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Michael A. Fearing, Ph.D.Sharon K. Inouye, M.D., M.P.H.Delirium

(Reprinted with permission from Fearing MA, Inouye SK: Delirium, in The American Psychiatric Publishing Textbook of Geriatric

Psychiatry. Edited by Blazer DG, Steffens DC. Washington, DC, American Psychiatric Publishing, 2009, pp 229–241)

Delirium, defined as an acute and sudden changein attention and overall cognitive function, is a sub-stantial medical problem for older persons—andone that may be preventable. Patients ages 65 yearsand older account for almost half (49%) of all daysof hospital care, and although delirium is the mostfrequent complication affecting this population, itoften goes unrecognized. In fact, delirium affectsover 2.5 million patients ages 65 and older duringhospitalization annually (Inouye et al. 1999; U.S.Department of Health and Human Services 2004).Delirium is a costly condition, leading to increasedcosts per hospital stay of at least $2,500 per patient,

which translates to $6.9 billion (values in U.S. dol-lars in 2004) of annual excess Medicare hospitalexpenditures directly related to delirium and itscomplications. Patients with delirium have a worseprognosis than patients without delirium and are atan increased risk of developing long-term cognitiveand functional decline (Inouye 2006; Jackson et al.2004), which in turn leads to additional posthospi-talization treatment costs, such as for institutional-ization, rehabilitation services, and home healthcare (Inouye 2006). Total health care costs relatedto delirium are estimated at $38 billion to $152

billion annually (Leslie et al. 2008).

DEFINITION AND EPIDEMIOLOGY

The diagnostic criteria for delirium that appearin DSM-IV-TR (American Psychiatric Association2000) are generally accepted as the current diagnos-tic standard (see Table 12-1). Expert consensus wasused to develop the DSM-IV-TR criteria, and sen-sitivity and specificity estimates of the criteria havenot been reported. The Confusion AssessmentMethod (CAM) (Inouye et al. 1990) provides a

simple diagnostic algorithm that has become widely used as a practical means for identification of delirium (see Table 12-1). The CAM diagnosis of delirium is based on an assessment of the clinicalfeatures of acute onset and fluctuating course, inat-tention, disorganized thinking, and altered level of consciousness. The CAM algorithm has a sensitiv-ity of 94%–100%, specificity of 90%–95%, posi-tive predictive accuracy of 91%–94%, and negativepredictive accuracy of 90%–100% compared withthe ratings of geropsychiatrists, as well as high in-terrater reliability (Inouye et al. 1990).

Delirium is often the only sign of an acute andserious medical condition affecting a patient, andit most commonly occurs in frail older persons with an underlying disease process. Occurrenceestimates suggest that delirium affects 14%–56%of hospitalized elderly patients (Cole 2004). De-lirium is a symptom in up to 30% of older pa-tients presenting to the emergency department(Agostini and Inouye 2003; Inouye 2006). De-lirium following surgery is common in patientsages 65 and older, occurring in 15%–53% post-operatively (Balasundaram and Holmes 2007;Inouye 2006; Olin et al. 2005). Not surprisingly,

incidence rates increase to 70%–80% of olderpatients in intensive care (Pisani et al. 2003) andto over 50% of those in nursing home or post-acute care settings (Kiely et al. 2004, 2006). Fol-lowing hospitalization, the estimated 1-yearmortality rate for patients with delirium is 35%–40% (Moran and Dorevitch 2001).

CLINICAL FEATURES AND COURSE OF

DELIRIUM

Sudden and acute onset, alteration in atten-

tion, and fluctuating course are the central fea-tures of delirium. Therefore, it is important toestablish a patient’s level of baseline cognitivefunctioning and the course of cognitive change when evaluating for the presence of delirium. A detailed and in-depth background interview witha proxy informant, such as a family member,caregiver, or medical professional who knows thepatient, proves invaluable when documentingchange in a patient’s mental status. It is impor-tant to differentiate between 1) cognitivechanges that increase and decrease in severity

over a period of days, which is indicative of de-lirium, and 2) changes that are more chronic andprogressive over a period of months to years, which is indicative of dementia. To fulfill thecriteria for delirium, the change in cognitive sta-tus must occur in the context of a medical illness,a metabolic disorder, drug toxicity, or drug with-drawal.

The cognitive evaluation for delirium should en-compass the following domains: global cognitivechanges, impairment in attention, disorganizedthought process, and altered level of consciousness.

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Global cognitive changes associated with deliriumcan be assessed through simple cognitive testingand close clinical observation during test adminis-tration and the patient’s completion of tasks. It isimportant not to underestimate the waxing and waning periods of delirium, because periods of lu-cidity and reversal of symptoms can often be de-ceiving. Impairment in attention, a hallmark fea-ture of delirium, is clinically manifested throughthe patient’s difficulty focusing on the task at hand,maintaining or following a conversation, and/orshifting attention, often leading to perseveration on

a previous topic or task. Disorganized thought ispresent when the patient’s speech is incoherent or jumbled and when the patient lacks a clear or logi-cal presentation of ideas; this problem can be sim-ilar to the “word salad” phenomenon seen inschizophrenia and other formal thought disorders. Alteration in consciousness is highly variable andcan range from an agitated or aggressive state to oneof lethargy or stupor. Other clinical features com-monly associated with delirium that are not in-cluded in the diagnostic criteria are psychomotoragitation, paranoid delusions, sleepwake cycle dis-

ruption, emotional lability, and perceptual distur-bances or hallucinations.

Clinically, delirium typically presents in one of two major forms: hypoactive or hyperactive (Ta-ble 12-2). The hypoactive form, which is morecommon in older patients, is characterized by lethargy and reduced psychomotor functioning.It is important to note that the hypoactive formof delirium is associated with an overall poorerprognosis and often goes unrecognized by clini-cians and caregivers (Liptzin and Levkoff 1992;Sandberg et al. 1999). The reduced level of pa-

tient activity associated with hypoactive deliriumis often attributed to low mood or fatigue, whichmay contribute to its misdiagnosis or under-recognition. The hyperactive form of delirium ischaracterized by agitation, increased vigilance,and often concomitant hallucinations. The hy-peractive form rarely goes unnoticed by caregiv-ers or clinicians. Clinicians should be aware of amixed form of delirium, in which patients fluc-tuate between the hypoactive and the hyperactiveforms. The mixed form creates a challenge indistinguishing symptoms of delirium from

symptoms of other psychotic or mood disorders.

P ATHOPHYSIOLOGY OF DELIRIUM

The fundamental pathophysiological mecha-nisms of delirium remain unclear, most likely be-cause many different etiologies may result in delir-ium through different mechanisms or pathways(Flacker and Lipsitz 1999). Historically, delirium was thought to result from a functional rather thana structural lesion; electroencephalographic find-ings demonstrated global functional impairments

and generalized slowing of alpha wave activity (Proand Wells 1977). Several studies of cerebral bloodflow using positron emission tomography (PET) orsingle-photon emission computed tomography (SPECT) have found that delirium is associatedmostly with decreased blood flow, especially in theprefrontal cortex, thalamus, basal ganglia, tem-poro-parietal cortex, and lingual gyri (Burns et al.2004; Fong et al. 2006; Trzepacz and van der Mast2002). However, results from previous imagingstudies have been highly variable.

Other neuroimaging studies, using either com-

Table 12-1. Diagnostic Criteria for Delirium

DSM-IV-TR diagnostic criteria

A. Disturbance of consciousness (i.e., reduced clarity of awareness of the environment) with reduced ability to focus, sustain, or shiftattention.

B. A change in cognition (such as memory deficit, disorientation, language disturbance) or the development of a perceptual disturbancethat is not better accounted for by a preexisting, established, or evolving dementia.

C. The disturbance develops over a short period of time (usually hours to days) and tends to fluctuate during the course of the day.

D. There is evidence from the history, physical examination, or laboratory findings that the disturbance is caused by the directphysiological consequences of a general medical condition.

The Confusion Assessment Method (CAM) diagnostic algorithma

See The American Psychiatric Publishing Textbook of Geriatric Psychiatry, 2009, pp 222–241 for the complete version of table 12-1.

a The CAM ratings should be completed following brief cognitive assessment of the patient, for example, with the Mini-Mental State Examination. The diagnosis ofdelirium by CAM requires the presence of features 1 and 2 and of either 3 or 4.

Source. Diagnostic criteria for delirium reprinted from American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, TextRevision. Washington, DC, American Psychiatric Association, 2000. Used with permission.CAM diagnostic algorithm adapted from Inouye SK, Vandyck CH, Alessi CA, et al.: “Clarifying Confusion: The Confusion Assessment Method—A New Method forDetection of Delirium. Annals of Internal Medicine 113:941–948, 1990. Used with permission. See The American Psychiatric Publishing Textbook of Geriatric Psy-chiatry, 2009, pp 222–241 for online version of table.

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puted tomography (CT) or magnetic resonanceim-aging (MRI), have demonstrated structural abnor-malities in the brains of patients with delirium,especially in the splenium of the corpus callosum,thalamus, and right temporal lobe (Bogousslavsky et al. 1988; Doherty et al. 2005; Naughton et al.1997; Ogasawara et al. 2005; Takanashi et al.2006). Results from neuropsychological testingalso suggest that delirium is related to disruptionsin higher cortical function, especially in the frontallobe region (Rudolph et al. 2006). The leading cur-

rent hypotheses view delirium as the final commonpathway of many different pathogenic mecha-nisms, including imbalances in neurotransmission,inflammation, and chronic stress.

The most frequently considered mechanism of delirium is dysfunction in the cholinergic system. Acetylcholine plays a key role in mediating con-sciousness and attentional process. Given that de-lirium is manifested by an acute confusional state,often with alterations of consciousness, it is likely tohave a cholinergic basis. Evidence for the cholin-ergic connection includes findings that anticholin-

ergic drugs can induce delirium in humans andanimals and that serum anticholinergic activity isincreased in patients with delirium (Marcantonioet al. 2006). Also, cholinesterase inhibitors havebeen found to reduce symptoms of delirium insome studies (Gleason 2003; Wengel et al. 1998). An excess of dopaminergic neurotransmitters hasalso been cited as a mechanism of delirium and ismost likely related to the role they play in regulatingthe release of acetylcholine (Trzepacz and van derMast 2002). Elevated serotonin, such as that seeninhepatic encephalopathy and “serotonin syndrome,”

is another proposed mechanism of delirium (Mar-cantonio et al. 2006).

Other neurotransmitters, including norepineph-rine, glutamate, and melatonin, have also been im-plicated in the development of delirium, mostlikely due to their interactions with cholinergic anddopaminergic pathways; however, support for theirinvolvement is less substantiated (Cole 2004; In-ouye 2006). Chronic stress induced by severe ill-ness, trauma, or surgery involves sympathetic andimmune system activation that may lead to delir-ium; this activation may include increased activity

of the hypothalamic-pituitary-adrenal axis with hy-percortisolism, release of cerebral cytokines that al-ter neurotransmitter systems, alterations in the thy-roid axis, and modification of blood-brain barrierpermeability.

A SSESSMENT TOOLS FOR DELIRIUM

The Confusion Assessment Method (introducedin “Definition and Epidemiology” earlier in thischapter) is a widely used assessment tool that has

been adapted for use in many settings, such as theintensive care unit (CAM-ICU; Ely et al. 2001) andnursing home (MDS Version 3.0; Centers forMedicare and Medicaid Services, n.d.). For use with nonverbal or intubated patients, the CAM-ICU applies the same four diagnostic criteria as theCAM for the diagnosis of delirium (Ely et al. 2001).In addition to the CAM, several other instrumentsare used to identify the presence or absence of de-lirium, including the Delirium Rating Scale—Re-vised—98 (Trzepacz et al. 2001) and the DeliriumSymptom Interview (Albert et al. 1992). In valida-

tion studies, each instrument has been found tohave a sensitivity of 0.83 or greater and a specificity of 0.75 or greater. In reliability studies, each instru-ment was found to have a kappa coefficient () or acorrelation coefficient (r ) of 0.90 or greater. Boththe Delirium Rating Scale—Revised–98 and the Me-morial Delirium Assessment Scale (MDAS; Breitbartet al. 1997) are used to rate delirium severity.

NEUROPSYCHOLOGICAL ASSESSMENT

OF DELIRIUM

Administering neuropsychological tests duringan acute delirium phase can prove to be difficult,due to the patient’s alteration in basic attentioncapabilities, and may provide minimal useful infor-mation beyond that obtained from global cognitivescreening tools such as the Mini-Mental State Ex-amination (Folstein et al. 1975) followed by theCAM. Given that the hallmark of delirium is alter-ation in attention, additional neuropsychologicalinstruments that target attention should be used when assessing delirium if possible.

Table 12-2. Features of Hypoactive and Hyperactive Delirium

Feature Hypoactive delirium Hyperactive delirium

Consciousness, behavior Fatigue, lethargy Hallucinations, vigilance, combativeness

Psychomotor functioning Reduced activity and functioning Increased activity, agitation

Clinical diagnosis Often goes unrecognized Rarely missed

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Deficits in attention can be measured using taskssuch as Digit Span forward and backward (Wech-sler 1989); backward reciting of the days of the week or the months of the year; Trail Making Test A (Reitan 1958); and the visual search and atten-tion task, which is a cancellation task that requiresthe patient to cross out letters and symbols that areidentical to a target (Trenerry et al. 1990). In oneprevious study, postoperative delirium was foundto be associated with preoperative deficits in atten-tion and executive function (Rudolph et al. 2006),both of which are useful to evaluate in delirium.Executive function measures that are both brief andinformative include the following: Trail MakingTest B (Reitan 1958), Digit Symbol ModalitiesTest (Wechsler 1997), Stroop NeuropsychologicalScreening Test (Trenerry et al. 1989), and Con-trolled Oral Word Association Test (Benton et al.1983). A study of the Clock Drawing Test foundthat although this instrument was a good detector

of overall cognitive impairment, it is not suitablefor detection of delirium (Adamis et al. 2005).Identification of cognitive measuresthat predict delir-ium onset has received some attention in the litera-ture. For example, a study of the Mini-Mental StateExamination demonstrated that four items (i.e., year,date, “sword” spelled backwards, and design copying)of the original 20 items are accurate screening mea-sures for delirium (Fayers et al. 2005).

R ISK FACTORS FOR DELIRIUM

Delirium usually occurs as a result of multifacto-rial causes (Inouye and Charpentier 1996). Al-though it can be caused by a single factor, deliriummore typically develops due to the interrelationshipbetween patient vulnerability at hospital admissionand noxious insults or precipitating factors occur-ring during the course of hospitalization. For exam-ple, a single dose of a sedative given to a patient whois cognitively impaired or severely ill may lead todelirium. However, a patient without severe illnessor cognitive impairment has greater resistance to

developing delirium unless he or she is repeatedly exposed to multiple insults such as surgery, anes-thesia, and psychoactive medications (Gleason2003). The observant clinician will recognize thataddressing only a single noxious insult or factormay not aid in improving delirium but that all pre-disposing and precipitating factors need to be ad-dressed for resolution of delirium.

Existing cognitive impairment and dementia arethe leading risk factors for the development of de-lirium. In fact, patients with dementia have a two-to fivefold increased risk for developing delirium,

and nearly two-thirds of cases of delirium occur inpatients with dementia (Cole 2004; Inouye 2006;Trzepacz and van der Mast 2002). Other predis-posing factors include advanced age, chronic or se-vere underlying illness, number and severity of co-morbid conditions, functional impairment, malegender, dehydration, vision or hearing impair-ments, chronic renal insufficiency, history of alco-hol abuse or dependence, and malnutrition (see Ta-ble 12-3) (Elie et al. 1998; Francis 1992;Rockwood 1989; Rogers et al. 1989).

Various chronic medical illnesses also serve aspredisposing factors to delirium, including neuro-logical disorders (e.g., Parkinson’s disease, cerebro-vascular disease, mass lesions, trauma, infection,collagen vascular disease); systemic or nonneuro-logical infections; metabolic alterations; and car-diac, pulmonary, endocrine, renal, and neoplasticconditions. A validated predictive model for devel-opment of delirium (Inouye et al. 1993) at the time

of hospital admission identified several indepen-dent risk factors, including severe underlying ill-ness, vision impairment, baseline cognitive impair-ment, and a high blood urea nitrogen to creatinineratio (used as an index of dehydration).

Predictive risk models that identify predisposingfactors for delirium have been developed in specificmedical populations, such as surgical patients, can-cer patients, and nursing home patients (Boyle2006; Hamann et al. 2005). A validated model forprediction of persistent delirium in hospitalizedolder patients at discharge has identified five risk

factors: dementia, vision impairment, functionalimpairment, high comorbidity, and use of physicalrestraints during delirium (Inouye et al. 2007).Overall, the development of these risk models aidsin understanding the contribution of patient char-acteristics to delirium risk.

Precipitating factors for delirium include medica-tions, immobilization, use of indwelling bladder cath-eters, use of physical restraints, dehydration, malnu-trition, iatrogenic events, medical illnesses, organinsufficiency or failure (particularly renal or hepatic),infections, electrolyte or metabolic derangement, al-

cohol or drug intoxication or withdrawal, environ-mental influences, and psychosocial factors (see Table12-3) (Agostini and Inouye 2003; Inouye 2006). De-creased mobility, including that associated with theuse of medical devices (e.g., indwelling bladder cath-eters and physical restraints), greatly increases the risk of delirium and functional decline (Lazarus et al.1991). Environmental factors (e.g., inadequate light-ing, increased noise levels), psychosocial factors (e.g.,depression, pain, anxiety), and iatrogenic events (e.g.,transfusion reactions, allergic reactions) can also pre-cipitate delirium.

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With the introduction of oxygen-saturation moni-toring (and subsequent decline of arterial blood gasdetermination), occult respiratory failurehas emergedas an increasing problem for the development of de-lirium in elderly patients. Acute myocardial infarctionand congestive heart failure commonly present withdelirium as well. Metabolic disorders, such as hyper-or hyponatremia, hyper- or hypoglycemia, hypercal-cemia, and thyroid or adrenal dysfunction, may alsocontribute to the development of delirium. Occultinfection due to a variety of medical conditions (e.g.,pneumonia, urinary tract infection, abdominal ab-scess) is a precipitating cause of delirium that is worthnoting because older patients may not present withleukocytosis orthetypicalfebrileresponse. A validatedmodel of precipitating factors for the development of delirium in hospitalized older patients includes fivefactors: the use of physical restraints, malnutrition,more than three medications added during the previ-ous day (over 70% of these were psychoactive drugs),

indwelling bladder catheter, and any iatrogenic event(Inouye and Charpentier 1996).

MEDICATIONS AND DELIRIUM

The role of medications in the development of delirium deserves special attention (Table 12-4).Medication use contributes to delirium in morethan 40% of cases (Inouye 1994; Inouye and Char-pentier 1996). The medications most frequently associated with delirium are those with psychoac-tive effects, such as sedative-hypnotics, anxiolytics,

narcotics, and histamine H2 blockers. Drugs withanticholinergic effects, including antipsychotics,antihistamines, antidepressants, anti-parkinsonianagents, and anticonvulsants, are also commonly as-sociated with delirium. Previous studies have dem-onstrated that the use of psychoactive medicationresults in a 4-fold increased risk of delirium, whereas the use of two or more psychoactive med-ications is associated with a 5-fold increased risk (Inouye and Charpentier 1996). Sedative-hypnoticdrugs are associated with a 3- to 12-fold increasedrisk of delirium, narcotics with a 3-fold risk, and

anticholinergic drugs with a 5- to 12-fold risk (Ag-ostini and Inouye 2003; Foy et al. 1995; Inouye2006; Marcantonio et al. 1994; Schor et al. 1992).

A greater number of medications prescribed leadsto a proportionately greater increased risk for devel-oping delirium. This is related to the direct toxicity of the medications themselves, as well as the in-creased risk of drug-drug and drug-disease interac-tions. Previous studies suggest that overuse of psy-choactive drugs and poor management of medications commonly occur in hospitalized geri-atric patients, providing support for the prevent-

Table 12-3. Predisposing andPrecipitating Factors forDelirium

Predisposing factors

Demographic characteristics Sensory impairment

Age of 65 years or older Visual impairment

Male sex Hearing impairment

Cognit ive status Functional status Dementia Functional dependence

Cognitive impairment Immobility

History of delirium Low level of activity

Depression History of falls

Drugs Decreased oral intake

Treatment withpsychoactive drugs

Dehydration

Treatment with manydrugs

Malnutrition

Alcohol abuse

Coexisting medical conditions

Severe il lness Metabol ic derangements

Multiple coexistingconditions

Neurological disease

Chronic renal orhepatic disease

Terminal illness

History of stroke Fracture or trauma

Infection with HIV

Precipitating factors

Drugs Surgery

Sedative-hypnotics Orthopedic surgery

Narcotics Cardiac surgery

Anticholinergic drugs Prolonged cardiopulmonarybypass

Treatment with multipledrugs Noncardiac surgery

Alcohol or drug withdrawal

Sensory impairment Primary neurological disease

Visual impairment Stroke, particularly nondominanthemispheric

Hearing impairment Intracranial bleeding

Meningitis or encephalitis

Intercurrent illnesses Environment

Infections Admission to intensive care unit

Iatrogenic complications Use of physical restraints

Severe acute illness Use of bladder catheter

Hypoxia Use of multiple procedures

Shock Pain

Fever or hypothermia Admission to intensive care unit

Anemia Emotional stress

Dehydration

Poor nutritional status

Low serum albuminlevel

Metabolic derangements(e.g., electrolytes)

Source. Adapted from Inouye SK: “Current Concepts: Delirium inOlder Persons.” New England Journal of Medicine 354:1157–1165, 2006. Used with permission.

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able nature of many cases of delirium (Bates et al.1995; Lindley et al. 1992). Some homeopathic orherbal therapies, especially those used for mood dis-orders (e.g., St. John’s wort, kava kava), may in-crease the risk of delirium, especially when used in

combination with prescribed psychoactive medica-tions.

Given the role of medications in contributing tothe development of delirium, it is essential to con-duct a complete review of all prescription and over-the-counter medications a patient is taking. Themajority of older patients take several prescribedmedications during hospitalization, increasing therisk for drug-drug and disease-drug interactions.Medications with known psychoactive effectsshould be discontinued or minimized wheneverpossible. At the very least, steps should be taken to

reduce dosage or to substitute medications with lesstoxic potential. In aging adults, medications may cause adverse effects even when given at the recom-mended dosages and with serum drug levels that are within the “therapeutic range.” Determining if thepatient has a history of chronic medication use oralcohol dependence is critical in assessing for with-drawal risk.

DIAGNOSIS AND DIFFERENTIAL

DIAGNOSIS OF DELIRIUM

The diagnosis of delirium is based on clinicalobservation and relies on a thorough cognitive as-sessment, a detailed history from an informantclose to the patient, and a comprehensive physicaland neurological examination. The goal of a thor-ough background history interview is to establishthat a change in cognition has occurred from thepatient’s baseline functioning. Acute alterations in

cognition, representing abrupt deteriorations inmental status, may occur over hours or weeks, al-though it is important to keep in mind that thesealterations may be superimposed on an underlyingdementia as well. Delirium goes unrecognized by clinicians in up to 70% of patients who develop thiscondition (Rockwood et al. 1994); therefore, care-ful clinical assessment for this condition is impera-tive. To facilitate immediate and effective diagnosisand treatment of delirium, it is important to iden-tify all multifactorial contributors. Identification of these factors relies on insightful clinical judgment

combined with a thorough medical evaluation.Guidelines have been established by the AmericanPsychiatric Association (1999) and the Royal Col-lege of Physicians (2006), both of which outlineapproaches to diagnosis and management of delir-ium in the older population.

The initial step during evaluation for deliriumshould be to determine the extent of change fromthe patient’s baseline cognitive status by a carefulhistory with a reliable proxy informant. The impor-tance of obtaining a complete history that focuseson the patient’s baseline cognitive status and chro-

nology of recent mental status changes cannot beunderestimated. The clinician should also assess re-cent changes or updates in medication regimen,new infections, or recent development of medicalillnesses that may contribute to delirium.

The next step involves conducting a careful as-sessment of the patient’s cognitive status (see “Neu-ropsychological Assessment of Delirium” sectionabove). Assessment of vital signs often aids in iden-tifying factors such as fever, tachycardia, or tachy-pnea, each of which may provide important etio-logical clues. Physical examination for signs of

Table 12-4. Drugs Associatedwith Delirium

Sedatives/hypnotics

Benzodiazepines (especially flurazepam, diazepam)

Barbiturates

Sleeping medications (diphenhydramine, chloralhydrate)

Narcotics (especially meperidine)

Anticholinergics

Antihistamines (diphenhydramine, hydroxyzine)

Antispasmodics (belladonna, Lomotil)

Heterocyclic antidepressants (amitriptyline,imipramine, doxepin)

Neuroleptics (chlorpromazine, haloperidol,thioridazine)

Incontinence (oxybutynin, hyoscyamine)

Atropine/Scopolamine

Cardiac

Digitalis glycosides

Antiarrhythmics (quinidine, procainamide, lidocaine)

Antihypertensives (-blockers, methyldopa)

Gastrointestinal

Histamine H2

receptor antagonists (cimetidine,ranitidine, famotidine, nizatidine)

Proton pump inhibitors

Metoclopramide (Reglan)

Herbal remedies (valerian root, St. John’s wort,kava kava)

Source. Reprinted from Hazzard WR, Blass JP, Halter JB, et al.(eds.): Principles of Geriatric Medicine and Gerontology, FifthEdition. New York, McGraw-Hill, 2003. Used with permission.

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medical illnesses or occult infections such as pneu-monia, urinary tract infection, or acute abdominalprocesses should also be conducted. Often, delir-ium may be the initial and only sign ofa serious andlife-threatening underlying illness, such as sepsis,pneumonia, or myocardial infarction. Addition-ally, a detailed neurological examination assessingfor focal changes or evidence of head trauma, infec-tion, or cerebrovascular disease should be per-formed during the evaluation.

The clinician’s most important and difficult task is to differentiate delirium from dementia. Tradi-tionally, delirium has been conceptualized as a brief and transient condition; however, many recentstudies have shown that delirium symptoms may persist for months or years (Levkoff et al. 1994;Marcantonio et al. 2003; McCusker et al. 2003).Previous studies have indicated that dementia is theleading risk factor for delirium and that nearly two-thirds of cases of delirium occur in patients with

dementia (Cole 2004; Inouye 2006). Patients withdementia who develop a superimposed delirium ex-perience a more rapid progression of cognitive dys-function and worse long-term prognosis (Fick andForeman 2000; Jackson et al. 2004).

The key diagnostic feature that aids in distin-guishing these two conditions is that delirium hasan acute and rapid onset, whereas dementia is muchmore gradual in progression. Alterations in atten-tion and changes in level of consciousness alsopoint to a diagnosis of delirium. However, estab-lishing the occurrence of those changes can be dif-

ficult in the face of missing baseline cognitive dataor if preexisting cognitive deficits are reported by aninformant. If the differentiation cannot be made with certainty, then given the life-threatening na-ture of delirium, the patient should be treated asdelirious until proven otherwise.

Other important diagnoses that must be differ-entiated from delirium include psychiatric condi-tions such as depression, mania, and nonorganicpsychotic disorders including schizophrenia. Ingeneral, these conditions do not develop suddenly in the context of a medical illness. Although hallu-

cinations and perceptual disturbances can occur within the context of delirium, alterations in atten-tion and global cognitive impairment are the key features that help to identify delirium. Differenti-ating among diagnoses is critical because deliriumcarries a more serious prognosis without properevaluation and management. For example, treat-ment for certain conditions such as depression oraffective disorders may involve the use of drugs with anticholinergic activity, which in turn couldexacerbate an unrecognized case of delirium. Estab-lishing the diagnosis can be difficult when the cli-

nician is faced with symptoms that are subtle, whena background history is unavailable, or when theclinician is faced with an uncooperative patient. Again, given the seriousness of delirium and the factthat certain medical treatments may actually worsen symptoms, it is best for the clinician to as-sume that delirium is present until further diagnos-tic information is available.

No specific laboratory tests currently exist that willaid in the definitive identification of delirium. Thelaboratory evaluation fordelirium is intended to iden-tifycontributingfactors that willneedto be addressed,and the approach should be guided by astute clinical judgment and tailored to the individual situation.Laboratory tests that should be considered in the de-lirium evaluation include complete blood count, elec-trolytes, kidney and liver function, oxygen saturation,and glucose levels. Evaluation of occult infection canbe obtained through blood cultures, urinalysis, andurine culture. Other laboratory tests, such as thyroid

function, arterial blood gas, vitamin B12 level, cortisollevel, druglevels, toxicology screen, and ammonia lev-els, are also helpful in identifying factors that contrib-ute to delirium. An electrocardiogram and/or chestradiograph may prove useful in patients with cardiacor respiratory diseases.

Brainimaging, using CT, PET, SPECT, or MRI, isindicated in the cases of head trauma or injury, evalu-ation of new focal neurological symptoms, evaluationfor suspected encephalitis, or development of fever of unknown origin. Electroencephalography serves alimited role in the diagnosis of delirium—it has a

false-negative rate of 17% and a false-positive rate of 22% (Pisani et al.2003; Trzepacz et al. 1988)—and ismost useful for detecting an occult seizure disorder.Cerebrospinal fluid examination, accomplishedthrough lumbar puncture, may be useful in cases of febrile delirium or to exclude meningitis or encepha-litis. Overall, the routine use of neuroimaging in de-lirium is not recommended, because the overall diag-nostic yield is low, and the findings fromneuroimaging change the management of patients inless than 10% of cases (Hirao et al. 2006).

PREVENTION AND MANAGEMENT OF

DELIRIUM

PREVENTION

Primary prevention—that is, preventing delir-ium before it develops—is the most effective strat-egy to alleviate symptoms associated with delirium.The Hospital Elder Life Program (HELP) (http:// www.hospitalelderlifeprogram.org) utilizes a mul-tidisciplinary team approach to aid in preventing

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delirium. HELP is a hospital-wide program that was designed to implement delirium preventionstrategies and to promote an overall increase inquality of medical care.

Several controlled clinical trials have also identi-fied successful strategies to help prevent delirium. A targeted multicomponent strategy resulted in a40% reduction in the risk of delirium in patientsfollowing hip fractures (Marcantonio et al. 2001).The targeted multifactorial strategy focused on 10domains: adequate brain oxygen delivery, fluid andelectrolyte balance, pain management, reduction inpsychoactive medications, bowel and bladder func-tion, nutrition, early mobilization, prevention of postoperative complications, appropriate environ-mental stimuli, and treatment of delirium (Mar-cantonio et al. 2001). Controlled trials of educa-tional strategies targeted toward training staff toassess, prevent, and treat delirium have demon-strated positive results in reducing episodes and du-

ration of delirium (Milisen et al. 2001; Tabet et al.2005). Controlled trials of multifactorial interven-tions, which usually consist of a combination of staff education and treatments tailored to meet theindividual needs of patients, have demonstrated re-ductions in delirium rate and/or duration (Berg-mann et al. 2005; Lundstrom et al. 2005; Naugh-ton et al. 2005; Pitkala et al. 2006). A recentcontrolled trial found that compared with rehabil-itation in the hospital setting, home rehabilitationof elderly patients after acute hospitalization wasassociated with lower risk of delirium and greater

patient satisfaction (Caplan et al. 2006). Overall,results from these controlled trials suggest that30%–40% of cases of delirium may be preventableand support the idea that prevention strategiesshould begin as soon as possible after hospital ad-mission.

M ANAGEMENT

In general, nonpharmacological approachesshould be implemented as the first-line treatmentof delirium. Nonpharmacological treatment ap-

proaches include reorientation (e.g., using orienta-tion boards, clocks, calendars), behavioral interven-tions, encouraging the presence of family members,and transferring a disruptive patient to a privateroom or closer to the nurse’s station for increasedsupervision. Consistent and compassionate staff areessential in facilitating contact and communication with the patient through frequent verbal reorient-ing strategies, clear instructions, frequent eye con-tact, and the inclusion of patients as much as pos-sible in all decision making regarding their daily and medical care. Sensory deficits should be as-

sessed and then corrected by ensuring that all assis-tive devices, such as eyeglasses and hearing aids, arereadily available, functioning, and being used prop-erly by the patient. The use of physical restraintsshould be minimized due to their role in prolong-ing delirium, worsening agitation, and increasingcomplications such as strangulation (Inouye et al.2007). Strategies that increase the patient’s mobil-ity, self-care, and independence should be pro-moted.

Other environmental interventions include lim-iting room and staff changes as well as providing aquiet patient care setting with low-level lighting atnight, allowing for an uninterrupted period forsleep. In fact, improving sleep in the patient withdelirium is a highly effective and important inter-vention. McDowell et al. (1998) developed andtested a nonpharmacological sleep protocol that in-cluded treatment strategies such as a back massage,a warm drink, relaxation techniques, and soothing

music. Use of the sleep protocol was highly effec-tive, reducing reliance on sleeping medicationsfrom 54% to 31% (P 0.002) in a hospital envi-ronment (McDowell et al. 1998). Implementationof this type of sleep enhancement program may require unitwide changes in the coordination andscheduling of nursing and medical procedures.Hospital-wide changes may also be warranted toensure a low level of noise at night by, for example,minimizing hallway noise and staff conversations.

Pharmacological management of delirium (seeTable 12-5) should be used only in patients who

have severe agitation that interferes with applica-tion of medical treatments (e.g., intubation) or inpatients who pose a danger to themselves, otherpatients, or staff. It is important to remember thatthe lowest dose of medication should be prescribedfor the shortest period of time possible, becausedrugs used to treat delirium can also lead to anincrease in acute confusion. The goal for drug man-agement should be an alert and manageable patient,not one who is lethargic and sedated.

If required, neuroleptics are the first line of phar-macological treatment. Haloperidol is the most

widely used agent with documented efficacy to de-crease agitation associated with delirium (Breitbartet al. 1996). Although haloperidol can be adminis-tered orally, intramuscularly, or intravenously, theoral route appears to be the most optimal due tofavorable pharmacokinetics. Even though rapid on-set of action is present during intravenous admin-istration of haloperidol, this route should beavoided because of the short duration of treatmenteffects. The average geriatric patient who has notreceived prior treatment with a neuroleptic shouldrequire a total loading dose not exceeding 3–5 mg

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of haloperidol. Subsequently, a maintenance dose

consisting of one-half of the loading dose should beadministered over the next 24-hour period, withdoses tapered during the next several days. It is im-portant that vital signs be monitored before eachadditional dose is administered. Side effects thatmay occur following treatment with haloperidol in-clude sedation, hypotension, extrapyramidal sideeffects, acute dystonias, and anti-cholinergic effects(e.g., dry mouth, constipation, urinary retention,increased confusion).

Atypical antipsychotics that have been used inthe treatment of delirium include risperidone,

olanzapine, and quetiapine; however, these agents

have been tested in only small, uncontrolled studiesand may be associated with a higher mortality rateamong older patients with dementia (Inouye2006). Extrapyramidal effects of atypical neurolep-tics may be equivalent to or slightly less than thoseassociated with haloperidol. Olanzapine in partic-ular has fewer extrapyramidal properties but greateranticholinergic properties when compared withhaloperidol. Olanzapine is generally less effectivethan haloperidol for controlling delirium symp-toms and poses the risk of inducing increased levelsof confusion. Benzodiazepines typically lead to

Table 12-5. Pharmacological Treatment of Delirium

Class and drug Dose Adverse effects Comments

Antipsychotic

Haloperidol 0.5–1.0 mg twice daily orally,with additional doses every4 hr as needed (peak effect, 4–6 hr)

Extrapyramidal symptoms, especiallyif dose is 3 mg per day

Usually agent of choice

0.5–1.0 mg intramuscularly;observe after 30–60 minand repeat if needed (peak effect, 20–40 min)

Prolonged corrected QT interval onelectrocardiogram

Effectiveness demonstrated inrandomized controlled trials(American Psychiatric Association1999; Breitbart et al. 1996)

Avoid in patients with withdrawalsyndrome, hepatic insufficiency,neuroleptic malignant syndrome

Avoid intravenous use because of shortduration of action

Atypical antipsychotic

Risperidone 0.5 mg twice daily Extrapyramidal effects equivalent toor slightly less than those withhaloperidol

Tested only in small uncontrolledstudies

Olanzapine 2.5–5.0 mg once daily Prolonged corrected QT interval on

electrocardiogram

Associated with increased mortality

rate among older patients withdementia

Quetiapine 25 mg twice daily

Benzodiazepine

Lorazepam 0.5–1.0 mg orally, withadditional doses every 4 hras neededa

Paradoxical excitation, respiratorydepression, oversedation

Second-line agent

Associated with prolongation andworsening of delirium symptomsdemonstrated in clinical trial(Breitbart et al. 1996)

Reserve for use in patients undergoingsedative and alcohol withdrawal,those with Parkinson’s disease, andthose with neuroleptic malignantsyndrome

Antidepressant

Trazodone 25–150 mg orally at bedtime Oversedation Tested only in uncontrolled studies

a Intravenous use of lorazepam should be reserved for emergencies.Source. Adapted from Inouye SK: “Current Concepts: Delirium in Older Persons.” New England Journal of Medicine 354:1157–1165, 2006. Used with permission.

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oversedation and exacerbation of confusion and aretherefore not recommended in treating most formsof delirium (Breitbart et al. 1996). However, ben-zodiazepines still remain the treatment of choice intreating alcohol or sedative-hypnotic drug with-drawal symptoms. For geriatric patients, lorazepamis the preferred agent for treating alcohol or seda-tive-hypnotic withdrawal symptoms because of itsshorter half-life, lack of active metabolites, andavailability in parenteral form.

KEY POINTS

● Delirium is a common problem for older per-sons that may be preventable.

● Delirium is the most frequent complicationaffecting older persons and often goes unrec-ognized.

● Patients with delirium have a worse prognosis

than patients without delirium and an in-creased risk of developing long-term cognitiveand functional decline.

● It is important to establish a patient’s level of baseline cognitive functioning and course of cog-nitive change when evaluating for delirium.

● The Confusion Assessment Method provides asimple diagnostic algorithm and has become widely used for identification of delirium.

● Although delirium can be caused by a singlefactor, it is usually multifactorial.

● Existing cognitive impairment and/or demen-

tia are the leading risk factors for developmentof delirium.

● Nonpharmacological approaches should beimplemented as the first line of treatment fordelirium.

● Pharmacological management of deliriumshould be used only in patients with severeagitation.

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