Abstract
Critical illness and its treatment often result in long-term neuropsychiatric morbidities. Consequently, there is a need to focus on means to prevent or ameliorate these morbidities. Animal models provide important data regarding the neurobiological effects of physical activity, including angiogenesis, neurogenesis, and release of neurotrophic factors that enhance plasticity. Studies in noncritically ill patients demonstrate that exercise is associated with increased cerebral blood flow, neurogenesis, and brain volume, which are associated with improved cognition. Clinically, research in both healthy and diseased human subjects suggests that exercise improves neuropsychiatric outcomes. In the critical care setting, early physical rehabilitation and mobilization are safe and feasible, with demonstrated improvements in physical functional outcomes. Such activity may also reduce the duration of delirium in the intensive care unit (ICU) and improve neuropsychiatric outcomes, although data are limited. Barriers exist regarding implementing ICU rehabilitation in routine care, including use of sedatives and lack of awareness of post-ICU cognitive impairments. Further research is necessary to determine whether prior animal and human research, in conjunction with preliminary results from existing ICU studies, can translate into improvements for neuropsychiatric outcomes in critically ill patients. Studies are needed to evaluate biological mechanisms, risk factors, the role of pre-ICU functional level, and the timing, duration, and type of physical activity for optimal patient outcomes.
Critical illness and its treatment often result in long-term physical and neuropsychiatric morbidities that require high resource use during and after intensive care unit (ICU) stays (1–4). Cognitive impairment is reported in 30 to 70% of ICU survivors (5), with two large epidemiological studies demonstrating that critical illness is associated with the development of new cognitive impairments (6, 7). Mechanisms of post-ICU cognitive impairment (e.g., hypoxemia [4, 8], glucose dysregulation [9, 10]) and risk factors associated with cognitive impairment and brain injury (e.g., delirium [11, 12]) are poorly understood but are likely multifactorial and synergistic (for a review, see Hopkins and Girard [13]). Given the evidence that neuropsychiatric morbidities are common after critical illness, there is a need to focus on means to prevent or ameliorate neuropsychiatric morbidity. Consequently, there is a growing body of research evaluating ICU-based interventions designed to improve long-term patient outcomes after ICU. For example, recent studies of physical rehabilitation in the ICU demonstrate improved physical function and reduced delirium, a risk factor for long-term neuropsychiatric morbidities (11, 14, 15).
Investigating the effects of ICU-based physical rehabilitation on neuropsychiatric outcomes is novel, as there are no data indicating that long-term neuropsychiatric morbidities are improved by physical activity in the ICU setting. To stimulate such investigation, existing data regarding the effects of physical activity on neurologic function must be understood. Evidence in animals and noncritically ill humans indicates that physical activity may be neuroprotective, facilitates synaptic transmission, increases release of neurotransmitter and neurotrophic factors, promotes neurogenesis and angiogenesis, improves cognitive function, and reduces symptoms of depression and anxiety. Based on these data, we hypothesized that neuropsychiatric outcomes in critically ill populations may be improved by physical activity during or after ICU treatment. The objectives of this Critical Care Perspective are to review and synthesize animal and human data evaluating the effects of physical activity on neuropsychiatric function and discuss the relevance and application of such data for critically ill patients. In addressing these objectives, we will review the effects of physical activity on neurobiology, brain morphology, and neuropsychiatric outcomes from non-ICU populations and then discuss the implications of these findings for ICU patients. Data regarding the mechanisms and neuropsychiatric effects of physical activity in non-ICU populations are outside the domain of most critical care providers; however, these results are needed to inform future critical care research and stimulate investigation in this area.
There is extensive mechanistic research evaluating the impact of physical activity on the brain. There are several neural mechanisms that are augmented by physical activity, including angiogenesis, neurogenesis, and release of neurotrophic factors (insulin-like growth factor-I (IGF-I), brain-derived neurotrophic factor (BDNF), and neuroplasticity.
Angiogenesis is crucial for delivery of oxygen and glucose to the brain and for recovery after neural injury (16). Angiogenic growth factors, such as vascular endothelial growth factor (VEGF) and angiopoietin 1 and 2, increase with physical activity (Table 1) (16, 17). In studies of rats and nonhuman primates, physical activity is associated with increased capillary growth and greater capillary density (18–20). As little as 1 week of exercise significantly increases angiopoietin 1 and 2 and VEGF, whereas 3 weeks of exercise increases capillary density (17). Mechanistically, physical activity increases precursors of angiogenesis, and this leads to new blood vessel formation.
| Study | Sample Characteristics | n | Significant Findings/Conclusions |
| Angiogenesis | |||
| Ding and colleagues, 2004 (17) | Rats exercised for 30 min/d for 1, 3, or 6 wk | 44 | Increased mRNA expression of angiopoietin 1 & 2; increased VEGF and increased density in micro blood vessels after 3 wk |
| Black and colleagues, 1990 (18) | Rats exercised for 30 d | 38 | Increased blood vessel density in exercise group |
| Swain and colleagues, 2003 (19) | Rats using running wheel for 1 mo | 28 | Increased cerebral blood volume and capillary growth in motor cortex |
| Rhyu and colleagues, 2010 (20) | Primates exercised on a treadmill for 1 h/d, 5 d/wk for 5 mo | 16 | Increased cortical vascular volumes in motor cortex |
| Neurogenesis | |||
| van Pragg and colleagues, 2005 (21) | Rats using running wheel at will vs. control group without exercise | 33 | Increased learning and cell genesis even in aged mice |
| Luo and colleagues, 2007 (22) | Mice in forced exercise | 29 | Increased new cell survival and improved memory |
| van Praag and colleagues, 1999 (23) | Mice in different exercise conditions | 70 | Enhanced neurogenesis in hippocampus |
| Eadie and colleagues, 2005 (24) | Rats using voluntary running wheel | 23 | Increased number and density of dendritic spines and increased dendritic length in hippocampus |
| Neurotrophic factors and plasticity | |||
| Carro and colleagues, 2001 (25) | Rats and mice using treadmill running with three groups: | NR | In all groups exercise improved recovery and prevents and protects the brain through increased uptake of IGF-I; benefits abrogated when IGF-I was blocked |
| Exercise for 2 wk before brain injury | |||
| Exercise for 5 wk after brain injury | |||
| Exercise 2 wk before and 6 wk after brain injury | |||
| Ploughman and colleagues, 2005 (26) | Rats using motorized and voluntary running wheels for 1 wk | 50 | Increased BDNF, synapsin-I, and IGF-I |
| Gomez-Pinilla and colleagues, 2008 (27) | Rats with free access to running wheel vs. sedentary rats | 28 | Increased expression of metabolic proteins in hippocampus |
| Increased BDNF, IGF-I, and ghrelin with enhanced learning | |||
| Abolishing BDNF decreased expression of metabolic proteins and learning | |||
| Vaynman and colleagues, 2004 (28) | Rats with free access to running wheel for 7 d | 28 | Increased BDNF, IGF-I, and synapsin in somatosensory cortex and hippocampus |
| Seifert and colleagues, 2010 (29) | Mice exercised on a treadmill for 5 wk | 8 | Increased BDNF expression in hippocampus, but not in cerebral cortex |
| Ploughman and colleagues, 2007 (30) | Rats using motorized and voluntary running wheels for 2 wk after focal ischemia | NR | Longer duration of elevation of BDNF |
| Griesbach and colleagues, 2004 (31) | Rats with free access to running wheel with two groups: | 161 | Early exercise was associated with impaired learning and memory and no activity-dependent BDNF up-regulation |
| Early exercise 6 d after injury | Late exercise was associated with improved learning and memory and increased BDNF | ||
| Late exercise 14-20 d after brain injury | |||
| Griesbach and colleagues, 2004 (32) | Rats with free access to running wheel | 18 | Exercise during Days 0–6 postinjury caused decreases in BDNF |
| Exercise during Day 4–20 caused increases in BDNF |
Physical activity promotes neurogenesis in brain regions important to neuropsychiatric functioning, such as the hippocampus, and is associated with better learning and memory (Table 1) (21–23). Specifically, physical activity increases new neuronal survival (21, 22), cell proliferation in the hippocampus (23), and dendritic spine density and dendritic length (24). In rats allowed free access to a running wheel, neurogenesis in the hippocampus is associated with enhanced learning and memory (21), even in the setting of preexisting neuronal damage and old age. Increased neurogenesis and cell survival are associated with improved memory (22). These data suggest that physical activity increases neurogenesis, with associated improved cognitive function.
Neurotrophic factors such as BDNF, IGF-I, synapsin-I, and ghrelin increase with exercise and support the survival of existing neurons while enhancing synaptic density and plasticity through growth and differentiation of new neurons (Table 1) (25–29). Because inhibition of BDNF prevents enhanced learning, it is likely that BDNF increases observed during physical activity explain enhanced cognitive function after exercise (25, 27). Even moderate exercise for a short duration increases BDNF, synapsin-I, and IGF-I in the somatosensory cortex and hippocampus (26, 28), whereas less intense and more frequent exercise is associated with prolonged BDNF increases (30).
Exercise after brain injury increases BDNF, but this increase may be time sensitive. Exercise is associated with a longer duration of BDNF elevation when initiated 2 weeks after ischemic brain injury (30). In contrast, early exercise (< 2 wk after injury) is associated with decreased BDNF and impaired learning (31, 32). Physical activity is associated with higher levels of BDNF, IGF-I, and synapsin-I that promote synaptic plasticity and improve learning and memory. Based on these animal studies, the timing of exercise in brain injury may be important for optimal remodeling.
In summary, animal models provide important data regarding the neurobiology of the cognitive benefits of physical activity, including mechanisms of angiogenesis, neurogenesis, and release of neurotrophic factors that enhance plasticity.
Normal aging is associated with decreased brain volumes, loss of cerebral vasculature, and increased vessel tortuosity that adversely affects neural blood flow (33). Magnetic resonance angiography comparing high versus low aerobic activity groups of elderly healthy adults demonstrates that high activity is associated with a decrease in vessel tortuosity and an increase in the number of small-diameter vessels, resulting in vessel morphology that is similar to younger subjects (34). In the aging brain, exercise is also associated with increased cerebral blood flow, oxygen extraction, and glucose use (35). Positron emission tomography demonstrates that older adults who are physically active have brain activity that is similar to young adults (36).
Normal human aging is a negative modifier of neurogenesis and is associated with cognitive decline. Age-related brain volume loss occurs in the prefrontal, parietal, and temporal cortices and in anterior white matter pathways. Older individuals who engage in aerobic exercise demonstrate the greatest brain volume increase in frontal and parietal white matter (37). Physical activity increases neurogenesis in brain regions associated with memory (e.g., hippocampus) (38, 39), and older adults who exercise have larger hippocampal volumes and better memory, with lower rates of cognitive impairment than those who do not exercise (40–42). Moreover, higher aerobic fitness is associated with better white matter integrity (43, 44). A study of functional magnetic resonance imaging in older adults found increased neuronal activation in the middle frontal gyrus and superior and inferior parietal lobes as a function of better cardiovascular fitness (45). Animal studies indicate increased brain volumes are due to increased capillary number and length (21), neurogenesis (38), and increased number and density of dendritic connections and increased dendritic length (24). In humans, exercise is associated with a brain that has increased blood flow, increased neurogenesis, and larger volumes that are associated with improved cognition.
In normal aging, some cognitive functions (e.g., verbal ability and general knowledge) are maintained, while others, including memory and executive function, may decline (46). Table 2 summarizes representative studies evaluating the relationships between physical activity and cognitive function in human populations. Even in modest amounts, physical activity has a positive effect on cognitive functioning and can prevent age-related decline. In a cross-sectional cohort study of 2,736 older women, the highest levels of daytime movement were associated with better executive function and higher Mini Mental Status Examination (MMSE) scores (47). Longitudinal prospective studies further support that physical activity is associated with less age-related cognitive decline (48). A recent meta-analysis of randomized controlled trials found that exercise in older adults resulted in significantly better executive function, spatial abilities, and mental processing speed (49). Even nonaerobic exercise may improve cognition. A randomized controlled trial of 12 months of resistance training in senior women resulted in improved executive function (50) that was sustained at 12-month follow-up (51). The literature suggests that activity in older adults is associated with sustained cognitive benefits.
| Study | Study Design | Sample Characteristics | n | Type of Exercise | Significant Findings/Conclusions |
| Healthy aging | |||||
| Barnes and colleagues, 2008 (47) | Cross-sectional cohort | Healthy women > 65 yr | 2,736 | Daytime movement assessed by actigraphy for 3 ± 0.8 d | Highest vs. lowest quartile of movement had better executive function and MMSE scores |
| Yaffe and colleagues, 2001 (48) | Prospective cohort with 1- and 8-yr follow-up | Healthy women | 5,925 | Physical activity—blocks walked | Greater baseline walking was associated with less cognitive decline over 8 yr |
| Women in highest vs. lowest quartile of walking were less likely to develop cognitive decline | |||||
| Liu-Ambrose and colleagues, 2010 (50) | Single blind randomized controlled trial | Healthy older women | 155 | 12 mo of exercise; three groups | Both resistance training groups had improved executive function vs. balance and toning group |
| N = 44, Once-weekly resistance training | |||||
| N = 52, Twice-weekly resistance training | |||||
| N = 49, Twice-weekly balance and tone training | |||||
| Davis and colleagues, 2010 (51) | Single blind randomized controlled trial, 1-yr follow-up | Healthy older women | 109 | 12 mo of exercise; three groups | Once-weekly resistance training group had a 15% improvement in executive function vs. the balance and toning group |
| N = 37, Once-weekly resistance training | |||||
| N = 41, Twice-weekly resistance training | |||||
| N = 31, Twice-weekly balance and tone training | |||||
| Dementia and mild cognitive impairment | |||||
| Laurin and colleagues, 2001 (52) | Prospective longitudinal cohort | Healthy older adults | 4,615 | Cognitive function at baseline and followed for 5 yr | At 5-yr follow-up 436 had cognitive impairment and 285 had dementia (baseline cognition was normal in both groups) |
| Higher physical activity levels associated with reduced risk of cognitive impairment, Alzheimer's disease, and dementia of any type | |||||
| Buchman and colleagues, 2012 (53) | Prospective longitudinal cohort | Older adults | 716 | Physical activity was measured continuously for up to 10 d with actigraphy | Higher physical activity was associated with lower risk of Alzheimer's disease and lower rate of cognitive decline in the group that had physical activity |
| Nagamatsu and colleagues, 2012 (54) | Randomized controlled trial | Women with MCI ages 70–80 yr | 77 | Twice-weekly training for 6 mo; three groups | Resistance training had improved executive function and memory vs. balance training |
| N = 26, Resistance training | Resistance training had increased brain activity in the right lingual and occipital–fusiform gyri and the right frontal pole vs. balance training | ||||
| N = 24, Aerobic training | Increased activity in the right lingual gyrus was associated with better memory | ||||
| N = 27, Control subjects, balance and toning training | |||||
| Vreugdenhil and colleagues, 2011 (55) | Randomized controlled trial | Alzheimer's disease in otherwise good health | 40 | Exercise supervised at home for 4 mo vs. no exercise | Increased MMSE and ADL scores in exercise group |
| Baker and colleagues, 2010 (56) | Randomized controlled trial | Sedentary older adults with MCI | 33 | High-intensity aerobic exercise or stretching control group for 6 mo | Improved executive function, attention, mental processing speed, and cognitive flexibility in exercise group |
| Yaguez and colleagues, 2011 (57) | Randomized controlled trial | Alzheimer's disease | 27 | Exercise and movement training for 6 wk | Improvements in attention and memory, and trend for working memory in exercise group |
| N = 15, Exercise | |||||
| N = 12, No exercise | |||||
| Palleschi and colleagues, 1996 (58) | Cohort | Alzheimer's disease | 15 | Moderate-intensity exercise 3 d/wk for 3 mo | Improved attention and MMSE scores |
| Stroke | |||||
| Rand and colleagues, 2010 (64) | Prospective cohort | Older chronic stroke | 11 | Aerobic exercise, stretching and balance for 6 mo | Improved in memory and executive function at 3 mo vs. baseline |
| Improved executive function at 6 mo vs. baseline | |||||
| Quaney and colleagues, 2009 (62) | Randomized controlled trial | Older chronic stroke | 38 | N = 19, Aerobic three times per wk for 8 wk | Improved information processing speed and attention in the aerobic exercise group compared with the stretching group |
| N = 19, Stretching exercises at home for 45 min, three times per wk for 8 wk | |||||
| Ozdemir and colleagues, 2001 (63) | Randomized controlled trial | Stroke patients < 3 mo post-stroke | 60 | N = 30, Intensive inpatient rehabilitation with stretching, range of motion, muscle strengthening, and mobilization for 2 h/d, 5 d/wk for 8 wk | Improved MMSE scores in intensive inpatient rehabilitation group compared with home-based rehabilitation group |
| N = 30, Home-based rehabilitation (bed positioning and exercise) by family member for 2 h/d, 7 d/wk | |||||
| Pyoria and colleagues, 2007 (61) | Randomized controlled trial | Stroke | 80 | N = 40, Activating physiotherapy (progressive strength and endurance training) for 9 mo | Improvements in memory, language, visuospatial function, and attention in the activating physiotherapy group compared with traditional rehabilitation group |
| The first week post-stroke | N = 40, Traditional rehabilitation group (movement and spasticity inhibition) | ||||
| Chronic obstructive pulmonary disease | |||||
| Etnier and Berry, 2001 (65) | Randomized controlled trial with 18-mo follow-up | Older adults | 40 | Walking, strength training, and stretching for 3 mo; randomized to continued exercise or no exercise for an 18-mo total period | After 3 and 18 mo, cognitive function improved vs. baseline for both groups. At 18 mo, cognitive performance did not significantly differ between the short- and long-term exercise groups. |
| Emery and colleagues, 1991 (66) | Prospective cohort | Older adults | 64 | Exercise rehabilitation for 30 d | Improved executive function and mental processing speed, reduced depression and anxiety symptoms |
| Emery and colleagues, 1998 (67) | Randomized controlled trial | Older adults | 79 | N = 29, Exercise with stress management | Exercise with stress management improved cognitive function and reduced anxiety and depression symptoms vs. stress management alone and control group |
| N = 25, Stress management only | |||||
| N = 25, Control group | |||||
| Emery and colleagues, 2003 (68) | Prospective cohort with 1-yr follow-up | Older adults | 28 | Exercise program for 10 wk, then maintain exercise group vs. no exercise group | Individuals who maintained exercise had better mental processing speed vs. the no exercise group |
| Individuals who maintained exercise had fewer symptoms of depression and anxiety vs. the no exercise group | |||||
Physical activity is associated with improved neuropsychiatric function in a variety of diseases, including dementia, stroke, and chronic obstructive pulmonary disease (COPD).
Physical activity is neuroprotective and is consistently shown to reduce the risk for developing cognitive decline and dementia (Table 2). A prospective study evaluating a random sample of 4,615 healthy community-dwelling older adults followed for 5 years demonstrated that physical activity was associated with lower rates of cognitive decline, Alzheimer's disease, and dementia (52). Similarly, higher activity was associated with a reduced risk of developing Alzheimer's disease and a slower rate of cognitive decline (53).
Physical activity also may decrease preexisting cognitive impairment. Patients with mild cognitive impairment randomized to resistance training had improved memory and executive function associated with increased functional neural activity in multiple brain regions (54), suggesting that nonaerobic activity can alter cognitive function in aging. Randomized trials also have demonstrated that even short durations of exercise improve cognitive function in dementia (55, 56). Cognition improved after only 6 weeks of nonaerobic movement programs (57) and after 3 months of aerobic exercise (58). A recent meta-analysis of randomized trials in patients with dementia found that exercise had a moderate effect on cognition (59). This literature demonstrates that in mild cognitive impairment and dementia, physical activity is associated with improved cognition.
A recent meta-analysis of exercise in individuals with stroke provides some evidence that increased physical activity improves cognitive function (Table 2) (60). Three studies demonstrated that patients who exercised or engaged in intensive rehabilitation had improved cognition compared with control groups (Table 2) (61–63). Another study demonstrated that 8 weeks of aerobic exercise improved memory and executive function (64).
In patients with COPD, physical activity improves neuropsychiatric outcomes (Table 2). In a randomized trial, 3 months of exercise was associated with improved cognitive function at 18 months (65). A 30-day physical rehabilitation program was associated with improved executive function, mental processing speed, and fewer symptoms of depression and anxiety (66). In a randomized trial, patients who exercised for 10 weeks had better cognitive function with reduced depression and anxiety symptoms (67). After a 10-week exercise program, patients engaging in a moderate level of physical activity for 1 year after the original program maintained cognitive, psychological, and physical gains initially achieved by exercise, whereas the nonexercise group experienced cognitive decline (68).
There are limited data regarding the benefits of physical activity in other disorders, such as traumatic brain injury and coronary artery disease. In a randomized crossover trial, individuals with traumatic brain injury who participated in exercise for 4 weeks had better attention, learning, and memory and faster mental processing speed than control subjects (69). In a retrospective cohort study, individuals with traumatic brain injury who exercised had fewer cognitive impairments, elevated mood, and a lower level of disability compared with individuals who did not exercise (70). Exercise in individuals with coronary artery disease is associated with increased levels of BDNF, higher MMSE scores, and faster mental processing speed (71, 72). Although limited, the available literature suggests a cognitive benefit of exercise in patients with coronary artery disease and traumatic brain injury.
In summary, studies in both healthy humans and humans with diseases suggest that physical exercise improves neuropsychiatric outcomes.
Critical illness is associated with nonspecific brain injury and neuropsychiatric impairments. Among ICU survivors, the prevalence of cognitive impairment is 30 to 70% during the first year after discharge, up to 45% at 2 years, and 25% at 6 years (73). Two separate longitudinal cohort studies prospectively collecting baseline data before critical illness demonstrated that new cognitive impairments were acquired during critical illness (6, 7). These impairments commonly affect memory, executive functioning, and attention (1), and adversely affect survivors’ daily functioning, ability to return to work, and quality of life (8, 74). To date, rehabilitation studies during and after the ICU have primarily focused on physical morbidities, with little investigation of neuropsychiatric effects or specific neuropsychiatric rehabilitation.
The benefits of early ICU physical rehabilitation include improved physical function, decreased ICU and hospital length of stay, reduced hospital readmission, and decreased mortality 12 months after discharge (14, 75, 76). Although many ICU patients could benefit from rehabilitation, few receive it (8, 77, 78). Moreover, even in ICUs where patients are actively involved in early mobilization, there may be less mobilization delivered than is perceived, and mobilization on wards may be lower than in the ICU (79, 80).
The previously summarized data (Table 2) suggest that physical activity is associated with improved neuropsychiatric function in many disease states. Currently, little research evaluates whether early physical rehabilitation in the ICU will similarly benefit survivors. A recent randomized trial demonstrated that early ICU-based physical rehabilitation significantly improved physical function and reduced delirium duration (14), a gross measure of cognitive impairment, by 50%. The reduced duration of delirium was likely due to physical and occupational therapy rather than sedation effects, as sedation use was very similar in both groups. The effects of such ICU interventions on post-ICU neurocognitive function are important for future research.
As previously noted, duration of delirium in the ICU is independently associated with long-term cognitive impairments (11, 81). Interventions that may reduce the duration of delirium, such as early ICU rehabilitation, have the potential to improve neuropsychiatric outcomes. Early ICU rehabilitation is an ideal candidate intervention because it has demonstrated safety and feasibility and is associated with reduced morbidity and mortality post-ICU (14, 75, 76, 82, 83). There are at least two ongoing randomized trials studying the neuropsychiatric effects of ICU rehabilitation. A group at Vanderbilt University is conducting a phase II trial of early physical and cognitive rehabilitation in the ICU that evaluates short- and long-term effects on neuropsychiatric outcomes (84). This trial has three randomized patient groups: usual care, once-daily physical rehabilitation, or once-daily physical rehabilitation plus twice-daily cognitive rehabilitation. Participants with cognitive impairment at hospital discharge will undergo 12 weeks of in-home cognitive rehabilitation (84). Study outcomes include executive and cognitive functioning at 3 months and health-related quality of life at 3 and 12 months (84).
A second trial by a group at University of Chile is evaluating the effect of early occupational therapy for delirium prevention in older ICU patients (Clinicaltrials.gov: NCT01555996). An intensive multifaceted rehabilitation program (positioning, upper limb motor stimulation, training in activities of daily living, sensory stimulation, cognitive stimulation [e.g., awareness, orientation, attention, memory, calculation, praxis, and language], and family involvement) is being compared with a nonpharmacologic delirium prevention program (including orientation, correcting sensory impairment [e.g., glasses, hearing aids], and environmental management [e.g., calendar, sleep protocol, minimizing medications]). Study outcomes include delirium duration and incidence, functional independence, grip strength, and cognitive function evaluated at Day 7 and hospital discharge.
The results of these studies may provide additional information about the effects of physical activity and cognitive rehabilitation on neuropsychiatric function and further encourage intensive rehabilitation.
Two small randomized trials studies have evaluated the effect of 6 weeks of physical rehabilitation on cognitive function in patients with prolonged mechanical ventilation (> 14 d). The first trial (n = 32) demonstrated improved cognitive function (20% increase) and improved physical function in the treatment group versus a 32% decline in cognitive function in the control group (85). The second trial (n = 34) demonstrated an increased survival rate (78 versus 25%) and significantly improved cognitive function in the exercise versus control group (86). In this study, the mean Functional Independence Measurement cognitive domain score (maximum score = 35) significantly improved from 13.5 at 6 months to 33.5 at 1 year in the exercise group (86), which was significantly higher than control subjects, who did not improve. Although both of these trials have significant limitations, including small sample size and limited evaluation of cognitive function, these studies raise interest for evaluating physical exercise for improving cognitive function in ICU patients.
In patients with acute critical illness, there is only one published study of physical and cognitive rehabilitation after hospital discharge (87). In this phase II trial, survivors were randomized to either usual care or to 12 weeks of physical rehabilitation via two-way video teleconference and cognitive rehabilitation via in-person visits. At 3-month follow-up, the rehabilitation group had improved executive function and better instrumental activities of daily living versus control subjects (87). Unfortunately, in this study, the isolated effect of physical rehabilitation on neuropsychiatric outcomes cannot be evaluated because physical and cognitive rehabilitation were administered concurrently.
Despite evidence supporting the benefits of early ICU rehabilitation, there are barriers to its implementation in routine care. Sedation negatively affects neuropsychiatric outcomes and limits participation in active rehabilitation (78, 88) and is associated with poor neuropsychiatric outcomes (11, 89, 90). Reducing sedation and delivering early rehabilitation may have synergistic benefits, especially if bundled with other evidence-based practices (89).
Another important barrier is a lack of awareness of post-ICU cognitive impairments among clinicians, survivors, families, and payers (91). Awareness regarding the importance of early ICU rehabilitation may promote interdisciplinary care between critical care and physical medicine and rehabilitation specialists (92). Greater awareness that rehabilitation must continue across the continuum of care, including ICU discharge to the wards and home, is important (80, 93). In addition, increased federal funding for rigorous research evaluating ICU survivors’ outcomes and related interventions is needed (91, 94). To improve ICU survivors’ neuropsychiatric outcomes, all stakeholders must view these and other barriers as surmountable and become facilitators of rehabilitation, starting early in the ICU and throughout the care continuum (92).
Studies are needed to assess the effects of physical activity in ICUs. Data in other populations (Table 2) indicate physical exercise can improve attention, learning, memory, general intellectual function, executive function, and mental processing speed and reduces depression and anxiety. Therefore, outcomes for future research should include cognitive function across a range of domains known to be impaired after critical illness, including attention, learning, memory, executive function, mental processing speed, and general intellectual function. Psychiatric outcomes, including depression, anxiety, and posttraumatic stress disorder, also should be assessed. There is no consensus regarding what measures best assess neuropsychiatric outcomes, and a review of outcome measures is beyond the scope of this manuscript (see Jackson and colleagues, 2003 [95]).
Assessing preillness physical activity and its effect on outcomes is also clearly important. It is unclear whether the type of physical rehabilitation is equally effective in all clinical circumstances and if it will have similar effects on cognitive and psychiatric morbidities. There is limited understanding of the effects of physical rehabilitation after the ICU due to variable methods and lack of information regarding exercise prescription (96). The optimal timing of physical rehabilitation in critically ill patients is unclear. Establishing biologically plausible mechanisms between physical activity (e.g., neurotransmission, muscular weakness, attenuation of inflammation, relationship to genetics, etc.) and neuropsychiatric morbidity is of crucial importance.
It is also important to extrapolate previous animal studies to possible implications in humans. Some previously summarized animal studies suggest that very early rehabilitation in ischemic brain injury may disrupt neuroplasticity and impair recovery (31, 32). However, a randomized trial of early ICU rehabilitation started within a median of 1.5 days after initiating mechanical ventilation demonstrated improved physical outcomes and reduced delirium duration. These observed benefits in medical ICU patients may outweigh the potential disadvantages observed in the animal models of ischemic brain injury (14). Ideally, a greater ability to actively monitor brain perfusion and neurological activity during critical illness would be invaluable.
The question of whether future studies should evaluate the impact of early physical rehabilitation alone versus combined physical and cognitive rehabilitation is unclear. Studies with three arms (physical rehabilitation only, combined physical and cognitive rehabilitation, and control) may help answer this question but would require larger sample sizes than a two-arm randomized trial. Finally, future investigation should further evaluate whether patients can be rehabilitated in their homes, perhaps using telemedicine techniques, to improve access, adherence, and cost (87).
Physical activity increases resistance to brain injury, facilitates synaptic transmission, increases neurotransmitter release, promotes neurogenesis and angiogenesis, improves cognitive function, and decreases depression and anxiety symptoms. Critically ill patients are at risk for long-term neuropsychiatric morbidities that might be attenuated with early rehabilitation in the ICU. Further research is necessary to rigorously evaluate whether prior animal and human research, and preliminary results from existing ICU studies, can translate into improvements for neuropsychiatric outcomes of critically ill patients.
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Originally Published in Press as DOI: 10.1164/rccm.201206-1022CP on October 11, 2012
Author disclosures are available with the text of this article at www.atsjournals.org.
