Outcomes after Intensive Care Delirium

The Delirium Dilemma - advances in thinking about
diagnosis, management, and importance of ICU Delirium

Part I: Impact of brain dysfunction on intensive care

Photo: Dr. Wes Ely, MD

E. Wesley Ely, MD, MPH Department of Medicine, Center for Health Services Research and Division of Allergy/Pulmonary/Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN; the Center for Health Services Research and the VA Tennessee Valley Geriatric Research, Education and Clinical Center (GRECC)

Correspondence: E. Wesley Ely, M.D., MPH, FACP, Division of Allergy/Pulmonary/Critical Care Medicine, Center for Health Services Research, Vanderbilt University Medical Center, Nashville, TN 37232-8300, USA. (E-mail and other contact info can be obtained from CWWJ's Editor-in-Chief).

Key Words: Delirium, Cognitive Impairment, Neuropsychological Assessment, Intensive Care

Grant Support: Dr. Ely is the Associate Director of Research for the VA Tennessee Valley Geriatric Research and Education Clinical Center (GRECC). He is a recipient of the Paul Beeson Faculty Scholar Award from the Alliance for Aging Research and is a recipient of a K23 from the National Institute of Health (#AG01023-01A1). No other financial support was provided

The article also available in PDF: 138KB

Impact of brain dysfunction on intensive care

Patients in the intensive care unit (ICU) who experience delirium are exhibiting an underrecognized form of "organ dysfunction." Delirium is extremely common in ICU patients due to factors such as co-morbidity, critical illness, and iatrogenesis. This neurologic complication can be extremely hazardous in hospitalized older persons and is associated with death, prolonged hospital stays, and institutionalization. Neurologic dysfunction compromises patients' ability to be removed from mechanical ventilation or achieve full recovery and independence. Unfortunately, health care providers in the ICU are unaware of delirium in many circumstances, especially those in which the patient's delirium is manifesting predominantly as the hypoactive (quiet) subtype as opposed to the hyperactive (agitated) subtype. In the last few years, research on ICU delirium has revealed the importance of this problem in critically ill patients as well as methods for routinely monitoring delirium at the bedside. The two parts of this article will review the definition and salient features of delirium, its primary risk factors, validated methods for bedside delirium assessment, pharmacological agents associated with the development of delirium as well as both pharmacological and non-pharmacological strategies in delirium management.

Historical terms, modern research, and our increasing knowledge

Historically, two words were used to describe confused patients. One was the Roman
word "delirium," which referred to an agitated and confused person (think of hyperactive delirium). The other was from the Greek word "lethargus," which was used to describe a quietly confused person (think of hypoactive delirium). ICU patients commonly demonstrate both of these motoric subtypes as they progress through different stages of their illness and therapy. In either case, the patient's brain is not functioning normally. It therefore makes sense that the original derivation of delirium comes from the Latin word deliria, which literally means to "be out of your furrow." For greater clarity and to avoid misuse of terms such as dementia and delirium, we have included basic definitions of some commonly referred to cognitive syndromes in Table 1.

Table 1: Highlights regarding cognitive syndromes

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).

The ICU literature often refers to delirium as "ICU psychosis," (3-8) 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. A series of investigations has recently been conducted that provided validated means of detecting delirium by non-psychiatrists (e.g., internists, nurses, or respiratory therapists). The CNS monitoring instruments and observations from these investigations are leading 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. Indeed, the most recent clinical practice guidelines of the Society of Critical Care Medicine (SCCM) (9) have recommended routine (daily) monitoring of delirium in all mechanically ventilated patients, which will be discussed later in this chapter.

Pathophysiology and etiology of delirium

Delirium is thought to be related to imbalances in the synthesis, release, and inactivation of neurotransmitters modulating the control of cognitive function, behavior, and mood (8,10). Three of the neurotransmitter systems involved in the pathophysiology of delirium are dopamine, gama-aminobutyric acid (GABA), and acetylcholine (11,12). While dopamine increases excitability of neurons, GABA and acetylcholine decrease neuronal excitability (11). An imbalance of one or multiple of these neurotransmitters results in neuronal instability and unpredictable neurotransmission. In general, an excess of dopamine and depletion of acetylcholine are two major physiological problems felt to be central to delirium. In addition to these neurotransmitter systems, others are thought to be involved in the development of delirium such as serotonin imbalance, endorphin hyperfunction, and increased central noradrenergic activity (10,12).

A number of causal factors lead to neurotransmitter imbalance including reduction in cerebral metabolism, primary intracranial disease, systemic diseases, secondary infection of the brain, exogenous toxic agents, withdrawal from substances of abuse such as alcohol or sedative-hypnotics agents, hypoxemia, metabolic disturbances, and the administration of psychoactive medications such as benzodiazepines and narcotics (13). Since the cerebral concentrations of these neurotransmitters are sensitive to many organic and biochemical changes, many things can result in their imbalance (12,13). Cognitive neuroscience and psychopharmacology are active areas of research, which will hopefully yield advances in our understanding and treatment of delirium.

"Confusion" regarding delirium terminology

There are over 25 terms in the literature used to refer to delirium such as "subacute
befuddlement" and "toxic confusional state." Others simply refer to delirium as confusion or neurological impairment. The neurology literature tends to use the term "delirium" exclusively to refer to the hyperactive subtype (14), while referring to hypoactive delirium as encephalopathy. These subtypes are discussed in the next sections. As mentioned above, "ICU psychosis" is a potentially dangerous misnomer, which refers to delirious patients who are demonstrating increased psychomotor activity and hallucinations (i.e., hyperactive delirium) (3-8).

Prevalence and subtypes of ICU delirium

The prevalence of delirium in ICU cohort studies has been reported as 20% (15), 70% (16), or 80% (17) depending upon the characteristics of the patient population and the instrument used. Its incidence is likely to increase in future years as older persons more frequently receive ICU care. 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 (18). Almost every patient in the ICU receives either narcotics or benzodiazepines at some point during their 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 in order to improve oxygenation, alleviate agitation, and to prevent them from removing support devices. However, age is only rarely factored into complex decisions regarding how to dose these potent medications, or when to remove sedatives and liberate patients from mechanical ventilation. The result is that it is now commonplace in the ICU to find most elderly patients receiving mechanical ventilation to be in a drug-induced state of "suspended animation." (19)

The motoric subtypes of delirium are hypoactive, hyperactive, and mixed. Peterson et al. (20) recently reported on delirium subtypes from a cohort of 613 ventilated and nonventilated ICU patients in whom delirium was monitored over 20,000 observations. These investigators found that among patients who developed delirium, pure hyperactive delirium was rare (<5%), while hypoactive and mixed types of delirium were the predominant subtypes (~45% each). Interestingly, the hypoactive subtype was significantly more common in older patients than in the young. The risk factors for and clinical implications of these meteoric subtypes are the subject of ongoing investigations.

The period surrounding cessation of sedation represents a typical scenario in the ICU setting in which delirium may either be easily recognized or completely missed by clinicians. Patients emerging 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 decreased mental and physical activity and inattention (6). Such mental status changes could lead to adverse outcomes such as reintubation, which itself has been shown to increase ten-fold the risk of nosocomial pneumonia and death. In 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 not only for self-extubation and subsequent reintubation, but also 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. This places patients at risk for being left in a cognitively impaired state and on mechanical ventilation unnecessarily (21). Because of this difficult cycle, it is important for health care professionals to avoid overuse of psychoactive medications and to develop better methods of assessing cognitive function, especially during the transition from druginduced or metabolic coma to wakefulness.

Missing the diagnosis of delirium

The above-mentioned "quiet" or hypoactive delirium is frequently overlooked by physicians and nurses (22-25). Delirium remains unrecognized by the clinician in as many as 66% to 84% of patients experiencing this complication (26,27), and it may be attributed incorrectly to dementia, depression, or just an "expected" occurrence in the critically ill, elderly patient (26). 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 (28,29).

Geriatric ICU concerns and pre-existing cognitive impairment

It is estimated that over the next 3 decades the cost of care for those over 65 will increase ten-fold (30). These data have been used to argue for limiting ICU care provided to the elderly in order to conserve resources (31-33). However, a recent report from Angus et al. documented that nearly 60% of all ICU days were incurred by patients older than 65 years (34). In fact, adults <65 had 37 ICU days per year per 1,000 person-years vs. 240 for those over 75 years. The incidence of acute respiratory failure requiring mechanical ventilation rises 10-fold from the age of 55 to 85 (35), resulting in greater numbers of elderly patients treated in our ICUs (36).

Because of these age-related demographics and the relationship between preexisting cognitive impairment and development of delirium, clinicians are likely to discover an increased burden of delirium among hospitalized patients across the country (37,38). It has 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 (39,40). Despite this, we know that more and more elderly patients are being admitted to the ICU than ever before (41), and certainly this will include older patients with pre-existing cognitive impairment ranging from mild to overt dementia. A cohort investigation by Pisani and others (42) studied the impact of pre-existing cognitive impairment (mostly mild) on ICU outcomes, and found that those with and without cognitive impairment had similar outcomes in terms of both ICU and hospital length of stay and mortality. However, the persistence of delirium symptoms in such patients could strongly effect discharge rates to nursing homes following hospitalization (24,26).

Prognostic significance of delirium

Reports indicate that central nervous system (CNS) organ dysfunction is associated with complications of mechanical ventilation including aspiration, nosocomial pneumonia, reintubation, and self-extubation (43-47). It has also been shown in mechanically ventilated neurosurgical patients that the strongest predictor of failed extubation was an abnormal Glasgow coma score (48). In medical ICU patients, Salam et al. (49) showed that there were important interactions between cognitive dysfunction and the likelihood of failed extubation. CNS "failure" is an important predictor of outcome from sepsis 2. In non-ICU populations, the development of delirium in the hospital is associated with an in-hospital mortality of 25% to 33%, prolonged hospital stay, and three times the likelihood of discharge to a nursing home (24,18,50). 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 (51). Francis and Kapoor (52) found that two-year mortality in patients having experienced delirium was 39% vs. 23% in controls, but multivariate analysis showed that this was largely explained by baseline cognitive and functional status. Perhaps the most convincing report of the independent association between delirium and mortality among non-ICU patients was published by McCusker and colleagues (53), showing an adjusted hazard of dying of 2.11 associated with the development of delirium. This mortality increase has now been shown independent of dementia status (54).

Among ICU patients, we now have evidence (55) that delirium is a predictor of mortality (Figure 1). In fact, the development of delirium is associated with a 3-fold increase in risk of death after controlling for pre-existing comorbidities, severity of illness, coma, and the use of sedative and analgesic medications. These data also showed that delirium is not simply a transition state from coma to normal, as delirium occurred just as often among those who never developed coma as it did among those with coma, and persisted in 11% of patients at the time of hospital discharge. Furthermore, three recent prospective studies found that delirium was associated with an increased risk for dementia over 2 to 3 years (56-58). In light of these findings, future studies should determine whether or not prevention or treatment of delirium changes clinical outcomes including mortality, length of stay, cost of care, and long-term neuropsychological outcomes among survivors of critical illness.

Figure 1. Relationship between delirium and six-month survival demonstrated as two Kaplan-Meier plots.


Costs associated with delirium in the ICU patient

Delirium complicates the hospital stay of more than 2 to 3 million elderly patients per year in the U.S., involving over 17.5 million in-patient days and accounting for over US$ 4 billion in Medicare expenditures (59). In the only study to date reporting on costs associated with delirium in the ICU, Milbrandt and colleagues (60) found that median ICU and hospital costs were significantly higher for those with at least one episode of delirium vs. those with no delirium (Figure 2). Even after controlling for important potentially confounding variables, such as baseline comorbidities and severity of illness, delirium was associated with a 40% relative increase in ICU and total hospital costs. In addition, the data demonstrated a "dose-response" in which cumulative delirium severity was associated with incrementally greater cost.

The associated annual cost of ICU delirium could be enormous. In the study by Milbrandt mentioned above (60), delirium occurred in 82% of mechanically patients and was associated with an incremental increase in ICU cost of over $9000 per patient. In the United States, there are approximately 880,000 to 2,760,000 ICU admissions annually for respiratory failure requiring mechanical ventilation. Therefore, the estimated number of cases of ICU delirium could range from 721,600 to 2,263,200 per year with an associated increase in health care costs ranging between $6.5 and $20.4 billion. If we use the incidence of delirium from a less severely ill ICU cohort in which delirium occurred in only 19% of patients (61), the estimated annual costs would still be in the range of US$ 1.5 to US$ 4.7 billion. Since some of the additional cost associated with delirium could be attributable to unmeasured differences between patient groups, these estimates represent the upper limit of the cost attributable to ICU delirium. However, even if only 20% of the difference in costs between patients with and without delirium were in fact due to delirium, this would still be a significant public health concern with US$ 300 million to US$ 4 billion in annual attributable costs.

Figure 2. Delirium is significantly associated with increased ICU and hospital cost.

Median costs per patient according to clinical categorization of Ever delirium vs. Never Delirium (See fig 1 for grouping (55)).

Note the readers

In this two-part article, there are a total of 111 scientific references. The second part: Strategies for Optimal Management of ICU Delirium, appears in issue 21 of the Clinical Window Web Journal - a combined list of references will be published in that article.

Last updated: 31 January 2006
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