Delirium - causes

Definition.  Delirium is an acute mental status change characterized by abnormal and fluctuating attention.

Prevalence: 

15%-24% on admission to hospitals

Incidence

6%-56% in hospitalized patients

11%-51% in postoperative elderly patients

80% or more in ICU patients.

Attention:  Ability to focus on specific stimuli and excluding others.

Awareness:  Ability to perceive or be conscious of events or experiences.

Arousal: Indicates responsiveness or excitability into action.

Consciousness: Clarity of awareness of environment.

Confusion: Inability for clear and coherent thought and speech.

Hypoactive delirium: Hypoactive level of psychomotor activity that may be accompanied by sluggishness and lethargy that approaches stupor.

Hyperactive delirium: Hyperactive level of psychomotor activity accompanied by mood lability, agitation and/or refusal to cooperate with medical care.  Typically: restraints, sitter, haldol, etc.

Mixed level of activity: Rapidly fluctuates between hypoactive and hyperactive.

Acute delirium: lasting few hours or days.

Persistent delirium: lasting weeks or months.

DSM-IV Criteria for Diagnosis of Delirium due to General Medical Condition:

• • Disturbance of consciousness (e.g,, reduced clarity of awareness of the environment) with reduced ability to focus, sustain, or shift attention.

  • A change in cognition (e.g., memory deficit, disorientation, and language disturbance) or the development of a perceptual disturbance that is not better accounted for by pre-existing, established or evolving dementia.

  • A disturbance that develops over a short time, usually hours to days, and tends to fluctuate during the course of the day.

  • Evidence from history, physical examination, or laboratory findings that the disturbance is caused by the direct physiologic consequences of a general medical condition.

Pathophysiology: 

• Delirium is theorized to occur in the setting of decreased cerebral reserve, resulting in reduced capacity to withstand a variety of insults that can trigger the acute confusional state.

  • Widespread dysfunction of both cortical and subcortical neurons.

• Alteration in cerebral oxidative metabolism

• Dysfunction locations:

  • • Anterior cingulate cortex

    • Bilateral prefrontal cortex

    • Right prefrontal cortex (dominant for attention)

    • Temporo-parietal 

    • Thalamus (small lesions can cause delirium)

    • Upper brainstem

  • Neurotransmitter dysfunction:

  • Cholinergic-dopaminergic imbalance. 

    • There is cholinergic deficit in delirium.

    • Cholinergic deficit leads to decreased perfusion in the prefrontal cortex

      • Affected by hypoglycemia, metabolic/toxic changes and hypoxia

    • Dopaminergic neurons are primarily found in the nigrostriatal and hypothalamic-pituitary, and ventral tegmental areas.  They, however, diffusely project to the frontal and temporal areas.  Thus localization in delirium is in these areas. 

      • Dopamine has an inhibitory effect on the release of acetylcholine.  

        • Thus, the delirium-producing effects of L-dopa and other antiparkinsonian medications. 

        • Intoxication with dopamine agonist commonly causes delirium.

        • Antidopaminergic (neuroleptics) actions are commonly used to manage delirium.

    • Inflammatory cytokines such as IL, IF, TNF-alpha, may contribute to delirium by altering BBB permeability and further affecting neurotransmission.

    • The combination of inflammatory mediators and dysregulation of the limbic-hypothalamic-pituitary axis may lead to exacerbation or prolongation of delirium. 

• Any patient with Alzheimer's disease who acutely develops symptoms of a confusional state and behavioral changes first warrants a workup to look for the underlying cause. Even mild changes in metabolic status, medications, or an infection such as of the urinary tract may precipitate confusion and behavioral changes.

• Literature suggests that patients who develop delirium or acute altered mental status in the hospital may have an incipient dementia and should undergo a full neurologic and cognitive evaluation outside of the hospital.

Predisposing and precipitating factors for Delirium:

• 4 factors that independent predispose to delirium:

  • Vision impairment (<20/70 OU), severity of systemic illness, cognitively impaired (elderly with dementia), age >80 years, dehydration (BUN/Cr elevation)

• 5 specific factors that can independently precipitate delirum:

  • Physical restraints, malnutrition or weight loss (albumin levels <30 g/L), use of indwelling bladder catheters, 3 or more medications added in <24 hour period, iatrogenic medical complication.

• Hearing impairment

• Functional limitation

• Alcohol abuse

• Malnutrition (indicated by an albumin < 3 g/dL)

• Dehydration (indicated by a blood urea nitrogen/creatinine ratio > 18)

• Infections: UTI, pulmonary, and AIDS

• Cardiorespiratory failure or hypoxemia

• Prior stroke or other nondementia brain disorder

• Iatrogenic Precipitants

  • Use of restraints

  • Urinary catheters

  • Multiple procedures

  • Sleep deprivation

  • Untreated pain

  • Drugs

    • Anticholinergics

    • Benzodiazepines

    • Opiates

    • Antihistamines

    • Antiepileptics

    • Muscle relaxants

    • Dopamine agonists

    • Monoamine oxidase inhibitors

    • Levodopa

    • Steroids

    • Antibiotics

      • Type 1:  seizures (PCN and cephalosporin)

      • Type 2:  symptoms of psychosis (procaine, PCN, sulfonamides, fluoroquinolones, and macrolides)

        • • Type 1 and 2, symptoms occurs within days of antibiotic use and subsided within days after discontinuation.

• • • • • Type 3:  abnormal brain scans and impaired muscle contraction, along with other brain dysfunction signs (metronidazole).

          • Type 3, symptoms took weeks to occur and took longer to dissipate after patients stopped taking them. 

• • • Beta-blockers

    • Digitalis

    • Lithium

    • Calcineurin inhibitors

  • Surgery

    • Thoracic (cardiac and noncardiac)

    • Vascular

    • Orthopedic surgery: Hip replacement, fracture (femoral neck/hip fractures)

    • Ophthalmological: cataract

    • TURP (bladder irrigation)

• Vulnerable heritable factors:  APOEe4, DRD2, DRD3 (dopamine receptor genes), SLC6A3 (dopamine transporter gene) polymorphisms.

Most common causes of delirium in elderly: metabolic disturbances, infections, stroke, drugs (anti-cholinergics, narcotics).  Also consider alcohol withdrawal and substance abuse.

ICU - Delirium (ICU psychosis)

- Stroke/ICH.

- Post-cardiac arrest

- Encephalitis

- Seizure

- Hypo/hyperthermia

- Drugs/ETOH withdrawal

- Thiamine deficiency

- Water intoxication

- Toxins

- Hyperthyroid (apathetic)

- Hypothyroid

- Medications

- Line sepsis

- Hypoxia, hypercapnia, ARDS

- Pneumonia

- CHF

- Hyper/hypotension

- Hepatic failure

- Biliary sepsis

- Hyper/hypoglycemia

- Pancreatitis

- Adrenal insufficiency

- Renal failure, urosepsis, post-dialysis

- Electrolyte imbalance

- Fat embolism

MEDICATIONS causing delrium in ICU

ETOH withdrawal, amphotericin, aminoglycosides, ACE-I, anticholinergics, anticonsvulsants, amiodarone, quinidine, disulfiram, bupropion, antiparkinsonian drugs, insulin, antipsychotics, benzodiazepines, beta-blocker, cephalosporins, cocaine, corticosteroids (high-dose), digitalis, cimetidine, ranitidine, INH, lidocaine, bupivicaine, metoclopramide, metronidazole, NSAIDs, Opioids, penicillin, TMP-SMX.

Major Causes of Delirium

Metabolic

• • Electrolytes:  hypo/hypernatremia, hypo/hypercalcemia, hypo/hypermagnesemia, hypo/hyperphosphatemia

  • Endocrine:  hypo/hyperthyroidism, hypo/hypercortisolism, hypo/hyperglycemia

  • Cardiac encephalopathy, hepatic encephalopathy, uremic encephalopathy

  • Hypoxia, hypercarbia

  • Vitamin deficiencies: thiamine, vitamin B12, nicotinic acid, folic acid

  • Toxic and industrial exposures: CO, organic solvents, Pb, Mn, CS2, heavy metals

  • Porphyria

Toxic

• • Intoxication and overdose

  • Withdrawal: alcohol, benzodiazepines, barbiturates, amphetamines, cocaine, coffee, phencyclidine, hallucinogens, inhalants, meperidine, and other narcotics

  • Drugs: anticholinergics, benzodiazepines, opiates, antihistamines, antiepileptics, muscle relaxants, dopamine agonists, MAO-I, levodopa, corticosteroids, antibiotics, beta-blockers, digitalis, lithium, clozapine, TCA, calcineurin inhibitors

Infectious

• • UTI, pneumonia, sepsis, meningitis, encephalitis

Neurologic

• • Vascular: ischemic stroke, ICH, SAH, vasculitis

  • Neoplastic: brain tumors, carcinomatous meningitis, paraneoplastic limbic encephalitis

  • Seizure-related: postictal state, NCSE

  • Trauma: concussion, SDH

Perioperative

• • Surgery: thoracic (cardiac and noncardiac)

  • Vascular

  • Hip replacement

  • Anesthetic and drug effects

  • Hypoxia and anemia

  • Hyperventilation

  • Fluid and electrolyte disturbances

  • Hypotension

  • Embolism

  • Infection or sepsis

  • Untreated pain

  • Fragmented sleep

  • Sensory deprivation or overload

Miscellaneous

• • Hyperviscosity syndrome

Elements in H&P and Clinical Characteristics of Delirium

• Acute onset of mental status change with fluctuating course.

  • • Sudden decline in hospital - incident delirium.  Incident delirium is new-onset delirium that occurs during the course of stay in a clinical setting.

      • What was the baseline mental and functional status?

      • Reason for hospitalization?

      • Collateral information?

• • Check for electrolyte abnormalities, respiratory, infectious, pain, medication list, sleep disorder, environmental alterations, novel situation, sensory overstimulation

• Attentional deficits

  • • Selectivity

    • Sustainability

    • Processing capacity

    • Ease of mobilization

    • Monitoring of the environment

    • Ability to shift attention when necessary

    • Perform serial recitation tasks (digit span 7 forward, 5 backward - WORLD backwards)

    • Continuous performance task includes the A vigilance test (SAVE HAART) 

    • Alternate response task (Luria manual sequencing task:  3-step motor sequence: palm-side-fist); also test frontal function.

• Confusion or disorganized thinking

  • • Unable to express organized, sequential, and organize goal-directed behavior

    • Speech is rambling, tangential, and circumlocutory with hesitations, repetitions, and perseveration.

• Perceptual disturbances

• Disturbed sleep/wake cycle

• Altered psychomotor activity

• Disorientation and memory impairment

• Behavioral and emotional abnormalities

Laboratory/Dxtic w/up: CMP, CBC with diff, LFTs, Sr. NH4, TSH, Vit B12, Folate, ABGs, UA, UDS, alcohol, HIV, RPR, ESR, Sr. cortisol, ECG, CXR, CT of head, LP - CSF, MRI of brain, MRA of head/neck, MRV, EEG, fMRI:  global hypometabolism or frontal hypoactivity; global hypermetabolism (DTs), brain bx

Diagnosis of delirium by the confusion assessment method

CAM-ICU

CAM-ICU Pocketcards

CAM-ICU video

Prevention and Management:

• Thiamine 100 mg IM/IV/PO

  • Early identification of patients predisposed to delirium (geriatric)

• HELP (hospital elder life program)

  • • Reorientation

    • Therapeutic activities

    • Reduction of use and/or dose of psychoactive drugs

    • Early mobilization

    • Promotion of sleep

    • Maintenance of adequate hydration, nutrition

    • Vision and hearing adaptations

  • Find the etiology and eliminate it.

  • Symptom management

    • Fluid and electrolyte balance

    • Nutritional status

    • Early treatment of infections

  • Medication review

  • Discontinue unnecessary drugs

  • Haloperidol, start at 0.25 mg daily (higher dopamine receptor potency, lower anticholinergic effects); can repeat q30 min upto 5 mg/day.  After the first 24 hr, 50% of the loading dose may be given in divided doses over the next 24 hour, then the dose should be tapered off over the next few days.

  • For patients with agitated delirium that precludes extubation, dexmedetomidine may facilitate successful extubation by anxiolysis without sedation.

  • Atypical antipsychotics (risperidone, olanzapine, quetiapine, and aripiprazole) may be used in low doses.

  • Melatonin, low dose and Ramelteon, a melatonin receptor agonist may be effective.

Environmental interventions

• • Frequent reorientation to place, time, and situation.

  • Patient safety: minimize risk of falls, wandering, or inadvertent self-harm

  • Reduce unfamiliarity by providing a calendar, clock, family pictures, and personal objects.

  • Maintain a sensory balance and avoid overstimulation or deprivation.

  • Minimize staff changes

  • Limit ambient noise and number of visits from strangers

  • When necessary provide eyeglasses, hearing-aids night-light, TV.

  • Soft music, warm baths, ambulation

  • Avoid physical restraints if possible, uses sitter instead

  • Proper communication

  • Delusions and hallucinations should not be challenged or endorsed

Prognosis:

• • Delirium at time of discharge is associated with a 2.6-fold of increased risk of death or NH placement

  • Delirium persisting at time of hospital discharge is associated with 2.9-fold risk of death in the following year.

  • In elderly, delirium may not be transient disorder.  They may not recover to baseline and may assume a new baseline (persistent delirium): 14.8% at 12 months after discharge)

  • Subsyndromal delirium is a partial nonprogressive delirium with some but not all criteria for delirium may persist in many elderly patients.

cam-ICU

A 2019 prospective cohort study of more than 15,000 patients in the ICU found that increased provision of components of one such bundle, the ABCDEF bundle (Assess, prevent, and manage pain; Both spontaneous awakening and breathing trials; Choice of analgesia and sedation; Delirium: assess, prevent, and manage; Early mobility and exercise; Family engagement and empowerment), is associated with less delirium, less coma, and improved survival ,