1. Neuroreceptor
Modulation Will
Deliver Many
Different Flavors
Denise H. Rhoney, Pharm.D., FCCP, FCCM
Associate Professor
Eugene Applebaum College of Pharmacy & Health Sciences
Wayne State University
Detroit, Michigan

2. What is Delirium?
 Otherwise known as ICU psychosis, acute brain
dysfunction, acute confusional state, toxic‐metabolic
encephalopathy, post‐op confusional state, organic brain
syndrome
 Complex neurobehavioral syndrome caused by the
transient disruption of normal neuronal activity
 Clinically characterized by :
 Acute confusion, fluctuating mental status, inattention,
disorganized thinking, altered levels of consciousness

3. ICU Delirium Facts
 60% to 80% of ventilated patients
develop delirium
 20% to 50% of lower severity ICU
patients develop delirium
 3 times higher risk of death by 6
months
 $15k to $25k higher hospital costs
 Estimated national $4 to $16 billion
associated costs
 5 fewer ventilator free days (days alive Ely EW ICM 2001;27:1892‐900
and off vent), adjusted P=0.03 Ely EW JAMA 2001;286,2703‐2710
Ely EW CCM 2001;29,1370‐79
 9 times higher incidence of cognitive McNicoll L, JAGS 2003;51:591‐98
impairment at hospital discharge, adj. Ely EW et al, JAMA 2004;291‐1753‐1762
P=0.002 Milbrandt E et al, Crit Care Med 2004;32:955‐962
Lin et al, Crit Care Med 2004;32:2254‐59

4. Delirium Subtypes*
Characteristic Hyperactive Hypoactive
% in ICU 0‐6% 43.5‐94%
Level of Consciousness Hyperalert/vigilant, distractibility Lethargy,  alertness, inattention
Cognition Diffuse deficits, speech Diffuse deficits, slow speech/quiet
loud/rapid/disorganized,
disorientation
Perceptual disturbances Hallucination/delusions None
Physiologic Low‐voltage fast EEG,  or normal Slow/diffuse EEG,  cerebral
cerebral metabolic activity metabolic activity
Behaviors  Psychomotor activity, restless,  psychomotor activity, apathetic,
combative, mood liability  stimuli response
Possible etiology BZD w/drawal, ETOH/drug BZD intoxication, hepatic
w/drawal, drug intoxication encephalopathy, hypoxia, metabolic
disturbance
Outcome Best Worst
*64% ICU patients with mixed forms

5. Overview of Acute Brain
Dysfunction
Normal & consistent Elderly patients show signs of ICU patients subjected to
connectivity between grey matter atrophy in PPC, medical and
posterior parietal cortex (PPC), MTL and PFC pharmacological challenges
dorsal prefrontal cortex (PFC), that disrupt normal CNS
& medial temporal/ Functional connectivity connectivity and weaken
hippocampal region (MTL) – remains intact but strength of functional links between
circuit is innervated & connections is no longer these cortical regions
maintained by ascending robust
reticular activating system
(ARAS) in the brainstem Gunther ML et al. Medical Hypotheses 2007;69:1179‐1182

6. Neuroimaging Studies
 Delirium results in significant hypoperfusion in several brain
regions (frontal, temporal, and subcortical regions)
 Critically ill patients with delirium (61% with abnormalities)
 Significant ventricular enlargement
 Generalized atrophy
 Focal lesions in frontal and parietal regions
 White matter lesions/hyperintensities
 Cortical and subcortical lesions
Fong TG et al. J Gerontol A Biol Sci Med Sci 2007;61A:1294‐9.
Sbordone R et al. Brain Inj 1998;12:505‐12.

7. Risk Factors for Delirium
Predisposing Host Factors Critical Illness Factors Iatrogenic Factors
Age Acidosis Few social interactions
APOE4 polymorphism Anemia Frequent nursing care
Cognitive impairment CNS pathology Immobilization
Depression Electrolyte disturbances Medications
Stroke History Endocrine derangement Oversedation
Vision/hearing impairment Fever Poorly controlled pain
Hepatic Failure Sleep disturbances
High severity of illness
Hypoperfusion
Hypotension
Hypoxia/anoxia
Infection/sepsis
Malnutrition
Metabolic disturbances
Respiratory failure
Shock
Trauma

8. Risk of Delirium with Commonly
Administered Drugs
High Risk
Opioids (particularly meperidine & morphine)
Antiparkinsonian agents
Antidepressants (particularly anticholinergic agents)
Benzodiazepines
Corticosteroids
Medium Risk
Alpha‐blockers
Beta‐blockers
NSAIDS
Low Risk
ACE‐I
H2 antagonists
Calcium channel blockers
Anticonvulsants
Maldonado JR. Crit Care Clin 2008;24:789‐856.

9. Pathophysiology of Delirium

10. Theories on the Development of
Delirium
 Oxygen deprivation hypothesis
 Neurotransmitter hypothesis
 Large neutral amino acid hypothesis
 Neuronal aging hypothesis
 Cellular‐signaling hypothesis
 Physiologic stress hypothesis
 Inflammatory hypothesis
 Genetic Factors
 Cortisol & HPA disruption
 Disruption in circadian rhythm
 Disruption in thalamic gating

11. Hypotheses of Delirium
Large neutral amino acid hypothesis
Neurotransmitter hypothesis
Oxygen deprivation hypothesis
Inflammatory hypothesis
Figueroa‐Ramos MI et al. Intensive Care Med 2009;35:781‐795

12. Neurotransmitter Hypothesis
Suggests that changes in neurotransmitter concentration or
receptor sensitivity may underlie the different symptoms
and clinical presentations of delirium
 Reduced cholinergic function
 Excess release of
 Dopamine
 NE
 Glutamate
 Both decreased and increased activity
 Serotonin
 Histamine
 GABA

13. Acetylcholine & Delirium
 Decreased ACh synthesis and release
 Ach is an important neuromodulator of cortical and hippocampal
neuronal function
 Widespread dysfunction of arousal seen in delirium correlates well
with the blockade of the muscarininc cholinergic system
 Low levels of ACh described in plasma and CSF of patients with
delirium
 Higher levels of serum anticholinergic activity (SAA) have been
associated with increase likelihood of delirium in surgical and
medical inpatients
 Detectable SAA levels have been reported even in patients with
delirium who were not exposed to anticholinergic agents
Flacker et al. J Gerontol A Biol Sci Med Sci 2001; Mach et al. J Am Geriatr Sco 1995; Mulsant et al. Arch Gen Psychiatry 2003.

14. Acetylcholine & Delirium
 Potential contributing
mechanisms
 Aging
 Dementia & other “organic
brain injury”
 Hypoxia  ACh production
  anticholinergic activity
 Drugs
 Endogenous anticholinergic
substances
Central cholinergic pathways overlap with locations of
neuroimaging abnormalities
Hshieh TT et al. J Gerontol A Biol Sci Med Sci 2008; 63:764‐72

15. Dopamine
Dopamine associated with many functions
inlcuding cognition, motor activity,
thinking, perceptual function,
motivation/reward, anxiety
Dopaminergic and cholinergic pathways
overlap significantly in the brain
Overactivity of DA neurons in
mesolimbic pathway
may account for symptoms
similar to those in schizophrenia:
agitation, disorganized behavior,
hallucinations and inattention
Dopaminergic neurons are among most
susceptible to oxidative stress  massive
DA release

16. Dopamine & Delirium
 Enhanced central dopaminergic activity
 DA agonists cause delirium
 DA antagonists treat delirium
 Follows an inverted U‐shaped curve
 Lack of dopamine = Parkinsonian symptoms
 Excess dopamine = psychosis
 D2 receptor density declines with age and correlates with frontal cognitive
test scores
 DA transporter gene allele A9 is more prevalent in alcoholics with
withdrawal delirium and seizures
 DA agonists cause EEG slowing
 DA release is increased in hypoxia (while ACh is decreased)
 Dopaminergic blockade can be used to reduce hypoxic damage in hippocampus
Trzepacz PT. Sem Clin Neuropsychiatry 2000;5:132‐148.

18. Pharmacology of Antipsychotics

19. GABA & Delirium
 Predominant inhibitory
neurotransmitter in CNS
  in hepatic encephalopathy and
benzodiazepine use
  sedative/alcohol withdrawal
 Flumazenil has improved hypoactive
delirium in cirrhotic patients
 Oversedation with GABAergic agents
has been found to be a risk factor for
transitioning to delirium and
prolonged mechanical ventilation
Maldonado JR. Crit Care Clin 2008;24:789‐856.
Pandharipande P et al. Anesthesiology 2006; 104:21‐6

20. GABA & Delirium
 GABAergic agents contribute to the development of
delirium via various possible mechanisms
 Interfering with physiologic sleep patterns
 Interfering with central cholinergeric function causing
centrally mediated acetylcholine deficient state
 Disrupting circadian rhythm of melatonin release
 Enhancing NMDA‐induced neuronal damage
 Disrupting thalamic gating function leading to sensory
overload and hyperarousal
Maldonado JR. Crit Care Clin 2008;24:789‐856.

21. Other Neurotransmitters & Delirium
Serotonin:
 Most abundant neurotransmitter in the brainstem, its synthesis and
release depends on its precursor tryptophan
 Increased and decreased serotonin levels are both associated with
development of delirium
 Cerebral serotonin is increased in hepatic encephalopathy, septic delirium
and serotonin syndrome
Histamine:
 HA1 & HA2 alter the polarity of hippocampal neurons
 Pharmacological antagonism of HA1 and HA2 causes delirium
 Both excess and deficiency of HA may be related to delirium
 H2 Blockers cimetidine, ranitidine may cause cognitive dysfunction and
delirium in elderly
Maldonado JR. Crit Care Clin 2008;24:789‐856.

22. Other Neurotransmitters & Delirium
Norepinephrine:
 Plays important role in modulating attention, anxiety & mood
 Enhanced central noradrengergic activity ( NE)
 Acute NE release due to hypoxia leads to further neuronal injury and worsening
delirium
 Cortisol release with injury may lead to further NE release and activity
 Up‐regulation of NE receptors due to chronic GABA suppression
 Dexmedetomidine has been shown to decrease NE conc. by up to 90%
 Significantly decreased incidence of delirium associated with Dex compared to
midazolam
Glutamate:
 Enhanced glutamate activity leading to neuronal injury via activation of NMDA
receptors
 Metabolized by glutamate decarboxylase into GABA
 DA may enhance GLU‐mediated injury
Hshieh TT et al. J Gerontol A Biol Sci Med Sci 2008; 63:764‐72 Engelhard K et al. Anesth Analg 2003;96:524‐31
Maldonado JR. Crit Care Clin 2008;24:789‐856 Riker R et al JAMA 2009;301:489‐99

23. Interaction Between
Neurotransmitters
Hshieh TT et al. J Gerontol A Biol Sci Med Sci 2008; 63:764‐72

24. Medications, alcohol withdrawal Medications, medical illness
Ach (-) Benzodiazepine and alcohol withdrawal
Ach (+)
Medications, Stroke
D(+)
Benzodiazepine, hepatic failure
Cytokine Excess
GABA (+)
5HT (+)
GLU (+)
Medications, substance withdrawal
Hepatic failure, alcohol withdrawal
5HT (-)
Cortisol excess
Tryptophan depletion
Glucocorticosteroids, Cushing’s syndrome
Surgical Illness, medical illness
Maldonado JR. Crit Care Clin 2008;24:789‐856.

25. Maldonado JR. Crit Care Clin 2008;24:789‐856.

26. Summary
 Firm understanding of pathophysiology of delirium
remains elusive despite improvements in diagnosis and
treatment
 Neurotransmitter imbalance along with a number of other
hypotheses have been implicated in the development of
delirium
 Understanding cellular response to critical illness,
including neurotransmitter activity and neuroreceptor
expression, may lead to innovative diagnostic and
treatment modalities