The dilemma of delirium: Clinical and research controversies regarding diagnosis and evaluation of delirium in hospitalized elderly medical patients

SPECIAL ARTICLES

The Dilemma of Delirium: Clinical and Research Controversies Regarding Diagnosis and Evaluation of Delirium in Hospitalized Elderly Medical Patients Sharon K. Inouye, MD, MPH, New /-hen, Connecticut Delirium, with occurrence rates from 14% to 56%, associated mortality rates from 10% to 65%, and excess annual health care expenditures from $1 to $2 billion, poses a common and serious problem for hospitalized elderly patients. Delirium is often unrecognized or misdiagnosed by physicians caring for .elderly patients. Cognitive testing is rarely done as part of the admission evaluation of elderly hospitalized patients. Specific diagnosis has been difficult, since diagnostic criteria and instruments are still being developed. The etiology of delirium is complex and multifactorial, and both predisposing (host vulnerability) and precipitating factors must be considered.The recommended approach to the evaluation of delirium is empiric, in the absence of objective efficacy data. The cornerstone of evaluation includes a careful history, physical examination, and review of the medication listsince medications are the most common reversible cause of delirium. Research is needed to establish a cost-effective approach and to clarify the role of further testing, such as cerebrospinal fluid examination, brain imaging, and electroencephalography. This article is intended to heighten the awareness of clinicians as well as to stimulate research to address this important, neglected problem for elderly hospitalized patients. elirium, a clinical syndrome characterized by an acute disruption of attention and cognition, has been described as far back as 2,500 years ag0.l Yet, only in 1980, with the publication of the third edition of the American Psychiatric Association’s Diagnostic and Statistical Manual (DSM-IID were standardized diagnostic criteria established. Despite its occur-

D

From the Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut. Requests for reprints should be addressed to Sharon K. Inouye, MD, MPH, Yale University School of Medicine, Yale-New Haven Hospital, 20 York Street, Tompkins 15, New Haven, Connecticut 06504. Supported in part by grants from the Retirement Research Foundation (Grant# 91-66) and the Sandoz Foundation for Gerontological Research (Grant #ll). Dr. lnouye is a Dana Foundation Faculty Scholar and recipient of Academrc Award #lK08AG0052401 from the National Institute on Aging. Manuscript submitted June 2, 1993, and accepted in revised form February 8, 1994

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rence in from 14% to 56% of elderly hospitalized medical patients,3-20 and an associated mortality rate ranging from 10% to 65%,3>5a6J7s21-30 only a handful of recent studies have prospectively studied risk factors for this important clinical problem.15J8-20~3133Thus, we know very little about diagnosing this prevalent and serious condition. The purpose of this article is to highlight areas of controversy and discrepancies in our knowledge base that will need to be addressed before meaningful clinical guidelines for diagnosis and evaluation of delirium in hospitalized elderly patients can be developed. Current barriers to the recognition and diagnosis of delirium will be addressed, including limitations in current diagnostic criteria and instruments. An overview of studies of the underlying etiology of delirium will be presented, as well as the evaluation of the delirious patient. Finally, we will highlight areas in which research is needed to fully address the problem of delirium in the hospitalized elderly medical patient.

BARRIERS TO RECOGNITION OF DELIRIUM Despite its clinical impact, delirium is often unrecognized by the clinicians caring for the patient. In recent studies, 32% to 67% of delirious patients went unrecognized by physicians (eg, housestaff, attendings).3,3436 Delirium is often overlooked, misdiagnosed as dementia or psychiatric illness, such as depression, or misattributed to “senescence” (ie, part of the normal aging process). We hypothesize several reasons for this lack of recognition. Foremost has been a lack of appreciation of delirium as a potential medical emergency. Many physicians are not aware that in elderly patients, delirium may be the sole manifestation of lifethreatening illness, such as sepsis or myocardial infarction. Secondly, delirium is not often regarded as an important clinical syndrome because its varied and multiple etiologies in the elderly defy the classic disease model and the tendency to look for single causes of disease. In addition, physicians and nurses expect delirium to present with agitation, hallucinations, and inappropriate behavior; whereas in older patients it often presents with lethargy and decreased activity (the hypoactive form of delirium), which is easily overlooked. Finally, the fluctuating nature of delirium may confound the diagnosis, since clinicians may fail to appreciate lucid intervals as characteristic of the syndrome. 97

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The technologic focus of current hospital care diverts time and attention from the clinician’s assessment and recognition of cognitive impairment. Knowledge of the course of cognitive impairment is essential to distinguish delirium from dementia, or to detect delirium superimposed on a pre-existing dementia. During medical evaluations at present, cognitive function is rarely formally assessed,12,37 and (particularly in the hospital setting) there is often minimal knowledge about the patient’s prior cognitive status or the course of any cognitive changes. Finally, the lack of easily applied diagnostic criteria and an accepted diagnostic instrument for delirium have undoubtedly contributed to the recognition problem. The crucial first step towards recognition of delirium is suspecting the diagnosis.

DIAGNOSTICCRITERIAAND INSTRUMENTS The diagnosis of delirium is primarily clinical, based on careful observation and awareness of its key features, which include: acute onset and fluctuating course, inattention, disorganized thinking, and altered level of consciousness38 (Table I). Although diagnostic instruments provide a useful means of standardizing and recording observations, they are by no means a substitute for clinical acumen. Due to the high prevalence of delirium in hospitalized elderly patients, any patient with deterioration in mental status is best presumed to be delirious until it is proved otherwise. While mental status in dementia does not change acutely, delirium by definition represents an acute change. A common catastrophe in the hospital setting is encountering elderly patients labelled as demented who have unrecognized delirium.

Diagnostic

Criteria

The development of diagnostic criteria for delirium has been a recent and evolving process. DSM-III and its revisedversion, DSM-III-R3g (Table I), provide standardized criteria that have been used as the gold standard (or criterion) for previous studies of delirium. However, these criteria have not been assessed for their diagnostic sensitivity and specificity. A simplified, operationalized diagnostic algorithm was developed for the Confusion Assessment Method38 (Table I), and was validated against the gold-standard ratings of psychiatrists. There is considerable disagreement on the features that are essential to the diagnosis of delirium, and those that are merely supportive. Thus, the definition of delirium has not yet stabilized, and new criteria are expected in DSM-IV40 and the International Classification of Diseases, tenth revision (ICD-10),41 based on consensus of expert opinion. Defining a gold standard for diagnosis of delirium, a syndromic diagnosis, has remained a difficult issue. Previous studies

TABLE I Diagnostic Criteria for Delirium DSM-III-RDiagnostic Criteria3g A. Reduced ability to maintain and shift attention to external stimuli B. Disorganized thinking, as indicated by rambling, irrelevant, or incoherent speech C. At least two of the following: 1. Reduced level of consciousness 2. Perceptual disturbances: misinterpretations, illusions, or hallucinations 3. Disturbance of sleep-wake cycle with insomnia or daytime sleepiness 4. Increased or decreased psychomotor activity 5. Disorientation to time, place, or person 6. Memory impairment D. Abrupt onset of symptoms (hours to days), with daily fluctuation E. Either one of the following: 1. Evidence from history, physical examination, or laboratory tests of specific organic etiologic factor(s) 2. Exclusion of nonorganic mental disorders when no etiologic organic factor can be identified The Confusion Assessment Method (CAM)‘ Diagnostic Algorithm3* Feature 1. Acute onset and fluctuating course This feature is usually obtained from a family member or nurse and is shown by positive responses to the following questions: Is there evidence of an acutechange in mental status from the patient’s baseline? Did the (abnormal) behavior fluctuate during the day, that is, tend to come and go, or increase and decrease in severity? Feature 2. Inattention This feature is shown by a positive response to the following question: Did the patient have difficulty focusing attention, for example, being easily distractible, or having difficulty keeping track of what was being said? Feature 3. Disorganized thinking This feature is shown by a positive response to the following question: Was the patient’s thinking disorganized or incoherent, such as rambling or irrelevant conversation, unclear or illogical flow of ideas, or unpredictable switching from subject to subject? Feature 4. Altered level of consciousness This feature is shown by any answer other than “alert” to the following question: Overall, how would you rate this patient’s level of consciousness? (alert [normal], vigilant [hyperalerd, lethargic [drowsy, easily aroused], stupor [difficult to arouse], or coma [unarousablel) ‘The diagnosis of delirium by CAM requires 1 and 2 and either 3 or 4.

the presence

of features

have relied on consensus of expert opinion or clinical judgment of a psychiatrist (or other “expert”). Prospective studies of the phenomenology of delirium, correlating features with the gold standard diagnosis, must be done to clarify key features and establish diagnostic criteria.

Diagnostic

Instruments

Of 18 published instruments17B8~42-56which have been specifically designed or used for evaluation of delirium, only two-the Confusion Assessment Method (CXiJQ3* and the Delirium Rating Scale

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(DRS)4Q-fulfiiled four essential criteria for usefulness in diagnosis of delirium: (1) validated specifically for use in delirium; (2) capability to distinguish delirium from dementia; (3) assessment of multiple features of delirium; and (4) feasibility for use in delirious patients (Table II). The Delirium Symptom Interview (DSlJh6 meets 3 of these 4 criteria, but has not been validated for its ability to distinguish delirium from dementia (Table II). However, when combined with a family or caretaker interview, this distinction can be made on the basis of temporal onset and course. In addition, the reference standard used for this study (Table II) is not widely accepted. The DRS and DSI require substantial training for appropriate use. The three instruments (CAM, DRS, DSI) have been studied in small numbers of patients (eg, CAM, 56 patients; DRS, 47 patients; and DSI, 50 patients). These instruments must be tested in larger samples with a broader spectrum of illness.

DEMENTIAVERSUSDELIRIUM:SEPARATE CONDITIONSOR A SPECTRUMOF COGNITIVEIMPAIRMENT? Dementia and delirium have been recognized and defined as two separate conditions in the medical and psychiatric literature. Yet, are they really two separate conditions, or do they represent two ends along a continuum of cognitive impairment? Several points of evidence suggest an interrelationship or overlap of these two conditions. First, “reversible dementia,“51-61 although less frequent than previously believed, has been well recognized as a clinical entity. Second, delirium may be far more persistent than previously believed.16@,6” In one recent study,@ only 21% and 18% of patients, respectively, resolved all new symptoms of delirium by 3 and 6 months after hospital discharge. Finally, dementia is recognized to be an important risk factor for delirium, and it is estimated that up to two thirds of cases of delirium occur superimposed on dementia.3@ Distinguishing delirium from worsening dementia in this setting can be particularly difficult, since current diagnostic instruments for delirium lose both sensitivity and specificity in the face of severe dementia.38a3g Does delirium lead to dementia? Previous investigators have postulated that delirium in the hospitalized elderly patient could actually represent um-ecognized dementia “unmasked” by acute illness or by close observation in the hospital setting. However, others hypothesize that the delirium itself may lead to chronic cognitive impairment.64 As yet, the question remains unanswered. All of these questions pose difficult yet fundamental issues that will need to be addressed through research. Future studies are needed to establish the specific clinical features of delirium, to improve 280

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diagnostic criteria (including criteria to diagnose delirium in the face of severe dementia), and to establish the most efficacious instruments for clinical and research purposes. Once useful methods are established, large-scale prospective clinical epidemiologic studies are needed to establish the prevalence, incidence, natural history, and long-term outcomes associated with delirium; and to further investigate its relationship with dementia.

UNDERLYINGETIOLOGY The etiology of delirium in the elderly is often complex and multifactorial, involving the interaction of precipitating factors superimposed on a vulnerable patient with predisposing conditions. Identifying the underlying causes for the delirium is of paramount importance, since many causes are easily treatable, and if left untreated, may result in significant morbidity and mortality. However, the search for the underlying causes requires a thorough and careful medical evaluation because the potential causes are innumerable. In addition, differential diagnosis is particularly difficult in elderly patients because of the frequently nonspecific, atypical, or muted presentation of the underlying illness in this group. In fact, mental status change is commonly the only sign of underlying illness, such as pneumonia, sepsis, or myocardial infarction, in an elderly patient.65-67

Identifying the Vulnerable Host: Predisposing Factors To date, seven prospective studies15J8-20,31-33 (Table III) have been published that systematically examine risk factors (eg, predisposing factors present at baseline) for delirium in the hospitalized elderly. These studies have discrepant results, since they were done in disparate populations (eg, varying age, medical versus surgical patients), with varying definitions of delirium, and different case-finding methods. In some, the risk factors were determined only at hospital admission, while in others, they could be measured at any time during hospitalization. Despite these disparities, some common risk factors were identified including: advanced age, pre-existing underlying cognitive impairment, severe chronic illnesses, and functional impairment. These studies (Table III) have important methodologic limitations for identifying the predisposing factors for delirium. Some of these studies failed to separate prevalent cases of delirium (present on admission) from incident cases (occurring during hospitalization), a necessary step to define risk factors that truly precede the onset of delirium. In addition, only one of the previous studies33 used a standardized, validated instrument for the identification of delirium. The others used instruments that were 97

DSM-III-R = Diagnostic

and Statistical

Sensitivity = 0.90; specificity = 0.80 (n = 30 “cases”, 15 noncases, 3 borderline, 2 disagreements by psychiatrist and neurologist). Ability to distinguish delirium and dementia not tested

Manual

Disorders,

and neurologist’s based on pres1 of 3 “critical (disorientation, of consciousness, disturbance) of Mental

Psychiatrists assessments ence of any symptoms” disturbance or perceptual

Consult-liaison psychiatrists diagnosis based on DSM-Ill2 criteria

Gero-psychiatrists’ diagnoses based on clinical judgement and DSM-lll-R3g criteria

Instruments Reference Standard

No overlap in scores between delirious group (n = 20) and 3 control groups: demented (n = 91, schizophrenic tn = 91, and normal (n = 9) Convergent agreement with two other cognitive measures Ability to distinguish delirium and dementia verified

3rd edition*;

Course Organization of thought Level of consciousness Orientation Perceptual problems Psychomotor behavior Sleep-wake cycle

Onset/course Cognitive status Perceptual problems Delusions Psychomotor behavior Emotional lability Sleep-wake cycle Physical disorder

DSM-ljl = Diagnostic and Statistical Manual of Mental Disorders, Examination43; K = Kappa coefficient; n = number of subjects.

Includes interview with brief cognitive assessment and rating scale for 7 symptom domains of delirium, by trained lay or clinical interviewer

Delirium Symptom Interview, DS15‘j

Ten-item rating scale, with additive score 0 to 32, designed to be completed by a psychiatrist after complete psychiatric assessment

Delirium Rating Scale, DRS4g

Sensitivity = 0.94-1.0 (n = 26 delirious patients); Specificity = 0.90-0.95 fn = 30 controls without delirium) Convergent agreement with four other cognitive measures Ability to distinguish delirium and dementia verified

Nine operationalized criteria from DSM-lll-R,3q scored according to CAM algorithm. Based on observations made during interview with MMSE,43 by trained lay or clinical interviewer

Onset/course Attention Organization of thought Level of consciousness Orientation Memory Perceptual problems Psychomotor behavior Sleep-wake cycle

Validation

Overview of Three Delirium

Description Domains Confusion Assessment Method, CAM3*

TABLE II

3rd edition

Inter-rater: K = 0.90

= 0.97

revised3g;

overall

Inter-rater: intraclass correlation coefficient

Inter-rater: K = 1.0 overall

Reliability

MMSE = Mini-Mental

State

Observer-rated in part; lO-15+ minutes for interview, plus additional time for completion of rating (not specified)

Observer-rated; based on lengthy interview and detailed assessment. (Time not specified)

Observer-rated; 10-15 minutes for cognitive testing and completion of rating

Feasibility

CONTROVERSIES ABOUT DELIRIUM/INOUYE TABLE Ill Prospective

Study Williams, 198515

Population, Age (~1, and Sample Size (n) Hip fracture patients, age 260, n = 170

Studies of Risk Factors for Delirium

Gustafson, 198831 Hip fracture patients, age 265, n = 111

Prospective, Delirium in 68 (61%) measured by the daily observations modified Organic Brain Syndrome Scale; “in accordance with DSM-IIIcriteria”. Did not separate prevalent and incident delirium

Foreman, 1989l*

Prospective, Acute confusion in 27 (38%), defined as daily observations the presence of any of 25 behaviors on the Clinical Assessment of Confusion checklist. Incident confusion only

Medical patients, age 2 60, n = 71

Independent Predictors l Age l Preoperative poor performance on cognitive testing. l Low pre-injury activity level

Outcome Study Type Prospective, daily Postoperative confusion in 88 (51%), defined as the presence of any of ratings by nurses 4 behaviors: postop days l-5 disorientation inappropriate communication inappropriate behavior illusions or hallucinations Incident confusion only

l l

l l l l l l

l

l

l

Rockwood, 19891g Medical patients, age 2 65, n = 80

Prospective, Delirium in 20 (25%) measured by the daily observations Glasgow Coma Scale; defined by DSM-III criteria. Did not separate prevalent and incident delirium

Rogers, 1989z2

Elective hip or knee surgery patients, age 2 60, n = 46

Prospective Delirium in 13 (28%) by 2 psychiatrists based on DSM-IIIcriteria. Incident delirium only. evaluations preand post-op (day 4)

Francis, 1990zo

Medical patients, age 2 70, n = 229

Prospective Delirium in 50 (22%), based on operationalized evaluations every DSM-III-Rcriteria. Did not separate prevalent 48 hours and incident delirium

l l l

l

l

l l

l l

l

Schor, 199233

Medical and surgical Prospective daily patients, age > 65, observations admitted from a long- for 14 days term care institution or the community of East Boston, Mass., n = 291

Delirium in 91 (31%) measured using the Delirium Symptom Interview; defined by DSM-IIIcriteria. Incident delirium only

l l

l l

l l

DSM-III = Diagnostic and Statistical vised39; postop = postoperative.

282

Manual of Mental Disorders,

3rd edition*; DSM-III-R = Diagnostic

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and Statistical

Age Dementia

Hypernatremia Hypokalemia Hyperglycemia Hypotension Azotemia High number of medications High confusion rating by nurses High number of orienting items in environment Low number of social interactions Age Dementia Unstable condition on admission Use of scopolamine, propranolol, or flurazepam Abnormal sodium level Severe illness Chronic cognitive impairment Fever/hypothermia Psychoactive drug use Azotemia Age > 80 years Chronic cognitive impairment Fracture on admission Neuroleptic or narcotic use Infection Male gender

Manual of Mental Disorders,

3rd edition re-

CONTROVERSIES

not validated for delirium or relied on “fulfillment of DSM-III” criteria (in an unspecified manner). Finally, a validated predictive model for delirium is needed.

Identifying the Precipitating Factors Many precipitating factors (eg, factors occurring during hospitalization) for delirium have been proposed in the literature, including medications, intercurrent illnesses, infections, metabolic disturbances, dehydration, alcohol withdrawal, acute urinary reenvironmental and psychosocial factention, tors.5,21,24,66,68-72 Medications are the most common reversible cause of delirium73~74 The most commonly associated medications are those with known psychoactive side effects, such as sedative-hypnotics, narcotics, and medications with anticholinergic side effects (Table IV). However, many other medications may also contribute to delirium, such as digitalis, beta-blockers, nonsteroidal anti-inflammatory drugs, and antibiotics-some rather unexpectedly.73-78 Psychosocial factors contributing to delirium in the hospital, such as depression, psychological stress, and lack of social supports, have been systematically examined in only a few studies.1s~31~7g-81 Small sample sizes and inconsistent results have prevented the drawing of definite conclusions from these studies. Finally, hospitalization-related factors contributing to delirium, such as sleep deprivation, unfamiliar environment, frequent room changes, lack of windows, pain, decreased mobility, use of intravenous infusions or indwelling bladder catheters, and other iatrogenic causes, have been suggested in a handful of studies.1”,1g,66,73,8a-84 However, all of the studies evaluated the precipitating factors in small samples, without adequate control for confounding factors (eg, age, underlying illness). Thus, conclusions about the independent role of the risk factors for delirium cannot be drawn from these studies, and multiple, interacting causes were not considered. F’uture studies must examine the independent contributions of predisposing and precipitating factors to the development of delirium. The interaction of host factors with precipitating factors will need to be examined. In addition, prevalent cases of delirium present on admission will need to be carefully separated from incident cases developing during hospitalization, which likely differ in etiology and prognosis. Studies should concentrate on identifying iatrogenic, hospitalization-related factors that contribute to delirium and are potentially remediable.

TABLE

ABOUT

DELIRIUM/lNOUYE

IV Medications

Associated

with

Delirium

Sedative-hypnotics Benzodiazepines (flurazepam, diazepam) Barbiturates Sleeping medications (chloral hydrate) Narcotics Anticholinergics Antihistamines (diphenhydramine, hydroxyzine) Antispasmodics (belladonna, diphenoxylate) Tricyclic antidepressants (amitriptyline, imipramine) Phenothiazines (haloperidol, thorazine, thioridazine) Antiparkinsonian agents (benztropine, trihexyphenidyl) Antiarrhythmics (quinidine, disopyramide) Cardiac (digitalis, lidocaine, amiodarone) Antihypertensives (propranolol, methyldopa, reserpine) Antibiotics (aminoglycosides, penicillins, cephalosporins, sulfonamides) Miscellaneous Lithium Cimetidine Steroids Anticonvulsants Metoclopramide Nonsteroidal anti-inflammatory drugs Levodopa Salicylates

include formal cognitive assessment. Such testing will establish the patient’s baseline status, determine the presence of delirium or dementia, and enable the physician to judge the patient’s decision-making capacity, communication ability, and ability to understand aspects of their medical care. Many excellent brief instruments are available, such as the 30-item MiniMental State Examination,43 the 30-item Cognitive Capacity Screening Examination,46 and others.44@ Since there are no objective data on the efficacy of specific diagnostic tests in the evaluation of delirium, formal evidence-based clinical guidelines cannot yet be developed. The current recommended approach, which is empiric and based on literature review and expert opinion (Table V), provides only broad, general guidelines. Each step requires careful clinical assessment and decision making. There is no standard, “knee-jerk” or “shotgun” approach to delirium; the evaluation must be carefully tailored to the individual situation, requiring substantial clinical judgment. An algorithmic approach is not feasible at present, due to the broad range of potential underlying causes, the varied clinical settings, and the lack of scientific data to facilitate the decision-making process and the choice of specific diagnostic tests. Ideally, the evaluation should proceed as schematically diagrammed in the Figure. However, at present, there is insufficient data to estimate the pretest probabilities for various underlying diseases as causes of delirium, and CLINICAL EVALUATION AND to define the sensitivity and specificity of various diagnostic tests for causes of delirium. With occurrence rates of delirium from 14% to 56%3The cornerstone of the evaluation of delirium is a 2o and dementia from 3% to 25%,85 the admission as- careful, comprehensive history and physical examination. The history should be targeted towards essessment in every elderly hospitalized patient should September

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CONTROVERSIES

ABOUT

DELIRIUM/lNOUYE

TABLE I

c

Approach in Hospitalized

To Evaluation of Delirium Elderly Patients

1. Comprehensive history and physical examination, including cognitive testing 2. Review medication list: discontinue all psychoactive medications (or substitute less toxic alternatives). Check side effects of all medications. 3. Targeted laboratory evaluation: complete blood count, electrolytes, blood urea nitrogen, creatinine, glucose, calcium, phosphate, liver enzymes

identify underlying cause(s) of delirium

I

V Empiric

I

/

Careful history and physical examination for clues to cause(s)

4. Search for occult infection: urinalysis, chest roentgenogram, selected cultures

1

Choose diagnostic tests based On their sensitivity and specificity for underlying diseases

I

I

Estimate the pretest probability for various underlying diseases

1

Approach to the evaluation of delirium in elderly hospitalized

Figure.

patients.

tablishing the course of the mental status change, and obtaining clues about any potentially precipitating factors, such as recent medication changes, signs of acute infection or other medical illnesses. The physical examination should be comprehensive and include a careful search for an infectious process, examination for signs of an acute abdomen, and a careful neurologic examination for focal deficits. Since medications contribute to 22% to 39% of cases of delirium in recent studies,34a51,73 review of the list of current medications, including over-the-counter medications, should be done in every patient. High-risk medications (Table IV), particularly those with psychoactive side effects-such as sedative-hypnotics (eg, flurazepam, diazepam), narcotics, and medications with anticholinergic side effects (eg, diphenhydramine)-should be removed, or less toxic alternatives substituted, whenever possible. Finally, the side effects and potential interactions of all the medications the patient is taking should be reviewed. An astute history and physical examination, review of medications, and targeted laboratory testing should be adequate to identify most potential underlying causes of delirium. Further testing should be tailored to the individual situation. Laboratory tests (eg, complete blood count, electrolytes, blood urea nitrogen, creatinine, glucose, calcium, phosphate, liver function tests) or search for occult infection (eg, urinalysis, chest radiography, selected cultures) may be indicated if the initial evaluation has not suggested a 284

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5. When no obvious cause revealed above, further targeted evaluation to consider in selected patients: Laboratory tests: magnesium, thyroid function tests, B,, level, drug levels, toxicology screen, ammonia level Arterial blood gas: indicated in patients with dyspnea, tachypnea, acute pulmonary process, or history of significant respiratory disease Electrocardiogram: indicated in patients with chest pain, shortness of breath, or cardiac history Cerebrospinal fluid examination: indicated in febrile patients where meningitis is suspected Brain imaging (CT or MR scan): indicated in patients with new focal neurologic signs, or history or signs of head trauma Electroencephalogram: useful in diagnosing occult seizure disorder and differentiating delirium from functional psychiatric disorders. See text for detailed explanation. CT = computed tomography; MR = magnetic

resonance

imaging.

potential underlying cause. In patients with underlying respiratory or cardiac diseases, an arterial blood gas or electrocardiogram may be indicated. Another controversial area in the evaluation of delirium is dete r-mining which patients should undergo cerebrospinal fluid examination, brain imaging, or electroencephalography. Clearly, cerebrospinal fluid examination should be carried out in the febrile delirious patient, whenever meningitis is suspected. However, prediction tools for estimating the risk of central nervous system infection in elderly patients are lacking. In addition, in the afebrile patient, cerebrospinal fluid examination has been advocated when no other organic Cause of delirium can be found, however, clinical yield in this setting remains relatively 10w.~~ The role of brain imaging, such as computed tomography or magnetic resonance imaging, remains uncertain in the evaluation of delirium. In a small, preliminary study, Francis and Kapoor@ found that patients with acute mental status change who fell into a high-risk group for delirium, based on prior risk factors (eg, illness severity, dementia, fever, renal impairment, or psychoactive drug use) and who had no 97

CONTROVERSIES ABOUT DELIRIUM/lNOUYE TABLE VI A Research Agenda for Delirium in Hospitalized Elderly Medical Patients Diagnosis: Development and validation of sensitive and specific diagnostic criteria and instruments for delirium. Methodologic issues to consider: l Identify the important clinical features of delirium l Develop methods sensitive to the transient and fluctuating nature of delirium * Define criteria to distinguish delirium from dementia (or delirium superimposed on a pre-existing dementia) Epidemiology: epidemiology, nautral history, and outcomes of delirium. Methodologic issues to consider: l Separate the prevalent cases (present on admission) of delirium from incident cases (developing during hospitalization) l Elucidate the relationship of delirium to dementia, specificially, does delirium often “unmask” an unrecognized dementia, or does delirium itself lead to chronic cognitive impairment? l Evaluate partial forms of the syndrome: what is their clinical and prognostic significance? l Assess the prognostic significance of delirium: does delirium simply serve as a marker for underlying severe illness, or does it independently contribute to poor long-term outcomes? Pathophysiology: Clarification of the underlying pathogenetic mechanisms of delirium at the cellular and molecular levels. Methodologic issues to consider: l Combined or sequential use of neuroanatomic, neurophysiologic, and neuropsychologic approaches-such as PET or SPECT scans, coupled with biochemical/neurotransmitter studies and neuropsychological testing of patients (before if possible), during and after delirium episodes, compared with appropriate controls. l Evaluation of effects of specific drug challenges under controlled conditions. Etiology: Analyze the complex multifactorial etiology of delirium, involving the interaction of precipitating factors superimposed on a vulnerable host. Methodologic issues to consider: l Develop methods to handle the time-dependent, yet variable nature of exposures and outcome l Clarify the “at-risk” period for exposure to precipitating factors. For the nondelirious patients, should the entire hospitalization be considered the at-risk period? How should early hospital discharges be handled? l Elucidation of the dose-response relationships of exposure with outcome. Are temporal patterns of exposure important? l Is one exposure sufficient, or are repeated exposures required? What is the required temporal proximity of the exposure to the onset of delirium? What “dose” is sufficient? l Address issues of handling repeated measures, such as reliability and stability of measures. Evaluation: Establish systematic cost-effective approaches to the evaluation of delirium. Methodologic issues to consider: l Determine the clinical utility of diagnostic tests of delirium (eg, cerebrospinal fluid examination, brain imaging, Physostigmine challenge test) l Predictive models to identify high-risk patients who would benefit from specific diagnostic approaches, eg, predictive model to identify which febrile delirious patients should receive a lumbar puncture. PET = positron emission tomography; SPECT= single photon emission computed tomography.

new focal neurologic signs, were unlikely to have clinically important findings on brain computed tomography scans. Another studySg showed that patients with delirium have a high frequency of abnormalities on brain imaging; however, these abnormalities were usually not the primary cause of the delirium but rather indications of the presence of underlying structural brain disease. Delirium is a relatively infrequent manifestation of a primary neurologic event,74 for instance, one study revealed that only 3% of 661 patients with stroke presented with deliriurngO Thus, brain imaging may be most useful in cases with new focal neurologic signs, history or signs of head trauma, or those without another identified cause for delirium. Future studies will be needed to clarify the precise role of brain imaging studies in delirium. Although the electroencephalogram has documented usefulness in diagnosing occult seizure disorder, its usefulness in the diagnosis of delirium appears more limited.g1~92Trzepacz et alg3 found that the

characteristic electroencephalographic finding of generalized slowing of background activity had a false-negative rate of 17% and false-positive rate of 22% in differentiating delirious and nondelirious subjects, with the reference standard of a psychiatrist’s ratings based on DSM-III2 criteria. The electroencephalogram is useful to differentiate delirium from functional psychiatric disorders. In patients taking drugs with anticholinergic side effects (Table IV), some investigators have advocated use of the physostigmine challenge test to diagnose delirium due to central anticholinergic toxicity. Rapid improvement in mental status in response to a test dose of 1 to 2 mg of parenteral physostigmine has been considered diagnostic of anticholinergic intoxication in previous studies. g4-g8However, its safety and efficacy have not been evaluated in elderly patients, where the etiology of delirium may be multifactorial. Severe potential toxicity (eg, increased secretions, bronchospasm, vomiting, aspiration, bradycardia) ex-

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ists, and most cases of anticholinergic toxicity can be readily treated by removing the offending agent and offering supportive care. Important areas to target for future research are to establish an efficacious, cost-effective approach to the evaluation of delirium in the hospitalized elderly patient, and to determine the clinical utility of various diagnostic tests, including cerebrospinal fluid examination, brain imaging, electroencephalography, and the physostigmine challenge test. This cost-effective approach could be developed through systematic, prospective evaluation of the empiric approach summarized in Table V and the Figure.

PROPOSALFOR A RESEARCHAGENDA Table VI proposes a research agenda to address delirium in hospitalized elderly patients. This Table provides broad, general guidelines, and only begins to highlight some of the methodologic difficulties that will need to be addressed in studying this difficult topic. In addition, myriad other related topics can undoubtedly be identified. Preliminary work has begun in many of these areas.

CONCLUSIONS Although our currently inadequate knowledge base precludes the development of evidence-based guidelines for the diagnosis and evaluation of delirium, it is hoped that this article will serve to heighten awareness of this important and neglected clinical problem for elderly hospitalized patients. Ultimately, it is hoped that the proposed research will lay the groundwork for randomized intervention trials to prevent and treat delirium. Levkoff et al3 estimated that if the length of stay of each delirious hospitalized elderly patient could be reduced by just one day, the savings to Medicare would amount to $1 to $2 billion annually. This extrapolation highlights the vast economic and health policy implications of delirium, and invokes a compelling imperative for timely research addressing this problem.

ACKNOWLEDGMENT The author acknowledges the support Subcommittee of the American College study. The author thanks Ms. Geraldine manuscript and Drs. Harold Sox, Leo Francis for helpful review of earlier drafts

of the Clinical Efficacy Assessment of Physicians for completion of this Hawthorne for preparation of the Cooney, Ronald Miller, and Joseph of this manuscript.

REFERENCES 1. Lipowski ZJ. Delirium: acute confusional states. Oxford: Oxford University Press; 1990: 1. 2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 3rd ed: Washington, DC: Am Psychiatric Assoc; 1980:104-107. 3. Levkoff SE, Besdine RW, Wetle T. Acute confusional states (Delirium) in the hospitalized elderly. Ann Rev Gerontol Genatr. 1986;6:1-26. 4. Rosin AJ, Boyd RV. Complications of illness in geriatric patients in hospital. J Chron Dis. 1966;19:307-313. 286

September

1994

The American

Journal

of Medicine”

Volume

5. Hodkinson HM. Mental impairment in the elderly. J R Co/l Physicians Land. 1973;7:305-317. 6. Bergman K, Eastham EJ. Psychogeriatric ascertainment and assessment for treatment in an acute medical ward setting. Age Ageing. 1974;3:174-188. 7. Seymour DG, Henschke PJ, Cape RDT, Campbell ACJ. Acute confusional states and dementia in the elderly: the role of dehydration/volume depletion, physical illness and age. Age Ageing. 1980;9:137-146. 8. Report of the Royal College of Physicians by the College Committee on Geriatrics. Organic mental impairment in the elderly. J R Co/l Physicians Land. 1981;15:141-167. 9. Chisholm SE, Deniston OL, lngrisan RM, Barbus AJ. Prevalence of confusion in elderly hospitalized patients. J Gerontol Nurs. 1982;8:87-96. 10. Gillick MR, Serrell NA, Gillick LS. Adverse consequences of hospitalization in the elderly. Sot Sci Med. 1982;16:1033-1038. 11. Warshaw GA, Moore JT, Friedman SW, et al. Functional disability in the hospitalized elderly. JAMA. 1982;248:847-850. 12. Cavanaugh S. The prevalence of emotional and cognitive dysfunction in a general medical population: using the MMSE, GHQ, and BDI. Gen Hosp Psychiatry. 1983;5:15-24. 13. Lipowski ZJ. Transient cognitive disorders (Delirium, acute confusional states) in the elderly. Am J Psychiatry. 1983;140:1429-1436. 14. Lipowski ZJ. Acute confusional states (Delirium) in the elderly. In: Albert ML, ed. Clinical Neurology of Aging. New York: Oxford University Press; 1984:279-297. 15. Williams MA, Campbell EB, Raynor WJ, et al. Predictors of acute confusional states in hospitalized elderly patients. Res Nurs Health. 1985;8:31-40. 16. Fields SD, MacKenzie CR, Charlson ME, Perry SW. Reversibility of cognitive impairment in medical inpatients. Arch Intern Med. 1986;146: 1593-1596. 17. Cameron DJ, Thomas RI, Mulvihill M, Bronheim H. Delirium: a test of the Diagnostic and Statistical Manual Ill Criteria on medical inpatients. J Am Geriatr Sot. 1987;35:1007-1010. 18. Foreman MD. Confusion in the hospitalized elderly: incidence, onset, and associated factors. Res Nurs Health. 1989;12:21-29. 19. Rockwood K. Acute confusion in elderly medical patients. J Am Geriatr Sot. 1989;37:150-154. 20. Francis J, Martin D, Kapoor WN. A prospective study of delirium in hospitalized elderly. JAMA. 1990;263:1097-1101. 21. Roth M. The natural history of mental disorder in old age. J Ment Sci. 1955; 101:281-303. 22. Kay DWK, Norris V, Post F. Prognosis in psychiatric disorders of the elderly: an attempt to define indicators of early death and early recovery. J Merit Sci. 1956;120:129-140. 23. Bedford PD. General medical aspects of confusional states in elderly people. BMJ. 1959;2:185-188. 24. Guze SB, Cantwell DP. The prognosis in “organic brain” syndromes. Am J Psychiatry. 1964;120:878-881. 25. Guze SB, Daengsurisri S. Organic brain syndromes: prognostic significance in general medical patients. Arch Gen Psychiatry. 1967;17:365-366. 26. Rabins PV, Folstein MF. Delirium and dementia: diagnostic criteria and fatality rates. Br J Psychiatry. 1982;140:149-153. 27. Weddington WW. The mortality of delirium: an underappreciated problem? Psychosomatics. 1982;23:1232-1235. 28. Trzepacz PT, Teague GB, Lipowski ZJ. Delirium and other organic mental disorders in a general hospital. Gen Hosp Psychiatry. 1985;7:101-106. 29. Black DW, Warrack G, Winokur G. The Iowa record-linkage study II. Excess mortality among patients with organic mental disorders. Arch Gen Psychiatry. 1985;42:78-81. 30. Fields SD, MacKenzie CR, Charlson ME, Sax FL. Cognitive impairment: can it predict the course of hospitalized patients? J Am Geriatr Sot. 1986;34: 579-585. 31. Gustafson Y, Berggren D, Brannstrom B, et al. Acute confusional states in elderly patients treated for femoral neck fracture. J Am Geriatr Sot. 1988;36: 525-530. 32. Rogers MP, Liang MH, Daltroy LH, et al. Delirium after elective orthopedic surgery: risk factors and natural history. lntl J Psychiatry in Med. 1989;19: 109-121. 97

CONTROVERSIES 33. Schor JD, Levkoff SE, Lipsltz LA, et al. Risk factors for delirium in hosprtallzed elderly. JAMA. 1992;267:827-831. 34. Francis J, Strong S, Martin D, Kapoor W. Delirium in elderly general medical patients: common but often unrecognized. Clin Res. 1988;36:711A. 35. Williams MA, Holloway JR, Winn MC, et al. Nursing activities and acute confusional states in elderly hip-fractured patients. Nurs Res. 1979;28:25-35. 36. Gustafson Y, Brannstrom B, Norberg A, et al. Underdiagnosis and poor documentation of acute confusional states in elderly hip fracture patients. J Am Genatr Sot. 1991;39:760-765. 37. McCartney JR, Palmateer LM. Assessment of cognitive deficit in geriatric patients. JAm Geriair Sot. 1985; 33:467-471. 38. lnouye SK, van Dyck CH, Alessi CA, et al. Clarifying confusion: the Confusion Assessment Method; a new method for detection of delirium. Ann Intern Med. 1990;113:941-948. 39. American Psychiatric Association. Diagnostic and Siatistical Manual of Mental Disorders. 3rd ed, rev. Washington, DC: Am Psychiatric Assoc; 1987: 97-124. 40. American Psychiatric Association. DSM-IV options book: work In progress. Washington, DC: Am Psychiatric Assoc; 1991:Dl-5. 41. World Health Organization. Manual of the International Statistical Classification of Diseases, Injuries, and Causes of Death. 10th Rev. Geneva, Switzerland: World Health Organization. In preparation. 42. Katz NM, Agle DT, DePalma RG, DeCosse JJ. Delirium in surgical patients under intensive care. Arch Surg. 1972;104:310-313. 43. Folstein MF, Folstein SE, McHugh PR. The Mini-Mental State Examination: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12:189-198. 44. Pfeiffer E. A short portable mental status questionnaire for the assessment of organic brain deficit in elderly patients. J Am Geriatr Sot. 1975;23:433-441. 45. Jacobs JW, Bernhard MR, Delgado A, Strain JJ. Screening for organic mental syndromes in the medically ill. Ann Intern Med. 1977;86:40-46. 46. Kiernan RJ, Mueller J, Langstron JW, van Dyck C. The Neurobehavioral Cognitive Status Examination: a brief but differentiated approach to cognitive assessment. Ann Intern Med. 1987;107:41-45. 47. Anthony JC, Leresche LA, Vokoff MR, et al. Screening for delirium on a general medical ward: tachistoscope and a global accessibility rating. Gen Hosp Psychiatry. 1985;7:36-42. 48. Reitan RN. Validity of the Trail-making test as an indicator of organic brain damage. Percept Moot Skills. 1958;8:271-276. 49. Trzepacz PT, Baker RW, Greenhouse J. A simple rating scale for delirium. Psychratty Res. 1988;23:89-97. 50. Lowy FH, Engelsmann F, Lipowski ZJ. A study of cognitrve functioning in a medical population. Compr Psychiatry. 1973;14:331-338. 51. Williams MA, Ward SE, Campbell ED. Confusion: testing versus observation. J Gerontol Nurs. 1986;14:25-30. 52. Champagne MT, Neelon VJ, McConnell ES, Funk S. The NEECHAM confusion scale: assessing acute confusion in the hospitalized and nursing home elderly. Gerontologist 1987;27:4a. 53. Gustafson L. Organic Brain Syndrome Scale COBS-scale). Abstract 128, Second International Congress on Psychogeriatric Medicine, Umea, Sweden, 1985. 54. Vermeersch PEH. The clinical assessment of confuslon-A. Appl Nur Res. 1980;3:128-133. 55. Johnson JC, Gottieb GL, Sullivan E, et al. Using DSM-III criteria to diagnose delirium in elderly general medical patients. J Gerontol Med Sci. 1990;45: 113-119. 56. Albert MS, Levkoff SE, Reilly CH, et al. The Delirium Symptom Interview: an interview for the detection of delirium symptoms in hospitalized patients. J Geriatr Psychiatry Neural. 1992;5:14-21. 57. Kramer SI, Reifler BV. Depression, dementia, and reversible dementia. Clin Geriatr Med. 1992;8:289-297. 58. Draper B. Potentially reversible dementia: a review. Aust NZ J Psychiatry. 1991;25:506-518. 59. Barry PP, Moskowitz MA. The diagnosis of reversible dementia in the elderly: a critical review. Arch Intern Med. 1988;148:1914-1918. 60. Clatfield AM. The reversible dementia’s: Do they reverse? Ann htern Med. 1988;109:476-486. September

ABOUT

DELIRIUM/lNOUYE

61. Larson EB, Reifier BV, Sumi SM, et al. Features of potentially reversible dementia in elderly outpatients. West J Med. 1986;145:488-492. 62. Levkoff SE, Evans DA, Liptzin B, et al. Delirium: the occurrence and persistence of symptoms among elderly hospitalized patients. Arch Intern Med. 1992;152:334-340. 63. Morse RM, Litin EM. The anatomy of a delirium, Am J Psychiat. 1971;128:111-116. 64. Francis J, Kapoor WN. Delirium in hospitalized elderly. J Gen Intern Med. 1990;5:65-79. 65. Arie T. Confusion in old age. Age Aging. 1978;7(suppl):72-76. 66. Millar HR. Psychiatric morbidity in elderly surgical patients. Br J Psychiatry. 1981;138:17-20. 67, Rosenthal G, Steel K. Difference in the presentation of disease. In: Hazzard WR, Andres R, Bierman EL, Blass JP, eds. Principles of Geriatric Medicine and Gerontology. 2nd ed. New York: McGraw-Hill; 1990:212-217. 68. Flint FJ, Richards SM. Organic basis of confusional states in the elderly. BMJ. 1956;2:1537-1539. 69. Sirois F. Delirium: 100 cases. Can J Psychiatry. 1988;33:375-378. 70. Seymour DG, Henschke PJ, Cape RDT, Campbell AJ. Acute confusional states and dementia in the elderly: the role of dehydration/volume depletion, physical illness and age. Age Aging. 1980;9:137-146. 71. Sier HC, Hartnell J, Morley JE, et al. Primary hyperparathyroidism and delirium in the elderly. J Am Geriatr Sot. 1988;36:157-170. 72. Blackburn T, Dunn M. Cystocerebral syndrome: acute urinary retention presenting as confusion in elderly patients. Arch Intern Med. 1990;150:2577-2578. 73. Purdie FR, Honigman B, Rosen P. Acute organic brain syndrome: a review of 100 cases. Ann Emerg Med. 1981;10:455-461. 74. Moses H, Van Kaden BA. Neurologic consultations in a general hospital: spectrum of iatrogenic disease. Am J Med. 1986;81:955-958. 75. The Medical Letter. Drugs that cause psychiatric symptoms. Med Lett Drugs Ther. 1989;31:113-118. 76. Larson ME, Kukell WA, Buchner D, Reifler BV. Adverse drug reactions associated with global cognitive impairment in elderly persons. Ann Intern Med. 1987;107:169-173, 77, Snavely SR, Hodges GR. Thk neurotoxicity of antibacterial medicine. Ann Intern Med. 1984;101:92-104. 78. Danielczyk W. Pharmacotoxic psychoses in patient’s with neurologic disorders in old age. Adv Neural. 1984;40:285-288. 79. Kral VA. Stress and mental disorders of the senium. Med Serv J (Canada). 1962;18:363-370. 80. Kahn RL, Zarit SH, Hilbert NM, Niederehe G. Memory cbmplaint and impairment in the aged: the effect of depression in altered brain function. Arch Gen Psychialry. 1975;32:1569-1573. 81. Reynolds CF, Hoch CC, Kupfer DJ, et al. Bedside differentiation of depressive pseudodementia from dementia. Am J Psychiatry. 1988;145: 1099-1103. 82. Koponen H, Stenback V, Mattla E, et al. Delirium among elderly persons admitted to a psychiatric hospital: clinical course during the acute stage and one-year follow-up. Acta Psychiatr Stand. 1989;79:579-585. 83. Wilson LM. Intensive care delirium: the effect of outside deprivation in a windowless unit. Arch Intern Med. 1972;130:225-226. 84. Mattice M. lntrahospital room transfers: a potential link to delirium in the elderly. Perspectives. 1989;13:10-12. 85. lneichen B. Measuring the rising tide: how many dementia cases will there be by 2001? Br J Psychiatry. 1987;150:193-200. 86. Nelson A, Fogel BS, Faust D. Bedside cognitive screening instruments: a critical assessment. J Nerv Ment Dis. 1986;174:73-83. 87. Wolfson L, Katzman R. The neurologic consultation at age 80. In: Katzman R, Rowe JW, eds. Principles of Geriatric Neurology. Philadelphia: FA Davis; 1992:84-85. 88. Francis J, Kapoor WN. Acute mental change: when are head scans needed? Clin Res. 1991;39:575A. 89. Koponen H, Hurri L, Stenback U, Riekkinen PJ. Acute confusional states in the elderly: a radiological evaluation. Acta Psychiatr Stand. 1987;76:726-731, 90. Dunne JW, Leedman PJ, Edis RH. In obvious stroke: a cause of delirium and dementia. Aust NZ J Med. 1986;16:71-78. 1994

The American

Journal

of Medicine”

Volume

97

287

CONTROVERSIES ABOUT DELIRIUM/lPiOUYE 91. Johnson JC. Delirium in the elderly. Emerg Med Clin North Am. 1990; 8:255-265. 92. Pro JD, Wells CE. The use of the electroencephalogram in the diagnosis of delirium. Dis Nerv Syst 1977;38:804-808. 93. Trzepacz TT, Brenner RP, Coffman G, Van Thiel DH. Delirium in liver transplantation candidates: discriminant analysis of multiple tests variables. Biol Psychiatry. 1988;24:3-14. 94. Granacher RT, Baldessarini RJ, Messner E. Physostigmine treatment of delirium induced by anticholinergics. Am Fam Physician. 1976;13:99-103.

288

September

1994

The American

Journal

of Medicine@

Volume

95. Granacher RP, Baldessarini RJ. Physostigmine: its use in acute anticholinergic syndrome with antidepressant and anti-Parkinson drugs. Arch Gen Psychiatry. 1975;32:375-380. 96. Mogelnicki SR, Wailer JL, Finlayson DC. Physostigmine reversal of cimetidineinduced mental confusion. JAMA. 1979;241:826-827. 97. Goff DC, Garber HJ, Jenike MA. Partial resolution of ranitidine-associated delirium with physostigmine: case report. J Clin Psychiatry. 1985;46:400-401, 98. Stern TA. Continuous infusion of physostigmine and anticholinergic delirium: case report. J Clin Psychiatry. 1983;44:463-464.

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