Delirium

Etiology

Delirium is a manifestation of stress on the function of the central nervous system in a vulnerable patient. The pathophysiology is not fully understood, and there is likely no single etiology. Multiple theories describe the potential pathophysiologic causes of delirium, and any single case of delirium probably involves one or more of these theories in a complex and interconnected process. Multifactorial models have been accepted, describing delirium as an interaction of a vulnerable patient with predisposing factors exposed to noxious insults or precipitant factors.[3]

There are 2 risk factors related to delirium: predisposing and precipitant factors. The most common predisposing factors are older age (older than 70 years), dementia (often not recognized clinically), functional disabilities, male gender, poor vision and hearing, and mild cognitive impairment. Alcohol use disorder and laboratory abnormalities have also been associated with an increased risk.[4] Precipitating factors vary. However, medication side effects account for up to 39% of delirium cases.[5] Many medications can precipitate delirium, especially psychoactive medications or anticholinergic drugs. Helpful references have been developed to aid healthcare providers in avoiding drugs that can precipitate delirium. The American Geriatric Society has published the "2019 Updated AGS Beers Criteria for Potentially Inappropriate Medication Use in Older Adults".[6] It is a list of medications with potentially harmful side effects for the elderly population, including those likely to cause delirium. A second helpful resource is the website "ACBcalc.com." This website reports the cumulative anticholinergic burden of a patient's medications and offers alternatives with lower anticholinergic activity.[7] 

Other precipitating factors include surgery, anesthesia, hypoxia, untreated pain, infections, acute illness, and an acute exacerbation of chronic illness. If the patient is highly vulnerable, possibly a patient with advanced dementia, smaller disturbances such as constipation, dehydration, sleep deprivation, urinary retention, or minor medical procedures can also precipitate delirium. The nature of delirium is transient but can persist in patients with predisposing factors. A systematic review showed that hospital delirium persisted until discharge in 45% of cases and persisted one month later in 33% of cases.[8]

Epidemiology

The prevalence of delirium is higher in the elderly population. It is a common surgical complication among older adults, with an incidence reported up to 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 hospital stay by 2 to 3 days.[9] Delirium in the general population increases healthcare utilization and is associated with increased complications and poor outcomes. The total healthcare cost 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 death at six months, and delirium in the ICU is associated with a 2 to 4-fold increased risk of overall mortality.[10] 

Pathophysiology

There is no single mechanism to explain the etiology of delirium. It is a complicated and multifactorial process. Several hypotheses describe different aspects of the pathophysiology of delirium, and multiple processes are likely to occur simultaneously to create the delirium syndrome. 

Increased Age

Changes associated with age lead to diminished physiologic reserve and increased vulnerability to physical stress and illness. Some changes associated with age include decreased brain blood perfusion, increased neuron loss, and changes in the proportion of stress-regulating neurotransmitters. 

Neuroinflammation

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

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. 

Circadian Rhythm Dysregulation

Disruption in sleep duration and architecture and melatonin secretion leads to dysfunction of many systems. Melatonin affects many functions in the central nervous system, including regulation of sleep-wake cycles, glucose regulation, core body temperature, antioxidant defenses, and immune system response.

Neurotransmitter Imbalance

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

Neuroendocrine

Increased glucocorticoid release in response to physiologic stress increases the vulnerability of neurons to subsequent damage and impacts the regulation of gene transcription, cellular signaling, and glial cell behavior.[3]

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, a complete physical exam, laboratory tests, and possible imaging. The test selections should be based on information obtained from the history and physical examination, considering that delirium is often multifactorial in etiology and can be influenced by several predisposing factors, precipitating factors, or both.

Delirium is often referred to in 3 main manifestations. 

1) Hyperactive Delirium: Patients present with increased agitation and sympathetic activity. They can present with hallucinations, delusions, and occasionally combative or uncooperative behavior.

2) Hypoactive Delirium: Patients have increased somnolence and decreased arousal. Hypoactive delirium is dangerous as it is often unrecognized or mistaken for fatigue or depression. It is associated with higher rates of morbidity and mortality. 

3) Mixed Presentation: Patients can fluctuate between Hyperactive and Hypoactive presentations.[3]

Delirium is defined by the DSM-5 (Diagnostic and Statistical Manual of Mental Disorders Fifth Edition) and includes the presence of all of the following criteria: 

• Disturbance in attention and awareness develops acutely and tends to fluctuate in severity.
• At least one additional disturbance in cognition
• Disturbances are not better explained by preexisting dementia.
• Disturbances do not occur in the context of a severely reduced level of arousal or coma.
• Evidence of an underlying organic cause or causes.[11]

Other features include alterations in the sleep-wake cycle, perceptual disturbances, delusions, inappropriate or unsafe behavior, and emotional lability.[12] Detection is the first step in evaluation and treatment. The syndrome of delirium presents over hours to days. A recent study estimated that delirium is unrecognized in up to 60% of cases. It is much easier to detect hyperactive delirium because patients often cause a disturbance in their environment. However, hypoactive delirium is often missed as patients are less disruptive. 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'm worried they are depressed; they just stay in their room all day." Several tools have been developed in a monitored setting to help detect delirium. One of the tools with the most widespread use is the Confusion Assessment Method (CAM). It has been validated with a sensitivity of 94% to 100% and specificity of 90% to 95% in the diagnosis of delirium, and it includes the following criteria:

The presence of delirium requires 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-ICU, which added nonverbal tasks for ventilated patients. Adaptations have also been made for the emergency department and those residing in nursing homes.[13] When evaluating a patient with delirium, it is important 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. Other important questions to ask while taking the history include: Have there been any medication changes? Drug-related causes account for up to 39% of delirium cases.[14] Have there been any new symptoms such as cough, fever, headache, dysuria, expressions of pain, or change in eating or bowel and urinary habits? Has there been any sleep deprivation or changes to their environment? Have there been any falls? This may prompt the need for brain imaging. It may also suggest the need for X-rays to evaluate for bone fractures. It is also imperative to carefully review recent and current medications. If possible, avoid drugs known to precipitate and perpetuate delirium, including psychoactive or anticholinergic medications. 

Evaluation

A head-to-toe physical examination should be performed, including, but not limited to, cardiac, pulmonary, neurological, mental status, abdominal, musculoskeletal, and skin exams. Vital signs should be evaluated. It is advised to take a targeted approach in the assessment, letting the physical exam findings and medical history inform the type of evaluation performed. Subjecting a delirious patient to medical evaluations can be stress-inducing and perpetuate delirium. It is advised to focus on the most probable diagnostic suspicions first. As an initial step, a complete blood count, arterial blood analysis (if appropriate), complete metabolic panel, and urinalysis are often recommended. Chest radiography, electrocardiography, and bladder scan are also recommended. Additional tests such as a lumbar puncture, electroencephalography, and toxicology studies are useful in select cases. Blood cultures should be taken if the clinician suspects sepsis of an indeterminate origin. Brain imaging may be indicated in select cases but is not routinely required. It is also recommended to evaluate for untreated sources of pain, including constipation.[15] The diagnosis of delirium is clinically based. Studies have been looking for biomarkers to help diagnose delirium, including inflammatory markers, cortisol, interleukins, and C-reactive protein. However, none have been validated for clinical application, such as diagnosis or monitoring.[16]

Treatment / Management

The main treatments for delirium are based on non-pharmacologic interventions, as there are no FDA-approved medications for the treatment or prevention of delirium. Preventing delirium from occurring is the most efficacious intervention. Identifying patients at risk for delirium and taking special precautions to prevent delirium is crucial. Non-modifiable risk factors include a history of 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 has been shown to reduce the incidence of delirium in elderly patients. This is an interdisciplinary program with many components. Interventions include decreasing environmental disturbances and prioritizing uninterrupted sleep. During the day, guidelines encourage the use of eyeglasses or hearing aids to optimize hearing and vision, the use of tools to improve orientation, including clocks and calendars to remind individuals where they are, early morning rise times, and adequate fluid intake. It supports frequent mobilization and reduction in tethers, such as urinary catheters or IV lines that limit mobility. Therapeutic activities such as music therapy are encouraged when appropriate. It is known these strategies are cost-effective and remain the primary treatment for delirium. The HELP program has also been shown to reduce the rate of falls by 42% and reduce hospital costs per patient by $1600 to $3800 (2018 U.S. dollars) and over $16,000 (2018 U.S. dollars) per person-year of long-term care costs in the year following a delirium episode.[17](A1)

While prevention and nonpharmacologic interventions are the mainstays of treatment for delirium, it may occasionally be necessary to utilize pharmacologic therapies, which are only considered appropriate in limited circumstances. Patients suffering from delirium due to substance withdrawal may need the appropriate pharmacologic treatments, for example, using benzodiazepines to treat alcohol withdrawal. Delirium at the end of life can require pharmacologic therapies to alleviate the patient's pain and suffering. There are no recommended pharmacologic treatments for hypoactive delirium. A patient with hyperactive delirium whose behavior is a threat to themselves or others may need pharmacologic treatment. Treating the underlying cause of delirium with necessary medications, such as antibiotics, in the instance of infection is always appropriate. 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.[11]

The agent of choice depends on mitigating side effects and the patient's underlying comorbidities. For example, quetiapine would be preferred, and haloperidol would be avoided in patients with Parkinsons disease.[18] The dose of antipsychotic medications should be optimized and adjusted every day until no longer needed. It is essential to monitor a patient's QTc interval with an electrocardiogram, as antipsychotics can cause QTc prolongation. Many medications have been evaluated for the prevention and treatment of delirium; however, multiple studies have shown no clear evidence that they reduce the incidence of delirium compared with placebo, possibly due to the multifactorial etiology of delirium. Melatonin is sometimes used for the desired benefit of regulating sleep patterns and its anti-inflammatory properties. Some studies have shown that melatonin can be used to decrease the incidence of delirium; however, another large meta-analysis has shown that it has no significant effect. Cholinesterase inhibitors have also been evaluated, but there is minimal evidence to support their efficacy, and potential risks may outweigh the benefits of their use.[2][11](A1)

Differential Diagnosis

The differential diagnosis for delirium include the following:

• 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 are as follows:

• Aspiration pneumonia
• Pressure ulcers
• Weakness, decreased mobility, and decreased function
• Falls and combative behavior leading to injuries and fractures
• Malnutrition, fluid, and electrolyte abnormalities
• Long-term cognitive impairment: Accumulating evidence shows that delirium is not only a transient, reversible acute confusion but also can give rise to persistent long-term cognitive impairment
• Increased mortality