Abstract
Background In the coming years, the number of survivors of critical illness is expected to increase. These survivors frequently develop newly acquired physical and cognitive impairments. Long-term cognitive impairment is common following critical illness and has dramatic effects on patients' abilities to function autonomously. Neuromuscular weakness affects similar proportions of patients and leads to equally profound life alterations. As knowledge of these short-term and long-term consequences of critical illness has come to light, interventions to prevent and rehabilitate these devastating consequences have been sought. Physical rehabilitation has been shown to improve functional outcomes in people who are critically ill, but subsequent studies of physical rehabilitation after hospital discharge have not. Post-hospital discharge cognitive rehabilitation is feasible in survivors of critical illness and is commonly used in people with other forms of acquired brain injury. The feasibility of early cognitive therapy in people who are critically ill remains unknown.
Objective The purpose of this novel protocol trial will be to determine the feasibility of early and sustained cognitive rehabilitation paired with physical rehabilitation in patients who are critically ill from medical and surgical intensive care units.
Design This is a randomized controlled trial.
Setting The setting for this trial will be medical and surgical intensive care units of a large tertiary care referral center.
Patients The participants will be patients who are critically ill with respiratory failure or shock.
Intervention Patients will be randomized to groups receiving usual care, physical rehabilitation, or cognitive rehabilitation plus physical rehabilitation. Twice-daily cognitive rehabilitation sessions will be performed with patients who are noncomatose and will consist of orientation, memory, and attention exercises (eg, forward and reverse digit spans, matrix puzzles, letter-number sequences, pattern recognition). Daily physical rehabilitation sessions will advance patients from passive range of motion exercises through ambulation. Patients with cognitive or physical impairment at discharge will undergo a 12-week, in-home cognitive rehabilitation program.
Measurements A battery of neurocognitive and functional outcomes will be measured 3 and 12 months after hospital discharge.
Conclusions If feasible, these interventions will lay the groundwork for a larger, multicenter trial to determine their efficacy.
With the aging of the American population, it is estimated that 1 in 5 Americans will be over the age of 65 years by the year 2030.1 The incidence of common critical illness syndromes, including sepsis and acute respiratory distress syndrome (ARDS), increases with age.2,3 Thus, there is likely to be a large increase in the number of patients developing and surviving an episode of critical care in the coming years. Over the last decade, advances in the management of critical illness with therapies such as early goal-directed sepsis resuscitation,4 low tidal volume ventilation for ARDS,5 sepsis treatment bundles,6 and paired sedation and ventilator weaning strategies7 have improved survival rates among people who are critically ill. Nevertheless, these survivors, particularly elderly people, frequently develop newly acquired physical and cognitive impairments (or experience an acceleration of existing difficulties) that lead to significant reductions in quality of life.8–11
Long-term cognitive impairment emerges in the majority (50% to 75% or more) of survivors of admission to an intensive care unit (ICU) as the enduring or residual injury after a life-threatening illness that is managed in the ICU setting. During patients' critical illness, this injury first manifests as acute brain dysfunction (delirium and coma) accompanying neuromuscular weakness or ICU-acquired weakness (ICU-AW).12 As knowledge of these short-term and long-term consequences of critical illness has come to light, the development of interventions to prevent and rehabilitate these devastating consequences has been sought. This article reviews short-term and long-term cognitive and physical impairments surrounding critical illness that are unrelated to an overt, gross, structural brain injury such as that related to stroke or trauma (ie, this article deals with injury in patients from general medical or surgical ICUs), describes emerging rehabilitation strategies for these impairments, and presents a novel investigational protocol of early and sustained cognitive rehabilitation paired with early physical rehabilitation of patients who are critically ill.
Cognitive and Physical Impairments Following Critical Illness
Cognitive Impairment
Patients who are critically ill frequently have acute brain dysfunction in the ICU, manifesting as either delirium or coma.13,14 Delirium is characterized by an acute change in mental status and a fluctuating course, inattention, and disorganized thinking.15 In the ICU, it affects 60% to 80% of patients who are mechanically ventilated and is associated with several adverse outcomes, including prolonged mechanical ventilation, delayed hospital discharge, an increased risk of death, and long-term cognitive impairment.16–19
Long-term cognitive impairment (LTCI) refers to the syndrome of significant, and often persistent, cognitive deficits following critical illness that varies widely in severity and at its worst can be functionally debilitating.20 This syndrome may be observed in one half to three fourths or more of ICU survivors, depending on the tests used to detect cognitive deficits and how these deficits are defined.21–23 These newly acquired deficits have been observed not only in investigations of ICU survivors but also among patients after acute non-ICU hospitalizations24,25 and after severe sepsis.26 Although specific risk factors have not been firmly established, 2 studies have shown the duration of delirium in the ICU to be an independent predictor of LTCI among survivors of critical illness.19,27 The exact mechanism or mechanisms that lead to these cognitive impairments remain unproven, although hypoxemia, inflammation, and glucose dysregulation each have been hypothesized to be involved.28 The most frequently reported impairments following critical illness involve the neurocognitive domains of executive functioning, memory, and attention.20 Impairments in executive functioning are particularly life changing and may manifest as difficulties with planning, problem solving, inhibition, and control of behavior in everyday life.29 In normal aging, impaired executive function is associated with impaired functional status.30 For survivors of critical illness, these newly acquired impairments, particularly those pertaining to executive functioning, may have dramatic, life-altering effects on the patients' lives, such as inability to return to work or to function autonomously.31
Physical Impairment
Physical impairment, frequently manifested as profound weakness, may be accompanied by a combined motor/sensory neuromyopathy, but also may exist in the absence of such findings, and affects between 25% and 60% of ICU survivors.12,32 Formal electrophysiologic testing is not routinely performed in these patients because treatment of these disorders generally does not differ, testing is difficult in sedated or uncooperative patients, and patients may have electrophysiologic abnormalities without significant weakness. Therefore, many experts recommend the use of the term “ICU-acquired weakness” to describe the clinical syndrome of neuromuscular weakness in patients who are critically ill, in whom there is no other plausible etiology other than the critical illness.12,33
Intensive care unit–acquired weakness presents as symmetric weakness that ranges from severe weakness to paralysis, with or without a reduction in deep tendon reflexes.34 Risk factors for the development of ICU-AW include multiple organ failure, sepsis, immobility, hyperglycemia, and corticosteroids.32 This disorder has been associated with poor short-term outcomes, including difficulty weaning from mechanical ventilation and prolonged ICU and hospital stays.35 The most severe cases of ICU-AW are associated with an 8-fold increase in the risk of death.36 Newly acquired functional impairment and physical disability related to neuromuscular weakness are common following critical illness, and recovery from ICU-AW often is incomplete.37,38 Despite similar levels of pre-illness impairment in activities of daily living (ADL), elderly patients who are hospitalized and undergo mechanical ventilation develop more profound ADL disability compared with those hospitalized without mechanical ventilation and those never hospitalized in the year following hospitalization.39 Survivors of ARDS followed at least 5 years after their illness had a significantly reduced 6-minute walk distance compared with population norms despite return to near-normal pulmonary function, indicating long-lasting physical impairment.31,40
Rehabilitation of Impairments in Patients Who Are Critically Ill
Despite the high prevalence of impairments after critical illness, formal rehabilitation pathways do not commonly exist for survivors of critical illness, as they do for patients surviving other diseases, such as cardiac disease, stroke, and traumatic brain injury.41 As awareness of functional and cognitive impairments after critical illness has grown, prevention and rehabilitation strategies have been developed, but these strategies focus mainly on rehabilitation of physical impairments, with little attention on cognitive rehabilitation of patients who are critically ill.
Cognitive Rehabilitation
Cognitive rehabilitation, focusing on interventions directed at specific cognitive impairments (eg, attention, memory, executive function), is commonplace in the treatment of patients with other acquired brain injuries, such as traumatic brain injury and stroke, and has been shown to be effective with many populations.42 The role of cognitive rehabilitation for the prevention and treatment of acquired cognitive dysfunction in patients who are critically ill is largely unknown. A small feasibility trial evaluated cognitive rehabilitation for survivors of critical illness.43 Over the 12-week study period, patients in the intervention group underwent 6 in-home cognitive rehabilitation sessions and, on alternating weeks, received individualized physical rehabilitation “visits” via tele-technology. In addition, patients underwent 4 tele-visits with an occupational therapist to aid in functional recovery. After 3 months of this multicomponent intervention, the intervention group demonstrated improved executive function and less disability in instrumental ADL compared with controls. Although encouraging, these results will require validation with a larger, multicenter trial to elucidate the magnitude of this effect and to determine whether these findings translate into “real-world” improvements in cognitive and physical functioning as well as quality of life.
To our knowledge, no prior study has evaluated the feasibility and potential benefits of providing early cognitive therapy to ICU patients and, indeed, few data exist on the benefits of early cognitive therapy in general among patients recovering from acute illness of any kind. In implementing in-hospital cognitive rehabilitation exercises, we relied on the theoretical principle referred to in both the popular and scholarly literature as “use it or lose it.”44,45 This principle, often applied to exercises and muscle training, suggests that brain exercise can have a beneficial effect on cognitive slowing and may stave off neuropsychological decline.44–46 Stated more mechanistically, this concept posits that neuronal activation can improve neuronal function and result in improved neuronal survival in the context of a brain injury. As ICU patients characteristically are cognitively inactive during extended hospitalizations, the use of cognitive stimulating exercises may have an effect via the “use it or lose it” paradigm of improving cognitive outcomes.
Physical Rehabilitation and Early Mobility
Early physical rehabilitation of patients who are critically ill was once thought to be an unsafe practice; however, there is a growing body of literature on the safety and feasibility of mobilizing these patients in the ICU to prevent functional impairments.47–51 The largest trial of early physical rehabilitation to date demonstrated that patients could safely begin physical therapy and occupational therapy within the first 72 hours following intubation.51 In this trial, patients in the intervention group received physical therapy and occupational therapy a median of 6 days sooner and reached the functional milestones of getting out of bed, standing, marching in place, transferring to a chair, and walking significantly sooner than those in the control group. Patients treated with this intervention were more likely to return to their baseline functional status upon hospital discharge. These results suggest that the timing of early physical rehabilitation is important in preventing and rehabilitating newly acquired functional impairments following critical illness. In addition, patients undergoing early physical and occupational rehabilitation had fewer days of delirium compared with those not undergoing early mobility. Thus, early physical rehabilitation may enhance attentional ability, although the exact mechanism of this effect is unclear.
Finally, the beneficial effects of early mobility in the ICU may persist following discharge. Follow-up of one cohort of patients who underwent an early mobility protocol showed an association between early mobility and reduced readmission rates or death in the year following hospitalization for critical illness.52
Randomized trials of physical rehabilitation beginning after hospital discharge have largely failed to demonstrate improved patient-centered outcomes underscoring the importance of early mobility.53,54 Patients undergoing an 8-week, in-home, supervised physical rehabilitation program did not demonstrate improvements in quality of life or 6-minute walk distance.54 Similarly, post-ICU outpatient rehabilitation with a self-directed physical rehabilitation manual did not improve quality of life compared with usual care.53 Conversely, an outpatient rehabilitation manual addressing psychological, psychosocial, and physical needs of ICU survivors, coupled with nurse telephone calls and follow-up clinic visits, improved physical components of quality of life compared with patients receiving usual care.55 Thus, the optimal duration and content of postdischarge physical rehabilitation and potential benefits of these interventions remain unknown.
Combined Early Cognitive and Physical Rehabilitation?
Whether patients who are critically ill can undergo early cognitive rehabilitation in much the same way they can undergo early physical rehabilitation has not been previously explored. Thus, this study primarily seeks to determine whether early cognitive therapy in patients who are critically ill is feasible.
In addition, physical exercise may have positive effects on cognition. Indeed, the benefits of vigorous physical exercise on cognitive functioning have been widely demonstrated in the context of clinical trials with diverse populations.56,57 Furthermore, evidence suggests that the cognitive domains of executive function and memory can be improved with exercise.58,59 Whether physical rehabilitation may have beneficial effects on post-ICU cognitive outcomes remains unknown.
Finally, the effects of a paired early and sustained cognitive rehabilitation and early physical rehabilitation program on cognitive and physical/functional status in ICU survivors have not been studied. To address these gaps in knowledge, we propose to study an interdisciplinary rehabilitation program aimed at providing early and sustained cognitive rehabilitation paired with early physical rehabilitation/early mobility to a cohort of medical and surgical patients who are critically ill.
Materials and Methods
Research Hypothesis and Aims
We hypothesize first that early and sustained cognitive rehabilitation can be combined with physical rehabilitation/early mobility to create a feasible and safe Activity and Cognitive Therapy in the Intensive Care Unit (ACT-ICU) protocol for the management of patients with critical illness. Second, we hypothesize that this protocol will improve recovery of cognitive and physical functioning among ICU survivors as well as improve quality of life. To test our first hypothesis, we will assess the feasibility and safety of this intervention in a single-center, pilot, randomized controlled trial of patients enrolled from medical and surgical ICUs at Vanderbilt University. Although the trial will not be powered to prove efficacy, we also will obtain preliminary data to examine our second hypothesis. Specifically, we will evaluate whether these combined interventions can decrease the presence and severity of cognitive and physical impairment compared with physical rehabilitation alone and with usual care through a variety of short-term and long-term outcome measures.
Study Protocols
Participants in the ACT-ICU trial will be recruited from adult patients admitted to the medical and surgical ICUs at Vanderbilt University Medical Center with respiratory failure, cardiogenic shock, septic shock, or hemorrhagic shock. As pre-existing cognitive and physical impairments may not be amenable to acute rehabilitation, we will screen patients for pre-existing impairments using validated tools (described below) and exclude those with significant pre-existing cognitive or functional impairments. Study inclusion and exclusion criteria are shown in Table 1. Because patients will be enrolled very early during critical illness, when acute brain dysfunction is widely prevalent, informed consent usually will be sought from an authorized surrogate. The patient, once cognitively able, can consent to continue in the trial or withdraw. Study interventions will begin within 24 hours of study enrollment.
Inclusion and Exclusion Criteriaa
At the time of study enrollment, demographic data and data on comorbidities and severity of illness (using the Acute Physiologic and Chronic Health Evaluation II)60 will be obtained. Baseline cognitive impairment will be evaluated using the Informant Questionnaire of Cognitive Decline in the Elderly (IQCODE),61 and a score of >3.3 will be used to determine the presence of cognitive impairment. Functional status in the 1 to 2 months prior to the patient's acute illness will be determined using the Katz Activities of Daily Living Scale,62 and a cutoff score of >3 will be used to define functional disability. In addition, surrogate information regarding a patient's prehospital functional status will be obtained using the Dysexecutive Questionnaire,63 AD8,64 and Functional Activities Questionnaire.65 Data on severity of illness will be collected daily for all patients.
Patients will be randomized in a 1:1:2 manner to 1 of 3 groups: group 1 will receive usual care, group 2 will undergo treatment with a physical rehabilitation/early mobility protocol, and group 3 will undergo treatment with a paired cognitive and physical rehabilitation/early mobility protocol (Fig. 1). Following hospital discharge, patients in group 3 with evidence of cognitive or physical impairment also will receive a 12-week, in-home cognitive rehabilitation program.
Flow diagram of the Activity and Cognitive Therapy in the ICU (ACT-ICU) Trial. Patients will be screened for pre-existing cognitive or physical impairments and then randomized to 1 of 3 groups. Group 1 will receive usual care, group 2 will undergo treatment with a physical rehabilitation/early mobility protocol, and group 3 will undergo treatment with a paired cognitive and physical rehabilitation/early mobility protocol. If patients in group 3 demonstrate evidence of cognitive or physical impairments at hospital discharge, they will undergo a 12-week in-home cognitive rehabilitation program (goal management training [GMT]). Short-term and long-term outcomes will be assessed at 3 and 12 months following hospital discharge. Each day, all mechanically ventilated patients will be managed with a protocol of paired spontaneous awakening and breathing trials. Tower Test=Delis-Kaplan Executive Function System (D-KEFS) Tower Test, TUG=Timed “Up & Go” Test, MMSE=Mini-Mental State Examination, ADL=activities of daily living, IADL=instrumental activities of daily living.
Intervention Protocols
All patients' level of consciousness will be assessed twice daily using the Richmond Agitation-Sedation Scale (RASS).66 Patients will be screened twice daily for the presence of delirium using the Confusion Assessment Method for the ICU (CAM-ICU).13 Mechanically ventilated patients will undergo daily spontaneous awakening and breathing trials.7
Cognitive rehabilitation protocol.
The cognitive rehabilitation protocol, performed in group 3 only, consists of inpatient and outpatient interventions. For the inpatient component, patients will be asked to work through progressively more challenging exercises pertaining to orientation, attention, and memory. Research nurses and physicians will perform cognitive rehabilitation sessions for 20 minutes, twice daily. Mechanically ventilated patients will be presented with a booklet from which to indicate correct answers for each exercise. The protocol will start once patients are able to open their eyes to voice (RASS −3 or −2) and will begin with an orientation exercise (Fig. 2). Once patients are alert and calm (RASS −1, 0, or +1), they will be asked to progress through additional exercises (in many cases, modifications of existing neuropsychological tests),67 including digit span forward, matrix puzzles, real-world exercises assessing comprehension and calculation abilities (eg, reading a bus schedule, calculating change), digit span backward, immediate noun list recalls, immediate story recalls, letter-number sequences, and pattern recognition sequences. These exercises were chosen to address attention and memory deficits commonly observed in patients who are delirious. The exercises do not overlap with items tested during the neuropsychological tests used for outcome assessments so as to reduce or minimize practice effects. Each exercise comprises 5 to 10 items. If a patient states the correct answer for an item, he or she then will move on to the next item in the exercise until the exercise is complete or 3 consecutive items have been answered incorrectly. The goal of the cognitive rehabilitation protocol is to provide cognitive engagement through the exercises, not necessarily to obtain the correct answer during the exercise. Thus, if a patient answers an item incorrectly, he or she will be provided with hints and cues to “coach” the patient to obtain the correct answer until 3 unsuccessful attempts have been made on an item. If a patient fails to complete 3 consecutive exercises, the remainder of the rehabilitation session will be spent in informal conversation with the patient.
Inpatient early cognitive rehabilitation protocol. Sessions will be provided twice daily throughout the hospitalization. Prior to starting the session, the patient's level of consciousness will be determined using the Richmond Agitation-Sedation Scale (RASS). A patient who is only arousable to physical stimuli (RASS −5/−4) will not receive any intervention. Once a patient is able to open his or her eyes to voice (RASS −3/−2), study personnel will perform an orientation exercise. Once a patient is awake and alert, he or she will work through a series of exercises beginning with orientation exercise and progressing through a series of progressively more difficult exercises of attention and memory. Finally, each patient will be provided with games and puzzles to work on independent of study personnel. ICU=intensive care unit.
At the conclusion of each formal cognitive therapy session, patients will be provided with additional optional exercises, including word and number games, puzzles, and hobbies such as crossword puzzles, word “jumbles,” anagrams, Scrabble, and Sudoku, if desired. In addition, we will encourage families and other visitors to actively engage the patients in discussions of topics and hobbies in which they were interested in prior to hospitalization. For example, if the patient is interested in sports, we will encourage the family to talk with the patient about his or her favorite teams, or if the patient enjoyed playing cards, to play cards with the patient.
The protocol will begin each day at the beginning of the exercises and progress as the patient is able. The second session will resume with the exercise the patient was working on when the first session ended.
Prior to hospital discharge, each patient's executive function and functional mobility will be objectively measured as described in the “Outcome Measures” section. Patients in group 3 exhibiting cognitive or functional impairment, defined as having scores >1 standard deviation below the norm reference mean, will be provided with outpatient cognitive rehabilitation. The outpatient cognitive rehabilitation will use modified goal management training (GMT).68 Goal management training is a protocolized approach to cognitive rehabilitation that has been modified and adapted slightly to be optimally tolerable for our study patients and feasible for our staff to deliver. This approach has been used in cognitive rehabilitation of patients with traumatic brain injury,68 frontal lobe dysfunction,69 and normal aging,70 and most recently in survivors of critical illness in a small pilot study by our group.43 It will be delivered either in the patient's home or during a return visit, every other week during the first 12 weeks following hospital discharge, by a master's-level psychologist or a licensed professional counselor.
Goal management training seeks to improve executive function by increasing goal-directed behavior by: (1) teaching patients compensatory strategies such as “stop” techniques (eg, to “stop and think” about consequences of a decision before making it) and (2) taking complex tasks and dividing them into manageable subtasks to increase the likelihood of completing the task. Each session builds on the previous one, so that a “dose” of rehabilitation is delivered. Patients also complete relevant homework assignments between sessions emphasizing real-world applications of the techniques learned.
Physical rehabilitation/early mobility protocol.
The physical rehabilitation/early mobility protocol will be performed by patients in groups 2 and 3. The protocol is modeled after those of Bailey et al,47 Morris et al,49 Thomsen et al,71 and Schweickert and colleagues51,72 and designed to advance patients from passive range of motion exercises to independent ambulation with a “sit, stand, then walk” approach. Sessions will be performed by physical therapists and occupational therapists specializing in the treatment of patients who are acutely ill, with additional therapies performed by research nurses and physicians under the guidance of the therapists. Each session will be guided by the patient's level of consciousness. In addition, the protocol will be implemented with flexibility and titrated according to the patient's ability with the goal of having a patient achieve his or her “maximum functional milestone” rapidly during each session.
Prior to each session, each patient will be assessed for the presence of any safety criteria that would preclude safely performing the protocol (Tab. 2, panel A).72 In addition, if the patient develops any safety criteria during the session, the session will be halted immediately, and the patient will be placed in a resting position (eg, seated in a chair, seated at the edge of the bed, lying supine in bed); the session then may proceed at the physical therapists' and occupational therapists' discretion (Tab. 2, panel B).47,72 Comatose patients (RASS −5/−4) will undergo passive range of motion of all major joints (eg, extension and flexion of fingers, wrists, elbows, knees, and ankles; shoulder flexion; flexion, abduction, and adduction of hips). Patients who open their eyes to voice (RASS −3/−2) will undergo passive range of motion and be placed in the chair position in the bed for up to 2 hours following the session. Awake and calm patients (RASS −1/0/+1) will progress through active range of motion exercises of all major joints, bed mobility exercises (eg, lateral rolling, supine to sit), dangling at the edge of the bed, postural retraining, balance exercises (eg, reaching in and out of the base of support, challenges to elicit “righting” reflexes), training in ADL (eating or simulated eating, grooming, bathing, dressing, and toileting), transfer from a seated to a standing position and from bed to chair or commode, standing exercises such as reaching in and out of the base of support, mini-squats, marching, and ambulation (with or without assistive devices) (Fig. 3). If a patient becomes more alert during passive range of motion exercises, the session will immediately progress to the appropriate level of exercises.
Safety Screening Criteria for Physical Rehabilitation Protocola and Safety Criteria for Cessation of the Physical Rehabilitation Protocolb
Physical rehabilitation protocol. Patient's level of consciousness using the Richmond Agitation-Sedation Scale (RASS) will be determined prior to the daily physical rehabilitation session. A patient who is only arousable to physical stimuli (RASS −5/−4) will undergo passive range of motion (ROM) exercises. Once a patient is able to open his or her eyes to voice (RASS −2/−3), passive ROM exercises will be performed, and the patient will be placed in the chair position in bed. Finally, once a patient is alert and calm, he or she will progress from active ROM up through ambulation as he or she is able. Sessions will continue until hospital discharge or a patient meets certain functional milestones. ICU=intensive care unit, ADL=activities of daily living. Figure modified from Morris et al.49
Physical rehabilitation sessions will be performed daily until a patient is able to perform all ADL tasks with supervision (Functional Independence Measure score of 5 or greater)73 and is able to ambulate more than 60.1 m (200 ft) with supervision on 2 consecutive days, or is discharged from the hospital.
Outcome Measures
To provide preliminary data on the efficacy of the in-hospital interventions, prior to hospital discharge, we will measure executive function using the Delis-Kaplan Executive Function System (D-KEFS) Tower Test,74 functional mobility with the Timed “Up & Go” Test (TUG),75 and overall cognitive functioning with the Mini-Mental State Examination (MMSE).76 As not all functional and cognitive impairments are evident while a patient is hospitalized, approximately 1 week following hospital discharge, patients will be assessed via telephone using the Dysexecutive Questionnaire,63 the Functional Activities Questionnaire,65 the Katz Activities of Daily Living (ADL) Scale,77 and the Activities-specific Balance Confidence Scale.78
The primary outcome of this study will be executive functioning at 3 months following hospital discharge, as measured using the D-KEFS Tower Test (higher scores indicate better performance).74 In addition, to measure the efficacy of the combined in-hospital and out-of-hospital interventions, we will assess secondary outcomes of global cognitive function, physical functioning, and health-related quality of life at 3 and 12 months by assessing scores on the following measures:
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Dysexecutive Questionnaire (test of executive function, where higher scores indicate greater impairment)63
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AD8 (assessment of change in cognitive abilities, scored as “Yes,” “No,” or “Don't know”)64
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Short-Informant Questionnaire of Cognitive Decline in the Elderly (assessment of cognitive decline, where higher scores indicate greater decline)61
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TUG (timed test of functional mobility, where slower times indicate worse performance)75
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MMSE (test of overall cognitive function, where lower scores indicate worse performance)76
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Katz ADL Scale (assessment of basic ADL, where higher scores indicate greater dependence)
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Activities-specific Balance Confidence Scale (rating of a patient's confidence of maintaining balance and remain steady while engaged in certain tasks, where higher scores indicate greater confidence)78
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Functional Activities Questionnaire (assessment of higher-level functional abilities, where higher scores indicate greater dependence)65
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Trials A & B Test (timed test of executive function [Trials A] and attention [Trials B]; T-scores adjusted for age, education, and sex are generated)79
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A general employment questionnaire (employment status before and after ICU hospitalization)
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Hospital Anxiety and Depression Scale (assessment of anxiety and depression, where higher scores indicate more severe disease)80
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EQ-5D (measure of health outcomes, where lower scores indicate worse quality of life)81
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Canadian Study of Health and Aging Frailty Scale (global rating of frailty, where higher scores indicate increased frailty)82
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Patient weight
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D-KEFS Tower Test74 at 12-month follow-up
We also will track readmission to the hospital and admission to a nursing home or skilled rehabilitation facility as secondary outcomes during the 12-month follow-up period.
Statistical Analysis Plan
Given the primary feasibility aim of our study and the high baseline mortality rates in patients who are critically ill, participants will be enrolled in the study until 60 patients survive until hospital discharge. This enrollment goal is based on our desire to gather data regarding both the inpatient and outpatient portions of our intervention rather than a formal power calculation.
To assess success of randomization, the distribution of baseline factors, such as age, sex, race, severity of illness, and sepsis, will be assessed by comparing summary measures among patients randomized into the 3 groups to identify clinically meaningful differences rather than relying on statistical testing. To determine the effect of the interventions on the primary outcome and other continuous outcomes, we will utilize the Kruskal-Wallis test to compare D-KEFS Tower Test scores among the 3 treatment groups. If the test is significant, we will use pair-wise Wilcoxon rank sum tests to compare each of the active intervention groups (groups 2 and 3) directly with the control group (group 1). To determine the effect of the interventions on ICU length of stay, survival, and other time-to-event outcomes, the cumulative incidence probability of these outcomes will be estimated using the Kaplan-Meier product limit method, and the log-rank test will be used to compare the 3 groups. With properly implemented randomization, which should result in balanced distribution of measured and unmeasured covariates among the treatment groups, the unadjusted analyses will provide the most conservative and unbiased estimate of the intervention effects. All data will be analyzed using the intention-to-treat principle.
Methodological Issues
We anticipate several difficulties in implementing the rehabilitation protocols, including delirium, varying manifestations of cognitive impairment throughout the study stages, newly acquired physical weakness, and lack of awareness of cognitive deficits leading to diminished interest in the cognitive rehabilitation protocols.
Inattention and disorganized thinking are hallmark features of delirium; therefore, we anticipate that some patients with delirium may struggle with the cognitive rehabilitation exercises. In particular, due to their poor attentional capacity, patients with delirium may have trouble following instructions. Cues will be provided to the patients to assist with completion of the exercises, and engaging them in a stimulating cognitive task will be emphasized.
With regard to extreme physical weakness, our protocol addresses the needs of individual patients. Each patient will progress along the protocol, under the direction of occupational therapists and physical therapists, who may use any treatments (eg, massage therapy and therapeutic exercise) or rehabilitation tools (eg, tilt table) needed to aid individual patients. The goal is to provide an earlier and increased “dose” of physical therapy and occupational therapy than what is typically done in many ICUs.
Newly developed cognitive impairments (eg, thinking and memory problems) are likely not as obvious to patients as physical impairments that are difficult not to notice (eg, inability to ambulate) while in the hospital. For example, patients will likely recognize physical limitations when they are unable to get out of bed unassisted, but it may not be as apparent that they are unable to balance a checkbook or follow a simple recipe. We will emphasize this point to patients and attempt to individualize portions of the study protocol to address their needs, specifically with regard to the optional exercises, where content is tailored to a patient's interests. In addition, there may be patients who have relatively preserved cognition while hospitalized but due to the length of their hospitalization become bored with our standardized inpatient rehabilitation protocol. We do not have a provision for patients to “test out” of the cognitive rehabilitation protocol but will make efforts to enhance patient interest and heighten their level of engagement by increasing the “optional” portions of the protocol (eg, games, puzzles, use of patients' own laptop computers and iPad tablets) to provide the twice-daily cognitive stimulation.
Once patients are discharged from the hospital, obstacles to performing the outpatient portions of the protocol may include discharge to rehabilitation facilities or nursing homes and maintaining contact with patients who may live some distance from our facility. Because we will only deliver outpatient cognitive rehabilitation once patients return home, those who are discharged to rehabilitation facilities or nursing homes will be phoned weekly to inquire about how they are doing and when they might be discharged. Once a patient has been discharged home, “make-up” sessions will be scheduled to provide as much of the cognitive rehabilitation protocol as possible within the 12-week follow-up period. We will work to establish relationships with the patient and his or her family while the patient is hospitalized, including having the patient meet the social worker and the psychologist who will perform the outpatient therapy prior to hospital discharge. We also will provide weekly telephone calls, as needed, to each patient to maintain contact during the follow-up period.
Conclusion
Cognitive and physical impairments are common in patients who survive critical illness. To date, rehabilitation strategies have focused on physical rehabilitation as a means of enhancing functional recovery. Cognitive rehabilitation, although common in other disease-specific states, rarely occurs following critical illness. We present a novel protocol pairing early and sustained cognitive rehabilitation with physical rehabilitation and early mobility in adults who are critically ill. If this protocol is found to be feasible, the findings of this study will lay the groundwork for a larger, multicenter trial to determine the efficacy of these cognitive, physical, or combined rehabilitation programs in improving cognitive and physical functioning as well as quality of life for survivors of critical illness.
Footnotes
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Dr Brummel, Dr Jackson, Dr Girard, Dr Pandharipande, Ms Schiro, Ms Work, Ms Pun, Ms Boehm, and Dr Ely provided concept/idea/research design. Dr Bummel, Dr Jackson, Dr Girard, Dr Pandharipande, and Dr Ely provided writing and data analysis. Dr Brummel, Ms Schiro, Ms Pun, and Ms Boehm provided data collection. Dr Bummel and Ms Boehm provided project management. Dr Brummel, Dr Jackson, Dr Girard, and Dr Ely provided fund procurement. Dr Brummel provided study participants. Dr Ely provided facilities/equipment. Dr Brummel, Ms Schiro, Ms Pun, and Dr Gill provided consultation (including review of manuscript before submission).
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Dr Ely has received a research grant and honoraria from Hospira, Eli Lilly, Aspect Medical Systems, Massimo, and Cumberland. Dr Girard has received honoraria from Hospira. Dr Pandharipande has received a research grant from Hospira and honoraria from Hospira, GlaxoSmithKline, and Orion Pharma. The other authors report no financial disclosures.
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Preliminary abstract data were presented at the Annual International Conference of the American Thoracic Society; May 18–23, 2012; San Francisco, California.
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The Vanderbilt University Institutional Review Board has approved the ACT-ICU protocol.
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Dr Brummel is supported by the National Institutes of Health (T32HL087738). Dr Jackson is supported by the National Institutes of Health (AG031322). Dr Girard is supported by the National Institutes of Health (AG034257). Dr Pandharipande is supported by the VA Clinical Science Research and Development Service (VA Career Development Award). Dr Ely is supported by the VA Clinical Science Research and Development Service (VA Merit Review Award) and the National Institutes of Health (AG027472 and AG035117). Dr Gill is the recipient of a Midcareer Investigator Award in Patient-Oriented Research (K24AG021507) from the National Institute on Aging and is supported, in part, by the Yale Claude D. Pepper Older Americans Independence Center (P30AG21342). Dr Ely and Dr Girard are supported by the Veterans Affairs Tennessee Valley Geriatric Research, Education and Clinical Center (GRECC). This work also is supported by the National Center for Research Resources (1 UL1 RR024975). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute or the National Institutes of Health.
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The trial is registered with ClinicalTrials.gov (NCT 01270269).
- Received November 16, 2011.
- Accepted April 27, 2012.
- © 2012 American Physical Therapy Association
References
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