Delirium and Dementia

Background

Delirium is an acute or subacute state of cognitive dysfunction caused by an underlying physiologic condition. Several key features are necessary for a diagnosis of delirium ( Box 90.1 ). The hallmark finding in delirium is the disturbance in attention and awareness, manifested as an inability to focus attention and reduced orientation to the environment. Patients with delirium may show changes in several other cognitive domains including memory, language, and perception. Arousal and awareness may be normal or impaired. These disturbances tend to develop during a short time (hours to days), but in certain cases they may last weeks to months despite treatment of the underlying cause. Symptoms often have a fluctuating course over time, in distinction to the progressive changes of dementia. Deficiencies in attention may be manifested by reduced maintenance of attention, increased distractibility, or reductions in task processing speed. Memory impairments can manifest as reduced recall of recent information or repeating oneself in conversation. Either expressive or receptive language may be affected. Perceptual disturbances include hallucinations and delusions. The extent of cognitive derangement may range from mildly disturbed to grossly disorganized. The patient’s sleep-wake cycle may be altered or reversed; agitation often is present during the night. The level of psychomotor activity in delirium can be specified as hyperactive, hypoactive, or a mixed level of activity. Hyperactive individuals demonstrate emotional lability, agitation, and may refuse care; hypoactive individuals demonstrate sluggishness and lethargy; the mixed type describes either a normal level of psychomotor activity but with disturbance of attention and awareness, or individuals having fluctuations in activity levels. Although hyperactive delirium is the most easily recognizable presentation, hypoactive delirium is the most common form and carries the highest risk of mortality.

Delirium occurs frequently, particularly in older ED patients, and it is associated with increased morbidity and mortality, particularly when unrecognized. Predisposing factors for delirium include comorbid illness, dementia, older age, male gender, medications, neurologic deficits, and psychiatric illness ( Table 90.1 ). Drug intoxication and withdrawal (including ethanol) are the most common cause of delirium in the younger adult population. Within the older population, medication side effects are another common cause of delirium; drugs with anticholinergic properties are often implicated but many drug classes can act as a precipitant. Environmental exposures (e.g., heavy metals, insecticides, cyanide, carbon monoxide), herbal medications, and ingestion of psychoactive botanicals (e.g., nutmeg, foxglove, jimsonweed, psilocybin-containing mushrooms) are yet other causes of delirium to consider.

Delirium can be a prominent feature of any CNS or systemic infection, particularly in the very young, older patients, and immunocompromised patients. Many metabolic disorders put patients at risk for delirium, with hypoglycemia and hypoxia being the most common. Delirium is common in patients with strokes, but isolated delirium without other neurologic abnormality is not a common stroke presentation. CNS vasculitis and paraneoplastic syndromes are additional considerations.

Pathophysiology

At a cellular level, delirium is the result of a widespread alteration in cerebral metabolic activity, with secondary deregulation of neurotransmitter synthesis and metabolism. Both the cerebral cortex and the subcortical structures are affected, producing changes in arousal, alertness, attention, information processing, and the normal sleep-wake cycle.

Although the exact pathophysiologic process is not well understood, multiple neurotransmitters have been implicated in causing delirium. ^, Given the phenotypic heterogeneity of delirium, it is likely that a number of various neurophysiologic mechanisms underlie the clinical presentation in different patients. Delirium has classically been associated with a derangement of central cholinergic transmission. Cholinergic deficiency is most pronounced in patients experiencing delirium secondary to anticholinergic drugs. Increased glutamatergic activity and neuroinflammation are seen in hepatic encephalopathy, uremic encephalopathy, sepsis, and alcohol withdrawal. Some of the disturbances that occur in delirium are deficiencies of substrates for oxidative metabolism (e.g., glucose, oxygen); GABA-ergic deficit; imbalance of normal noradrenergic, serotoninergic, dopaminergic, and cholinergic tone; and disturbance of the neuroendocrine axis.

Drugs and exogenous toxins can produce delirium through direct effects on the CNS. Although the limbic system appears to be particularly vulnerable to the effects of drugs, the cerebral hemispheres and the brainstem also can be profoundly affected. Tricyclic antidepressants can cause delirium by cholinergic inhibition; sedative-hypnotics depress activity in the CNS, especially in the limbic system, thalamus, and hypothalamus. Narcotics affect CNS activity primarily by interacting with various opioid receptor sites. Psychedelic drugs may act via agonism at serotonin receptor sites. Phencyclidine (PCP) antagonizes the NMDA receptor and inhibits dopamine reuptake.

Hyperthermia and hypothermia can cause delirium due to changes in the cerebral metabolic rate. Patients suffering from heatstroke may have cerebral edema and degenerative neuronal changes leading to the development of oxidative stress and neuroinflammation. Normalizing the core temperature can reverse these changes. Delirium occurring at temperatures below 40°C is not usually caused solely by increased core temperature, and infection should be considered in cases not meeting the criteria for heatstroke.

Delirium caused by metabolic abnormalities, such as hyponatremia, hypernatremia, hyperosmolarity, hypercapnia, and hyperglycemic disorders, is associated with a variety of metabolic disturbances at the cellular level. Such disturbances may include impairments in energy supplies, changes in resting membrane potentials, in cellular morphology, and in the brain water volume.

Most patients with delirium have reduced cerebral metabolic activity. This reduction in cerebral metabolism is reflected by a slowing of background electrical activity on the electroencephalogram (EEG). Exceptions are hyperthermia, sedative-hypnotic withdrawal, delirium tremens, and certain drug-induced states, in which the cerebral metabolism is either normal or increased. In addition, patients experiencing delirium due to a postictal state or to nonconvulsive status epilepticus can show abnormal epileptiform discharges.

Clinical Features

Delirium can present as the first manifestation of underlying disease. The natural history of a patient’s delirium can progress from apathy to marked agitation over hours (see Box 90.1 ). Nonspecific prodromal symptoms such as anxiety, restlessness, and insomnia may emerge in the hours to days before diagnosis.

Key aspects of cognitive impairment should become evident during a careful history and physical examination. Disturbance in attention is central to the diagnosis of delirium. The patient can be easily distractible or have difficulty remaining focused on a particular topic or interacting with a single person. Disorientation often accompanies the inattention but is not an invariable feature. The patient usually is disoriented with respect to time and occasionally to place; in extreme cases, disorientation to person also may be noted. Delirium, however, may be present in a patient who is completely oriented to person, place, and time. A mental status examination that consists solely of questions that assess orientation will not detect delirium in these instances.

The patient with delirium frequently has some degree of memory impairment, with the greatest impact on short-term memory. Thought processes and speech may be disorganized in patients with previously normal cognition. Disturbance in the sleep-wake cycle often occurs early in the course of delirium. Perceptual disturbances, including poorly formed delusions and hallucinations, are common. Delusions may involve a perception of harmful intent of others. Hallucinations are classically visual, but can also be auditory, tactile, gustatory, or olfactory. In addition, the delirious patient has a reduced capacity to modulate fine emotional expression and may demonstrate extreme emotional lability.

The cognitively impaired patient may provide an unreliable history. Valuable information often can be obtained from family, friends, in-home medical care providers, and paramedics. The baseline premorbid mental condition of the patient in relation to the current presentation should be established early in the examination. Specific inquiry should be made about the patient’s current medical problems and previous medical history, including diabetes, hypertension, kidney or liver disease, immune status, and any neurologic or psychiatric problems. A detailed medication history, including the use of prescribed and over-the-counter medications, dietary supplements, and alcohol or other substances, is essential. Information about the home environment, medication bottles belonging to the patient or found near the patient, and the possibility of trauma can help clarify the underlying condition leading to the delirium.

The physical examination should begin with a careful assessment of vital signs. The delirious patient often exhibits autonomic nervous system abnormalities, including elevated or decreased pulse rate, blood pressure, respiratory rate, and temperature. The examination also includes assessment of the head for signs of trauma and the pupils for size, symmetry, and light reflex; evaluation of the neck for nuchal rigidity, bruits, and thyroid enlargement; assessment of the heart and lungs; evaluation of the abdomen for organomegaly and ascites; and examination of the extremities for cyanosis. The skin should be carefully examined for rashes, petechiae, ecchymosis, splinter hemorrhages, and needle tracks.

The neurologic examination includes assessment of the cranial nerves, motor strength, sensation, reflexes, and presence of abnormal movements (e.g., ophthalmoplegia, tremor, asterixis, myoclonus). The reflexes are assessed for symmetry and presence of hyperreflexia or hyporeflexia. Signs that suggest either a metabolic or a structural neurologic problem are helpful but can be nonspecific. For example, asterixis is a hallmark of hepatic encephalopathy but can also be seen in uremia and hypercapnia. Likewise, focal neurologic signs typically associated with structural CNS lesions also can be present in metabolic abnormalities such as hypoglycemia, hyperglycemia, hepatic encephalopathy, uremia, and hypercalcemia. A specific constellation of physical and neurologic findings may suggest a diagnosis. One such example is the classic triad of Wernicke encephalopathy: ophthalmoplegia, ataxia, and confusion. Other examples would include the classic toxidromes found in the presence of sympathomimetic, anticholinergic, sedative/hypnotic, and opioid medications.

Standardized screening tools can facilitate recognizing delirium and avoid missing the diagnosis. Similar to the diagnostic algorithm in other conditions, a fast, sensitive screen may first be applied before proceeding with a longer, more specific test. The most recent guidelines for geriatric emergency care recommend the Delirium Triage Screen (DTS) followed by the brief Confusion Assessment Method (bCAM). The DTS can be performed in less than one minute and is 98% sensitive for delirium. The bCAM, a modification of the full Confusion Assessment Method (CAM) often used during inpatient evaluations, is 84% sensitive and 96% specific for delirium in older emergency department patients. The bCAM uses four key features in screening for delirium: (1) acute onset and fluctuating course, (2) inattention, (3) disorganized thinking, and (4) altered level of consciousness. For a definitive diagnosis of delirium, the first two features, and one of the last two, must be present ( Table 90.2 ).

In addition to the above recommended tools, there are several other delirium assessments in clinical use, but these instruments lack similar acceptance and utility within the ED setting. The Richmond Agitation-Sedation Scale (RASS) can be performed rapidly but has reduced sensitivity and specificity when used alone. The Mini-Mental State Examination (MMSE) evaluates cognition in multiple domains, but it takes longer to perform and is best used for baseline assessments of dementia, rather than delirium. Other screening tools include the 4A’s Test (4AT), the Nursing Delirium Symptom Checklist (Nu-DESC), and 3-Minute Diagnostic Assessment (3D-CAM), among others.

Differential Diagnosis

Considerations in the differential diagnosis for delirium include dementia and psychiatric disorders. Dementia, depression, mania, paranoia, and schizophrenia all may resemble delirium but can be distinguished using historical and clinical features such as onset, time course, fluctuating mental status, and inattention ( Table 90.3 ). Unlike delirium, dementia and psychiatric disorders tend to be insidious processes that develop over months to years. Typically, the patient’s vital signs are normal. In addition, cognitive impairment of dementia exhibits little fluctuation during hours or days and occurs primarily in elders. However, patients with dementia are more likely to develop delirium, and as such, the two may often coexist.

Diagnostic Studies

Because delirium results from an underlying medical disorder, a comprehensive evaluation looking for structural, metabolic, and infectious etiologies is indicated ( Table 90.4 ). Despite these diagnostic evaluations, no cause may ultimately be found for many patients. Basic laboratory tests, such as serum electrolytes, have variable diagnostic yield. An elevated anion gap (>15 mEq/L) may indicate the presence of unmeasured anions, such as ketoacids in diabetic or alcoholic ketoacidosis; lactate in postictal states or associated with hypotension; sulfate in renal failure; and exogenous toxins, such as ethylene glycol, methanol, and salicylates.

In addition to a pulse oximetry measurement to screen for hypoxemia, blood gas analysis from an arterial or venous sample is warranted in patients at risk for respiratory failure with hypercarbia. Urinalysis and chest radiography may be obtained to exclude an occult infection, which is the most common cause of delirium in older patients.

An electrocardiogram and troponin may be obtained to assess for an acute coronary syndrome in patients at risk for heart disease, including older patients. Thyroid hormone testing may reveal hypothyroid or hyperthyroid state. Furthermore, additional laboratory studies outside the usual scope of the ED evaluation may be appropriate when the cause of delirium remains unknown or when suggested by the clinical history and exam. These additional studies may include vitamin B ₁₂ and folic acid assays in cases of possible malnutrition, rapid plasma reagin test to exclude neurosyphilis, measurement of serum antinuclear antibodies if lupus encephalitis is suspected, urinary porphobilinogen assay in acute porphyria, and screens for heavy metals in intentional or accidental ingestions.

Adverse prescription medication effects, including drug-drug interactions, are another common cause of delirium and may occur at therapeutic doses and levels. A comprehensive review of all medications should be performed, with testing for levels when indicated and available. Standard toxicology screens may have limited usefulness in the evaluation of patients with delirium, since both false-positive and false-negative results may occur, and early diagnostic closure based on these tests may result in an incorrect diagnosis.

Neuroimaging with a head computed tomography (CT) scan should be performed on patients with a history or signs of trauma (especially those taking anticoagulant medications), recent neurosurgical procedures or with implanted devices (e.g., cerebrospinal fluid shunt), or focal neurologic signs to detect structural lesions causing delirium. Advanced imaging may be indicated if there is suspicion for early infarctions, small brainstem lesions, closed head injuries, sagittal venous sinus thrombosis, or small isodense subdural hematomas that may be missed on a CT scan. In addition, a small percentage of acute subarachnoid hemorrhages are not detected by head CT scan and require LP for diagnosis.

The role of magnetic resonance imaging (MRI) in the evaluation of the delirious patient has not been clearly established. MRI is superior to CT for detection of small intracerebral and brainstem lesions, small brain contusions, certain infectious and inflammatory encephalitides, and abnormalities of white matter (e.g., leukoencephalopathy). The posterior reversible encephalopathy syndrome (PRES) can present with confusion, visual changes, and headache in the setting of malignant hypertension, with MRI abnormalities often, but not exclusively, in the posterior cerebrum.

Cerebrospinal fluid (CSF) analysis is an essential part of the evaluation in selected patients with delirium. In patients with fever and cognitive dysfunction, a LP should be considered to rule out infectious, inflammatory or neoplastic etiologies particularly in cases of new headache, meningismus, seizures, community-living adults, recent neurosurgery, or when other testing has failed to identify an infectious source. This test is particularly important in children under age 5, older adults over age 65, and immunocompromised patients, who are less likely to show classic signs of meningitis. Patients with focal neurologic deficits, immunocompromised states, or evidence of increased intracranial pressure should undergo head CT before LP. Antibiotic therapy should not be delayed for the results of LP testing.

Although it is rarely practical in the ED setting, the EEG can be a valuable tool for ruling out nonconvulsive status epilepticus (NCSE) in the presence of delirium. Typical EEG findings in delirium from metabolic causes include nonspecific generalized slowing without epileptiform discharges. In critically ill inpatients with no alternative explanation for decreased level of consciousness, observational studies have shown up to one-third of patients had NCSE on EEG. This condition, even when diagnosed promptly, may be associated with poor patient outcomes in acutely ill patients when mental status abnormalities fail to resolve.

Management

Delirium is a medical emergency. The outcome depends on the cause, the patient’s overall health status, and the timeliness of treatment. The hypoactive form of delirium tends to be more common in older adults and carries a worse overall prognosis, perhaps because it often goes unrecognized. Acute recognition and management of delirium in older patients is essential because delirium in this population is associated with increased risk of long-term institutionalization, development of dementia, and increased overall mortality. ^,

After recognition of delirium, patients should be screened quickly for readily treatable causes, such as hypoglycemia, hyperglycemia, hypoxia, hypercarbia, and opioid overdose. Acute intoxication due to medications or illicit substances requires prompt attention, and antidotes provided when available.

Initial management of agitation in hyperactive delirium should be accomplished with nonpharmacologic interventions such as verbal reassurance, assistance from family caregivers when present, and calming environment. When nonpharmacologic measures fail, or in the setting of immediate threat to the patient or staff, sedative medications may be administered through an intravenous or intramuscular route to prevent unsafe behavior and facilitate rapid clinical assessment and management.

Supportive care for all patients with delirium ideally includes an environment with adequate lighting and minimization of sensory overload; the patient should be placed in an area that can be easily observed by staff, and use of stretcher side rails to prevent falls. Use of “sitters” may be necessary to provide continuous supervision on a 1:1 or 1:2 basis with the patient. The patient must be protected from self-harm or from injuring other patients or staff. In cases of hyperactive delirium, the patient may need to be initially physically restrained until pharmacologic control takes effect. Physical restraints should be viewed only as a temporizing action because they can increase agitation and the risk of injury to the patient. Death in restraint is a recognized phenomenon, occurring more frequently in patients restrained in nonsupine positions and with agitated delirium.

Following the initial evaluation, care should be directed towards conditions requiring immediate medical intervention. Patients with signs of acute meningitis or sepsis should rapidly receive antibiotics along with appropriate fluid resuscitation. Other conditions that may manifest as delirium and necessitate immediate intervention include severe hypothermia, hyperthermia, and CNS vascular conditions, including hypertensive encephalopathy, acute epidural or subdural hematoma, subarachnoid hemorrhage, and stroke. Patients with Wernicke encephalopathy require immediate treatment with 200 to 500 mg of intravenous (IV) thiamine, with titration of additional doses until the ophthalmoplegia resolves. Traditionally, glucose administration in patients with severe thiamine deficiency was deferred given concern for precipitating Wernicke encephalopathy, but evidence for this phenomenon occurring is poor.

The specific treatment of delirium tremens (and other alcohol withdrawal syndromes) involves the substitution of a long-acting drug that is cross-tolerant with the alcohol. Benzodiazepines are the agents of choice in treatment of delirium due to sedative withdrawal, but caution should be used with these medications in other conditions because they may worsen delirium severity. Treatment for delirium secondary to dehydration or electrolyte abnormality begins in the ED, but care is needed to prevent overcorrection in patients with sodium abnormalities because this can lead to permanent neurologic damage. In patients with hepatic or renal disease, inpatient treatment with medications for hepatic encephalopathy or dialysis for renal disease may be required before disturbances in cognition resolve.

Pharmacologic interventions are a cornerstone of behavioral management while the underlying medical condition that caused the delirium is being addressed. Antipsychotics and benzodiazepines have been used in the management of acute agitation in the undifferentiated patient with delirium ( Table 90.5 ); opioids have no role.

Antipsychotic medications used to treat delirium include the typical antipsychotics, especially the butyrophenones including haloperidol and droperidol, and the newer atypical antipsychotic agents. Evidence for the superiority of any individual agent is limited, and no one drug is ideal for treatment of all cases. The typical antipsychotic, haloperidol, a potent dopamine-blocking medication with minimal anticholinergic and vasodilatory side effects, is recommended as monotherapy for controlling agitation in acute delirium on the basis of extensive clinical experience and best evidence base. The main acute response to the drug is tranquilization. The incidence of extrapyramidal side effects in patients receiving IV haloperidol for management of delirium with agitation is relatively low, generally less than 10% of patients.

As with all the antipsychotics, haloperidol can prolong the QTc interval, more so when given intravenously, but this effect is clinically insignificant in most patients and does not require a pretreatment electrocardiogram. Caution is warranted with use of this agent in patients taking medications that prolong the QTc and in patients with acute coronary ischemia, uncompensated congestive heart failure, or hepatic dysfunction. Another agent in this class, droperidol, received a “black-box” warning from the US Food and Drug Administration (FDA) in 2001 for concerns of QTc prolongation. Although an effective therapy for agitation in many patients, this warning led to a reduction in the use of droperidol and research into its effects in comparison to other agents. Large observational studies of droperidol use in the emergency department have not supported this concern and we consider droperidol a viable option in the management of acute agitation.

Dosing of haloperidol should be adjusted for the patient’s level of agitation, age, weight, and response to treatment. In most patients, 2.5 to 5 mg intramuscularly or intravenously (adjusted according to weight and comorbidities) is well tolerated as an initial dose, and levels can be titrated as needed. For older patients, a lower initial dose of 0.5 to 1 mg is recommended. In highly agitated patients, combination therapy with haloperidol and lorazepam, 0.5 to 2 mg IV or IM, may be more effective than monotherapy with haloperidol. Combinations of sedatives with anticholinergics, such as diphenhydramine, is discouraged, given the likelihood of prolonging the delirium state.

The newer atypical antipsychotic agents (risperidone, olanzapine, ziprasidone, aripiprazole) may have similar efficacy but different side effect profiles, which may be desirable in some cases of acute agitation. The mechanism of action includes antagonism of alpha ₁ -adrenergic, serotonin, dopamine, and histamine receptors. These drugs can also block the reuptake of dopamine and serotonin. Olanzapine, since it has both IV and IM formulations, has received support in the literature as being a safe and effective treatment for acute agitation in the ED, with reduced need for additional sedation in comparison to haloperidol. Because of the limited dopamine antagonism effect, atypical antipsychotics are preferred over haloperidol for patients with Parkinsonism and agitation, although benzodiazepines may be a better choice in this population given concerns about increased mortality with the use of atypical antipsychotics in Parkinson disease.

Benzodiazepines are another means to effectively sedate patients with acute undifferentiated agitation, but they are especially useful in cases of substance intoxication or withdrawal syndromes. Lorazepam, with onset of sedation within 2 to 3 minutes, is the preferred agent for treatment of withdrawal symptoms. Midazolam has a similar onset of action to lorazepam, but shorter duration of effect, and may be preferable in some cases. Diazepam should be avoided as an agent for treatment of agitated behavior in most delirious patients because of its long half-life and risk of drug accumulation with repeated dosing. Both midazolam and diazepam have prolonged half-lives in hepatic and renal impairment.

The management of acute behavior change in elderly patients in the emergency department has been identified by national groups as an area requiring further research. Based on the best available evidence, we recommend screening and treatment of readily reversible causes of delirium and initial nonpharmacologic management followed by a selection of pharmacologic agents based upon the etiology of delirium and patient comorbidities. We recommend an antipsychotic (typical or atypical) be used as monotherapy for undifferentiated patients with agitated delirium, or benzodiazepines for patients suspected of having substance intoxication or withdrawal who require sedation. As an alternative, a combination of a low-dose antipsychotic plus benzodiazepine (e.g., haloperidol 5 mg plus lorazepam 2 mg IM) can be used in combative patients with immediate safety threats. The combination approach has been found to be superior to monotherapy in the control of undifferentiated acute agitation. ^,

Disposition

Patients with delirium secondary to acute drug intoxication may be discharged from the ED provided the process resolves during a short period of observation and the drug has no potentially serious delayed toxicity. For most patients with delirium from metabolic, infectious, or CNS processes, hospitalization is necessary for further diagnostic evaluation and treatment. The only readily reversible metabolic problem associated with delirium that can be completely managed in the ED is hypoglycemia.

For most patients with treatable medical illness who have delirium, the outcome is full recovery. Time for return to baseline function can be prolonged, particularly in older patients. In some patients, a persistent decline in their baseline level of functioning may occur despite resolution of the acute cognitive dysfunction. Delirium in older adults hospitalized without baseline dementia is associated with higher 1-year mortality rates, higher rates of institutionalization, and a greater risk for development of dementia. These long-term consequences can occur despite optimal supportive multidisciplinary care.

Principles