Delirium

Etiology

Delirium represents a state of acute cerebral dysfunction triggered when a vulnerable brain is exposed to physiologic stressors. The pathophysiology is not fully understood, and there is likely no single etiology. Multiple theories describe potential pathophysiologic causes of delirium, and any single episode likely involves one or more of these mechanisms in a complex, interconnected process. Multifactorial models describe delirium as an interaction between a vulnerable patient with predisposing factors and exposure to noxious insults or precipitating factors.[4]

There are 2 broad categories of risk factors: predisposing and precipitating. Predisposing factors reduce cognitive reserve and increase susceptibility to acute cognitive dysfunction.[5] These include advanced age (older than 70), dementia or mild cognitive impairment (often not recognized clinically), functional disabilities, male sex, poor vision and hearing, frailty, malnutrition, multimorbidity, and substance use disorders. Metabolic or laboratory abnormalities have also been associated with increased risk.[6] Structural and functional vulnerabilities can heighten susceptibility to delirium, making individuals more likely to experience cognitive breakdown even with modest physiological stressors.[7] 

Precipitating factors vary. Emerging evidence supports the roles of neuroinflammation, blood-brain barrier dysfunction, and impaired frontoparietal connectivity in reducing neural resilience to physiological stress. These mechanisms help explain why seemingly modest noxious factors can precipitate delirium in susceptible brains.[8] However, medication adverse effects account for up to 39% of delirium cases.[9] Many medications can precipitate delirium, especially psychoactive medications or anticholinergic medications.

Several resources are available to help clinicians avoid medications that can precipitate delirium. The American Geriatrics Society (AGS) has published the 2023 Updated AGS Beers Criteria for Potentially Inappropriate Medication Use in Older Adults,[10] which lists medications with potentially harmful effects for older adults, including those likely to cause delirium. A second helpful resource is the ACBcalc.com website, which reports a patient's cumulative anticholinergic burden from medications and offers alternatives with lower anticholinergic activity.[11] 

Other precipitating factors include surgery, anesthesia, hypoxia, untreated pain, infections, acute illness, and an acute exacerbation of chronic disease. If patients are highly vulnerable, such as those with advanced dementia, more minor disturbances, such as constipation, dehydration, sleep deprivation, urinary retention, or minor medical procedures, can also precipitate delirium. Delirium is usually transient but can persist in patients with predisposing factors. Results from a systematic review found that hospital delirium persisted until discharge in 45% of cases and up to 1 month in 33% of cases.[12]

Epidemiology

Delirium is common in hospitalized older adults, affecting an estimated 15% to 30% of those admitted to general medical wards, with substantially higher rates among individuals undergoing major surgery or requiring care in intensive care units.[2] Delirium is a common surgical complication among older adults, with an incidence reported at 10% to 20% after major elective surgery and up to 50% after high-risk procedures. Postoperative delirium is associated with a 7% to 10% increased risk of 30-day mortality and increases the length of hospital stay by 2 to 3 days.[13] 

Delirium in the general population increases healthcare utilization and is associated with higher complication rates and poorer outcomes. The total healthcare cost in the United States attributable to delirium is estimated at $164 billion annually. In patients presenting to the emergency department with delirium, there is a 70% increased risk of 6-month mortality, and delirium in the intensive care unit is associated with a 2- to 4-fold increase in overall mortality.[14] Persistent cognitive decline following delirium episodes has been demonstrated in extensive cohort studies.[15]

Pathophysiology

There is no single mechanism that fully accounts for the etiology of delirium, as it is a complex, multifactorial process. Several hypotheses describe different aspects of delirium's pathophysiology, and multiple mechanisms overlap, reflecting a multifactorial disruption of brain function. Recent evidence describes delirium as an acute form of brain failure, characterized by the breakdown of coordinated neural network activity in response to physiological stressors.[2]

Older Age

Age-related changes diminish physiologic reserve and increase vulnerability to physical stress and illness. Some age-related changes include decreased cerebral perfusion, increased neuronal loss, and changes in the proportions of stress-regulatory neurotransmitters. These changes lower cognitive reserve and increase susceptibility to acute cognitive dysfunction.[16]

Neuroinflammation

Peripheral inflammatory insults damage endothelial cell-cell adhesions at the blood-brain barrier. Increased endothelial permeability promotes inflammation in the central nervous system, thereby causing further damage, ischemia, and neuronal death.[4]

Reactive Oxidation Species

Reactive oxygen species and reactive nitrogen species are mediators of cellular damage. The central nervous system is particularly vulnerable to reactive oxygen species due to its high lipid content and low antioxidant capacity. Oxidative stress is increasingly recognized as a contributor to neuronal vulnerability in delirium, although it is insufficient as a standalone explanatory model.[17]

Circadian Rhythm Dysregulation

Disruption of sleep duration and architecture, and of melatonin secretion, leads to multisystem dysfunction. Melatonin affects many functions in the central nervous system, including regulation of the sleep-wake cycle, glucose metabolism, core body temperature, antioxidant defenses, and immune responses.[4]

Neurotransmitter Imbalance

Delirium is associated with decreased cholinergic activity and increased dopaminergic activity. The brain's dopaminergic and cholinergic pathways overlap, and their balance is vital to brain function.[4]

Neuroendocrine

Increased glucocorticoid release in response to physiologic stress increases neuronal vulnerability to subsequent damage and affects the regulation of gene transcription, intracellular signaling, and glial cell function.[4]

Network Dysconnectivity

Results from advanced neuroimaging and electrophysiology studies demonstrate disruptions in large-scale brain networks, particularly the frontoparietal and thalamocortical circuits, that correlate with impaired attention and fluctuating arousal. These studies support the contemporary concept of delirium as a disorder of brain connectivity rather than of isolated neurotransmitter pathways.[16]

History and Physical

Delirium is a potential indicator of a life-threatening illness, and every episode of delirium should be appropriately evaluated. The evaluation involves taking a thorough history, performing a complete physical examination, obtaining laboratory testing, and obtaining imaging when indicated. Test selection should be based on information from the history and physical examination, recognizing that delirium is often multifactorially etiologic and can be influenced by predisposing, precipitating, or both.

Delirium is often classified into 3 main clinical subtypes:

• Hyperactive delirium: Patients present with increased agitation and sympathetic activity. They can also present with hallucinations, delusions, and occasionally combative or uncooperative behavior.
• Hypoactive delirium: Patients have increased somnolence and decreased arousal. Hypoactive delirium is dangerous when unrecognized or mistaken for fatigue or depression because it is associated with higher rates of morbidity and mortality. 
• Mixed presentation: Patients can fluctuate between hyperactive and hypoactive presentations.[4]

Delirium is defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, and requires the presence of all of the following criteria: 

• A disturbance in attention and awareness that develops acutely and fluctuates in severity must be present.
• At least one additional cognitive disturbance must be present.
• The disturbances are not better explained by preexisting dementia.
• The disturbances do not occur in the context of severely reduced arousal or coma.
• There is evidence that the disturbances are caused by one or more underlying medical conditions, substance intoxication, withdrawal, or exposure to a toxin.[18]

Other features include alterations in the sleep-wake cycle, perceptual disturbances, delusions, inappropriate or unsafe behavior, and emotional lability.[19] Detection is the first step in evaluation and treatment. The syndrome of delirium presents for hours to days. Results from a recent study estimated that delirium is unrecognized in up to 60% of cases. Hyperactive delirium is much easier to detect because patients are often agitated. However, hypoactive delirium is usually missed, as patients are more withdrawn. Caregivers may provide clues to the presence of hypoactive delirium with comments such as "They are sleeping more than usual," "They haven't eaten much in the last few days," or "I am worried they are depressed; they just stay in their room all day." 

Several tools have been developed to detect delirium. One of the most widely used tools is the Confusion Assessment Method (CAM). This tool has been validated with a sensitivity of 94% to 100% and a specificity of 90% to 95% in the diagnosis of delirium, and it includes the following criteria:

The presence of delirium using the CAM requires the presence of features 1 and 2 and either 3 or 4:

1. Acute change in mental status with a fluctuating course
2. Inattention (reduced ability to sustain attention and follow conversations)
3. Disorganized thinking (problems with memory, orientation, or language)
4. Altered level of consciousness (hypervigilance, drowsiness, or stupor) 

The CAM has been adapted for target populations, including the CAM-intensive care unit (CAM-ICU), which added nonverbal tasks for ventilated individuals. Adaptations have also been made for the emergency department and for nursing home residents.[20] The 4AT is a brief (<2-minute) screening tool that performs well across acute care settings, with a sensitivity 76% and specificity of 94%, and has been validated across multiple languages.[21]

When evaluating a patient with delirium, it is essential to speak with caregivers or other people who know the patient well. Many patients with delirium have underlying dementia, and knowing the baseline functional status of a patient is critical to understanding whether acute changes have occurred. Medication changes should be reviewed carefully because drug-related causes account for up to 39% of delirium cases. Other important questions to ask during the history-taking include: Have there been any medication changes? Drug-related causes account for up to 39% of delirium cases.[22] 

Furthermore, patients and caregivers should be asked whether there are any new symptoms, such as cough, fever, headache, dysuria, pain, or changes in eating, bowel, or urinary habits; whether there is any sleep deprivation; and whether there are any changes in their environment. A history of falls may prompt the need for brain imaging or radiography to evaluate for bone fractures. A review of recent and current medications should be performed, and drugs known to precipitate and perpetuate delirium should be avoided or discontinued, including psychoactive or anticholinergic medications.

Evaluation

A complete physical examination should be performed, including cardiac, pulmonary, neurological, mental status, abdominal, musculoskeletal, and cutaneous examinations. Vital signs should also be assessed. A targeted assessment is recommended, with the physical examination findings and medical history informing the diagnostic evaluation. Excessive or prolonged evaluation can worsen agitation and perpetuate delirium symptoms, so the most probable diagnosis should be investigated first. 

As an initial step, a complete blood count, arterial blood gas analysis (if indicated), complete metabolic panel, and urinalysis are often recommended. Chest radiography, electrocardiography, and bladder scanning are also recommended. Additional testing, such as a lumbar puncture, electroencephalography, and toxicology studies, may be helpful in select cases. Blood cultures should be obtained if sepsis of an indeterminate origin is suspected. Brain imaging is not routinely required and should be reserved for specific indications.

Focal neurologic deficits (rather than anticoagulation status) are the strongest predictors of abnormal head computed tomography findings; these findings support guideline recommendations to obtain neuroimaging only when red flags are present, such as new focal signs, trauma, unexplained depressed consciousness, or suspicion of intracranial infection or hemorrhage.[23] Untreated sources of pain, including constipation, should also be assessed and addressed.[24] The diagnosis of delirium is clinical. Biomarkers for diagnosing delirium, including inflammatory markers, cortisol, interleukins, and C-reactive protein, have been studied. However, none have been validated for clinical use, including diagnosis or monitoring.[25]

Treatment / Management

The main treatments for delirium are nonpharmacologic interventions, as there are no United States Food and Drug Administration (FDA)-approved medications for its treatment or prevention. Identifying patients at risk of delirium and implementing targeted preventive measures are crucial. Nonmodifiable risk factors include an underlying neurodegenerative disorder, such as dementia, and increasing age. Modifiable factors include medications, infections, environmental factors, and reduced sensory input. 

The American Geriatrics Society has supported the Hospital Elder Life Program (HELP), which reduces the incidence of delirium in older adults. This interdisciplinary, multicomponent program includes interventions such as decreasing environmental disturbances and prioritizing uninterrupted sleep. During the day, guidelines encourage the use of eyeglasses and hearing aids to optimize hearing and vision; the use of tools to improve orientation, including clocks and calendars; early mobilization with morning wake times; and adequate fluid intake.

Frequent mobilization and reduction of tethers, such as urinary or intravenous catheters that limit mobility, are also recommended. Therapeutic activities such as music therapy are encouraged when appropriate. These strategies are cost-effective and remain the primary treatment for delirium. The HELP program reduces the rate of falls by 42% and lowers per-patient hospital costs by $1600 to $3800 (2018 values). Long-term care costs per person-year are greater than $16,000 in the year following a delirium episode.[26](A1)

While prevention and nonpharmacologic interventions are the mainstays of treatment for delirium, pharmacologic therapy may occasionally be required in limited circumstances. Patients with delirium due to substance withdrawal may need the appropriate pharmacologic therapies, such as benzodiazepines for alcohol withdrawal. Delirium at the end of life can require pharmacologic therapies to alleviate pain and agitation. There are no recommended pharmacologic treatments for hypoactive delirium. Treating the underlying cause of delirium with appropriate medications, such as antibiotics for infection, is always relevant. In the case of hyperactive delirium with behaviors presenting a risk to the patient or others, antipsychotics are the recommended first-line treatment if not contraindicated due to another comorbidity. Frequently used options include haloperidol, quetiapine, and risperidone.[18]

The agent of choice depends on the goal of minimizing adverse effects and the patient's underlying comorbidities. For example, quetiapine is preferred, and haloperidol should be avoided in patients with Parkinson disease.[27] The dose of antipsychotic medications should be optimized and adjusted daily, and discontinued as soon as clinically feasible. The QTc interval should be monitored with an electrocardiogram, as antipsychotics can cause QTc prolongation. Importantly, contemporary evidence does not support the routine use of antipsychotics to shorten delirium duration, hasten cognitive recovery, or prevent new episodes; their use should be restricted to scenarios involving severe agitation that threatens patients' safety.[28] (B2)

Many medications have been evaluated for the prevention and treatment of delirium; however, results from multiple studies have shown no clear evidence that they reduce the incidence and duration of delirium compared with placebo, possibly due to the multifactorial etiology. Melatonin is sometimes used to regulate sleep patterns and for its anti-inflammatory properties. Some studies' results have shown that melatonin can reduce the incidence of delirium; however, results from a large meta-analysis found no significant effect. Cholinesterase inhibitors have also been evaluated, but there is minimal evidence supporting their efficacy, and potential risks may outweigh their benefits.[3][18] Other agents sometimes used off-label, such as valproate, gabapentinoids, or nonbenzodiazepine sedatives, have not shown clinical benefit and may worsen cognition or mobility.[10](A1)

Differential Diagnosis

The differential diagnosis of delirium includes the following conditions:

• Dementia
• Psychosis
• Depression
• Paranoia
• Coma
• Catatonia
• Central nervous system malignancy
• Nonconvulsive status epilepticus

Prognosis

The overall prognosis for patients with delirium is guarded.

Complications

The complications that can manifest with delirium include:

• Aspiration pneumonia
• Pressure ulcers
• Weakness, decreased mobility, and functional decline
• Falls and combative behavior leading to injuries and fractures
• Malnutrition, dehydration, or fluid overload, and electrolyte abnormalities
• Long-term cognitive impairment
  • Accumulating evidence shows that delirium is not only a transient, reversible acute confusional state but also can lead to persistent long-term cognitive impairment.
• Increased mortality