Delirium in the Intensive Care Unit: An Under ...

Delirium in the Intensive Care Unit: An Under-Recognized Syndrome of Organ Dysfunction E. Wesley Ely, M.D., M.P.H.,1 Mark D. Siegel, M.D.,2 and Sharon K. Inouye M.D., M.P.H.3

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The intensivist should think of delirium, or acute central nervous system dysfunction, as the brain’s form of “organ dysfunction.” Delirium is extremely common in intensive care unit (ICU) patients due to factors such as comorbidity, critical illness, and iatrogenesis. This complication of hospital stay is extremely hazardous in older persons and is associated with prolonged hospital stays, institutionalization, and death. Neurologic dysfunction compromises patients’ ability to be removed from mechanical ventilation or achieve full recovery and independence. Yet ICU nurses and physicians are usually unaware of the presence of hypoactive delirium and only recognize this disturbance in agitated patients (hyperactive delirium). More importantly, there are few studies that have included ICU patients in the assessment or prevention of delirium. This article reviews the definition and salient features of delirium, its primary risk factors, a newly validated instrument for delirium assessment that is being developed for ICU nurses and physicians, and pharmacological agents associated with the development of delirium and used in its management. KEYWORDS: Delirium, aging, geriatrics, cognitive impairment, mechanical

ventilation, sedatives, analgesics, respiratory diseases, critical care

Objectives: Upon completion of this article, the reader will have increased his/her awareness of delirium as a potentially serious and sometimes preventable complication in ICU patients. Furthermore, he/she will have learned that nursing-delivered tools are being developed to facilitate the monitoring of delirium in mechanically ventilated patients. Accreditation: The University of Michigan is accredited by the Accreditation Council for Continuing Medical Education to sponsor continuing medical education for physicians. Credit: The University of Michigan designates this educational activity for a maximum of 1.0 hours in category one credit toward the AMA Physicians Recognition Award.

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elirium is derived from the Latin word deliria, which literally means to “be out of your furrow.” Historically, two words were used to describe confused patients. One was the Roman word delirium, which referred to an

agitated and confused person. The other was from the Greek word lethargus, which was used to describe a quietly confused person. The above case demonstrates both of these subtypes of delirium within the same patient.

Seminars in Respiratory and Critical Care Medicine, volume 22, number 2, 2001. Reprint requests: E. Wesley Ely, M.D., M.P.H., F.A.C.P., Division of Allergy/Pulmonary/Critical Care Medicine, Vanderbilt University Medical Center, 6th floor, Medical Center East, Room 6109, Nashville, TN 37232–8300. Email: [email protected]. 1Department of Medicine, Center for Health Services Research and Division of Allergy/Pulmonary/Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee; 2Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Yale University School of Medicine, New Haven, Connecticut; 3Department of Internal Medicine, Division of Geriatrics, Yale University School of Medicine, New Haven, Connecticut. Copyright © 2001 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662. 1069-3424,p;2001,22,02,115,126,ftx,en;srm00066x.

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This will be described in greater detail later in the article, but serves as a nice context within which to consider this important and yet under-recognized problem in critically ill patients. Basic definitions of some commonly used terms are presented in Table 1. In the ICU we aggressively monitor many organ systems for the development of dysfunction or failure. For example, we use pulse oximetry and blood gases to monitor for pulmonary dysfunction, blood pressure and electrocardiography to monitor for cardiac dysfunction, and urine output and serum creatinine to monitor for renal dysfunction. Health care professionals in the ICU have traditionally used inadequate monitoring devices to detect dysfunction in arguably the most important organ of all-the brain. Delirium, acute central nervous system (CNS) dysfunction resulting from any number of common insults that ICU patients experience, has largely been overlooked in critical care research until the past few years. Recent discussions of encephalopathy and organ dysfunction secondary to sepsis fail to mention delirium as one of the clinical manifestations of CNS dysfunction.1,2 Delirium develops in over 80% of ICU patients, and its incidence is likely to increase in future years as older persons more frequently receive ICU care. Delirium is associated with prolonged hospital stays and medical complications that can contribute to increased mortality,3–12 and it may predispose ICU survivors to prolonged neuropsychological deficits. This article will focus on the definition, detection, management, and potential for prevention of delirium in the ICU. Many manuscripts in this important issue of Seminars are devoted to aspects of sedation, central nervous system monitoring, and ongoing advances in this field. In fact, the recent validation of improved sedation scales and new data regarding objective monitoring de-

vices such as the Bispectral EEG will hopefully lead to improved CNS outcomes for our critically ill patients in future years. The ICU literature often refers to delirium as “ICU psychosis,13–18 which represents a potentially dangerous misnomer. The development of delirium often goes unnoticed in the ICU because we think of it as “part of the scenery,” or an expected and inconsequential outcome of mechanical ventilation and other therapies necessary to save lives in the ICU. At Vanderbilt, Yale, and Virginia Commonwealth Universities, a series of investigations are being conducted that are aimed toward improving the working definition and detection of delirium for nonpsychiatrists (e.g., internists, nurses, or respiratory therapists). The CNS monitoring instruments and observations from these investigations will hopefully lead to a change of culture and practice in the ICU whereby we more closely follow patients for the development of delirium and modify their care to help prevent this potentially disastrous complication.

THE OCCURRENCE OF DELIRIUM IN THE ICU—IMPORTANT REALIZATIONS According to the National Research Council, “For many aging people in good physical condition who succumb to an acute illness, cognitive decline is the main threat to their ability to recover and enjoy their favorite activities; for those whose physical activities were already limited, cognitive decline is a major additional threat to quality of life.”19 Two major developments that are frequently linked during older persons’ ICU course are the need for mechanical ventilation and the development of profound and possibly persistent cognitive impairment.20 Most patients in the ICU receive either narcotics or benzodiazepines at some point during their

Table 1 Definitions of Cognitive Syndromes Confusion: A characteristic occurring in delirium resulting in an altered state of consciousness, and characterized by deficits in attention, memory, visuconstructional ability, and executive functions. Think: disturbed orientation with respect to person, place, and time. Delirium: A disturbance of consciousness characterized by an acute onset and fluctuating course of impaired cognitive functioning, so that a patient’s ability to receive, process, store, and recall information is strikingly impaired. Delirium develops over a short period of time (hours to days), is usually reversible, and is a direct consequence of a medical condition, substance intoxication or withdrawal, use of a medication, toxin exposure, or a combination of these factors. Think: rapid onset, clouded consciousness (bewildered/confused), often worse at night, fluctuating. Dementia: Development of a state of generalized cognitive deficits in which there is a deterioration of previously acquired intellectual abilities usually developing over weeks and months. The deficits include memory impairment and at least one of the following: aphasia, apraxia, agnosia, or a disturbance in executive functioning. The cognitive deficits must be sufficiently severe to cause impairment in occupational or social functioning, and they may be progressive, static, or reversible depending on the pathology and the availability of effective treatment. Think: gradual onset, intellectual impairment, memory disturbance, personality/mood change, no clouding of consciousness. Psychosis: A major mental disorder characterized by hallucinations, delusions, or the inability to distinguish reality from fantasy, which lead to an inability to maintain interpersonal relations and to compromised daily functioning. Think: hallucinations/delusions, impaired reality testing, inappropriate mood and impulse control, no clouding of consciousness.

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stay, yet physicians rarely modify the quantity or dosing intervals of these drugs based on patients’ age. Patients on mechanical ventilation are frequently sedated to the point of stupor or coma to improve oxygenation and alleviate agitation and to prevent patients from removing support devices. However, age is only rarely factored into complex decisions regarding when to remove sedatives and liberate patients from mechanical ventilation. As a result, it is now commonplace in the ICU to find that most elderly patients receiving mechanical ventilation are in a drug-induced state of “suspended animation.”21

Case History A 75-year-old woman, status post–median sternotomy and repair of aortic dissection, was extubated uneventfully on post-operative day 3. Two days later she developed confusion and visual hallucinations while still in the intensive care unit (ICU). Her physician noted that she was developing “possible ICU psychosis” and commented, “She is agitated and pulling at her lines, asking to leave the hospital despite being reassured that she needs to stay for recovery.” An order was placed to start haloperidol IV bolus therapy to achieve sedation and avoid benzodiazepines. Subsequent notes confirmed “ICU psychosis,” a high risk of aspiration due to mental status changes, and further administration of haloperidol. There was no mention of precipitating factors or correctable issues regarding the development of her delirium. In fact, several notes stated that ICU psychosis was “an expected complication of her care.” On postoperative day 8, the patient was found to be hypoxemic, and she experienced a respiratory arrest requiring intubation. At that time, the patient was found to have pneumonia on chest x-ray and multiple metabolic disturbances. Benzodiazepines and narcotics were then administered to achieve deep sedation while she was on the ventilator. The patient was on the mechanical ventilator for 6 days (receiving sedation throughout), and then she was allowed to wake up and was weaned from the ventilator. After extubation, the patient’s ICU team asked her how she was doing and she commented that she was fine, but ready to leave. The patient appeared calm and reserved and seemed able to follow commands. Only upon further questioning, however, was she found to have a fluctuating mental status, transient lethargy, and the inability to focus attention. She was transferred to a ward bed, but remained in the hospital for an additional 10 days due to confusion and a “markedly slow recovery process.” Delirium is an acute disorder of attention and cognition, and it is categorized as having two motoric subtypes, hypoactive and hyperactive. We will define delirium in greater detail later in the article, but it is appropriate to outline here a practical ICU scenario in which delirium may either be easily recognized or com-

pletely missed by clinicians. When patients are allowed to emerge from the effects of sedation, they may do so peacefully or in a combative manner. On one extreme are the “peaceful” patients, who are often erroneously assumed to be thinking clearly. Delirium in this context is referred to as “hypoactive delirium” and is characterized by inattention and decreased mental and physical activity.16 Such changes in mental status can lead to adverse outcomes such as reintubation,12,22,23 which itself has been shown to increase 10-fold the risk of nosocomial pneumonia24 and death.25In addition, hypoactive delirium is associated with aspiration, pulmonary embolism, decubitus ulcers, and other complications related to immobility. On the other extreme are agitated or combative patients (i.e., hyperactive delirium), who are at risk for selfextubation and subsequent reintubation, pulling out central venous access, and even falling out of bed. These patients are most often given higher doses of sedatives that commit them to at least another day of mechanical ventilation, which places them at risk for being left in a cognitively impaired state and on mechanical ventilation unnecessarily.26 Because of this difficult cycle, it is important for health care professonals to avoid overuse of psychoactive medications and to develop better methods of assessing cognitive function, especially during the transition from drug-induced or metabolic coma to wakefulness.

“CONFUSION” REGARDING THE DIAGNOSIS OF DELIRIUM There are over 25 terms in the literature used to refer to delirium, such as subacute befuddlement and toxic confusional state. As already mentioned, ICU psychosis is a potentially dangerous misnomer that refers to delirious patients who are demonstrating increased psychomotor activity and hallucinations (i.e., hyperactive delirium).13–18 The more common type of “quiet” or hypoactive delirium is frequently overlooked by physicians and nurses.8,27,28 Delirium remains unrecognized by the clinician in as many as 66 to 84% of patients experiencing this complication,7,29 and it may be attributed incorrectly to dementia, depression, or just an “expected” occurrence in the critically ill, elderly patient.7 Many clinicians expect delirium to present with agitation or hallucinations, features that are not required for the diagnosis. Other reasons for the lack of recognition of delirium include infrequent cognitive assessments and the fluctuating nature of delirium. It has been shown that the very development of delirium is associated with fewer interactions and less time spent by nurses and physicians in direct patient care.30,31 This supports the need to validate and determine the reliability of a nursing-delivered assessment instrument to improve the bedside recognition of delirium in this high-risk population.

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DEMOGRAPHICS OF DELIRIUM Incidence and Cost Among general medical or surgical patients, the frequency of delirium varies from 15 to 60% and is the most frequent complication of hospitalization in older patients.5,7,20,29,32,33 Delirium complicates the hospital stay of more than 2 to 3 million elderly patients per year in the United States, involving over 17.5 million inpatient days and accounting for over $4 billion in Medicare expenditures.34 Although medical ICU patients are among the sickest in our entire medical system, with median costs of $25,000 to $30,000 per patient,9,35 it is unknown what percentage of these expenditures are the result of cognitive impairment. Recent data on long-term outcomes after the acute respiratory distress syndrome (ARDS) demonstrated impaired neuropsychological function in 78% of patients at 1-year follow-up.36 No study of elderly ICU patients with diverse causes of respiratory failure has performed neuropsychological evaluations beyond their ICU stay to determine prevalence of persistent deficits or define risk factors for its development. The incidence of “intensive care syndrome” or ICU psychosis, which is a motoric subtype of delirium,16,17 ranges from 7 to 72%.13,15 In a recent investigation, the development of delirium was selected as one of the top three most important target areas for quality of care improvement in vulnerable older adults.37 However, most studies of delirium n the elderly have excluded intubated patients in the ICU because of their inability to communicate verbally,7,29,32,38,39–41 leaving a paucity of data regarding the incidence and outcomes of delirium among older persons recovering from critical illness.

Aging It is estimated that over the next 3 decades the cost of care for those over 65 will increase 10-fold.42 These data have been used to argue for limiting ICU care provided to the elderly in order to conserve resources.43–45 However, a recent report from Angus et al documented that nearly 60% of all ICU days were incurred by patients older than 65 years.46 In fact, adults under 65 years had 37 ICU days per year per 1000 person-years versus 240 for those over 75 years. The incidence of acute respiratory failure requiring mechanical ventilation rises 10fold from the age of 55 to 85,47 resulting in greater numbers of elderly patints treated in our ICUs.48,49 Without appropriate preventive and management strategies, the aging of the population will result in an increased burden of delirium among hospitalized patients across the country,5,38,50 a factor that could strongly affect discharge rates to nursing homes following hospital discharge.7,8 It has also been shown that advanced age and cognitive decline lead to reductions in the level of interactions and potentially life-saving therapeutic interventions from

clinicians and caregivers.51,52 An ongoing study sponsored by the National Institutes of Health found that less than 10% of elderly ICU patients had been admitted from a nursing home, while rates of discharge to nursing homes were between 25% and 50% (personal communication from Luke Chelluri, University of Pittsburgh). However, this study did not objectively investigate cognitive impairment, which likely contributed greatly to the rates of nursing home placement. We believe that studying acute and persistent neuropsychological deficits in elderly ICU patients could have substantial health and economic benefits in the future.

OUTCOMES AND PROGNOSTIC SIGNIFICANCE OF DELIRIUM Among ICU patients, it remains uncertain if delirium is merely a marker of illness and physical frailty or whether it may contribute independently to poor outcomes. However, there are reports indicating that neurologic injury in the form of underlying central nervous system disease is associated with complications of mechanical ventilation including aspiration, nosocomial pneumonia, reintubation, and self-extubation.12,22–25 We recently showed that the strongest predictor of failed extubation was an abnormal Glagow coma score,10,11 and Russell and colleagues have shown that CNS “failure” is prognostically important in outcome from sepsis.2 In nonICU populations, the development of delirium in the hospital is associated with an inhospital mortality of 25 to 33%, prolonged hospital stay, and three times the likelihood of discharge to a nursing home.8,20,53 In a three-site study of medical non-ICU patients, delirium was found to be an independent predictor of the combined outcome of death or nursing home placement. Francis and Kapoor54 found that 2year mortality in patients having expeienced delirium was 39% versus 23% in controls, but multivariate analysis showed that this was largely explained by baseline cognitive and functional status. Levkoff found that only 4% of her 125 patients with delirium had resolution of all new symptoms by hospital discharge, and only about 1 in 5 had resolution of all new symptoms by 6 months. This study was criticized for not using a standardize baseline cognitive assessment tool such as the Blessed dementia rating scale, and may have underestimated the level of underlying dementia among these patients.

NEUROLOGIC STATUS PREDICTS OUTCOME FROM MECHANICAL VENTILATION Few studies have shown that mental status was an independent predictor of outcome from mechanical ventilation. We studied prospectively the application of a weaning protocol in a group of 100 neurosurgical patients.10,11 The importance of this work is that it has al-


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RISK FACTORS FOR DELIRIUM Many investigations over the past decade, using a variety of patient populations, have identified numerous risk factors for the development of delirium.53 Patients who are highly vulnerable to delirium may develop the disorder following only minor physiologic stressors, whereas those with low baseline vulnerability require a

more noxious insult to become delirious (Fig. 1).56 Importantly, clinical prediction rules have repeatedly shown that it is possible to stratify patients into risk groups depending upon the number of risk factors present.7,39,56,57 In fact, with three or more risk factors, the likelihood of developing delirium is around 60% or higher. It is a rare patient in the ICU who would not be in the high-risk group. In fact, most ICU patients in our studies have over 10 risk factors for delirium.11,50 In practical terms, the risk factors can be divided into three categories: (1) the acute illness itself, (2) host factors including age or chronic health problems, and (3) iatrogenic or environmental factors (Table 2).7,14,20,28,33,39,40,57,58 The confirmation and importance of these factors in ventilated ICU patients has not been investigated.

The Role of Sedative and Analgesic Medications Psychoactive medications are the leading iatrogenic risk factors for delirium.8,56,59,60 Benzodiazepines, narcotics, and other psychoactive drugs are associated with a 3- to 11-fold increased relative risk for the development of delirium.8 In addition, the number and rate of adding psychoactive medications increase the risk of delirium by 4 to 10 times.8 Extreme variability exists in the pharmacokinetics of these agents according to age, ethnicity, drug metabolizing ability, and other factors.61–64 In fact, the half-life of narcotics can increase 6-fold in critically ill patients and the elderly.65–69 Although the use of sedatives and analgesics clearly has a major impact on length of stay and other outcomes (data presented in the following text),70,71 the impact on neuropsychological outcomes from these extremely commonly used med-

Figure 1 The development of delirium involves a complex interrelationship between baseline patient vulnerability (left axis) and precipitating factors or noxious insults occurring during hospitalization (right axis). Many patients in the intensive care unit have a high vulnerability due to their severe underlying illness and may develop delirium with relatively benign insults. (Adapted with permission from Figure 1 in Inouye SK and Carpentier PA. Precipitating factors for delirium in hospitalized elderly persons: predictive model and interrelationship with baseline vulnerability. JAMA 1996;275:852–857.)


lowed us to begin investigating the interaction of the mental status with the ability to remove mechanical ventilation. The interaction between lung mechanics and sensorium are major determinants of safe extubation, but their interplay in weaning patients has been incompletely defined. To identify useful predictors of extubation during a prospective investigation of 100 mechanically ventilated neurosurgical patients, we reviewed demographic and physiologic information including Glasgow Coma Scale (GCS), respiratory rate, tidal volume, arterial partial pressure of oxygen, and fraction of inspired oxygen to extubation outcomes. Multivariate analysis demonstrated that GCS (p < 0.0001) was an independent predictor of successful extubation. Patient age, gender, race, or neurologic diagnosis did not predict successful extubation. Failed extubation occurred in 47% (51/109) of all attempts, an exceedingly high failure rate. GCS 8 [confirmed as the “best” cut-off via receiver operating characteristic (ROC) curve analysis] was associated with failure in 33% versus 79% for GCS < 8 (P < 0.0001). Although these patients certainly had neurologic deficits beyond delirium, this adds to the support that the assessment of CNS dysfunction should assume a higher priority for health care professionals who manage patients receiving mechanical ventilation.

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Table 2 Risk Factors for Deliriuma BUN / Creatinine ratio 18 Renal failure (creatinine > 2.0 mg/dl) Liver disease (bilirubin > 2.0 mg/dl) History of congestive heart failure Cardiogenic or septic shock Human immunodeficiency virus infection Tube feeding Rectal or bladder catheters Central venous catheters Malnutrition Use of physical restraints or posey vest Visual or hearing impairment

Age over 70 Transfer from a nursing home Prior history of depression Prior history of dementia History of stroke, epilepsy Alcohol abuse within a month Administration of psychoactive medications Drug overdose or illicit drug use within week Hypo- or hypernatremia Hypo- or hyperglycemia Hypo- or hyperthyroidism Hypothermia or fever aSee

references 7, 14, 20, 28, 33, 39, 40, 57, 58.

ications in ICU patients is not known. The American Psychiatric Society has recently published its guidelines on delirium, which included a list of substances that can cause delirium through intoxication or withdrawal (Table 3).53

CONTROLLING THE DELIVERY OF SEDATIVES REDUCES TIME ON THE VENTILATOR One randomized controlled investigation, using a nursing-implemented protocol to manage the delivery of sedation, showed a reduction in the duration of mechanical ventilation by 2 days (P = 0.008), decreased

length of stay in the ICU by 2 days (P < 0.0001), and a lower tracheostomy rate among the treatment group (6% vs 13%, P = 0.04).70 In another recently published controlled trial among 128 ICU patients receiving mechanical ventilation, those in whom sedative infusions were interrupted daily had a shorter duration of mechanical ventilation and earlier discharge from the ICU than patients in whom infusions were not interrupted.71 These two studies monitored only the “arousal” component of consciousness (see explanation in the following text), and tracked relatively few adverse events, none of which included patients’ distress during awakening, recollections of discomfort after their stay in the ICU, delirium, or persistent neuropsychological outcomes.21

Table 3 Substances That Can Cause Delirium Through Intoxication or Withdrawala Drugs of Abuse

Medications

Toxins

Alcohol Cannabis Cocaine Hallucinogens Inhalants Opioids Phyncyclidine Sedatives Hypnotics Other

Anesthetics Analgesics Antiasthmatic agents Anticonvulsants Antihistamines Antihypertensive and cardiovascular Antimicrobials Antiparkinsonian medication Corticosteroids Gastrointestinal medications (e.g., H2 blockers)

Anticholinesterase Organophosphate insecticides Carbon monoxide Carbon dioxide Volatile substances (e.g., fuel) Organic solvents

Muscle relaxants Immunosuppressive agents Lithium and psychotropic medications with anticholinergic properties aAmerican Psychiatric Association. Practice Guidelines for the Treatment of Patients with Delirium. Am J Psychiatry 1999;156(5 suppl):1–20.


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Arousal Assessment Arousal, a basic mental process in which the patient can respond to stimuli in the environment, is usually assessed in the ICU in a very subjective fashion with little or no standardization. For the past 25 years, the commonly applied scales for arousal assessment have been the Glasgow Coma Scale74 or the Ramsay Scale,75 neither of which were ever validated for this use in the ICU.76 Recently, there have been several attempts to develop and validate improved scales.77–79 However, these scales have not been shown to have prognostic value, nor do they attempt to measure delirium, the state that many of our patients remain in once we remove their sedation and analgesia.

Attention Assessment The second component of consciousness is attention, which refers to higher mental function that allows the patient to attend and screen out irrelevant stimuli. Attentiveness is a complex interaction of limbic, neocortical, and ascending activating function, and is vulnerable to diffuse injury during times of critical illness. “Attention presupposes alertness, but alertness does not necessarily imply attentiveness.”72 Unfortunately, attentiveness is rarely objectively monitored in the ICU. Attention is assessed in psychiatric and geriatric literature using a variety of instruments. Delirium is defined in the Diagnostic and Statistical Manual (DSM) of Mental Disorders (Table 3) as a disorder of both attention and arousal.80 The confusion assessment method (CAM) was developed so that nonpsychiatrists, such as nurses and other physicians, could assess key delirium features and identify patients with delirium quickly and accurately. Inouye and colleagues designed the CAM to assist clinicians without formal psychiatric training.41 Briefly, the CAM has four features: (1) an acute onset of mental status changes and a fluctuating course, (2) inattention, (3) disorganized thinking, and (4) a level of consciousness other than alert. Patients are determined to be delirious (i.e., CAM positive) if they have both features 1 and 2

and either feature 3 or 4. This is the most widely implemented and user-friendly method of objectively measuring delirium, and it has a sensitivity of 94 to 100%, a specificity between 90 and 95%, and excellent interobserver reliability (kappa of 0.81 to 1.0).41 The CAM has been compared to other instruments by external reviewers and found to have the best combination of ease, speed of use, data acquisition, reliability, and validity.81,82 Use of delirium assessment tools has only recently been brought into the arena of the ICU. Dr. Robert Hart and colleagues from the Virginia Commonwealth University have studied the use of a visual attention and memory instrument in the ICU.83,84 Though promising, these instruments have not been applied in studies beyond these validation cohorts of ICU patients or been followed with neuropsychological evaluation at a later date.

MEASURING DELIRIUM IN THE ICU We have conducted a series of investigations in the ICU over the past 2 years that have focused on the development and monitoring of delirium in patients who are unable to speak, such as those on mechanical ventilation. To explore the feasibility of a multicomponent cognitive assessment program, we conducted an observational cohort investigation in 48 medical and coronary ICU patients.50 In this investigation, patients were assessed using both a sedation scale (i.e., a delirium assessment) and the above-mentioned CAM (i.e., a content assessment), modified for use in intubated, nonverbal patients in the ICU. We have referred to this instrument as the CAM-ICU, and it takes only 2 to 4 minutes to perform in the most difficult patients (Table 5). Independently, a geriatric psychiatric specialist served as a reference standard and rated each patient as either normal, delirious, stuporous, or comatose using DSM-IV criteria for delirium80 or standardized definitions for stupor and coma (Tables 3 and 4). Preliminary results indicate that the CAM-ICU is both valid and reliable in the assessment of delirium, with sensitivities and specificities ranging from 85–100% and interrater reliabilities ranging from 0.92 to 0.96.50 The adaptions for use in the nonverbal ICU patient will be published in forthcoming articles.

IMPORTANCE OF DELIRIUM AND ASSOCIATION WITH OUTCOMES In the above-mentioned study, the geriatric or psychiatric specialist found that 69% of the 293 patient evaluations were abnormal: 27% delirious, 15% stuporous, and 27% comatose.50 Of patients who were awake and following commands with a GCS of 14 or 15, 25%


INSTRUMENTS FOR THE ASSESSMENT OF COGNITIVE IMPAIRMENT AND DELIRIUM As mentioned above, our knowledge regarding the clinical significance of delirium in the ICU is limited by the fact that few investigations have included mechanically ventilated patients in their delirium studies. We aggressively monitor oxygenation, blood pressure, and a myriad of other physiologic factors, yet our scales to monitor the development of delirium remain crude and poorly validated. Consciousness is defined as having two components: arousal and attention,72,73 both of which become abnormal in delirium.

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Table 4 DSM-IV Criteria for Deliriuma A. Disturbance of consciousness (i.e., reduced clarity of awareness of the environment) with reduced ability to focus, sustain, or shift attention. B. A change in cognition (such as memory deficit, disorientation, language disturbance) or the development of a perceptual disturbance that 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 one of the following: i. the direct physiological consequences of a general medical condition ii. the direct result of medication use or substance intoxication (Substance Intoxication Delirium) iii. the direct result of a withdrawal syndrome (Substance Withdrawal Delirium ) iv. the direct result of more than one of the above etiologies (Delirium Due to Multiple Etiologies) aAmerican

Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, D.C.: American Psychiatric Association; 1994:122–138.

were delirious. Future investigations will need to use multivariate analysis to determine the relative importance of severity of illness, age, gender, race, admission diagnosis, the onset of delirium in the ICU, and its duration as predictors of length of stay in the ICU and hospital. At the time of hospital discharge in this small cohort, the Folstein Mini-Mental State Examination85 was abnormal (< 24 out of a possible 30 points) in 58% of the patients, and the CAM-ICU was found to be abnormal in 35% of patients at hospital discharge.

STRATEGIES FOR OPTIMAL MANAGEMENT Primary Prevention and Nonpharmacological Approaches In a recently conducted trial of 852 general medical patients over the age of 70,32 strategies for primary prevention of delirium resulted in a 40% reduction in the odds of developing delirium (15% in controls vs 9.9% in the intervention patients). The protocol32 focused on optimization of risk factors via the following methods:

Table 5 The Confusion Assessment Method for the ICU (CAM-ICU)a FEATURE 1. ACUTE ONSET OF MENTAL STATUS CHANGES OR FLUCTUATING COURSE • Is there evidence of an acute change in mental status from the baseline? • Did the (abnormal) behavior fluctuate during the past 24 hours, that is, tend to come and go, or increase and decrease in severity? FEATURE 2. INATTENTION • Did the patient have difficulty focusing attention? • Is there a reduced ability to maintain and shift attention? FEATURE 3. DISORGANIZED THINKING • 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? • Was the patient able to follow commands throughout the assessment? FEATURE 4. ALTERED LEVEL OF CONSCIOUSNESS (any level of consciousness other than “alert”) Alert—normal, spontaneously fully aware of environment and interacts appropriately Vigilant—hyperalert Lethargic—drowsy but easily aroused, unaware of some elements in the environment, or not spontaneously interacting appropriately with the interviewer; becomes fully aware and appropriately interactive when prodded minimally Stupor—difficult to arouse, unaware of some or all elements in the environment, or not spontaneously interacting with the interviewer; becomes incompletely aware and inappropriately interactive when prodded strongly Coma—unarousable, unaware of all elements in the environment, with no spontaneous interaction or awareness of the interviewer, so that the interview is difficult or impossible even with maximal prodding Scoring: The diagnosis of delirium by the confusion assessment method (CAM) requires the presence of Features 1 and 2 and either Feature 3 or Feature 4. aAdapted

from Inouye SK, van Dyck CH, Alessi CA, Balkin S, Siegal AP, Horowitz RI. Clarifying confusion: the confusion assessment method. Ann Intern Med 1990;113:941–948.


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repeated reorientation of the patient by trained volunteers and nurses, provision of cognitively stimulating activities for the patient three times per day, a nonpharmacological sleep protocol to enhance normalization of sleep/wake cycles, early mobilization activities and range of motion exercises, timely removal of catheters and physical restraints, institution of the use of eyeglasses and magnifying lenses, hearing aids and earwax disimpaction, and early correction of dehydration. However, this study of primary prevention did not focus on critically ill patients, and excluded mechanically ventilated patients. Considering that pilot studies to date have estimated an incidence of delirium approaching 50 to 90%,50,83 one might view the “room for improvement” in delirium management in the ICU or after ICU discharge as far greater than for noncritically ill medical patients. Although primary prevention of delirium is preferred, some degree of delirium is likely to be inevitable in the ICU. In these cases, the above-mentioned basic tenets of patient management, some of which have already been studied,86–90 should be applied to reduce the duration of delirium and its associated complications. Preventive and management strategies for delirium in the ICU represent an important area for future investigation.

Drug Therapy Pharmacological approaches to delirium management should be used only after giving adequate attention to correction of modifiable contributing factors (e.g., sleep disturbance, restraints, etc.) as previously discussed. It is important to recognize that delirium could be a manifestation of an acute, life-threatening problem that requires immediate attention (such as hypoxia, hypercarbia, hypoglycemia, metabolic derangements, or shock). After such concerns have been addressed, severely agitated patients should be considered for pharmacological management of their delirium in order to prevent danger to either the patient or the medical staff. It should be recognized that all agents available for such use will obviously have psychoactive effects that may further cloud the sensorium and promote a longer overall duration of cognitive impairment. Therefore, the drugs should be used judiciously in the smallest possible dose and for the shortest time necessary, a practice infrequently adhered to in most ICUs. Benzodiazepines, which are used most commonly in the ICU for the treatment of anxiety (see other articles in this issue of Seminars), are not recommended for the management of delirium because of the likelihood of oversedation, exacerbation of confusion, respiratory suppression, and prolongation of the confusional state. However, they remain the drugs of choice for the treatment of delirium tremens (and other withdrawal syndromes) and seizures. The amnestic qualities of benzodiazepines make these agents especially useful

when noxious or unpleasant procedures are required. It is likely, however, that the residual accumulation of these drugs may lead to persistent cognitive impairment, which may contribute to delirium long after the drugs have been discontinued. In certain populations, particularly the elderly, patients with underlying dementia, and those already suffering from delirium, benzodiazepines may lead to increased confusion and agitation. In such cases, other agents such as haloperidol may be a better choice. Haloperidol is a butyrophenone, which has likely been underutilized in the ICU for the treatment of agitation.91–93 This is the most widely used neuroleptic agent for the treatment of delirium. Potential advantages of haloperidol include the fact that it does not suppress the respiratory drive and that it is largely nonsedating. In the non-ICU setting, the recommended starting dose of haldoperidol is 0.5 to 1.0 mg orally or parenterally, with repeated doses every 20 to 30 minutes until the desired effect is achieved [maximal recommended doses for the elderly should not exceed 12 mgs in 24 hours in non-ICU settings]. Because of the urgency of the situation in many ICU patients (due to the potential for inadvertent removal of central lines, endotracheal tubes, or even aortic balloon pumps), the doses of haloperidol necessary to relieve anxiety in the ICU may be higher in comparison to non-ICU settings. Unfortunately, there are little data in the way of formal pharmacological investigations to guide dosage recommendations in the ICU. Once calm, the patient usually requires much lower maintenance doses of haloperidol. Side effects to consider include hypotension, acute dystonias, extrapyramidal effects, and anticholinergic effects such as dry mouth, constipation, and urinary retention. The most dangerous potential side effect of using high dose haloperidol is torsades de pointes,94,95 and this agent should be minimized in patients with prolonged QT intervals. Patents who receive substantial quantities of haloperidol or coadministered arrhythmogenic drugs should be monitored closely with electrocardiography. Having mentioned these potential difficulties, this drug is usually very well tolerated from both the hemodynamic and the respiratory standpoint.

CONCLUSION Although well-documented to result in adverse patient outcomes in non-ICU populations, delirium has not been well-studied in mechanically ventilated patients. The medical community knows little regarding the prevalence and prognostic significance of delirium in elderly ICU patients. Our pilot investigation was the first attempt to show the validity and reliability of combining sedation and delirium assessment instruments in ICU patients. The data are very promising, but these findings must be confirmed in a larger group of elderly

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and mechanically ventilated patients and correlated with long-term neuropsychological outcomes. If well validated, this system of bedside assessment could become part of standard ICU monitoring and could be used in future outcomes investigations to reduce delirium or persistent neuropsychological deficits in older, critically ill patients. Such a system could help to determine the prevalence of acute delirium in elderly ICU patients and its association with clinical outcomes in patients recovering from critical illnesses. Furthermore, we need to determine factors associated with persistent neuropsychological deficits in older persons at 6 months following their ICU stay. The optimal management of delirium in the ICU may require implementation of system-wide changes in the handling of patients. This process of implementation is sure to be challenging yet rewarding, and lessons can be learned from the process of implementing weaning protocols in ICU patients.96 If the ongoing prospective cohort investigations demonstrate that delirium is an important and independent risk factor for poor outcomes among critically ill patients, it will send an important wake-up call to the ICU community. We believe that delirium will become an important quality-of-care issue for ICU patients. Due to the costs associated with the development of delirium, monitoring its rate of development could conceivably become a quality assurance/quality improvement item tracked by hospital administrations. For now, however, there is much to be learned about the best ways to standardize the diagnosis of delirium in mechanically ventilated patients with extremely limited communication abilities, the prognostic significance of delirium, and the relative importance of risk factors for its development in the ICU. GRANT SUPPORT

Dr. Ely is a recipient of the AFAR Pharmacology in Aging Grant and is a Geriatric Research and Education Clinical Center (GRECC) investigator. He is an NIH Career Development Award (K23) recipient, and was named a Paul Beeson Scholar in Aging Research by the American Federation for Aging Research. Dr. Inouye is a recipient of a research grant (RO1AG12551) and a Midcareer Award (#K24AG00949) from the National Institute on Aging and a Donaghue Investigator Award (#DF98–105) from the Patrick and Catherine Weldon Donaghue Medical Research Foundation.

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