Confusion and Delirium¶

Chapter 29 | Part 2: Cardinal Manifestations and Presentation of Diseases

KEY CLINICAL POINTS¶

Delirium is an acute decline in cognition with fluctuating course; the hallmark is a deficit of attention affecting all cognitive domains
Two subtypes exist: hyperactive (agitation, hallucinations, autonomic instability) and hypoactive (withdrawal, apathy, psychomotor slowing) - hypoactive is often missed
Major risk factors include age >65, baseline cognitive dysfunction, sensory deprivation, polypharmacy, and underlying neurologic disease
In-hospital mortality rates of delirious patients range from 25-33%, similar to sepsis; delirium is associated with 5-fold higher mortality in months following illness
Treatment focuses on addressing underlying etiology first; supportive care with reorientation, sleep-wake cycle maintenance, and environmental modification is essential

1. DEFINITION & OVERVIEW¶

Confusion is a mental and behavioral state of reduced comprehension, coherence, and capacity to reason. It is one of the most common problems encountered in medicine, accounting for a large number of emergency department visits, hospital admissions, and inpatient consultations. Delirium is the term used to describe an acute confusional state. It remains a major cause of morbidity and mortality, costing billions of dollars yearly in health care costs in the United States alone. Despite increased efforts targeting awareness of this condition, delirium often goes unrecognized despite evidence that it is often the cognitive manifestation of serious underlying medical or neurologic illness.

1.1 Terminology¶

Multiple terms are used to describe patients with delirium: - Encephalopathy - Acute brain failure - Acute altered mental status - Acute confusional state - Postoperative psychosis - ICU psychosis All these terms describe the same clinical entity characterized by relatively acute decline in cognition that fluctuates over hours or days.

1.2 Key Characteristics¶

Hallmark: Deficit of attention
All cognitive domains variably involved (memory, executive function, visuospatial tasks, language)
Fluctuating course over hours or days
May worsen at night (sundowning)
Associated features may include: altered sleep-wake cycles, perceptual disturbances (hallucinations, delusions), affect changes, autonomic instability

2. CLINICAL FEATURES¶

Delirium is a clinical diagnosis made at the bedside. The presentation varies widely, but all patients demonstrate some degree of attentional deficit and acute cognitive change from baseline.

2.1 Hyperactive Subtype¶

Classic example: Alcohol withdrawal (delirium tremens) Features: - Prominent hallucinations - Agitation - Hyperarousal - Tremor - Autonomic instability (often life-threatening) These patients are easily recognized due to their characteristic severe agitation.

2.2 Hypoactive Subtype¶

Classic example: Benzodiazepine intoxication Features: - Withdrawn and quiet - Prominent apathy - Psychomotor slowing - Decreased responsiveness IMPORTANT: These patients are often overlooked and underdiagnosed on medical wards and in the ICU.

2.3 Mixed Presentation¶

Most patients fall somewhere along a spectrum between hyperactive and hypoactive extremes, sometimes fluctuating from one to the other. Clinicians must recognize this broad range of presentations to identify all patients with this potentially reversible cognitive disturbance.

2.4 Course and Reversibility¶

Reversibility is emphasized because many etiologies (infection, medication effects) can be treated easily. However: - Some episodes continue for weeks, months, or even years - Persistence may be due to inadequate initial treatment of underlying etiology - Delirium may cause permanent neuronal damage and long-term cognitive decline - Prevention strategies are important - Patient recall after delirium varies from complete amnesia to repeated reexperiencing (similar to PTSD)

3. EPIDEMIOLOGY¶

Delirium is extremely common but its reported incidence varies widely based on diagnostic criteria used.

3.1 Incidence and Prevalence¶

Hospitalized patients: 10% to >50%
Higher rates in elderly patients and hip surgery patients
ICU patients (especially elderly): approaches 75%
Nursing home patients: nearly 25%
End-of-life patients: 50-80% NOTE: The condition is not recognized in up to one-third of delirious inpatients. Diagnosis is especially problematic in ICU settings where cognitive dysfunction is difficult to appreciate in the context of serious systemic illness and sedation.

3.2 Morbidity and Mortality¶

An episode of delirium was previously viewed as transient with benign prognosis. This is now known to be incorrect. - In-hospital mortality: 25-33% (similar to sepsis) - 5-fold higher mortality in months after illness compared to age-matched nondelirious hospitalized patients - Longer hospital length of stay - More likely to be discharged to nursing home - Higher frequency of readmission - More likely to experience subsequent episodes of delirium and cognitive decline - Enormous economic cost

4. RISK FACTORS¶

Effective primary prevention begins with identification of high-risk patients. Some hospital systems screen most or all patients upon admission or before elective surgery, with positive screens triggering focused prevention measures.

4.1 Predisposing Risk Factors¶

Most consistently identified risk factors: - Age >65 years - Baseline cognitive dysfunction - Patients with low scores on standardized cognitive tests develop delirium at rates approaching 50% upon hospitalization Other predisposing factors: - Sensory deprivation (preexisting hearing and visual impairment) - Baseline immobility - Malnutrition - Underlying medical or neurologic illness

4.2 In-Hospital (Precipitating) Risk Factors¶

Use of physical restraints
Bladder catheterization
Sleep deprivation
Sensory deprivation
Addition of ≥ 3 new medications Avoiding these risks is a key component of delirium prevention and treatment.

4.3 Surgical and Anesthetic Risk Factors¶

Cardiopulmonary bypass procedures
Inadequate OR excessive treatment of postoperative pain
Specific agents: inhalational anesthetics, benzodiazepines

4.4 Relationship with Dementia¶

The relationship between delirium and dementia is complex with significant overlap: - Dementia and preexisting cognitive dysfunction are major risk factors for delirium - At least two-thirds of delirium cases occur in patients with coexisting underlying dementia - Dementia with Lewy bodies is characterized by fluctuating course, prominent visual hallucinations, parkinsonism, and attentional deficit resembling hyperactive delirium - Patients with Lewy body dementia are particularly vulnerable to delirium - Delirium in elderly often reflects insult to brain vulnerable due to underlying neurodegeneration - Development of delirium sometimes heralds onset of previously unrecognized brain disorder

5. PATHOGENESIS¶

The pathogenesis and anatomy of delirium are incompletely understood.

5.1 Neuroanatomy¶

The attentional deficit has diffuse localization within: - Brainstem - Thalamus - Prefrontal cortex - Parietal lobes Rarely, focal lesions (ischemic strokes) have led to delirium in otherwise healthy persons: - Right parietal lesions (most commonly reported) - Medial dorsal thalamic lesions (most commonly reported) In most cases, delirium results from widespread disturbances in cortical and subcortical regions. EEG often reveals symmetric slowing, supporting diffuse cerebral dysfunction.

5.2 Neurotransmitter Abnormalities¶

Acetylcholine deficiency may play a key role: - Medications with anticholinergic properties commonly precipitate delirium - Patients with preexisting dementia are particularly susceptible - Alzheimer's disease, dementia with Lewy bodies, and Parkinson's disease dementia are all associated with cholinergic deficiency due to degeneration of acetylcholine-producing neurons in basal forebrain Dopamine excess: - Increases in dopamine can lead to delirium - Parkinson's patients on dopaminergic medications can develop delirium-like state with visual hallucinations, fluctuations, and confusion

5.3 Vulnerability Model¶

Not all individuals exposed to the same insult develop delirium. The current most widely accepted pathogenic construct is that delirium develops as the result of an insult in predisposed individuals. Example: A low dose of anticholinergic medication may have no cognitive effects on a healthy young adult but produce florid delirium in an elderly person with known underlying dementia. However, even healthy young persons develop delirium with very high doses of anticholinergic medications. CLINICAL PEARL: If a previously healthy individual with no history of cognitive illness develops delirium in the setting of a relatively minor insult (elective surgery, UTI, hospitalization), consider an unrecognized underlying neurologic illness such as: - Neurodegenerative disease - Multiple previous strokes - Other diffuse cerebral cause Delirium can be viewed as a "stress test for the brain" whereby exposure to inciting factors can unmask decreased cerebral reserve and herald a serious underlying and potentially treatable illness.

6. ETIOLOGY¶

A large, diverse group of insults can lead to delirium, and the cause in many patients is multifactorial.

Table 29-1: Differential Diagnosis of Delirium¶

Category	Specific Etiologies
TOXINS - Prescription medications	Especially those with anticholinergic properties, narcotics, and benzodiazepines
TOXINS - Drugs of abuse	Alcohol intoxication and withdrawal, opiates, ecstasy, LSD, GHB, PCP, ketamine, cocaine, "bath salts," marijuana and synthetic forms
TOXINS - Poisons	Inhalants, carbon monoxide, ethylene glycol, pesticides
METABOLIC - Electrolyte disturbances	Hypoglycemia, hyperglycemia, hyponatremia, hypernatremia, hypercalcemia, hypocalcemia, hypomagnesemia
METABOLIC - Temperature	Hypothermia and hyperthermia
METABOLIC - Organ failure	Pulmonary failure (hypoxemia, hypercarbia), liver failure/hepatic encephalopathy, renal failure/uremia, cardiac failure
METABOLIC - Nutritional	Vitamin deficiencies (B12, thiamine, folate, niacin), dehydration and malnutrition, anemia
INFECTIONS - Systemic	Urinary tract infections, pneumonia and other respiratory infections, skin and soft tissue infections, sepsis
INFECTIONS - CNS	Meningitis, encephalitis, brain abscess
ENDOCRINE	Hyperthyroidism, hypothyroidism, hyperparathyroidism, adrenal insufficiency
CEREBROVASCULAR	Global hypoperfusion states, hypertensive encephalopathy, focal ischemic strokes and hemorrhages (rare - especially nondominant parietal and thalamic lesions)
AUTOIMMUNE	CNS vasculitis, cerebral lupus, neurologic paraneoplastic and autoimmune encephalitis
SEIZURE-RELATED	Nonconvulsive status epilepticus, intermittent seizures with prolonged postictal states
NEOPLASTIC	Diffuse metastases to brain, diffuse glioma, carcinomatous meningitis, CNS lymphoma

Category	Specific Etiologies
OTHER	Hospitalization itself, terminal end-of-life delirium

6.1 Medications¶

Prescribed, over-the-counter, and herbal medications all can precipitate delirium. Most common offenders: - Anticholinergic drugs - Narcotics/opioids - Benzodiazepines Nearly any compound can lead to cognitive dysfunction in a predisposed patient. Correlation of timing of recent medication changes (dose and formulation) with onset of cognitive dysfunction is critical.

6.2 Drugs and Toxins¶

Common in younger patients: - Fentanyl - Synthetic cannabis - "Bath salts" - MDMA (ecstasy) - GHB ( γ -hydroxybutyrate) - Ketamine - Phencyclidine (PCP) - Oral narcotics and benzodiazepines (prescription drug abuse) - Alcohol Alcohol and benzodiazepine withdrawal should be considered in ALL cases of delirium, including in the elderly. Even patients who drink only a few servings of alcohol daily can experience relatively severe withdrawal symptoms upon hospitalization.

6.3 Metabolic Abnormalities¶

Electrolyte disturbances (sodium, calcium, magnesium, glucose) - even mild derangements can lead to substantial cognitive disturbances in susceptible individuals
Liver failure (hepatic encephalopathy)
Renal failure (uremia)
Hypercarbia and hypoxemia
Vitamin deficiencies (thiamine, B12)
Endocrinopathies (thyroid, adrenal disorders)

6.4 Infections¶

Systemic infections: - Common scenario: Acute cognitive decline in setting of UTI in patient with baseline dementia - Pneumonia - Skin infections (cellulitis) - Sepsis (septic encephalopathy - probably due to release of proinflammatory cytokines and diffuse cerebral effects) CNS infections (less common but high morbidity/mortality if untreated): - Meningitis - Encephalitis - Brain abscess - Autoimmune or paraneoplastic encephalitis Clinicians must always maintain a high index of suspicion for CNS infections.

6.5 Cerebrovascular Causes¶

Usually due to global hypoperfusion from: - Systemic hypotension (heart failure, septic shock, dehydration, anemia) Rarely, focal strokes can cause delirium: - Right parietal lobe strokes - Medial dorsal thalamic strokes More common scenario: New focal stroke/hemorrhage causing confusion in patient with decreased cerebral reserve.

Due to fluctuating course, intermittent seizures may be overlooked. - Nonconvulsive status epilepticus - Recurrent focal or generalized seizures followed by postictal confusion EEG remains essential for diagnosis and should be considered whenever etiology remains unclear. Seizure activity spreading from an electrical focus in a mass or infarct can explain global cognitive dysfunction caused by relatively small lesions.

6.7 Hospitalization and End-of-Life¶

Hospital environment itself can contribute to delirium in susceptible individuals: - Usually part of multifactorial delirium - Should be diagnosis of exclusion after thorough investigation End-of-life delirium: - Extremely common in palliative care settings - Must be identified and treated aggressively (important cause of patient and family discomfort) - These patients may also have more common etiologies (systemic infection)

7. DIAGNOSIS & EVALUATION¶

The diagnosis of delirium is clinical and made at the bedside. A careful history and physical examination are necessary, with ancillary testing guided by clinical findings.

Table 29-2: Stepwise Evaluation of a Patient with Delirium¶

Evaluation Tier	Tests/Assessments
INITIAL EVALUATION	History with special attention to medications (including OTC and herbals)
	General physical examination and neurologic examination
	Complete blood count
	Electrolyte panel including calcium, magnesium, phosphorus
	Liver function tests, including albumin
	Renal function tests

Evaluation Tier	Tests/Assessments
FIRST-TIER FURTHER EVALUATION	Systemic infection screen: urinalysis and culture, chest radiograph, blood cultures
	Electrocardiogram
	Arterial blood gas
	Serum and/or urine toxicology screen (perform earlier in young persons)
	Brain imaging with MRI with diffusion and gadolinium (preferred) or CT
	Suspected CNS infection/inflammatory disorder: lumbar puncture after brain imaging
	Suspected seizure-related etiology: EEG (if high suspicion, perform immediately)
SECOND-TIER EVALUATION	Vitamin levels: B12, folate, thiamine
	Endocrinologic laboratories: TSH, free T4, cortisol
	Serum ammonia
	Sedimentation rate
	Autoimmune serologies: ANA, complement levels, p-ANCA, c-ANCA
	Consider paraneoplastic/autoimmune encephalitis testing in serum and CSF
	Infectious serologies: RPR, fungal and viral serologies if high suspicion, HIV antibody
	Lumbar puncture (if not already performed)
	Brain MRI with and without gadolinium (if not already performed)

7.1 Screening Tools¶

Validated instruments for identifying delirium: - Confusion Assessment Method (CAM) - most widely validated - Nursing Delirium Screening Scale (NuDESC) - Organic Brain Syndrome Scale - Delirium Rating Scale - ICU-CAM (for ICU patients) - Delirium Detection Score IMPORTANT: These scales may not identify the full spectrum of delirium. All patients who are acutely confused should be presumed delirious regardless of presentation.

7.2 Confusion Assessment Method (CAM) Criteria¶

Diagnosis of delirium is made if there is: 1. Acute onset AND fluctuating course PLUS 2. Inattention PLUS either: 3. Disorganized thinking 4. Altered level of consciousness

7.3 History¶

It may be difficult to elicit accurate history from delirious patients. Information from collateral source (spouse, family member) is invaluable. Three most important elements: 1. Patient's baseline cognitive function - Can be assessed through collateral source or review of outpatient records - Validated instruments: modified Blessed Dementia Rating Scale, Clinical Dementia Rating (CDR) - Without knowledge of baseline, patients with dementia or longstanding depression may be mistaken as delirious 2. Time course of present illness - Delirium develops over hours to days - Important to correlate onset with potentially treatable etiologies (medication changes, systemic infection) 3. Current medications - Include ALL prescription, over-the-counter, and herbal substances - Note any recent changes in dosing or formulation (including generic substitutions) - Approximately one-third of all delirium cases are secondary to medications, especially in elderly Additional history elements: - Symptoms of organ failure or systemic infection - History of illicit drug use, alcoholism, or toxin exposure (especially in younger patients) - Associated symptoms (depression, anxiety) that may identify therapeutic targets

7.4 Physical Examination - General¶

Signs of infection: fever, tachypnea, pulmonary consolidation, heart murmur, meningismus
Fluid status: Both dehydration and fluid overload with hypoxemia associated with delirium
Skin examination: jaundice (hepatic encephalopathy), cyanosis (hypoxemia), needle tracks (IV drug use)

7.5 Neurologic Examination¶

Mental Status Assessment: - Level of consciousness: Ranges from hyperarousal to lethargy to coma; present in most patients with delirium - Due to fluctuating course, assessment at single time point may miss diagnosis - For patients with sundowning, assessment only during morning rounds may be falsely reassuring Attention Testing: - Can be assessed while taking history: tangential speech, fragmentary flow of ideas, inability to follow complex commands suggest attentional problem - Digit Span Forward Test: - Ask patient to repeat successively longer random strings of digits (one per second) - Healthy adults: can repeat 5-7 digits - Digit span ≤ 4: usually indicates attentional deficit (unless hearing or language barriers) - Many delirious patients: digit span ≤ 3 Formal Testing: - MMSE provides information on orientation, language, visuospatial skills - However, many MMSE tasks (spelling "world" backward, serial subtraction) are impaired by attentional deficits, rendering test unreliable in delirium Other Neurologic Findings: - Screen for new focal neurologic deficits - Signs of neurodegenerative conditions (parkinsonism - seen in Parkinson's disease, Alzheimer's, Lewy body dementia, PSP) - Multifocal myoclonus or asterixis: nonspecific but usually indicates metabolic or toxic etiology

7.6 Laboratory Evaluation¶

Basic screening tests for ALL patients with delirium: - Complete blood count - Electrolyte panel (including calcium, magnesium, phosphorus) - Liver function tests (including albumin) - Renal function tests Geriatric patients - infection screening: - Chest radiography - Urinalysis and culture - Blood cultures (consider) Younger patients: - Serum and urine drug/toxicology screening (earlier in workup) Additional testing if diagnosis unclear: - Autoimmune serologies - Endocrinologic laboratories - Metabolic testing - Infectious serologies

7.7 Imaging¶

Multiple studies demonstrate brain imaging in delirium is often unhelpful. However, if initial workup unrevealing, most clinicians move toward imaging. Noncontrast CT: - Can identify large masses and hemorrhages - Otherwise unlikely to determine etiology MRI (test of choice): - Identifies nearly all acute ischemic strokes - Provides neuroanatomic detail for infectious, inflammatory, neurodegenerative, and neoplastic conditions - Limited by: availability, speed, patient cooperation, contraindications Typical approach: Begin with CT, proceed to MRI if etiology remains elusive.

7.8 Lumbar Puncture¶

Indications: - Must be obtained immediately after neuroimaging for all patients with suspected CNS infection - Should be considered in any delirious patient with negative workup Utility: - Identifies CNS infection - Identifies autoimmune, other inflammatory, and neoplastic conditions

7.9 Electroencephalogram (EEG)¶

Remains invaluable if: - Seizures are considered - No cause readily identified Typical finding in delirium: Symmetric slowing (nonspecific, supports diffuse cerebral dysfunction) Essential for diagnosing: - Nonconvulsive status epilepticus - Recurrent seizures with postictal confusion

8. TREATMENT¶

Management of delirium begins with treatment of the underlying inciting factor. Blindly targeting symptoms pharmacologically only serves to prolong the confused state and may mask important diagnostic information.

8.1 Treat Underlying Cause¶

Primary treatment targets the underlying etiology: - Systemic infections: Appropriate antibiotics - Electrolyte disturbances: Judicious correction - Medication-induced: Remove offending agent - Metabolic derangements: Correct underlying abnormality These treatments often lead to prompt resolution of delirium.

8.2 Supportive Care Measures¶

Relatively simple methods of supportive care can be highly effective: Reorientation: - Nursing staff and family reorientation - Visible clocks and calendars - Outside-facing windows Sensory optimization: - Provide glasses and hearing aids to patients who need them - Prevent sensory isolation Sleep-Wake Cycle Management: - Daytime: Well-lit room, activities/exercises to prevent napping - Nighttime: Quiet, dark environment with limited staff interruptions - Consider melatonin before bed to promote sleep - Especially important in ICU where constant 24-hour activity commonly provokes delirium Home Environment Simulation: - Allow visits from friends and family throughout day (minimizes anxiety from constant flow of new faces) - Allow access to home bedding, clothing, and nightstand objects - Makes hospital environment less foreign and less confusing Nursing Practices: - Maintain proper nutrition - Maintain adequate volume status - Pain management - Incontinence management - Skin breakdown prevention

8.3 Prevention Strategies¶

Hospital-based Prevention Programs: - Comprehensive delirium programs screen most or all patients upon admission or before elective surgery - Positive screens trigger focused prevention measures Modifiable Risk Factor Reduction: - Avoid physical restraints - Minimize bladder catheterization - Optimize sleep environment - Minimize sensory deprivation - Careful medication management (avoid adding ≥ 3 new medications when possible) - Avoid high-risk medications (anticholinergics, benzodiazepines, narcotics)

9. SPECIAL POPULATIONS¶

9.1 ICU Patients¶

Highest rates of delirium approaching 75% in older ICU patients
Diagnosis especially problematic due to serious systemic illness and sedation
Delirium in ICU should be viewed as important manifestation of organ dysfunction (like liver, kidney, or heart failure)
Sleep-wake cycle interventions especially important as constant 24-hour activity commonly provokes delirium

9.2 Elderly Patients¶

Age >65 is one of the two most consistently identified risk factors
Higher incidence (10% to >50% of hospitalized elderly)
One-third of delirium cases secondary to medications
More susceptible to anticholinergic medication effects
Delirium often reflects insult to brain vulnerable due to underlying neurodegeneration
Development of delirium may herald previously unrecognized brain disorder
After acute episode clears, careful screening for underlying condition should occur outpatient

9.3 Patients with Baseline Cognitive Impairment¶

Baseline cognitive dysfunction is one of the two most consistently identified risk factors
At least two-thirds of delirium cases occur in patients with coexisting dementia
Lower threshold for delirium with even minor insults
Dementia with Lewy bodies patients are particularly vulnerable
Patients with Alzheimer's, Lewy body dementia, and Parkinson's dementia have cholinergic deficiency predisposing to delirium

9.4 Surgical Patients¶

Risk factors for postoperative delirium: - Cardiopulmonary bypass procedures - Inadequate or excessive treatment of postoperative pain - Inhalational anesthetics - Benzodiazepines Preoperative screening recommended in some hospital systems.

9.5 End-of-Life Patients¶

Extremely common (50-80%)
Must be identified and treated aggressively
Important cause of patient and family discomfort
May also have common etiologies (systemic infection)

10. KEY POINTS & CLINICAL PEARLS¶

10.1 Diagnostic Pearls¶

Delirium is a CLINICAL diagnosis made at the bedside - no laboratory test or imaging confirms the diagnosis
Hypoactive delirium is frequently missed - maintain high suspicion in quiet, withdrawn patients
Fluctuating course means single time point assessment may miss diagnosis
Digit span ≤ 4 (or ≤ 3) suggests significant attentional deficit
Collateral history is invaluable - cannot diagnose delirium without knowing baseline cognitive function
All acutely confused patients should be presumed delirious regardless of specific presentation

10.2 Etiologic Pearls¶

Approximately one-third of delirium cases are medication-related, especially in elderly
Always consider alcohol and benzodiazepine withdrawal, even in elderly with minimal alcohol intake
If previously healthy individual develops delirium with minor insult, suspect unrecognized underlying neurologic disease
Delirium is a "stress test for the brain" - can unmask decreased cerebral reserve
The cause is often MULTIFACTORIAL - look for multiple contributing factors

10.3 Treatment Pearls¶

TREAT THE UNDERLYING CAUSE - not just the symptoms
Blindly targeting symptoms pharmacologically prolongs confusion and may mask diagnostic information
Simple supportive measures (reorientation, sleep-wake cycles, sensory optimization) are highly effective
Prevention is key - avoid modifiable risk factors when possible

10.4 Prognostic Considerations¶

Delirium is NOT benign - mortality similar to sepsis (25-33%)
Long-term consequences: increased mortality, nursing home placement, readmissions, subsequent delirium and cognitive decline
Some episodes persist for weeks, months, or years
May cause permanent neuronal damage
After resolution, screen for underlying neurodegenerative disease