia
v) prior brain vulnerability

Question 10

CEREBRAL METABOLIC INSUFFICIENCY HYPOTHESIS

i) how may glucose be implicated in delirium?
ii) name three adverse effects of reduced oxygen that can lead to delirium?

Answer 10

i) brain relies on large amounts of energy (glucose) > unmet energy needs can result in del
- hypogly can cause this directly
- can also get impaired glucose uptake with insulin insensitivity (cells cant use glucose effectively in illness)

ii) hypoxaemia (PE, Sepsis etc) > reduces Ach (responsible for alertness and awareness - impaired in del)
reduced ceb perfusion/microcirc impairmeent (anything reducing CO eg GI bleed, sepsis)
oxidative stress > DA release (may cause perceptual problems in delirium)

• need good O2 supply and good glucose supply > without these can trigger delirium

Question 11

NEUROENDOCRINE HYPOTHESIS

i) what does activation of HPA axis cause to be released from adrenals? what happens after this normally?
ii) what happens in delirium? what does this result in?
iii) which drugs can therefore trigger delerium?

Answer 11

i) glucocorticoid (cortisol)
- meet demands of maint homeo through a stressful event then should be switched off post stress

ii) in delirium > physiol reac to stress is mediated by abnormally high GC levels > chronic exposure to GCs
- results in hippocampal dysfunc and aberrant stress response > increased risk of cell death

iii) exogenous steroids

Question 12

CIRCADIAN RHYTHM DYSREG HYPOTHESIS

i) what is released from the pineal gland to maintain sleep wake cycle? where is the biological clock found in the brain?
ii) how may acute and chronic sleep deprivation cause delirium?
iii) which hormone may therefore be useful in delirium prevention?

Answer 12

i) melatonin
- biol clock in suprachiasmatic nucleus in the hypothal is sync to enviro light dark cycles

ii) increases inflam, cortisol and symp activity
- sleep dep > ppt delirium espec in ITU or post op as dont have light dark cycles

iii) melatonin

Question 13

NEUROTRANSMITTER HYPOTHESIS

i) what can happen to Ach?
ii) what can happen to DA, NA, glu?
iii) what can happen to histamine, serotonin, GABA
iv) what state is delirium considered to be?

Answer 13

i) reduced availability of Ach
ii) excess release of DA, NA, Gly
iii) alterations (up or down)
iv) hypocholinergic, hyperdominergic state

Question 14

NTS IN DELIRIUM

i) what can disruption to cholinergic function cause? is it always present?
ii) is there evidence of Achesterase inhibitors in delirium?
iii) what effect can H1 and H2 antagonists have on delirium?
iv) which drugs can incerase GABA and worsen delirium? which pathological condition can also inc GABA
v) what levels of DA are commonly seen in delirium? do APs work to reduce this?

Answer 14

i) can trigger delirium but not always present
ii) no
iii) reduce brain arousal > sedation > delirium

iv) benzos and hepatic encephalopathy can inc GABA
- see decreased GABA in benzo withdrawal
- GABA can be problematic in both high and low states

v) high levels of DA but APs dont really work

Question 15

NORADRENALINE IN DELIRIUM

i) what are low NA states and high NA states responsible for? which type of delirium may each play a role on?
ii) name three things that increase SNS activation? which medical situation has high NA levels been associated with?
iii) withdrawl from which drug can show excessive NA? name three things this can lead to?
iv) which drugs increase NA in the PFC?

Answer 15

i) low NA - reduced wakefulness (hypoactive delirium)
high NA - poor attention, emotional responses, fear/threat (hyperactive delirium)

ii) SNS activated by inflammatory trauma, sepsis, psych stress, pain
- increased NA signficantly associated with post op delirium in older adults having major surgery

iii) alcohol withdraw
- lead to high BP, agitation and tremor

iv) opiates

Question 16

DRUGS ASSOCIATED WITH DELIRIUM

i) which drugs can increase DA, glu activity and reduce Ach availability?
ii) which drugs are a sedative that increase GABA?
iii) name four drugs that can have anti cholinergic effects and ppt delirium?
iv) name two other drugs that can be assoc with delirium

Answer 16

i) opiates
ii) benzodiazepines
iii) anti histamines, cardiac glycosides eg digoxin, tricyclics, anti parkinsons, bladder drugs (oxybutynin)
iv) H2 receptor antagonists eg ranitidine, steroids, NSAIDs, neuroleptics (APs eg chlorpromazine)

Question 17

NEUROANATOMICAL NETWORK CONNECTIVITY

i) give two roles of functional networks between brain areas? what may impairement of neural connectivity drive?
ii) which two things can drive failure of functional connectivity? what does this lead to?
iii) name three areas that may be implicated?
iv) which two main NTs are important in maintaining neural connectivity?

Answer 17

i) maintain adequate processing of sensory info and motor responses
- to preserve attention and intact conciousness
- can be the fonal driver in delirium

ii) vulnerabilities and stressors
- can lead to profound failure of brain function

iii) corpus callosum, hippocampus, thalamus, basal forebrain, cerebellum
iv) GABA and Ach

Question 18

PATHWAY TO DELIRIUM

i) predisposing factors come first - name three
ii) name three consequent precipitating factors
iii) name four things ppt factors can lead to
iv) which two things can then lead to widespread systems failure (‘brain failure’) and then delirium?
v) what are the three outcomes from delirium?

Answer 18

i) predis = age, dementia, ETOH excess
ii) ppts = infection, hypoglycaemia, hypoxia
iii) ppt factors > neuronal ageing, neuro inflam, HPA dysfunction, oxidative stress, energy mismatch, circadian dysreg
iv) NT dysregulation and neural networks disconnectivity > widespread systems failure > delirium
v) recovery, persistent delirium, dementia

Question 19

IDENTIFICATION OF DELIRIUM

i) which test is commonly used in elderly medicine (outside of ITU)? what does it test?
ii) what needs to be known for the above test to be valid?
iii) name two other ways delirium can be monitored?
iv) what needs to be identified in the history?
v) do all patients need neuroimaging?

Answer 19

i) 4ATs test (>4 possible delirium)
- tests alertness, cognition (AMTS), attention (months backwards) and acute change/fluctuating course

ii) need to know baseline levels - track on day 1

iii) SQUID - single question in delirium (is the person more confused or drowsy than usual)
- NEWS2 - AVPU

iv) are there any ppt factors? is the patient on any new drugs? go through things that may be cause ppt eg hypoxia, hypogly, ETOH use, baseline cog function
v) no - only around 11% have imaging changes

Question 20

MANAGEMENT OF DELIRIUM

i) what can be done with drugs?
ii) what must quickly be addressed
iii) how may reorientation be managed?
iv) how can safe mobility be maintained?
v) how can sleep wake cycle be normalised?
vi) which patients should pharma management be reserved for? which drug is preffered

Answer 20

i) limit pharmacological treatment success
- look at pre existing drugs
- reduce/remove psychoactive drugs eg anti Ach, sedatives, opioids
- sub with less toxic alternatives and look for non pharma approaches for sleep and anxiety

ii) address acute medical issues such as infection, hypoxia, hydration and nutrition
iii) encourage family involvement, address sensory impairment, provide glasses and hearing aids

iv) avoid use of physical restrains/alarms
- ambulate patient 3 times per day and encourage self care

v) discourage napping and increase exposure to bright light, encourage uninterruputed sleep at night
- non pharma sleep intervention > quiet room with low level lighting

vi) pts with severe agitation that interrupts essential treatment eg intubation or pts with severe psychotic symptoms
- start with low doses then titrate up
- haloperidol twice a day (atypical APs are close in effectiveness)

Question 21

MULTI DOMAIN TREATMENT

i) which three things should be treated first
ii) in which situtation may an AP be useful?
iii) which drug class can be given to manage distress/hyperactive delirium? what is the risk of this?

Answer 21

i) treat identified triggers, correct abnormal physiology, treat symptoms eg distress (may need pharma tx)
ii) if patient has psychosis and delirium

iii) single dose of benzo (shouldnt be routine)
- risk of converting someone with hyperactive to hypoactive delirium

Question 22

RECOVERY OF DELIRIUM AND DEMENTIA

i) what is the median duration of delirium?
ii) what may duration depend on? give an example
iii) what proportion of patients have symptoms that persist 3 months later?
iv) what is the leading RF for delirium?

Answer 22

i) 1 week

ii) duration can depend on ppt
- short lived/reversible if its a drug effect or withdrawal
- longer if hypoxia or inflammation

iii) 1/3 patients
iv) dementia (delirium is also a RF for dementia)