Exercise limitation in recipients of lung transplants.

Key Words: Exercise physiology; Muscles, skeletal; Transplantation.

Lung transplantation is a viable option for improving survival and quality of life in selected patients with end-stage lung diseases such as chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis, and cystic fibrosis. (1) Following lung transplantation, there are substantial improvements in pulmonary function and a subsequent improvement in exercise capacity; however, peak exercise remains reduced to 40% to 60% of predicted values even up to 2 years after transplantation. Williams et al (2) tested maximal exercise capacity in recipients of a single-lung transplant (SLT) (n=6) and in recipients of a double-lung transplant (DLT) (n=7) at 3 months and again at 1 to 2 years after transplantation. At 3 months after transplantation, peak oxygen consumption ([Vo.sub.2]peak) 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 ([Vo.sub.2]max) 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 al (3) 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 [Vo.sub.2]peak taken during cycling were reduced in the SLT group compared with the control group (P<.001) and were only 36.8% [+ or -] 3.1% ([bar.X] [+ or -] 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 ([sup.31]P-MRS), Evans et al (3) 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 [Vo.sub.2]peak. 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 al (4) 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 (FE[V.sub.1]) (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)

The purpose of this review is to describe the relative contributions of the factors limiting aerobic exercise in recipients of lung transplants. With an understanding of exercise limitation, physical therapists will be able to design and implement effective exercise programs that lead to improvements in functional capacity in this population.

Ventilatory Limitation to Exercise

In people without known pathology or impairments, the respiratory system has an enormous capacity to meet the increased oxygen demands required during exercise. Minute ventilation can increase by 20 times resting values, pulmonary blood vessels can accommodate large increases in cardiac output, and the equilibration of oxygen between the red blood cells and the alveoli requires a relatively short time (approximately 250 milliseconds). (6) Together, these properties of the respiratory system allow for adequate oxygenation of blood during maximal exercise. Studies examining peak exercise performance in patients following SLT and DLT have demonstrated that ventilatory factors do not play a major role in exercise limitation. During an incremental cycling test to [Vo.sub.2]peak, 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 ([Sao.sub.2]) 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 al (8) 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 al (9) 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 authors (9) 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 al (10) 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 [Vo.sub.2]peak, 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

Similar to people who are deconditioned, patients following lung transplantation show an early onset of the lactate threshold at submaximal levels of oxygen consumption ([Vo.sub.2]). This response may be a result of impaired delivery of oxygen to the periphery due to inadequate cardiac response with exercise. Hemodynamic response to incremental exercise was measured in 9 recipients of HLT (33 [+ or -] 15 months [[bar.X] [+ or -] SD] after transplantation). (12) The subjects' [Vo.sub.2]peak was 61% [+ or -] 8% ([bar.X] [+ or -] 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/[m.sup.2]. 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 al (14) 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 [Vo.sub.2]peak before transplantation (29% [+ or -] 3% [[bar.X] [+ or -] SD] of predicted values), and their [Vo.sub.2]peak remained lower than predicted after transplantation (42% [+ or -] 2% [[bar.X] [+ or -] SD]). Lactate threshold, as determined by the inflection point of arterial lactate versus [Vo.sub.2], occurred at 27% [+ or -] 2% ([bar.X] [+ or -] SD) of [Vo.sub.2]peak, indicating an early onset of anaerobic metabolism. Maximal stroke volume was higher following lung transplantation compared with the pretransplant condition (51 [+ or -] 4 versus 37 [+ or -] 2 [[bar.X] [+ or -] SD] mL/beat/[m.sup.2]) 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 [Vo.sub.2]peak. (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

A number of studies have documented impaired oxidative capacity of the quadriceps femoris muscle following lung transplantation, which may be a result of a number of factors such as deconditioning, prolonged period of bed rest following surgery, use of immunosuppressant medications, and other factors related to the pretransplant condition (eg, poor nutritional status, abnormal blood gases). In the pretransplant condition of COPD, reduced muscle mass, reduced proportion of type I muscle fibers, and decreased concentrations of oxidative enzymes in the quadriceps femoris muscle have been reported. (5) These changes have been associated with an increased reliance on glycolytic metabolism, early onset of lactic acidosis, and reduction in peak exercise capacity. (15)

Similar to findings in patients with COPD, the quadriceps femoris muscles of recipients of lung transplants show reduced oxidative capacity. Wang et al (16) 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% [+ or -] 4.4% [[bar.X] [+ or -] SD] versus 56.1% [+ or -] 2.4% [[bar.X] [+ or -] 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 [Vo.sub.2]peak and early onset of lactic acidosis observed in recipients of lung transplants. (16) Morton et al (17) 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), bronchiectasis (n=5), cystic fibrosis (n=3), pulmonary fibrosis (n=l), 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, [sup.13]P-MRS. This technique measures the concentration of phosphocreatine (PCr) and inorganic phosphate (Pi), from which pH of the exercising muscle can be calculated. Using [sup.31]P-MRS, Evans et al (3) 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 [Vo.sub.2]peak 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 al (18) 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 age-and 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 al (15) 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 [+ or -] 4 months ([bar.X] [+ or -] 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 [Vo.sub.2]peak after transplantation compared with before transplantation (31% [+ or -] 3% [[bar.X] [+ or -] SD] of predicted pretransplant values versus 45% [+ or -] 5% [[bar.X] [+ or -] SD] of predicted posttransplant values), but [Vo.sub.2]peak 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 [+ or -] 1.2 mL/dL [[bar.X] [+ or -] SD] before transplantation compared with 9.3 [+ or -] 0.9 mL/dL [[bar.X] [+ or -] 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, [Vo.sub.2]peak remained diminished at 47% [+ or -] 4% [[bar.X] [+ or -] 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 monophosphate 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 al (16) 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

A number of immunosuppressant medications, including corticosteroids and cyclosporine, are routinely prescribed following transplantation to avoid organ rejection. (1) These medications have been shown to have profound effects on cellular features of skeletal muscle in patients with COPD (23,24) and in animals. (25,26) The histology of skeletal muscle and its relationship to muscle function has not been reported in recipients of lung transplants and warrants further examination.

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 respirator), 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 al (26) 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 [Vo.sub.2]peak during exercise because hemoglobin levels are normal or only mildly reduced in most patients, and reduced [Vo.sub.2]peak 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 reviews (5,30) for a full discussion of factors that may contribute to poor muscle function in patients with COPD.

Implications for Rehabilitation

Following lung transplantation, patients have reported a substantial gain in their functional capacity and have shown marked improvement in scores on the physical function subscales of quality-of-life questionnaires. (1,31) Recipients of lung transplants showed higher scores on the physical subscale of the Rand-36 Item Health Survey 1.0 compared with pretransplant candidates. (31) Functional status, as reflected by the total and physical dimension scores of the Sickness Impact Profile, showed improvement 3 months after lung transplantation (n=10); the ambulation category showed the greatest improvement, whereas scores for the work category did not change. (32) A report following patients over a longer term stated that 55% of patients awaiting lung transplants indicated extreme limitation in performing their usual activities, whereas 3 years after SLT, DTL, and HLT, decreased numbers of patients reported extreme limitation (15%, 4%, and 0%, respectively). (33) Although improvements in quality of life are noted among recipients of lung transplants, up to 40% do not return to work. (34) This figure may not be reflected in studies examining exercise capacity, because these studies likely are limited by selection bias and include only those recipients of transplants who are well enough to perform their regular occupation (2) and are interested and eligible to participate in exercise studies.

Despite improved scores on the physical function subscales 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 [[+ or -] SD]=1.5 [+ or -] 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 therapy (18); however, cause and effect and proportionate contribution of the perioperatire 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 al (40) studied the effect of an inpatient exercise training program in 10 recipients of HLT who were 45 [+ or -] 23 days ([bar.X] [+ or -] 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. Inspiratory 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 ([bar.X] [[+ or -] SD]=41 [+ or -] 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 authors (40) 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 [Vo.sub.2]peak, 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' [Vo.sub.2]peak, however, reached its highest value at 6 mouths (56 [+ or -] 18% [[bar.X] [+ or -] SD] of predicted values) and did not change at 12 and 18 months (51 [+ or -] 20% and 48 [+ or -] 18% [[bar.X] [+ or -] 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 [Vo.sub.2]peak at 12 and 18 months after transplantation.

Steibellehner et al (39) 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 [+ or -] 6 months [[bar.X] [+ or -] 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 [+ or -] 5 weeks [[bar.X] [+ or -] 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 [Vo.sub.2]peak 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 [Vo.sub.2]peak. (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.

Table 1.
Summary of Key Studies Examining Exercise Limitation in Recipients of
Lung Transplants (a)

Exercise Limiting Factor    Author        Sample

Ventilatory
  VE and Sa[O.sub.2]:       Miyoshi       SLT: n = 6, 18 [+ or -] 4 mo
  VE does not exceed          et al (7)     ([bar.X] [+ or -] SD) after
    maximum ventilation                     transplantation
    during exercise                       DLT: n = 6, 10 [+ or -] 5 mo
  Sa[O.sub.2] does not                      after transplantation
    decrease with exercise
    after transplantation
                            Levy          SLT (obstructive): n = 10,
                              et al (8)     6.6 [+ or -] 2.4 mo
                                            ([bar.X] [+ or -] SD) after
                                            transplantation
                                          SLT (restrictive): n = 6, 6.0
                                            [+ or -] 1.4 mo ([bar.X]
                                            [+ or -] SD) after
                                            transplantation
                                          DLT: n = 6, 6 [+ or -] 2.4 mo
                                            ([bar.X] [+ or -] SD) after
                                            transplantation
                                          Controls: n = 28

Breathing pattern: similar  Scuirba       HLT: n = 7, 14.4 [+ or -]
  to that of people           et al (9)     11.8 mo ([bar.X] [+ or -]
  without known pathology                   SD) after transplantation
  or impairments and                      HT: n = 7, 14.6 [+ or -] 11.8
  recipients of HT; does                    mo ([bar.X] [+ or -] SD)
  not seem to limit                         after transplantation
  exercise
                            Kimoff        HLT: n = 4, 3-9 mo after
                              et al (10)    transplantation
                                          Controls: n = 10, age-and
                                            sex-matched

Cardiovascular
  HR: adequate to maintain  Williams      SLT: n = 6, 3 and 12-24 mo
    maximal workload          et al (2)     after transplantation
    achieved after                        DLT: n = 7, 3 and 12-24 mo
    transplantation                         after transplantation

  Stroke volume: adequate   Ross          SLT: n = 7, before
    to maintain maximal       et al (14)    transplantation and 6-12 mo
    workload achieved                       after transplantation
    after transplantation                 DLT: n = 1 before
                                            transplantation and 12 mo
                                            after transplantation
Skeletal muscle
  Lactate threshold:        Evans         SLT: n = 8, 5-38 mo after
    occurs at lower work      et al (3)     transplantation
    output                                DLT: n = 2, 7-34 mo after
                                            transplantation
                                          Controls: n = 8

  Lower-extremity work      Lands         SLT: n = 9, median = 37.6 mo
    capacity: reduced in      et al (4)     after transplantation
    recipients of                         DLT: n = 10, median = 25.7 mo
    transplants and                         after transplantation
    correlates to peak
    exercise capacity

  Oxidative capacity:       Wang          SLT: n = 2, 9-15 mo after
    reduced oxidative         et al (16)    transplantation
    capacity of quadriceps                DLT: n = 4, 8-21 mo after
    femoris muscle                          transplantation
                                          HLT: n = 1, 24 mo after
                                            transplantation
                                          Controls: n = 7, age- and
                                            sex-matched

Exercise Limiting Factor    Key Findings

Ventilatory
  VE and Sa[O.sub.2]:       VE = 46.8% of MVV at peak exercise in SLT
  VE does not exceed          group and 33.4% in DLT group
    maximum ventilation     Sa[O.sub.2] = 97.2% at rest; at peak
    during exercise           exercise: 94.3% in SLT group and 96.7% in
  Sa[O.sub.2] does not        DLT group
    decrease with exercise
    after transplantation
                            VE = 47.9% of MVV at peak exercise in SLT
                              [obstructivel group, 70.1% in SLT
                              (restrictive) group, and 53.7% in DLT
                              group
                            Sa[O.sub.2] at peak exercise = 94.4% in SLT
                              (obstructive) group, 90.1% in SLT
                              (restrictive) group, and 96.7% in DLT
                              group

Breathing pattern: similar  VE = 47% [+ or -] 11% ([bar.X] [+ or -] SD)
  to that of people           of MVV in HLT group and 56% [+ or -] 13%
  without known pathology     ([bar.X] [+ or -] SD) of MVV in HT group
  or impairments and          at maximal exercise
  recipients of HT; does    HLT group showed more rapid increase in VT
  not seem to limit           and gradual increase in RR than HT group
  exercise
                            VE = 45.5% [+ or -] 9.9% ([bar.X] [+ or -]
                              SD) of MVV in HLT group and 50.6%
                              [+ or -] 4.2% ([bar.X] [+ or -] SD) of
                              MVV in controls at maximal exercise
                            VT increased similarly throughout exercise
                              and RR was similar at peak exercise in
                              HLT group compared with controls

Cardiovascular
  HR: adequate to maintain  HR at maximal exercise was 133 [+ or -] 24
    maximal workload          bpm ([bar.X] [+ or -] SD) (75% of age-
    achieved after            predicted HRmax) and 132 [+ or -] 20 bpm
    transplantation           ([bar.X] [+ or -] SD) (74% of age-
                              predicted HRmax) at 3 and 12-24 mo,
                              respectively, in SLT group
                            HR at maximal exercise was 136 [+ or -] 12
                              bpm ([bar.X] [+ or -] SD) (73% of age-
                              predicted HRmax) and 129 [+ or -] 19 bpm
                              ([bar.X] [+ or -] SD) (69% of age-
                              predicted HRmax) at 3 and 12-24 mo,
                              respectively, in DLT group

  Stroke volume: adequate   V[O.sub.2]peak: 29% [+ or -] 3% ([bar.X]
    to maintain maximal       [+ or -] SD) of predicted_ values before
    workload achieved         transplantation and 42% [+ or -] 2%
    after transplantation     ([bar.X] [+ or -] SD) of predicted values
                              after transplantation
                            Maximal stroke volume: 37 [+ or -] 2 mL/
                              beat/[m.sup.2] before transplantation and
                              51 [+ or -] 4 mL/beat/[m.sup.2] after
                              lung transplantation

Skeletal muscle
  Lactate threshold:        V[O.sub.2]peak: 28.3% [+ or -] 1.8%
    occurs at lower work      ([bar.X] [+ or -] SD) of predicted
    output                    values; lactate threshold occurred at
                              lower metabolic rate in recipients of
                              transplants

  Lower-extremity work      Lower-extremity work capacity was 63.3% of
    capacity: reduced in      predicted values and correlated to peak
    recipients of             exercise capacity on a cycle ergometer
    transplants and           (r =.84)
    correlates to peak
    exercise capacity

  Oxidative capacity:       Lower proportion of type I muscle fibers,
    reduced oxidative         lower oxidative enzyme activity, and
    capacity of quadriceps    higher glycolytic enzyme activity in
    femoris muscle            vastus lateralis muscle of recipients of
                              transplants compared with controls

(a) DLT = double-lung transplant, SLT = single-lung transplant, HT =
heart transplant, HLT = heart-lung transplant, Sa[O.sub.2] = oxygen
saturation, VE = minute ventilation, MVV = maximum voluntary
ventilation, VT = tidal volume, RR = respiratory rate, HR = heart rate,
Hrmax = maximum heart rate, V[O.sub.2]peak = peak oxygen consumption,
bpm = beats per minute.

References

(1) Trulock EP. Lung transplantation. Am J Respir Crit Care Med. 1997; 155:789-818.

(2) Williams TJ, Patterson GA, McClean PA, et al. Maximal exercise testing in single and double lung transplant recipients. Am Rev Respir Dis. 1992;145:101-105.

(3) Evans AB, Al-Himyary AJ, Hrovat MI, et al. Abnormal skeletal muscle oxidative capacity after lung transplantation by [sup.31]P-MRS. Am J Respir Crit Care Med. 1997;155:615-621.

(4) Lands LC, Smoutas AA, Mesiano G, et al. Maximal exercise capacity and peripheral skeletal muscle function following lung transplantation. J Heart Lung Transplant. 1999;18:113-120.

(5) American Thoracic Society/European Respiratory Society (ATS/ ERS). Skeletal muscle dysfunction in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1999;159:S1-S40.

(6) West JB. Respiratory Physiology: The Essentials. 6th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2000:21-28.

(7) Miyoshi S, Trulock EP, Schaefers H-J, et al. Cardiopulmonary exercise testing after single and double lung transplantation. Chest. 1990; 97:1130-1136.

(8) Levy RD, Ernst P, Levine SM, et al. Exercise performance after lung transplantation. J Heart Lung Transplant. 1993;12:27-33.

(9) Sciurba FC, Owens GR, Sanders MH, et al. Evidence of an altered pattern of breathing pattern during exercise in recipients of heart-lung transplants. N Engl J Med. 1988;319:1186-1192.

(10) Kimoff RJ, Cheong TH, Cosio MG, et al. Pulmonary denervation in humans. Am Rev Respir Dis. 1990;142:1034-1040.

(11) Grassi B, Ferretti G, Xi L, et al. Ventilatory response to exercise after heart and lung denervation in humans. Respir Physiol. 1993;92: 289-304.

(12) Vachiery J-L, Niset G, Antoine M, et al. Haemodynamic response to dynamic exercise after heart-lung transplantation. Eur Respir J. 1999; 14:1131-1135.

(13) Otuluna BA, Higenbotooam TW, Wallwork J. Causes of exercise limitation after heart-lung transplantation. J Heart Lung Transplant. 1992;11:S244-S251.

(14) Ross DJ, Waters PF, Mohsenifar Z, et al. Hemodynamic responses to exercise after lung transplantation. Chest. 1993;103:46-53.

(15) Oelberg DA, Systrom DM, Markowitz DH, et al. Exercise performance in cystic fibrosis before and after bilateral lung transplantation. J Heart Lung Transplant. 1998;17:1104-1112.

(16) Wang XN, Williams TJ, McKenna MJ, et al. Skeletal muscle oxidative capacity, fiber type, and metabolites alter lung transplantation. Am J Respir Crit Care Med. 1999;160:57-63.

(17) Morton JM, McKenna MJ, Fraser SF, et al. Reductions in type I fibre proportions and oxidative enzyme activity in skeletal muscle exist pre and post lung transplantation [abstract]. J Heart Lung Transplant. 1999; 18:52.

(18) Tirdel GB, Girgis R, Fishman RS, Theodore J. Metabolic myopathy as a cause of the exercise limitation in lung transplant recipients. J Heart Lung Transplant. 1998;17:1231-1237.

(19) Boushel R, Langberg H, Oiesen J, et al. Monitoring tissue oxygen availability with near infrared spectroscopy (NIRS) in health and disease. Scand J Med Sci Sports. 2001;l1:213-222.

(20) Systrom DM, Pappagianopoulos P, Fishman RS, et al. Determinants of abnormal maximum oxygen uptake after lung transplantation for chronic obstructive pulmonary disease. J Heart Lung Transplant. 1998; 17:1220-1230.

(21) Krieger AC, Szidon P, Kesten S. Skeletal muscle dysfunction in lung transplantation. J Heart Lung Transplant. 2000;19:392-400.

(22) Pouw EM, Schols AM, van der Vusse GJ, Wouters E. Elevated inosine monophosphate levels in resting muscle of patients with stable chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1998;157: 453-457.

(23) Decramer M, de Bock V, Dora R. Functional and histologic picture of steroid-induced myopathy in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1996;153:1958-1964.

(24) Decramer M, Lacquet LM, Fagard R, Rogiers P. Corticosteroids contribute to muscle weakness in chronic airflow obstruction. Am J Respir Crit Care Med. 1994;150:11-16.

(25) Hokanson JF, Mercier JG, Brooks CA. Cyclosporine A decreases rat skeletal muscle mitochondrial respiration in vivo. Am J Respir Crit Care Med. 1995;151:1848-1851.

(26) Mercier JG, Hokanson JF, Brooks GA. Effects of cyclosporine A on skeletal muscle mitochondrial respiration and endurance time in rats. Am J Respir Crit Care Med. 1995;151:1532-1536.

(27) Dekhuijzen PN, Decramer M. Steroid-induced myopathy and its significance to respiratory disease: a known disease rediscovered. Eur Respir J. 1992;5:997-1003.

(28) Bloomfield SA. Changes in musculoskeletal structure and function with prolonged bedrest. Med Sci Sports Exerc. 1997;29:197-206.

(29) Fitts RH, Riley DR, Widrick JJ. Functional and structural adaptations of skeletal muscle to microgravity. J Exp Biol. 2001;204:3201-3208.

(30) Maltais F, LeBlanc P, Jobin J, Casaburi, R. Peripheral muscle dysfunction in chronic obstructive pulmonary disease. Clin Chest Med. 2000;21:665-677.

(31) Limbos MM, Joyce DP, Chang CKN, Kesten S. Psychological functioning and quality of life in lung transplant candidates and recipients. Chest. 2000;118:408-416.

(32) Lanuza DM, Lafaiver CA, McCabe M, et al. Prospective study of functional stares and quality of life before and after lung transplantation. Chest. 2000;118:115-122.

(33) Anyanwu AC, McGuire A, Rogers CA, Murday AJ. Assessment of quality of life in lung transplantation using a simple generic tool. Thorax. 2001;56:218-222.

(34) Lanuza DM, Lafaiver CA, Farcas GA. Research on quality of life of lung transplant candidates and recipients: an integrative review. Heart Lung. 2000;29:180-195.

(35) Beilby S, Moss-Morris R, Painter L. Quality of life before and after heart, lung and liver transplantation. New Zealand Medical Journal 2003;116:U381.

(36) MacNaughton KL, Rodrigue JR, Cicale M, Staples EM. Health-related quality of life and symptom frequency before and after lung transplantation. Clin Transplant. 1998;12:320-323.

(37) Lanuza DM, McCabe M, Norton-Rosko M, et al. Symptom experiences of lung transplant recipients: comparisons across gender, pretransplantation diagnosis and type of transplantation. Heart Lung. 1999;28:429-437.

(38) van Den Berg JW, Geertsma A, Van Der Bij W, et al. Bronchiolitis obliterans syndrome after lung transplantation and health-related quality of life. Am J Respir Crit Care Med. 2000;161:1937-1941.

(39) Steibellehner L, Quittan M, End A, et al. Aerobic endurance training program improves exercise performance in lung transplant recipients. Chest. 1998;113:906-912.

(40) Ambrosino N, Bruschi C, Callegari G, et al. Time course of exercise capacity, skeletal and respiratory muscle performance after heart-lung transplantation. Eur Resp J. 1996;9:1508-1514.

(41) McArdle WD, Katch FI, Katch VL. Exercise Physiolagy: Energy, Nutrition, and Human Performance. 5th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2001:458-499.

(42) Casaburi R, Patessio A, Ioli F, et al. Reductions in lactate acidosis and ventilation as a result of exercise training in patients with obstructive lung disease. Am Rev Repir Dis. 1991:143:9-18.

(43) Maltais F, LeBlanc P, Simard C, et al. Skeletal muscle adaptations to endurance training in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1996;154:442-447.

(44) Maltais F, LeBlanc P, Jobin J, et al. Intensity of training and physiologic adaptation in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1997;155:555-561.

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 ([e-mail]). Address all correspondence to Ms Mathur.

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.

All authors provided concept/idea/project design and writing. Dr Reid provided institutional liaisons, and Dr Reid and Dr Levy provided consultation (including review of manuscript before submission).