Abstract
Background Exercise capacity, muscle function, and physical activity levels remain reduced in recipients of lung transplantation. Factors associated with this deficiency in functional exercise capacity have not been studied longitudinally.
Objective The study aims were to analyze the longitudinal change in 6-minute walking distance and to identify factors contributing to this change.
Design This was a longitudinal historical cohort study.
Methods Data from patients who received a lung transplantation between March 2003 and March 2013 were analyzed for the change in 6-minute walking distance and contributing factors at screening, discharge, and 6 and 12 months after transplantation. Linear mixed-model and logistic regression analyses were performed with data on characteristics of patients, diagnosis, waiting list time, length of hospital stay, rejection, lung function, and peripheral muscle strength.
Results Data from 108 recipients were included. Factors predicting 6-minute walking distance were measurement moment, diagnosis, sex, quadriceps muscle and grip strength, forced expiratory volume in 1 second (percentage of predicted), and length of hospital stay. After transplantation, 6-minute walking distance increased considerably. This initial increase was not continued between 6 and 12 months. At 12 months after lung transplantation, 58.3% of recipients did not reach the cutoff point of 82% of the predicted 6-minute walking distance. Logistic regression demonstrated that discharge values for forced expiratory volume in 1 second and quadriceps or grip strength were predictive for reaching this criterion.
Limitations Study limitations included lack of knowledge on the course of disease during the waiting list period, type and frequency of physical therapy after transplantation, and number of missing data points.
Conclusions Peripheral muscle strength predicted 6-minute walking distance; this finding suggests that quadriceps strength training should be included in physical training to increase functional exercise capacity. Attention should be paid to further increasing 6-minute walking distance between 6 and 12 months after transplantation.
Lung transplantation (LTx) as a treatment in end-stage lung disease has become generally accepted for appropriately selected patients. In total, 673 single and double LTxs were performed in the Eurotransplant region in 2013 (5.9 LTxs per 106 people).1 In Australia and New Zealand, 144 LTxs (6.3/106 people) and 13 LTxs (3.2/106 people), respectively, were performed in 2012.2 In the United States, a total of 1,923 LTxs were performed in 2013.3 Transplantation leads to a substantial improvement in quality of life4,5 and an increase in exercise performance, that is, exercise capacity and muscle function. However, recipients of LTxs do not achieve normal levels6,7; physical activity levels 1 year after transplantation were considerably lower than those in people who were healthy (controls).8
The main factor limiting exercise performance after LTx, as ascertained with maximal exercise testing, is the reduced work capacity of the peripheral skeletal muscles.7,9–13 It is expected that the physiological processes underlying this reduced capacity will also be present at submaximal or functional exercise levels in recipients of LTxs. It is not clear, however, to what extent. Functional exercise capacity is generally tested with 6-minute walking distance (6MWD).14 In patients with chronic obstructive pulmonary disease (COPD), a strong correlation between 6MWD and quadriceps muscle force was shown.15 Unfortunately, little attention has been paid to factors predicting 6MWD after LTx.
Only a few studies have used longitudinal data to study the relationship between 6MWD and peripheral muscle force, posttransplantation recovery rate, and other predicting factors.7,16–18 The generalizability of the results of these studies is restricted because of small sample sizes (8–36 patients),7,16–18 a limited follow-up period (4 months),16 and a limited number of measurement moments (2 moments).7,17,18
Overall, knowledge about the course of submaximal exercise capacity and the factors limiting this capacity in recipients of LTxs is limited. Therefore, the aims of this study were to analyze the course of functional exercise capacity by modeling the change in 6MWD longitudinally and to explore factors predicting this change. This study should provide insight into intervention targets and the timing of interventions with the goal of increasing functional exercise capacity in recipients of LTxs.
Method
Study Design
A longitudinal historical cohort analysis was performed with data collected as part of the routine clinical evaluation (including screening and evaluation after LTx) of recipients of single and double LTxs between March 2003 and March 2013 at the University Medical Center Groningen, Groningen, the Netherlands. Pre-LTx screening before placement on the waiting list consisted of medical, social (intake medical social work, psychological analysis when indicated), and physical screening (T0 [screening]). During the medical screening, lung function testing was performed. The physical screening consisted of a 6MWD test and measurements of peripheral muscle force. Patients were retested at discharge from the hospital after LTx (T1 [day of discharge or days preceding discharge]), at 6 months after LTx (T2), and at 12 months after LTx (T3). Data from all patients 18 years of age or older on the date of transplantation were included when data from at least 3 of the 4 measurement moments were available. Data from patients receiving retransplantation or receiving heart-lung transplantations were excluded. Data were coded and processed anonymously.
Data regarding the characteristics of the patients, diagnosis, duration on the waiting list, length of hospital stay (from transplantation to discharge, reflective of health status, disease severity, postoperative complications, and recovery rate), and number of rejection episodes (number of rejection treatments applied) in the first year after transplantation were gathered from medical records. At hospital discharge, all patients were instructed to exercise regularly. No predescribed training program was provided, but training under the supervision of a physical therapist was advised, and oral and written referral were provided. All patients received optimal immunosuppression therapy (tacrolimus [Prograf, Astella Pharma US Inc, Northbrook, Illinois], mycophenolate mofetil [CellCept, Genentech USA Inc, South San Franscisco, California], and prednisone).
Indications for transplantation were categorized into 4 groups: COPD and emphysema, including alpha1-antitrypsin deficiency and bronchiectasis (COPD group); pulmonary vascular diseases, including primary pulmonary hypertension and Eisenmenger syndrome (pulmonary vascular disease group); cystic fibrosis (CF group); and pulmonary fibrosis, including idiopathic pulmonary fibrosis, sarcoidosis (with mean pulmonary artery pressure of >30 mm Hg), scleroderma, and bronchiolitis obliterans (pulmonary fibrosis group).
Outcome Measures
6MWD.
Functional exercise capacity was determined with the 6MWD performed in accordance with American Thoracic Society guidelines14 over a 40-m distance and supervised by an experienced physical therapist. In accordance with American Thoracic Society guidelines, no practice tests were performed before measurement. The number of 6MWD tests that patients performed in the screening and posttransplant periods ensured that a learning effect was largely ruled out. If possible, patients would walk without an assistive device. An assistive device (walker) was used only by patients receiving oxygen supplementation in daily life (before transplantation); the oxygen container was placed on the walker. No additional oxygen supplementation was used. Predicted walking distance (for adults who were healthy) was calculated, and a 6MWD below 82% of the predicted walking distance was considered indicative of impairment.19
Pulmonary function.
For all patients, flow volume measurements, including forced expiratory volume in 1 second (FEV1), forced vital capacity, and Tiffeneau index (FEV1/forced vital capacity, as a percentage), were obtained. Body plethysmography (Jaeger, Wurzburg, Germany) was used to determine total lung capacity, residual volume, and diffusing capacity of the lung for carbon monoxide (DLCO) for some of the recipients (of the total of 346 lung function measurements, 247 included measurement of total lung capacity and residual volume and 212 included measurement of DLCO). Measurements were obtained in accordance with American Thoracic Society/European Respiratory Society guidelines.20
Peripheral muscle strength.
Maximal voluntary isometric strength was measured for the quadriceps, biceps brachii, and triceps brachii muscles and for the 3-point grip with a handheld dynamometer (MicroFET II, Hoggan Health Industries, West Jordan, Utah) by experienced physical therapists. Measurements were obtained bilaterally 3 times for each muscle group and in the testing positions described earlier.21 The break method was applied; with this method, muscle force was gradually overcome, and the measurement ceased at the moment of “giving way.”22 Three-point grip strength was tested in a seated position with the upper arm in a neutral position and the elbow in 90 degrees of flexion. The index and middle fingers were placed on the force pad of the dynamometer, and the thumb was placed on the opposite side. With the thumb facing the floor, the patient was instructed to pinch as hard as possible. The mean measured peak force (in newtons) of the dominant side of the patient was used for further analysis. Predicted values were calculated23; however, reference values for grip strength, as measured, were not available.
Data Analyses
Descriptive statistics were applied for baseline characteristics. Normality assumptions were tested with the Shapiro-Wilk test. Data are presented as means and standard deviations or medians and interquartile ranges for variables with a skewed distribution. For categorical data, proportions are shown. To predict changes in 6MWD over time and to account for intrarecipient correlations between multiple measurements, we applied a linear mixed model with the restricted maximum-likelihood method and an unstructured correlation structure. With this repeated-measures analysis, all available data points were used; if a single score was missing, then other data from that patient were not omitted from the analysis. Measurement moment and diagnosis category were set as factors.24 Possible explanatory variables (including age, sex, quadriceps force, grip strength, lung function values, type of transplantation [single versus double], length of hospital stay, rejection, and body mass index) were selected on the basis of clinical relevance and were explored by being entered into the linear mixed-model analysis. Variables were maintained in the model on the basis of the minimum Akaike information criterion.
To increase clinical interpretability and to avoid large correlations between estimates,24 we centered quadriceps strength at 250 N, grip strength at 91 N, FEV1 at 65% of the predicted value, and length of hospital stay at 39 days (means of the study population). All variables were included as fixed effects. Interaction effects and a random intercept were explored. Additional linear mixed-model analyses were performed after 5 separate imputations of missing data (multivariate imputation with chained equation). The results were subsequently pooled to gain further insight into the robustness of the predicted effects. The intercept of the model represents the estimated 6MWD that would be obtained if all predictor variables were defaults. The β hats of the variables in the model represent the difference between 6MWD and the reference category (categorical data) or the change in 6MWD that was expected with 1-unit change in a given variable (continuous variables).
Differences between recipients reaching 82% of the predicted 6MWD and recipients not reaching this distance were analyzed. Categorical variables were tested with the chi-square test, and for continuous data, the Student t test or the Welch t test was used. Variables at discharge that were significantly related to “reaching 82%” at 12 months after LTx were entered into a logistic regression analysis (backward method). Two-sided significance tests were used (α<.05). Analyses were performed with statistical programming language R (version 2.12.0) and IBM SPSS statistical software (version 20.0, IBM SPSS, Armonk, New York).
Results
Characteristics of Study Sample
The initial database comprised 269 patients, 111 of whom met the inclusion criteria (Fig. 1). Three patients were excluded from the analyses because of the limited representation of their conditions (2 patients received a transplantation because of graft-versus-host disease after leukemia treatment, and 1 patient was diagnosed with histiocytosis X). The mean age at transplantation of the 108 included recipients was 51.5 years (SD=11.3), 49 (45.4%) were men, and the median waiting list time was 505 days (interquartile range=191–861). Double lung transplantation was performed in 90 recipients (83.3%). The recipients were grouped as follows: approximately half in the COPD group (53 [49.1%]), 11 (10.2%) in the pulmonary vascular disease group, 16 (14.8%) in the CF group, and 28 (25.9%) in the pulmonary fibrosis group.
Flowchart of inclusion of recipients of lung transplantation in data analysis. TX=transplantation.
Almost half (48%) of the patients used oxygen supplementation during 6MWD testing at T0, 3 (3%) used oxygen supplementation at T1, and none used oxygen supplementation at T2 and T3. At T0 (screening, n=65), 59% of the patients received physical therapist intervention in the home situation; this number increased to 87% at T2 (6 months, n=102) and decreased slightly to 77% at T3 (12 months, n=87). The longitudinal data for potential predictors and 6MWD are shown in Table 1. The longitudinal change in 6MWD (in meters) for each diagnosis category is shown in Figure 2.
Main Outcome Measures for Included Recipients of Lung Transplantation at Each Measurement Moment (T0–T3)a
Means and standard deviations of 6-minute walking distance (6MWD) for each primary diagnosis category over time. Horizontal line indicates predicted 6MWD. △=chronic obstructive pulmonary disease group, ▽=pulmonary vascular disease group, □=cystic fibrosis group, ○=pulmonary fibrosis group. T0=screening, T1=day of discharge or days preceding discharge, T2=6 months after lung transplantation, T3=12 months after lung transplantation.
Sixty-one of the 158 patients who did not meet the inclusion criteria received a transplantation; 44 (72.1%) received double LTx. The mean age of these 61 patients was 48.4 years (SD=13.9), 28 (45.9%) were men, and the distributions over diagnosis categories were as follows: 34 (55.7%) in the COPD group, 4 (6.6%) in the pulmonary vascular disease group, 14 (23.0%) in the CF group, and 9 (14.8%) in the pulmonary fibrosis group. The patients who received a transplantation but were excluded did not differ significantly from the included recipients. The remaining 97 patients were deceased (without receiving a transplantation; n=34) or were still on the waiting list at the time of the analyses (n=63).
Predictive Variables for 6MWD
The linear mixed-model analysis for 6MWD resulted in significant effects for the variables measurement moment, diagnosis category, sex, quadriceps and grip strength, FEV1, and length of hospital stay. A random intercept significantly increased the model fit. Grip strength did not have a significant coefficient (P=.139), but the model fit decreased significantly (Akaike information criterion) when grip strength was omitted; therefore, grip strength was retained in the model.
The results showed that women were expected to walk 30 m less and that a change of 0.3 m was expected with every newton change in quadriceps and grip strength. Furthermore, a change of 1.4 m was expected with every percentage change in FEV1, and with every additional day in the hospital, the expected 6MWD was reduced by 1.6 m (Tab. 2). The intercept indicated that, on average, a man with pulmonary vascular disease, a hospital stay of 39 days, a quadriceps strength of 250 N, a grip strength of 91 N, and an FEV1 65% of the predicted value was expected to walk 432 m at T0. Age, body mass index, type of transplantation (double versus single), DLCO, total lung capacity, and rejection did not improve the model fit, and no interaction effect was found. To facilitate comparison, we added the model without grip strength to Table 2.
Results of Mixed-Model Analyses for Predicting 6-Minute Walking Distance (6MWD) in Recipients of Lung Transplantationa
The pooled results from the mixed-model analysis after a series of 5 imputations of missing data were comparable to the results obtained without data imputation. Significant effects remained for measurement moment, diagnosis category, quadriceps strength, FEV1, and length of hospital stay. Sex and grip strength were not shown to be significant in the model after data imputation.
Reaching the Cutoff Point for 6MWD
Of the 84 recipients for whom data were available at T1 (discharge) and T3 (12 months), 35 (41.7%) reached the cutoff point of 82% of the predicted 6MWD or higher at T3, and 49 (58.3%) did not. Exploratory analyses showed significant between-group differences for 6MWD (percentage of predicted) at T1 and for diagnosis category, sex, length of hospital stay, FEV1, DLCO, and quadriceps and grip strength at T1 and T3 (Tab. 3). These significant variables were entered into the logistic regression analysis. It was not possible to retrieve reliable data on the contribution of DLCO from the regression analysis because of an insufficient number of data points.
Comparison of Recipients Who Reached 82% of Predicted 6-Minute Walking Distance (6MWD) at 12 Months After Lung Transplantation (LTx) and Recipients Who Did Nota
A significant effect found for FEV1 at T1 could be interchangeably combined with quadriceps force at T1 or grip strength at T1 (Tab. 4). Both models showed an increase in odds (to reach 82% of the predicted 6MWD at T3) of 4% with every percentage increase in predicted FEV1. In the model with quadriceps strength, the odds additionally increased by 2% for every newton increase in quadriceps strength; for grip strength, a 6% increase in odds was observed with every newton increase. Because quadriceps force and grip strength were substantially correlated at T1 (r=.631, P<.001), they were not entered into the model simultaneously so as to prevent multicollinearity.
Logistic Regression Analyses (Models 1 and 2) of 6-Minute Walking Distance Performance of Recipients of Lung Transplantationa
Discussion
The findings of this longitudinal study suggest that, besides LTx itself increasing lung function, quadriceps strength was the only directly modifiable variable that predicted 6MWD and thereby functional exercise capacity. Additionally, quadriceps strength and FEV1 were factors significantly predicting recipients reaching the lower bound of 82% of the predicted 6MWD. Another factor contributing significantly to 6MWD and to reaching the lower bound of 82% of the predicted value was grip strength. The initial improvement in 6MWD between discharge and 6 months was not continued up to 12 months after LTx. At 12 months after LTx, more than half of the recipients had an inadequate walking distance (<82% of the predicted value).
The results for 6MWD at 12 months after LTx may be explained by the sedentary lifestyle that was previously shown for recipients of LTxs.8,25 With 6MWD being an indicator of sedentary behavior25 as well as a good representative of the ability to perform physical activity in daily life,26 increasing 6MWD, potentially by increasing quadriceps strength, seems to be important. A sufficient exercise capacity is highly relevant in recipients of LTxs; it not only is expected to increase the possibility of performing activities of daily life25 and to increase the quality of life27 but also is related to survival.28–30 Performance on the 6MWD test during the waiting list period has been shown to be a predictor for surviving this waiting list period28–30 and for survival after LTx across all lung disease categories,30 with shorter 6MWD values being associated with increased mortality rates. Lower exercise capacity at 1 year after LTx was also indicated to be independently associated with increased mortality.31
The results of the present study suggest that, as for maximal exercise capacity, peripheral muscle function—that is, quadriceps muscle function—seems to be the main target for intervention in submaximal exercise. However, whether quadriceps training on its own would contribute to a clinically relevant increase in submaximal exercise capacity is questionable. To achieve the reported minimal clinically important difference of 54 m,32 an increase of 180 N (54/0.3), which is substantial, must be reached. These data suggest that therapy should not focus solely on quadriceps training but should be more extensive.
Higher grip strength values also were associated with longer 6MWD values in the first linear mixed-model analysis, but this association was not confirmed by an additional analysis with data imputation. Grip strength has been associated with general well-being and prediction of mortality.33,34 Furthermore, grip strength has been associated with health-related quality of life,35 the metabolic syndrome,36 and frailty.37 Frailty, in turn, has been proposed as a factor that should be considered in the screening process because it reflects muscle mass (sarcopenia), the immune process, and inflammatory responses.38 Overall, it is not likely that grip strength training would increase walking distance because grip strength appears to be reflective of an underlying general construct.
The longitudinal analyses provide a distinctive insight into the change in 6MWD over time. Relative to the baseline value, a significant decrease that was evident between screening and discharge after LTx was followed by a significant increase at 6 months and 12 months after LTx. The initial decline could be attributed to surgery, intensive care unit and hospital stay, and (relative) immobilization, especially directly after transplantation. Another contributing factor was the decline in exercise capacity that may have occurred between screening and transplantation. The increase in the period after discharge was expected as a result of recovery from surgery, increased lung function, an increase in daily activities, and training.
Remarkably, the initial increase in 6MWD between discharge and 6 months did not persist up to 12 months. A so-called “ceiling effect” may have been reached but, considering the low average values and the amount of interrecipient variation, it is more likely that other factors contributed to this finding. The use of immunosuppressants,13,39 a lower proportion of type I (oxidative) muscle fibers,10,12,13 and an early lactate threshold6,7 likely contributed to the decreased exercise capacity to a certain extent. Other possible explanatory factors could be a reduction in the frequency of physical therapist treatment, an insufficient training load because of a lack of familiarity of the physical therapist, end of treatment, or relapse into pre-LTx sedentary behavior patterns. Furthermore, it is possible that patients were satisfied when improved functioning relative to the pre-LTx situation was evident and did not strive for optimal functioning.
Future studies into increasing exercise capacity in recipients of LTxs should take the period between 6 and 12 months after LTx into account and provide insight into physical activity levels of daily life. Digital monitoring during this period or regular follow-up therapy or counseling at a lower frequency could provide opportunities. In addition, whether the focus should be on maximal peripheral muscle strength or maximal exercise capacity is questionable. In contrast to focusing on the often proposed need to train 2 or 3 times per week, further research into increasing functional exercise capacity by increasing general daily physical activity levels, possibly by recipients altering their lifestyles, appears to be worthwhile.
Potential limiting factors of the present study were the lack of knowledge about the course of disease during the waiting list period and the lack of knowledge about the duration, frequency, and type of training after LTx. Likewise, comorbidities were not systematically recorded and remained an unknown confounder. Regarding grip strength, only values measured with the MicroFET II were available; preferably, the Jamar dynamometer (Sammons Preston Rolyan, Bolingbrook, Illinois) would have been used to facilitate comparisons with other studies and reference values. Furthermore, because all measurements took place over a period of 10 years, outcomes were measured by different personnel; this situation may have caused bias. However, we used standardized and reliable measurement methods14,20,26,40 to minimize this risk. Moreover, the number of missing data points may have influenced the outcome. However, the additional analysis after data imputation confirmed the robustness of most of the predictive variables. The contribution of DLCO to the logistic regression analysis on reaching 82% of the predicted 6MWD could not be determined because of insufficient data points and must be clarified in future research. Finally, the models presented were based on data from recipients who survived at least half a year (data from 3 measurement moments were available); this situation may have influenced the outcome. However, because the main outcome measurement was related to the course of recovery up to 1 year after LTx, the models addressed this population. Overall, these limitations suggest the need for some caution in the interpretation of the data and confirmation by additional research.
In conclusion, the findings of the present study are in line with previous findings and provide additional evidence that physical therapist interventions should include quadriceps muscle force training to increase functional exercise capacity; however, the program should be more extensive. The course of recovery after transplantation indicates that attention should be paid to the period between 6 and 12 months.
Footnotes
Mr van Adrichem, Ms Reinsma, Ms van den Berg, Dr van der Bij, Dr Erasmus, Dr Dijkstra, and Dr van der Schans provided concept/idea/research design. Mr van Adrichem, Dr Dijkstra, and Dr van der Schans provided writing. Mr van Adrichem, Ms Reinsma, and Ms van den Berg provided data collection. Mr van Adrichem, Dr Krijnen, Dr Dijkstra, and Dr van der Schans provided data analysis. Mr van Adrichem and Dr van der Schans provided project management. Dr van der Bij and Dr Erasmus provided participants and facilities/equipment. All authors provided consultation (including review of manuscript before submission).
The Institutional Review Board of the University Medical Center Groningen provided approval for the use of clinical data (M13.146042).
- Received January 15, 2014.
- Accepted November 26, 2014.
- © 2015 American Physical Therapy Association
References
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