We investigated the impact of lung transplantation and outpatient pulmonary rehabilitation after lung transplantation on skeletal muscle function and exercise tolerance. Skeletal muscle force (Quadriceps force, QF), exercise tolerance (six minute walking distance, 6MWD) and lung function were assessed in 36 patients before and after lung transplantation. Seventeen male and 19 female patients (age 57 ± 4) showed skeletal muscle weakness before the transplantation. A further 32 ± 21% reduction was seen 1.2 (interquartile range 0.9 to 2.0) months after LTX. The number of days on the intensive care unit was significantly related to the observed deterioration in muscle force after LTX. At this time point 6MWD was comparable to pre-LTX.
Rehabilitation started 37 (IQR 29 to 61) days after LTX. 6MWD and QF improved significantly (140 ± 91 m, and 35 ± 48%, respectively; p < 0.05) with rehabilitation. QF remained below pre-LTX values. The evolution of the 6MWD with the transplantation and the subsequent rehabilitation was less in female compared to male subjects.
We conclude that muscle strength deteriorates after lung transplantation, particularly in patients with long ICU stay. Outpatient pulmonary rehabilitation is feasible after lung transplantation and leads to recovery of skeletal muscle function. In female patients this recovery is significantly less compared to male recipients.
Lung transplantation has now become a valid option to treat end-stage lung disease (1). Lung transplant recipients nowadays have significantly improved survival compared to a decade ago. Much less is known on the recovery of functional exercise tolerance and skeletal muscle force after lung transplantation. Despite the significant improvement in lung function, several studies have reported that exercise tolerance remains abnormally low, even years after the lung transplantation (2–7). The remaining exercise intolerance is at least partially mediated through skeletal muscle abnormalities, which are seen after lung transplantation. Evans et al. reported impaired skeletal muscle bio-energetics an average of 2 years post-lung transplantation (8). In line with these observations is the significantly reduced fraction of oxidative fiber types, which was seen before exercise training in lung transplant recipients (9).
The effects of the lung transplant procedure, followed by an intensive care unit stay and often several weeks of hospital stay, on skeletal muscle force and exercise tolerance are not studied. To our knowledge no longitudinal study attempted to assess skeletal muscle and exercise tolerance before and immediately after lung transplantation in a cohort of patients. It is, however, important to know whether the intervention itself further reduces muscle force in lung transplant recipients. It is known that these patients suffer from muscle weakness even before they undergo lung transplantation (7). The latter authors report that quadriceps force (QF) improved from 62% of the predicted value before lung transplantation to 67% of the predicted normal value 1 year after the transplantation. Values immediately posttransplantation, however, were not obtained.
Exercise training may reverse part of these abnormalities (9), but the effects of formal exercise training have not been extensively studied after lung transplantation (9–11) or heart-lung transplantation (12). Altogether the number of patients who received rehabilitation after lung transplantation reported on in observational studies is only 29 (9–11). It is unclear whether all patients respond to the same extent to an exercise training program established after lung transplantation or whether there are differences. One study suggests that the functional exercise tolerance is more impaired in female patients after lung transplantation (13), but gender differences in the response to exercise training are not investigated. Exercise training may be particularly relevant in patients not resuming work, who may remain particularly inactive after the lung transplantation.
The aim of the this cohort study was to assess muscle force and exercise tolerance of lung transplant candidates and to describe the changes immediately following discharge after the grafting and again after 3 months of outpatient pulmonary rehabilitation in lung transplant recipients.
This observational study includes a cohort of 36 consecutive patients (17 males) scheduled for a first lung transplantation and referred for pulmonary rehabilitation after lung transplantation. Patients on the waiting list for retransplantation were excluded. Thirty-four of these patients were known in our center before the lung transplantation and had assessment of their skeletal muscle function and exercise tolerance 2.8 (interquartile range (IQR) 1.1 to 5.1) months before lung transplantation. All patients were reassessed after the lung transplantation (1.2 [IQR 0.9 to 2.0] months post-LTX, which was before starting rehabilitation) and after 3 months of pulmonary rehabilitation.
Static and dynamic lung volumes were assessed according to the guidelines of the American Thoracic Society and the European Respiratory Society (14). Spirometry data are reported as the best of at least three acceptable and reproducible attempts. Since all patients are adult Caucasians values are expressed as a percentage of the predicted values for European Caucasians (14).
Isometric quadriceps peak torque was measured using a Cybex Norm (Enraf-Nonius, Delft, The Netherlands). Peak extension torque was evaluated in sitting position at 60° of knee flexion and 90° of hip flexion. The test was performed at least three times, and the best peak torque of two reproducible tests was used for analysis. Values were related to reference values obtained in our laboratory.
Isometric handgrip force was assessed using a hydraulic handgrip dynamometer (Jamar Preston, Jackson, MI) and related to predicted normal values (15).
Functional exercise capacity
Functional exercise performance was measured by a 6-min walking test. This test was performed in a 50-m hospital corridor. Patients were asked to cover as much ground as possible in 6 min. Encouragement was standardized: every 30 sec a time indication was given and patients were encouraged to keep walking as fast as possible. Patients were allowed to rest if symptoms became intolerable. Transcutaneous oxygen saturation and heart rate were measured during this test for safety reasons. If saturation dropped below 80% patients were asked to stop walking. To further standardize the test, they could resume walking if saturation increased to 85% and they felt fit to continue. Patients requiring oxygen during ambulation were allowed to use supplemental oxygen. In this case, the oxygen cylinder was carried by the test supervisor. The best of two tests was used and expressed as a percentage of the predicted value defined in our laboratory (16).
Exercise training program
Patients were invited to attend the outpatient rehabilitation program in the University Hospital, Leuven, three times per week during 3 months. Rehabilitation started a median of 37 (IQR 29 to 61) days after the lung transplantation. Exercise training sessions were organized in the afternoon and had a duration of 1.5 h. Exercise training included cycling (Lode, Groningen, the Netherlands) and treadmill walking (Tunturi J800, Tunturipyörä oy, Finland). Furthermore, patients performed stair-climbing exercises in 2 min blocks (1–3 repetitions) and peripheral muscle resistance training (quadriceps muscle) on a multi-gym device (Atech, AT 1000B). Three series of eight repetitions were performed, starting at 60% of the one repetition maximum. No upper extremity exercises were performed. If needed, oxygen was supplied to maintain oxygen saturation above 90%. Guidelines for increasing training intensity were provided to the physiotherapists conducting the training program. Patients had to report a Borg score for dyspnea or leg fatigue of 4–6. Physiotherapists ensured close supervision and continuous encouragement of the patients. The patients' performance was recorded in a file and training duration was calculated. Cycle exercise work load was progressively increased from 27 ± 8 W to 39 ± 14 W for women and from 35 ± 11 W to 53 ± 16 W for men. Similarly, the exercise time was increased.
All patients received triple immune-suppressive therapy comprising of (i) either cyclosporine (maintenance trough levels 180–250 ng/mL) or tacrolimus (maintenance trough levels 7–12 mg/L), (ii) azathioprine (0.5–1 mg/kg/day adjusted to leukocyte count) or mycophenolate (maintenance trough levels 2–4 mg/mL) and (iii) methylprednisolone (375 mg on the day of the transplantation followed by a dose of 0.4 mg/kg/day, tapered to a maintenance dose 2–4 mg/day) 1 year after transplantation. The average daily dose of methylprednisolone was calculated during the rehabilitation program and expressed in mg/kg/day. The use of paralyzing agents was restricted to the immediate preoperative phase and was avoided afterward.
Results are expressed as mean ± standard deviation. Repeated measure analysis of variance (ANOVA) testing was conducted checking for a ‘time’ effect (pre-transplant, posttransplant and post-rehabilitation), a ‘gender’ effect and a ‘gender’×‘time’ interaction. Baseline characteristics of men and women were compared by nonpaired T-tests. For variables with a skewed distribution, the appropriate nonparametric test was used and data are presented as median and IQR. Correlation analysis was performed calculating the Pearson correlation coefficient. A p-value < 0.05 was considered significant.
Seventeen male and 19 female patients were followed in the study. Before lung transplantation patients suffered from end stage COPD (n = 27), interstitial lung disease (n = 8) or bronchiectasis (n = 1). Patient characteristics are displayed in Table 1. The age at the time of grafting was similar in men and women (57 ± 4 vs. 57 ± 5, respectively, p = 0.93). As expected, patients had significant lung function impairment. Skeletal muscle weakness was similarly present in men (QF: 72 ± 23% pred) and women (QF: 71 ± 37% pred, p = 0.98 male vs. female). Similarly, the 6-min walking distance (6MWD) was significantly reduced in these patients without differences between genders (male 313 ± 115 m, female 308 ± 136 m; p = 0.92). Handgrip strength (HGF) was less affected than lower limb strength, both in men (83 ± 22% pred) and women (83 ± 20% pred, p = 0.98 male vs. female). Fifteen patients received a single lung transplantation, 21 received a double lung transplantation.
Table 1. Patient characteristics
BMI: Values for body mass index; FEV1: Forced expiratory volume in 1 second, lung function; 6MWD: Six-minute walking distance; QF: quadriceps force; HGF: handgrip force; pre-LTX: in patients before; Post-LTX: after lung transplantation; and after 3 months of pulmonary rehabilitation (postrehabilitation). In bold are the variables with a significant time effect in repeated measures ANOVA. For body weight the repeated measures ANOVA did not reach significance (p = 0.10). Similarly, for BMI there was a trend for a time effect (p = 0.07). Post-hoc analysis revealed a significant reduction in body weight after transplantation, which recovered after rehabilitation. P values refer to the post-hoc tests as follows:
*p < 0.05 vs. pre-LTX.
†p < 0.05 vs. post-LTX.
22.7 ± 4.2
21.7 ± 4.2
23.1 ± 3.7
62.7 ± 13.8
60.2 ± 13.5*
62.6 ± 13.6
0.85 ± 0.47
1.96 ± 0.85*
2.20 ± 0.99*
31 ± 15
70 ± 21*
78 ± 25*
311 ± 124
320 ± 138
449 ± 128*,†
45 ± 19
46 ± 19
65 ± 17*,†
72 ± 30
51 ± 28*
59 ± 26*,†
83 ± 20
63 ± 20*
73 ± 21*,†
The impact of the lung transplant procedure and pulmonary rehabilitation
Patients spent postoperatively a median of 6 (IQR 4–11) days on the intensive care unit and another 7 (6–10) days on the medium care unit. The total hospitalization time reached a median of 30 (23–44) days, after which all patients were discharged home. A significant time effect was noted for most functional outcome variables. As expected, after the lung transplantation, lung function was significantly improved (Table 1). For body weight the repeated measures ANOVA did not reach significance (p = 0.10). Similarly, for BMI there was a trend for a time effect (p = 0.07).
Functional exercise capacity was not significantly changed immediately after the transplantation. QF was significantly reduced after the lung transplantation compared to the value before lung transplantation (−32 ± 21%). A significant negative relation was found between the time patients stayed in the intensive care and medium care unit and the reduction in skeletal muscle force (r = 0.41, p = 0.02). Linear regression analysis suggests a decline of 0.8 ± 0.38 Nm QF per day spent in the ICU and medium care unit (Figure 1).
Patients followed 27 ± 10 sessions of outpatient rehabilitation. Lung function tended to further improve. The 6MWD improved 140 ± 91 m (median 45% (IQR: 15 to 94% compared to before rehabilitation, p < 0.05) and QF increased by 35 ± 48% compared to the values obtained before rehabilitation (p < 0.05). The latter, however, represents only a modest change, when the change is expressed as a percentage of the predicted normal value (9 ± 19%pred). After 3 months of rehabilitation, patients' 6MWD exceeded the pre-transplant value (191 ± 186% of the pre-transplant value). QF was 87 ± 30% of the pre-transplant value. HGF was 93 ± 27% of the pre-transplant value.
Differences in functional outcome after transplantation between male and female patients
A significant gender × time interaction effect was noted for the 6MWD. This is illustrated in Figure 2. In female patients the 6MWD did not improve immediately after the transplantation, whereas in male patients there was a slight improvement. After 3 months of rehabilitation a significant gender effect was found for the 6MWD. QF was significantly reduced in both male and female patients immediately after the transplantation. Rehabilitation started after a median of 38 (IQR 33–78) days in male and 35 (26–43) days after the lung transplantation in female patients. Although both groups significantly benefited from rehabilitation, the progression in female recipients appears slower, although this did not reach statistical significance on the average. Figure 3 illustrates the individual responses to the exercise training program on QF in male and female patients (p = 0.06).
The average daily dose of steroids (methylprednisolone) during the 3 months rehabilitation was 0.35 ± 0.12 mg/kg/day for men and 0.32 ± 0.09 mg/kg/day for women (p = 0.38). Acute rejection occurred in 6 (31%) women and 8 (47%) men (chi-square 0.9, p = 0.34) in the period between the transplantation and the end of the rehabilitation period. Sixty-four percent of the patients received treatment with cyclosporine and there was no difference in the number of patients treated with cyclosporine between male and female. Four male and nine female patients received treatment with tacrolimus (p = 0.13). In multiple regression analysis only two factors were significantly associated with an enhanced skeletal muscle force after training. Twenty-three percent of the variability in the improvement in QF with training was explained by the number of training sessions that patients followed (partial R2 0.12, p = 0.05) and gender (partial R2 0.10 p = 0.05). The use of cyclosporine was not predictive of the training effect.
This study shows the significant impact of lung transplantation on skeletal muscle function. Muscle force is impaired before the transplantation, but is further impaired immediately after the lung transplantation. Exercise training reverses this abnormality at least partially. In female patients this recovery seems to be somewhat slower compared to male patients.
Decline of muscle force immediately after LTX
Lung transplantation has an immediate beneficial impact in improving lung function. This study, however, focused on skeletal muscle function in the weeks after the intervention. We found muscle weakness to be present before the lung transplantation. This is no surprise as skeletal muscle weakness is generally reported in end stage lung disease (17). This study showed a clinically significant reduction in skeletal muscle strength immediately following lung transplantation. Several factors may explain the acute decline in skeletal muscle force. First, lung transplantation is a serious and long-lasting surgical procedure followed by a number of days of stay in the ICU with immobilization and inactivity. Previously, Helliwell et al. reported a 3% to 4% decline in muscle cross-sectional area per day of stay in the ICU in critically ill patients (18). Patients in this study did spend a median of 6 days (IQR 4 to 11 days) in the ICU and a total of 15 (IQR 10.5–21 days) in the ICU and medium care unit. Long-term stay in the intensive care unit may lead to critical illness neuropathy or critical illness-related myopathies (19). In this study, we found a significant relation between the decline in skeletal muscle force and the time patients spend in the intensive and medium care unit. While mechanical ventilation is provided only in the intensive care unit, in the medium care unit, mobilizations and physical activity are limited. The total hospital stay in the present cohort was 30 days (IQR 23 to 44 days), which is clearly longer than that reported in some centers (20), but typical for our center (21) and others (22,23). On the ward patients in this study received routine chest physiotherapy, mobilization, light exercises and functional rehabilitation (i.e. walking, stair climbing) but no formal exercise training was applied. Unfortunately, the present single center study does not allow extrapolating our data to centers where ICU and medium care unit stay may be shorter. This should be investigated in multi-center studies.
Second, patients receive high doses of corticosteroids immediately after the lung transplantation. In the authors' center, patients received 375 mg/kg/day of methylprednisolone on the day of the transplantation and 0.4 mg/kg/day of methylprednisolone in the first days after the transplantation. These relatively high doses of corticosteroids surely can induce steroid-induced myopathy (24). Calcineurin inhibitors, via the vehicle of cyclosporine A and tacrolimus may further contribute to muscle dysfunction. This has been suggested in animal research (25).
It is clear that patients after lung transplantation in this study unanimously show skeletal muscle weakness. Since their ventilatory capacity is acutely improved these are excellent candidates for a pulmonary rehabilitation program (26). It remains unclear whether our findings can be extrapolated to somewhat younger recipients with cystic fibrosis, not included in the present trial.
Rehabilitation after LTX
Surprisingly, few studies investigated the effects of exercise training after lung transplantation. One study conducted 1 year after lung transplantation in nine lung transplant recipients showed that a 6-week exercise training program resulted in a 13% increase in peak VO2 (10). Another study was conducted in 12 lung transplant recipients 35 months after the lung transplantation. This study showed a 16% increase in peak oxygen consumption (9). A last study showed an improvement of lumbar spine muscle strength after specific lumbar spine resistance training showing resistance training did improve muscle strength (11). Only one study investigated the effects of a pulmonary rehabilitation program in heart-lung transplant recipients (12). Our data show remarkable similarity with this study. Ambrosino et al. observed that the 6MWD improved from 351 to 422 m after an inpatient rehabilitation program of 75 ± 28 days. Skeletal muscle strength improved from 41% to 47% predicted.
An important caveat in this study is the absence of a control group. It is clear that the improvements seen in the present trial can theoretically reflect the natural course of the recovery after the transplantation procedure. However, it should be mentioned that the studies investigating skeletal muscle function years after the transplantation showed still significantly reduced oxidative capacity (9) and peak oxygen consumption (3). Exercise training does at least partially reverse these abnormalities. It seems reasonable to start as soon as possible after the lung transplantation with exercise training. This study shows that it is feasible to start with outpatient pulmonary rehabilitation in the weeks after discharge from the hospital. Patients started with the outpatient program a median of 37 days after the lung transplantation (IQR 29–61 days). The effects of rehabilitation are clinically relevant. For example, the 6MWD improved by 139 m, which is more than twice the minimally clinically important difference (27). QF improved by more than 35% on the average.
It is noteworthy that even after 3 months of exercise training skeletal muscle strength or exercise tolerance were not normalized. In fact QF was still below the pre-lung transplant values. Acute deconditioning-induced atrophy is generally reversed within weeks of exercise training (28). Our data indicate that rehabilitation after lung transplantation is a long-term endeavor and quadriceps weakness immediately after lung transplantation is complex and probably depends not only on deconditioning. Restoration of muscle function and exercise tolerance clearly takes a long time after LTX, even when rehabilitation is established as soon as possible. The factors facilitating or hindering recovery of skeletal muscle function after transplantation are poorly understood. Exercise training induced rises in intracellular calcium may be a crucial stimulus to mitochondrial biogenesis through the activation of calcium/calmodulin-dependent protein phosphatase calcineurin. It has been shown that administration of calcineurin inhibitors has an impact on the metabolic response of skeletal muscle to exercise (29). In mice, administration of tacrolimus and cyclosporine blunted the response of skeletal muscle to an overload stimulus, which is comparable to exercise training (30). Whether the administration of calcineurin inhibitors at physiological doses influence the recovery of muscle function in humans is debated (31,32) and should be subject to further research. Furthermore, it is clear that calcineurin inhibitors play a key role in the current immune-suppressive regimen of transplant recipients. In this study the type of immune-suppressive therapy did not explain the variability in the skeletal muscle training response.
We cannot extrapolate from the present data whether the slow recovery of skeletal muscle function is also seen in patients with cystic fibrosis. These patients are typically younger and often resume paid employment (33). Perhaps these enhanced daily physical activity levels may facilitate recovery in these patients. As these patients are not frequently referred to our rehabilitation program we were unable to investigate this in this study.
Difference between male and female patients
This study highlights an intriguing difference in the impact of the transplantation and the recovery of exercise tolerance and skeletal muscle force with rehabilitation between male and female recipients. A significant difference in the impact of lung transplantation and rehabilitation was seen between male and female recipients for the 6MWD (Figure 2, left panel). In addition, QF tended to recover less in the female patients after 3 months of rehabilitation (Figure 3). Clearly, this study was only observational in nature and we cannot address the reasons of this discrepancy in much detail. Several factors, which may have influenced muscle function, were similar between male and female recipients. Steroid dose immediately after the transplantation and during rehabilitation were similar, as well as the proportion of patients treated with tacrolimus. Eight male and six female patients had episodes of acute rejection and the time spent in the ICU was not different. Hence we can only speculate as to the potential reasons for this discrepancy. The anabolic hormone testosterone has been reported to be reduced (34,35) after transplantation. It is tempting to speculate that anabolic hormones may be down-regulated and this phenomenon could be more pronounced in female patients, compromising the recovery of skeletal muscle function. The finding that low testosterone levels were related to poor training response in otherwise healthy middle-aged woman (36) supports this hypothesis. An alternative hypothesis could be that women may have less daily physical activity compared to men, as was suggested after heart transplantation (37). Nevertheless, the current observation is of clinical importance. Specific attention should be given to the recovery of skeletal muscle function after transplantation in female patients. Regardless of the mechanism our data would suggest that recovery of muscle force and exercise tolerance might take longer in female compared to male subjects.
This study is the first to demonstrate an important reduction in skeletal muscle force immediately after lung transplantation, particularly in patients who had a longer stay on the ICU after the lung transplantation. Skeletal muscle force and exercise tolerance do recover with exercise training in the months after the transplantation. After 3 months of exercise training, however, skeletal muscle weakness is still observed. In female patients the recovery after transplantation appears slower compared to male recipients with 3 months of rehabilitation. Further studies should focus on the mechanisms of the relatively slow recovery of skeletal muscle function after transplantation, particularly in female subjects.
The authors would like to thank the Lung Transplantation and Pulmonary Rehabilitation teams of the University Hospitals Leuven. Prof. Eric Marchand is acknowledged for his suggestions regarding the paper. This work was supported by FWO-KAN2005 1.5.139.06, FWO: G. 0523.06, G 0386.05 and an unrestricted grant of Astra-Zeneca Pharmaceuticals.