Delirium in ICUDr. Parag MoonSenior resident

Dept. of NeurologyGMC, Kota.

Defined by Diagnostic and Statistical Manual of Mental Disorders(DSM)-IV

Disturbance of consciousness and cognition that develops over short period of time (hours to days) and fluctuates over time.

Three subtypes of delirium: hyperactive, hypoactive, and mixed

Hypoactive delirium-decreased responsiveness, withdrawal, apathy.

Hyperactive delirium-agitation, restlessness, and emotional lability.

Mixed.

Prevalence of delirium in ICU was 32.3%. Incidence of delirium in ICU ranges from

45% to 87%. Incidence appears to vary according to

mechanically ventilated patients. 20% in nonintubated ICU patients 83% in mechanically ventilated patients.

Epidemiology

Hyperactive delirium rare (1.6%). Hypoactive delirium-43.5% Mixed delirium-54.1% Hypoactive delirium more frequently in

older patients and has worse prognosis. Prolonged periods of ICU delirium

associated with increased risk for long-term cognitive impairment at 3 months.

Poorly understood.1. Neurotransmitter imbalance Imbalances in synthesis, release, and inactivation of

neurotransmitters that normally control cognitive function, behavior, and mood.

Greatest focus given to dopamine and acetylcholine. Imbalance in one or both results in neuronal

instability and unpredictable neurotransmission. Excess of dopamine or depletion of acetylcholine. Other neurotransmitters- γ- aminobutyric acid

(GABA), serotonin, endorphins, glutamate

Pathophysiology

2. Inflammation Inflammatory abnormalities induced by

endotoxin and cytokines probably contributes Tumor necrosis factor-α, interleukin-1,other

cytokines and chemokines initiate cascade of endothelial damage, thrombin formation, and microvascular compromise

May incite brain dysfunction by decreasing cerebral blood flow via formation of microaggregates of fibrin, platelets, neutrophils, and erythrocytes in cerebral microvasculature.

Constricting cerebral vasculature-activation of α1-adrenoceptors

Interfering with neurotransmitter synthesis and neurotransmission

Inflammatory mediators cross blood-brain barrier, increase vascular permeability,

Blunted anti-inflammatory response

Higher plasma concentrations tumor necrosis factor receptor-1, and lower plasma concentrations of protein C, matrix metalloproteinase-9 were associated with increased risk of delirium

3. Impaired oxidative metabolism Delirium as behavioral manifestation of

‘widespread reduction of cerebral oxidative metabolism resulting in imbalance of neurotransmission’.

Engel and Romano believed diffuse slowing on EEG to represent a reduction in brain metabolism.

Oxidative stress responsible for multi-organ dysfunction in critically ill patients.

4. Availability of large neutral amino acids Neurotransmitter levels and function affected

by changes in plasma concentrations of various amino acid precursors

Proposed that altered availability of large neutral amino acids contributes to development of delirium.

Amino acid entry into brain regulated by sodium-independent large neutral amino acid transporter type 1 (LAT1).

Tryptophan, essential amino acid and precursor for serotonin, competes with large neutral amino acids (for eg, tyrosine, phenylalanine, valine, leucine, and isoleucine) for transport across BBB via LAT1.

Phenylalanine competes with large neutral amino acids

Increased cerebral uptake of tryptophan and phenylalanine, compared with other large neutral amino acids, leads to elevated levels of dopamine and norepinephrine (noradrenaline).

Predisposing factors (host factors) Present before ICU admission

1. Age2. Alcoholism3. Smoking4. Hypertension 5. APOE4 polymorphism6. Cognitive impairment7. Hearing/visual impairment8. Depression

Risk factors

Precipitating factors. Occur during course of critical illness May involve factors of acute illness or be

iatrogenic; Represent potential preventive or

therapeutic intervention.

Factors of critical illness1. Acidosis2. Anemia3. Infection/sepsis4. Hypotension5. Metabolic

disturbances6. Respiratory disease7. High severity of

illness

Iatrogenic factors1. Immobilization2. Medication (opoids,

BDZ)3. Sleep disturbances

Pandharipande et al (2006) fpund patients treated with lorazepam were more likely to be delirious

Treatment with fentanyl, morphine, propofol were not significantly associated with transition to delirium.

Sedative agents that are GABA receptor sparing (Opioids, dexmedetomidine (a novel α2-receptor agonist) may reduce risk for delirium in ICU patients as compared to BZD

Sedatives and delirium

ICU patients sleep only 2 hours per day, less than 6% of their sleep

Sleep deprivation impairs cognition Factors affecting sleep-metabolic

derangements, mechanical ventilation, exposure to sedative, analgesic medications

Excessive noise and patient care activities-minor role.

Constellation of symptoms with acute onset and fluctuating course

Cognitive symptoms-disorientation, inability to sustain attention, impaired short-term memory, impaired visuospatial ability, reduced level of consciousness, perseveration.

Behavioral symptoms-sleep-wake cycle disturbance, irritability, hallucinations, delusions

Clinical manifestation

Clinical manifestations vary according to precipitating factors.

For eg. Bacteremia present with encephalopathy and declined mental status and with alcohol withdrawal syndrome present with symptoms of overactive sympathetic central nervous system.

Intensive Care Delirium Screening Checklist (ICDSC) and the Confusion Assessment Method for the ICU (CAM-ICU)

Using ICDSC, each patient is assigned a score from 0 to 8; a cut-off score of 4 has sensitivity 99% and specificity 64% for identifying delirium

Diagnosis

CAM-ICU has a more modest sensitivity ranging from 64% to 81%, high specificity from 88% to 98%.

S100B protein indicator of glial activation and/or death

Shown to be elevated in patients with delirium

Higher baseline levels of procalcitonin or C-reactive protein were associated with more days with delirium

Other biomarkers elevated-brain-derived neurotrophic factor, neuron-specific enolase, interleukins, cortisol

Biomarkers

Multicomponent strategies Repeated reorientation of patient Provision of cognitively stimulating activities Nonpharmacologic sleep protocol Intermittent boluses rather than continuous

infusions Promoting daily interruption of sedatives

and analgesics

Prevention and treatment

Early mobilization activities and range of motion exercises

Timely removal of catheters and physical restraints

Use of eyeglasses, magnifying lenses, and hearing aids, ear plugs.

Early correction of dehydration. Correction of infection, electrolyte

imbalance

First address complication of critical illness that may lead to delirium (hypoxia, hypercapnia, hypoglycemia, shock)

Any drug intended to improve cognition may have adverse psychoactive effects thus paradoxically exacerbating delirium.

Pharmacological treatment

Haloperidol recommended as drug of choice for treatment of ICU delirium by SCCM

Blocks D2 dopamine receptors, resulting in amelioration of hallucinations, delusions, unstructured thought patterns

SCCM guidelines-hyperactive delirium to be treated with 2 mg intravenously, followed by repeated doses (doubling previous dose) every 15 to 20 minutes while agitation persists

Once agitation subsides scheduled doses (every 4 to 6 hours) may be continued for few days, followed by tapered doses for several days.

Common doses for ICU patients range from 4 to 20 mg/day

Atypical antipsychotics (risperidone, ziprasidone, quetiapine, olanzapine) may also be helpful in delirium.

Skrobik et al (2004) compared olanzapine with haloperidol and reported that resolution of delirium symptoms was similar in both but more side effects were observed in haloperidol

Medications should be avoided in with prolonged QT intervals

Dexmedetomidine, novel α2- receptor agonist that does not act on GABA receptors, may to be alternative sedative agent less likely to cause delirium.

Pandharipande P. et al (2007) showed ICU patients sedated with dexmedetomidine spent fewer days in coma and more days neurologically normal than lorazepam.

Benzodiazepines are not recommended for management of delirium

Delirium is associated with 3.2-fold increase in 6-month mortality and 2-fold increase in hospital stay duration.

Also dependent on duration. Increasing duration of delirium was

independently associated with cognitive impairment

Prognosis

Thank you

Delirium in the intensive care unit;Timothy D Girard, Pratik P Pandharipande, E Wesley; Critical Care 2008, 12(Suppl 3):S3

Delirium in the ICU: an overview:Rodrigo Cavallazzi1, Mohamed Saad, Paul E Marik; Annals of Intensive Care 2012, 2:49

Delirium Management In The Icu; Department of Surgical Education, Orlando Regional Medical Center;approved in 04/2011

SCCM guidelines for management of Delirium in ICU.

References