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Critical Care Medicine:
doi: 10.1097/CCM.0b013e3182a16946
Creating and Implementing the 2013 ICU Pain, Agitation, and Delirium Guidelines for Adult Icu Patients

Cognitive Dysfunction in ICU Patients: Risk Factors, Predictors, and Rehabilitation Interventions

Wilcox, M. Elizabeth MD, MPH1; Brummel, Nathan E. MD, MSCI2; Archer, Kristin DPT, PhD3; Ely, E. Wesley MD, MPH2,4,5; Jackson, James C. PsyD2,5,6; Hopkins, Ramona O. PhD7,8

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Author Information

1Interdepartmental Division of Critical Care Medicine, Toronto Western Hospital, Toronto, ON, Canada.

2Division of Allergy, Pulmonary, and Critical Care Medicine and Center for Health Services Research, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN.

3Division of Orthopaedic Surgery and Rehabilitation, Vanderbilt University School of Medicine, Nashville, TN.

4Department of Medicine, Center for Quality of Aging, Vanderbilt University School of Medicine, Nashville, TN.

5Geriatric Research, Education and Clinical Center Service, Department of Veterans Affairs Medical Center, Tennessee Valley Healthcare System, Nashville, TN.

6Department of Psychiatry, Vanderbilt University Medical Center, and Clinical Research Center of Excellence, Department of Veterans Affairs Medical Center, Tennessee Valley Healthcare System, Nashville, TN.

7Department of Medicine, Pulmonary and Critical Care Division, Intermountain Medical Center, Murray, UT.

8Psychology Department and Neuroscience Center, Brigham Young University, Provo, UT.

Dr. Brummel has received a grant from the National Institutes of Health (NIH). Dr. Archer has held a consultancy with Synergy; received grants from American Physical Therapy Association, Foundation for Physical Therapy, Department of Defense, National Institute of Arthritis and Musculoskeletal Skin Disease, and National Institute of Disability and Rehabilitation Research; received payment for travel/accommodations/meeting expenses from the NIH; and received payment from the American Pain Society for development of educational presentations. Dr. Ely holds consultancies with Hospira, Abbott, Masimo, and Orion and has received honoraria for lectures from Hospira, Orion, and Abbott. The remaining authors have disclosed that they do not have any potential conflicts of interest.

For information regarding this article, E-mail: elizabeth.wilcox@mail.utoronto.ca

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Abstract

In contrast to other clinical outcomes, long-term cognitive function in critical care survivors has not been deeply studied. In this narrative review, we summarize the existing literature on the prevalence, mechanisms, risk factors, and prediction of cognitive impairment after surviving critical illness. Depending on the exact clinical subgroup, up to 100% of critical care survivors may suffer some degree of long-term cognitive impairment at hospital discharge; in approximately 50%, decrements in cognitive function will persist years later. Although the mechanisms of acquiring this impairment are poorly understood, several risk factors have been identified. Unfortunately, no easy means of predicting long-term cognitive impairment exists. Despite this barrier, research is ongoing to test possible treatments for cognitive impairment. In particular, the potential role of exercise on cognitive recovery is an exciting area of exploration. Opportunities exist to incorporate physical and cognitive rehabilitation strategies across a spectrum of environments (in the ICU, on the hospital ward, and at home, posthospital discharge).

Critical illness adversely affects short- and long-term cognitive function. Profound and persistent deficits in memory, attention/concentration, and executive function negatively impact the functional status and health-related quality of life (HRQOL) of survivors of critical illness. Recent investigations demonstrate that cognitive impairment (CI) is associated with psychological morbidity (anxiety and depression) and influences the ability to return to work (1–6). This article provides a state-of-the-art review of the prevalence of CI in survivors of critical illness, describes risk factors associated with long-term cognitive function in these patients, and finally, reports on studies for appropriate prevention and rehabilitation.

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STUDIES OF CI IN CRITICAL ILLNESS

Methods

A literature search for all articles pertaining to critical illness and cognitive outcome was conducted using MEDLINE (1996 to January week 4 2013) and EMBASE/EMBASE classic (1947 to 2013 week 4) databases. Search terms included “critical illness,” “intensive care,” “ICU,” “dementia,” “cognition disorders,” “mild cognitive impairment,” “cognitive impairment,” “cognitive sequelae,” “neuropsychological impairment,” “dementia,” and “neurocognitive tests.” Specific inclusion criteria were applied; studies had to assess neurocognitive outcomes in a critically ill patient population and in so doing, have employed an objective measure of cognitive function.

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Results

The search identified 1,008 citations of potential relevance; six citations were identified through hand searches. After applying the inclusion criteria, 34 studies were considered in this review; study abstracts published more than 5 years prior to our search and still not published as full text were not included.

Of these 34 studies, 11 studies reported cognitive outcomes in acute respiratory distress syndrome (ARDS) survivors (4, 7–16) and 20 in mixed populations of medical and surgical ICU patients (17–36); three studies were excluded as patient populations with moderate to severe traumatic brain injury. The time to follow-up and the measures used in assessing cognitive function were highly variable. Furthermore, definitions used to establish CI were inconsistent.

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PREVALENCE OF CI IN CRITICAL CARE SURVIVORS

In survivors of ARDS (n = 487, 11 studies, seven distinct patient cohorts), the median time to follow-up was 12 months (range, 1–241 mo). At hospital discharge, 70% to 100% of patients were determined to have CI (10–14) (Table 1). At 1- and 2-year follow-up, the prevalence of CI was 46% to 78% and 25% to 47%, respectively. The domains of cognitive function most commonly affected were attention and concentration (4, 9–11), memory (7–10, 15, 16), and executive function (9, 10, 15, 16), although these domains were not assessed with equal depth or breadth across studies.

Table 1.
Table 1.
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Twenty studies (n = 2,072) have evaluated cognitive outcomes in mixed populations of medical and surgical ICU patients (Table 2), although the majority focused on certain subsets of patients; these included studies in mixed critically ill patients requiring prolonged mechanical ventilation (17), studies in sepsis and septic shock (22, 29), and medical patients undergoing elective surgery (37) to name a few. Again, there was a variable length of time to follow-up cognitive testing, with a median of 12 months (range, 2 wk to 8.3 yr). CI in varying domains was seen in 39% to 51% of patients at the time of hospital discharge, 13% to 79% at 3- to 6-month follow-up, and 10% to 71% at 12 months. Comparison of CI rates across studies is difficult as different populations have been studied, varied cognitive batteries have been used, and widely divergent definitions of impairment used.

Table 2.
Table 2.
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FACTORS ASSOCIATED WITH CI

Studies to date have largely focused on describing cognitive outcomes in survivors of critical illness, with relatively few describing possible risk factors or mechanisms linking critical illness to subsequent impairment. The pathogenesis of CI following critical illness is not fully understood but may represent an accelerated neurodegenerative process that develops in vulnerable hosts (e.g., older age, preexisting cognitive dysfunction, genetic predisposition via apolipoprotein E4 [APOE4], and diminished cognitive reserve) (32, 38) or newly acquired brain injury due to insults associated with critical illness (e.g., hypoxemia, hypotension, anemia, fever, hyperglycemia, systemic inflammation, severe sepsis, pharmacologic agents, renal failure, and liver failure) (10, 13, 16, 19, 22, 29, 36).

Histopathology and neuroimaging studies indicate specific patterns of brain injury associated with sepsis or ARDS (39–42). A single small case series reported brain autopsy findings of patients whose critical illness was complicated by delirium and reported that ischemic and hypoxemic hippocampal lesions were present in of five of seven patients (71%) (39). Hopkins et al (40), in an observational study of imaging (CT) in ARDS survivors, found that significant brain atrophy and ventricular enlargement was present when compared with matched control subjects. Recently, Gunther et al (42) reported correlations between findings on brain imaging and neurocognitive testing. In a cohort of medical and surgical ICU patients who were screened daily for delirium, patients who suffered a longer duration of delirium had greater overall brain atrophy and ventricular enlargement as well as smaller superior frontal lobes and hippocampal volumes 3 months following hospital discharge. At 1 year, these anatomic findings were associated with worse overall cognitive performance (in the case of overall brain atrophy) and worse executive functioning (in the case of superior frontal lobe atrophy) (42). A second study, from the same cohort, reported that delirium duration was also associated with loss of white matter in the corpus callosum and internal capsule (representing disruptions of functional connectivity within the brain). These findings were present in survivors of critical illness at the time of hospital discharge and persisted at 3-month follow-up. Changes on neuroimaging were associated with worse overall neurocognitive performance at 1-year follow-up (41). Finally, left hippocampal volumes on MRI were markedly reduced in a cohort of patients with septic shock, compared with healthy controls, at 6- to 24-month follow-up (29). The results of these preliminary histopathological and neuroimaging studies suggest that a variety of anatomic changes and disruption of functional connectivity are present among survivors of critical illness and that these changes may be responsible for the deficits seen on cognitive testing. The lack of baseline cognitive and neuroimaging data precludes definitive conclusions regarding strength of association or any causal associations, although it is increasingly clear that—in most cases—the CI observed after critical illness is not simply a continuation of preexisting deficits.

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PATIENT-ASSOCIATED RISK FACTORS

Preexisting CI

Although patients can develop CI following critical illness de novo (20, 22), the role of preexisting CI as a risk for CI following critical illness is unknown. Studies to date have enrolled younger cohorts of patients (e.g., where rates of preexisting CI are typically extremely low) or have excluded patients with severe dementia. One study, using data from the Mayo Clinical Study of Aging, reported the prevalence of preexisting CI was higher (35%; n = 136/387 patients) in patients admitted or transferred to the ICU, as compared with elderly patients admitted to hospital who did not require ICU admission (18%; n = 391/1,733) (32). Compared with patients without preexisting CI requiring ICU admission, patients with CI were more likely to be older (not surprisingly), were male, and have a higher initial severity of illness score (Acute Physiology and Chronic Health Evaluation [APACHE] III) (32). These results suggest that some preexisting CI may be common among elderly patients admitted to ICUs. A study of patients with Alzheimer disease who were hospitalized for an acute illness and in whom delirium developed found a significant acceleration of cognitive decline over the course of next 5 years compared with patients who were never delirious (43). These results suggest that among patients with preexisting CI, complications occurring during hospitalization may adversely affect cognitive trajectories following acute illness, perhaps due to the effects of decreased cognitive reserve. Whether these findings can be applied to patients with less severe forms of preexisting CI following critical illness requires further study.

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Apolipoprotein E4

Although there are no large studies of genetic susceptibility to CI following critical illness, data suggest the APOE4 allele (a well-known genetic risk factor for Alzheimer’s disease) may have an effect on the acute cognitive status of critically ill patients. In a study by Ely et al (38), the APOE4 allele was associated with a seven-fold increase in the odds of a longer duration of delirium (odds ratio [OR], 7.3 [95% CI, 1.8–30]). The presence of APOE4 was found to have a stronger association with duration of delirium than age, severity of illness score (APACHE II), sepsis, or benzodiazepine use (38). Although duration of delirium is associated with worse cognitive performance after the ICU, the specific role of the APOE4 genotype in this association is unknown. Recent work in noncritically ill elderly patients by Pomara and colleagues (44, 45) found that benzodiazepine administration in healthy elderly subjects (n = 42) with the APOE4 allele was associated with more pronounced CI and slower to recovery of cognitive functioning. Furthermore, this association was found to be independent of deranged pharmacokinetics. Thus, the possibility arises that APOE4 may herald a more pronounced vulnerability to drug-related brain toxicity. The idea that certain genetic alleles may mediate and amplify the effects of specific drugs on the development of CI has been relatively little studied. This concept, however, highlights a possible interaction between a susceptible host and an effect modifier through which worse CI in survivors of critical illness might develop.

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Psychiatric Impairment (Preexisting Depression)

Few studies have explored the relationship between preexisting psychiatric morbidity and long-term cognition following critical illness. Furthermore, these studies used a variety of methods of varying rigor (e.g., prescription practices, chart review, or surrogate reporting) to diagnose preexisting psychiatric illness. For instance, studies evaluating the prevalence of baseline depression have shown rates ranging from 18% to 28% (27, 46, 47). Unfortunately, none of these studies explored the association between preexisting depression and long-term cognitive outcomes among survivors of critical illness. Nevertheless, depression is highly prevalent among survivors of critical illness, occurring in 10–58% of survivors of critical illness (7, 8, 46, 48). A recent systematic review examined 14 studies of depression in survivors of critical illness and found that one in three survivors of critical illness will suffer moderate to severe depressive symptoms, the exploration into the precise types of depression experienced by these individuals (e.g., major depressive disorder vs dysthymia vs depressive disorder not otherwise specified) has been minimal (48). In a cross-sectional survey of 79 self-selected ARDS patients, nearly half reported psychiatric morbidities and half of them had concomitant CI (15). The most common deficiencies were in short-term memory and executive function. In another study, depressive symptoms (Beck Depression Inventory [BDI]-II) and memory complaints (Memory Assessment Clinics Self-Rating Scale) were shown to persist to 2- and 5-year follow-up (7, 8). Median BDI-II scores were approximately 25% above age-adjusted population norms at 2 and 5 years. BDI-II scores can be influenced by physical complaints and the contributions to fatigue, lethargy, and sleepiness to elevated depression scores needs to be explored further. A higher BDI-II score at 2-year follow-up, longer duration of mechanical ventilation, and delay in organ function recovery predicted worse BDI-II score at 5-year follow-up (7, 8). In another prospective 2-year longitudinal study by Bienvenu et al (49), preexisting depressive symptoms were a risk factor for incident impaired physical function. Thus, although the role of preexisting depression on long-term cognitive outcomes is unclear, emerging data suggest that depression in the post-ICU period is associated with impaired cognition.

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CLINICAL VARIABLES

Hypoxia and Hypotension

Data regarding the association between hypoxemia and hypotension and long-term cognitive outcomes in ICU survivors are mixed. In one of the first studies to assess CI in survivors of ARDS (n = 55), severity of hypoxemia was found to correlate with the degree of CI; Pao2 at enrollment was significantly associated with decrements in the General Memory Index (p = 0.04), Attention and Concentration Index (p = 0.03), and Delayed Recall Index (p = 0.002) (10). More recently, in a subset of patients from the Fluid and Catheter Treatment Trial factorial randomized trial of pulmonary artery versus central venous catheter-directed conservative versus liberal fluid administration for patients with ARDS, CI assessed at 2 months and 1 year after hospital discharge was common; 55% of survivors had CI (decrements in memory, verbal fluency, and executive function) at 1 year (16). Risk factors for long-term CI included lower Pao2 (p = 0.02), lower central venous pressure (p = 0.04), and enrollment in the conservative fluid-management strategy (p = 0.004) (16). Furthermore, these factors were also associated with worse executive function (16). The findings of this study are challenged by incomplete data and low enrollment of eligible patients, but are nonetheless intriguing, as they would suggest that both hypoxia and even relative hypotension could contribute to long-term CI in ARDS survivors.

On the other hand, other studies of survivors of general critical illness have found no association between hypoxemia and CI. In a report by Suchyta et al (30) (n = 64), despite a high prevalence (64%) of patients with abnormalities on brain imaging (CT or MRI), there was no association with episodes of hypoxemia. Furthermore, among patients admitted to a general trauma ICU (n = 108), hypoxemia was not associated with incident delirium or CI at 1 year (36). Overall, these data suggest that the causal relationship between anoxia and short- or long-term CI is unclear but could relate to the mechanism of brain injury. It is possible that hypoxia or hypotension is independent risk factors for CI; their effects could be mediated directly or indirectly through a systemic inflammatory response inducing the activation of brain parenchymal cells and expression of proinflammatory cytokines and inflammatory mediators within the CNS (50, 51).

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Sepsis

Iwashyna et al (22) recently found a persistent reduction in functional status and increased prevalence of moderate to severe CI after sepsis and critical illness. In their study of older patients (median age, 77 yr), they observed a statistically significant increase in the prevalence of clinically significant CI in those who survived an episode of severe sepsis (OR, 3.34 [95% CI, 1.53–7.25]) (22). Furthermore, they observed that cognitive and functional decline persisted for at least 8 years after the episode of sepsis, representing an important decline in the patients’ ability to live independently (22). In a case series of younger patients (50–60 yr), permanent CI was seen in several domains in both septic and nonseptic patients (29). Sepsis survivors had deficits in verbal learning and memory and were seen to have significant reductions in left hippocampal volume compared with healthy controls (29). In addition, patients with sepsis were more likely to have more low-frequency activity on electroencephalography (EEG) indicating a nonspecific brain dysfunction (29). Further study into the specific mechanism of sepsis-mediated acute brain dysfunction is needed.

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Dysglycemia

Derangements in blood glucose are associated with CI after critical illness. The review by Hopkins et al (13) of blood glucose control data among patients being treated for ARDS showed that after adjusting for covariates, patients with a highest blood glucose level (> 153.5 mg/dL) and those with greater fluctuations in blood glucose had three times the odds of being cognitively impaired at 1 year compared with patients who did not experience either glycemic condition. Hypoglycemia may also contribute to CI; in a case-control study of 74 surgical ICU patients, those who suffered at least one hypoglycemic event (< 40 mg/dL) demonstrated visual-spatial deficits at 1-year follow-up (19). Interestingly, hyperglycemia and fluctuations in blood glucose levels were also associated with deficits in visual-spatial skills.

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Delirium

Delirium is an acute change in mental status that is characterized by inattention and a fluctuating course. It is highly prevalent in acutely ill patients, particularly among the critically ill where up to 80% of patients may develop it during their illness (52–54). Risk factors for delirium in the ICU are many; it is particularly common among elderly persons and those with preexisting CI (55–58). It is associated with longer lengths of stay, increased duration of mechanical ventilation, and higher risk of death (59–61). At 1-year follow-up, 71% of survivors of general medial and cardiac ICUs that experience delirium in the ICU have CI (25). After adjusting for age, education, preexisting cognitive function, severity of illness, and exposure to sedative medications in the ICU, increasing duration of delirium was an independent predictor of worse CI (21). The link between acute brain dysfunction (delirium) and chronic brain dysfunction (CI) has been hypothesized to be mediated directly or indirectly through a systemic inflammatory response inducing the activation of brain parenchymal cells and expression of proinflammatory cytokines and inflammatory mediators within the CNS (50, 51). This acute inflammatory response to critical illness then may prime microglia, activating them from a resting state. Activated microglia may then perpetuate a state of chronic neuroinflammation and neurotoxicity that may, in part, explain impaired long-term CI (62).

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Sleep Efficiency

In general, sleep disorders appear to be associated with CI. Data regarding sleep disorders following the ICU is only beginning to emerge (63). One large prospective multicenter cohort study (n = 1,625) reported no change in self-reported sleep quality in the year following critical illness, using a nonvalidated single instrument assessment (64). A second, small case series reported sleep disruption and poor sleep efficiency as measured by polysomnography in five of seven survivors of ARDS who did in fact report difficulties 6 months after hospital discharge (65). Neither study reported cognitive outcomes among these cohorts; thus, the effects of poor sleep on long-term cognitive effects in survivors of critical illness are unknown. In a prospective cohort study of community dwelling older adults, however, a high index of sleep fragmentation (quantified by actigraphy) was associated with a nearly 1.5-fold increased risk of incident Alzheimer disease after controlling for demographics, total daily rest time, chronic medical conditions, and the use of medications, which commonly affect sleep, suggesting that long-term sleep disturbances can alter cognition (66). Further research is needed to determine the impact of poor sleep efficiency both within the ICU and after ICU discharge on long-term cognitive function.

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PREDICTING LONG-TERM CI

Studies have so far been unable to identify patients at higher risk of CI using brief cognitive screening tools. For example, in a study by Woon et al (35) neither performance on the Mini-Mental State Examination or Mini-Cog at the time of hospital discharge predicted CI at 6-month follow-up. Performance on more sensitive tests of CI may have predictive value, but these have not been used in prediction-focused investigations to date. The lack of predictive ability restricts the ability of clinicians and researchers to adequately risk stratify patients to their individual rehabilitation needs (Fig. 1).

Figure 1.
Figure 1.
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One candidate predictor for CI might be quantitative EEG. Serial quantitative EEG has been used to diagnose delirium in older patients (n = 25), both with and without underlying dementia, on an inpatient geriatric psychiatry service (67). Not only did quantitative EEG prove sensitive in diagnosing delirium across a range of underlying etiologies (medication intoxication, hypoxia, electrolyte disturbances, etc), but it also was able to measure severity of delirium. In the ICU, quantitative EEG has been found to be a sensitive but not entirely specific predictor of mortality in patients with severe sepsis (68, 69). Well-defined categories of progressively slower EEG waveforms have been associated with an increased risk of death (highest mortality risk being associated with findings of burst suppression). Similar findings were found in a prospective observational study of sedation in a medical ICU patient population, where burst suppression was found to be an independent predictor of death at 6 months (70). A recent study of sepsis survivors showed promise for EEG as a candidate predictor of CI. Deficits in verbal learning and memory were associated with a significant reduction in left hippocampal volume and low-frequency activity on routine EEG (indicative of nonspecific brain dysfunction) (29). Although it is likely an imperfect tool, EEG may be able to provide prognostic information, possibly in combination with other modalities.

Biomarkers might add further predictive power should CI develop as a result of chronic inflammation of the CNS. Systemic inflammatory changes may adversely affect learning, memory, and other cognitive domains by altering hippocampal function (71, 72). Elevated serum interleukin-6 and C-reactive protein concentrations are associated with reduced cognition and contribute to accelerated functional decline in both the elderly and in cardiopulmonary bypass patients postoperatively (50, 72). Given the prevalence of delirium in disease states with a higher systemic inflammatory burden, such as sepsis, cancer, and the postoperative period, inflammatory markers may be useful for monitoring delirium disease activity and predicting risk of long-term CI (50, 72, 73). Further study of biomarkers in the prediction of long-term CI in survivors of critical illness is therefore needed.

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TREATING CI: THE POTENTIAL ROLE OF EXERCISE

In the general population, the prevalence of CI and functional disability increases with age. The human brain on average loses 15% of cerebral cortex and 25% of cerebral white matter between the third and ninth decades of life (74). Associated with this gradual loss of brain tissue is a decline in cognitive function (75). Previous research has demonstrated that physical exercise improves cognition in older adults and can improve brain health in aging laboratory animals (76), possibly via increases in brain volume, blood flow, and neurogenesis (77). Tyndall et al (78) recently published a study protocol to better understand how cerebrovascular mechanisms might explain how exercise promotes healthy brain aging. Testing the strong biologic basis for the benefits of exercise in healthy brain aging, they plan to enroll over 250 sedentary, but not obese, adults who are 55–80 years old. In a multiphase exercise intervention strategy, they will examine whether exercise improves resting state cerebral blood flow or “cerebrovascular reserve” (78). These data could demonstrate a mechanistic link between exercise and cognition through improved cerebrovascular function. As a recognized and modifiable risk factor of cognitive decline in older adults, exercise would be a biologically plausible treatment for impaired cognition in a critically ill patient population. Identifying exercise as a mechanism that reverses or alters the trajectory of CI would have an important impact on HRQOL in survivors of critical illness.

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RANDOMIZED TRIALS TO IMPROVE COGNITIVE RECOVERY

Research to prevent and rehabilitate survivors of critical illness is an important priority given that CI prevents survivors from returning to work and older persons from returning home (1, 2, 4, 79, 80). The Returning to Everyday Tasks Using Rehabilitation Networks study randomized 21 medical and surgical ICU survivors to 12 weeks of either in-home combined cognitive and physical rehabilitation or usual care (characterized by sporadic rehabilitation) (81). Despite nearly equivalent scores on a measure of executive functioning at baseline, at the end of the intervention, patients in the intervention group demonstrated significantly better executive functioning and reported fewer disabilities in instrumental activities of daily living (IADLs) (81). These encouraging results require further study in a larger patient population.

A search of ClinicalTrials.gov and Controlled-Trials.com uncovered two ongoing randomized controlled trials studying cognitive benefits of prevention and rehabilitation. First, a group of Chilean investigators (ClinicalTrials.gov; NCT01555996) are evaluating the effect of early occupational therapy for delirium prevention in older (> 60 yr) ICU patients who have not been mechanically ventilated or have preexisting CI. Patients are randomized to receive either a nonpharmacologic delirium prevention program arm (early mobilization by physical therapist, reorientation protocol, correction of sensory impairment [e.g., provision of glasses and hearing aids], environmental management [e.g., clock, calendar, noise reduction, supervision by family to avoid restraints]) or the early occupational therapy arm which adds multisensory stimulation (e.g., intense external stimulation), positioning (e.g., dorsa-flex splints), cognitive stimulation (awareness, orientation, attention, memory, calculation, praxis), activity of daily living (ADL) training, and upper limb motor stimulation with an occupational therapist bid. The outcome measures will include delirium prevalence and duration, functional independence, grip strength, and cognitive function at day 7 and hospital discharge. Another United States-based randomized trial in medical and surgical patients with respiratory failure or shock (82) will explore the effect of early physical and cognitive rehabilitation on short- and long-term cognitive outcomes. This trial has three randomized groups: 1) usual care, including daily awakening and breathing trials; 2) once-daily physical rehabilitation protocol; or 3) once-daily physical and cognitive rehabilitation protocol and additional in-home cognitive rehabilitation for 12 weeks (orientation, digit span, memory and problem solving, reverse digit span, letters, numbers, puzzles, and games). Study outcomes include executive and cognitive functioning at 3 months, functional disability (ADLs and IADLs), physical function, and HRQOL at 3 and 12 months. The results of these studies will inform future research with regard to exercise and cognitive rehabilitation interventions.

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IMPROVING COGNITIVE OUTCOMES: ROLE OF IMPROVED SLEEP EFFICIENCY

If unrecognized, poor sleep efficiency could contribute to CI, leading to reductions in HRQOL and fatigue precluding effective participation in physical rehabilitation. Accordingly, Kamdar et al (83) recently introduced an ICU sleep-promotion quality improvement initiative to reduce incident delirium and CI. This multifaceted intervention (nighttime: minimizing overhead pages, turning off patient electronic devices, dimming lights, and grouping care activities; daytime: natural light, promotion of wakefulness, encouraging mobilization, and minimization of caffeine prior to sleep) showed an insignificant increase in the overall rating on the Richards-Campbell Sleep Questionnaire (primary outcome) but did show significant improvement in daily noise ratings (p =0.001), prevalence of delirium/coma (OR, 0.46 [95% CI, 0.23–0.89]; p = 0.02), and daily delirium/coma-free status (OR, 1.64 [95% CI, 1.04–2.58]; p = 0.03) (83). Further research is needed to determine the effect of poor sleep efficiency on cognitive outcomes and whether or not improved sleep lends to less CI.

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BARRIERS TO NEUROCOGNITIVE TESTING

Although much attention has been paid to determining barriers to early mobility (84), we believe that barriers to assessing cognitive function are of equal importance. These include both social stigmatization and financial strain (i.e., disclosure in returning to work or application for health insurance) associated with age-inappropriate or accelerated CI. High follow-up rates have been successfully, and repeatedly, achieved by a number of groups (11–13, 25, 49, 81). An extreme case of difficulty in recruitment, obstacles in testing, and failure of retention strategies was nicely illustrated in the ARDS Cognitive Outcomes Study (ACOS) (16). In the ACOS, of the 406 eligible patients, 18% declined participation (11% on initial approach; 6% after consent obtained). Another 145 patients (36%) were unable to be contacted; it is unclear whether this was a result of CI, change in contact information, or other reasons. Finally, 25% of enrolled patients were lost to follow-up on subsequent testing. Of those patients that did participate, several participants expressed frustration during testing despite reassurances of performance and requested to stop (n = 8) (16). Inquiry into barriers to neurocognitive testing, or modifications of these tests to improve efficiency while retaining diagnostic properties, will require further investigation.

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CONCLUSIONS

Impaired cognitive functioning is common and persists after critical illness, and although improvement is seen with time, only a minority of critical care survivors return to their cognitive baseline. The mechanisms of CI remain incompletely understood. Interventional trials to improve cognitive outcomes for ICU survivors through prevention and rehabilitation are only now beginning. Further study to elucidate the causes and pathophysiology of this newly acquired chronic brain injury in different patient populations and strategies to return patients to their baseline cognitive status are important research priorities. For now, CI in survivors of critical illness highlights opportunities to improve care, possibly through risk reduction, in the ICU (e.g., timely resuscitation, sedation stewardship), on the hospital ward (e.g., assessment of sleep efficiency, mobilization), and after discharge in the posthospital recovery period (e.g., ongoing cognitive or physical therapy, screening for psychological morbidity).

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Keywords:

adult respiratory distress syndrome; cognitive impairment; critical illness; disability; ICU; intervention; rehabilitation

Copyright © 2013 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins

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