Critical Care Medicine:
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
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.
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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.
STUDIES OF CI IN CRITICAL ILLNESS
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.
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.
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.
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.
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.
PATIENT-ASSOCIATED RISK FACTORS
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.
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.
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.
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).
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.
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.
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).
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.
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).
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.
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.
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.
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.
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.
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).
1. Herridge MS, Cheung AM, Tansey CM, et al.Canadian Critical Care Trials Group. One-year outcomes in survivors of the acute respiratory distress syndrome. N Engl J Med. 2003;348:683–693
2. Herridge MS, Tansey CM, Matté A, et al.Canadian Critical Care Trials Group. Functional disability 5 years after acute respiratory distress syndrome. N Engl J Med. 2011;364:1293–1304
3. Hough CL, Herridge MS. Long-term outcome after acute lung injury. Curr Opin Crit Care. 2012;18:8–15
4. Rothenhäusler HB, Ehrentraut S, Stoll C, et al. The relationship between cognitive performance and employment and health status in long-term survivors of the acute respiratory distress syndrome: Results of an exploratory study. Gen Hosp Psychiatry. 2001;23:90–96
5. Hopkins RO, Brett S. Chronic neurocognitive effects of critical illness. Curr Opin Crit Care. 2005;11:369–375
6. Needham DM, Dinglas VD, Bienvenu OJ, et al.NIH NHLBI ARDS Network. One year outcomes in patients with acute lung injury randomised to initial trophic or full enteral feeding: Prospective follow-up of EDEN randomised trial. BMJ. 2013;346:f1532
7. Adhikari NK, Tansey CM, McAndrews MP, et al. Self-reported depressive symptoms and memory complaints in survivors five years after ARDS. Chest. 2011;140:1484–1493
8. Adhikari NK, McAndrews MP, Tansey CM, et al. Self-reported symptoms of depression and memory dysfunction in survivors of ARDS. Chest. 2009;135:678–687
9. Christie JD, Biester RC, Taichman DB, et al. Formation and validation of a telephone battery to assess cognitive function in acute respiratory distress syndrome survivors. J Crit Care. 2006;21:125–132
10. Hopkins RO, Weaver LK, Pope D, et al. Neuropsychological sequelae and impaired health status in survivors of severe acute respiratory distress syndrome. Am J Respir Crit Care Med. 1999;160:50–56
11. Hopkins RO, Weaver LK, Chan KJ, et al. Quality of life, emotional, and cognitive function following acute respiratory distress syndrome. J Int Neuropsychol Soc. 2004;10:1005–1017
12. Hopkins RO, Weaver LK, Collingridge D, et al. Two-year cognitive, emotional, and quality-of-life outcomes in acute respiratory distress syndrome. Am J Respir Crit Care Med. 2005;171:340–347
13. Hopkins RO, Suchyta MR, Snow GL, et al. Blood glucose dysregulation and cognitive outcome in ARDS survivors. Brain Inj. 2010;24:1478–1484
14. Larson MJ, Weaver LK, Hopkins RO. Cognitive sequelae in acute respiratory distress syndrome patients with and without recall of the intensive care unit. J Int Neuropsychol Soc. 2007;13:595–605
15. Mikkelsen ME, Shull WH, Biester RC, et al. Cognitive, mood and quality of life impairments in a select population of ARDS survivors. Respirology. 2009;14:76–82
16. Mikkelsen ME, Christie JD, Lanken PN, et al. The adult respiratory distress syndrome cognitive outcomes study: Long-term neuropsychological function in survivors of acute lung injury. Am J Respir Crit Care Med. 2012;185:1307–1315
17. Ambrosino N, Bruletti G, Scala V, et al. Cognitive and perceived health status in patient with chronic obstructive pulmonary disease surviving acute on chronic respiratory failure: A controlled study. Intensive Care Med. 2002;28:170–177
18. de Rooij SE, Govers AC, Korevaar JC, et al. Cognitive, functional, and quality-of-life outcomes of patients aged 80 and older who survived at least 1 year after planned or unplanned surgery or medical intensive care treatment. J Am Geriatr Soc. 2008;56:816–822
19. Duning T, van den Heuvel I, Dickmann A, et al. Hypoglycemia aggravates critical illness-induced neurocognitive dysfunction. Diabetes Care. 2010;33:639–644
20. Ehlenbach WJ, Hough CL, Crane PK, et al. Association between acute care and critical illness hospitalization and cognitive function in older adults. JAMA. 2010;303:763–770
21. Girard TD, Jackson JC, Pandharipande PP, et al. Delirium as a predictor of long-term cognitive impairment in survivors of critical illness. Crit Care Med. 2010;38:1513–1520
22. Iwashyna TJ, Ely EW, Smith DM, et al. Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA. 2010;304:1787–1794
23. Jackson JC, Hart RP, Gordon SM, et al. Six-month neuropsychological outcome of medical intensive care unit patients. Crit Care Med. 2003;31:1226–1234
24. Jackson JC, Obremskey W, Bauer R, et al. Long-term cognitive, emotional, and functional outcomes in trauma intensive care unit survivors without intracranial hemorrhage. J Trauma. 2007;62:80–88
25. Jackson JC, Girard TD, Gordon SM, et al. Long-term cognitive and psychological outcomes in the Awakening and Breathing Controlled trial. Am J Respir Crit Care Med. 2010;182:183–191
26. Jackson JC, Archer KR, Bauer R, et al. A prospective investigation of long-term cognitive impairment and psychological distress in moderately versus severely injured trauma intensive care unit survivors without intracranial hemorrhage. J Trauma. 2011;71:860–866
27. Jones C, Griffiths RD, Slater T, et al. Significant cognitive dysfunction in non-delirious patients identified during and persisting following critical illness. Intensive Care Med. 2006;32:923–926
28. Sacanella E, Pérez-Castejón JM, Nicolás JM, et al. Functional status and quality of life 12 months after discharge from a medical ICU in healthy elderly patients: A prospective observational study. Crit Care. 2011;15:R105
29. Semmler A, Widmann CN, Okulla T, et al. Persistent cognitive impairment, hippocampal atrophy and EEG changes in sepsis survivors. J Neurol Neurosurg Psychiatry. 2013;84:62–69
30. Suchyta MR, Jephson A, Hopkins RO. Neurologic changes during critical illness: Brain imaging findings and neurobehavioral outcomes. Brain Imaging Behav. 2010;4:22–34
31. Sukantarat KT, Burgess PW, Williamson RC, et al. Prolonged cognitive dysfunction in survivors of critical illness. Anaesthesia. 2005;60:847–853
32. Teeters D, Moua T, Biehl M, et al. The incidence of preexisting cognitive impairment before ICU admission: A population based study. Abstr. Chest. 2011;140:A349
33. Tembo AC, Higgins I, Parker V. Cognitive impairment in critical illness survivors—A phenomenological inquiry. Abstr. Neuroepidemiology. 2012;39:A159
34. Tobar E, Galleguillos T, Delgado C, et al. Hypoactive delirium in septic mechanically ventilated patient. Preliminary data of cognitive and psychiatric follow up. Abstr. Crit Care Med. 2009;37:A781
35. Woon FL, Dunn CB, Hopkins RO. Predicting cognitive sequelae in survivors of critical illness with cognitive screening tests. Am J Respir Crit Care Med. 2012;186:333–340
36. Guillamondegui OD, Richards JE, Ely EW, et al. Does hypoxia affect intensive care unit delirium or long-term cognitive impairment after multiple trauma without intracranial hemorrhage? J Trauma. 2011;70:910–915 Erratum in J Trauma
37. Torgersen J, Hole JF, Kvåle R, et al. Cognitive impairments after critical illness. Acta Anaesthesiol Scand. 2011;55:1044–1051
38. Ely EW, Girard TD, Shintani AK, et al. Apolipoprotein E4 polymorphism as a genetic predisposition to delirium in critically ill patients. Crit Care Med. 2007;35:112–117
39. Janz DR, Abel TW, Jackson JC, et al. Brain autopsy findings in intensive care unit patients previously suffering from delirium: A pilot study. J Crit Care. 2010;25:538.e7–538.12
40. Hopkins RO, Gale SD, Weaver LK. Brain atrophy and cognitive impairment in survivors of acute respiratory distress syndrome. Brain Inj. 2006;20:263–271
41. Morandi A, Rogers BP, Gunther ML, et al.VISIONS Investigation, VISualizing Icu SurvivOrs Neuroradiological Sequelae. The relationship between delirium duration, white matter integrity, and cognitive impairment in intensive care unit survivors as determined by diffusion tensor imaging: The VISIONS prospective cohort magnetic resonance imaging study. Crit Care Med. 2012;40:2182–2189
42. Gunther ML, Morandi A, Krauskopf E, et al.VISIONS Investigation, VISualizing Icu SurvivOrs Neuroradiological Sequelae. The association between brain volumes, delirium duration, and cognitive outcomes in intensive care unit survivors: The VISIONS cohort magnetic resonance imaging study. Crit Care Med. 2012;40:2022–2032
43. Gross AL, Jones RN, Habtemariam DA, et al. Delirium and long-term cognitive trajectory among persons with dementia. Arch Intern Med. 2012;172:1324–1331
44. Pomara N, Willoughby L, Wesnes K, et al. Apolipoprotein E epsilon4 allele and lorazepam effects on memory in high-functioning older adults. Arch Gen Psychiatry. 2005;62:209–216
45. Pomara N, Bruno D. Lower plasma β-amyloid levels are associated with moderately greater rate of cognitive decline among older people without dementia. Evid Based Ment Health. 2011;14:41
46. Weinert CR. Epidemiology of psychiatric medication use in patients recovering from critical illness at a long-term acute-care facility. Chest. 2001;119:547–553
47. Kress JP, Gehlbach B, Lacy M, et al. The long-term psychological effects of daily sedative interruption on critically ill patients. Am J Respir Crit Care Med. 2003;168:1457–1461
48. Davydow DS, Gifford JM, Desai SV, et al. Depression in general intensive care unit survivors: A systematic review. Intensive Care Med. 2009;35:796–809
49. Bienvenu OJ, Colantuoni E, Mendez-Tellez PA, et al. Depressive symptoms and impaired physical function after acute lung injury: A 2-year longitudinal study. Am J Respir Crit Care Med. 2012;185:517–524
50. Khan BA, Zawahiri M, Campbell NL, et al. Biomarkers for delirium—A review. J Am Geriatr Soc. 2011;59(Suppl 2):S256–S261
51. Hall RJ, Shenkin SD, Maclullich AM. A systematic literature review of cerebrospinal fluid biomarkers in delirium. Dement Geriatr Cogn Disord. 2011;32:79–93
52. Girard TD, Pandharipande PP, Ely EW. Delirium in the intensive care unit. Crit Care. 2008;12(Suppl 3):S3
53. Pun BT, Boehm L. Delirium in the intensive care unit: Assessment and management. AACN Adv Crit Care. 2011;22:225–237
54. Morandi A, Jackson JC. Delirium in the intensive care unit: A review. Neurol Clin. 2011;29:749–763
55. McNicoll L, Pisani MA, Zhang Y, et al. Delirium in the intensive care unit: Occurrence and clinical course in older patients. J Am Geriatr Soc. 2003;51:591–598
56. Inouye SK. Prevention of delirium in hospitalized older patients: Risk factors and targeted intervention strategies. Ann Med. 2000;32:257–263
57. Inouye SK. Delirium in older persons. N Engl J Med. 2006;354:1157–1165
58. Barr J, Fraser GL, Puntillo K, et al. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit: Executive summary. Am J Health-Syst Pharm. 2013;70:53–58
59. Ely EW, Gautam S, Margolin R, et al. The impact of delirium in the intensive care unit on hospital length of stay. Intensive Care Med. 2001;27:1892–1900
60. Pisani MA, Kong SY, Kasl SV, et al. Days of delirium are associated with 1-year mortality in an older intensive care unit population. Am J Respir Crit Care Med. 2009;180:1092–1097
61. Ely EW, Shintani A, Truman B, et al. Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit. JAMA. 2004;291:1753–1762
62. van Gool WA, van de Beek D, Eikelenboom P. Systemic infection and delirium: When cytokines and acetylcholine collide. Lancet. 2010;375:773–775
63. Kamdar BB, Needham DM, Collop NA. Sleep deprivation in critical illness: Its role in physical and psychological recovery. J Intensive Care Med. 2012;27:97–111
64. Orwelius L, Nordlund A, Nordlund P, et al. Prevalence of sleep disturbances and long-term reduced health-related quality of life after critical care: A prospective multicenter cohort study. Crit Care. 2008;12:R97
65. Lee CM, Herridge MS, Gabor JY, et al. Chronic sleep disorders in survivors of the acute respiratory distress syndrome. Intensive Care Med. 2009;35:314–320
67. Jacobson SA, Leuchter AF, Walter DO, et al. Serial quantitative EEG among elderly subjects with delirium. Biol Psychiatry. 1993;34:135–140
68. Young GB, Blume WT, Campbell VM, et al. Alpha, theta and alpha-theta coma: A clinical outcome study utilizing serial recordings. Electroencephalogr Clin Neurophysiol. 1994;91:93–99
69. Young GB, Bolton CF, Archibald YM, et al. The electroencephalogram in sepsis-associated encephalopathy. J Clin Neurophysiol. 1992;9:145–152
70. Watson PL, Shintani AK, Tyson R, et al. Presence of electroencephalogram burst suppression in sedated, critically ill patients is associated with increased mortality. Crit Care Med. 2008;36:3171–3177
71. Myers JS. The possible role of cytokines in chemotherapy-induced cognitive deficits. Adv Exp Med Biol. 2010;678:119–123
72. Hudetz JA, Gandhi SD, Iqbal Z, et al. Elevated postoperative inflammatory biomarkers are associated with short- and medium-term cognitive dysfunction after coronary artery surgery. J Anesth. 2011;25:1–9
73. Seruga B, Zhang H, Bernstein LJ, et al. Cytokines and their relationship to the symptoms and outcome of cancer. Nat Rev Cancer. 2008;8:887–899
74. Jernigan TL, Archibald SL, Fennema-Notestine C, et al. Effects of age on tissues and regions of the cerebrum and cerebellum. Neurobiol Aging. 2001;22:581–594
75. Park DC, Polk TA, Mikels JA, et al. Cerebral aging: Integration of brain and behavioral models of cognitive function. Dialogues Clin Neurosci. 2001;3:151–165
76. Hopkins RO, Suchyta MR, Farrer TJ, et al. Improving post-intensive care unit neuropsychiatric outcomes: Understanding cognitive effects of physical activity. Am J Respir Crit Care Med. 2012;186:1220–1228
77. Colcombe SJ, Erickson KI, Raz N, et al. Aerobic fitness reduces brain tissue loss in aging humans. J Gerontol A Biol Sci Med Sci. 2003;58:176–180
78. Tyndall AV, Davenport MH, Wilson BJ, et al. The brain-in-motion study: Effect of a 6-month aerobic exercise intervention on cerebrovascular regulation and cognitive function in older adults. BMC Geriatr. 2013;13:21
79. Schweickert WD, Pohlman MC, Pohlman AS, et al. Early physical and occupational therapy in mechanically ventilated, critically ill patients: A randomised controlled trial. Lancet. 2009;373:1874–1882
80. Hoffmann T, Tornatore G. Early physical and occupational therapy in mechanically ventilated, critically ill patients resulted in better functional outcomes at hospital discharge. Aust Occup Ther J. 2009;56:438–439
81. Jackson JC, Ely EW, Morey MC, et al. Cognitive and physical rehabilitation of intensive care unit survivors: Results of the RETURN randomized controlled pilot investigation. Crit Care Med. 2012;40:1088–1097
82. Brummel NE, Jackson JC, Girard TD, et al. A combined early cognitive and physical rehabilitation program for people who are critically ill: The activity and cognitive therapy in the intensive care unit (ACT-ICU) trial. Phys Ther. 2012;92:1580–1592
83. Kamdar BB, King LM, Collop NA, et al. The effect of a quality improvement intervention on perceived sleep quality and cognition in a medical ICU. Crit Care Med. 2013;41:800–809
84. Adler J, Malone D. Early mobilization in the intensive care unit: A systematic review. Cardiopulm Phys Ther J. 2012;23:5–13
85. Angus DC, Carlet J2002 Brussels Roundtable Participants. . Surviving intensive care: A report from the 2002 Brussels Roundtable. Intensive Care Med. 2003;29:368–377
adult respiratory distress syndrome; cognitive impairment; critical illness; disability; ICU; intervention; rehabilitation
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