Neuroreceptor Neuroreceptor Modulation Will Modulation Will
Deliver Many Deliver Many Different FlavorsDifferent Flavors
Denise H. Rhoney, Pharm.D., FCCP, FCCMDenise H. Rhoney, Pharm.D., FCCP, FCCMAssociate ProfessorAssociate Professor
Eugene Applebaum College of Pharmacy & Health SciencesEugene Applebaum College of Pharmacy & Health SciencesWayne State UniversityWayne State University
Detroit, MichiganDetroit, Michigan
What is Delirium?What is Delirium?
Otherwise known as ICU psychosis, acute brain Otherwise known as ICU psychosis, acute brain dysfunction, acute confusional state, toxicdysfunction, acute confusional state, toxic‐‐metabolic metabolic encephalopathy, postencephalopathy, post‐‐op confusional state, organic brain op confusional state, organic brain syndromesyndrome
Complex neurobehavioral syndrome caused by the Complex neurobehavioral syndrome caused by the transient disruption of normal neuronal activitytransient disruption of normal neuronal activity
Clinically characterized by :Clinically characterized by : Acute confusion, fluctuating mental status, inattention, Acute confusion, fluctuating mental status, inattention,
disorganized thinking, altered levels of consciousnessdisorganized thinking, altered levels of consciousness
ICU Delirium FactsICU Delirium Facts
60% to 80% of ventilated patients 60% to 80% of ventilated patients develop delirium develop delirium
20% to 50% of lower severity ICU 20% to 50% of lower severity ICU patients develop deliriumpatients develop delirium
3 times higher risk of death by 6 3 times higher risk of death by 6 monthsmonths
$15k to $25k higher hospital costs$15k to $25k higher hospital costs
Estimated national $4 to $16 billion Estimated national $4 to $16 billion associated costs associated costs
5 fewer ventilator free days (days alive 5 fewer ventilator free days (days alive and off vent), adjusted P=0.03and off vent), adjusted P=0.03
9 times higher incidence of cognitive 9 times higher incidence of cognitive impairment at hospital discharge, adj. impairment at hospital discharge, adj. P=0.002P=0.002
Ely EW ICM 2001;27:1892‐900Ely EW JAMA 2001;286,2703‐2710Ely EW CCM 2001;29,1370‐79McNicoll L, JAGS 2003;51:591‐98Ely EW et al, JAMA 2004;291‐1753‐1762Milbrandt E et al, Crit Care Med 2004;32:955‐962Lin et al, Crit Care Med 2004;32:2254‐59
Delirium Subtypes*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 loud/rapid/disorganized, disorientation
Diffuse deficits, slow speech/quiet
Perceptual disturbances Hallucination/delusions None
Physiologic Low‐voltage fast EEG, or normal cerebral metabolic activity
Slow/diffuse EEG, cerebral metabolic activity
Behaviors Psychomotor activity, restless, combative, mood liability
psychomotor activity, apathetic, stimuli response
Possible etiology BZD w/drawal, ETOH/drug w/drawal, drug intoxication
BZD intoxication, hepatic encephalopathy, hypoxia, metabolic disturbance
Outcome Best Worst
*64% ICU patients with mixed forms
Overview of Acute Brain Overview of Acute Brain DysfunctionDysfunction
Normal & consistent connectivity betweenposterior parietal cortex (PPC),dorsal prefrontal cortex (PFC),& medial temporal/ hippocampal region (MTL) –circuit is innervated & maintained by ascendingreticular activating system (ARAS) in the brainstem
Elderly patients show signs of grey matter atrophy in PPC, MTL and PFC
Functional connectivity remains intact but strength of connections is no longer robust
ICU patients subjected to medical and pharmacological challenges that disrupt normal CNS connectivity and weaken functional links between these cortical regions
Gunther ML et al. Medical Hypotheses 2007;69:1179‐1182
Neuroimaging StudiesNeuroimaging Studies
Delirium results in significant hypoperfusion in several brain Delirium results in significant hypoperfusion in several brain regions (frontal, temporal, and subcortical regions)regions (frontal, temporal, and subcortical regions)
Critically ill patients with delirium (61% with abnormalities)Critically ill patients with delirium (61% with abnormalities) Significant ventricular enlargementSignificant ventricular enlargement
Generalized atrophyGeneralized atrophy
Focal lesions in frontal and parietal regionsFocal lesions in frontal and parietal regions
White matter lesions/hyperintensitiesWhite matter lesions/hyperintensities
Cortical and subcortical lesionsCortical 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.
Risk Factors for DeliriumRisk Factors for Delirium
Predisposing Host FactorsAgeAPOE4 polymorphismCognitive impairmentDepressionStroke HistoryVision/hearing impairment
Critical Illness FactorsAcidosisAnemiaCNS pathologyElectrolyte disturbancesEndocrine derangementFeverHepatic FailureHigh severity of illnessHypoperfusionHypotensionHypoxia/anoxiaInfection/sepsisMalnutritionMetabolic disturbancesRespiratory failureShockTrauma
Iatrogenic FactorsFew social interactionsFrequent nursing careImmobilizationMedicationsOversedationPoorly controlled painSleep disturbances
Risk of Delirium with Commonly Risk of Delirium with Commonly Administered DrugsAdministered Drugs
High RiskOpioids (particularly meperidine & morphine)Antiparkinsonian agentsAntidepressants (particularly anticholinergic agents)BenzodiazepinesCorticosteroids
Medium RiskAlpha‐blockersBeta‐blockersNSAIDS
Low RiskACE‐IH2 antagonistsCalcium channel blockersAnticonvulsants
Maldonado JR. Crit Care Clin 2008;24:789‐856.
Pathophysiology of DeliriumPathophysiology of Delirium
Theories on the Development of Theories on the Development of DeliriumDelirium
Oxygen deprivation hypothesisOxygen deprivation hypothesis Neurotransmitter hypothesisNeurotransmitter hypothesis Large neutral amino acid hypothesisLarge neutral amino acid hypothesis Neuronal aging hypothesisNeuronal aging hypothesis CellularCellular‐‐signaling hypothesissignaling hypothesis Physiologic stress hypothesisPhysiologic stress hypothesis Inflammatory hypothesisInflammatory hypothesis Genetic FactorsGenetic Factors Cortisol & HPA disruptionCortisol & HPA disruption Disruption in circadian rhythmDisruption in circadian rhythm Disruption in thalamic gatingDisruption in thalamic gating
Hypotheses of DeliriumHypotheses of Delirium
Figueroa‐Ramos MI et al. Intensive Care Med 2009;35:781‐795
Oxygen deprivation hypothesis
Inflammatory hypothesis
Neurotransmitter hypothesis
Large neutral amino acid hypothesis
Neurotransmitter HypothesisNeurotransmitter Hypothesis
Suggests that changes in neurotransmitter concentration or Suggests that changes in neurotransmitter concentration or receptor sensitivity may underlie the different symptoms receptor sensitivity may underlie the different symptoms and clinical presentations of deliriumand clinical presentations of delirium ReducedReduced cholinergic functioncholinergic function
ExcessExcess release of release of DopamineDopamine
NENE
GlutamateGlutamate
BothBoth decreased and increased activitydecreased and increased activity SerotoninSerotonin
HistamineHistamine
GABAGABA
Acetylcholine & DeliriumAcetylcholine & Delirium
Decreased ACh synthesis and releaseDecreased ACh synthesis and release Ach is an important neuromodulator of cortical and hippocampal Ach is an important neuromodulator of cortical and hippocampal
neuronal functionneuronal function
Widespread dysfunction of arousal seen in delirium correlates weWidespread dysfunction of arousal seen in delirium correlates well ll with the blockade of the muscarininc cholinergic systemwith the blockade of the muscarininc cholinergic system
Low levels of ACh described in plasma and CSF of patients with Low levels of ACh described in plasma and CSF of patients with deliriumdelirium
Higher levels of serum anticholinergic activity (SAA) have beenHigher levels of serum anticholinergic activity (SAA) have beenassociated with increase likelihood of delirium in surgical and associated with increase likelihood of delirium in surgical and medical inpatientsmedical inpatients
Detectable SAA levels have been reported even in patients with Detectable SAA levels have been reported even in patients with delirium who were not exposed to anticholinergic agentsdelirium 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.
Acetylcholine & DeliriumAcetylcholine & Delirium
Potential contributing Potential contributing mechanismsmechanisms AgingAging
Dementia & other Dementia & other ““organic organic brain injurybrain injury””
Hypoxia Hypoxia ACh productionACh production
anticholinergic activityanticholinergic activity DrugsDrugs
Endogenous anticholinergic Endogenous anticholinergic substancessubstances
Hshieh TT et al. J Gerontol A Biol Sci Med Sci 2008; 63:764‐72
Central cholinergic pathways overlap with locations of neuroimaging abnormalities
DopamineDopamineDopamine 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 symptomssimilar to those in schizophrenia: agitation, disorganized behavior,hallucinations and inattention
Dopaminergic neurons are among most susceptible to oxidative stress massive DA release
Dopamine & DeliriumDopamine & Delirium Enhanced central dopaminergic activityEnhanced central dopaminergic activity
DA agonists cause deliriumDA agonists cause delirium DA antagonists treat deliriumDA antagonists treat delirium
Follows an inverted UFollows an inverted U‐‐shaped curveshaped curve Lack of dopamine = Parkinsonian symptomsLack of dopamine = Parkinsonian symptoms Excess dopamine = psychosisExcess dopamine = psychosis
D2 receptor density declines with age and correlates with frontaD2 receptor density declines with age and correlates with frontal cognitive l cognitive test scorestest scores
DA transporter gene allele A9 is more prevalent in alcoholics wiDA transporter gene allele A9 is more prevalent in alcoholics with th withdrawal delirium and seizureswithdrawal delirium and seizures
DA agonists cause EEG slowingDA agonists cause EEG slowing
DA release is increased in hypoxia (while ACh is decreased)DA release is increased in hypoxia (while ACh is decreased) Dopaminergic blockade can be used to reduce hypoxic damage in hiDopaminergic blockade can be used to reduce hypoxic damage in hippocampusppocampus
Trzepacz PT. Sem Clin Neuropsychiatry 2000;5:132‐148.
Pharmacology of AntipsychoticsPharmacology of Antipsychotics
GABA & DeliriumGABA & Delirium
Predominant inhibitory Predominant inhibitory neurotransmitter in CNSneurotransmitter in CNS in hepatic encephalopathy and in hepatic encephalopathy and
benzodiazepine usebenzodiazepine use sedative/alcohol withdrawalsedative/alcohol withdrawal
Flumazenil has improved hypoactive Flumazenil has improved hypoactive delirium in cirrhotic patientsdelirium in cirrhotic patients
Oversedation with GABAergic agents Oversedation with GABAergic agents has been found to be a risk factor for has been found to be a risk factor for transitioning to delirium and transitioning to delirium and prolonged mechanical ventilationprolonged mechanical ventilation
Pandharipande P et al. Anesthesiology 2006; 104:21‐6Maldonado JR. Crit Care Clin 2008;24:789‐856.
GABA & DeliriumGABA & Delirium
GABAergic agents contribute to the development of GABAergic agents contribute to the development of delirium via various possible mechanismsdelirium via various possible mechanisms Interfering with physiologic sleep patternsInterfering with physiologic sleep patterns
Interfering with central cholinergeric function causing Interfering with central cholinergeric function causing centrally mediated acetylcholine deficient statecentrally mediated acetylcholine deficient state
Disrupting circadian rhythm of melatonin releaseDisrupting circadian rhythm of melatonin release
Enhancing NMDAEnhancing NMDA‐‐induced neuronal damageinduced neuronal damage
Disrupting thalamic gating function leading to sensory Disrupting thalamic gating function leading to sensory overload and hyperarousaloverload and hyperarousal
Maldonado JR. Crit Care Clin 2008;24:789‐856.
Other Neurotransmitters & DeliriumOther Neurotransmitters & Delirium
SerotoninSerotonin:: Most abundant neurotransmitter in the brainstem, its synthesis aMost abundant neurotransmitter in the brainstem, its synthesis and nd
release depends on its precursor tryptophanrelease depends on its precursor tryptophan
Increased and decreased serotonin Increased and decreased serotonin levels are both associated with levels are both associated with development of deliriumdevelopment of delirium
Cerebral serotonin is increased in hepatic encephalopathy, septiCerebral serotonin is increased in hepatic encephalopathy, septic delirium c delirium and serotonin syndrome and serotonin syndrome
HistamineHistamine:: HAHA11 & HA& HA22 alter the polarity of hippocampal neuronsalter the polarity of hippocampal neurons
Pharmacological antagonism of HAPharmacological antagonism of HA1 1 and HAand HA22 causes deliriumcauses delirium
Both Both excess and deficiency of HA excess and deficiency of HA may be related to deliriummay be related to delirium
HH2 2 BlockersBlockers cimetidine, ranitidine may cause cognitive dysfunction and cimetidine, ranitidine may cause cognitive dysfunction and delirium in elderlydelirium in elderly
Maldonado JR. Crit Care Clin 2008;24:789‐856.
Other Neurotransmitters & DeliriumOther Neurotransmitters & Delirium
NorepinephrineNorepinephrine:: Plays important role in modulating attention, anxiety & moodPlays important role in modulating attention, anxiety & mood Enhanced central noradrengergic activity (Enhanced central noradrengergic activity ( NE)NE) Acute NE release due to hypoxia leads to further neuronal injuryAcute NE release due to hypoxia leads to further neuronal injury and worsening and worsening
deliriumdelirium Cortisol release with injury may lead to further NE release and Cortisol release with injury may lead to further NE release and activityactivity UpUp‐‐regulation of NE receptors due to chronic GABA suppressionregulation of NE receptors due to chronic GABA suppression Dexmedetomidine has been shown to decrease NE conc. by up to 90Dexmedetomidine has been shown to decrease NE conc. by up to 90%%
Significantly decreased incidence of delirium associated with DeSignificantly decreased incidence of delirium associated with Dex compared to x compared to midazolammidazolam
Glutamate:Glutamate: Enhanced glutamate activity Enhanced glutamate activity leading to neuronal injury via activation of NMDA leading to neuronal injury via activation of NMDA
receptorsreceptors Metabolized by glutamate decarboxylase into GABAMetabolized by glutamate decarboxylase into GABA DA may enhance GLUDA may enhance GLU‐‐mediated injurymediated injury
Hshieh TT et al. J Gerontol A Biol Sci Med Sci 2008; 63:764‐72Maldonado JR. Crit Care Clin 2008;24:789‐856
Engelhard K et al. Anesth Analg 2003;96:524‐31Riker R et al JAMA 2009;301:489‐99
Interaction Between Interaction Between NeurotransmittersNeurotransmitters
Hshieh TT et al. J Gerontol A Biol Sci Med Sci 2008; 63:764‐72
Medications, Stroke
Cytokine Excess
Medications, substance withdrawal
Surgical Illness, medical illnessGlucocorticosteroids, Cushing’s syndrome
Hepatic failure, alcohol withdrawal
Benzodiazepine, hepatic failure
Benzodiazepine and alcohol withdrawal
Medications, medical illnessMedications, alcohol withdrawal
Ach (-)Ach (+)
GLU (+)
D(+)
GABA (+)
5HT (-)
5HT (+)
Tryptophan depletionCortisol excess
Maldonado JR. Crit Care Clin 2008;24:789‐856.
Maldonado JR. Crit Care Clin 2008;24:789‐856.
SummarySummary
Firm understanding of pathophysiology of delirium Firm understanding of pathophysiology of delirium remains elusive despite improvements in diagnosis and remains elusive despite improvements in diagnosis and treatmenttreatment
Neurotransmitter imbalance along with a number of other Neurotransmitter imbalance along with a number of other hypotheses have been implicated in the development of hypotheses have been implicated in the development of deliriumdelirium
Understanding cellular response to critical illness, Understanding cellular response to critical illness, including neurotransmitter activity and neuroreceptor including neurotransmitter activity and neuroreceptor expression, may lead to innovative diagnostic and expression, may lead to innovative diagnostic and treatment modalitiestreatment modalities