Civetta, Taylor, & Kirby's: Critical Care, 4th Edition

Section XIV - Neurologic Disease and Dysfunction

Chapter 150 - Behavioral Disturbances in the Intensive Care Unit

 

Ramona O. Hopkins

James C. Jackson

Advances in critical care have led to improved survival rates among those admitted to intensive care units (ICUs). In the United States approximately 55,000 patients are treated in ICUs each day (1). At least 40% of adult ICU patients require mechanical ventilation (2). Patients who require long-term mechanical ventilation (>3 days) represent 4% to 10% of critical care admissions and consume 30% to 50% of critical care resources (3). Critical illness often results in multiple system organ dysfunction, including neurologic dysfunction, and is associated with poor neurologic outcomes (4). Investigations of the effects of critical illness on neurologic dysfunction have been relatively neglected compared to other organ systems. The incidence of neurologic dysfunction or injury has been underestimated, underreported, and only recently studied in critically ill patients. The only study that assessed neurologic organ dysfunction in critically ill patients found that a higher severity of the initial neurologic dysfunction (e.g., lower Glasgow coma score) was associated with higher 30-day mortality. No change or worsening of the severity of the Glasgow coma score from the first to third ICU day was also associated with higher 30-day mortality (5). Neurologic injury following critical illness involves both the central and peripheral nervous systems and contributes to mortality and morbidity (6). Neurologic morbidities include polyneuropathy, encephalopathy, delirium, and cognitive impairments.

Medical and surgical management of critical illnesses can, and frequently does, result in de novo behavioral disturbances, including delirium and cognitive impairments. This chapter will focus on behavioral disturbances associated with critical illness, with an emphasis on delirium and chronic cognitive impairments.

Delirium: An Acute Behavioral Disturbance

Delirium is a neurobehavioral syndrome characterized by acute confusion, inattention, disorganized thinking, and a fluctuating course of mental status changes (7,8). Although delirium is often thought of as a unitary construct, such a concept is simplistic and potentially misleading. The motoric subtypes of delirium are hypoactive, hyperactive, and mixed (8). Hypoactive or “quiet” delirium is characterized by reduced mental and physical activity and inattention (8). In contrast, hyperactively delirious patients are agitated, combative, and at risk for self-extubation, reintubation, pulling out central lines, and falls. Delirium is a dynamic condition and often fluctuates between the hypoactive or hyperactive delirium (9). In ICU populations, a mixed clinical picture is common (10). Given the multiple possible presentations, it is not uncommon for clinicians to miss the diagnosis of delirium (11). A large survey found delirium to be underdiagnosed by 80% of physicians (12). Standardized ICU examinations using the reliable, sensitive, and specific CAM (Confusion Assessment Method)-ICU (13) allows for accurate detection and analysis of delirium.

As others have observed (14), delirium may be the most common psychiatric condition experienced by hospitalized elderly, affecting between 15% and 20% of hospitalized medical patients (15,16), 25% to 65% of surgical patients (17), and as many as 80% of patients in ICU settings (13,18). Although once considered benign (19), recent evidence has linked delirium with various adverse outcomes, including prolonged hospitalization (20,21,22), poor surgical recovery (23), and increased morbidity and mortality (24). Delirium is also associated with adverse cognitive outcomes in critically ill patients (25) (see section on the association between delirium and cognitive outcomes below). Although delirium may be a sign of emerging cognitive impairment, it is clearly not the case that the cognitive decline experienced by many patients with delirium is solely or primarily related to pre-existing cognitive impairment. For example, Jackson et al. (25) excluded patients with probable early dementia and found nearly one third of the ICU patients (all with delirium) with cognitive impairments at 6 months. Thus, delirium is not simply a marker of pre-existing subclinical or early dementia.

Chronic Cognitive Impairments

Critical illness and its medical and surgical management can and frequently do result in de novo cognitive impairments. Cognitive processes or functions are defined as ways of experiencing and thinking about the world and include intelligence, attention, learning, memory, language, visual spatial abilities, and executive function (e.g., reasoning, decision making, planning, problem solving, working memory, sequencing, and executive control). Research is limited regarding cognitive outcomes in survivors of critical illness; however, these patients are at risk to develop long-term or chronic cognitive impairments (25,26,27,28,29). In ICU survivors, approximately one third or more will develop chronic cognitive impairment (25). Although it is difficult to make comparisons across studies due to different definitions of cognitive sequelae, neuropsychological tests administered, time to follow-up, patient population, study design (prospective vs. retrospective), or inclusion of a control group, current data suggest that cognitive impairments are common in survivors of critical illness.

Nature of Cognitive Impairments

Currently, there are 10 cohorts totaling approximately 455 patients that have assessed long-term cognitive impairments following critical illness (30,31,32,33,34,35,36,37,38,39,40). The populations of the patient cohorts include five studies in acute respiratory distress syndrome (ARDS) patients (30,34,35,38,41,42)— one study of acute lung injury (40), one study in patients with respiratory failure (42), one study in medical ICU patients (39), and two studies in general ICU patients (32,36). The time to cognitive assessment is variable, with most of the cognitive follow-up occurring during the first year post hospital discharge (43). The evidence suggests that 25% to 78% of ICU survivors experience cognitive impairments (30,31,33,34,35,36,37,38,39,40,42). Among specific populations, such as patients with ARDS, the prevalence of cognitive impairments is as high as 78% at hospital discharge, 46% at 1 year (30), and 25% at 6 years (40). A prospective study found cognitive impairments in 70% of ARDS patients at hospital discharge, 45% at 1 year, and 47% at 2 years (42), with almost half of the patient scores falling below the sixth percentile of the normal distribution of cognitive function. The cognitive impairments occur in various cognitive domains (Table 150.1). The cognitive impairments in critically ill patients are similar to those reported in other populations such as carbon monoxide poisoning (44) and following elective coronary artery bypass graft surgery (45).

In the general population of critically ill patients, Jackson et al. (25) found that 33% had chronic cognitive impairments (defined using a very conservative definition of impairment of 2 test scores 2 standard deviations below the mean or 3 test scores 1.5 standard deviations below the mean). The cognitive deficits were mild to moderate in severity. Although 34 patients completed a 6-month cognitive follow-up, 128 patients, all without pre-existing cognitive impairment assessed using the Informant Questionnaire of Cognitive Decline in the Elderly (IQCODE), were administered an initial Mini Mental State Exam (MMSE) at ICU discharge. Of the critically ill survivors who did not complete cognitive follow-up, mean MMSE scores were below the impairment cutoff of 24 and were significantly lower than those of the patients who completed follow-up. This finding suggests that cognitive impairments may be more common than reported in current outcome studies, as the patients with the lowest MMSE scores were lost to follow-up (25). Similar findings of cognitive impairments come from a prospective cohort of 32 critically ill medical patients who underwent long-term mechanical ventilation (5 or more days). Of the patients with long-term mechanical ventilation, 91% at hospital discharge and 41% at 6 months had cognitive impairments (33).

Table 150.1 Cognitive Impairments Observed Following Critical Illness

COGNITIVE DOMAINS

SPECIFIC COGNITIVE IMPAIRMENTS

Attention

Divided attention
Focused attention
Sustained attention

Memory

Explicit or declarative
Recall (verbal and nonverbal)
Recognition (verbal and nonverbal)
Short-term memory

Intelligence

Verbal intelligence
Performance intelligence
Full-scale (general) intelligence

Language

Verbal fluency

Visual spatial

Apraxia
Visuoconstruction

Executive function

Decision making
Executive control
Impulsivity
Perseveration
Planning
Problem solving
Shifting sets
Working memory

Mental processing speed

Slow mental processing speed

Motor

Grip strength

Cognitive impairments in ICU survivors occur in various cognitive domains, although information regarding the nature and severity of the impairments is incomplete. Studies conducted to date have inconsistently assessed cognitive domains, with some investigations focusing on a wide range of cognitive functioning and others focusing on a narrower range of capacities. The neuropsychological test batteries used to assess cognitive function in critically ill survivors have generally been fairly brief (they were designed to accommodate the fatigue that is common in ICU survivors) rather than comprehensive neuropsychological test batteries designed to investigate a complete range of cognitive abilities. The cognitive domains impaired in survivors of critical illness may depend on the nature of the insults experienced and their treatment, the presence of pre-existing neurologic abnormalities, and individual vulnerabilities such as older age or comorbid disorders that might render specific domains more vulnerable to critical illness–induced brain injury. For example, hypoxia is associated with impaired memory and hippocampal damage (46).

In general, memory is the most frequently observed deficit, followed by impaired executive function and attention (43). For example, a memory questionnaire administered to a prospective cohort of 87 ARDS survivors found 20% of patients rated their memory as poor 18 months after ICU discharge (38). One study predominately assessed executive function in general ICU survivors at 3 and 9 months and found that 35% of the patients had impaired executive function (36). Similar findings were found in mechanically ventilated, nondelirious patients who had impaired memory and problem-solving abilities (i.e., executive dysfunction) during ICU treatment, during hospital treatment, and at 2-month follow-up (32). While in the ICU, 100% of the patients had impaired executive function and 67% had impaired memory. At 2-month follow-up, 50% had impaired executive function and 31% had impaired memory (32).

In addition to impairments in specific cognitive domains, Hopkins et al. (42) compared ARDS patients' premorbid estimated intelligence quotient (IQ) to their measured IQ. The ARDS patients had a significantly lower measured IQ compared to their premorbid estimated IQ at hospital discharge. However, the measured IQ returned to the premorbid level at 1 year follow-up, with no additional improvement in IQ at 2 years. The finding that general intellectual function recovered over time, however, does not necessarily suggest a comparable recovery in all cognitive domains, as data from the traumatic and anoxic brain injury literature suggest that some cognitive abilities are more likely to improve than others.

Duration of the Cognitive Impairments

Many critically ill patients have significant chronic cognitive impairments that persist for long periods of time. Cognitive impairments have been reported at 2 months (32), 6 months (33,39), 9 months (36), 1 year (30,34,38), 2 years (42), and up to 6 years (35,40). Cognitive post hospital discharge impairments appear to improve during the first 6 to 12 months post hospital discharge. For example, 70% of ARDS survivors had cognitive impairments at hospital discharge, whereas only 45% had cognitive impairments at 1 year, with no additional improvement at 2 years (42). A retrospective cohort study (N = 46) found 25% of ARDS survivors had cognitive impairments 6 years following ICU treatment; only 21 patients returned to full-time employment, and all patients with cognitive impairments were disabled (40). A second study in ARDS survivors found impaired memory, attention, concentration, executive dysfunction, and motor impairments from 6 months to more than 6 years post hospital discharge (35). The above studies suggest that the cognitive impairments in survivors of critical illness are long lasting and likely permanent. The persistent effects of critical illness on cognitive function may be particularly striking in geriatric patients with pre-existing mild cognitive impairment or dementia, as critical illness–related neurologic insults may serve to heighten their cognitive decline and lead to what could be characterized as “ICU-accelerated dementia or cognitive decline.” Such a pattern (e.g., medical illness accelerating the trajectory of dementia or cognitive decline) has been observed in other populations but has not been investigated in critically ill cohorts (47,48).

Indicators of Cognitive Impairments

A consistent finding across investigations is the lack of association between some indicators of illness severity and the development of cognitive impairments. Cognitive impairments in survivors of critical illness have not been associated with ICU length of stay, Acute Physiology and Chronic Health Evaluation II (APACHE II) scores, tidal volume, or number of days receiving sedative, narcotic, or paralytic medications (39,42). The above finding suggests that the cognitive impairments experienced by ICU survivors cannot be explained simply in terms of the degree of acute illness severity, as one might intuitively conclude. Alternatively, Jones et al. (32) found that impaired executive function measured during ICU treatment was associated with ICU and hospital length of stay, and impaired memory measured during ICU and hospital treatment was associated with admission APACHE II scores; however, these relationships were not present by 2-month follow-up. One limitation of the current data are the small sample sizes, which can result in insufficient power to detect real differences when they may actually exist. Thus, new studies with larger samples may find relationships between cognitive impairments or indicators of illness severity.

Similar to indicators of illness severity, age has not been associated with cognitive impairments (30,39,40), although most of the patients in the 10 cohorts studied to date were young or middle-aged adults (mean age, 54 years). Several studies used demographically corrected scores that account for the possible effects of age, gender, and education (30,34,42,49), and other studies used multivariable analysis to adjust for age (39). Elderly patients (age >65 years) were included in all studies (30,31,33,34,35,36,37,38,39,40,42); however, only one study included a predominately older population (36). Data from the existing studies indicate that age is not associated with cognitive outcomes, likely due to a restricted range. Additional studies in larger and older ICU cohorts are needed to confirm this finding. Although critical illness may affect cognitive functioning regardless of age, patients of an advanced age may be more vulnerable to the development of cognitive impairment due to pre-existing age-related vulnerabilities.

Delirium and Its Relation to Adverse Cognitive Outcomes

Studies of the association between delirium and adverse cognitive outcomes have generally been carried out in non-ICU populations, although data from these investigations likely apply to intensive care unit cohorts. One important difference between delirium and cognitive impairments is that delirium fluctuates, whereas cognitive impairments do not. Table 150.2 shows a comparison of characteristics of delirium, dementia, and cognitive impairments. A total of nine studies have explored the relationship between new-onset delirium and subsequent development of cognitive decline. Four of these investigations found a greater cognitive decline at follow-up among hospitalized patients who experienced delirium compared to matched controls. Geriatric patients with hip fractures who developed delirium (excluding those with a diagnosis of dementia) were almost twice as likely to have cognitive impairment 2 years post surgery (21). In hospitalized, community-dwelling geriatric patients, patients with delirium had slightly lower Mini Mental Status Examination (MMSE) scores at 6-month follow-up and experienced further cognitive decline over the next 18 months (50). In hospitalized geriatric medical patients following treatment in the emergency department (excluding patients with pre-existing dementia), MMSE scores were nearly 5 points lower in patients with delirium compared to patients without delirium at 1 year after adjusting for premorbid function, comorbid diseases, and illness severity (51). Finally, geriatric nursing home and assisted-living residents who developed delirium during medical hospitalization had a significant decline in cognitive function, including lower MMSE scores (52).

Four studies found a higher incidence of dementia in hospitalized elderly patients with a history of delirium at follow-up evaluations. Of nondemented community-dwelling patients older than 65 years who were hospitalized due to acute delirium, 14 were diagnosed with dementia immediately following delirium, and 14 additional patients developed dementia at 2-year follow-up (53). Rahkonen et al. (54) studied patients 85 years or older, excluding those with dementia, and found that patients with an episode of delirium during hospitalization were significantly more likely to be diagnosed with dementia at 3-year follow-up compared to patients without delirium. Over a 3-year period, 60% of geriatric medical patients with delirium at hospital admission (after evaluating for dementia at baseline) developed dementia compared to only 18.5% of the patients without delirium. The incidence of dementia was 18.1% per year for patients with delirium compared to 5.6% per year for patients without delirium (55). Koponen et al. (56) in 1989 reported MMSE scores at 1-year follow-up in 70 patients diagnosed with delirium during psychiatric hospitalization which revealed that one third evidenced cognitive deterioration (56).

Table 150.2 Comparisons Between Components Of Delirium, Dementia, And Cognitive Impairments

 

Delirium

Dementia

Cognitive Impairments

Mental status

Marked fluctuation

Chronically impaired—appears stable but deteriorates over time

Normal

Cognitive function

Sudden onset
Acute cognitive impairment characterized by disorientation and confusion

Insidious onset
Chronic cognitive impairment
Often memory is the first observed cognitive impairment
Progressive loss of cognitive functions (impaired judgment, executive function, etc.)
Progressive decline over time
Interferes with daily functioning and work
May include changes in personality, mood, and behavior

Sudden onset
Chronic cognitive impairment
May affect one or multiple cognitive domains, with memory, executive function, and information processing most commonly affected
Initially there may be some recovery or improvement of cognitive function
Stable over time
May interfere with daily functioning and work

Duration

Temporary

Permanent

Permanent

Only one study assessed delirium and cognitive outcomes in critically ill patients. This study found that one in three patients with delirium had cognitive impairments at 6-month follow-up (25). The patients were not primarily geriatric (mean age of 53 years) as were the patients in the other studies cited above (25). The above findings suggest that the presence of delirium may be critical in predicting adverse long-term cognitive outcome.

Brain Imaging Findings in Association With Delirium and Cognitive Impairments

Neuroimaging data are lacking in critically ill patients with delirium or those who develop long-term cognitive impairments. However, various central nervous system insults, such as stroke and traumatic brain injury, can cause delirium and cognitive impairments, suggesting that widely distributed central nervous system abnormalities can occur (57). A study using brain computed tomography (CT) scans found significant ventricular enlargement and generalized atrophy in elderly delirious patients admitted to a psychiatric ward compared to controls (58). Greater brain atrophy correlated with lower MMSE scores in these patients. Focal lesions (infarcts and hemorrhage) have also been observed in the right frontal and parietal regions in the delirious patients (58). Delirium induced by electroconvulsive therapy is associated with basal ganglia lesions and subcortical white matter hyperintensities (59). A study in critically ill patients who underwent CT brain imaging for a diminished level of consciousness, confusion, altered mental status, or prolonged delirium showed that 61% had abnormalities on brain imaging, including generalized brain atrophy, ventricular enlargement, white matter lesions/hyperintensities, and cortical and subcortical lesions (60). Similarly, significant brain atrophy was found in critically ill ARDS patients. The ARDS patients underwent brain CT imaging during ICU treatment and had significant brain atrophy, ventricular enlargement, and a large ventricle-to-brain ratio compared to age- and sex-matched normal control subjects (61). In addition to generalized brain atrophy, radiologic reports identified structural lesions in the central pons and left parietal lobe, subcortical white matter hyperintensities in the right frontal lobe, and hippocampal atrophy (61). These findings parallel those reported by Koponen et al. in patients with delirium. Although the data are limited, future studies using brain imaging may help advance our understanding of the neurologic effects of delirium and cognitive impairments following critical illness and its treatment.

Impact of Cognitive Impairments

The relationship between cognitive impairments and quality of life following critical illness has only recently been studied. Two studies found that cognitive impairments were not related to a decreased quality of life in ARDS patients (34) and in medical critically ill patients (36). In contrast, other studies indicate that ARDS patients with cognitive impairments had a worse quality of life compared to patients without cognitive impairments (31,40). Cognitive impairments have been linked to a worse quality of life following stroke (62,63), multiple trauma resulting in ICU treatment (64), traumatic brain injury (65), and carbon monoxide poisoning (66,67). Cognitive impairments can lead to the inability to return to work, poor work productivity, and decreased life satisfaction following ALI (acute lung injury)/ARDS (40).

The impact of critical illness on patients and their families is substantial and frequently includes significant financial burdens. The Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatment examined 2,661 patients hospitalized with a serious illness regarding the impact of returning home. Twenty percent of patients reported that a family member had to quit work, 29% lost the major source of family income, and 31% lost most of the family savings (68). The financial implications of a growing population of survivors of critical illness with cognitive and emotional sequelae are enormous. For example, cognitive decline in a previously high-functioning older person predicts institutionalization (69,70) and carries an eightfold risk of hospitalization (71). The annual per-patient societal cost burden is estimated to be approximately $15,000 for mild cognitive impairment and $35,000 for more severe impairments (72). Over half of critically ill survivors require caregiver support 1 year after treatment, resulting in an additional $18 billion (U.S. dollars) annual financial burden (73).

Lack of Recognition of Cognitive Impairments

Studies suggest that in non-ICU clinical settings, many physicians fail to recognize (or assess) cognitive impairment in 35% to 90% of patients (74). Cognitive impairments are rarely evaluated in critically ill patients (25) and may be overlooked in one of every two cases (75). For example, in 42% of ARDS survivors who underwent rehabilitation therapy, most were not evaluated for cognitive impairments, and only 12% of the patients were identified as having cognitive impairments by the clinical rehabilitation team (42). Thus, cognitive impairments appear to be underrecognized by both ICU and rehabilitation providers. This may be partly because the manifestations of cognitive impairments are often subtle, and patients may experience impairment in select cognitive domains even if they are alert, oriented, and appear generally cognitively intact. Education of clinical care providers regarding clinical manifestations of cognitive impairments in patients prior to ICU discharge may help increase the identification rates (76). Increased identification of cognitive impairment may benefit patients by raising physician awareness, potentially leading to increased referrals to rehabilitation specialists, neuropsychologists, speech and language therapists, and other health care providers who can provide interventions such as cognitive remediation. There is a paucity of data regarding interventions for cognitive impairments or the potential benefit of such interventions in critically ill patients.

The consequences of cognitive impairments are far-reaching and may contribute to decreased ability to perform activities of daily living and the inability to return to work. Two years after hospital discharge, 34% of ARDS survivors had returned to full-time work or were full-time students, 34% were receiving disability payments started after hospital discharge for ARDS, and 32% (20 of 62) were not working or were retired (42). An investigation that focused on 1-year outcomes found 51% of ARDS survivors had not returned to work; most of these individuals reported physically as opposed to cognitively related reasons for failure to return to work (27).

Potential Mechanisms of Delirium and Long-Term Cognitive Impairments

Many physiologic and pharmacologic perturbations affect the central nervous system in critically ill patients. Although the precise mechanisms that contribute to delirium and cognitive impairment or both are unknown, various theories have been proposed. The theories include the following:

· The potentially adverse effects of medical illness on cognition (77,78)

· Pathologic processes underlying delirium and cognitive impairments (79,80)

· The impact of psychoactive medications, including sedatives and analgesics (81,82)

Delirium and cognitive impairments rarely have one causal mechanism, and they are thought to be multifactorial (83); as such, the pathogeneses are likely due to interactions between patient vulnerability and precipitating factors or insults (84), including critical illness and its treatment. Studies have not focused on putative mechanisms, and a number of studies address and, in some cases, offer opinions regarding potential mechanisms. The investigation of the mechanisms of delirium and long-term cognitive impairments remains a promising area of neuroscientific study.

Psychoactive Medications

The role of certain medications such as sedatives, narcotics, and paralytics in the development of delirium are well known (85). Many medications used for sedation or pain control—including those used in the ICU setting—are known to cause or worsen delirium, although findings from some studies are negative or equivocal (86). An association exists between the high delirium prevalence rates in surgical and critically ill populations and the use of sedatives and narcotics (87,88,89). Although data on the impact of anesthetics and sedatives on long-term cognitive functioning are conflicting, reports suggest they may have neurotoxic effects, particularly for high-risk groups such as the very old (>75 years) and/or those with a recent history of cognitive impairment (90,91).

In some individuals, the effects of medications on cognition may be mediated by genetic factors. For example, the apolipoprotein E4 (APOE4) allele is one probable genetic factor that may affect individual sensitivity to drug effects. The APOE4 allele is a significant risk factor for the development of certain forms of Alzheimer disease (92), hippocampal atrophy (93), worse recovery of neurologic function following traumatic brain injury (94), cognitive decline following cardiopulmonary bypass surgery (95), and delirium (96). Although more research is needed, it appears that certain anticholinergic agents may have particularly adverse effects on cognition when administered to patients possessing the APOE4 allele. In particular, lorazepam—commonly used in ICU settings—increases susceptibility to impaired verbal learning and related cognitive deficits in patients with the APOE4 allele compared to patients without this polymorphism (97).

Delirium as A Mechanism of Cognitive Impairments

The findings of cognitive decline among hospitalized patients, particularly the older patients, are consistent with the literature showing that medical illnesses in general and cumulative illnesses in particular may signal the beginning of cognitive deterioration (77,98). For the so-called frail elderly (99) who are in an unstable state of vulnerability due to factors such as diminished physical status and compromised nutrition and immune system functioning, even minor insults can have a profound impact and lead to cognitive impairment and functional disability (100). Delirium may be such an insult.

Some researchers have speculated that delirium is a marker of subclinical dementia or cognitive impairment, which might not otherwise develop for years or decades. Data suggest that common pathogenic mechanisms might underlie both Alzheimer disease and delirium (79) although, from a clinical standpoint, there are similarities and differences. For example, inflammatory processes contribute to the development of delirium and are present in the brains of patients with Alzheimer disease (101). Other studies have suggested that elevated cytokines (interleukin-1) may play a central role in the pathogenesis of delirium (102) and cognitive impairments (103,104). Another possible connection between delirium and Alzheimer disease is diminishing neuroplasticity acting as an effect modifier, leading to greater neurodegeneration and cognitive deficits (105,106). Evidence suggests that the greater the neuronal loss or dysfunction, the higher the risk of cognitive impairments (49,61,106,107). Delirium may directly result in structural neural damage to vital brain regions, particularly subcortical regions (e.g., brainstem and thalamus) (108), limbic structures (e.g., hippocampus), and prefrontal and right parietal cortex (83). These brain regions are involved in attention, memory, and executive function, cognitive domains in which survivors of critical illness frequently experience impairments (25,42).

Cognitive rehabilitation

Cognitive rehabilitation has been used widely with patients following traumatic brain injury, stroke, and other neurologic insults (109). Evidence suggests that cognitive rehabilitation can be highly effective, which may be mediated by factors such as the cause of the brain injury and the cognitive domain (i.e., memory, executive functioning, etc.) of focus (110). For example, patients with hypoxic brain injuries may be less responsive to cognitive rehabilitation than those with traumatic brain injury or stroke (111). Questions exist regarding the applicability of the cognitive rehabilitation literature to critically ill populations, as ICU-related cognitive impairment is rarely due to a brain injury, as classically defined. However, there is no inherent reason to imagine that the potential benefits of cognitive rehabilitation would not apply to those experiencing neuropsychological dysfunction following critical illness and ICU treatment. Although previous and ongoing studies have focused on the identification of modifiable risk factors as a way of reducing cognitive impairment after critical illness, future trials should focus not only on modifiable risk factors, but also on development and implementation of cognitive rehabilitation interventions. Along with this venue, physicians should consider referring patients for specialized cognitive rehabilitation when possible, particularly cases in which patients are referred to physical rehabilitation facilities where such treatments are widely available.

Emotional Disorders

Psychiatric morbidity following critical illness is common and includes depression, anxiety, and posttraumatic stress disorder (PTSD). The prevalence and severity of depression, anxiety, and PTSD in survivors of critical illness are heterogenous (26,40,112,113). It is unclear whether emotional disorders are a psychological reaction to extraordinary emotional and physiologic stress, sequelae of brain injury sustained due to critical illness and its treatment, or all of the above. The combination of medications, physiological changes, pain, altered sensory inputs, and an unfamiliar environment may contribute to emotional changes (113,114,115). Recent evidence suggests that mood disorders secondary to medical illness constitute discrete entities in which the symptoms are similar to primary mood disorders, but there is a male predominance and earlier onset (116).

Posttraumatic Stress Disorder (PTSD)

Estimates of PTSD prevalence in critically ill cohorts are as high as 63% (117) and generally exceed those of other high-risk populations. Although alarming, caution should be used when interpreting these findings due to some methodologic shortcomings of investigations of PTSD in critically ill populations, such as overreliance on screening tools (as opposed to diagnostic tools), questionable interpretation of available data, the lack of evaluation of non-ICU-related causes of PTSD, low follow-up rates, and other limitations. With these caveats, PTSD clearly occurs and persists in a subset of ICU survivors.

Among critically ill subjects, general medical ICU cohorts have been shown to have both the lowest and highest rates of PTSD compared to more specialized populations. In studies of general medical ICU patients, reported prevalence rates of PTSD range from 9.7% (118) to 63% (117), with rates of PTSD in specialized populations ranging from 18.5% (119) to 43% (120). Risk factors for the development of PTSD and related symptoms have not been systematically studied; however, several probable risk factors have been identified. One risk factor of interest is delusional memories, with two investigations reporting associations between delusional memories and development of PTSD in survivors of critical illness (112,121). Other risk factors include younger age, the existence of a prior mental health history (122), anxiety (123), and female gender (124).

Although the clinical impact of PTSD on the quality of life and overall functioning of ICU survivors has not been explored, the real-world impact of PTSD has been extensively studied in wide-ranging clinical samples. Although a survey of this literature is beyond the scope of this chapter, the effects of PTSD can be far-reaching and profound. Individuals with PTSD have lower rates of employment (125), decreased quality of life (126), increased rates of depression (127), and increased use of health care services (128). For these and other reasons, the identification and early treatment of ICU survivors with PTSD should be a priority.

Depression and Anxiety

Depression is common among medically ill cohorts due both to the specific physical effects of certain illnesses and/or the effects of illness on quality of life, independence, employment, and other factors (129,130,131). Depression occurs in 25% (42) to over 50% of ARDS survivors (26). For example, 43% of ALI patients and 50% of ARDS survivors had symptoms of depression following ICU treatment (26). The Toronto ARDS outcomes group found that 58% of ARDS survivors had depressive symptoms 2 years after ICU discharge (38). In the most comprehensive study conducted to date, Weinert (131) administered 105 interviews using a comprehensive diagnostic tool (Structured Clinical Interview for DSM-IV Disorders) 2 months after hospital discharge in survivors of acute respiratory failure. Weinert reported prevalence and incident rates of major depressive disorder (MDD) of 15% and 11%, respectively. He further noted that another 16% of patients met criteria for a diagnosis of adjustment disorder with depressed mood. The investigators found antidepressant use was widespread (37%), while observing that the safety and efficacy of antidepressants is unknown in critically ill patients (131).

Although the evidence up to the present suggests that depression is indeed a concern in ICU survivors, much remains unknown. In particular, the rates of pre-existing depressive symptoms or clinical depression in critically ill populations are unknown but may be high due to the many medical comorbidities experienced by a high percentage of these patients. Key questions remain about the nature of depressive symptoms following critical illness. Although the study by Weinert et al. used a diagnostic interview, most studies have merely used brief self-report instruments. Such instruments often fail to distinguish between cognitive and somatic symptoms. Thus, it may be the case that some of the depressive complaints expressed by ICU survivors (i.e., fatigue, sleeping difficulties) may actually be manifestations of physical illness.

Although data are accumulating regarding depression following critical illness, less is known regarding anxiety, with the exception of PTSD. Anxiety occurs in 4% to 41% of ARDS survivors (120,132). Anxiety has been reported in 24% of ARDS survivors at 1 and 2 years (34,42). Possible factors that may be associated with development of depression and anxiety following critical illness include a current smoking status or prior alcohol abuse. In ARDS survivors, smokers had higher depression scores at 1 year but not at 2 years compared to nonsmokers. There was no difference in anxiety for smokers at 1 year, but at 2 years, smokers reported significantly more anxiety than nonsmokers. The ARDS patients with a history of alcohol abuse had higher depression and anxiety scores at 1 and 2 years compared to nonabusers. Thus, smoking and alcohol abuse may be related to symptoms of depression and anxiety in ARDS survivors (133).

Significance of Cognitive and Behavioral Sequelae

The significance of cognitive and behavioral sequelae in the intensive care unit is becoming increasingly clear. Cognitive and behavioral sequelae have a negative impact on the patients' quality of life, return to work, emotional state, and financial impact. Although the treatment and management of serious medical conditions is of obvious importance, it is not the only goal. Intensive care unit clinicians should be aware of the impact of critical illness on emotional and neuropsychological functioning and be prepared to respond in a sensitive and informed fashion to the problems that patients present. In particular, they may consider building formal relationships with specialists from other disciplines, such as psychology and psychiatry, and possibly including them as members of ICU treatment teams. Intensive care unit clinicians may wish to develop unit-wide programs and protocols that involve the routine assessment and monitoring of common conditions such as delirium as well as mental status and mood. Furthermore, they should inquire about cognitive and emotional functioning at follow-up (76).

Intensive care unit researchers should follow the lead of their counterparts in other medical disciplines such as cardiac surgery, oncology, and infectious disease, and make the investigation of cognitive and emotional outcomes in critical care survivors a priority. Fruitful areas of emphasis may include determining the causes and modifiable risk factors for conditions such as ICU-related depression and cognitive impairment. Other explorations might focus on whether critical illness accelerates and/or alters the trajectory of pre-existing cognitive impairment and whether cognitive rehabilitation might enhance long-term cognitive outcomes. The nature of the impact of cognitive and emotional difficulties on daily functioning in survivors of critical illness is an extremely important topic, yet it has rarely been explored (134).

Although technologic and medical advances have saved the lives of thousands of critically ill patients who would have died a decade or two ago, the cognitive and emotional problems encountered by ICU survivors are real and long lasting. Through careful attention to such problems and through the development of clinical interventions and research programs, it may be possible to alleviate a measure of the suffering associated with critical illness. During patient follow-up, on a more personal level, clinicians should be careful to express the same degree of concern about patients' cognitive and emotional complaints as their medical complaints.

Summary

Physicians and other health care providers need to be mindful of adverse behavioral outcomes in critically ill patients. Current data suggest that the delirium, cognitive impairments, and emotional morbidity are common following critical illness. Cognitive and emotional morbidity may persist years after ICU discharge. Cognitive impairments are ubiquitous at hospital discharge and appear to improve during the first 12 months, but a significant percent of patients still have chronic cognitive impairments years after ICU treatment. The adverse behavioral impairments can have a significant impact on the quality of life and the ability to return to work, in addition to substantial economic consequences. Research is needed to determine strategies for the early identification of patients with cognitive impairments and emotional sequelae, mechanisms of neural injury, and treatments to prevent or decrease the frequency and severity of cognitive and emotional sequelae. Such research will likely yield valuable insights into identification, natural history, prognosis, potential mechanisms, and treatment of behavioral impairments in survivors of critical illness.

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