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S Mathur, PT, MSc, is a doctoral student in the School of Human Kinetics, University of British Columbia, T325-2211 Wesbrook Mall, Vancouver, British Columbia, Canada V6T-2B5 (smathur{at}interchange.ubc.ca)
WD Reid, PT, PhD, is Associate Professor, School of Rehabilitation Sciences, University of British Columbia
RD Levy, MD, FRCPC, is Head, Division of Respirology, St Paul's Hospital, Vancouver, British Columbia, Canada; Medical Director, Lung Transplant Program, British Columbia Transplant Society; and Associate Professor of Medicine, University of British Columbia
Address all correspondence to Ms Mathur
Key Words: Exercise physiology • Muscles, skeletal • Transplantation
 | Introduction |
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O2peak) was 46% of predicted values in the SLT group and 50% of predicted values in the DLT group. At 1 to 2 years after transplantation, there was no improvement in maximal oxygen consumption (O2max) or maximal work capacity in either group, despite improvements in lung function and return to regular activities (ie, school or work) in most of the recipients of transplants. Evans et al3 compared whole-body exercise (cycling) in 9 recipients of SLT who were 5 to 38 months after transplantation versus a control group of subjects without known pathology or impairments. Measurements of O2peak taken during cycling were reduced in the SLT group compared with the control group (P<.001) and were only 36.8%±3.1% (
±SD) of predicted values in the SLT group. This reduction in exercise capacity poses an interesting challenge to physical therapists. An understanding of the potential factors contributing to exercise limitation in this population, therefore, is imperative to prescribing an exercise program that emphasizes the appropriate body systems and leads to improvement in functional capacity of these people.
There are a number of factors that may limit maximal exercise in recipients of lung transplants, including abnormal ventilatory limitation, cardiac and peripheral vascular factors, and impaired oxidative capacity of peripheral skeletal muscle (Table, Figure). A growing body of evidence points to the role of lower-limb skeletal muscle dysfunction following lung transplantation as the major factor in exercise limitation. This evidence is consistent with the observation that the majority of recipients of lung transplants report lower-extremity fatigue rather than dyspnea as the reason for terminating maximal exercise on a cycle ergometer.2 Using phosphorus magnetic resonance spectroscopy (31P-MRS), Evans et al3 found that recipients of SLT (n=9) demonstrated a lower resting pH of the quadriceps femoris muscle and an earlier drop in pH during bilateral knee extension exercise to exhaustion. In addition, the work rate at which pH fell was correlated with whole-body O2peak. These findings suggest that an intrinsic abnormality of the skeletal muscle may exist in recipients of transplants and may play a role in exercise limitation. Lands et al4 reported that in 9 recipients of SLT and 10 recipients of DLT, most of whom were over 18 months after transplantation, maximal work capacity on a cycle ergometer was most strongly correlated with 30-second work capacity during isokinetic cycling (r=.84), rather than with pulmonary function variables such as forced expiratory volume in 1 second (FEV1) (r=.58) and residual volume/total lung capacity (RV/ TLC) (r=–.52). In addition, the pretransplant condition (ie, COPD) is associated with skeletal muscle abnormalities that contribute to exercise limitation, and these changes may persist following lung transplantation.5 These changes include reduced muscle mass and muscle fiber atrophy, muscle weakness and increased fatigability, a decrease in the proportion of type 1 muscle fibers, and increased reliance on anaerobic metabolism.5
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| Ventilatory Limitation to Exercise |
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 TopIntroduction Ventilatory Limitation to... Cardiac Limitation to ExercisePeripheral Limitation to...Effect of Immunosuppressant...Implications for RehabilitationReferences |
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O2peak, minute ventilation was reported to reach 46.8% of maximum voluntary ventilation (MVV) at peak exercise in recipients of SLT (n=6) and 33.4% of MVV in recipients of DLT (n=6).7 Oxygen saturation was maintained close to resting values in both groups. At rest, mean arterial oxygen saturation (SaO2) was 97.2% in both groups and dropped to 94.3% in recipients of SLT and 96.7% in recipients of DLT at maximal exercise. Similarly, Levy et al8 reported that peak ventilation during incremental cycling reached 53.7% of MVV in recipients of DLT (n=6), 47.9% of MVV in recipients of SLT with pre-existing obstructive lung disease (n=10) and 70.1% of MVV in recipients of SLT with pre-existing restrictive lung disease (n=6).8 Oxygen saturation at peak exercise ranged from 96.7% in the DLT group to 90.1% in the SLT (restrictive) group. The results of these studies suggest that exercise stops at a level that is well below maximal ventilation and that changes in oxygen saturation are minimal and remain well above 90%. Therefore, these ventilatory factors are unlikely to contribute to exercise limitation in recipients of lung transplants.7,8
Ventilatory response to exercise, as reflected by breathing pattern, theoretically could be disrupted due to denervation of the lungs or alterations in respiratory system mechanics following transplantation. However, ventilatory response during exercise appears to be relatively unaffected in lung transplant recipients. Sciurba et al9 compared ventilatory response during maximal exercise between heart transplant recipients, who have cardiac denervation but intact pulmonary innervation, and recipients of heart-lung transplants (HLT), who have both cardiac and pulmonary denervation. Both groups showed an equivalent level of ventilation at a given level of carbon dioxide production, although the HLT group showed a more brisk rise in tidal volume and a slower rise in respiratory rate. The authors9 suggested that peripheral input may be necessary to modulate the pattern of breathing but that central neural mechanisms are responsible for the level of ventilation in relation to carbon dioxide levels. Kimoff et al10 reported that recipients of HLT compared with people without known pathology or impairments demonstrate an appropriate level of ventilation for a given concentration of carbon dioxide and similar ratings of dyspnea for similar levels of minute ventilation with maximal exercise.10 During steady-state submaximal exercise at 50% of O2peak, recipients of HLT also demonstrated a ventilatory response that was not different from that of controls.11 These findings suggest that pulmonary-mediated feedback may play a role in regulating the pattern of ventilation, but that minute ventilation and dyspnea are likely centrally controlled and do not prematurely limit exercise in individuals with pulmonary denervation.
| Cardiac Limitation to Exercise |
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O2). This response may be a result of impaired delivery of oxygen to the periphery due to inadequate cardiac response with exercise. Hemo-dynamic response to incremental exercise was measured in 9 recipients of HLT (33±15 months [±SD] after transplantation).12 The subjects' O2peak was 61%±8% (±SD) of predicted values. Peak ventilation reached 51% of predicted MVV, and all subjects stopped exercising due to lower-extremity fatigue. As expected with cardiac denervation, heart rate showed a slow initial increase and a delayed return to baseline levels upon termination of exercise. Stroke volume increased initially but reached a plateau at 40% of the predicted maximal workload, reaching 47 mL/m2. Cardiac output doubled from the resting values, but most of the increase occurred in the initial phase of exercise, between rest and 40% of the maximal predicted workload. The results of this study showed an impairment of both inotropic and chronotropic responses to exercise in recipients of HLT. These impairments were likely due to denervation of the transplanted heart and partially accounts for the reduced exercise capacity of these patients.12,13
In recipients of lung transplants, heart rate has been shown to increase as predicted during incremental cycling exercise and to reach an adequate level (60%–70% of age-predicted maximum) to meet the demands of the final workload of the exercise test.2,7 Ross et al14 used Swan-Ganz catheters and thermodilution to directly measure stroke volume during peak exercise in 8 patients (7 recipients of SLT and 1 recipient of DLT) before and 6 to 12 months after lung transplantation. Following transplantation, these patients participated in an outpatient exercise program 3 times per week for 6 to 8 weeks and were encouraged to maintain their physical activity following the exercise program. These patients had reduced O2peak before transplantation (29%±3% [±SD] of predicted values), and their O2peak remained lower than predicted after transplantation (42%±2% [±SD]). Lactate threshold, as determined by the inflection point of arterial lactate versus O2, occurred at 27%±2% (±SD) of O2peak, indicating an early onset of anaerobic metabolism. Maximal stroke volume was higher following lung transplantation compared with the pretransplant condition (51±4 versus 37±2[±SD] mL/beat/m2) and was sufficient to maintain the maximal workload attained. Therefore, a possible reduction in stroke volume following lung transplantation cannot explain the early onset of the lactate threshold and lower O2peak.14 Although recipients of HLT experience reduced heart rate and stroke volume due to cardiac denervation, cardiac function following lung transplantation is sufficient for their level of exercise and does not prematurely limit maximal exercise in this group.
| Peripheral Limitation to Exercise |
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Similar to findings in patients with COPD, the quadriceps femoris muscles of recipients of lung transplants show reduced oxidative capacity. Wang et al16 examined biopsies from the vastus lateralis muscle in 7 recipients of lung transplants (2 with SLT, 4 with DLT, and 1 with HLT) 3 to 24 months after transplantation and compared them with 7 control subjects matched for age and sex. The muscle from transplant recipients had a lower proportion of type I (oxidative) fibers (24.9%±4.4% [±SD] versus 56.1%±2.4% [±SD]), lower oxidative enzyme activity (ie, citrate synthase, 3-hydroxyacyl-CoA dehydrogenase), and higher activity of the glycolytic enzyme, phosphofructokinase, compared with that of matched controls. The findings of reduced muscle oxidative capacity are in line with the consistent observation of a reduced O2peak and early onset of lactic acidosis observed in recipients of lung transplants.16 Morton et al17 showed that the reduction in proportion of type I muscle fibers and oxidative enzymes of the quadriceps femoris muscle also was present before transplantation in 18 candidates for lung transplant compared with controls. These patients had severe, end-stage lung disease and a primary diagnosis of COPD (n=8), bronchi-ectasis (n=5), cystic fibrosis (n=3), pulmonary fibrosis (n=1), and Eisenmonger syndrome (n=1). Three months after transplantation, a second muscle biopsy was taken in 13 of these patients and no change was observed in oxidative capacity or proportion of type I muscle fibers compared with the pretransplant condition. The results of this study suggest that, although changes in muscle oxidative capacity are seen following lung transplantation, these changes may be a reflection of changes in muscle that occur in the pretransplant condition.
Skeletal muscle metabolism has been examined in recipients of lung transplants with a nuclear imaging technique, 31P-MRS. This technique measures the concentration of phosphocreatine (PCr) and inorganic phosphate (Pi), from which pH of the exercising muscle can be calculated. Using 31P-MRS, Evans et al3 demonstrated that recipients of lung transplants (5–38 months after transplantation) had a greater decline in PCr/Pi, greater increases in lactate concentrations, and lower resting intracellular pH of the quadriceps femoris muscle, which dropped at a lower metabolic rate with incremental bilateral lower-extremity exercise. The early drop in pH was associated with a shorter exercise endurance time and lower O2peak in recipients of transplants. These findings indicate a greater reliance on anaerobic metabolism and may be a result of poor uptake or utilization of oxygen by the muscle.
Tirdel et al18 suggested that recipients of lung transplants have a defect at the level of the mitochondria that results in a reduced ability for working muscle to extract oxygen. Four recipients of SLT and 2 recipients of DLT underwent near-infrared spectroscopy (NIRS) in conjunction with a standard exercise test to examine peripheral oxygen uptake of the quadriceps femoris muscle. The recipients of transplants were tested 5 to 28 months after transplantation and were compared with an ageand sex-matched control group. With NIRS, the change in the combined hemoglobin and myoglobin concentration compared with a stable baseline level (ie, rest) is measured and reflects the balance between oxygen delivery and utilization by the working tissue.19 In the study by Tirdel et al,18 recipients of lung transplants demonstrated less oxygen desaturation at the level of the vastus lateralis muscle during peak cycling exercise compared with controls, indicating an impaired ability of the muscle to uptake and utilize the available oxygen.
Reduced systemic oxygen extraction, measured from arterial-venous oxygen content during incremental exercise, also has been reported in patients with cystic fibrosis and COPD before and after lung transplantation.15,20 Oelberg et al15 compared arterial-venous oxygen content difference during incremental cycling exercise as an indication of the muscle's ability to extract oxygen during exercise. Ten recipients of DLT were tested before and 16±4 months (±SD) after transplantation and compared with an age-matched control group. All recipients of transplants had pre-existing cystic fibrosis. In the pretransplant condition, systemic oxygen extraction was reduced throughout incremental exercise compared with the control group, indicating poor oxygen extraction. There was an improvement in O2peak after transplantation compared with before transplantation (31%±3% [±SD] of predicted pretrans-plant values versus 45%±5% [±SD] of predicted post-transplant values), but O2peak remained reduced in the DLT group compared with the control group. The ability of the muscle to extract oxygen also remained depressed after transplantation in the DLT group compared with the control group and was not different from that of their pretransplant condition (7.1±1.2 mL/dL [±SD] before transplantation compared with 9.3±0.9 mL/dL [±SD] after transplantation). These results suggest that the ability of working skeletal muscle to extract oxygen is impaired in the pretransplant condition and does not improve after transplantation.15
Similar findings have been reported in recipients of SLT with pre-existing COPD.20 Twelve patients with COPD who were awaiting lung transplantation underwent an incremental cycle ergometer test to exhaustion during which arterial-venous oxygen content were measured. The test was repeated 3 to 6 months after transplantation in 8 patients. Following transplantation, improvements in resting pulmonary function and maximum work rate were achieved on the cycle ergometer; however, O2peak remained diminished at 47%±4% [±SD] of predicted values. Peak exercise oxygen extraction also remained low following transplantation, despite normal hemoglobin levels and oxygen saturation. As all other physiologic measurements related to respiratory and cardiovascular factors were normal, the authors attributed the abnormal oxygen extraction to intrinsic metabolic abnormalities of skeletal muscle.
Reduced adenosine triphosphate (ATP) concentrations and increased inosine monophosphate concentrations have been observed in muscle biopsy samples from the vastus lateralis muscle of recipients of lung transplants.16 Inosine monophosphate, a product of adenosine mono-phosphate deamination, is not detectable at rest in people without known pathology or impairments. Its presence in the resting muscle of recipients of transplants indicates an imbalance of ATP resynthesis and utilization (ie, a greater rate of utilization compared with resynthesis) and may be a result of reduced substrate availability or a deficit in mitochondrial function.16,21,22 Wang et al16 also showed a lower mitochondrial ATP production rate (corrected for mitochondrial protein content), suggesting that a defect in mitochondrial function is present. Possible causes of impaired mitochondrial function include the effect of immunosuppressant medications or severe deconditioning.
| Effect of Immunosuppressant Medications and Deconditioning on Skeletal Muscle Function |
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Skeletal muscle myopathy associated with chronic corticosteroid use has been well documented and results in muscle fiber atrophy, predominantly affecting type II fibers.5 Long-term use of corticosteroids has been associated with proximal-limb muscle weakness and selective type II fiber atrophy in peripheral muscle and the diaphragm.23,27 Histologic analysis of steroid-induced myopathy of the quadriceps femoris muscle revealed a number of abnormalities, including increased variation of fiber size and presence of angulated fibers, centrally located nuclei, and basophilic staining fibers.23 These changes may be related to a reduction in the force-generating capacity of the muscle or increased susceptibility to fatigue. In patients with COPD, reductions in quadriceps femoris muscle force and respiratory muscle force have been observed and correlate with the average daily dose of corticosteroids.24
The immunosuppressant agent cyclosporine has been shown to impair mitochondrial function. Animal studies have shown that cyclosporine in therapeutic doses can decrease the capacity of the electron transport chain (a source of ATP production during oxidative metabolism) by blocking a calcium-dependent pore in the inner mitochondrial membrane, thus affecting calcium efflux from the mitochondria and impairing mitochondrial respiration.25 This impairment in calcium transport may lead to an inability of working muscle to utilize oxygen and an early shift toward glycolytic metabolism, especially during exercise, resulting in limited exercise capacity.25,26 Mercier et al26 reported that the impairment in mitochondrial respiration was associated with reduced endurance time in treadmill running in rats given cyclosporine. Similarly, tacrolimus, which is also a calcineurin inhibitor and is prescribed instead of cyclosporine for many recipients of lung transplants, may have similar effects in muscle.1 Cyclosporine also may cause chronic anemia in some recipients of transplants, resulting in reduced oxygen-carrying capacity of blood.13 However, anemia likely has a minimal effect on O2peak during exercise because hemoglobin levels are normal or only mildly reduced in most patients, and reduced O2peak is seen in recipients of transplants.8,14
In addition to changes associated with medications, recipients of transplants are exposed to a period of reduced muscle activity from bed rest and low levels of physical activity due to pretransplant illness and during their recovery period. Models of decreased muscle use in humans, such as that occurring during immobilization and exposure to microgravity, have demonstrated profound muscle atrophy and changes in metabolic capacity of muscle, especially in muscles of the lower limb.28 Therefore, reduced activity also may account for changes seen in muscle following transplantation and may contribute to reduced muscle mass, force, and oxidative capacity.28,29 The reader is referred to 2 excellent reviews5,30 for a full discussion of factors that may contribute to poor muscle function in patients with COPD.
| Implications for Rehabilitation |
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Despite improved scores on the physical function sub-scales of health status questionnaires after lung transplantation, scores remain lower than normative values.35,36 Frequently occurring symptoms related to functional limitation such as shortness of breath, muscle weakness, and fatigue have been reported; these symptoms have been reported to cause moderate to extreme distress in 20% to 40% of 48 subjects after transplantation (average [±SD]=1.5±0.7 years).37 Symptom distress associated with changes in body appearance was greater in women than in men.37 Recipients of SLT and individuals with a pretransplant diagnosis of COPD expressed greater symptom distress related to shortness of breath during activity and muscle weakness.37 Recipients of lung transplants with a pretransplant diagnosis of cystic fibrosis tended to report the lowest levels of symptom distress.37
Greater deficits in perceived physical function and increased symptoms are usually shown in recipients of SLT compared with recipients of DLT. Further, those individuals who develop bronchiolitis obliterans show even further reductions in self-perceptions of energy and physical mobility.38 Signs and symptoms of physical limitation have been attributed to deconditioning and immunosuppressant therapy18; however, cause and effect and proportionate contribution of the perioperative interventions have not been established. Specific limitations in activities of daily living that require different muscle groups (upper versus lower extremity, proximal versus distal musculature, ventilatory muscles) have not been identified. Furthermore, whether impairment in physical function can be prevented, minimized, and reversed is not known. Exercise training following transplantation may result in physiological adaptations, such as improved skeletal muscle function, which may improve physical functioning and quality of life. Only a few studies,39,40 however, have examined exercise training adaptations in recipients of lung transplants.
In sedentary individuals, aerobic exercise training results in skeletal muscle adaptations, including a shift in fiber-type proportion from type II to type IIa fibers, increased concentration of oxidative enzymes, increased capillarization, and increased mitochondrial density.41 Few studies have examined the effects of exercise training following lung transplantation.
Ambrosino et al40 studied the effect of an inpatient exercise training program in 10 recipients of HLT who were 45±23 days (±SD) after discharge from transplant surgery. The subjects underwent 2 daily, 30-minute sessions of treadmill walking at 70% of maximum workload achieved on an incremental exercise test. Inspira-tory muscle training was done for 10 minutes, 4 times per day, using a Threshold trainer* at a resistance of 50% of maximal inspiratory pressure. The program also included abdominal exercises and upper- and lower-extremity weight training. The frequency, intensity, and type of exercises used in the weight training program were not described. The duration of the program ranged from 20 to 70 days ( [±SD]=41±19 days), and no formal home exercise program was provided upon discharge. Maximal exercise capacity, 6-minute walk test distance, maximal inspiratory and expiratory pressure (measures of respiratory muscle force), and lower-extremity muscle force were measured before and after training and at 6, 12, and 18 months after discharge.
The authors40 noted no improvements in muscle force or peak exercise capacity following exercise training, which may have been due to the residual effects of the perioperative period or insufficient progression of training intensity. They noted that the subjects participated in the exercise program for 20% to 76% of the total number days that they were in hospital. This finding may indicate that factors associated with recovery after transplantation may have precluded participation in exercise and prevented adequate inpatient exercise training. However, at the 6 month follow-up, there were improvements in O2peak, 6-minute walk test distance, maximal inspiratory and expiratory pressure, and lower-extremity muscle force compared with the values obtained upon admission. Maximal inspiratory and expiratory pressure, lower-extremity muscle force, and 6-minute walk test distance continued to improve at 12 and 18 months. The subjects' O2peak, however, reached its highest value at 6 months (56±18% [±SD] of predicted values) and did not change at 12 and 18 months (51±20% and 48±18% [±SD] of predicted values, respectively). Improvements in maximal inspiratory and expiratory pressure in the follow-up period may have been attributable to improvements in lung function following transplantation, which would decrease chest hyperinflation. Improvements in lower-extremity muscle force and 6-minute walk test distance during the follow-up period may have been due to a return to normal daily activity following a long period of deconditioning and bed rest before and immediately after transplantation. A return to daily activity, however, was likely of insufficient intensity to improve O2peak at 12 and 18 months after transplantation.
Steibellehner et al39 studied the effect of aerobic exercise training compared with normal daily activities on exercise capacity in 9 recipients of lung transplants (2 with SLT and 7 with DLT), 12±6 months [±SD] after transplantation. Each participant was tested initially, then continued with his or her normal daily activities for at least 6 weeks (average time for the group was 11±5 weeks [±SD]). This baseline phase was followed by a 6-week aerobic exercise program. The exercise program consisted of aerobic training on a cycle ergometer, 3 to 5 times per week. The initial training time was 60 minutes, and training time was increased by 12 minutes per week, for a final training duration of 120 minutes. Training intensity was prescribed to maintain training heart rate at 60% of heart rate reserve, calculated using the Karvonen method, and closely monitored using a heart rate monitor. The program was supervised for the first 3 weeks, and the last 3 weeks of training was done at home. All participants were provided with a training log that outlined the details of the program and allowed them to record their actual exercise. Compared with the period of normal daily activity, there was an increase in peak power output and O2peak in 8 of the 9 participants. There were also reductions in resting minute ventilation and in both submaximal minute ventilation and heart rate. No change was observed in arterial lactate levels or anaerobic threshold following aerobic training, which may indicate that improvements in skeletal muscle oxidative capacity did not occur. Because the authors did not provide details of the actual training intensity or of progression and duration achieved by each participant, it is difficult to determine whether the training stimulus was adequate to induce improvements in skeletal muscle oxidative capacity.
A number of training studies of patients with COPD have shown that 8 to 12 weeks of exercise training at 60% to 90% of peak workload can result in improvement in the oxidative capacity of the quadriceps femoris muscle, which is associated with a delay in the onset of lactic acidosis and an increase in O2peak.42–44 These findings suggest that if the changes in muscle are primarily due to the pretransplant condition, and not accentuated by use of medications and disuse after transplantation, adaptation at the level of skeletal muscle also may be possible after transplantation and can result in improvements in exercise capacity.
Exercise limitation is multifactorial in both health and disease, and it is often difficult to determine a single factor limiting peak exercise in an individual. There is little evidence to suggest that ventilatory and cardiac factors result in abnormal limitations to exercise following lung transplantation, and skeletal muscle oxygen delivery, uptake, and utilization are the most important factors in exercise limitation in these individuals. There is reduced capacity for oxidative metabolism in the quadriceps femoris muscle, which likely plays a key role in limiting peak exercise capacity.3,16 Reduced oxidative capacity appears to be due largely to the effects of the use of immunosuppressant medication and deconditioning.18 Improvements in quality of life and physical functioning are reported by recipients of lung transplants, although a large proportion of these people do not return to work. Exercise training may provide a means by which skeletal muscle function can be improved after transplantation. Further research to determine optimal exercise prescription guidelines in individuals who have undergone lung transplantation and are receiving immunosuppressant therapy is warranted.
| Footnotes |
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* HealthScan Products Inc, 41 Canfield Rd, Cedar Grove, NJ 07009-1201. 
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