18: Delirium

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CHAPTER 18 Delirium

OVERVIEW

Delirium has likely replaced syphilis as “the great imitator,” as its varied presentations have led to misdiagnoses among almost every major category of mental illness. A syndrome, caused by an underlying physiological disturbance (and marked by a fluctuating course with impairments in consciousness, attention, and perception), delirium is often mistaken for depression (with a “withdrawn” or “flat” affect), for mania (with agitation and confusion), for psychosis (with hallucinations and paranoia), for anxiety (with restlessness and hypervigilance), for dementia (with cognitive impairments), and for substance abuse (with impairment in consciousness). With so diverse an array of symptoms, delirium assumes a position of diagnostic privilege in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), in that almost no other diagnosis can be made in its presence.

Perhaps even more noteworthy is that delirium is a signifier of (often serious) somatic illness.1 Delirium has been associated with increased length of stay in hospitals2 and with an increased cost of care.3,4 Among intensive care unit (ICU) patients prospective studies have noted that delirium occurs in 31% of admissions5; when intubation and mechanical ventilation are required the incidence soars to 81.7%.1

Sometimes, delirium is referred to as an acute confusional state, a toxic-metabolic encephalopathy, or acute brain failure; unquestionably, it is the most frequent cause of agitation in the general hospital. Delirium ranks second only to depression on the list of all psychiatric consultation requests. Given its prevalence and its importance (morbidity and mortality), the American Psychiatric Association issued practice guidelines for the treatment of delirium in 1999.6

Placed in this context, the consequences of misdiagnosis of delirium can be severe; prompt and accurate recognition of this syndrome is paramount for all clinicians.

DIAGNOSIS

The essential feature of delirium, according to the DSM-IV, is a disturbance of consciousness that is accompanied by cognitive deficits that cannot be accounted for by past or evolving dementia (Table 18-1).7 The ICD-10 includes disturbances in psychomotor activity, sleep, and emotion in its diagnostic guidelines (Table 18-2).8

Table 18-1 DSM-IV Diagnostic Criteria for Delirium

A disturbance of consciousness (i.e., reduced clarity of awareness of the environment) with reduced ability to focus, sustain, or shift attention
A change in cognition (e.g., memory deficit, disorientation, or a language disturbance) or the development of a perceptual disturbance that is not better accounted for by a preexisting, established, or evolving dementia
The disturbance develops over a short period (usually hours to days) and tends to fluctuate during the course of the day
Evidence from the history, physical examination, or laboratory findings that the disturbance is caused by the direct physiological consequences of a general medical condition

Table 18-2 ICD-10 Diagnostic Guidelines for Delirium

Impairment of consciousness and attention (on a continuum from clouding to coma; reduced ability to direct, focus, sustain, and shift attention)
Global disturbance of cognition (perceptual distortions, illusions, and hallucinations—most often visual; impairment of abstract thinking and comprehension, with or without transient delusions, but typically with some degree of incoherence; impairment of immediate recall and of recent memory but with relatively intact remote memory; disorientation for time, as well as, in more severe cases, for place and person)
Psychomotor disturbances (hypoactivity or hyperactivity and unpredictable shifts from one to the other; increased reaction time; increased or decreased flow of speech; enhanced startle reaction)
Disturbance of the sleep-wake cycle (insomnia or, in severe cases, total sleep loss or reversal of the sleep-wake cycle; daytime drowsiness; nocturnal worsening of symptoms; disturbing dreams or nightmares, which may continue as hallucinations after awakening)
Emotional disturbances (e.g., depression, anxiety or fear, irritability, euphoria, apathy, or wondering perplexity)

Disturbance of the sleep-wake cycle is also common, sometimes with nocturnal worsening (“sundowning”) or even by a complete reversal of the night-day cycle, though it should be emphasized that (despite previous postulation) sleep disturbance alone does not cause delirium.9 Similarly, the term “ICU psychosis” has entered the medical lexicon; this is an unfortunate misnomer because it is predicated on the beliefs that the environment of the ICU alone is capable of inducing delirium and that the symptomatology of delirium is limited to psychosis.9

Despite wide variation in the presentation of the delirious patient, the hallmarks of delirium (although perhaps less immediately apparent) remain quite consistent from case to case. Both Chedru and Geschwind10 and Mesulam and co-workers11 regard impaired attention as the main deficit of delirium. This inattention (along with an acute onset, waxing and waning course, and overall disturbance of consciousness) forms the core of delirium, while other related symptoms (e.g., withdrawn affect, agitation, hallucinations, and paranoia) serve as a “frame” that can sometimes be so prominent as to detract from the picture itself.

Psychotic symptoms (such as visual or auditory hallucinations and delusions) are common among patients with delirium.12 Sometimes the psychiatric symptoms are so bizarre or so offensive (e.g., an enraged and paranoid patient shouts that pornographic movies are being made in the ICU) that diagnostic efforts are distracted. The hypoglycemia of a man with diabetes can be missed in the emergency department (ED) if the accompanying behavior is threatening, uncooperative, and resembling that of an intoxicated person.

While agitation may distract practitioners from making an accurate diagnosis of delirium, disruptive behavior alone will almost certainly garner some attention. The “hypoactive” presentation of delirium is more insidious, since the patient is often thought to be depressed or anxious because of his or her medical illness. Studies of quietly delirious patients show the experience to be equally as disturbing as the agitated variant13; quiet delirium is still a harbinger of serious medical pathology.14,15

The core similarities found in cases of delirium have led to postulation of a final common neurological pathway for its symptoms. Current understanding of the neurophysiological basis of delirium is one of hyperdopaminergia and hypocholinergia.16 The ascending reticular activating system (RAS) and its bilateral thalamic projections regulate alertness, with neocortical and limbic inputs to this system controlling attention. Since acetylcholine is the primary neurotransmitter of the RAS, medications with anticholinergic activity can interfere with its function, resulting in the deficits in alertness and attention that are the heralds of delirium. Similarly, it is thought that loss of cholinergic neuronal activity in the elderly (e.g., due to microvascular disease or atrophy) is the basis for their heightened risk of delirium. Release of endogenous dopamine due to oxidative stress is thought to be responsible for the perceptual disturbances and paranoia that so often lead to the delirious patient being mislabeled as “psychotic.” As we shall discuss later, both cholinergic agents (e.g., physostigmine) and dopamine blockers (e.g., haloperidol) have proven efficacious in the management of delirium.

DIFFERENTIAL DIAGNOSIS

Treatment relies on a careful diagnostic evaluation; there is no substitute for a systematic search for the specific cause of delirium. The temporal relationship to clinical events often gives the best clues to potential causes. For example, a patient who extubated himself was almost certainly in trouble before self-extubation. When did his mental state actually change? Nursing notes should be studied to help discern the first indication of an abnormality (e.g., restlessness, mild confusion, or anxiety). If a time of onset can be established as a marker, other events can be examined for a possible causal relationship to the change in mental state. Initiation or discontinuation of a drug, the onset of fever or hypotension, or the acute worsening of renal function, if in proximity to the time of mental status changes, become more likely culprits.

Without a convincing temporal connection, the cause of delirium may be discovered by its likelihood in the unique clinical situation of the patient. In critical care settings, as in EDs, there are several (life-threatening) states that the clinician can consider routinely. These are states in which intervention needs to be especially prompt because failure to make the diagnosis may result in permanent central nervous system (CNS) damage. These conditions are (1) Wernicke’s disease; (2) hypoxia; (3) hypoglycemia; (4) hypertensive encephalopathy; (5) hyperthermia or hypothermia; (6) intracerebral hemorrhage; (7) meningitis/encephalitis; (8) poisoning (whether exogenous or iatrogenic); and (9) status epilepticus. These conditions are usefully recalled by the mnemonic device WHHHHIMPS (Table 18-3). Other, less urgent but still acute conditions that require interven-tion include subdural hematoma, septicemia, subacute bacterial endocarditis, hepatic or renal failure, thyrotoxicosis/myxedema, delirium tremens, anticholinergic psychosis, and complex partial seizures. If not already ruled out, when present, these conditions are easy to verify. A broad review of conditions frequently associated with delirium is provided by the mnemonic I WATCH DEATH (Table 18-4).

Table 18-3 Life-Threatening Causes of Delirium as Recalled by Use of the Mnemonic WHHHHIMPS

Wernicke’s disease
Hypoxia
Hypoglycemia
Hypertensive encephalopathy
Hyperthermia or hypothermia
Intracerebral hemorrhage
Meningitis/encephalitis
Poisoning (whether exogenous or iatrogenic)
Status epilepticus

Table 18-4 Conditions Frequently Associated with Delirium, Recalled by the Mnemonic I WATCH DEATH

Infectious Encephalitis, meningitis, syphilis, pneumonia, urinary tract infection
Withdrawal Alcohol, sedative-hypnotics
Acute metabolic Acidosis, alkalosis, electrolyte disturbances, hepatic or renal failure
Trauma Heat stroke, burns, postoperative
CNS pathology Abscesses, hemorrhage, seizures, stroke, tumors, vasculitis, normal pressure hydrocephalus
Hypoxia Anemia, carbon monoxide poisoning, hypotension, pulmonary embolus, pulmonary or cardiac failure
Deficiencies Vitamin B12, niacin, thiamine
Endocrinopathies Hyperglycemia or hypoglycemia, hyperadrenocorticism or hypoadrenocorticism, hyperthyroidism or hypothyroidism, hyperparathyroidism or hypoparathyroidism
Acute vascular Hypertensive encephalopathy, shock
Toxins or drugs Medications, pesticides, solvents
Heavy metals Lead, manganese, mercury

Bacteremia commonly clouds an individual’s mental state. In prospectively studied seriously ill hospitalized patients, delirium was commonly correlated with bacteremia.17 In that study, the mortality rate of septic patients with delirium was higher than in septic patients with a normal mental status. In the elderly, regardless of the setting, the onset of confusion should trigger concern about infection. Urinary tract infections (UTIs) and pneumonias are among the most common infections in older patients, and when bacteremia is associated with a UTI, confusion is the presenting feature nearly one-third (30%) of the time.18 Once a consultant has eliminated these basic conditions as possible causes of a patient’s disturbed brain function, there is time enough for a more systematic approach to the differential diagnosis. A comprehensive list of differential diagnoses, similar to the one compiled by Ludwig19 (slightly expanded in Table 18-5), is recommended. A quick review of this list is warranted even when the consultant is relatively sure of the diagnosis.

Table 18-5 Differential Diagnoses of Delirium

General Cause Specific Cause
Vascular Hypertensive encephalopathy; cerebral arteriosclerosis; intracranial hemorrhage or thromboses; emboli from atrial fibrillation, patent foramen ovale, or endocarditic valve; circulatory collapse (shock); systemic lupus erythematosus; polyarteritis nodosa; thrombotic thrombocytopenic purpura; hyperviscosity syndrome; sarcoid
Infectious Encephalitis, bacterial or viral meningitis, fungal meningitis (cryptococcal, coccidioidal, Histoplasma), sepsis, general paresis, brain/epidural/subdural abscess, malaria, human immunodeficiency virus, Lyme disease, typhoid fever, parasitic (toxoplasma, trichinosis, cysticercosis, echinococcosis), Behçet’s syndrome, mumps
Neoplastic Space-occupying lesions, such as gliomas, meningiomas, abscesses; paraneoplastic syndromes; carcinomatous meningitis
Degenerative Senile and presenile dementias, such as Alzheimer’s or Pick’s dementia, Huntington’s chorea, Creutzfeldt-Jakob disease, Wilson’s disease
Intoxication Chronic intoxication or withdrawal effect of sedative-hypnotic drugs, such as bromides, opiates, tranquilizers, anticholinergics, dissociative anesthetics, anticonvulsants, carbon monoxide from burn inhalation
Congenital Epilepsy, postictal states, complex partial status epilepticus, aneurysm
Traumatic Subdural and epidural hematomas, contusion, laceration, postoperative trauma, heat stroke, fat emboli syndrome
Intraventricular Normal pressure hydrocephalus
Vitamin deficiency Deficiencies of thiamine (Wernicke-Korsakoff syndrome), niacin (pellagra), vitamin B12 (pernicious anemia)
Endocrine-metabolic Diabetic coma and shock; uremia; myxedema; hyperthyroidism, parathyroid dysfunction; hypoglycemia; hepatic or renal failure; porphyria; severe electrolyte or acid/base disturbances; paraneoplastic syndrome; Cushing’s/Addison’s syndrome; sleep apnea; carcinoid; Whipple’s disease
Metals Heavy metals (lead, manganese, mercury); other toxins
Anoxia Hypoxia and anoxia secondary to pulmonary or cardiac failure, anesthesia, anemia
Depression—other Depressive pseudodementia, hysteria, catatonia

Modified from Ludwig AM: Principles of clinical psychiatry, New York, 1980, Free Press.

To understand the acute reaction of the individual patient, one should begin by completely reviewing the medical record. Vital signs may reveal periods of hypotension or fever. The highest temperature recorded will also be key. Operative procedures and the use of anesthetics may also induce a sustained period of hypotension or reveal unusually large blood loss and its replacement. Laboratory values should be scanned for abnormalities that could be related to an encephalopathic state.

The old chart, no matter how thick, cannot be overlooked without risk. Some patients have had psychiatric consultations for similar difficulties on prior admissions. Others, in the absence of psychiatric consultations, have caused considerable trouble for their caregivers. Similar to a patient’s psychiatric history, the family psychiatric history can help make a diagnosis, especially if a major mood or anxiety disorder, alcoholism, schizophrenia, or epilepsy is present.

Examination of current and past medications is essential because pharmacological agents (in therapeutic doses, in overdose, or with withdrawal) can produce psychiatric symptoms. Moreover, these considerations must be routinely reviewed, especially in patients whose drugs have been stopped because of surgery or hospitalization or whose drug orders have not been transmitted during transfer between services. Of all causes of an altered mental status, use of drugs and withdrawal from drugs are probably the most common. Some, such as lidocaine, are quite predictable in their ability to cause encephalopathy; the relationship is dose related. Other agents, such as antibiotics, usually cause delirium only in someone whose brain is already vulnerable, as in a patient with a low seizure threshold.20 Table 18-6 lists some drugs used in clinical practice that have been associated with delirium.

Table 18-6 Drugs Used in Clinical Practice That Have Been Associated with Delirium

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Antiarrhythmics
Disopyramide
Lidocaine
Mexiletine
Procainamide
Propafenone
Quinidine
Tocainide
Antibiotics
Aminoglycosides
Amodiaquine
Amphotericin
Cephalosporins
Chloramphenicol
Gentamicin
Isoniazid
Metronidazole
Rifampin
Sulfonamides
Tetracyclines
Ticarcillin
Vancomycin
Anticholinergics
Atropine
Scopolamine
Trihexyphenidyl
Benztropine
Diphenhydramine
Tricyclic antidepressants
Amitriptyline
Clomipramine
Desipramine
Imipramine
Nortriptyline
Protriptyline
Trimipramine
Thioridazine
Eye and nose drops
Anticonvulsants
Phenytoin
Antihypertensives
Captopril
Clonidine
Methyldopa
Reserpine
Antiviral agents
Acyclovir
Interferon
Ganciclovir
Nevirapine
Barbiturates
β-Blockers
Propranolol
Timolol
Cimetidine, ranitidine
Digitalis preparations
Disulfiram
Diuretics
Acetazolamide
Dopamine agonists (central)
Amantadine
Bromocriptine
Levodopa
Selegiline
Ergotamine
GABA agonists
Benzodiazepines
Zolpidem
Zaleplon
Baclofen
Immunosuppressives
Aminoglutethimide
Azacytidine
Chlorambucil
Cytosine arabinoside (high dose)
Dacarbazine
FK-506
5-Fluorouracil
Hexamethylmelamine
Ifosfamide