The document discusses delirium, including its definition, subtypes, risk factors, pathophysiology, management, and prevention. It defines delirium as a disturbance in consciousness and cognition caused by a medical condition or substance. The two main subtypes are hyperactive and hypoactive delirium. Risk factors include older age, dementia, medical illness, surgery, medications, sleep deprivation, and inflammation. The pathophysiology involves an imbalance between cholinergic and dopaminergic neurotransmitters. Management focuses on treating the underlying cause, avoiding medications that can worsen delirium, and addressing non-pharmacological factors. Prevention emphasizes good patient care, such as avoiding dehydration, hypoxia, and unnecessary medications.

1. What is delirium?
Why is it important?
Clinical Spectrum
General Risk Factors
Pathoetiological Model
Management
References
1

2. What is delirium?
Why is it important?
Clinical Spectrum
General Risk Factors
Pathoetiological Model
Management
References
2

3. I will not be discussing Delirium Tremens as the pathophysiology of
this form of delirium while not distinct, is somewhat different.
3

4. 4
Delirium is a neurobehavioral syndrome caused by the transient disruption of
normal neuronal activity secondary to systemic disturbances.
A delirious integrates external information incorrectly, which produces behavioral
responses that are inadequate to the environment.

5. DEFINITION:
A. Disturbance of consciousness with reduced ability to focus, sustain or shift
attention.
B. A change in cognition or a perceptual disturbance that is not better counted
for by dementia.
C. e disturbance develops acutely and fluctuates during the course of the day.
D. e disturbance is a the direct physiological consequence of a general medical
condition, medication, or other drug.
CAM is a standardized screening tool for patient with suspected delirium
It is 95% sensitive and specific, is easily googled and is essentially the DSM definition turned
into an algorithm
5

6. 6
Delirium often initiates a cascade of events culminating in loss of independence,
increased morbidity and mortality, and increased health care costs.
Delirium occurs up to 56% of hospitalized patients, up to 80% of mechanically
ventilated ICU patients and up to 70% of non-ventilated ICU patients
ICU delirium predicts a 3- to 11-fold increased risk of death at 6 months even after
controlling for relevant covariates such as severity of illness.
increased hospital cost of $2,500 per patient directly attributable to delirium. is
adds up $6.9 billion each year.

7. Subtypes noted as far back as the Greeks, and largely hold to this day.
hyperactive type was characterized by cognitive and behavioral disturbances
as well as sleep disruption and was termed “Phrenitis” It was marked by
excited, restless behavior and increased level of arousal.
Hypoactive type was termed ‘Lethargus’, and was characterized by
sleepiness, listlessness, memory loss, and inertia. Decreased psychomotor
activity is a predominant symptom and patients appear somnolent.
7

8. 8
Dementia and old age are the leading risk factors for delirium
Dementia:
• At least two thirds of cases of delirium occur in patients with underlying dementia
or cognitive impairment,
• Both delirium and dementia have been shown to be associated with decreased
cerebral oxidative metabolism, cholinergic deficiency, and inflammation.
Age:
It is useful to Apply the concept of "homeostenosis" (the age-associated decline in
physiologic reserve in body systems) when considering how age-related changes in
the brain predispose older persons to delirium during physiologic disturbances that
are tolerated in younger individuals.
Changes in the brain with normal aging include:
• a 28% decline in brain blood flow,
• neuron loss in many regions as high as 35%
• Decreasing concentrations norepinephrine, acetylcholine, dopamine, and GABA
e role of these changes as well as the other risk factors listed will be elaborated
shortly…

9. is is a basic model of delirium, and I stress the word basic.
While I don’t want to go through each piece of this model
individually, I intend to make the main components of it clear.
Understanding the pathophysiology of delirium is essential to the
management because of the numerous possible etiologies.
9

10. In case you couldn’t find it in this simple schematic, I’ve
highlighted the endpoint of interest, delirium
10

11. e current consensus is that
overactivity of the dopaminergic system
underactivity of the cholinergic system
are the key factors in delirium.
11

12. Risk factors highlighted that I’ll be going through
12

13. 13

14. e major pathogenic mechanism in delirium is thus often presumed to be central cholinergic
deficiency.
e cholinergic system is widely involved in arousal, attention, memory, and rapid-eye-
movement (REM) sleep.
Acetylcholine plays an important role in consciousness, perhaps by modulating the signal-noise
ratio of sensory and cognitive input and focusing awareness
A deficiency of cholinergic function relative to that of other neurotransmitters can be expected to
alter the efficiency of these mental mechanisms
Low levels of acetylcholine (ACh) in plasma and cerebrospinal fluid (CSF) have been described
in delirious patients.
is belief stems from a well-described association between delirium and anticholinergic toxins
such as Angel's Trumpet Jimson weed and medications such as atropine.
e administration of anticholinergic substances results in the characteristic manifestations of
delirium including typical electroencephalogram (EEG) changes.
Age-related overall reductions in acetylcholine release and muscarinic receptor function which
predisposes elderly persons to harmful effects of cholinergic inhibition.
And because of the decreased cerebral perfusion, even mild hypoxia in the elderly inhibits ACh
synthesis and release.
14

15. Higher levels for serum anticholinergic activity (SAA) have been associated with an
increased likelihood of delirium
resolving delirium is correlated with decreasing SAA suggesting A dose-response
relationship between symptoms of delirium and SAA
A high SAA (i.e., >20) has a predictive value for delirium defined as confusion
assessment method positive of 100%.
15

16. Many reasons the elderly are susceptible to cholinergic decline is because of
problems surrounding cerebral profusion and hypoxia
16

17. I don’t think I need to list the numerous factors in the critically ill and
postoperative patients that can lead to decreased oxygen exchange,
increased O2 demand, and decreased cerebral perfusion
With aging comes a broad decline in cardiovascular and respiratory
reserves. Studies suggest that by age 85, vital capacity is reduced by nearly
40% and the arterio-alveolar gradient widens.
delirious patients experienced a 42% reduction in overall cerebral blood
flow (CBF).
Cerebral hypoxia ➙ oxidative metabolism failure ➙ ATP-ase pump system
failure ➙ ionic gradients cannot be maintained ➙ neuronal membrane
instability and possible cell death, Na+ & Ca++ influx, K+ efflux.
It is theorized that the excess inward flux of Ca++ that precipitates the most
significant neurobehavioral disturbances observed in delirious patients.
Cholinergic neurotransmission is particularly sensitive to metabolic insults,
because ACh synthesis requires acetyl CoA, a key intermediate linking the
glycolytic pathway and the citric acid cycle.
17

18. Elderly and demented at increased susceptibility of older adults to
dehydration and the resulting complications, including delirium
Dehydration can lead to
• hypoperfusion (both cerebral and renal)
• increased concentration of drugs and/or their metabolites,
• extravascular changes, leading to water and electrolyte
imbalances,
18

19. e other key neurotransmitter is dopamine
19

20. Elevations of DA have long been associated with the development
of delirium.
Impaired oxidative conditions lead to significant increases in DA
because
e influx of Ca++ also stimulates DA release,.
Ca++ influx stimulates tyrosine hydroxylase which converts DOPA to DA ➙
increased DA production.
e breakdown in ATP-dependent transporters ➙ decrease in DA reuptake.
Decreased ATP ➙ decreased COMT activity ➙ decreased DA degradation.
DA agonists can create slower EEG in spite of motor hyperactivity,
which represents a perfect symptomatological match to hyperactive
delirium.
20

21. It has long been recognized that acute stress and non-CNS illness frequently affect
attention, cognition, motivation, mood, and perception
severity of the patient’s initial injury or underlying medical problem as measured by
APACHE scores is significantly directly correlated with the development of delirium
One of the characteristic features of POD is the LUCID INTERVAL, namely time
delay between the triggering insult (operation) and POD development
they mostly appear on the second or third postoperative day.
Explanation is offered by the common course of inflammatory cascade: while its
development begins quickly after stimulation, terminal effectors reach the peak
activity after 24 h or later. Increasing extravascular edema formation and
intravascular leukocyte adhesion further impair nutritive function of brain
capillaries.
Inflammation helps explain why dementia is such an important risk factor
21

22. Normally the BBB blocks most cytokines which disrupt neuronal function, but
chronic neurodegeneration seen in dementia primes microglia to respond more
vigorously to increased levels of the pro-inflammatory cytokine induced by systemic
insults
systemic inflammation as a response to surgical trauma may cause diffuse
microcirculatory impairment via leukocyte adhesion and endothelial activation
Perivascular edema causes longer diffusion distance for oxygen to reach the nerve
cells leading to hypoxia and all its consequences just mentioned.
22

23. Hypercortisolism has adverse effects on mood, sleep, energy, and cognition,
especially in elderly persons and is known to cause delirium in association with
surgery, Cushing’s syndrome, and dementia.
In demented patients, cortisol concentrations as measured by DST correlates with
the severity of the delirium
Excessive glucocorticoid levels seem to induce a vulnerable state in neurons.
Glucocorticoid excess has numerous adverse effects including
• inhibition of calcium efflux or sequestration,
• and cause energy failure of neurons by inhibiting glucose transport into cells
e hippocampus is a major target for these effects with its dense concentration of
GR.
e hippocampal formation is of prime importance for normal HPA axis shut-off.
is disruption of normal hippocampal activity will further disinhibit the release of
cortisol, thus sustaining high levels of circulating cortisol
23

24. It is well know the delirium causes disruptions in the circadian rhythms, but it is
little appreciated how iatrogenic disruptions in the circadian rhythms cause delirium.
chronic partial sleep deprivation’’ (i.e., sleeping limited to 4 hours per night, for 5
consecutive nights) translates into cumulative impairment in attention, critical
thinking, reaction time, recall, and emotional imbalance (i.e., short temper, mood
swings, and excessive emotional response)
the average ICU patient sleeps just under 2 hours in 24-hour period
24

25. 25

26. GABAergic medications have been shown to be some of the most significant and frequent
culprits to cause delirium
the use of benzodiazepines has been identified as an independent risk factor for the development
of delirium as shown in this graph
ere are several mechanisms by which sedative agents (e.g., benzodiazepines, propofol)
contribute to delirium:
(1) interfere with physiologic sleep patterns
(2) cause a centrally mediated acetylcholine deficient state
(3) disruption of thalamic gating function leading to sensory overload and hyper-arousal.
26

27. Homeostenosis of aging
Inflammatory priming of dementia
Stress induced neuronal vulnerability of critical illness
Human and pharmacologic disturbance of natural rhythms and balances
Lead to
Arousal, attention, and memory impairment because decreased cholinergic function.
&
Agitation, aggression, and psychosis because increased dopaminergic activity.
Any one of these could be the main etiology in any given case of delirium and that is
why it is critical to know how they all interact to prevent and manage delirium
27

28. I have only been on the floors a few months now, and already I’ve seen this scenario
countless times:
A critically ill patient is agitated, so the intern, resident or attending just throws some
benzos or opioids at the problem and follow up later.
it should be clear from the pathophysiology that not only is the patient likely
delirious but that both options are exactly the wrong choice not only in that they
will potentially exacerbate the patient’s delirium but my also tip a marginally hypoxic
patient to a critically hypoxic one.
28

29. Because delirium is so multifactorial prevention is essentially just good patient care.
at said, I’d like to highlight
1. Avoid/discontinue inappropriate or unnecessary medications.
2. judicious analgesic prescription.
3. avoid the routine use of sedatives.
4. Promote physiologic rhythms in sleep, bowel and bladder function,
5. Avoid dehydration and even minor hypoxia
6. Provide reorientation and sensory aids (e.g., eyeglasses, hearing aids)
29

30. Knowing the major offenders is half the battle and so I’ve highlighted them here
30

31. Drugs with anticholinergic side effects are as diverse as there are many.
31

32. Directed at finding underlying or exacerbating factors
32

33. Non pharmacologic treatment is the same as prevention but with
•Monitor the older person’s physiological condition/mental status.
•Evaluate response to care provided and modify as indicated.
33

34. 1. e use of psychotropic medications to treat the symptoms of delirium
should be reserved:
a) for patients in significant distress due to agitation or psychotic
symptoms;
b) in order to carry out essential investigations or treatment; and/or
c) to prevent older delirious persons from endangering themselves or
others.
2. When using psychotropic medications aim for monotherapy, the lowest
effective dose and tapering as soon as possible.
3. Antipsychotics are the treatment of choice. Haloperidol, when used
appropriately, is a reasonable choice for most patients.
4. Atypical antipsychotics are alternative agents to haloperidol, and are preferred
for patients who also have Parkinson’s Disease or Lewy Body Dementia.
5. Baseline and follow up ECG recommended with antipsychotics. For
prolongation of QTc intervals to >450 msec or a >25% increase over baseline,
consider cardiology consultation and antipsychotic discontinuation.
6. Benzodiazepines can exacerbate delirium. eir use should be reserved for
older persons with delirium caused by withdrawal from alcohol/sedative-
hypnotics.
34

35. 35

36. 36