Delirium

Delirium

Delirium (also known as acute confusional state, toxic metabolic encephalopathy) is the behavioral response to widespread distur-bances in cerebral metabolism. Like dementia, delirium is not a disease but a syndrome with many possible causes that result in a similar constellation of symptoms. DSM-IV-TR describes five categories of delirium based on etiology. These include delirium due to a general medical condition, substance intoxication, with-drawl delirium, delirium due to muttiple etiologies and delirium not otherwise specified.

Epidemiology

The overall prevalence of delirium in the community is low, but delirium is common in hospitalized patients. Lipowski (Saito, 1987) reported studies of elderly patients and suggested that about 40% of them admitted to general medical wards showed signs of delirium at some point during the hospitalization. Because of the increasing numbers of elderly in this country and the influence of life-extending technology, the population of hospitalized elderly is rising; and so is the prevalence of delirium. The intensive care unit, geriatric psychiatry ward, emergency department, alcohol treatment units and oncology wards have particularly high rates of delirium. Massie and colleagues (Lipowski, 1987) reported that 85% of terminally ill patients studied had symptoms that met criteria for delirium, as did 100% of postcardiotomy patients in a study by Theobald (Lipowski, 1989). Overall, it is estimated that 10% of hospitalized patients are delirious at any particular point in time.

Predisposing factors in the development of delirium in-clude old age, young age (children), previous brain damage, prior episodes of delirium, malnutrition, sensory impairment (espe-cially vision) and alcohol dependence. In general, the mortality and morbidity of any serious disease are doubled if delirium en-sues. The risk of dying after a delirious episode is greatest in the first two years after the illness, with a higher risk of death from heart disease and cancer in women and from pneumonia in men. Overall, the 3-month mortality rate for persons who have an epi-sode of delirium is about 28%, and the 1-year mortality rate for such patients may be as high as 50%.

Pathophysiology

ACh is the primary neurotransmitter believed to be involved in delirium, and the primary neuroanatomical site involved is the reticular formation. Thus, one of the frequent causes of delirium is the use of drugs with high anticholingeric potential. As the principal site of regulation of arousal and attention, the reticular formation and its neuroanatomical connections play a major role in the symptoms of delirium. The major pathway involved in de-lirium is the dorsal tegmental pathway projecting from the mes-encephalic reticular formation to the tectum and the thalamus.

Clinical Features

According to DSM-IV-TR, the primary feature of delirium is a diminished clarity of awareness of the environment (American Psychiatric Association, 1994). Symptoms of delirium are char-acteristically global, of acute onset, fluctuating and of relatively brief duration. In most cases of delirium, an often overlooked pro-drome of altered sleep patterns, unexplained fatigue, fluctuating mood, sleep phobia, restlessness, anxiety and nightmares occurs. A review of nursing notes for the days before the recognized onset of delirium often illustrates early warning signs of the condition.

Several investigators have divided the clinical features of delirium into abnormalities of 1) arousal, 2) language and cognition, 3) perception, 4) orientation, 5) mood, 6) sleep and wake-fulness, and 7) neurological functioning (Kaplan et al., 1994

The state of arousal in delirious patients may be increased or decreased. Some patients exhibit marked restlessness, height-ened startle, hypervigilance and increased alertness. This pattern is often seen in states of withdrawal from depressive substances (e.g., alcohol) or intoxication by stimulants (phencyclidine, am-phetamine, lysergic acid diethylamide). Patients with increased arousal often have such concomitant autonomic signs as pallor, sweating, tachycardia, mydriasis, hyperthermia, piloerection and gastrointestinal distress. These patients often require seda-tion with neuroleptics or benzodiazepines. Hypoactive arousal states such as those occasionally seen in hepatic encephalopathy and hypercapnia are often initially perceived as depressed or de-mented states. The clinical course of delirium in any particular patient may include both increased and decreased arousal states. Many such individuals display daytime sedation with nocturnal agitation and behavioral problems (sundowning).

Perceptual abnormalities in delirium represent an inability to discriminate sensory stimuli and to integrate current percep-tions with past experiences. Consequently, patients tend to per-sonalize events, conversations and so forth that do not directly pertain to them, become obsessed with irrelevant stimuli and misinterpret objects in their environment. The misinterpreta-tions generally take the form of auditory and visual illusions. Patients with auditory illusions, for example, might hear the sound of leaves rustling and perceive it as someone whispering about them. Paranoia and sleep phobia may result. Typical visual illusions are that intravenous tubing is a snake or worm crawling into the skin, or that a respirator is a truck or farm vehicle about to collide with the patient. The former auditory illusion may lead to tactile hallucinations, but the most common hallucinations in delirium are visual and auditory.

Orientation is often abnormal in delirium. Disorientation in particular seems to follow a fluctuating course, with patients unable to answer questions about orientation in the morning, yet fully oriented by the afternoon. Orientation to time, place, person and situation should be evaluated in the delirious patient. Gener-ally, orientation to time is the sphere most likely impaired, with orientation to person usually preserved. Orientation to significant people (parents, children) should also be tested. Disorientation to self is rare and indicates significant impairment. The examiner should always reorient patients who do not perform well on any portion of the orientation testing of the mental status examination, and serial testing of orientation on subsequent days is important.

Language and Cognition

Patients with delirium frequently have abnormal production and comprehension of speech. Nonsensical rambling and incoherentspeech may occur. Other patients may be completely mute. Memory may be impaired, especially primary and second-ary memory. Remote memory may be preserved, although the patient may have difficulty distinguishing the present from the distant past.

Mood

Patients with delirium are susceptible to rapid fluctuations in mood. Unprovoked anger and rage reactions occasionally occur and may lead to attacks on hospital staff. Fear is a common emo-tion and may lead to increased vigilance and an unwillingness to sleep because of increased vulnerability during somnolence. Apathy, such as that seen in hepatic encephalopathy, depression, use of certain medications (e.g., sulfamethoxazole [Bactrim]) and frontal lobe syndromes, is common as is euphoria secondary to medications (e.g., corticosteroids, DDC, zidovudine) and drugs of abuse (phencyclidine, inhalants).

Neurological Symptoms

Neurological symptoms often occur in delirium. These include dysphagia as seen after a CVA, tremor, asterixis (hepatic en-cephalopathy, hypoxia, uremia), poor coordination, gait apraxia, frontal release signs (grasp, suck), choreiform movements seizures, Babinski’s sign and dysarthria. Focal neurological signs occur less frequently.

Sleep–Wakefulness Disturbances

Sleeping patterns of delirious patients are usually abnormal. During the day they can be hypersomnolent, often falling asleep in midsentence, whereas at night they are combative and restless. Sleep is generally fragmented, and vivid nightmares are com-mon. Some patients may become hypervigilant and develop a sleep phobia because of concern that something untoward may occur while they sleep.

Causes of Delirium

The cause of delirium may lie in intracranial processes, extrac-ranial ones, or a combination of the two. The most common etio-logical factors are as follows (Francis et al., 1990).

Infection Induced

Infection is a common cause of delirium in hospitalized patients and typically, infected patients will display abnormalities in he-matology and serology. Vital signs are noted except in persons (elderly, chronic alcohol abusers, chemotherapy patients, those with HIV spectrum disease) who may not be able to mount the typical response. Bacteremic septicemia (especially that caused by gram-negative bacteria), pneumonia, encephalitis and menin-gitis are common offenders. The elderly are particularly suscep-tible to delirium secondary to urinary tract infections.

Metabolic and Endocrine Disturbances

Metabolic causes of delirium include hypoglycemia, electro-lyte disturbances and vitamin deficiency states. The most com-mon endocrine causes are hyperfunction and hypofunction of the thyroid, adrenal, pancreas, pituitary and parathyroid. Meta-bolic causes may involve consequences of diseases of particu-lar organs, such as hepatic encephalopathy resulting from liver disease, uremic encephalopathy and postdialysis delirium re-sulting from kidney dysfunction, and carbon dioxide macrosis and hypoxia resulting from lung disease. The metabolic dis-turbance or endocrinopathy must be known to induce changes in mental status and must be confirmed by laboratory deter-minations or physical examination, and the temporal course of the confusion should coincide with the disturbance (Francis et al., 1990). In some individuals, particularly the elderly, brain injured and demented, there may be a significant lag time be-tween correction of metabolic parameters and improvement in mental state.

Low-perfusion States

Any condition that decreases effective cerebral perfusion can cause delirium. Common offenders are hypovolemia, congestive heart failure and other causes of decreased stroke volume such as arrhythmias and anemia, which decreases oxygen binding. Main-tenance of fluid balance and strict measuring of intake and output are essential in delirious states.

Intracranial Causes

Intracranial causes of delirium include head trauma, especially involving loss of consciousness, postconcussive states and hem-orrhage; brain infections; neoplasms; and such vascular abnor-malities as CVAs, subarachnoid hemorrhage, transient ischemic attacks and hypertensive encephalopathy.

Postoperative States

Postoperative causes of delirium may include infection, atel-ectasis, postpump confusion from maintenance on a heart–lung machine, lingering effects of anesthesia, thrombotic and embolic phenomena, and adverse reactions to postoperative analgesia. General surgery in an elderly patient has been reported to be fol-lowed by delirium in 10 to 14% of cases and may reach 50% after surgery for hip fracture (Lipowski, 1989).

Sensory and Environmental Changes

Many clinicians underestimate the disorienting potential of an unfamiliar environment. The elderly are especially prone to de-velop environment-related confusion in the hospital. Individuals with preexisting dementia, who may have learned to compensate for cognitive deficits at home, often become delirious once hos-pitalized. In addition, the nature of the intensive care unit often lends itself to periods of high sensory stimulation (as during a “code”) or low sensory input, as occurs at night. Often, patients use such external events as dispensing medication, mealtimes, presence of housekeeping staff, and physicians’ rounds to mark the passage of time. These parameters are often absent at night, leading to increased rates of confusion during night-time hours. Often, manipulating the patient’s environment or removing the patient from the intensive care unit can be therapeutic.

Substance Intoxication Delirium

The list of medications that can produce the delirious state is extensive (Table 32.9). The more common ones include such antihypertensives as methyldopa and reserpine, histamine (H₂) receptor antagonists (cimetidine), corticosteroids, antide-pressants, narcotics (especially opioid) and nonsteroidal anal-gesics, lithium carbonate, digitalis, baclofen, anticonvulsants, antiarrhythmics, colchicine, bronchodilators, benzodiazepines, sedative-hypnotics and anticholinergics. Of the narcotic anal-gesics, meperidine can produce an agitated delirium with trem-ors, seizures and myoclonus. These features are attributed to its active metabolite normeperidine, which has potent stimulant and anticholingeric properties and accumulates with repeated intravenous dosing. In general, adverse effects of narcotics are more common in those who have never received such agents before (the narcotically naive) or who have a history of a similar response to narcotics.

Lithium-induced delirium occurs at blood levels greater than 1.5 mEq/L and is associated with early features of lethargy, stuttering and muscle fasciculations. The delirium may take as long as 2 weeks to resolve even after lithium has been discon-tinued, and other neurological signs such as stupor and seizures commonly occur. Maintenance of fluid and electrolyte balance is essential in lithium-induced delirium. Facilitation of excretion with such agents as aminophylline and acetazolamide helps, but hemodialysis is often required.

Principles to remember in cases of drug-induced delirium include the facts that 1) blood levels of possibly offending agents are helpful and should be obtained, but many persons can be-come delirious at therapeutic levels of the drug, 2) drug-induced delirium may be the result of drug interactions and polypharmacy and not the result of a single agent, 3) over-the-counter medica-tions and preparations (e.g., agents containing caffeine or phenyl-propanolamine) should also be considered, and 4) delirium can be caused by the combination of drugs of abuse and prescribed medications (e.g., cocaine and dopaminergic antidepressants).

The list of drugs of abuse that can produce delirium is ex-tensive. Some such agents have enjoyed a resurgence after years of declining usage. These include lysergic acid diethylamide, psi-locybin (hallucinogenic mushrooms), heroin and amphetamines. Other agents include barbiturates, cannabis (especially depend-ent on setting, experience of the user and whether it is laced with phencyclidine [“superweed”] or heroin), jimsonweed (highly an-ticholingeric) and mescaline. In cases in which intravenous use of drugs is suspected, HIV spectrum illness must be ruled out as an etiological agent for delirium.

The physical examination of a patient with suspected illicit drug-induced delirium may reveal sclerosed veins, “pop” scars caused by subcutaneous injection of agents, pale and atrophic na-sal mucosa resulting from intranasal use of cocaine, injected con-junctiva and pupillary changes. Toxicological screens are helpful but may not be available on an emergency basis.

Substance Withdrawal Delirium

Alcohol and certain sedating drugs can produce a withdrawal delirium when their use is abruptly discontinued or signifi-cantly reduced. Withdrawal delirium requires a history of use of a potentially addicting agent for a sufficient amount of time to produce dependence. It is associated with such typical physical findings as abnormal vital signs, pupillary changes, tremor, dia-phoresis, nausea and vomiting, and diarrhea. Patients generally

complain of abdominal and leg cramps, insomnia, nightmares, chills, hallucinations (especially visual) and a general feeling of “wanting to jump out of my skin”. Some varieties of drug with-drawal, although uncomfortable, are not life threatening (e.g., opioid withdrawal). Others such as alcohol withdrawal delirium are potentially fatal. Withdrawal delirium is much more common in hospitalized patients than in patients living in the community. The incidence of delirium tremens, for example, is found in 1% of all alcoholics, but in 5% of hospitalized alcohol abusers. Im-provement of the delirium occurs when the offending agent is reintroduced or a cross-sensitive drug (e.g., a benzodiazepine for alcohol withdrawal) is employed. The causes of delirium are summarized in Table 32.10).

Diagnosis

Appropriate workup of delirious patients includes a complete physical status, mental status and neurological examination.

History taking from the patient, any available family, pre-vious physicians, the old chart and the patient’s current nurse is essential. Previous delirious states, etiologies identified in the past and interventions that proved effective should be elucidated. The appropriate evaluation of the delirious patient is reviewed in Figure 32.9

Differential Diagnosis

Delirium must be differentiated from dementia because the two conditions may have different prognoses. In contrast to the changes in dementia, those in delirium have an acute onset. The symptoms in dementia tend to be relatively stable over time, whereas clinical features of delirium display wide fluctuation with periods of relative lucidity. Clouding of consciousness is an essential feature of delirium, but demented patients are usu-ally alert. Attention and orientation are more commonly dis-turbed in delirium, although the latter can become impaired in advanced dementia. Perception abnormalities, alterations in the sleep–wakefulness cycle, and abnormalities of speech are more common in delirium. Most important, a delirium is more likely to be reversible than is a dementia.

Delirium and dementia can occur simultaneously; in fact, the presence of dementia is a risk factor for delirium. Some stud-ies suggest that about 30% of hospitalized patients with dementia have a superimposed delirium.

Delirium must often be differentiated from psychotic states related to such conditions as schizophrenia or mania and factitious disorders with psychological symptoms or malinger-ing. Generally, the psychotic features of schizophrenia are more constant and better organized than are those in delirium, and pa-tients with schizophrenia seldom have the clouding of conscious-ness seen in delirium. The “psychosis” of patients with factitious disorder or malingering is inconsistent, and these persons do not exhibit many of the associated features of delirium. Apathetic and lethargic patients with delirium may occasionally resemble depressed individuals, but tests such as EEG distinguish between the two. The EEG demonstrates diffuse slowing in most delirious states, except for the low-amplitude, fast activity EEG pattern seen in alcohol withdrawal. The EEG in a functional depression or psychosis is normal.

Management

Once delirium has been diagnosed, the etiological agent must be identified and treated. For the elderly, the first step generally involves discontinuing or reducing the dosage of potentially of-fending medications. Some delirious states can be reversed with medication, as in the case of physostigmine administration for anticholinergic delirium. However, most responses are not as immediate, and attention must be directed toward protecting the patient from unintentional self-harm, managing agitated and psy-chotic behavior, and manipulating the environment to minimize additional impairment. Supportive therapy should include fluid and electrolyte maintenance and provision of adequate nutrition. Reorienting the patient is essential and is best accomplished in a well-lit room with a window, clock and visible wall calendar. Familiar objects from home such as a stuffed animal, favorite blanket, or photographs are helpful. Patients who respond incor-rectly to questions of orientation should be provided with the correct answers. Because these individuals often see many con-sultants, physicians should introduce themselves and state their purpose for coming at every visit. Physicians must take into ac-count that impairments of vision and hearing can produce confu-sional states, and the provision of appropriate prosthetic devices may be beneficial. Around-the-clock accompaniment by hospi-tal-provided “sitters” or family members may be required (see Table 32.11).

these conservative interventions, the delirious pa-tient often requires pharmacological intervention. The liaison psy-chiatrist is the most appropriate person to recommend such treat-ment. The drug of choice for the agitated delirious patients has traditionally been haloperidol. It is particularly beneficial when given by the intravenous route and some authors have reported using dosages as high as 260 mg/day without adverse effect. Ex-trapyramidal symptoms may be less common with haloperidol administered intravenously as opposed to orally and intramuscu-larly. In general, doses in the range of 0.5 to 5 mg intravenously are used, with the frequency of administration depending on a variety of factors including the patient’s age. An electrocardio-gram should be obtained before administering haloperidol. If the QT interval is greater than 450, use of intravenous haloperidol can precipitate an abnormal cardiac rhythm known as Torsades de pointes. Lorazepam has also been proven effective in doses  of 0.5 to 2 mg intravenously. Some authors have suggested that haloperidol and lorazepam act synergistically when given to the agitated delirious patient. If the delirium is secondary to drug or alcohol abuse, benzodiazepines or clonidine should be used

For patients who are mildly agitated or amenable to taking medi-cations by mouth, oral haloperidol or lorazepam is appropriate. Recent studies have advocated the use of newer atypical antipsy-chotics for management of behavior and psychotic features in de-lirium. Such agents as quetiapine, olanzapine, and risperdal and ziprasidone have been used successfully to treat delirium. Newer agents may have lower incidences of dystonias and dyskinesias, but still carry the risk of QT interval prolongation, particularly in patients with electrolyte abnormalities. Quetiapine and olanzap-ine are quite sedating, and occasionally a combination of bedtime olanzapine and “as needed” haloperidol is utilized. Olanzapine may raise blood glucose levels and precipitate weight gain, but is available as a Zydis preparation, which is absorbed through the oral mucosa and can therefore be given to patients who are unable to take medications by mouth. A parenteral form of ziprasidone is also available. Whatever antipsychotic is chosen, the patient should be carefully monitored for muscle rigidity, unexplained fever, tremor and other warning signs of neuroleptic side effects.

Outcome of Delirium

After elimination of the cause of the delirium, the symptoms gradually recede within 3 to 7 days. Some symptoms in certain populations may take weeks to resolve. The age of the patient and the period of time during which the patient was delirious affect the symptom resolution time. In general, the patient has a spotty memory for events that occurred during delirium. These remem- brances are reinforced by comments from the staff (“You’re not as confused today”), or the presence of a sitter, or use of wrist restraints. Patient should be reassured that they were not respon-sible for their behavior while delirious, and that no one hates or resents them for the behavior they may have exhibited. As men-tioned earlier, delirious patients have an increased risk of mortal-ity in the year following their first episode. Patients with underly-ing dementia show residual cognitive impairment after resolution of delirium, and it has been suggested that a delirium may merge into a dementia (Kaplan et al., 1994).