The document discusses the cognitive impairments associated with critical illness, including 'critical illness brain syndrome' and its manifestations in ICU patients. It examines the role of neuroinflammation and inflammatory cytokines in inducing cognitive dysfunction and depression, highlighting the complex relationship between stress responses, neurocognitive impairment, and systemic inflammation. The findings suggest that cytokines not only influence mood and cognition but also play a significant role in neurological damage during critical care, emphasizing the need for further research in this area.

1. CEREBRAL DYSFUNCTION IN
CRITICALLY ILL PATIENTS
REZA NEJAT, M. D.,
ANESTHESIOLOGIST, FCCM,
FORMER ASSISTANT PROFESSOR, SBMU,
BAZARGANAN HOSPITAL,
TEHRAN, IRAN

2. CEREBRAL DYSFUNCTION IN CRITICALLY ILL
PATIENTS
Many patients in the ICU develop a global
alteration in cognitive function:
‘‘critical illness brain syndrome’’
‘‘critical illness–associated cognitive dysfunction’’
‘‘critical illness encephalopathy’’

3. CEREBRAL DYSFUNCTION IN CRITICALLY ILL
PATIENTS
Critically ill patients frequently manifest
cognitive impairment.
Neurocognitive dysfunction:
improves with time, although not to normalize.
35% of survivors of critical illness manifested profound
cognitive impairment at 3 months,
only 4% were severely impaired at 9 months

4. CEREBRAL DYSFUNCTION IN CRITICALLY ILL
PATIENTS
Critical Illness
Strenuous Stress

5. CEREBRAL DYSFUNCTION IN CRITICALLY ILL
PATIENTS
Stress Response:
Tries to maintain homeostasis in
the face of derangement of
physiological phenomena:
Injury, trauma, ….

6. CEREBRAL DYSFUNCTION IN CRITICALLY ILL
PATIENTS
Stress Response:
Neuro-endocrine
Inflammatory-Immunological

7. CEREBRAL DYSFUNCTION IN CRITICALLY ILL
PATIENTS
Stress Response:
Various degree of illness severity
HPA axis?
Symapatho-Adrenal System
In critically ill patients:
High and Low ACTH,
High Glucocorticoids:
Functional deficiency

8. CEREBRAL DYSFUNCTION IN CRITICALLY ILL
PATIENTS
Stress Response:
Endogenous Glucocorticoids Control:
the feeling of hunger,
sleep-wake cycle,
affect the processes of:
Φlearning and memory in the:
prefrontal cortex,
hippocampus,
basolateral amygdala

9. CEREBRAL DYSFUNCTION IN CRITICALLY ILL
PATIENTS
 High levels of circulating glucocorticoids:
 allow dopamine to suppress the function
of hypothalamic ANF neurons through D2
receptor activation.
Endocrinology. 1995 Dec;136(12):5570-6
 renders dopamine to act as a potent
suppressor of neurons both through D5
and D2 receptors
Mol Psychiatry. 2000 May;5(3):332-6

10. CEREBRAL DYSFUNCTION IN CRITICALLY ILL
PATIENTS
ACTH and Glucocorticoid dissociation:
Critical illness
Inflammation
Mental disorders
Cytokines, neuropeptides, vasoactive agents:
Modulates the adrenal response to severe stress;
Independent of ACTH

11. CEREBRAL DYSFUNCTION IN CRITICALLY ILL
PATIENTS
•Inflammation/Immunological
Response:
•An essential evolutionary conserved
physiological surviving process
against infection, injury and trauma
which helps to preserve and restore
tissue homeostasis.

12. CEREBRAL DYSFUNCTION IN CRITICALLY ILL
PATIENTS
•Inflammation has been figured out to be
the common mechanism in many
disorders:
• Cardiac, Cancer, DM,…
•Neuropsychiatric disorders:
• Neurodegenerative
• Mood and anxiety
• Schizophrenia

13. CEREBRAL DYSFUNCTION IN CRITICALLY ILL
PATIENTS
•Inflammation/Immunological
Response:
•The brain monitors immune status
and peripheral inflammation:
• Neural Pathway (Vagus Afferent
Fibers)
• Humoral Pathway (Cytokines)

14. CEREBRAL DYSFUNCTION IN CRITICALLY ILL
PATIENTS
•Inflammation:
•Pro-inflammatory mediators:
• TNF-α, IL-1, HMGBp, vasoactive
agents, adhesion molecules,…
•Anti-inflammatory mediators:
• IL-4, IL-10, sTNFR, TGF-β, IL-1Ra

15. CEREBRAL DYSFUNCTION IN CRITICALLY ILL
PATIENTS
•Inflammation:
•Immuno-modulation pathways:
• TNF-α and IL-1 induce:
• HPA axis
• Sympatho-adrenal system

16. CEREBRAL DYSFUNCTION IN CRITICALLY ILL
PATIENTS
Inflammation is associated with a range of
depression symptoms:
tiredness,
lack of energy,
sleep problems,
changes in appetite
cognitive and emotional symptoms
anhedonia, depressed mood, feelings of self-worth,
concentration problem, suicidal ideation

17. CEREBRAL DYSFUNCTION IN CRITICALLY ILL
PATIENTS
Patients with sepsis may acquire
neurological damage during hospitalization
through:
Cerebral ischemia,
Metabolic derangements,
Neuro-inflammation
Sepsis:
an independent risk factor of stress disorders
after critical illness

18. CEREBRAL DYSFUNCTION IN CRITICALLY ILL
PATIENTS
•Inflammatory signaling:
• a contributor to the short- and
long-term modulation of
mood and cognition

19. CEREBRAL DYSFUNCTION IN CRITICALLY ILL
PATIENTS
CNS dysfunction during systemic infection:
sickness behavior,
Delirium,
septic encephalopathy,
Pathogenesis, the key element:
the systemic production of pro-inflammatory cytokines:
TNF-a and IL-1β,
BBB cytokine transport systems; likely to play a
role in the passage of these signals

20. CEREBRAL DYSFUNCTION IN CRITICALLY ILL
PATIENTS
In health, cytokines:
Make the brain alert of eruption of
immune responses to peripheral
inflammatory processes:
infection,
injury,
diseases by signaling an immuno-
neuropsychiatric (INP) cascade of events.

21. CEREBRAL DYSFUNCTION IN CRITICALLY ILL
PATIENTS
• Cytokines participate in the modulation of the
Central Nervous System (CNS) physiology and
behavior:
• cognition
• memory modulation
• temperature regulation,
• appetite,
• drinking,
• analgesia,
• release of hormones from the hypothalamus,
• locomotor activity

22. CEREBRAL DYSFUNCTION IN CRITICALLY ILL
PATIENTS
•Activating inflammatory response may
provoke neuropsychiatric disorders:
• IFN-α (in hepatitis C and cancer)
• Depression and anxiety,
• ameliorated with SSRI.
• Administration of endotoxin or typhoid
vaccination to healthy volunteers:
• symptoms of depression and anxiety

23. CEREBRAL DYSFUNCTION IN CRITICALLY ILL
PATIENTS
•a subpopulation of patients with major
depression exhibit features of:
• ⇈ inflammatory cytokines:
• Blood and CSF:
• (IL-6, TNF-α, CRP, among the others)
• ⇈ blood level of :
• Acute phase reactant,
• Chemokines
• Adhesion molecules

24. CEREBRAL DYSFUNCTION IN CRITICALLY ILL
PATIENTS
•⇈ inflammatory mediators was shown in:
•PTSD (NF-κB)
•Panic attacks
•Obsessive-compulsive disorders
•Anxiety-related personality
dimensions

25. CEREBRAL DYSFUNCTION IN CRITICALLY ILL
PATIENTS
• Inhibition of inflammatory cytokines
ameliorates depression and anxiety:
• Etanercept (anti-cytokine)
• improvement of depressive symptoms
• Infliximab (anti-cytokine)
• Reducing depression and anxiety in patients with
high CRP
• acetylsalicylic acid (anti-inflammatory agents)
• antidepressant efficacy

26. CEREBRAL DYSFUNCTION IN CRITICALLY ILL
PATIENTS
•IL-1β, IL-6 and TNFα (after
manipulations in the periphery or
brain):
• strongly expressed in the
hippocampus
• well placed to modulate memory

27. CEREBRAL DYSFUNCTION IN CRITICALLY ILL
PATIENTS
• IL-1β:
• is required for hippocampal dependent
plasticity and learning
• chronic overexpression in the hippocampus:
• leads to impairments of spatial memory and
context fear conditioning! (age dependent)
• application: (age dependent)
• impairs induction and maintenance of LTP
• induces deficit in hippocampal memory
processes.

28. CEREBRAL DYSFUNCTION IN CRITICALLY ILL
PATIENTS
• TNF-α:
• overexpression in neurons or glial cells impairs:
• passive avoidance memory,
• synaptic plasticity,
• cerebellar learning
• mediates memory deficits after chronic LPS
administration

29. CEREBRAL DYSFUNCTION IN CRITICALLY ILL
PATIENTS
• IL-6:
• Shows similar effects like TNF-α in learning and
plasticity;
• limits the plasticity during memory formation
even in the absence of inflammation
• Overexpression or application cause:
• cognitive dysfunction,
• broad memory impairments,
• diminished LTP; learning
• In stroke, plays role in the onset of:
• apathetic-amotivational and loss of appetite and
sleep disorders.

30. CEREBRAL DYSFUNCTION IN CRITICALLY ILL
PATIENTS
activation individual
cytokines
vs
activation a network of
cytokines

31. CEREBRAL DYSFUNCTION IN CRITICALLY ILL
PATIENTS
•IL-1β, TNF-α, and IL-6:
• exert their effects directly and at the same
time indirectly via network of inflammatory
signaling:
• IL-1β:
• does not increase in isolation,
• leads to increases in TNFα, IL-6, IL-1 family
proteins, and cytokine receptors across multiple
brain regions
• TNF-α or IL-6 may change the expression of
other inflammatory cytokines

32. CEREBRAL DYSFUNCTION IN CRITICALLY ILL
PATIENTS
• cytokines in the brain are not limited to:
• IL-1β, TNF-α, and IL-6
• these may regulate the expression of others:
• IL-4, IL-10
• Chemokines:
• macrophage inflammatory protein (MIP-2, CXCL2),
• monocyte chemotactic protein (MCP-1, CCL2),
• karatinocyte derived cytokine (KC; CXCL1)
• growth factors:
• NGF, BDNF

33. CEREBRAL DYSFUNCTION IN CRITICALLY ILL
PATIENTS
• IL-4 and IL-10:
• alleviate the deleterious impact of
inflammatory processes on memory and
plasticity
• can abrogate learning and memory
deficits in inflammatory models of
Alzheimer’s disease

34. CEREBRAL DYSFUNCTION IN CRITICALLY ILL
PATIENTS
• Delirium and cytokines:
• The cytokines, along with producing
symptoms of fever, weakness, and
lethargy, causes:
• impaired concentration,
• sleep disturbances,
• agitation,
• some of the cardinal symptoms of
delirium.

35. CEREBRAL DYSFUNCTION IN CRITICALLY ILL
PATIENTS
• Delirium and cytokines:
• cytokines may induce a reduction in
cholinergic activity;
• repetitive cycle of inadequate
regulation of inflammation due to
cholinergic depletion

36. CEREBRAL DYSFUNCTION IN CRITICALLY ILL
PATIENTS
• Delirium and cytokines:
• Acetylcholine may inhibit
the release of pro-
inflammatory cytokine IL-6
• depleted acetylcholine
stores may predispose to
delirium

37. CEREBRAL DYSFUNCTION IN CRITICALLY ILL
PATIENTS
•Cytokines:
• play a role in symptoms of
dementia,
• are dysregulated in:
• dementia,
• psychiatric disorders in the
cognitively normal population.

38. CEREBRAL DYSFUNCTION IN CRITICALLY ILL
PATIENTS
• CNS cytokines:
• regulate the production of other
cytokines,
• alter the BBB,
• recruit inflammatory cells,
• influence neurotransmitter
metabolism
• monoamines, serotonin, dopamine and
glutamate

39. CEREBRAL DYSFUNCTION IN CRITICALLY ILL
PATIENTS
•Dopamine:
• big role in motivation and reward.
•Serotonin:
• (low levels) believed to be related to
depression,
• but it is really not the case:
• SSRIs have an anti-inflammatory effect.

40. CEREBRAL DYSFUNCTION IN CRITICALLY ILL
PATIENTS
• inflammatory cytokines can influence the
synthesis of monoamine neurotransmitters:
• Cytokine-induced activation of indole-amine
2,3 di-oxygenase (IDO)
• Converts more tryptophan into kynurenine,
• Reduces the availability of serotonin,
• Provokes depressive-like behavior

41. CEREBRAL DYSFUNCTION IN CRITICALLY ILL
PATIENTS
• IFN-α administration is associated with major
depression and depressive symptoms
• ⇈ in kynurenine and ⇊ in tryptophan:
• implicated in the symptoms
• In astrocytes:
• kynurenine ⇉ kyneurenic acid (KYNA)
• In microglia:
• Quinolone ⇉ quinolinic acid (QUIN)

42. CEREBRAL DYSFUNCTION IN CRITICALLY ILL
PATIENTS
• IFN-α administration:
• associated with major depression and
depressive symptoms
• KYNA and QUIN level in CSF increases in
patients receiving IFN- α
• QUIN level in CSF correlates significantly with
depressive symptoms

43. CEREBRAL DYSFUNCTION IN CRITICALLY ILL
PATIENTS
• inflammatory cytokines can influence the
reuptake of monoamine neurotransmitters:
• The serotonin transporter (SERT):
• reuptakes serotonin from the synaptic
cleft,
• regulates synaptic serotonin (5-HT)
concentrations and signaling,
• 5-HT synapses play a central role in the neural
circuitry controlling mood and temperament

44. CEREBRAL DYSFUNCTION IN CRITICALLY ILL
PATIENTS
• inflammatory cytokines can influence the synthesis of
monoamine neurotransmitters:
• Through inactivation of tetrahydrobiopterin (BH4)
• (BH4) is an essential cofactor for enzymes TyrH and
PhenylH:
• tryptophan ⇉ serotonin
• phenylalanine ⇉ tyrosine
• tyrosine ⇉ dopamine/norepinephrine
• arginine ⇉ NO

45. CEREBRAL DYSFUNCTION IN CRITICALLY ILL
PATIENTS
• inflammatory cytokines can influence
the neurotransmitters (glutamate):
• ⇊ the expression of glutamate
transporters on relevant glial elements
• ⇈ the release of glutamate from
astrocytes

46. CEREBRAL DYSFUNCTION IN CRITICALLY ILL
PATIENTS

47. CEREBRAL DYSFUNCTION IN CRITICALLY ILL
PATIENTS
• ANY QUESTION?
• rezanejat.com
• icuaticu.com
• 2icuedu.com
• rezanejat@yahoo.com