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Long-term Cognitive and Functional Impairments After Critical Illness

Rengel, Kimberly F., MD; Hayhurst, Christina J., MD; Pandharipande, Pratik P., MD; Hughes, Christopher G., MD

doi: 10.1213/ANE.0000000000004066
Neuroscience and Neuroanesthesiology: Narrative Review Article
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As critical illness survivorship increases, patients and health care providers are faced with management of long-term sequelae including cognitive and functional impairment. Longitudinal studies have demonstrated impairments persisting at least 1–5 years after hospitalization for critical illness. Cognitive domains impacted include memory, attention, and processing speed. Functional impairments include physical weakness, reduced endurance, and dependence on others for basic tasks of daily living such as bathing or feeding. In characterizing the trajectory of long-term recovery, multiple risk factors have been identified for subsequent impairment, including increased severity of illness and severe sepsis, prolonged mechanical ventilation, and delirium. Preadmission status including frailty, high level of preexisting comorbidities, and baseline cognitive dysfunction are also associated with impairment after critical illness. Development of cognitive and functional impairment is likely multifactorial, and multiple mechanistic theories have been proposed. Neuroinflammation, disruption of the blood–brain barrier, and structural alterations in the brain have all been observed in patients with long-term cognitive dysfunction. Systemic inflammation has also been associated with alterations in muscle integrity and function, which is associated with intensive care unit–acquired weakness and prolonged functional impairment. Efforts to ease the burden of long-term impairments include prevention strategies and rehabilitation interventions after discharge. Delirium is a well-established risk factor for long-term cognitive dysfunction, and using delirium-prevention strategies may be important for cognitive protection. Current evidence favors minimizing overall sedation exposure, careful selection of sedation agents including avoidance of benzodiazepines, and targeted sedation goals to avoid oversedation. Daily awakening and spontaneous breathing trials and early mobilization have shown benefit in both cognitive and functional outcomes. Multifactorial prevention bundles are useful tools in improving care provided to patients in the intensive care unit. Data regarding cognitive rehabilitation are limited, while studies on functional rehabilitation have conflicting results. Continued investigation and implementation of prevention strategies and rehabilitation interventions will hopefully improve the quality of life for the ever-increasing population of critical illness survivors.

From the Department of Anesthesiology, Division of Anesthesiology Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.

Published ahead of print 7 January 2019.

Accepted for publication January 7, 2019.

Funding: None.

The authors declare no conflicts of interest.

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Reprints will not be available from the authors.

Address correspondence to Pratik P. Pandharipande, MD, Department of Anesthesiology, Division of Anesthesiology Critical Care Medicine, Vanderbilt University School of Medicine, 422 Medical Arts Bldg, 1212 21st Ave S, Nashville, TN 37212. Address e-mail to pratik.pandharipande@vumc.org.

Advances in the management of critically ill patients have led to an increase in survival but not necessarily the quality of survivorship. After surviving critical illness, many patients experience long-term cognitive and functional impairments that lead to a protracted recovery, need for institutionalization, decreased employment, and significant caregiver burden, all of which represent a major public health problem. Cognitive impairment represents deficits in the domains of memory, attention, processing speed, visual-spatial ability, and executive function. Functional impairment refers to physical weakness and reduced endurance, which may lead to disability—an inability to perform physical tasks such as feeding, bathing, or dressing. The following review examines current literature on the epidemiology, risk factors, and mechanisms of these impairments and strategies to prevent patients from developing long-term impairment after critical illness.

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EPIDEMIOLOGY

Early studies on the epidemiology of long-term cognitive impairment after critical illness varied widely with reported prevalence from 4%–62%. The variability represents data obtained from multiple small cohort studies limited to a single disease state (eg, sepsis, acute respiratory distress syndrome [ARDS]) or type of intensive care unit and collected at time points ranging from 2 months to >10 years.1 One of the largest multicenter cohorts to characterize postintensive care unit cognitive and functional impairment is the Bringing to Light the Risk Factors and Incidence of Neuropsychological Dysfunction in Intensive Care Unit Survivors study. In this prospective trial, 821 patients with respiratory failure or shock were enrolled from both medical and surgical intensive care units. Cognitive and functional status were assessed at 3 and 12 months after discharge with surrogate tests used to determine critical illness baseline. Global cognition and executive function were measured using the Repeatable Battery for the Assessment of Neuropsychological Status and Trail Making Test (part B), respectively. Among survivors of critical illness at 3 months postdischarge, 40% scored lower than 1.5 SD below age-adjusted norms, which is comparable to scores seen in patients after mild to moderate traumatic brain injury, and 26% were >2 SD below normal, comparable to scores of patients with mild Alzheimer’s disease. The effect persisted at those levels in 34% and 24%, respectively, of patients at 12 months. In addition, participants demonstrated depressed executive function at 3 and 12 months.2 Among all patients with scores indicative of cognitive impairment, the cognitive testing score distribution displayed a subcortical pattern of deficits as seen in vascular dementia, as opposed to Alzheimer’s dementia, at both 3 and 12 months.3

Long-term functional outcomes after critical illness were first examined in survivors of ARDS. A study of 109 patients who survived hospitalization for ARDS and completed evaluations 3, 6, and 12 months after discharge found that patients had persistently lower than expected results in the 6-minute walk test and Medical Outcomes 36-item Short-Form Survey. This provided some of the first evidence of long-term functional disability after discharge from an intensive care unit.4 In the Bringing to Light the Risk Factors and Incidence of Neuropsychological Dysfunction in Intensive Care Unit Survivors study, basic functional ability was assessed with the Katz Activities of Daily Living questionnaire and higher order functioning was evaluated with the Pfeffer Functional Activities Questionnaire for Instrumental Activities of Daily Living. At 3 months, 32% of individuals demonstrated at least partial disability in activities of daily living, and 26% demonstrated disability in instrumental activities of daily living. Disability in activities of daily living persisted in 22%, and disability in instrumental activities of daily living persisted in 23% of individuals at 12 months.5 In evaluating the cooccurrence of these impairments (ie, newly acquired cognitive impairment, disability, depression), often termed postintensive care syndrome, additional analysis found that ≥1 postintensive care problems were present in over 50% of patients up to 12 months.6 Problems in ≥2 domains were present in approximately 20% at 12 months, while problems in all 3 domains were present in only 4% at 12 months.

Another study of long-term trajectories used data from the Group Health Cooperative, a longitudinal evaluation of 2929 subjects over the age of 65 without baseline dementia.7 Assessment of cognitive trajectories was completed with administration of the Cognitive Abilities Screening Instrument every 2 years. Lower scores triggered further assessment for dementia. Investigators found that hospitalization for acute care and critical illness was associated with an increased likelihood of abrupt cognitive decline when compared to those who were not hospitalized. Data also indicated that noncritical illness hospitalization significantly increased the risk of incident dementia by 50% and suggested that critical illness may double the risk of incident dementia; the study, however, was not sufficiently powered to detect a difference in the latter.7 In addition to long-term cognitive decline, critical illness was associated with a decline in physical function indicated by a significant reduction in gait speed and chair-stand speed and difficulty or dependence in ≥1 activities of daily living. Specifically, critical illness was associated with almost 8 times greater odds of developing dependence in ≥1 activity of daily living. Of note, the median time between hospital discharge and evaluation was 359 days, demonstrating that functional decline often persisted up to 1 year after discharge.8

The deleterious effects of critical illness on cognitive and functional status have been shown to impact patients well beyond the first year of survival. In a long-term evaluation of 743 patients who required mechanical ventilation during critical illness, 61% survived and returned to functional baseline as measured by the Barthel Index at 1 year after discharge, and only 53% survived and returned to functional baseline at 5 years.9 The previously mentioned study of 109 survivors of ARDS continued to perform evaluations 5 years after discharge. At the 5-year evaluation, participants demonstrated a persistent reduction in the 6-minute walk test indicating a continued impairment in exercise endurance.10 Further, scores on the physical component of the Medical Outcomes Study 36-Item Short-Form Health Survey remained 1 SD below normal, consistent with a reduced physical quality of life.10 These results are similar to a more recent cohort of 222 patients with ARDS that demonstrated that physical quality of life and endurance testing had the largest decrease out to 2 years after diagnosis, followed by upper extremity muscle strength.11

Large retrospective database studies have also indicated high rates of impairments after critical illness. A retrospective analysis of 66,540 patients admitted to a skilled nursing facility after severe sepsis sought to demonstrate the trajectory for recovery. Investigators found that 34% demonstrated severe or very severe cognitive impairment, and 72.5% demonstrated maximal or total dependence in activities of daily living at the time of admission to the skilled nursing facility. Cognitive impairment and dependence in activities of daily living were each associated with shorter survival.12 A study of over 10,000 intensive care patients who survived to hospital discharge (randomly selected from a sample of Medicare beneficiaries) found an approximately 50% increased risk of subsequent dementia diagnosis within 3 years compared to matched controls. Interestingly, risk factors accrued during the period of critical illness accounted for almost the entire additional risk of dementia,13 highlighting the potential impact clinicians can have in reducing the burden of long-term impairments.

Overall, extensive data from prospective observational studies of critically ill patients, prospective community observation studies, and large retrospective studies demonstrate that survivors of critical illness are at significant risk for cognitive and functional impairments that may persist for years after the incident illness. This represents a growing public health problem as intensive care unit survival continues to increase.

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RISK FACTORS FOR LONG-TERM IMPAIRMENT

Many risk factors have been identified for developing long-term cognitive (Table 1) or functional (Table 2) impairment, and frequently factors are related or may increase risk for both types of impairment. Sepsis is frequently associated with critical illness and acute organ dysfunction but appears to also have longer reaching consequences. Using data from a prospective cohort, the Health and Retirement Study analyzed pre- and postillness cognitive and functional assessments in survivors of sepsis.14 Investigators found that severe sepsis was independently associated with up to a threefold increase in moderate to severe cognitive impairment and 1.5 new functional limitations.14 Other shared risk factors for long-term cognitive and functional impairment include increasing age, baseline cognitive impairments, higher preillness burden of comorbidities, and longer duration of mechanical ventilation.9 , 15

Table 1

Table 1

Table 2

Table 2

In evaluating long-term cognitive dysfunction, the Bringing to Light the Risk Factors and Incidence of Neuropsychological Dysfunction in Intensive Care Unit Survivors study determined that duration of in-hospital delirium was associated with worse global cognitive function at 3 and 12 months after discharge, independent of sedative and analgesic medications, age, preexisting cognitive impairment, comorbidities, or number of intensive care unit organ failures. Increasing years of education, however, was protective from developing worse cognitive function.2 This observation was again seen in a larger analysis that added data from the MIND-ICU Study: Delirium and Dementia in Veterans Surviving Intensive Care Unit Care to the Bringing to Light the Risk Factors and Incidence of Neuropsychological Dysfunction in Intensive Care Unit Survivors cohort. Longer duration of in-hospital delirium was associated with worse global cognition, whereas higher baseline education was protective.3 This analysis also demonstrated that exposure to surgery or anesthesia per se did not increase the risk for long-term cognitive impairment in this critically ill cohort.3 Delirium after cardiac surgery, most commonly in the cardiovascular intensive care unit, has also been linked to worse cognitive decline and altered cognitive trajectories in several cohorts.16–18 In a study of 114 patients without documented dementia having cardiac surgery, 26% went on to develop dementia within 5 years, with the development of postoperative delirium being associated with over 7-fold increased risk.17 Most recently, a study of 142 patients undergoing cardiac surgery with bypass found that patients who developed postoperative delirium had greater overall cognitive decline at 3 months and worse cognitive processing speed up to 1 year.18 Additional factors beyond acute brain dysfunction postulated to impact long-term outcomes associated with critical illness include hypoxemia, pathological changes in blood pressure, dysglycemia, sedative exposure, and blood transfusions; studies on the impact of these factors, however, have been inconclusive.15 Thus, the evidence strongly points to presence of delirium and increasing delirium duration as strong predictors of later cognitive impairment, highlighting the importance of delirium prevention strategies in the intensive care unit and warranting prognostic consideration for those patients who develop delirium in the intensive care unit.

Baseline functional status and weakness acquired throughout the course of critical illness comprise 2 major risk categories for developing long-term functional impairment. The Precipitating Events Project followed a cohort of 754 community-dwelling individuals >70 years of age without baseline disability. Comprehensive assessments were conducted every 18 months in all participants. Of the participants who were hospitalized for critical illness during the course of the study, those with preadmission frailty demonstrated 41% greater disability over the 6 months after the critical illness.19 Preadmission deficits in hearing and vision were also associated with poor functional recovery after intensive care unit admission.20 Individuals with a higher baseline body mass index and functional self-efficacy (confidence in performing functional activities) were more likely to recover to their functional baseline.20 In recent years, intensive care unit–acquired weakness has emerged as a well-described phenomenon of weakness that develops after the onset of critical illness and is commonly associated with sepsis and multiorgan dysfunction. Advancing age and each additional day of bed rest have also been found to increase risk of intensive care unit–acquired weakness.11 A diagnosis of intensive care unit–acquired weakness at discharge after critical illness requiring mechanical ventilation has been associated with decreased physical function at 6 months.21 Additionally, while weakness may resolve over time, presence of intensive care unit–acquired weakness at discharge was associated with persistence of substantially impaired physical function and decreased physical health-related quality of life at 24 months in survivors of acute lung injury.11 Increasing severity of illness and prolonged intensive care unit stay >14 days have also been associated with more functional impairment.9 , 22 Emerging evidence has also demonstrated that as many as one-third of intensive care unit survivors will develop chronic pain after critical illness, which in turn may interfere with functional status.23 Within the Bringing to Light the Risk Factors and Incidence of Neuropsychological Dysfunction in Intensive Care Unit Survivors cohort, 77% and 74% of patients reported pain symptoms at 3 and 12 months respectively, with 59% and 62% reporting that pain symptoms interfered with daily life at 3 and 12 months.24 In considering long-term recovery, establishing a patient’s baseline level of functioning and frailty and evaluating for intensive care unit–acquired weakness are important steps to help providers identify those patients at highest risk for long-term functional impairment.

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MECHANISMS OF LONG-TERM IMPAIRMENT

The mechanisms of injury that lead to long-term cognitive and functional impairment have not been well characterized, likely due to the complex and multifactorial nature of the disease processes (Figure) and to the early stages of this line of research. Neuroimaging studies of patients with in-hospital delirium and long-term cognitive impairment have identified structural changes including cerebral atrophy and white matter disruption. Individuals with intensive care unit delirium imaged at discharge were found to have an increased ventricle-to-brain ratio consistent with brain atrophy, which, if still present at 3-month follow-up, was associated with cognitive impairment for up to 12 months after discharge.25 Similarly, prolonged periods of intensive care unit delirium have been associated with white matter changes of the corpus callosum and anterior limb of the internal capsule. Failure of resolution at 3 months was, again, associated with cognitive impairment up to 12 months after discharge.26 Postoperative delirium has also been associated with subsequent decreased integrity and increased diffusion in periventricular, frontal, and temporal white matter.27 It would appear, therefore, that the injury processes leading to acute brain dysfunction likely progress to chronic structural changes that affect long-term cognition.

Figure

Figure

Inflammatory changes are frequently encountered in critical illness and may induce a cycle of neuroinflammation leading to apoptosis and the atrophy observed with neuroimaging. Sepsis is a highly proinflammatory condition that is characterized by overproduction of cytokines including tumor necrosis factor and interleukins such as interleukin-1, interleukin-6, and interleukin-10.28 Analysis of inflammatory cytokine levels in patients within 48 hours of discharge who had been admitted to an intensive care unit during hospitalization revealed elevated levels of interleukin-6 and interleukin-10 at the highest 25th percentile were associated with worse cognitive performance at up to 48 months.29 It is hypothesized that elevated peripheral cytokine activity induces an inflammatory cascade that primes centrally located microglia—macrophage cells that are quiescent under normal conditions—to produce proinflammatory cytokines and reactive oxygen species and to recruit monocytes to the brain, leading to neuronal apoptosis and cerebral edema.14 , 30–32 Peripheral cytokines also bind to the endothelium of the blood–brain barrier, altering adhesion and permeability and promoting active cytokine transport across the blood–brain barrier.32 , 33 Elevated levels of S100B in plasma indicate blood–brain barrier or astrocyte injury and elevated E-selectin serves as a marker of endothelial injury. Elevations in both S100B and E-selectin at the onset of critical illness have been associated with worse cognitive function at 3 and 12 months after critical illness.34

Similar to cognitive function, inflammatory processes associated with critical illness (eg, sepsis) likely play a role in the development of physical impairment. This was demonstrated in a cohort of intensive care unit patients who developed intensive care unit–acquired weakness and were found to have significantly higher levels of interleukin-6, interleukin-8, interleukin-10, and fractalkine than those who did not.35 Intensive care unit–acquired weakness demonstrates features of 2 pathophysiological processes: polyneuropathy and myopathy. Critical illness polyneuropathy is characterized by symmetric weakness in the proximal limbs with possible respiratory muscle involvement. It is not a process of tissue destruction, as creatine kinase levels remain within normal limits and demyelination is not observed. Critical illness myopathy is a primary myopathy with reduced amplitude and increased duration of compound muscle action potentials on electrophysiological studies and reduced muscle excitability on direct stimulation.36 Histological analysis of muscle biopsies of 202 critically ill patients compared to controls showed upregulation of proteolysis and decreased expression of genes involved in protein synthesis. Critically ill patients had muscle atrophy, decreased myofiber size, and preferential loss of myosin within the muscle.37 Sustained muscle atrophy after intensive care unit–acquired weakness does not appear to be associated with ongoing proteolysis, inflammation, or dysregulated metabolic activity, rather it is associated with decreased satellite cell content indicating a compromised capacity for regrowth and regeneration of affected muscle.38

In summary, although ongoing research continues to provide insight into the complex mechanisms of cognitive and functional injury, the inflammatory cascade associated with critical illness appears to have an integral role in initiating structural changes in the nervous system and musculature that lead to worse long-term cognitive and functional outcomes.

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PREVENTION

The consequences of cognitive and functional impairment after critical illness may last years and significantly impact the lives of patients and caregivers, making it imperative that members of the critical care team tailor care and target preventable causes of impairment. This includes avoiding delirium and hypoxemia, carefully managing blood glucose, and minimizing pathological changes in blood pressure. A major area of study is preventing and treating reversible causes of delirium, and evidence increasingly indicates that choice of sedation strategy in the intensive care unit may significantly impact delirium development. Recent investigations have repeatedly shown benzodiazepine administration to be associated with increased risk of brain dysfunction and prolonged periods of mechanical ventilation.39–41 As compelling evidence has emerged, trends have begun shifting away from the use of benzodiazepines toward short-acting alternatives, including the γ-aminobutyric acid–mediated agent propofol and the α-2 agonist dexmedetomidine. The Maximizing Efficacy of Targeted Sedation and Reducing Neurological Dysfunction Study randomized medical and surgical intensive care unit patients to receive lorazepam or dexmedetomidine for sedation. Patients receiving dexmedetomidine were more likely to achieve targeted sedation levels, had more days alive without delirium or coma, and had a 60% lower risk of developing delirium.42 Similar results were seen in the Safety and Efficacy of Dexmedetomidine Compared with Midazolam study, where dexmedetomidine sedation led to decreased time on the ventilator and less delirium compared to midazolam.43 Comparison of propofol to dexmedetomidine for sedation after cardiac surgery has shown decreased risk of delirium development and duration of delirium in patients receiving dexmedetomidine.44 , 45 Analgesia-based sedation strategies also offer an alternative to benzodiazepines; the relationship between this strategy and brain dysfunction, however, has not been well studied. In a trial of postoperative cardiac patients that compared a morphine-based sedation strategy to dexmedetomidine, a decreased duration of delirium was found in the group receiving dexmedetomidine.46 Now that the impact of these sedation strategies on delirium reduction has been established, studies looking at their effect on subsequent long-term impairments are underway.

A vital second component in intensive care unit sedation management, in addition to choice of agent, is monitoring depth of sedation and targeting light sedation. Deep sedation levels have been associated with worse clinical outcomes, including prolonged mechanical ventilation, more intensive care unit days, increased frequency of radiological evaluations for change in mental status, and increased likelihood of developing delirium.39 , 40 , 47–49 Lighter sedation targets have been shown to lead to increased ventilator-free days and intensive care unit–free days50 compared to deep sedation targets, and amnesia from deep sedation increases risk of neurocognitive sequelae up to 2 years after discharge.51 When monitored with electroencephalogram, deep sedation with a burst suppression pattern has been independently associated with higher mortality.52 Further, number of deep sedation episodes classified as a Richmond Agitation Sedation Scale of −3 to −5 has been associated with increased mortality up to 2 years.53–55 Conversely, daily interruption of sedative medication infusions decreases the duration of mechanical ventilation and intensive care unit days.49 Building on this, the Awakening and Breathing Controlled Trial56 coordinated daily spontaneous awakening and breathing trials and found that sedative use decreased by up to 50%, patients experienced more coma- and ventilator-free days while in the intensive care unit, and reduced 12-month mortality. In addition to daily awakening, implementing a sedation protocol based on the Richmond Agitation Sedation Scale has been associated with decreased sedative administration and reduction in intensive care unit and hospital stay.57

Included in the paradigm shift away from deep sedation in the intensive care unit are efforts to prevent functional decline through early mobilization and physical therapy. Dispelling conventional notions that mechanically ventilated patients are unable to participate in mobilization, many studies have demonstrated the safety and feasibility of initiating early physical therapy including passive and active range of motion, bed mobility, transferring, sitting, pregait exercise, and walking.58–61 Early physical therapy during septic shock has been shown to counteract the pathological effects of critical illness on muscle with preserved muscle fiber cross-sectional area and a tendency toward downregulated expression of genetic markers for the ubiquitin-proteasome pathway (a mechanism for muscle breakdown) when compared to delayed physical therapy.62 Early exercise intervention with bedside ergometer was associated with higher scores on the physical function scores on the 36-Item Short-Form Health Survey, increased 6-minute walking distance, and increased isometric quadriceps force at the time of discharge from the hospital when compared to usual care.63 Early physical therapy has also been clinically associated with a higher likelihood of return to baseline function at discharge. Mechanically ventilated patients randomized to receiving early physical therapy and occupational therapy during daily spontaneous awakening trials were significantly more likely to return to baseline function at discharge and have shorter durations of delirium and more ventilator-free days than those receiving awakening trials alone.61 More recently, a randomized controlled trial found that early goal-directed mobilization versus usual care in surgical intensive care unit patients reduced the incidence of intensive care unit delirium, increased intensive care unit delirium-free days, increased functional independence measures at discharge, and increased the ability to discharge to home versus a rehabilitation facility.64 Importantly, outcomes, including delirium, length of stay, and functional independence at discharge, are most improved in trials with early mobility initiation combined with a sedation protocol.

In an effort to optimize critical care provided to patients and prevent short- and long-term sequelae of critical illness, evidence-based, multicomponent liberation and animation bundles have been implemented with overall improvement in outcomes. Building on early bundles designed to reduce delirium in medical and surgical inpatients, the Awakening and Breathing Coordination, Delirium Monitoring/Management, and Early Exercise/Mobility bundle was developed to address care specific to intensive care unit patients.65 Implementation of this bundle led to a reduction in incidence and duration of delirium.66 Recently, this multicomponent strategy has been adapted and expanded as part of the Society of Critical Care Medicine Intensive Care Unit Liberation collaborative to become the ABCDEF bundle: Assess, prevent, and manage pain; Both spontaneous awakening trials and spontaneous breathing trials should be performed daily; Choice of sedation; Delirium assessment, prevention, and management; Early mobilization; and Family engagement and empowerment.67 Large-scale implementation trials of the ABCDEF bundle have shown that increasing compliance with the multicomponent intervention was associated with an increase in survival, as well as an increase in the number of days alive without delirium or coma.68 , 69 Unfortunately, data on the impact of this bundle in reducing long-term impairments are currently lacking. A summary of strategies to prevent long-term impairment is provided in Table 3.

Table 3

Table 3

Strategies to prevent long-term cognitive and functional impairment are not well-established and draw on existing data targeted to improve delirium, reduce time on a ventilator, and improve survival. As cognitive and functional impairment are complex and multifactorial problems, multicomponent prevention bundles are promising interventions that require further investigation into long-term benefit.

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REHABILITATION

The growing prevalence of physical and cognitive impairment after critical illness has increased the rehabilitation requirements of survivors, ranging from outpatient therapy sessions to institutionalization. Rehabilitative interventions vary widely and lack standardization of therapies and goals of treatment. Further, studies examining rehabilitation strategies are often small and produce conflicting results. A Cochrane review of 6 studies of exercise rehabilitation after intensive care unit discharge, involving a total of 483 intensive care unit survivors who required ≥24 hours of mechanical ventilation, was inconclusive on the effects of exercise-based therapy.70 The studies varied widely in the type of exercise prescribed, measurement of functional exercise capacity of participants, and presentation of results, rendering the reviewers unable to perform any statistical tests on study findings. Patient assessment at discharge is also highly variable with the majority of studies enrolling any patient requiring mechanical ventilation in an intensive care unit. Connolly et al71 observed that further robust work in assessing and identifying patients most at need for rehabilitation is needed. Current evidence is lacking as to which patients would benefit from rehabilitative interventions after critical illness, how those patients should be identified, and what type of intervention should be provided. To address these challenges, a Delphi consensus study identified essential handover information for providers and physical therapy interventions to address a core set of outcomes including exercise capacity, muscle strength, functional ability in activities of daily living, mobility, functional quality of life, and pain.72

Rehabilitative interventions provided to patients after hospital discharge have primarily focused on physical and occupational therapy interventions. Most commonly used in patients with traumatic brain injury, early cognitive rehabilitation has shown promise in improving cognitive outcomes in intensive care unit survivors. The Returning to Everyday Tasks Utilizing Rehabilitation Networks73 trial randomized 21 survivors of a medical or surgical intensive care unit admission with cognitive or functional deficits at discharge to a 12-week in-home cognitive, physical, and functional rehabilitation program or usual care. The cognitive rehabilitation used goal management training, a targeted and progressive approach to rehabilitating executive function. At the conclusion of the 12-week time period, the intervention group demonstrated a significant improvement in executive function, as well as an improvement in functional status.73

Combining the concepts of early therapeutic intervention with a combined cognitive and functional rehabilitation strategy, the Activity and Cognitive Therapy in Intensive Care Unit74 trial evaluated the safety and feasibility of implementing an early combined physical and cognitive therapy protocol in medical and surgical intensive care units. Patients (N = 87) were randomized into 1 of 3 groups: usual care, early physical therapy, or early physical and targeted cognitive therapy. The in-hospital cognitive therapy program focused on memory, attention, orientation, delayed memory, problem-solving, and processing speed. Patients randomized to the cognitive therapy arm with ongoing impairment in executive function at discharge also received 12 weeks of goal management training after discharge. The study demonstrated that it is safe and feasible to administer combined cognitive and physical therapy in an inpatient critical care setting. Although Activity and Cognitive Therapy in Intensive Care Unit used a similar goal management training program as was used in the Returning to Everyday Tasks Utilizing Rehabilitation Networks study, there was no difference in executive function or functional outcomes between the groups in Activity and Cognitive Therapy in Intensive Care Unit; however, the study may have been underpowered to detect a difference.74 A pilot study of 24 survivors of critical illness with cognitive improvement demonstrated improvement in cognitive abilities with a computer gaming approach to cognitive rehabilitation that positively correlated with the amount of training performed.75 These studies are small and highlight the need for further large randomized trials to identify the most effective rehabilitation strategies and the survivors who would benefit most from an intervention in the growing population of intensive care unit survivors with newly acquired impairment. In addition, in-person goal management training is resource intensive, and alternative interventions that can be scalable to larger populations (eg, adaptive computerized training) will be required to meet the public health burden of cognitive and functional impairments after critical illness and improve survivorship.

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CONCLUSIONS

As improvements in critical care therapies lead to increasing intensive care unit survival, it is imperative that care of the critically ill patient includes consideration of long-term cognitive and functional outcomes to improve quality of survivorship. The growing prevalence of newly acquired disability after critical illness negatively affects the health-related quality of life in survivors and their families and is a costly public health problem. Current research demonstrates persistence of cognitive and functional impairment up to 5 years after critical illness, and the impact may be longer lasting than is presently reported. Improving rehabilitation programs and increasing patient access to rehabilitation services offers promise in improving these outcomes. It is also critical that providers recognize the risk factors for developing long-term dysfunction and use prevention strategies including sedation management strategies, early mobilization, and liberation/animation bundles to improve patient care and lessen the long-term effects of critical illness.

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DISCLOSURES

Name: Kimberly F. Rengel, MD.

Contribution: This author was the primary author.

Name: Christina J. Hayhurst, MD.

Contribution: This author helped edit and revise the manuscript and format the figures/tables.

Name: Pratik P. Pandharipande, MD.

Contribution: This author helped edit, revise, and rewrite the manuscript.

Name: Christopher G. Hughes, MD.

Contribution: This author helped edit, revise, and rewrite the manuscript.

This manuscript was handled by: Gregory J. Crosby, MD.

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REFERENCES

1. Wolters AE, Slooter AJ, van der Kooi AW, van Dijk D. Cognitive impairment after intensive care unit admission: a systematic review. Intensive Care Med. 2013;39:376–386.
2. Pandharipande PP, Girard TD, Ely EW. Long-term cognitive impairment after critical illness. N Engl J Med. 2014;370:185–186.
3. Hughes CG, Patel MB, Jackson JC, et al. Surgery and anesthesia exposure is not a risk factor for cognitive impairment after major noncardiac surgery and critical illness. Ann Surg. 2016;265:1126–1133.
4. 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.
5. Jackson JC, Pandharipande PP, Girard TD, et al; Bringing to Light the Risk Factors And Incidence of Neuropsychological Dysfunction in ICU Survivors (BRAIN-ICU) Study Investigators. Depression, post-traumatic stress disorder, and functional disability in survivors of critical illness in the BRAIN-ICU study: a longitudinal cohort study. Lancet Respir Med. 2014;2:369–379.
6. Marra A, Pandharipande PP, Girard TD, et al. Co-occurrence of post-intensive care syndrome problems among 406 survivors of critical illness. Crit Care Med. 2018;46:1393–1401.
7. 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.
8. Ehlenbach WJ, Larson EB, Curtis JR, Hough CL. Physical function and disability after acute care and critical illness hospitalizations in a prospective cohort of older adults. J Am Geriatr Soc. 2015;63:2061–2069.
9. Wilson ME, Barwise A, Heise KJ, et al. Long-term return to functional baseline after mechanical ventilation in the ICU. Crit Care Med. 2018;46:562–569.
10. 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.
11. Fan E, Dowdy DW, Colantuoni E, et al. Physical complications in acute lung injury survivors: a two-year longitudinal prospective study. Crit Care Med. 2014;42:849–859.
12. Ehlenbach WJ, Gilmore-Bykovskyi A, Repplinger MD, et al. Sepsis survivors admitted to skilled nursing facilities: cognitive impairment, activities of daily living dependence, and survival. Crit Care Med. 2018;46:37–44.
13. Guerra C, Hua M, Wunsch H. Risk of a diagnosis of dementia for elderly Medicare beneficiaries after intensive care. Anesthesiology. 2015;123:1105–1112.
14. Iwashyna TJ, Ely EW, Smith DM, Langa KM. Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA. 2010;304:1787–1794.
15. Sakusic A, Rabinstein AA. Cognitive outcomes after critical illness. Curr Opin Crit Care. 2018;24:410–414.
16. Saczynski JS, Marcantonio ER, Quach L, et al. Cognitive trajectories after postoperative delirium. N Engl J Med. 2012;367:30–39.
17. Lingehall HC, Smulter NS, Lindahl E, et al. Preoperative cognitive performance and postoperative delirium are independently associated with future dementia in older people who have undergone cardiac surgery: a longitudinal cohort study. Crit Care Med. 2017;45:1295–1303.
18. Brown CHt, Probert J, Healy R, et al. Cognitive decline after delirium in patients undergoing cardiac surgery. Anesthesiology. 2018;129:406–416.
19. Ferrante LE, Pisani MA, Murphy TE, Gahbauer EA, Leo-Summers LS, Gill TM. The association of frailty with post-ICU disability, nursing home admission, and mortality: a longitudinal study. Chest. 2018;153:1378–1386.
20. Ferrante LE, Pisani MA, Murphy TE, Gahbauer EA, Leo-Summers LS, Gill TM. Factors associated with functional recovery among older intensive care unit survivors. Am J Respir Crit Care Med. 2016;194:299–307.
21. Wieske L, Dettling-Ihnenfeldt DS, Verhamme C, et al. Impact of ICU-acquired weakness on post-ICU physical functioning: a follow-up study. Crit Care. 2015;19:196.
22. Pintado MC, Villa P, Luján J, et al. Mortality and functional status at one-year of follow-up in elderly patients with prolonged ICU stay. Med Intensiva. 2016;40:289–297.
23. Baumbach P, Götz T, Günther A, Weiss T, Meissner W. Prevalence and characteristics of chronic intensive care-related pain: the role of severe sepsis and septic shock. Crit Care Med. 2016;44:1129–1137.
24. Hayhurst CJ, Jackson JC, Archer KR, Thompson JL, Chandrasekhar R, Hughes CG. Pain and its long-term interference of daily life after critical illness. Anesth Analg. 2018;127:690–697.
25. 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.
26. 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.
27. Cavallari M, Dai W, Guttmann CRG, et al; SAGES Study Group. Longitudinal diffusion changes following postoperative delirium in older people without dementia. Neurology. 2017;89:1020–1027.
28. Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med. 2003;348:138–150.
29. Maciel M, Benedet SR, Lunardelli EB, et al. Predicting long-term cognitive dysfunction in survivors of critical illness with plasma inflammatory markers: a retrospective cohort study. Mol Neurobiol. 2019;56:763.
30. Alexander JJ, Jacob A, Cunningham P, Hensley L, Quigg RJ. TNF is a key mediator of septic encephalopathy acting through its receptor, TNF receptor-1. Neurochem Int. 2008;52:447–456.
31. D’Mello C, Le T, Swain MG. Cerebral microglia recruit monocytes into the brain in response to tumor necrosis factoralpha signaling during peripheral organ inflammation. J Neurosci. 2009;29:2089–2102.
32. Cerejeira J, Firmino H, Vaz-Serra A, Mukaetova-Ladinska EB. The neuroinflammatory hypothesis of delirium. Acta Neuropathol. 2010;119:737–754.
33. Hughes CG, Pandharipande PP, Thompson JL, et al. Endothelial activation and blood-brain barrier injury as risk factors for delirium in critically ill patients. Crit Care Med. 2016;44:e809–e817.
34. Hughes CG, Patel MB, Brummel NE, et al. Relationships between markers of neurologic and endothelial injury during critical illness and long-term cognitive impairment and disability. Intensive Care Med. 2018;44:345–355.
35. Witteveen E, Wieske L, van der Poll T, et al; Molecular Diagnosis and Risk Stratification of Sepsis (MARS) Consortium. Increased early systemic inflammation in ICU-acquired weakness: a prospective observational cohort study. Crit Care Med. 2017;45:972–979.
36. Kress JP, Hall JB. ICU-acquired weakness and recovery from critical illness. N Engl J Med. 2014;371:287–288.
37. Derde S, Hermans G, Derese I, et al. Muscle atrophy and preferential loss of myosin in prolonged critically ill patients. Crit Care Med. 2012;40:79–89.
38. Dos Santos C, Hussain SN, Mathur S, et al; MEND ICU Group; RECOVER Program Investigators; Canadian Critical Care Translational Biology Group. Mechanisms of chronic muscle wasting and dysfunction after an intensive care unit stay. A pilot study. Am J Respir Crit Care Med. 2016;194:821–830.
39. Pandharipande P, Cotton BA, Shintani A, et al. Prevalence and risk factors for development of delirium in surgical and trauma intensive care unit patients. J Trauma. 2008;65:34–41.
40. Pandharipande P, Shintani A, Peterson J, et al. Lorazepam is an independent risk factor for transitioning to delirium in intensive care unit patients. Anesthesiology. 2006;104:21–26.
41. Pandharipande PP, Sanders RD, Girard TD, et al; MENDS Investigators. Effect of dexmedetomidine versus lorazepam on outcome in patients with sepsis: an a priori-designed analysis of the MENDS randomized controlled trial. Crit Care. 2010;14:R38.
42. Pandharipande PP, Pun BT, Herr DL, et al. Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated patients: the MENDS randomized controlled trial. JAMA. 2007;298:2644–2653.
43. Riker RR, Shehabi Y, Bokesch PM, et al; SEDCOM (Safety and Efficacy of Dexmedetomidine Compared With Midazolam) Study Group. Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial. JAMA. 2009;301:489–499.
44. Djaiani G, Silverton N, Fedorko L, et al. Dexmedetomidine versus propofol sedation reduces delirium after cardiac surgery: a randomized controlled trial. Anesthesiology. 2016;124:362–368.
45. Liu X, Xie G, Zhang K, et al. Dexmedetomidine vs propofol sedation reduces delirium in patients after cardiac surgery: a meta-analysis with trial sequential analysis of randomized controlled trials. J Crit Care. 2017;38:190–196.
46. Shehabi Y, Grant P, Wolfenden H, et al. Prevalence of delirium with dexmedetomidine compared with morphine based therapy after cardiac surgery: a randomized controlled trial (DEXmedetomidine COmpared to Morphine-DEXCOM Study). Anesthesiology. 2009;111:1075–1084.
47. Agarwal V, O’Neill PJ, Cotton BA, et al. Prevalence and risk factors for development of delirium in burn intensive care unit patients. J Burn Care Res. 2010;31:706–715.
48. Kollef MH, Levy NT, Ahrens TS, Schaiff R, Prentice D, Sherman G. The use of continuous i.v. sedation is associated with prolongation of mechanical ventilation. Chest. 1998;114:541–548.
49. Kress JP, Pohlman AS, O’Connor MF, Hall JB. Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. N Engl J Med. 2000;342:1471–1477.
50. Treggiari MM, Romand JA, Yanez ND, et al. Randomized trial of light versus deep sedation on mental health after critical illness. Crit Care Med. 2009;37:2527–2534.
51. 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.
52. Watson PL, Shintani AK, Tyson R, Pandharipande PP, Pun BT, Ely EW. Presence of electroencephalogram burst suppression in sedated, critically ill patients is associated with increased mortality. Crit Care Med. 2008;36:3171–3177.
53. Shehabi Y, Bellomo R, Kadiman S, et al; Sedation Practice in Intensive Care Evaluation (SPICE) Study Investigators and the Australian and New Zealand Intensive Care Society Clinical Trials Group. Sedation intensity in the first 48 hours of mechanical ventilation and 180-day mortality: a multinational prospective longitudinal cohort study. Crit Care Med. 2018;46:850–859.
54. Shehabi Y, Bellomo R, Reade MC, et al; Sedation Practice in Intensive Care Evaluation (SPICE) Study Investigators; ANZICS Clinical Trials Group. Early intensive care sedation predicts long-term mortality in ventilated critically ill patients. Am J Respir Crit Care Med. 2012;186:724–731.
55. Balzer F, Weiß B, Kumpf O, et al. Early deep sedation is associated with decreased in-hospital and two-year follow-up survival. Crit Care. 2015;19:197.
56. Girard TD, Kress JP, Fuchs BD, et al. Efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (Awakening and Breathing Controlled trial): a randomised controlled trial. Lancet. 2008;371:126–134.
57. Dale CR, Kannas DA, Fan VS, et al. Improved analgesia, sedation, and delirium protocol associated with decreased duration of delirium and mechanical ventilation. Ann Am Thorac Soc. 2014;11:367–374.
58. Bailey P, Thomsen GE, Spuhler VJ, et al. Early activity is feasible and safe in respiratory failure patients. Crit Care Med. 2007;35:139–145.
59. Morris PE, Goad A, Thompson C, et al. Early intensive care unit mobility therapy in the treatment of acute respiratory failure. Crit Care Med. 2008;36:2238–2243.
60. Morris PE, Griffin L, Berry M, et al. Receiving early mobility during an intensive care unit admission is a predictor of improved outcomes in acute respiratory failure. Am J Med Sci. 2011;341:373–377.
61. 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.
62. Hickmann CE, Castanares-Zapatero D, Deldicque L, et al. Impact of very early physical therapy during septic shock on skeletal muscle: a randomized controlled trial. Crit Care Med. 2018;46:1436–1443.
63. Burtin C, Clerckx B, Robbeets C, et al. Early exercise in critically ill patients enhances short-term functional recovery. Crit Care Med. 2009;37:2499–2505.
64. Schaller SJ, Anstey M, Blobner M, et al; International Early SOMS-Guided Mobilization Research Initiative. Early, goal-directed mobilisation in the surgical intensive care unit: a randomised controlled trial. Lancet. 2016;388:1377–1388.
65. Morandi A, Hughes CG, Girard TD, McAuley DF, Ely EW, Pandharipande PP. Statins and brain dysfunction: a hypothesis to reduce the burden of cognitive impairment in patients who are critically ill. Chest. 2011;140:580–585.
66. Balas MC, Vasilevskis EE, Olsen KM, et al. Effectiveness and safety of the awakening and breathing coordination, delirium monitoring/management, and early exercise/mobility bundle. Crit Care Med. 2014;42:1024–1036.
67. Marra A, Ely EW, Pandharipande PP, Patel MB. The ABCDEF bundle in critical care. Crit Care Clin. 2017;33:225–243.
68. Barnes-Daly MA, Phillips G, Ely EW. Improving hospital survival and reducing brain dysfunction at seven California community hospitals: implementing PAD guidelines via the ABCDEF bundle in 6,064 patients. Crit Care Med. 2017;45:171–178.
69. Pun BT, Balas MC, Barnes-Daly MA, et al. Caring for critically ill patients with the ABCDEF bundle: results of the ICU liberation collaborative in over 15,000 adults. Crit Care Med. 2019;47:3–14.
70. Connolly B, Salisbury L, O’Neill B, et al. Exercise rehabilitation following intensive care unit discharge for recovery from critical illness. Cochrane Database Syst Rev. 2015:CD008632.
71. Connolly B, Denehy L, Brett S, Elliott D, Hart N. Exercise rehabilitation following hospital discharge in survivors of critical illness: an integrative review. Crit Care. 2012;16:226.
72. Major ME, Kwakman R, Kho ME, et al. Surviving critical illness: what is next? An expert consensus statement on physical rehabilitation after hospital discharge. Crit Care. 2016;20:354.
73. 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.
74. 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.
75. Wilson JE, Collar EM, Kiehl AL, et al. Computerized cognitive rehabilitation in intensive care unit survivors: returning to everyday tasks using rehabilitation networks-computerized cognitive rehabilitation pilot investigation. Ann Am Thorac Soc. 2018;15:887–891.
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