The American Psychiatric Association’s Diagnostic and Statistical Manual, 5th edition, text revision (DSM-5-TR), defines delirium as:

• •Disturbance of consciousness with reduced ability to focus, sustain, or shift attention.
• •The disturbance develops over a short period of time (usually hours to days) and tends to fluctuate during the course of a day.
• •An additional disturbance in cognition (e.g., memory deficit, disorganization, language, visuospatial ability, or perception).
• •A change in cognition or development of a perceptual disturbance that is not better accounted for by a preexisting, established, or evolving dementia.
• •There is evidence from history, physical exam, or laboratory findings that the disturbance is caused by a medical condition, substance intoxication or withdrawal (i.e., due to a drug of abuse or to a medication), exposure to a toxin, or is due to multiple etiologies.

• Acute confusional state
• Toxic or metabolic encephalopathy
• ICU psychosis

• •Neuronal aging, increasing vulnerability to acute insult¹
• •Neuroinflammation, with increased permeability of the blood-brain barrier²
• •Oxidative stress
• •HPA axis dysregulation
• •Circadian rhythm dysfunction

Hyperactive, hypoactive, and mixed subtype

Nearly 30% of older patients experience delirium at some time during the hospital course. In older surgical patients, the prevalence varies from 10% to 50%. The highest incidence, estimated to be 60% to 80%³, is found in patients requiring intubation in the intensive care unit. Delirium can be subtyped by motoric functioning, with hypoactive delirium being most common, followed by mixed, and hyperactive delirium being least common. Predisposing factors for delirium among older adults hospitalized for a medical or surgical illness are summarized in Table 1. Delirium is the most common neuropsychiatric disorder in patients with medical illness. Any age, race, or gender can be affected. Predisposing factors for the development of delirium during hospitalization are summarized in Table 2. Pediatric delirium is often missed but remains important because delirium is associated with longer hospital stays, decreased cognitive performance, and increased mortality. Risk factors include extremes of age, severe pain, medication effect, states of intoxication or withdrawal, vital sign derangement leading to reduced cerebral blood flow, metabolic derangement including hypoxia/hypercarbia, poor cognitive baseline, and kidney or liver failure.^4-8

• •One of the earliest symptoms is change in level of awareness and ability to focus, sustain, or shift attention. Symptoms may differ both among patients and within one patient. Family members or caregivers report that the patient "isn’t acting quite right." Symptoms may include poor attention, sleepiness, agitation, or psychosis.
• •Acuteness of presentation helps in differentiating delirium with dementia. Change in cognition, perceptual problems (such as visual, auditory, or somatosensory hallucination usually with lack of insight), memory loss, disorientation, difficulty with speech and language are frequent findings. It is important to ascertain from family member or caregivers the patient’s level of functioning before onset of delirium.
• •Delirium is classically described as having a fluctuating or waxing and waning course. The fluctuations typically occur on the order of minutes to hours and may be subtle. For this reason, cross-sectional assessments may be less reliable, and those with longitudinal perspectives (nurses, physical therapists) may be best at detecting delirium.
• •Elderly patients with delirium often do not look sick, but patients with delirium are sick by definition.
• •Hyperactive delirium represents only 25% of cases with the others having hypoactive (quiet) delirium.
• •Physical examination should be performed, focusing on signs of infection, dehydration, or chronic disease that may be exacerbated. Vital signs are key. Consider using the Mini-Mental Status Exam or the Montreal Cognitive Assessment to assess specific deficits.
• •Fig. 1 describes a delirium protocol.
• •Table 3 summarizes delirium assessment tools.

Figure 1 Delirium protocol as a part of the ABCDEF Bundle.

(From Vincent JL et al: Textbook of critical care, ed 8, Philadelphia, 2024, Elsevier.)

Can be multifactorial; often falls into one of the following categories (Table 4):

• •Drugs: Benzodiazepines, narcotics, anticholinergics, beta-blockers, steroids, and certain antibiotics (e.g., cefepime) can cause delirium as can withdrawal states such as those from alcohol and benzodiazepines⁹
• •Infection or inflammation: states of systemic inflammation, such as associated with burns, long-bone fractures or certain surgeries like abdominal aortic aneurysm repair are highly associated with delirium; there is some evidence that premorbid use of anti-inflammatory medications such as NSAIDs is protective in this regard⁷
• •States of reduced cerebral perfusion: often seen postoperatively, accompanying cardiac arrythmias, or in sepsis/hypotension; those with history of vascular disease are most vulnerable
• •Metabolic: Hypoxia, kidney or liver failure, thyroid, adrenal, or glucose dysregulation, anemia, vitamin deficiencies such as thiamine, B12, folate, vitamin D, vitamin C
• •Fluids, electrolytes, nutrition (FEN): Dysregulation of calcium, magnesium, potassium, or sodium; dehydration; volume overload; altered pH
• •Brain disorder: Central nervous system (CNS) infection, traumatic brain injury, hypertensive encephalopathy

• •Primary psychiatric illness (including depression and anxiety in hypoactive delirium and mania and schizophrenia in hyperactive delirium)
• •Cerebrovascular accident
• •Major neurocognitive disorders (Dementia)
• •Nonconvulsive status epilepticus

Remember, delirium may coexist with any of the listed conditions. Table 5 summarizes the differential diagnosis of delirium. Table 6 describes clinical factors that help differentiate delirium and dementia from psychiatric disease. Potentially life-threatening causes of delirium are described in Table 7.

• •Complete blood count, electrolytes, liver function tests, ammonia, drug levels (digoxin, lithium)
• •Toxicology screen, urinalysis, urine culture
• •Thyroid function tests, vitamin B₁₂, vitamin D, and folate levels
• •Rapid plasma reagin for syphilis, blood, urine, and spinal fluid culture
• •Arterial blood gas
• •Lumbar puncture is mandatory when cause of delirium is not obvious

• •Consider head CT (to look for bleed, trauma, tumor, atrophy, dementia, stroke)
• •Consider brain MRI (to look for white matter disease, structural abnormalities)
• •Chest radiograph (to look for tumor, infection)

EEG showing generalized slowing in delta or theta ranges, and/or the absence of a posterior dominant rhythm >8 Hz is suggestive of delirium.¹⁰

• •The most important consideration is to keep the patient safe by using a variety of methods, including frequent reorientation.
• •A quiet, restful, simplified environment with cues to time and location such as clock or calendar is helpful, as well as consistent staff providing both personal and medical care. If possible, encourage familiar family members and friends to keep the patient company.¹¹
• •Early mobilization and minimized use of physical restraints (use of physical restraints if necessary to ensure safety).
• •Visual and hearing aids for patients with these impairments.
• •The ABCDEF bundle has been associated with reduced rates of delirium in ICU settings.

• •Reverse any treatable cause, such as volume repletion for patients with dehydration, antibiotics for urinary tract infection.
• •Manage sedation with less deliriogenic agents, avoiding benzodiazepines (except in cases of alcohol or benzodiazepine withdrawal) and opiates as able. In the critical illness, benzodiazepines used for sedation have been linked to worsened delirium. On the other hand, dexmedetomidine has been demonstrated to increase the number of days without delirium.¹² The use of opiate medications for analgesia and sedation can also contribute to the development and duration of delirium.
• •Antipsychotic agents should not be used routinely for preventing or treating delirium, as they have not reliably been shown to shorten the course of delirium. They can, however, be extremely useful for managing sequelae of delirium. Pharmacologic treatment with antipsychotic agents should be initiated in two general scenarios: when agitation in the setting of delirium endangers patients or staff, or when perceptual disturbances (e.g., hallucinations, delusions, paranoia) occur and are significantly distressing to patients. In general these agents are similarly effective and the choice among them is usually made on the basis of side effects. For example, haloperidol is the least sedating but has a risk of extrapyramidal side effects (EPS), especially when given orally or intramuscularly; quetiapine causes relatively less EPS but is highly sedating (especially if higher doses are required to treat agitation) and also causes orthostatic hypotension.^13,14 General principles of the administration of antipsychotics for the treatment of agitation or perceptual disturbance in delirium include starting with relatively lower doses, monitoring at least 30 min before giving additional doses, and minimizing polypharmacy.
• •Haloperidol can be used with caution to control agitation, with starting doses ranging from 0.25 to 5 mg orally/intramuscularly/intravenously (PO/IM/IV). IV haloperidol has a wide dose range. Lower doses are recommended for older patients, at least initially. Although head-to-head studies have not been completed comparing PO/IM/IV formulations of haloperidol with regard to EPS, placebo-controlled studies have consistently shown little EPS with IV haloperidol.¹⁵
• •Olanzapine is more sedating than haloperidol and may similarly be used to control agitation at doses ranging from 2.5 to 5 mg orally/intramuscularly/intravenously (PO/IM/IV). There is also a sublingual formulation of olanzapine, which still requires enteric absorption and first-pass hepatic metabolism. Olanzapine has a relatively lower risk of EPS. Coadministration of IV/IM olanzapine and IV/IM benzodiazepines is strictly contraindicated due to risk of respiratory depression and death. This is the most concerning in patients with pre-existing risk of oversedation such as related to substance use. The maximum dose of olanzapine in a 24-hr period is 30 mg.
• •Chlorpromazine is the most sedating antipsychotic medication, due to ant-histamine and anti-α1-adrenergic effects. It also often precipitates orthostatic hypotension and tachycardia for this reason, and carries risk of EPS. It is used in doses ranging from 12.5 to 50 mg orally/intramuscularly/intravenously. The intravenous formulation needs to be administered over 30 to 45 min, so it is not an optimal agent for acute agitation in delirium. Repeated use of intramuscular chlorpromazine may cause sterile abscess.
• •Quetiapine is an antipsychotic frequently used in delirium due to its sedating properties and relatively lower risk of EPS. Quetiapine is only available orally, in starting doses of 12.5 to 50 mg. Given its relatively stronger anticholinergic properties, quetiapine may precipitate side effects including urinary retention and dry mouth, but it carries a low risk of EPS.
• •Most antipsychotics can prolong the QT interval and increase the risk of torsades de pointes, though the risk is modest with most agents. Ten placebo-controlled trials of low-dose (20 mg) IV haloperidol demonstrated no QTc prolongation despite its reputation. Of all agents commonly used for delirium, ziprasidone is the most likely to prolong the QT interval. Most other antipsychotics, including IV haloperidol, do not separate out from one another with regards to risk. In the hospital setting, it is common to monitor ECG daily while using antipsychotics and essential to replete electrolytes to potassium above 4 mmol/L and magnesium above 2 mmol/L.
• •Valproic acid 250 mg twice to three times daily (off-label use, non-FDA approved) can be used in cases of hyperactive delirium, with monitoring of liver function tests, serum ammonia, and platelet count.

While delirium is not a chronic condition, it may persist for weeks or months. This is more likely in patients with an impoverished neurologic substrate and those for whom their underlying insult causing the delirium is slow to resolve.

Requires frequent monitoring often necessitating hospital level of care to ensure safety and assess cause. Delirium is an independent risk factor for the development of cognitive decline and dementia, and some patients may not recover to their previous cognitive baseline as dementia emerges.¹⁶ This may require a higher level of care even in the sub-acute setting, such as rehab or skilled nursing care.

Consider neurologic or psychiatric consultation if not improved in several days or in complicated cases.

• •Although benzodiazepines are frequently used in hospitalized patients for sedation and are the mainstay of therapy for alcohol withdrawal, they must be used with caution in the elderly because of the high risk of provoking delirium.
• •The use of atypical antipsychotics in managing patients with postoperative delirium has increased over the past decade due to the perception that they are less harmful than haloperidol; however, research does not show any major difference in in-hospital adverse events between atypical antipsychotics and haloperidol.¹⁷

• •Avoid polypharmacy as much as possible.
• •Optimize chronic medical conditions.
• •Provide frequent reorientation and a soothing environment for high-risk patients (e.g., lights on during the day, off at night; open curtains during the day so patient can see the weather).
• •In patients over 70 without dementia, regular exercise has been associated with lower risk for developing delirium, and early return to physical activity can improve outcomes in ill patients.

Inform about the above preventive techniques, especially polypharmacy risks.

• Delirium Tremens (Related Key Topic)