1. The first step is to determine whether this state represents delirium or dementia. The clinical findings may be subtle, and establishment of the diagnosis can be challenging, especially because delirium may be superimposed on dementia and dementia remains an independent risk factor for delirium.2,3 Early symptoms and signs may go unrecognized unless an adequate history is obtained from the patient, family members, and caregivers. A careful examination must include memory and cognitive assessment with a mental status screening examination.

2. Supportive care must be provided. This care may range in extent from aggressive airway and cardiovascular support to pharmacologic or physical restraint to simply placing the patient in a quiet room with appropriate environmental support.

3. A diligent search must be initiated for the underlying precipitating stressors in patients presenting with delirium.

Definition and Background

Delirium is a syndrome that can be defined as an acute or subacute state of cognitive dysfunction caused by an underlying physiologic condition. Terms that have been used interchangeably with delirium include acute organic brain syndrome, acute confusional state, reversible cerebral dysfunction, metabolic encephalopathy, toxic encephalopathy, and febrile delirium. The word delirium is derived from the Latin delirare, which literally means “to go out of the furrow” (in a more modern sense, “to derail”), but it is used figuratively to mean “crazy” or “deranged.”

Several key features are necessary for a diagnosis of delirium (Box 104-1). Patients with delirium have disturbances in consciousness, memory, cognition, and perception. These disturbances tend to develop during a short time (hours to days). The disturbance in consciousness may be manifested initially as an inability to focus attention. The fluctuating course of symptoms and inattention are the hallmarks of delirium. Deficiencies in cognition may be manifested by disorientation and memory deficits. Perceptual disturbances include hallucinations and delusions. The delirious patient may be somnolent or agitated, and the thought process may range from mildly disturbed to grossly disorganized. The clinical presentation may be subdued or explosive. The patient’s sleep-wake cycle may be altered or reversed; agitation often is present during the night. Historically, delirium referred to a hyperactive state marked by agitation and emotional lability (e.g., delirium tremens). An important point, however, is that delirium has several psychomotor subtypes: hyperactive (mania), hypoactive (depressed), and mixed type.⁴

The exact incidence of delirium in the overall ED population is unknown. However, the prevalence of delirium among elders who present to the ED is approximately 10 to 20%.⁵ Geriatric patients are at particularly high risk for the development of delirium. Advanced age, dementia, and underlying medical illness are strongly associated with delirium. Multiple medications, drugs, and alcohol also are associated with delirium.⁶ Severe psychological stress and sleep deprivation may facilitate the development of delirium.

Pathophysiology

At a cellular level, delirium is the result of 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. One theory is that delirium is associated with a derangement of central cholinergic transmission. Serum anticholinergic activity is increased, and low levels of acetylcholine are seen in older patients with delirium.⁷ Increased serotonin levels have been found in hepatic encephalopathy, serotonin syndrome, sepsis, and psychedelic drug ingestion.⁸ Some of the disturbances that occur in delirium are deficiencies of substrates for oxidative metabolism (e.g., glucose, oxygen); disturbances of ionic passage through excitable membranes; increase in cytokines; imbalance of normal noradrenergic, serotoninergic, dopaminergic, and cholinergic homeostasis; and, in some cases, synthesis of false neurotransmitters.⁹ 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 these 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. Depending on the opioid receptor type affected, the physiologic response may be analgesia, euphoria, sedation, dysphoria, delusions, or hallucinations. Psychedelic drugs probably act as agonists at serotonin receptor sites. Phencyclidine (PCP) inhibits reuptake of dopamine, norepinephrine, serotonin, and α-aminobutyric acid and also may act as a false neurotransmitter.

Hyperthermia and hypothermia can cause delirium, probably as a result of changes in the cerebral metabolic rate. In hypothermia, cerebral metabolism decreases 6 to 7% for each 1° C decrease in temperature from 35 to 25° C. In hyperthermia, cellular damage with uncoupling of oxidative phosphorylation begins to occur at temperatures higher than 42° C. Patients suffering from heatstroke may have cerebral edema, degenerative neuronal changes (especially involving Purkinje cells of the cerebellum), and petechiae in the walls of the third and fourth ventricles. Delirium occurring at temperatures below 40° C is multifactorial in origin and not caused solely by increased core temperature.

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

Most patients with delirium have reduced cerebral metabolic activity. This reduction in cerebral metabolism is reflected by a decrease in the frequency 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.

Etiology

The causes of delirium are legion (Table 104-1). Within the geriatric population, medications are a common cause of delirium, whereas drugs (including ethanol) are the most common cause of delirium in the younger adult population. Acute cognitive dysfunction may be secondary to drug overdose, withdrawal syndromes, and adverse or idiosyncratic reactions.

The list of commonly prescribed drugs causing delirium is extensive and includes antibiotics (antifungal, antimalarial, and antiviral agents; numerous antibacterial agents, including the quinolones and macrolides), anticholinergic drugs (antihistamines, antispasmodics, muscle relaxants, tricyclic antidepressants), anticonvulsants, anti-inflammatory agents (corticosteroids, salicylates, and other nonsteroidal anti-inflammatory drugs), various cardiovascular medications (beta-blockers, antidysrhythmics, antihypertensives, cardiac glycosides), sympathomimetics (phenylpropanolamine), sedative-hypnotics, narcotics (transdermal fentanyl [Duragesic], morphine sulfate [Roxanol], hydromorphone HCl [Dilaudid], oxycodone HCl [OxyContin]), miscellaneous drugs (aminophylline, cimetidine, lithium, chlorpropamide), over-the-counter medications with anticholinergic properties, and caffeine-containing products.⁶

Many “street drugs” with significant abuse potential, such as hallucinogens, amphetamines, PCP, cocaine, and methylenedioxymethamphetamine (MDMA, ecstasy), can cause delirium, as can intoxication with any of the alcohols (e.g., ethanol, methanol, ethylene glycol).

Exposure to industrial chemicals (e.g., carbon disulfide, heavy metals, insecticides, cyanide, carbon monoxide) can cause a wide range of symptoms that include acute delirium. In addition, ingestion of certain plants (e.g., nutmeg, foxglove, jimsonweed, psilocybin-containing mushrooms) can cause delirium.

Delirium can be one of the protean manifestations of a metabolic or nutritional abnormality. The most common metabolic disorder causing acute cognitive changes is diabetes mellitus. Hypoglycemia is the most common and readily reversible cause of acute confusion in the diabetic patient. Other causes of acute cognitive impairment in the diabetic patient are hyperglycemia, hyperosmolarity, and acid-base abnormalities. Severe metabolic abnormalities, including electrolyte disturbances, hypoxemia, hepatic insufficiency, renal insufficiency, and dysfunction of various endocrine glands (hyperthyroidism, hypothyroidism, Cushing’s syndrome, hyperparathyroidism, and other endocrine disorders), can cause delirium. Deficiency of niacin, pyridoxine, folic acid, or vitamin B₁₂ may be associated with an acute confusional state.

Delirium can be a prominent feature of any systemic infection, particularly in the very young, elders, and immunocompromised patients. Infectious and host factors together determine the degree of cognitive impairment. Extracranial infections that are associated with delirium include sepsis (particularly gram-negative sepsis), subacute bacterial endocarditis, Legionnaires’ disease, Rocky Mountain spotted fever, malaria, typhoid fever, toxic shock syndrome, and several viral infections including influenza. Patients with CNS infections, including meningitis, encephalitis, and intracerebral abscess, may have acute cognitive dysfunction.

Another less common cause of delirium is CNS infarction in the distribution of the nondominant middle cerebral artery and the posterior cerebral artery. In patients who have a collagen vascular disease with CNS vasculitis, neuropsychiatric manifestations, including acute delirium, may be prominent. Paraneoplastic syndromes may include encephalopathy, with symptoms of confusion, catatonia, and dementia.

Patients who are immunocompromised may have multiple and unusual causes of acute delirium. Patients with immunosuppression secondary to malignant disease, drugs, or human immunodeficiency virus type 1 (HIV-1) infection may have acute brain dysfunction secondary to infection, complications of drug therapy, or the underlying disease itself.

Acute confusional states have been reported to be a more common herald of the onset of physical illness in the elderly than are fever, pain, and tachycardia.2,3,10 Factors that predispose elders to delirium include the effects of aging on the brain, reduced capacity for homeostatic regulation, impaired vision and hearing, and age-related changes in the pharmacokinetics and pharmacodynamics of drugs.¹¹ The etiology of delirium in elders is usually multifactorial.

Clinical Features

The clinical manifestations of delirium are as variable as the causes. The clinical presentation can be so subtle as to go unrecognized or may be dramatic enough to disrupt the entire ED. The natural history of a patient’s delirium can progress from apathy to marked agitation in the course of hours (see Box 104-1). Nonspecific prodromal symptoms such as anxiety, restlessness, and insomnia typically emerge during hours to days.

Key aspects of cognitive impairment should become evident during a careful history and examination. Disturbance in attention is central to the diagnosis of delirium. The patient is easily distractible and has difficulty remaining focused on a particular topic or interacting with a single person. Disorientation often accompanies the deficit 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 always has some degree of memory impairment, with the greatest impact on short-term memory. Thought processes and speech may be disorganized. Disturbance in the sleep-wake cycle often occurs early in the course of delirium. Perceptual disturbances, including misperception of the environment, poorly formed delusions, and hallucinations, are common. The delirious patient may experience visual, auditory, tactile, gustatory, or olfactory hallucinations, in contrast to patients with acute functional psychosis, who typically experience only auditory hallucinations. 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, and out-of-hospital personnel. Specific inquiry should be made about the patient’s current medical problems and previous medical history, including diabetes, hypertension, kidney or liver disease, and any neurologic or psychiatric problems. It is important to determine whether the patient is immunosuppressed or has risk factors for immunosuppression. A detailed medication history, including the use of prescribed and over-the-counter medications, dietary supplements, and alcohol or other substances, is essential. Out-of-hospital personnel should be able to provide information about the home environment, medication bottles belonging to the patient or found near the patient, and the possibility of trauma.

The physical examination should begin with a careful assessment of vital signs including pulse oximetry and a pain assessment. The delirious patient often exhibits abnormalities on such evaluation, including elevated or decreased pulse, blood pressure, respiratory rate, and temperature. The examination includes assessment of the head for signs of trauma and the pupils for symmetry of light reflex; funduscopic examination for hemorrhage or papilledema; examination of the ears for hemotympanum; 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, and presence of abnormal movements (e.g., tremor, asterixis, myoclonus). The reflexes are assessed for symmetry and presence of hyperreflexia or hyporeflexia. Findings that typically suggest either a metabolic or a structural neurologic problem are not necessarily specific for that category of disorder. For example, asterixis is a hallmark of metabolic encephalopathy but can be seen in focal brain disease. Likewise, focal neurologic signs that typically are associated with structural CNS lesions also can be present in various metabolic abnormalities, such as hypoglycemia, hyperglycemia, hepatic encephalopathy, uremia, and hypercalcemia.

The physical examination is not often helpful in determining the specific drug or class of drugs causing acute cognitive impairment. The one exception to this rule is toxidromes, which are constellations of signs and symptoms characteristic of intoxication with certain drugs or classes of drugs (see Chapter 147).

A brief mental status examination should be performed in all patients thought to have acute brain dysfunction. Although the concept is rather obvious, few physicians proceed beyond questions about the patient’s orientation to person, place, and time when assessing mental status. Failure to diagnose subtle forms of delirium when they are present is directly related to omission of mental status testing.¹²

Several standardized tools for assessment of mental status have been successfully applied in the ED.12–14 Mental status testing includes assessment of orientation, memory, attention, and concentration; several tests also incorporate assessments of constructional tasks, spatial discrimination, arithmetic ability, and writing. Cognitive functioning can be rapidly assessed in approximately 7 to 10 minutes. Memory assessment requires testing of the patient’s ability to repeat short series of words or numbers (immediate recall), to learn new information (short-term memory), and to retrieve previously stored information (long-term memory). Constructional apraxia is assessed by having the patient perform tasks such as drawing interlocking geometric figures or clock faces and connecting dots. Dysnomia (inability to name objects correctly) and dysgraphia (impaired writing ability) are two of the most sensitive indicators of delirium. Almost all acutely confused patients exhibit writing impairments, including spatial disorganization, misspelling, and tremor.^13,15

No single bedside cognitive test that can be administered quickly is ideal. The Mini-Mental State Examination (MMSE) developed by Folstein and colleagues has been validated more than any other test and most frequently is recommended as a rapid screening tool.10,13,15,16 For hospitalized patients, this test has a sensitivity of 87% and a specificity of 82% for detection of organic brain syndrome. Some investigators report slightly better results when the test is modified and age is added as a variable in the analysis.¹⁶ The MMSE does not measure executive function and is insensitive for detection of early signs of mild cognitive impairment (without dementia) or early dementia.¹⁷

The MMSE consists of a short series of questions that test orientation, registration (memory), attention, calculation, recall, and language (Fig. 104-1). The time for the test to be administered can be reduced to 5 minutes by elimination of the writing and drawing components with only a modest reduction in sensitivity. The registration section tests both immediate and short-term memory; the recall section also assesses short-term memory. The ability to recall two of three objects has 81% sensitivity and 74% specificity for exclusion of organic brain syndrome. Asking the patient to subtract “serial sevens” backward from 100 assesses attention, concentration, and arithmetic ability. This test is specific but not sensitive for absence of an organic brain syndrome; up to 40% of nondelirious, nondemented people fail to perform the tasks of this test correctly, reflecting limitations due to language ability and education. A total score of 23 or less is considered markedly abnormal and indicates an organic brain syndrome. As a general rule, patients with mild cognitive impairment have a score of 18 to 26 of 30, those with moderate impairment have a score of 10 to 18, and those with severe impairment have a score of less than 10.

The Quick Confusion Scale represents another attempt to quantify the attention aspects of mental status (see Chapter 17, Fig. 17-2). It has significant correlation with the MMSE, can be administered more quickly, and does not require constructional tasks.¹⁸ Another useful diagnostic tool is the Confusion Assessment Method; it has a sensitivity of 93 to 100% and specificity of 90 to 95%.¹⁹ This simple tool has four key features used for screening of delirium: acute onset and fluctuating course, inattention, disorganized thinking, and altered level of consciousness. For a definitive diagnosis of delirium, the first two features and one of the last two must be present. It has proved to be a valuable tool because of its ease and interobserver reliability. In addition, it has been shown to be more sensitive than clinical impression alone.^18,20 The Six-Item Screener is another brief test of cognition that was found to be 94% sensitive and 86% specific in identifying disturbance of cognition in older patients.¹⁵

All bedside tests of cognition have limitations and can miss mild degrees of impairment. The patient’s level of education and general intelligence can substantially affect the outcome. Furthermore, a single bedside test reflects a patient’s cognitive functioning at only one point in time. For a diagnosis of delirium (or dementia) to be established, an essential criterion is a documented decline from the patient’s baseline level of cognitive functioning, and the sensitivity of these tests increases when they are repeated over time.

Diagnostic Evaluation and Ancillary Studies

Some reversible causes of delirium can be diagnosed by a number of basic, readily available tests. The following laboratory tests can be helpful in evaluation of the delirious patient: a complete blood count (CBC; hemoglobin, leukocyte count with differential, platelet count, and mean corpuscle volume), serum electrolyte values, glucose concentration, calcium concentration, and urinalysis. The CBC may suggest unusual but potentially treatable abnormalities, such as thrombotic thrombocytopenic purpura, megaloblastic anemia, hyperviscosity from myelogenous leukemia, and unsuspected infection. The anion gap should be determined in all patients with altered mental status. An elevated anion gap (>15 mEq/L) may indicate the presence of unmeasured anions, such as sulfate in renal failure; keto acids in diabetic or alcoholic ketoacidosis; lactate in postictal states or associated with hypotension; and exogenous toxins, such as ethylene glycol, methanol, and salicylates. A pulse oximetry measurement should be obtained in all patients to screen for hypoxemia, and an arterial blood gas analysis is warranted in those patients at risk for respiratory failure with carbon dioxide retention. Suspected occult infection warrants urinalysis and chest radiography. In elders, an electrocardiogram should be obtained to exclude a silent acute coronary syndrome. Ammonia level should be considered in patients with cirrhosis, ascites, or asterixis. Despite these diagnostic evaluations, no cause is found for delirium in up to 16% of patients.⁶

Toxicology screens are overused as diagnostic tests and have limited usefulness in the evaluation of most patients with delirium. Additional laboratory studies outside the scope of the ED evaluation that may be appropriate when the cause of delirium remains unknown include thyroid function studies, vitamin B₁₂ and folic acid assays, rapid plasma reagin test, measurement of serum antinuclear antibodies, urinary porphobilinogen assay, and screens for heavy metals.

Patients with a history of trauma (especially those taking anticoagulant medications), previous neurosurgical procedures, immunodeficiency, or focal neurologic signs require a head computed tomography (CT) scan to detect structural lesions causing delirium. Early infarctions, small brainstem lesions, meningitis or encephalitis, closed head injuries, sagittal vein thrombosis, and small isodense subdural hematomas may be missed on a CT scan. In addition, approximately 2 to 8% of acute subarachnoid hemorrhages are not detected by head CT scan and require lumbar puncture 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 intercerebral and brainstem lesions, small brain contusions, certain encephalitides, and abnormalities of white matter (e.g., leukoencephalopathy). MRI perfusion scans are more sensitive in detecting an acute vascular event.

Cerebrospinal fluid (CSF) analysis is an essential part of the evaluation in selected patients with delirium. In patients with fever and cognitive dysfunction, even without meningismus, a lumbar puncture should be performed to rule out meningitis. This test is particularly important in the very young, elders, 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 lumbar puncture, and they should receive antibiotics before the CT scan.

Although it is rarely practical in the ED setting, the EEG can be a valuable diagnostic tool in determining the presence of delirium. Bilateral diffuse symmetrical electroencephalographic abnormalities are a relatively consistent feature of delirium. In most cases, the changes consist of a nonspecific generalized slowing from the baseline activity and can be useful in distinguishing delirium from other neurobehavioral abnormalities.

Differential Diagnosis

Considerations in the differential diagnosis for apparent delirium include functional psychiatric disorders and dementia. Depression, mania, paranoia, and schizophrenia all may resemble delirium. Several clinical features are helpful in distinguishing between organic and functional syndromes (Table 104-2).