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Physical, Cognitive, and Psychological Disability Following Critical Illness: What Is the Risk? Jennifer E. Jutte, MPH, PhD1
Christopher T. Erb, MD, PhD2
1 Department of Rehabilitation Medicine, University of Washington
School of Medicine, Harborview Medical Center, Seattle, Washington 2 Section of Pulmonary, Critical Care, and Sleep Medicine, Yale University School of Medicine, New Haven, Connecticut 3 Division of Critical Care/Center for Health Services, Vanderbilt University Medical Center, Nashville, Tennessee 4 Department of Veterans Affairs Medical Center, Tennessee Valley Healthcare System, Nashville, Tennessee
James C. Jackson, PsyD3,4
Address for correspondence Jennifer E. Jutte, MPH, PhD, Department of Rehabilitation Medicine, University of Washington/Harborview Medical Center, 325 9th Avenue, Box 359740, Seattle, WA 98104 (e-mail:
[email protected]).
Semin Respir Crit Care Med 2015;36:943–958.
Abstract
Keywords
► ► ► ► ► ► ►
cognition critical care critical illness delirium rehabilitation psychosocial respiratory distress syndrome ► acute ► sepsis
Critical illnesses affect millions of individuals annually in the United States. As advances in patient care continue to improve, the number of survivors is rapidly growing. Critical illness survivors endure profoundly severe illnesses and live through often frightening experiences throughout the course of ICU hospitalization, resulting in a variety of “survivorship” challenges, expressed through a condition known as post–intensive care syndrome (PICS). Questions abound regarding the ideal protocols for ensuring the best physical, cognitive, and psychological outcomes for these survivors. Organizational change is likely to be a key factor, though the specific components have not yet been established. Throughout this article, we highlight some of the barriers and facilitators to enhancing patient care across the spectrum of critical care environments, while also highlighting the challenges inherent to studying a complex patient population. We address each of the areas potentially affected by critical illness and ICU hospitalization— physical, cognitive, and psychological functional domains—experienced by patients as well as their family caregivers.
Millions of individuals in North America develop critical illnesses annually, more than the total number of patients diagnosed each year with breast cancer, diabetes, multiple sclerosis, and Parkinson’s disease combined.1,2 Of these, as many as half will develop a wide array of acquired difficulties due to the effects of insults and injuries including sepsis, hypoxia, and delirium, among others. These problems are particularly concerning currently because they affect an expanding population of patients. That is, as mortality rates are decreasing due to advances in patient care in recent years, the “pool” of survivors is expanding. For example, Iwashyna and colleagues estimated that in 2008, there were 225,000 new 3-year and 120,000 new 5-year survivors of severe sepsis, which represents an increase of 119% (since 1999) and 79% (since 2010), respectively.3 These individuals, having
Issue Theme Controversies and Evolving Concepts in Critical Care; Guest Editors: Wassim H. Fares, MD, MSc, and Mark D. Siegel, MD
endured profoundly severe illnesses in the context of lengthy hospitalizations, bear the scars of these experiences and grapple with the challenges of “survivorship,” expressed prominently through a condition known as post–intensive care syndrome or PICS.4 First described by a Society of Critical Care Medicine (SCCM) task force in 2010, PICS refers to a newly recognized clinical entity characterized by deficits in domains of physical functioning, cognitive functioning, and psychological functioning.4 Individuals with PICS experience symptoms of varying persistence and severity and while impairment in all three domains is likely relatively infrequent, this needs to be studied more in depth. Nevertheless, these three domains are the ones that must crucially be addressed, both during and after ICU hospitalization for critical illness. They form the
Copyright © 2015 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0035-1566002. ISSN 1069-3424.
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basis of the biopsychosocial model, which highlights the multidimensional nature of the individual as well as factors that may either hinder or facilitate daily life functioning and their intensive care and post-hospitalization experiences. During an ICU hospitalization, patients can experience difficulties including a loss of autonomy, fear/anxiety, depressive symptoms, confusion/delirium, sleep/wake cycle dysregulation, and/or pain. These issues not only affect ICU and acute care hospitalization but also can affect the rehabilitation process and recovery. The role of the environment in rehabilitation outcomes is pivotal and the role of the ICU environment can be particularly instrumental in facilitating or hindering physical, emotional, and cognitive outcomes from critical illness. Regardless of the reason for hospitalization, the ICU experience in and of itself can affect patients emotionally and cognitively during their hospital stay and for years afterward. Critical illnesses, as well as their associated treatments, present patients with a host of physical, psychological, and cognitive stressors that can affect function both during and after hospitalization (►Fig. 1). One of the main barriers to enhancing awareness of these potential areas of dysfunction is the existence of “silos” among the variety of clinicians and health care providers working with patients who are critically ill and beyond acute care hospitalization.4 A variety of potential “gaps” exist between providers on a single team, let alone providers across ICU and acute ward environments, and transition into outpatient and community settings. We must first develop an understanding of the “risk” of ICU hospitalization and the long-term effects on patients and family members before we can provide education and support to care providers along the spectrum of critical, trauma, and rehabilitation care environments. This article addresses each of these domains potentially affected by critical illness and ICU hospitalization, among patients and their family members/caregivers.
Physical Outcomes Physical debility after critical illness is common and even 5 years after discharge, few survivors fully return to their premorbid level of physical function. Risk factors for physical decrements among ICU survivors need to be studied more fully, but prior functional status appears to be a significant predictor of post-ICU debility. Mechanical ventilation status during critical illness also appears to influence physical outcomes as mechanically ventilated individuals have reported 30% more disability and 14% greater difficulty with mobility than their counterparts who did not require mechanical ventilation.5 Using acute respiratory distress syndrome (ARDS) as an archetypal critical illness diagnosis, studies have shown that pulmonary function may return to normal, but symptoms of dyspnea and performance on a 6-minute walk test (6MWT) do not return to baseline.6 In a group of previously ventilated ARDS survivors, 6MWT did steadily improve over the first year after discharge from ICU, but never returned to age-predicted levels. In a recent study of elderly critical illness survivors, 49% of older patients with minimal disability before ICU admission, defined as less than two functional impairments, remained in the “minimal disability” category after ICU admission; 53% experienced severe functional decline or early death after critical illness.7 Mechanical ventilation, shock, and cognitive impairment were associated with increased risk of death and functional impairment at 30 days and 1 year postdischarge from ICU.7 Almost 75% of ICU survivors required some level of enhanced care after discharge, either in a nursing or rehabilitation facility, or at home with services.7 Major functional decline is frequent following critical illness hospitalization, among those with and without prior functional deficit.3,5,6,8–11 For example, survivors of severe sepsis experience persistent functional impairments, such as
Fig. 1 Patient, ICU care, and systemic factors associated with physical, cognitive, psychological, and family outcomes following ICU hospitalization. Seminars in Respiratory and Critical Care Medicine
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Disability Following Critical Illness a reduction in their ability to walk independently, bathe, use the toilet, dress, shop for and prepare food, use the telephone, take medications, and manage money.12 In a large study of patients who had undergone more than 4 days of mechanical ventilation, only 15% returned directly home, while the remaining 85% required short- or long-term institutional care (including rehabilitation facility environments).11 In another study, 75% of patients who were mechanically ventilated for at least 2 days, and had survived 2 months beyond mechanical ventilation, were unable to perform activities of daily living independently and required caregiver support.13 Another study found that 2 years after ICU discharge, 80% of ARDS survivors required care assistance.14 In addition to prolonged morbidity, increased mortality risks for ICU survivors can persist for up to 15 years or more.15 Indeed, surviving critical illness to discharge is no guarantee of prolonged health, as patients remain at high risk for recurrent illness, readmission, increased utilization of health care services, and may experience high levels of chronic disability.12,15–17 Mechanical ventilation and shock have consistently been shown to be associated with increased mortality and functional disability after ICU discharge. In older patients in particular, hospitalization and exposure to mechanical ventilation are associated with significant excess 1-year mortality (24 and 73%, respectively, vs. 9% in agematched controls).5 Epidemiologically, factors shown to be associated with increased mortality and functional disability include age, comorbidities, severity of illness and organ dysfunction, and the type of critical illness (e.g., trauma, sepsis, cardiac surgery, cardiac arrest).15 The need for recovery in a rehabilitation facility after receiving care in an ICU is also associated with increased 6-month mortality.1 Survivors of critical care may experience four or more transitions of care after discharge (e.g., skilled nursing facilities, post–acute care, ventilator weaning facilities, and rehabilitation facilities) prior to returning home.18 Increasing concern has focused on patients with chronic critical illness (CCI), a group needing weeks to months of ventilator support after acute illness, though definitions of CCI differ across studies.19–21 In the United States, more than 100,000 patients have CCI and the numbers are growing.21 CCI patients do poorly: Most are institutionalized for extended periods or left permanently with profound cognitive and functional disabilities.19–21 Within a year, 48 to 68% of patients die and less than 12% are alive and independent 1 year after becoming ill.21 Hospital readmission following a critical illness is common, especially among individuals living with CCI. An observational cohort study of survivors of severe sepsis found that 67% were readmitted to the hospital in the year following discharge; 74% of their “alive days” were spent hospitalized or in post–acute care facilities; and 65% of the cohort reported severe or complete functional dependency at 1 year.16 Readmission is common after an index hospitalization for sepsis, whether or not the patient was admitted to the ICU, though readmission is more likely if the patient spent time in the ICU. Other independent risk factors for readmission included severity of illness, hospital length of stay, medical comorbidities, and higher prehospitalization health
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care utilization,17 as well as age, diagnosis of malignancy, nonelective index admission, requiring a procedure during the index admission, and anemia at the time of discharge.22 Readmission within 30 days after index hospitalization, in turn, is associated with increased risk of death or transition to hospice care at the time of readmission.22 ARDS is a common form of critical illness.23 Long-term pulmonary dysfunction has been studied most frequently among ARDS survivors and tends to vary in the type of impairment.9,24 Long-term impairments have been noted through the first year after ARDS, and health-related quality of life (HRQL) may be impaired for 5 years or more after ARDS diagnosis.25,26 With regard to duration and mode of mechanical ventilation, the association with long-term pulmonary complications is mixed in the extant literature, but there is a clear association between the number of pulmonary function-related impairments and long-term HRQL after mechanical ventilation.25,27,28 Patients with clinically apparent weakness attributable to critical illness are diagnosed as having ICU-acquired weakness, or ICUAW.29 There is a subset of patients with ICUAW who have electrophysiologically documented axonal polyneuropathy (critical illness polyneuropathy, or CIP) and another subset with documented myopathy (critical illness myopathy), which often co-occur and are termed critical illness neuromyopathy.29 Approximately 50% of critically ill patients with sepsis, multiorgan failure, or prolonged mechanical ventilation have critical illness neuromyopathy, as well as increased ICU and hospital stay and difficulties ambulating or breathing unassisted following discharge.29,30 Those who experience ICUAW as a result of prolonged bedrest, sedation, steroid use, or neuromuscular blockade during critical illness31 tend to have increased functional dependence, increased health-related costs, and increased mortality for a year or more after surviving their initial critical illness.32,33 These patients often continue to experience neuromuscular abnormalities up to 5 years following discharge.34,35
Improvement of Physical Function in the Context of Critical Illness One area in which ICU-based interventions have been shown convincingly to affect longer-term physical outcomes is in early mobilization of mechanically ventilated patients. Physical rehabilitation after an ICU stay of even a minimally intensive amount has been shown to improve functional outcomes. A program of guided self-rehabilitation based on printed material with diagrams, illustrations, and instructions for exercises, as well as follow-up phone calls, was shown to improve function scores at 8 weeks and 6 months and to improve symptoms of depression among survivors of critical illness who required mechanical ventilation in an ICU for longer than 48 hours.36 Early mobilization has been shown to be feasible and result in short- and long-term benefits to patients in reasonably large clinical trials.37,38 Implementation of a physical therapy program within the first day after ICU admission has been shown to result in decreased episodes of delirium and more ventilator-free days Seminars in Respiratory and Critical Care Medicine
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while in the ICU.38 The most striking finding in the study of Schweickert et al on early physical therapy in mechanically ventilated critically ill patients was the 2.5-fold increase in the likelihood of returning to independent functional status after discharge among the intervention group.38 While this was a highly compelling finding, the ongoing challenge in the early mobilization story has been to disseminate the strategy more broadly into clinical practice across the United States and elsewhere. Early mobilization has not been studied specifically as an intervention for patients with severe sepsis, either in the ICU or elsewhere in the hospital,39 so it is unclear whether similar results would be found in patients with other forms of critical illness, such as sepsis without respiratory failure. Implementing early mobility programs in ICUs has required changing the culture of ICU care that had been developed over many years.40,41 The early mobility experience, however, provides an important model for how changes in other arenas may evolve. For example, conceptualizing major changes in ICU culture as “quality improvement” projects and using multidisciplinary team approaches with buy-in and participation from multiple stakeholders and “champions” may enhance the process of implementation of new ideas in other realms.42–44 Our modern ICUs may now be primed for more rapid culture shifts, as newer interventions are developed and introduced into clinical practice.
Cognitive Outcomes and Long-Term Cognitive Impairment Neurocognitive impairments following critical illness have been identified as a major public health problem.45 Over 20 prospective investigations including more than 2,500 critically ill patients have assessed cognitive functioning46–52 and found that new and persistent cognitive impairment occurs in at least 40 to 60% of individuals regardless of the reason for hospitalization.46,48,50 Moreover, it has been shown that nearly all survivors of ICU hospitalization demonstrate cognitive disruptions at the time of hospital discharge,53 regardless of whether they go on to improve. These disruptions may be temporary in some patients but, for the majority, they remain problematic over the longer term.46 Although older age increases the likelihood of developing cognitive impairment,48 even young and previously healthy individuals often experience new cognitive impairment after critical illness.45 Memory, attention, and executive functioning deficits have been highlighted by the majority of the extant literature as primary cognitive domain areas impacted by critical illness and these are the areas most important to daily function.54–58 The pathophysiological and external influences thought to be associated with new cognitive impairment resulting from critical illness include delirium, hypoxia, glucose and metabolic dysregulation, inflammation, and the effects of medications (e.g., sedatives and narcotics).45,59 It is unclear the extent to which each of these possible contributors may affect cognitive outcomes from critical illness. There likely is no “single common pathway” that drives the development of Seminars in Respiratory and Critical Care Medicine
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cognitive impairment. On the contrary, the aforementioned mechanisms likely work in tandem and may enhance the effects of each other. The natural history of cognitive impairment after critical illness has been little studied and questions remain pertaining to whether there are distinct patterns that are consistently characteristic of ICU survivors. Although numerous patterns of change have been identified among persons with Alzheimer’s dementia,60 and although distinct trajectories have been shown to occur among individuals who underwent coronary artery bypass graft surgery,61 few studies of neuropsychological functioning after intensive care have been sufficiently long to identify prolonged trajectories of change.59 It is unclear at this point whether the cognitive functioning of patients characteristically improves (after a typical initial decline), remains stable (i.e., worse than prehospitalization, but evidencing neither subsequent improvement nor subsequent decline), or continues to erode following critical illness and ICU hospitalization. Moreover, it is unclear whether the existence of progressive decrements in some survivors is a “dementia” and, if so, what dementia variant. One study found a hazard ratio for incident dementia of 2.3 after a hospitalization for critical illness (p ¼ 0.09) versus a hazard ratio of 1.4 for incident dementia after a general hospitalization (p ¼ 0.001).62 The cognitive impairment that occurs in survivors of critical illness is often, though not always, accompanied by the neuroanatomical changes seen in dementia.63 These may include whole brain atrophy, ventricular enlargement, and hippocampal shrinkage.63,64 Several hypothesized risk factors common to critical illnesses are thought to set processes in motion for acute and long-term disruptions in cognitive function. A systemic inflammatory response is a common feature in conditions of critical illness (e.g., sepsis). The inflammatory response is characterized by production of proinflammatory cytokines such as interleukin-6 (IL-6), IL-1, and tumor necrosis factor-α (TNF-α),65,66 which also have been associated with Alzheimer’s and vascular dementia.67 Inflammation is thought to be associated with an irreversible shift in brain chemistry and likely is a major contributor to chronic brain dysfunction. Also common in critical illness is hypoxia, especially among patients with ARDS68 and hypoxia has been associated with marked disruptions in memory function.69–71 Patients admitted to the ICU for critical illnesses tend to be of older age, which in turn is a risk factor for proinflammatory responses, delirium, and cognitive decline.72,73 And, lastly though perhaps most intuitively, preexisting cognitive impairment is a risk factor for cognitive impairment and accelerated decline following ICU hospitalization and critical illness.74 Delirium is rarely an “outcome” of critical illness, as it typically occurs in the midst of critical illness or for a relatively abbreviated time thereafter. Persistent delirium after hospital discharge is fairly uncommon, except among survivors of critical illness with dementia or among those who receive prolonged treatment in nursing home or long-term weaning facilities (►Table 1). This neuropsychiatric syndrome plays such a significant role in the cognitive outcomes of patients who were critically ill that it deserves detailed mention here.
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Table 1 Delirium and dementia in the context of critical illness hospitalization Delirium
Dementia
Consciousness
Decreased or hyper alert “Clouded”
Alert
Orientation
Disorganized
Disoriented
Course
Fluctuating
Steady slow decline
Onset
Acute or subacute
Chronic
Attention
Impaired
Usually normal
Psychomotor
Agitated or lethargic
Usually normal
Hallucinations
Perceptual disturbances; may have hallucinations
Usually not present
Sleep/wake cycle
Abnormal
Usually normal
Speech
Slow, incoherent
Aphasic, anomic difficulty finding words
Delirium, by definition, is “time limited” and prone to fluctuation and thus distinct from the entrenched cognitive impairment common during ICU hospitalization, with estimated incidence rates varying between 50 and 70%.75,76 While not all ICU hospitalized patients experience delirium, a majority do, and those who do tend to experience longer hospital duration and higher mortality rates, as well as more long-term cognitive impairment.50 The risk factors for development of delirium are many and they may be genetic (e.g., APOE-4 allele), pathophysiological (e.g., infection), medical (e.g., sedating medications), or environmental (e.g., chaotic ICU environment, dysregulation of sleep/wake cycle).75,76 Cognitive vulnerability may also play a role, as reflected in the fact that delirium is particularly pervasive among individuals with dementia.77 The exact mechanisms by which delirium may confer a higher likelihood of cognitive impairment following critical illness also are unknown, though inflammation and neuronal death are each associated with delirium and may lead to brain atrophy.78 Furthermore, an association has been shown to exist between delirium and cerebral hypoperfusion in frontal, temporal, and subcortical regions.79
Assessment and Treatment of Cognitive Impairment in the Context of Critical Illness: Delirium Once a delirium diagnosis has been established via clinical examination, the etiologic determination is often based on the integrated review of the patient’s unique history in light of current laboratory, radiologic, and metabolic studies. It is important to thoroughly review all medications and potential interaction effects, determine if infection or sepsis is present, and identify trends and patterns of confusion to determine how these coincide with treatment delivery, time of day, or other external factors. In 2013, SCCM published seminal guidelines for the clinical practice and management of pain, agitation, and delirium among critically ill patients. These guidelines were created following a 6-year collaboration consisting of a 20-person multidisciplinary multi-institutional task
force developed by the American College of Critical Care Medicine. 80 The guidelines recommend “routine” monitoring of delirium in adult ICU patients. At many institutions, “routine” is defined as daily to twice daily assessment, though this certainly differs across practice environments. Although several measures exist for delirium assessment, according to the guidelines the Confusion Assessment Method for the ICU (CAM-ICU) and the Intensive Care Delirium Screening Checklist (ICDSC) are the most valid and reliable instruments for use with adult ICU patients.80 At times, however, formal measures may be difficult to administer to a delirious patient and results may thus be confounded; therefore, a flexible approach to assessment often is required. A good clinical interview and basic mental status examination often is sufficient to diagnose delirium, while the recording of objective scores can be helpful in tracking clinical course and response to treatment. Because delirium may be related to underlying disease or infection, timely identification and management of the cause is essential to reduce the severity and duration of delirium.80 Exposure to various medications also has been associated with onset and duration of delirium (e.g., benzodiazepine and opioid medications) as well as environmental culprits such as physical restraint or immobilization. Therefore, critically ill patients in the ICU should be continuously evaluated for identifiable and avoidable risk factors, and prevention strategies may include medical (treatment of underlying infection, change in medication), environmental (reduced use of restraints for patient agitation), or physical (engagement in early mobilization).80 Among all the various psychological, behavioral, and environmental interventions thought to prevent delirium, the one with the most promise may be early mobilization (e.g., ambulation, exercise, and range of motion implemented within the first days of ICU hospitalization).38 Although haloperidol and other antipsychotics often are used in an effort to reduce the severity and duration of delirium, they have not been studied comprehensively, as they relate to delirium specifically; thus, they are not formally recommended by guidelines to date.80 Seminars in Respiratory and Critical Care Medicine
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Delirium also can be quite distressing for family members who often are at patient’s bedsides witnessing their deterioration into waxing and waning states of confusion and psychosis. Thus, provision of support, information, guidance, and education are of pivotal importance. Psychologists who work in the hospital setting often are in a unique position to provide these value-added services.
Assessment and Treatment of Cognitive Impairment in the Context of Critical Illness Cognitive impairment can be assessed in the ICU or thereafter, but early assessment brings significant challenges.53 Among patients who are delirious (see earlier), cognitive assessment tends to be unhelpful and the results of such assessment are potentially misleading, as the attention deficits so common in delirium tend to limit the ability of patients to perform effectively on virtually all cognitive tests. In short, delirious patients appear to be even more limited on tests of memory, executive ability, and processing speed than they actually are and their performance in these domains may be significantly different after delirium subsides. Even in nondelirious patients, however, inpatient assessment is challenging, partly due to practical considerations which include extreme physical fatigue, the presence of a noisy and chaotic environment, and competing demands (e.g., a patient completing a cognitive battery has to leave multiple times during the assessment to get physical therapy, to receive a magnetic resonance imaging scan, etc.).53 Thus, assessment in a hospital setting should be necessarily brief and may rely largely on challenging but easily feasible screening tools such as brief global cognitive evaluation tools and Trails A and B, brief paper and pencil tests evaluating attention and executive functioning.47 While debates continue over the prognostic value of such tests, one valuable benefit of these tests is that they often uncover striking difficulties that might otherwise be unidentified but which are important for clinicians to recognize. For example, a patient in an ICU setting may pass a delirium screening tests such as the CAM-ICU and may appear fully able to understand what is going on around them. However, a brief cognitive screening test might reveal that they are actually quite impaired, so much so that a nurse or physician might want to take particular pains to explain even simple concepts or instructions or to more fully involve the family in decision making. It is difficult to know how to understand cognitive deficits that are identified early. For example, although cognitive assessments are easier to perform following discharge, data suggest that rapid improvement in patient performance often occurs in a subset of patients between 3 and 12 months.10 However, many of the problems identified in the early postdischarge period persist. Experts continue to grapple with how to best treat cognitive deficits in ICU survivors (even as specialists grapple with this question generally). Recent efforts to treat cognitive impairment have focused on cognitive rehabilitation, which has been shown to be promising in other patient groups including populations of medical patients without obvious neurologic disease. In the first study to test cognitive rehabilitation in ICU survivors, Jackson and Seminars in Respiratory and Critical Care Medicine
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colleagues showed that a meta-cognitive compensatory approach called goal management training improved tower test performance (i.e., planning ability) relative to placebo.81 While this study was clearly limited by a very small sample size, it highlighted the potential viability and effectiveness of cognitive rehabilitation as one possible solution for improving neuropsychological functioning. Other potentially effective approaches to improving cognition after critical illness may include treatment of psychiatric difficulties which could be driving the development of cognitive complaints, the use of medications that have been effectively used to manage cognitive difficulties similar to those seen in ICU survivors (e.g., the use of stimulants to treat attention-deficit disorder and vigorous physical exercise, which has the potential benefit of not only improvement in cognition but in mood as well). These approaches, while intriguing to consider, have largely been untested in the context of cognitive impairment due to PICS.
Psychological Outcomes Critical illnesses can have a significant impact on psychological outcomes by fostering the development of psychological difficulties or exacerbating the psychological difficulties that previously existed.82 Investigating psychological issues has been identified as a critical research priority for critically ill patients by professional societies.83 Increasingly the mental health effects of critical illnesses are engaged in popular media forums such as the Washington Post, the Philadelphia Inquirer, and the New York Times. Despite being highlighted throughout these various media outlets, the psychological problems that occur in ICU survivors—prominently including anxiety, posttraumatic stress disorder (PTSD), and depression —remain largely under-recognized. To date, few efforts have been made to prevent the development of psychiatric problems in ICU survivors, though researchers have begun to explore ways to modify potential risk factors such as delirium and sedation. As it relates to sedation, in particular, a clear paradigm shift has emerged so that patients are typically lightly sedated to whatever degree possible. While the medical benefits of this are obvious, the psychiatric benefits may also be considerable—namely, patients who are aware and alert during critical illness may be less likely to experience the vivid delusional memories that are so frightening to them and that often form the basis for the development of future anxiety symptoms, symptoms of PTSD, and depression.
General Anxiety General anxiety symptoms are especially common among survivors of critical illness with up to 50% of survivors experiencing clinically important anxiety symptoms at 1 year after discharge,82,84 which is much higher than the US general population’s 18% prevalence for any type of anxiety disorder.85 Although anxiety is a normal reaction to stress (e.g., critical illness and ICU hospitalization), it also can hinder a patient’s physical and psychological well-being and recovery from critical illness. Anxiety also can adversely
Disability Following Critical Illness impact important aspects of participation in care, such as rehabilitation engagement. Given the burgeoning importance of early mobilization of patients during ICU hospitalization, addressing anxiety may be important for improving functional status, reducing duration of hospitalization, and improving rehabilitation outcomes. General anxiety symptoms experienced during ICU hospitalization can have an adverse impact on post-ICU psychological function, and is associated with longer-term PTSD86,87 and impaired quality of life.46,87–92 While there are limited studies of risk factors for ICU-related anxiety, those that have been published to date have highlighted historical variables (e.g., premorbid history of anxiety); in-ICU medical and physiological variables (e.g., duration of mechanical ventilation, severity of illness, use of anxiolytic or sedating medications during hospitalization); and environmental variables (e.g., stressful/noisy/chaotic ICU environment) as enhancing risk for anxiety associated with critical illness hospitalization.93
Assessment and Treatment of Anxiety in the Context of Critical Illness Anxiety assessment in the setting of physiological compromise and a chaotic ICU environment can be complicated. Although it is possible to assess anxiety via physiological and behavioral signs such as increased heart rate, blood pressure, muscle tension, facial expression, and restlessness, no physiological measure of anxiety is validated in critical illness, as patients frequently have major abnormalities in vital signs, cortisol levels, and other biomarkers due to life-threatening illness, dysregulation of homeostatic processes (e.g., relative adrenal insufficiency in sepsis), and exogenous administration of catecholamines and corticosteroids. Although physiological assessment of anxiety often is prohibitive, several psychological instruments have been validated for anxiety assessment in the ICU. A Visual Analog Anxiety Scale (VAS-A), ranging from “not anxious at all” (score ¼ 0) to “the most anxious I have ever felt” (score ¼ 100) (vertically oriented) is a valid and reliable measure of anxiety in the ICU.94,95 Moreover, the VAS-A is feasible and appropriate in the ICU because it is easily understood, easily seen, and rapid to administer with patients who are critically ill and may not be able to communicate via traditional means.95–97 The Faces Anxiety Scale (FAS) also has been developed for providing a brief, easily understood, and rapid assessment of anxiety in critically ill hospitalized patients.98 The FAS is a single-item scale consisting of pictures of five faces ranging from “neutral” to “extreme fear” (score ¼ 1 through 5).98 It has been shown to be a valid means of anxiety measurement for patients who are critically ill in the ICU.99,100 Finally, a brief version of the State Anxiety Inventory (SAI) also is well validated in the ICU95,101 and can provide complementary information alongside the VAS-A or FAS (e.g., evaluation of cognitive symptoms of anxiety), while the VASA and FAS are particularly useful for ICU patients who may have difficulties with attention and fatigue.95 The SAI includes 6 questions, derived through factor-analytic strategies, of the original 20 questions in the full State Trait Anxiety Inventory
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(STAI) created by Spielberger.102 The brief SAI has good internal consistency and concurrent validity with the original STAI, and is more feasible for administration to ICU patients than its lengthier counterpart.95,101 Although we have anecdotal evidence that a variety of treatment approaches are used for anxiety management during critical illness (based on our personal experiences and those of our colleagues), there are a limited number of studies that have tested these. The main published studies of nonpharmacologic treatment approaches tested in the ICU include randomized trials of nurse-administered music therapy103,104 and a pre-post study of nonspecific psychological intervention in an Italian trauma ICU.105 Nurses are at the forefront of patient care and, as such, are in an optimal position to provide needed anxiety management strategies to patients who may not have access to a mental health provider or psychologist. However, a study of critical care nurses’ beliefs about anxiety and management strategies suggested that while critical care nurses do value the importance of anxiety management during critical illness, they tend to rely on pharmacologic and communication strategies, which may not be effective for many patients.106 And there are limitations inherent in each of the aforementioned studies (i.e., music therapy and pre-post psychological intervention). Music therapy, while an effective treatment approach during ICU hospitalization, has not been found efficacious for anxiety management in other settings and may not be effective in the long run. The pre-post intervention was observational and nonspecific—it did not specify the role of the psychologist, or the exact components of the intervention. Despite these issues, what we do know is that music interventions are easily administered in chaotic ICU environment, they are feasible and inexpensive to administer, and they seem to help with management of acute anxiety states. Based on results from the study of Peris et al, though, it may be important to incorporate a psychologist into the critical care environment to provide treatments that have been found efficacious and effective in other settings and may result in longer-term management of symptoms; moreover, implementation of a psychologist(s) into the critical care environment may result in reduced rates of general anxiety, PTSD, and depressive symptoms among survivors.105 It is quite possible that early prevention and treatment of these debilitating symptoms may also positively affect other important patient-level outcomes, such as overall quality of life and employment.
Acute and Posttraumatic Stress Critical illness survivors can develop acute stress symptoms during the course of hospitalization and posttraumatic stress (PTS) symptoms afterward.86,107 It has been estimated that at least 20% of ICU survivors experience clinically significant symptoms of PTS during the first year after ICU discharge, which is nearly fourfold higher than the lifetime prevalence of PTS symptoms in the general U.S. population.86,108 Although these symptoms can manifest following a traumatic injury, they also can be a reaction to exposure to critical illness and/ or the ICU environment, and they tend to be related to Seminars in Respiratory and Critical Care Medicine
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delusional memories or delirious states experienced during hospitalization.86,109 PTS symptoms after critical illness often include fear of recurrence of the medical condition and/or functional decline that could result in another fear-invoking hospitalization. Avoidant symptoms tend to predominate and manifest as denial of difficulties, apprehension about discussing any signs or symptoms of a possible medical condition with providers, and reluctance to seek help in the first place. Patients often avoid medical appointments and, as a result, may experience greater severity of chronic conditions that have gone untreated.
Assessment and Treatment of Acute and Posttraumatic Stress in the Context of Critical Illness Assessment of PTS symptoms during hospitalization tends to be nonstandardized and a variety of measures have been described in the extant literature, limiting our ability to identify a gold standard method of assessment.86,110 This tendency has been changing, however, with more researchers using the same measures so that comparisons can be made.107 At present, only the Impact of Events Scale-Revised (IES-R) and the Post-Traumatic Stress Syndrome 10-question inventory (PTSS-10) have been cross-validated against clinician diagnosis for use during critical illness.111 Despite the high prevalence of PTS symptoms among critical illness survivors, there have been limited studies of nonpharmacologic interventions,105 though several practice guidelines focused in the outpatient environment have been published in the last decade.112–114 Across these guidelines, there is strong support for the use of early psychological intervention for patients and their caregivers for prevention and treatment.107,112,114–118 However, the guidelines do not advocate the use of early psychological debriefing to treat or prevent PTSD.119 During ICU hospitalization, symptom management should consist of normalizing symptoms (e.g., nightmares and flashbacks); offering reassurance that we expect the symptoms to decrease in frequency and intensity over time; and regulating sleep/wake cycles, which includes effective pain management while avoiding overuse of opioid medications, as these can have a severe effect on sleep architecture.120 Although exposure therapy, or a combination of exposure with cognitive therapy or stress inoculation training, has the strongest evidence as first-line therapeutic approaches in the outpatient setting,121 these have not been trialed in the ICU. Exposure therapy involves having the patient confront memories of their trauma through a retelling of the experience with the guidance of a trained mental health provider. Although exposure therapy has not yet been tested in the ICU with patients who are critically ill, there are some recent studies that suggest that brief exposure and virtual reality (i.e., visual stimuli and a “virtual world” that the patient can experience under safe and controlled conditions) may be effective for the treatment of early signs of PTS symptoms and prevention of longer-term adverse outcomes.112,114,122,123 There is growing interest in the use of ICU diaries to prevent or ameliorate PTS in patients and families.116–118,124 Diaries may help patients and families make sense of the ICU Seminars in Respiratory and Critical Care Medicine
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experience and improve cognitive and psychological outcomes.117 Whether the use of ICU diaries may also help improve functional outcomes is not known. Typical ICU diaries are maintained by ICU nurses, and sometimes other staff and family members, and contain written information about the patient’s illness and ICU stay using common, compassionate language. Photographs of the ICU, equipment, and of the patient and family prior to the illness may be included. A pilot study showed that diaries were associated with a lower incidence of new-onset PTS symptoms in relatives 3 months after the ICU stay.118 The authors suggested that diaries could foster discussions between families and patients to help the latter understand their illness and treatment and also help relatives express feelings. Although psychological intervention is recommended as a first-line treatment for PTS symptoms before initiating pharmacological options,125 there are also several medications that have been shown to be effective for symptom amelioration. Among these, D-cycloserine, an antibiotic used in conjunction with prolonged exposure treatment, seems to have the most potential.126–129 D-cycloserine is a partial agonist at the Nmethyl-D-aspartate receptor, which plays a role in learning and memory, and DCS has been shown to facilitate extinction learning in animal models, though it has not yet been trialed in persons with PTSD.126 Propranolol, a nonselective β-adrenergic blocker used for hypertension treatment, may be a promising agent for PTS prevention through the blockage of epinephrine receptors.130 There is evidence to suggest that prazosin also may be a promising adjunctive treatment for targeting specific sleep-related (e.g., nightmares, distressed awakenings) disturbances in persons with PTSD, though additional randomized controlled trails are needed.131–135 Available guidelines also suggest the use of selective serotonin reuptake inhibitors (SSRIs) as adjunctive treatment alongside psychological intervention, though they do not recommend benzodiazepine medications for this purpose.136
Depression Depression and depressive symptoms also are very common in the setting of critical illness and ICU hospitalization. It is estimated that the median point prevalence of clinically significant depressive symptoms may be as high as 28%,137 which is much higher than the U.S. general population’s 7% for major depressive disorder or 10% for any mood disorder (which includes major depressive disorder, dysthymia, and bipolar I and bipolar II).85 Depression is a leading cause of psychiatric disability worldwide and is estimated to affect 16%, or 34 million U.S. adults each year.138 Depression includes cognitive-affective and somatic symptoms and it has been suggested that cognitive-affective symptoms in particular (e.g., hopelessness, depressed affect, low perceived social support) may underlie the relationship between depression and chronic diseases such as heart disease through mechanisms such as dysregulated cortisol and nonadherence to medical regimens.139 Alternatively, in survivors of medical and surgical critical illness, somatic symptoms of depression such as fatigue, sleeping problems, and problems initiating physical
Disability Following Critical Illness activity seem to predominate.140 Depressive symptoms may enhance the risk profile for development of critical illnesses, as they may affect one’s propensity to engage in maladaptive health-related behaviors, such as smoking, sedentary lifestyle, alcohol consumption, poor dietary choices, and noncompliance with recommended preventive or treatment regimens. There is evidence that individuals with major depression die 5 to 10 years earlier than their nondepressed counterparts from health conditions such as cardiovascular diseases, diabetes, and chronic obstructive pulmonary disease (COPD), likely due to early onset of maladaptive health behaviors.141,142 Maladaptive health-related behaviors can be difficult to change for many individuals, particularly if those behaviors serve to momentarily enhance mood or reduce tension or fatigue.143 Chronic exposure to mental stress, such as that associated with depressive symptoms, may lead to dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis. Behavioral changes that typically accompany HPA-axis dysregulation include decreased appetite, fatigue, irritability, depressed mood, and social withdrawal, all of which are signs of depression. Repeated exposure to internal and external stressors, accompanied by an inadequate neuroendocrine response, can result in compensatory oversecretion of inflammatory cytokines caused by inadequate or dysregulated secretion of glucocorticoids by the HPA axis.144 Critical illnesses and ICU hospitalization may be considered stressful life events. Stressful life events have been shown to cause changes in immune function.145 Dysregulation of the HPA axis increases susceptibility to infection and can lead to immunosuppression, and activation of the HPA axis contributes to hypercortisolemia which is a key feature of depression.146 Therefore, many studies in the extant literature have highlighted the importance of hyperactivity of the HPA axis in depression.147 Dysregulated immune response and proinflammatory cytokines have been associated with stress, depression, and suicide.148–150 Proinflammatory cytokines (e.g., IL-6 and TNF-α) are abnormal in the serum of patients who are depressed148 and the administration of interferons (IFN) and other cytokines has been shown to induce depression in persons with chronic hepatitis C151 and some forms of cancer.152,153 The administration of IFN-α also has been shown to result in cognitive changes (e.g., memory, speed of information processing or “thinking speed,” and executive function), which may provide the essential pathophysiological link between critical illness, depression, and cognitive dysfunction.150 Additional risk factors for ICU-related depressive symptoms can include lifetime history of major depression, prior trauma exposure, pre-ICU physical function, alcohol dependence, female gender, younger age, and in-hospital symptoms of acute stress, as well as the presence of cognitive dysfunction, though some studies have shown that several of these are not risk factors for incident depression.93,154,155
Assessment and Treatment of Depression in the Context of Critical Illness Much like assessment of anxiety, depression assessment can be problematic during ICU hospitalization when the majority
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of measures currently available are somewhat lengthy and cumbersome. In the context of severe physical compromise, patients often are not able to communicate in the traditional sense which also complicates assessment practice. In addition, to our knowledge no measures of depression or depressive symptoms have yet been validated for use during ICU hospitalization, although many instruments have been validated with other medical populations and in other settings. For example, the Center for Epidemiologic Studies Depression Scale (CES-D) and its revision (CESD-R) are self-report scales that have been tested within both psychiatric and nonpsychiatric samples of the population, and also have been used with persons who are critically ill.154,156–159 The Patient Health Questionnaire 9-item measure (PHQ-9) and its briefer counterpart, the PHQ-2, also have been validated for use with medical and primary care samples160,161; although they have not yet been validated for use in the ICU with critically ill patients, the PHQ-9 has been used in studies involving critically ill patients.155 Only the Hospital Anxiety and Depression Scale (HADS) has recently been validated for use with survivors of critical illness, but only 3 months following hospital discharge, not during acute hospitalization.162 The EuroQol Group has a measure that consists of one question designed to assess anxiety/depressive symptoms, and while this measure is found to have good convergent validity with the longer HADS, it is thought to be a measure of general distress rather than anxiety or depression more specifically.162,163 Typically, because of the lack of validated measures, and the need for brevity and clear patient understanding (in the context of physical compromise and compromised communication abilities) in the ICU setting, depressive symptoms are assessed via clinical interview. Similar to anxiety, there have been very few studies that have empirically tested nonpharmacologic treatment approaches for depression which have been found effective for other patient populations and in other treatment settings. Although some hospitals have the luxury of having psychologist and psychiatrist consultants on staff, the vast majority do not, despite a clear need for accurate and timely mental health/emotional and cognitive assessment. That said, we do not yet know what types of interventions for depression may be helpful during critical illness nor what the optimal time point or dose of administration may be. There is only one randomized controlled trial of which we are aware that was effective in improving physical function and depression at both 8 weeks and 6 months following critical care hospitalization, although this was not a depression intervention per se.36 In other patient populations (e.g., cardiovascular, diabetes), a collaborative care approach that incorporated problem-solving therapy (PST) was found to be helpful. PST is a brief (6–10 sessions) evidence-based treatment approach originally developed for use in primary care settings.164 PST assists patients with solving the “here-and-now” problems contributing to their depressive symptoms and helps increase their sense of self-efficacy.164 PST has been shown to be more effective in reducing depressive symptoms than a more traditional primary care approach.165 Because somatic symptoms tend to predominate in the setting of critical illnesses, it Seminars in Respiratory and Critical Care Medicine
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could be that participation in physical activity (e.g., early mobilization) could lead to improvements in depressive symptoms. In other treatment settings, physical activity has been shown to be effective for mood management and reduction in depressive symptoms. Whatever the case, it remains crucial to develop a full-orbed, holistic view of the emotional challenges faced by individuals after critical illness and to seriously consider the use of exercise as a way of effectively helping to improve mood-related complaints, whether as a standalone approach in cases of subclinical or mild depression or as an adjunct to more traditional approaches in the cases of more severe depressive conditions. The majority of depression trials during critical illness have included antidepressant medications as the sole “therapeutic” approach. The prevalence of antidepressant medication use in critically ill patients is 50% and the incidence is 30% with the majority of medications being in the SSRI class. Notably, citalopram was the most commonly prescribed new antidepressant.154 In patients with comorbid depression and coronary heart disease or congestive heart failure, several large antidepressant trials have shown varied improvement of depressive symptoms with sertraline (e.g., SADHEART).166
Social Support Evidence from psychology and wide ranging areas of medicine almost uniformly heralds the value of social support in improving patient outcomes; though, curiously, social support has been only very minimally explored in ICU survivors. The effects of adverse health behaviors and direct pathophysiological changes on inflammatory and metabolic factors, HPA axis, and autonomic nervous system function may be cushioned by a strong perceived sense of social support.142 Over the years, social support has been conceptualized as the size of one’s social network, the frequency of contact with one’s social network, and the perceived level of support provided by one’s social network.167 “Perceived” support can be distinguished from “received” support and is defined as the subjective appraisal of the match between the amount and type of support needed and the amount that is actually available, as well as internal personality factors that affect one’s perception of the amount of support available and the amount provided.167 Individuals who feel less socially connected may be less physically and mentally healthy and experience worse health consequences than those who do feel connected. Individuals who are critically ill and hospitalized can experience a flurry of visitors initially, which then declines substantially as patients experience less medical compromise, which over time can lead to feelings of isolation and distress. Individuals with a low perceived sense of social support may be at risk for re-hospitalizations, for the reemergence of illnesses, or for the worsening of conditions such as depression which can directly contribute to poor health-related functioning. Identifying these individuals is an important first step, but perhaps more importantly, we need to develop creative ways to help them develop deep and enduring connections with other people. One way this has been Seminars in Respiratory and Critical Care Medicine
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increasingly done with other medical populations (e.g., persons with diabetes) has been to develop peer support programs, where patients are paired with individuals of similar age or background who have successfully navigated the challenges of living with the medical condition of interest. Owing to their success in improving clinical outcomes with other populations, they should be considered for use with ICU survivors, particularly those with few social resources.
Family/Caregiver Burden Forty-six million people provide informal supportive care to adult survivors of critical illness in the United States. Most of these caregivers are family members and they often are untrained and unpaid.168 The typical informal caregiver is a female spouse, although an array of relatives and friends may also provide financial, emotional, and physical support.13,169–171 This care is not only provided at home but also as supplemental care at rehabilitation and extended care facilities—often for weeks, months, or years.13,171 For many caregivers, this new role is a source of satisfaction, but it can also become an overwhelming task with physical, financial, and psychological consequences for the caregiver and the patient.172 When a spouse in particular assumes a caregiver role, the dynamics of the romantic relationship and roles can change substantially, adding to the stress associated with the transition from health to illness and recovery. Caregiver burden may be experienced in a variety of ways including (1) direct monetary cost; (2) caregiver fatigue (physical, mental, and cognitive); (3) time lost for pursuit of pleasurable or alternative activities and hobbies; (4) reduced quality of life; (5) and inability to perform caregiving. When formally questioned, 49% of caregivers reported “a lot” or “severe” stress related to caregiving and 84% quit their jobs or altered their work schedule as a result of caring for a loved one.173 Families of critical illness survivors often overestimate the likelihood that their loved one will survive ICU hospitalization and return to independent breathing and function and go home; as a result, they underestimate the intensity of support their relatives will need after discharge.19,21,174 In addition to describing new and worsening impairments among survivors of critical illness, PICS also is used to describe emotional issues experienced by family members and caregivers of critical illness survivors.4,175–181 Families and caregivers of critical illness survivors can experience a host of adverse outcomes related to their loved one’s illness and hospital experiences, including symptoms of general anxiety and depression, PTSD, and caregiver burden.176–178 Unfortunately, insufficient systemic planning and infrastructure is in place to help survivors, their families, or other informal caregivers.169 ICU survivors need help with countless physical, psychological, and cognitive problems, requiring many hours of attention and care per day.13,169,176 Some of the risks to caregivers of ICU survivors include unemployment, depressive symptoms, sleep disruptions, health problems, and lifestyle restrictions.169,171,182,183 Such risks to caregiver health may be related to immune dysfunction, cardiovascular disease, infections, delayed
Disability Following Critical Illness wound healing, faster cancer growth and chromosomal aging, autoimmune disease, diabetes, metabolic syndrome (e.g., obesity, hypercholesterolemia), depression, and early death, as has been reported in caregivers of seriously ill patients.184–186
Assessment and Treatment in the Context of Critical Illness: Family/Caregiver Burden Caregiver stress and PTS symptoms among caregivers tend to be related to communications and decision-making processes with the health care team.4,187 For example, when caregivers experience dissatisfaction with the type and/or amount of communication with the patient’s care providers, when the ICU providers are perceived as “uncaring,” or when there are discrepancies between caregiver preference for decision making and the involvement that is required of them, they may experience added stress and can develop PTS symptoms.4 It is therefore increasingly important to properly assess the type and level of information and involvement caregivers are equipped to receive throughout the patients’ hospitalization, rather than making undue assumptions. We also need to remain mindful that caregivers, like patients, have complex physical, psychological, social, and cognitive histories. Although within a chaotic ICU environment and during the often fluctuating course of critical illness, it is not feasible to do a thorough psychosocial assessment of caregivers, it is important to assess caregivers’ (1) comprehension of information provided; (2) preferred mode of communication as well as type and amount of information provided; (3)
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satisfaction with care; (4) and perceived burden. Although caregiver distress (e.g., depression, anxiety, stress) also is an important area of assessment, formal assessment typically is not performed. However, there are several assessment tools recommended to assess caregiver burden including the Family Satisfaction in the ICU (FS-ICU)188 and Critical Care Family Satisfaction Survey (CCFSS).189 As noted earlier, ICU diaries have been shown to positively affect caregiver stress and some studies have shown they may be as effective in prevention of family members’ PTS symptoms as they are with patients’.116 Multidisciplinary support networks also may help ameliorate caregiver stress.181 The high prevalence of caregivers who experience adverse psychological consequences related to their loved ones’ critical illnesses suggests a need for screening during the index ICU stay190 as well as in the primary care setting.179
Conclusion, Lingering Questions, and Controversies Just as with ICU “bundles” or protocols for sepsis, ARDS, or diabetic ketoacidosis, it may be that protocols for ICU “survivorship” are what will be required in the future, and organizational change is likely to be key. The specific vital components of this have not been established, but stakeholders have created an agenda for what should be included for advancing research and practice in this realm.191 First, and critically important, is recognizing, preventing and treating signs and symptoms associated with the “post-intensive care
Table 2 Potential strategies to improve ICU survivor and caregiver outcomes
In the ICU
After discharge
Patients
Family/caregivers
Sedation holidays
Assess preferred mode of communication
Early mobilization
Assess comprehension of information provided
Maintain sleep cycle
Determine level of satisfaction with care
Preparation for post-ICU needs
Information on post-discharge level/type of care
ICU diaries
ICU diaries
Multidisciplinary support networks
Multidisciplinary support networks
Referral to psychologist
Referral to psychologist
Communication with primary provider
ICU follow-up clinics?
ICU follow-up clinics? Future directions
Continued identification and treatment of PICS: understanding “survivorship phenotypes” Further identification of factors contributing to positive outcomes beyond ICU hospitalization Identify and address needs and build institutional capacity to support survivors and families Continue to study and develop an understanding of barriers and facilitators to patient care across the spectrum of care environments Test effectiveness of interventions to improve these outcomes through changes in practice Identify optimal time points for intervention: physical, cognitive, psychological ICU follow-up clinics: randomized clinical trials
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syndrome,” or PICS. Second, we must continue to identify and address needs and build institutional capacity to support survivors and families. And, we must continue to study, and develop an understanding of barriers and facilitators to optimal patient outcomes across the spectrum of care environments. Much of the work on long-term functional outcomes after critical illness has been epidemiologic and descriptive: what proportion of patients are discharged to home, what is their level of function, their perceived quality of life, how frequently are they readmitted, and how long do they survive? Important gaps remain in our knowledge about effective interventions to improve these outcomes through changes in practice as well as the optimal time points for intervention (i.e., during the episode of critical illness or later during the recovery period). Understanding the various “phenotypes” of ICU survivors may help us better understand risk and prognosis and better target interventions both in the ICU and later during the fragile recovery period (►Table 2).192
15 Williams TA, Dobb GJ, Finn JC, et al. Determinants of long-term
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