American Journal of Respiratory and Critical Care Medicine

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 (14). 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 (1820). 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.


StudySample CharacteristicsnSignificant Findings/Conclusions
 Ding and colleagues, 2004 (17)Rats exercised for 30 min/d for 1, 3, or 6 wk44Increased 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 d38Increased blood vessel density in exercise group
 Swain and colleagues, 2003 (19)Rats using running wheel for 1 mo28Increased 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 mo16Increased cortical vascular volumes in motor cortex
 van Pragg and colleagues, 2005 (21)Rats using running wheel at will vs. control group without exercise33Increased learning and cell genesis even in aged mice
 Luo and colleagues, 2007 (22)Mice in forced exercise29Increased new cell survival and improved memory
 van Praag and colleagues, 1999 (23)Mice in different exercise conditions70Enhanced neurogenesis in hippocampus
 Eadie and colleagues, 2005 (24)Rats using voluntary running wheel23Increased 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:NRIn 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 wk50Increased BDNF, synapsin-I, and IGF-I
 Gomez-Pinilla and colleagues, 2008 (27)Rats with free access to running wheel vs. sedentary rats28Increased 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 d28Increased BDNF, IGF-I, and synapsin in somatosensory cortex and hippocampus
 Seifert and colleagues, 2010 (29)Mice exercised on a treadmill for 5 wk8Increased 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 ischemiaNRLonger duration of elevation of BDNF
 Griesbach and colleagues, 2004 (31)Rats with free access to running wheel with two groups:161Early exercise was associated with impaired learning and memory and no activity-dependent BDNF up-regulation
 Early exercise 6 d after injuryLate 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 wheel18Exercise during Days 0–6 postinjury caused decreases in BDNF
Exercise during Day 4–20 caused increases in BDNF

Definition of abbreviations: BDNF = brain-derived neurotrophic factor; IGF-I = insulin-like growth-I factor; NR = not reported; VEGF = vascular endothelial growth factor.


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) (2123). 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 and Plasticity

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) (2529). 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 (4042). 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.

Neuropsychiatric Effects of Physical Activity in Normal Human Aging

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.


StudyStudy DesignSample CharacteristicsnType of ExerciseSignificant Findings/Conclusions
Healthy aging
 Barnes and colleagues, 2008 (47)Cross-sectional cohortHealthy women > 65 yr2,736Daytime movement assessed by actigraphy for 3 ± 0.8 dHighest 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-upHealthy women5,925Physical activity—blocks walkedGreater 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 trialHealthy older women15512 mo of exercise; three groupsBoth 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-upHealthy older women10912 mo of exercise; three groupsOnce-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 cohortHealthy older adults4,615Cognitive function at baseline and followed for 5 yrAt 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 cohortOlder adults716Physical activity was measured continuously for up to 10 d with actigraphyHigher 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 trialWomen with MCI ages 70–80 yr77Twice-weekly training for 6 mo; three groupsResistance training had improved executive function and memory vs. balance training
 N = 26, Resistance trainingResistance training had increased brain activity in the right lingual and occipital–fusiform gyri and the right frontal pole vs. balance training
 N = 24, Aerobic trainingIncreased 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 trialAlzheimer's disease in otherwise good health40Exercise supervised at home for 4 mo vs. no exerciseIncreased MMSE and ADL scores in exercise group
 Baker and colleagues, 2010 (56)Randomized controlled trialSedentary older adults with MCI33High-intensity aerobic exercise or stretching control group for 6 moImproved executive function, attention, mental processing speed, and cognitive flexibility in exercise group
 Yaguez and colleagues, 2011 (57)Randomized controlled trialAlzheimer's disease27Exercise and movement training for 6 wkImprovements in attention and memory, and trend for working memory in exercise group
 N = 15, Exercise
 N = 12, No exercise
 Palleschi and colleagues, 1996 (58)CohortAlzheimer's disease15Moderate-intensity exercise 3 d/wk for 3 moImproved attention and MMSE scores
 Rand and colleagues, 2010 (64)Prospective cohortOlder chronic stroke11Aerobic exercise, stretching and balance for 6 moImproved 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 trialOlder chronic stroke38N = 19, Aerobic three times per wk for 8 wkImproved 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 trialStroke patients < 3 mo post-stroke60N = 30, Intensive inpatient rehabilitation with stretching, range of motion, muscle strengthening, and mobilization for 2 h/d, 5 d/wk for 8 wkImproved 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 trialStroke80N = 40, Activating physiotherapy (progressive strength and endurance training) for 9 moImprovements in memory, language, visuospatial function, and attention in the activating physiotherapy group compared with traditional rehabilitation group
The first week post-strokeN = 40, Traditional rehabilitation group (movement and spasticity inhibition)
Chronic obstructive pulmonary disease
 Etnier and Berry, 2001 (65)Randomized controlled trial with 18-mo follow-upOlder adults40Walking, strength training, and stretching for 3 mo; randomized to continued exercise or no exercise for an 18-mo total periodAfter 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 cohortOlder adults64Exercise rehabilitation for 30 dImproved executive function and mental processing speed, reduced depression and anxiety symptoms
 Emery and colleagues, 1998 (67)Randomized controlled trialOlder adults79N = 29, Exercise with stress managementExercise 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-upOlder adults28Exercise program for 10 wk, then maintain exercise group vs. no exercise groupIndividuals 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

Definition of abbreviations: ADL = activities of daily living; MCI = mild cognitive impairment; MMSE = Mini-Mental Status Exam.

Neuropsychiatric Effects of Physical Activity in Human Disease

Physical activity is associated with improved neuropsychiatric function in a variety of diseases, including dementia, stroke, and chronic obstructive pulmonary disease (COPD).

Dementia and mild cognitive impairment

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) (6163). 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).

Other disorders

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.

Rehabilitation in the ICU

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 ( 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.

Rehabilitation after the ICU

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.

Barriers to Rehabilitation in Critically Ill Patients

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).

Areas for Future Investigation

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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Correspondence and requests for reprints should be addressed to Ramona O. Hopkins, Ph.D., Department of Medicine, Pulmonary and Critical Care Division, Intermountain Medical Center, Murray, UT 84107. E-mail:

Originally Published in Press as DOI: 10.1164/rccm.201206-1022CP on October 11, 2012

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