Delirium, also known as the acute confusional state, is a clinical syndrome that usually develops in the elderly. It is characterized by an alteration of consciousness and cognition with reduced ability to focus, sustain, or shift attention. It develops over a short period and fluctuates during the day. The clinical presentation can vary, but usually, it flourishes with psychomotor behavioral disturbances such as hyperactivity or hypoactivity with increased sympathetic activity and impairment in sleep duration and architecture. It is caused by a medical condition, substance intoxication, or withdrawal in addition to the medication side effects, as well as; it is no better explained by another preexisting, involving, or established neurocognitive disorder. The diagnosis is often missed, especially in hypoactive type because of the poor clinical manifestation. Efforts should focus on prevention and early diagnosis.[1][2][3]


Delirium is a medical condition complex to understand; a single factor can cause it; however, it is not the common course. The multifactorial model has been accepted as an interaction of a vulnerable patient with predisposing factors, exposed to noxious insults or precipitant factors.[4][5][6]

There are two groups of 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 been associated with an increased risk.

Precipitating factors usually vary among the population. However, drugs are the most important factor. There are many drugs related to delirium, especially sedative-hypnotic agents and anticholinergic, but opioid analgesics (especially meperidine), nonbenzodiazepines, sedatives, hypnotics, antihistamines (especially first generation), alcohol, anticholinergics, anticonvulsants, tricyclic antidepressants, histamine H2-receptor blockers, antiparkinsonian agents, antipsychotics (especially low-potency typical antipsychotics), barbiturates, digoxin, and antibiotics have been reported as well. The risk increases as high as four and a half times if the patient consumes three or more drugs (polypharmacy), and the medication is psychoactive.

Among other precipitating factors are surgery, anesthesia, high pain levels, anemia, infections, acute illness, and acute exacerbation of chronic illness.

The nature of delirium is transient, but it can persist in patients with predisposing factors. A systematic review showed that hospital delirium persisted at hospital discharge in 45% of cases, and one month later in 33% of cases.

As can be seen, the etiology is not fully understood, and many variables contribute to its development. It is important to identify if the patient started to take any medication related to delirium before the onset of symptoms, if it is the case, always attribute the acute event to the drug and discontinue it.


The prevalence of delirium is higher in the elderly population; in fact, it is the most common surgical complication among older adults with an incidence reported up to 15% to 25% after major elective surgery and 50% after high-risk procedures (hip-fracture repair or cardiac surgery).[7][8]

One-third of general medical patients who are 70 years of age or older have delirium. The condition is present in half of these patients on admission and develops during hospitalization in the other half. Usually, this condition drives the patient to an emergency department, where delirium presents in 10% to 24%. Mortality is strongly related to an accurate diagnosis. A misdiagnosis can translate into mortality that varies from 10% to 36%, and there is a 70% increased risk of death during the first six months after the visit.

Patients, who develop delirium in intensive care until (ICU), have a two to four-fold increased risk of death out of the hospital, and those on general medical or geriatric wards have one and a half times increased the risk for death in the year following hospitalization. It is important to notice that at the end of life, this setting approaches 85% in palliative care.

Delirium increases the risk of medical complications, institutionalization, functional decline, and dementia; it contributes to $6.9 billion in Medicare hospital costs annually.


The isolated mechanism to explain delirium remains poorly understood. The multifactorial theory tries to elucidate the cause. The increase in blood-brain barrier permeability secondary to cytokines release and the direct neurotoxic effect of drugs can explain the prevalence among the elderly. The hypothesis is based on neuroinflammation, neurotransmitter imbalance, and chronic stress.


Patients who develop delirium have shown elevated cortisol, although IL-8 is prevalent among patients in and out of ICU. The cytokines activate the endothelium and the coagulation cascade, which predisposes to microvascular thrombosis and blood flow dysfunction. The neuroinflammation leads to infiltrate cytokines and leukocytes to the hematoencephalic barrier and then in the central nervous system in which produces ischemia and neuronal apoptosis. The neuroinflammation activates the microglia. However, the exaggerated response to stimuli includes molecule expression and adhesion, cytokines production (IL-1B, TNF-a, ILGF-1) and metalloproteinases, reactive oxygen species secretion, and increment of nitrous oxide synthase. This reaction generates neural lesion, neural apoptotic loss, and continuous microglia proinflammatory activation. It damages the hippocampus and produces cognition disability because of the synaptic plasticity impairment.

The positive regulation of GABAa receptors is mediated by inflammation, which triggers the inhibitory brain tone and reduces the brain synaptic connections. The administration of GABA-mediated drugs contributes to inhibiting the neuronal routes previously damaged by neuroinflammatory insult and increases the risk of developing acute brain dysfunction.

Cholinergic Deficiency Hypothesis

Acetylcholine is a very important neurotransmitter in attention and consciousness. It is known, acetylcholine acts as a modulator in sensory and cognitive input so, an impairment in the route leads to develop symptoms of hypoactive or hyperactive delirium, including inattention, disorganized thinking, and perceptual disturbances. Cholinergic pathways project from basal forebrain and pontomesencephalon to interneurons in the striatum and finally targets throughout the cortex.

Neurotransmitter Imbalance

The dopamine excess contributes to hyperactive delirium and is related to decreased acetylcholine. The dopaminergic and cholinergic pathways overlap in the brain. This explains why dopamine receptors impact acetylcholine levels and explain the clinical manifestations of delirium, including hyperactive and hypoactive forms. The imbalance between neurotransmitters and the cholinergic pathway may result in delirium.

Chronic Stress

Chronic stress activates the sympathetic nervous system and the hypothalamus-hypophysis-suprarenal glands axis, which elevates the cytokines levels and results in chronic hypercortisolism that can cause an alteration in the hippocampus function. Cortisol is the main hormone in response to stress and has deleterious effects among 5HT 1A receptors. The association between these receptors and delirium is not conclusive. High cortisol levels produce a reduction in GABA release and impairment in neuronal energy bombs.

History and Physical

Delirium can be a life-threatening emergency. Affected patients require an appropriate evaluation with history taking, physical, and neurologic examination and laboratory tests.

Physical examination should evaluate head-to-toe and vital signs to determinate any possible cause. Neurologic examination should focus on evaluating new focal findings that suggest an intracranial cause, for example, a stroke.

It is important to know the previous mental state of the patient because it can help us to make a difference with dementia. A reliable interviewee should contribute the information.

Our approach would be a focus on the most probable diagnostic suspicion so that the laboratory test may confirm or exclude the precipitating factor as a possible cause. As an initial step, we can consider complete blood count, arterial blood analysis, electrolytes, creatinine, blood urea nitrogen, liver function test, and urinalysis. Chest radiography and electrocardiography should be done in any hospitalized patient. Additional tests like a lumbar puncture, electroencephalography, and toxicology studies are useful in select cases. Cultures should be taken for the study if the clinician suspects sepsis of an indeterminate origin.

The test selection should be based on information obtained from the history and physical examination, keeping in mind that delirium is often multifactorial in etiology and can be influenced by a number of predisposing factors, precipitating factors, or both.

There are three types of delirium: hyperactive, which represents 25% of cases, hypoactive, and mixed level of activity. The hypoactive form is associated with higher rates of complications and morality because of its fluctuating nature and challenging diagnosis.

The DSM-5 defines delirium as the presence of all the following criteria:

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

Other features include alterations in the sleep-wake cycle, perceptual disturbances, delusions, inappropriate or unsafe behavior, and emotional lability.


Only 12% to 35% of delirium cases are recognized. The first thing one has to do is determinate the patient baseline mental status and the acuity of the symptom presentation, delirium presents over hours to days. This step requires a knowledgeable informant to obtaining the history. Although, it is necessary for the diagnosis to know if the disturbance in mental status started alone or with other symptoms as dyspnea or dysuria or with medication changes.[9][10][11]

The Confusion Assessment Method (CAM) is recognized as the most useful assessment tool, as a result of its high sensitivity of 94% to 100% and specificity of 90% to 95% to diagnosis 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)

Brief CAM-based instruments show better sensitivity. These include CAM-ICU, bCAM (emergency department patients), the 3-minute Diagnostic Interview for Delirium using CAM (3D-CAM) for general medical patients. Although, the CAM-S (severity scale) has high predictive validity for important clinical outcomes related to delirium as the length of stay, hospital costs, nursing home, and death at 30 and 90 days.

Interview-based methods need to be applied multiple times a day to obtain better sensitivity and specificity.

There are recent studies that try to find a biomarker to diagnosis delirium, including inflammatory markers, interleukins, and C-reactive protein. However, none have been yet validated for clinical application, such as diagnosis or monitoring.

Sometimes a CT scan of the head is done to ensure that there is no CNS pathology.

EEG will typically show slowing of the posterior dominant rhythm and an increase in generalized slow activity.

A lumbar puncture should be done to rule out a CNS infection.

Differential Diagnosis






  • 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.

Deterrence and Patient Education

To reduce delirium:

  • Promote sleep hygiene
  • Mobilize patient early
  • Make sure the patient has a hearing aid and glasses
  • Manage pain adequately
  • Maintain good hydration and nutrition
  • Monitor bowel and bladder function
  • Try to detect delirium early
  • Optimize the environment
  • Avoid any type of stress
  • Communicate with the patient
  • Refer to a specialist ASAP

Enhancing Healthcare Team Outcomes

Delirium is a very common disorder seen in hospitalized patients. Its diagnosis and management are very complex and best done with an interprofessional team that includes a neurologist, psychiatrist, internist, intensivist, and ICU nurses. Nurses are often the first to detect the presence of delirium and should communicate ASAP with the team; because the sooner the condition is managed, the better the outcomes. At the same time, the nurses should maintain a quiet environment for the patient, ensure patient safety, and communicate with the patient and family.

The pharmacist should ensure that the patient is on no medication that causes CNS stimulation. The nurses should continue to promote good sleep, ensure the patient has no pain, and is optimally hydrated.

The main treatment for delirium is based on non-pharmacologic interventions because there are no medications FDA-approved. The modifiable factors as medication, infection, environmental factors, and reduced sensory input are the cornerstone of the management.[15][16][17]

The Hospital Elder Life Program (HELP) reduced the incidence in elderly patients. These interventions include the decrease of environmental disturbances, including the use of sleep masks and hearing aids to keep an area dark and quiet at night to enhance sleep, which nursing and other ancillary staff can work to ensure are in place, in coordination with the treating clinician.

Pharmacological agents are used for severe adverse behavior. There should be open communication between the members of the interprofessional team to ensure that the patient is receiving goal-directed treatment. [Level 5]


The overall prognosis for patients with delirium is guarded. [10]

Article Details

Article Editor:

Manju Paul


11/18/2020 6:14:26 PM

PubMed Link:




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