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.
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.
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.
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.
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.
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.
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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