Delirium, also known as the acute confusional state, is a clinical syndrome that usually develops in 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 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 medication side effect, 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.
Delirium is a medical condition complex to understand; a single factor can cause it, however, 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.
There are two groups of risk factors related to delirium: predisposing and precipitant factors. 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 abuse 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 sedative 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 1 month later in 33% of cases.
As we can see 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).
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 a mortality increased from 10% to 36%, and a 70% increased risk of death during the first 6 months after the visit.
Patients, who develop delirium in the 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 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 for medical complications, institutionalization, functional decline and dementia; it contributes to $6.9 billion in Medicare hospital cost 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 elderly. The hypothesis is based on neuroinflammation, neurotransmitter imbalance, and chronic stress.
Patients who develop delirium have shown an elevated PCR and 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 produce 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 a 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 inhibiting the neuronal routes previously damaged by neuroinflammatory insult and increases the risk to develop 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.
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 neurotransmitter and cholinergic pathway may result in delirium.
Activates the sympathetic nervous system and de hypothalamus-hypophysis-suprarenal glands axis, which elevate 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 this receptors and delirium is not conclusive. High cortisol levels produce a reduction in GABA release and impairment in neuronal energy bombs.
Delirium can be a life-threatening emergency. Affected patients require an appropriate evaluation with history taking, physical, and neurologic examination and laboratory test.
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 known the previous mental state of the patient because it can help us to make the difference with dementia. A reliable interviewee should contribute the information.
Our approach would be a focus on the most probable diagnostic suspicion, so the laboratory test may include the necessary to confirm or exclude the precipitating factor we are thinking is the cause. As an initial step, we can consider complete blood count, arterial blood analysis, electrolytes, creatinine, blood urea nitrogen, liver-function test, and urinalysis. A 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 study if the clinician suspects sepsis of any 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:
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 we have 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.
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:
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 a 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 a 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.
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.
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 mask and hearing aids to keep an area dark and quiet at night to enhance sleep. During the day, guidelines encourage the use of eyeglasses or hearing tools to optimize hearing and vision, the use of tools to improve orientation including clocks, calendars to remind individuals where they are, early morning rise times, and adequate fluid intake. It is known these strategies are cost-effective and remain the main treatment for delirium.
Clinicians should consider the pharmacologic approach in patients with symptoms that threat its or others safety, especially in older adults. This intervention includes antipsychotics. However, it is important to note that there is no current evidence to support its use in patients without hyperactive delirium. The options include haloperidol, which is the first choice if we need a minimal sedating effect. Nevertheless, clinicians can administer quetiapine if the desired effect is the opposite. The initial dose of haloperidol, olanzapine and quetiapine are 0.25 mg, 2.5 mg, and 12.5 mg respectively. Antipsychotic doses should be optimized and adjusted every day until no longer needed.
Other medications have been proposed to prevent and decrease the incidence of delirium, for example, melatonin and its analogs, but a recent Cochrane review concludes that is no clear evidence they reduce the incidence of delirium as compared with placebo. The use of cholinesterase inhibitors also demonstrates a minimal evidence to support the decrease in delirium incidence.
Complications can be urinary incontinence, immobility or falls, pressure ulcers, sleep disturbance, and feeding disorders. To prevent them clinicians need a to provide a scheduled program for patients to mobilize, go to the toilet and get feeding assistance if needed.
Delirium is a very common disorder seen in hospitalized patients. Its diagnosis and management are very complex and best done with a multidisciplinary team that includes a neurologist, psychiatrist, internist, intensivist, and ICU nurses. 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.
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 mask and hearing aids to keep an area dark and quiet at night to enhance sleep.
Pharmacological agents are used for severe adverse behavior. The overall prognosis for patients with delirium is guarded. 
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