Lung transplantation is being increasingly provided to older patients and those with comorbid conditions who may be at higher risk for skeletal muscle dysfunction.1,2 Skeletal muscle dysfunction is an encompassing term that refers to the structural and functional changes observed in limb muscles.3 Thus, the evaluation of skeletal muscle dysfunction can span the spectrum from alterations in bioenergetics, contractility, and structural integrity at the muscle fiber level to noninvasive measures of muscle mass, muscle strength, and performance of functional activities.3,4
Skeletal muscle dysfunction is an important concern in older adults and those with chronic disease. The age-related loss of muscle mass and function is termed sarcopenia and potentially accelerated with chronic disease.5 Sarcopenia is prevalent in up to 33% of community dwelling older adults based on the European working group expert consensus definition of sarcopenia, low muscle mass plus one of low muscle strength or function.5,6 Sarcopenia has been associated with increased physical disability, poor quality of life and mortality in older adults.7,8 In patients with chronic obstructive pulmonary disease (COPD), skeletal muscle deficits such as low fat-free mass (FFM) from bioelectrical impedance (BIA),9 quadriceps strength,10 and mid-thigh cross-sectional area11 have been associated with increased morbidity and mortality. Similarly, quadriceps muscle weakness is observed in individuals with interstitial lung disease (ILD) and associated with reduced exercise capacity12 and physical activity levels13; both of which are related to reduced survival in ILD.14,15
Lung transplant candidates have impairments in muscle function including reduced muscle mass, strength and physical performance.16 In addition to muscle dysfunction, the majority of these patients have significant limitations in exercise capacity, activities of daily living, and health-related quality of life (HRQL).17,18 Recent studies in lung transplant candidates have shown that low physical function and abdominal muscle cross-sectional area from computed tomography have been associated with pretransplant delisting/mortality19 and posttransplant hospital length of stay,20,21 respectively. Despite skeletal muscle dysfunction being prevalent, the contribution of these measures to daily function and HRQL has not been investigated in lung transplant candidates. Similarly, the clinical implications of low muscle mass, strength, and/or physical performance have not been well characterized.
The primary aims of this study were to characterize skeletal muscle deficits (low muscle mass, strength, and physical performance) in lung transplant candidates and assess the association of muscle deficits with exercise capacity, activities of daily living, and HRQL. As a second aim, we assessed the association between muscle deficits and pretransplant and early posttransplant clinical outcomes. We hypothesized that a greater number of muscle deficits would be associated with impaired exercise capacity, HRQL, and early posttransplant outcomes.
MATERIALS AND METHODS
Participants
Fifty adult lung transplant candidates listed for single or double lung transplant at University Health Network between April 2014 and April 2015 were included in the study. The exclusion criteria were as follows: (1) awaiting a retransplant or multiorgan transplant; (2) previous diagnosis of neuromuscular disease; (3) unable to communicate in English; (4) presence of ascites or significant peripheral edema, which could confound BIA assessment22; (5) presence of cardiac pacemaker which is a contraindication to BIA (6) listed as “rapidly deteriorating” or inpatient status; and (7) respiratory exacerbation within 4 weeks. All participants provided written informed consent and the study was approved by University Health Network (REB 13-6696-BE) and University of Toronto (REB 30045).
Study Design
This was a prospective cohort study where participants were evaluated for skeletal muscle deficits: FFM using BIA, respiratory and peripheral muscle strength (quadriceps and handgrip), and physical performance using the Short Physical Performance Battery (SPPB). Exercise capacity, activities of daily living, and HRQL were also assessed. Study assessments were performed 4 weeks after transplant listing.
All subjects were participating in a mandatory, supervised outpatient pulmonary rehabilitation program 3 times per week for the duration of their waitlist period. The exercise sessions were 90 minutes in length and comprised of aerobic, resistance, and flexibility training. Aerobic exercise consisted of treadmill walking and cycling for 20 minutes each with intensity progressed by the physical therapist ensuring appropriate oxygen saturation (SpO2 ≥ 88%), target heart rate (50-80% of age-predicted maximum heart rate), and dyspnea rating scale23 (modified Borg rating scale of 3 to 5). Resistance training was focused on the larger muscle groups (triceps, biceps, quadriceps, hamstrings, and hip muscles) with training loads progressed to maintain a maximum of 10 repetitions per set for each muscle group. A detailed description of the outpatient rehabilitation program has been previously described.24 The assessment time point of 4 weeks after listing was chosen to allow optimization of the exercise training program during this period, and we do not expect any functional gains at this early stage. This time point has been used in other cross-sectional studies of lung transplant candidates at our center.13,25 Pretransplant and posttransplant clinical outcomes were ascertained at the time of hospital discharge and 3 months posttransplant. Study enrolment began on April 1, 2014, and participants were followed up until September 30, 2016.
Skeletal Muscle Assessments
Muscle Mass
FFM was assessed using 50-kHz BIA commercial instrument (Bodystat 1500MDD; Body Stat Limited, UK). Participants were provided written instructions to avoid physical exercise for 12 hours and avoid eating or drinking for 2 hours before testing.22 BIA was performed in the morning after 5 minutes of rest in the supine position. FFM was standardized for height and expressed as FFM index (FFMI).26 FFMI was expressed as absolute (kg/m2) and low muscle mass was defined if below the normative value derived from proprietary equations based on age, sex, and height (Body Stat, UK).27
Peripheral Muscle Strength
Handgrip force was evaluated using a handgrip dynamometer (Jamar, Lafayette Instruments). Peak handgrip force was assessed on the dominant hand with the arm by their side and elbow flexed to 90 degrees. The highest of 3 maximal isometric voluntary contractions, with 1-minute rest interval between trials, was used, and low handgrip force was defined as greater than 1 SD below the mean of predicted values.28
Quadriceps peak torque was assessed using a computerized dynamometer (Biodex Medical Systems 4, New York, NY), according to a previously established protocol.29 Maximal isometric quadriceps torque on the dominant leg was assessed with the hip at 90 degrees and knee at 60 degrees flexion. The highest torque, from 5 maximal voluntary contractions 1 minute apart, was used for analysis. Low quadriceps muscle strength was defined as more than 1 SD below the mean for age, sex, and height values described using a published equation by Gosselink et al30 and consistent with previous characterizations of low quadriceps strength.31,32
Respiratory Muscle Strength
Maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP) were evaluated per standard methods in the pulmonary function lab within 2 weeks of peripheral muscle testing. The highest of 3 values (within 20%) was obtained for MIP and MEP and expressed as a percent of predicted using equations derived from a Canadian population.33,34
Physical Performance
The SPPB was used to evaluate physical performance. SPPB score is a summation of scores on 3 functional tests: balance, gait speed, and chair stands with each test weighed equally with a score of 0 to 4; and a maximal cumulative score of 12. A total score of 9 or lower has been defined as low performance and was used to categorize low physical function.35-37
Exercise Capacity
The 6-minute walk test was performed by a physical therapist in accordance with the American Thoracic Society Guidelines at 4 to 6 weeks after transplant listing.38 Six-minute walk distance (6MWD, m) was recorded and expressed as percent predicted based on a Canadian population reference equation.39
Quality of Life and Activities of Daily Living
Patients completed a generic health index (Short Form-36 [SF-36]) and respiratory disease-specific index (St. George’s Respiratory Questionnaire [SGRQ]) administered through a single internet site, as previously described.40 The SF-36 physical function domain and the activity domain of the SGRQ were included given their previously described associations with physical activity in lung transplant patients.41,42 The London Chest Activity of Daily Living (LCADL) was used to characterize participation in activities of daily living. This questionnaire has been used in lung transplant candidates.43,44
Demographic Data and Clinical Measures
The following information was obtained from medical records at the time of transplant listing: age, sex, body mass index, indication for transplant, lung allocation score, oxygen requirements for exercise, pulmonary function, and corticosteroid use.
Self-reported healthcare utilization (number of emergency department visits, hospitalizations, and antibiotic or corticosteroid requirements) along with unintentional weight loss in the last 1 year were obtained through a standardized questionnaire at initial assessment. Self-reported physical activity was ascertained using the Physical Activity Scale for the Elderly (PASE).45
Charts were reviewed to assess pretransplant medical delisting/mortality, posttransplant intensive care unit (ICU) and hospital length of stay, discharge disposition (home, inpatient rehabilitation), and mortality during the transplant hospital admission. Three-month posttransplant mortality and 6MWD were obtained from chart review, and 6MWD was expressed as percent predicted using the reference equation for Canadian adults.39
Sample Size Calculation
Based on a previous study of lung transplant candidates and low quadriceps strength,41 we determined that a sample size of 44 participants (33% prevalence of at least 2 of 3 muscle deficits) would yield 80% power (α = 0.05) to detect differences in 6MWD (100 m, effect size = 0.9). We hypothesized that there would be greater limitation in 6MWD with 2 muscle deficits than quadriceps strength alone. A sample size of 50 was used to account for attrition rates pretransplant.
Statistical Analysis
Analysis was performed using Graph-Pad Prism (Version 7.0). Continuous variables were expressed using mean ± standard deviation or median (interquartile range [IQR], 25-75%) with categorical variables described using frequencies. Distribution of data was assessed using Kolmogorov-Smirnov and Pearson omnibus normality tests.
Comparison between cumulative number of skeletal muscle deficits (low muscle mass, strength and physical performance) and exercise capacity, activities of daily living, and HRQL were assessed using 1-way analysis of variance with post hoc Bonferroni analysis. Associations between individual muscle measurements were also assessed using Pearson and Spearman correlations.
Associations with skeletal muscle deficits and pretransplant medical delisting/death and posttransplant outcomes, such as ICU and hospital length of stay, discharge disposition, and posttransplant 6MWD at 3 months, were assessed using Fisher exact tests and Spearman correlation. A P value less than 0.05 was considered significant for all analyses.
RESULTS
Participants
Fifty lung transplant candidates (58% men, 59 ± 9 years) participated in the study (Figure 1). The cohort is described in Table 1. All but 3 participants were on oxygen therapy for activity with the following requirements: nasal prongs ranging from 2 to 8 L/min (n = 27), Venturi mask 50% (n = 5), high oxygen flow rates ranging from 8 to 15 L/min (n = 8), and 15 L nonrebreather mask (n = 7). Self-reported physical activity was significantly reduced with a PASE score of 83.5 ± 44.4 (low score defined in frail elderly as < 89.6).46 Self-reported unintentional weight loss (≥10 lb/year) was seen in 13 (26%) participants.
;)
FIGURE 1: Flow diagram of study participants.
TABLE 1: Baseline characteristics for lung transplant candidates (n = 50)
Skeletal Muscle Mass, Strength, and Performance
There were no significant differences between lung disease (COPD, ILD, and pulmonary hypertension/cystic fibrosis) in percent predicted handgrip or quadriceps strength, FFMI, or SPPB, whereas MIP was reduced in patients with COPD compared with ILD (77 ± 25% vs 109 ± 37 %, P = 0.01). FFMI, muscle strength and physical performance are summarized in Table 2.
TABLE 2: Muscle mass, strength, and physical performance
The distribution of peripheral and respiratory muscle strength based on predicted values for quadriceps, hand-grip, MIP, and MEP is outlined in Figures 2A-D. The proportion of lung transplant candidates with quadriceps muscle weakness was more common (greater than 1 SD below the mean observed in 54% of participants) relative to handgrip strength (36%), MIP (19%), and MEP (5%) (P < 0.0001, Figure 2).
FIGURE 2: Distribution of peripheral (panels A and B) and respiratory muscle strength (panels C and D). Outlined percentage represents number of lung transplant candidates with measures > 1 SD below the mean from predicted equations for quadriceps strength,
30 handgrip strength,
28 and respiratory muscle strength.
34There was significant overlap between reduced skeletal muscle mass, quadriceps strength, and physical performance in lung transplant candidates (Figure 3). Thirty-seven (74%) individuals had at least 1 muscle deficit. Low quadriceps strength (n = 27, 54%) and low performance on the SPPB (n = 24, 48%) were more commonly observed compared with impairments in muscle mass (n = 8, 16%). Individuals who had low muscle mass (n = 8, 16%) were generally observed to have either low muscle strength or SPPB score (6/8, 75%), whereas a functional deficit in strength or SPPB was present in 29 (83%) of 35 participants with normal muscle mass. Low muscle mass was more likely to be present in COPD patients (5/12, 41%) compared with other lung conditions (3/38, 8%) (P = 0.01).
FIGURE 3: Distribution of skeletal muscle deficits in lung transplant candidates (n = 50). Low muscle mass: low FFMI from bio-electrical impedance (Body Stat Limited).
27 Low muscle strength: quadriceps strength > 1 SD below the mean for age, sex, and height predicted values.
30 Low physical performance: score of ≤ 9 on the SPPB.
35-37Exercise Capacity, Activities of Daily Living, and Quality of Life
6MWD (52 ± 13 % predicted), activities of daily living, and HRQL were significantly impaired in lung transplant candidates (Table 3). Quadriceps strength and SPPB had moderate associations with 6MWD, LCADL, and HRQL; however, no associations were observed with FFMI (Table 3). Lung transplant candidates with either 2 or 3 skeletal muscle deficits had significantly lower 6MWD, worse LCADL and HRQL scores than those with no deficits (Table 4).
TABLE 3: Associations of skeletal muscle measures with exercise capacity, LCADL, and HRQL
TABLE 4: Exercise capacity, LCADL, and HRQL based on number of skeletal muscle deficits
Pretransplant and Posttransplant Clinical Outcomes
Healthcare utilization in the year before transplant listing is described in Table 1. No difference was observed between healthcare utilization in the year before listing and number of skeletal muscle deficits (not shown). Similarly, number of skeletal muscle deficits was not associated with age (r = −0.08, P = 0.59) or lung allocation score (r = 0.03, P = 0.85).
Forty-six (94%) participants attained a waiting list endpoint of transplantation, death or medical delisting during the follow-up period (Figure 1). The median waitlist duration of these 46 patients was 156 (IQR, 97-287) days after musculoskeletal assessment. Thirty-eight (83%) of the 46 patients survived to hospital discharge posttransplant (Figure 1) with 5 (13%) recipients discharged to inpatient rehabilitation. The median length of stay in the ICU and hospital for the 38 participants surviving to hospital discharge was 5 days (IQR, 3-16) and 23 days (IQR, 17-48), respectively. Total number of skeletal muscle deficits pretransplant was associated with posttransplant hospital length of stay (r = 0.34, P = 0.039), but not ICU duration (r = 0.11, P = 0.50). Of the individual skeletal muscle deficits, quadriceps strength was associated with hospital length of stay (r = −0.34, P = 0.038), whereas no associations were found with FFMI (r = −0.21, P = 0.21) or SPPB (r = −0.17, P = 0.30).
Low quadriceps strength (>1 SD below the mean for predicted values) was observed in 5 (63%) of 8 participants who were medically de-listed or died pretransplant or posttransplant compared with 20 (53%) of 38 (P = 0.71) surviving to hospital discharge posttransplant. There were no differences in the proportion of individuals with low muscle mass (2/8, 25% vs 6/38, 18%; P = 0.61) or reduced score of 9 or less on the SPPB (2/8, 25% vs 21/38, 55%; P = 0.24) who were medically delisted or died pretransplant or posttransplant compared with those discharged from hospital, respectively.
All 38 lung transplant recipients discharged from hospital survived to 3 months posttransplant. Their mean 6MWD was 432 ± 110 m (66 ± 16%, n = 35) and they demonstrated an improvement in 6MWD of 96 ± 104 m from the pretransplant measurement. No association was observed between number of skeletal muscle deficits and posttransplant 6MWD (r = −0.23, P = 0.18) or with the change in 6MWD from pretransplant values (r = 0.05, P = 0.76).
DISCUSSION
We observed that skeletal muscle dysfunction was prevalent in lung transplant candidates, and a greater number of skeletal muscle deficits was associated with worse exercise capacity, activities of daily living, HRQL, and longer hospital length of stay posttransplant. Skeletal muscle deficits in our population were characterized predominantly by impairments in lower-extremity strength and physical performance, rather than low muscle mass. We also observed that impaired muscle function could be present even when muscle mass was within the normal range.
This is the first study to measure muscle mass, strength, and physical performance in lung transplant candidates consistent with the framework of sarcopenia.5 Previous work in COPD patients described the prevalence of sarcopenia as 15%, and quadriceps weakness was present in more than half of the patients.31 These findings are in keeping with our study, demonstrating that impairments in lower-extremity strength and physical function are common in advanced lung disease and not necessarily concordant with low muscle mass. In community dwelling older adults, muscle mass is often preserved with aging relative to loss of muscle strength and physical function.47 Impairments in muscle quality (ie, fat infiltration), reduction in intrinsic force generating properties, and neuromuscular changes in voluntary control are a few factors that could contribute to the differential loss of muscle function relative to muscle mass.48,49 The concept of dynapenia,50 defined by the loss of muscle strength and physical function, might be more predictive of clinical outcomes in advanced lung disease and requires further attention.
There are multiple factors which contribute to skeletal muscle dysfunction such as hypoxemia, malnutrition, physical inactivity/disuse, hospitalizations, corticosteroids, and systemic inflammation.3,51 The lung transplant candidates in the present study had multiple risk factors for muscle dysfunction. Most study participants (>90%) were using long-term oxygen therapy for exertion and one third were taking daily oral corticosteroids. In addition, unintentional weight loss of 10 lb or greater in the prior year was observed in about a quarter of our study participants, which could be related to protein imbalance as previously described in cardiopulmonary disease.52 Unfortunately, given the cross-sectional study design, we are unable to identify the contributing factors to muscle dysfunction. It is possible that the impaired lower extremity function (quadriceps weakness and low SPPB) observed in this study could be in part related to general disuse or deconditioning, as evident from the low physical activity levels on the PASE. Thus, strategies targeting strength training of the lower extremities and increased physical activity could be beneficial in improving the skeletal muscle weakness observed in these patients.
Skeletal muscle deficits (mainly quadriceps weakness and physical performance) were associated with impairments in exercise capacity, activities of daily living, and HRQL. Previous reports have described independent associations of quadriceps strength with exercise capacity30,53,54 and activities of daily living in patients with COPD and ILD.55 Similarly, Singer et al19 demonstrated that SPPB correlated strongly with exercise capacity and disability in lung transplant candidates. However, the association of HRQL measures and skeletal muscle deficits has not been previously described in lung transplant candidates. The striking difference across skeletal muscle deficits suggests that muscle dysfunction is a significant contributor to HRQL, which is only partially captured with disease severity markers, such as Lung Allocation Score score56 or resting lung function measures as seen in COPD57,58 and ILD studies.59 Thus, measurement of skeletal muscle deficits might provide additional insight into daily functioning, disability, and health status of lung transplant candidates.
We observed that a greater number of skeletal muscle deficits was associated with a longer hospital length of stay, but not with exercise capacity posttransplant. Specifically, pretransplant quadriceps strength proved to be the only muscle determinant associated with hospital length of stay, which is consistent with previous reports describing quadriceps strength as an important prognostic marker in COPD patients.10 We did not measure quadriceps specific muscle size which may have been more informative than a whole body composition measure as loss of muscle mass may be regional and not necessarily captured by FFMI.60 The lack of association of skeletal muscle deficits with posttransplant exercise capacity at 3 months is interesting since lower extremity muscle dysfunction has been attributed to reduced oxidative capacity and peak oxygen consumption in the posttransplant period.61,62 However, recovery of exercise capacity in the early posttransplant period is multifactorial and is influenced by preoperative conditioning and postoperative factors such as immune-suppression and physical activity levels,41,63 which encompass changes beyond muscle atrophy and quadriceps weakness with hospitalization.64,65 In the present study, we did not measure posttransplant quadriceps strength, which may have had a stronger association with posttransplant 6MWD.65,66 Walsh et al66 previously demonstrated that the improvement in 6MWD up to 26 weeks post lung transplant was independently associated with the recovery in quadriceps strength from pretransplant baseline values. We also did not observe a relationship between SPPB and clinical outcomes, which is somewhat surprising given the previously described association with increased pretransplant mortality/delisting in lung transplant candidates19 and disability in community dwelling elderly.35,67 It is possible that we were underpowered given the range of SPPB scores was narrow in our study sample. Given the complexity of lower extremity skeletal muscle dysfunction in the pretransplant and posttransplant period, a better understanding of the clinical implications of lower extremity muscle atrophy and function on clinical outcomes are needed.
There are several study limitations that should be noted. First, we recruited a select group of stable lung transplant candidates who were participating in a mandatory outpatient pulmonary rehabilitation program. Thus, our results may not be representative of the entire lung transplant population because skeletal muscle dysfunction may be more pronounced in patients declined for transplant listing or those hospitalized or too ill to participate in outpatient rehabilitation. Second, skeletal muscle function was evaluated close to the time of transplant listing; however, the effect of waitlist duration or pretransplant rehabilitation on skeletal muscle function was not considered, and may have influenced posttransplant outcomes, which represents an important area of future investigation. Third, we characterized upper and lower extremity muscle strength using handgrip force and quadriceps torque, respectively. Even though quadriceps strength was more commonly reduced, we are unable to comment on the proximal muscles of the upper extremity since they are not necessarily captured with measurement of handgrip force. Furthermore, lower extremity muscle atrophy or muscle quality (ie, fat infiltration) were not evaluated, which could be important clinical determinants in future studies given their association with quadriceps muscle weakness.68,69 Although ILD represents the largest group of patients referred for lung transplantation in the present era,70 this study cohort had a larger number of participants with ILD than expected compared with other diagnoses. Thus, the findings in the present study might not be applicable across all disease groups, such as cystic fibrosis and pulmonary arterial hypertension, which were underrepresented in our cohort. We were also not powered to make comparisons among disease groups for any differential effects of skeletal muscle deficits on exercise capacity, HRQL, and activities of daily living. Future studies could aim to examine the relationship between skeletal muscle deficits and daily function across the various indications for lung transplantation.
CONCLUSIONS
This study demonstrates that a greater number of skeletal muscle deficits (muscle mass, strength, and physical function) was associated with worse exercise capacity, activities of daily living, HRQL, and posttransplant hospital length of stay. These skeletal muscle deficits were characterized predominantly by reductions in lower-extremity strength and physical performance, which were present even in individuals with preserved muscle mass. Further research is needed to identify whether modifying skeletal muscle dysfunction in the pretransplant period will influence early and late posttransplant outcomes.
ACKNOWLEDGMENTS
The authors would like to thank the lab staff volunteers Laura Lopez-Hernandez and Matthew Rhim for their assistance with data collection. The authors would like to also acknowledge the physiotherapists Denise Helm and Chaya Gottesman who helped with study recruitment.
REFERENCES
1. Weill D, Benden C, Corris PA, et al. A consensus document for the selection of lung transplant candidates: 2014—an update from the Pulmonary Transplantation Council of the International Society for Heart and Lung Transplantation.
J Heart Lung Transplant. 2015;34:1–15.
2. Hook JL, Lederer DJ. Selecting lung transplant candidates: where do current guidelines fall short?
Expert Rev Respir Med. 2012;6:51–61.
3. Maltais F, Decramer M, Casaburi R, et al. An official American Thoracic Society/European Respiratory Society statement: update on limb muscle dysfunction in chronic obstructive pulmonary disease.
Am J Respir Crit Care Med. 2014;189:e15–e62.
4. Mador MJ, Bozkanat E. Skeletal muscle dysfunction in chronic obstructive pulmonary disease.
Respir Res. 2001;2:216–224.
5. Cruz-Jentoft AJ, Baeyens JP, Bauer JM, et al. Sarcopenia: European consensus on definition and diagnosis: report of the European Working Group on Sarcopenia in Older People.
Age Ageing. 2010;39:412–423.
6. Cruz-Jentoft AJ, Landi F, Schneider SM, et al. Prevalence of and interventions for sarcopenia in ageing adults: a systematic review. Report of the International Sarcopenia Initiative (EWGSOP and IWGS).
Age Ageing. 2014;43:748–759.
7. Delmonico MJ, Harris TB, Lee JS, et al. Alternative definitions of sarcopenia, lower extremity performance, and functional impairment with aging in older men and women.
J Am Geriatr Soc. 2007;55:769–774.
8. Goodpaster BH, Park SW, Harris TB, et al. The loss of skeletal muscle strength, mass, and quality in older adults: the health, aging and body composition study.
J Gerontol A Biol Sci Med Sci. 2006;61:1059–1064.
9. Slinde F, Gronberg A. Energy requirement in COPD.
Clin Nutr. 2005;24:862; author reply 863.
10. Swallow EB, Reyes D, Hopkinson NS, et al. Quadriceps strength predicts mortality in patients with moderate to severe chronic obstructive pulmonary disease.
Thorax. 2007;62:115–120.
11. Marquis K, Debigare R, Lacasse Y, et al. Midthigh muscle cross-sectional area is a better predictor of mortality than body mass index in patients with chronic obstructive pulmonary disease.
Am J Respir Crit Care Med. 2002;166:809–813.
12. Nishiyama O, Taniguchi H, Kondoh Y, et al. Quadriceps weakness is related to exercise capacity in idiopathic pulmonary fibrosis.
Chest. 2005;127:2028–2033.
13. Wickerson L, Mathur S, Helm D, et al. Physical activity profile of lung transplant candidates with interstitial lung disease.
J Cardiopulm Rehabil Prev. 2013;33:106–112.
14. Caminati A, Bianchi A, Cassandro R, et al. Walking distance on 6-MWT is a prognostic factor in idiopathic pulmonary fibrosis.
Respir Med. 2009;103:117–123.
15. Wallaert B, Monge E, Le Rouzic O, et al. Physical activity in daily life of patients with fibrotic idiopathic interstitial pneumonia.
Chest. 2013;144:1652–1658.
16. Rozenberg D, Wickerson L, Singer LG, et al. Sarcopenia in lung transplantation: a systematic review.
J Heart Lung Transplant. 2014;33:1203–1212.
17. Wickerson L, Mathur S, Brooks D. Exercise training after lung transplantation: a systematic review.
J Heart Lung Transplant. 2010;29:497–503.
18. Langer D. Rehabilitation in patients before and after lung transplantation.
Respiration. 2015;89:353–362.
19. Singer JP, Diamond JM, Gries CJ, et al. Frailty phenotypes, disability, and outcomes in adult candidates for lung transplantation.
Am J Respir Crit Care Med. 2015;192:1325–1334.
20. Weig T, Milger K, Langhans B, et al. Core muscle size predicts postoperative outcome in lung transplant candidates.
Ann Thorac Surg. 2016;101:1318–1325.
21. Kelm DJ, Bonnes SL, Jensen MD, et al. Pre-transplant wasting (as measured by muscle index) is a novel prognostic indicator in lung transplantation.
Clin Transplant. 2016;30:247–255.
22. Kyle UG, Bosaeus I, De Lorenzo AD, et al. Bioelectrical impedance analysis-part II: utilization in clinical practice.
Clin Nutr. 2004;23:1430–1453.
23. Borg GA. Psychophysical bases of perceived exertion.
Med Sci Sports Exerc. 1982;14:377–381.
24. Wickerson L, Rozenberg D, Janaudis-Ferreira T, et al. Physical rehabilitation for lung transplant candidates and recipients: an evidence-informed clinical approach.
World J Transplant. 2016;6:517–531.
25. Mendes P, Wickerson L, Helm D, et al. Skeletal muscle atrophy in advanced interstitial lung disease.
Respirology. 2015;20:953–959.
26. Walter-Kroker A, Kroker A, Mattiucci-Guehlke M, et al. A practical guide to bioelectrical impedance analysis using the example of chronic obstructive pulmonary disease.
Nutr J. 2011;10:35.
27. Body Stat. Bodystat®1500MDD.
http://www.bodystat.com/products/1500MDD. Updated 2017. Accessed December 1, 2016.
28. Mathiowetz V, Kashman N, Volland G, et al. Grip and pinch strength: normative data for adults.
Arch Phys Med Rehabil. 1985;66:69–74.
29. Mathur S, Hernandez P, Makrides L. Test-retest reliability of isometric and isokinetic torque in patients with chronic obstructive pulmonary disease.
Physiother Can. 2004;56:94–101.
30. Gosselink R, Troosters T, Decramer M. Peripheral muscle weakness contributes to exercise limitation in COPD.
Am J Respir Crit Care Med. 1996;153:976–980.
31. Jones SE, Maddocks M, Kon SS, et al. Sarcopenia in COPD: prevalence, clinical correlates and response to pulmonary rehabilitation.
Thorax. 2015;70:213–218.
32. Seymour JM, Spruit MA, Hopkinson NS, et al. The prevalence of quadriceps weakness in COPD and the relationship with disease severity.
Eur Respir J. 2010;36:81–88.
33. American Thoracic Society/European Respiratory S. ATS/ERS Statement on respiratory muscle testing.
Am J Respir Crit Care Med. 2002;166:518–624.
34. Gutierrez C, Ghezzo RH, Abboud RT, et al. Reference values of pulmonary function tests for Canadian Caucasians.
Can Respir J. 2004;11:414–424.
35. Guralnik JM, Simonsick EM, Ferrucci L, et al. A Short Physical Performance Battery assessing lower extremity function: association with self-reported disability and prediction of mortality and nursing home admission.
J Gerontol. 1994;49:M85–M94.
36. Perera S, Mody SH, Woodman RC, et al. Meaningful change and responsiveness in common physical performance measures in older adults.
J Am Geriatr Soc. 2006;54:743–749.
37. Patel MS, Mohan D, Andersson YM, et al. Phenotypic characteristics associated with reduced Short Physical Performance Battery score in COPD.
Chest. 2014;145:1016–1024.
38. Laboratories ATSCoPSfCPF. ATS statement: guidelines for the six-minute walk test.
Am J Respir Crit Care Med. 2002;166:111–117.
39. Gibbons WJ, Fruchter N, Sloan S, et al. Reference values for a multiple repetition 6-minute walk test in healthy adults older than 20 years.
J Cardiopulm Rehabil. 2001;21:87–93.
40. Bhinder S, Chowdhury N, Granton J, et al. Feasibility of internet-based health-related quality of life data collection in a large patient cohort.
J Med Internet Res. 2010;12:e35.
41. Wickerson L, Mathur S, Singer LG, et al. Physical activity levels early after lung transplantation.
Phys Ther. 2015;95:517–525.
42. Langer D, Burtin C, Schepers L, et al. Exercise training after lung transplantation improves participation in daily activity: a randomized controlled trial.
Am J Transplant. 2012;12:1584–1592.
43. Garrod R, Bestall JC, Paul EA, et al. Development and validation of a standardized measure of activity of daily living in patients with severe COPD: the London Chest Activity of Daily Living scale (LCADL).
Respir Med. 2000;94:589–596.
44. Muller JP, Gonçalves PA, Fontoura FF, et al. Applicability of the London Chest Activity of Daily Living scale in patients on the waiting list for lung transplantation.
J Bras Pneumol. 2013;39:92–97.
45. Washburn RA, Ficker JL. Physical Activity Scale for the Elderly (PASE): the relationship with activity measured by a portable accelerometer.
J Sports Med Phys Fitness. 1999;39:336–340.
46. Cawthon PM, Marshall LM, Michael Y, et al. Frailty in older men: prevalence, progression, and relationship with mortality.
J Am Geriatr Soc. 2007;55:1216–1223.
47. Mitchell WK, Williams J, Atherton P, et al. Sarcopenia, dynapenia, and the impact of advancing age on human skeletal muscle size and strength; a quantitative review.
Front Physiol. 2012;3:260.
48. Clark BC, Taylor JL. Age-related changes in motor cortical properties and voluntary activation of skeletal muscle.
Curr Aging Sci. 2011;4:192–199.
49. Delbono O. Expression and regulation of excitation-contraction coupling proteins in aging skeletal muscle.
Curr Aging Sci. 2011;4:248–259.
50. Manini TM, Clark BC. Dynapenia and aging: an update.
J Gerontol A Biol Sci Med Sci. 2012;67:28–40.
51. Panagiotou M, Polychronopoulos V, Strange C. Respiratory and lower limb muscle function in interstitial lung disease.
Chron Respir Dis. 2016;13:162–172.
52. Bouras EP, Lange SM, Scolapio JS. Rational approach to patients with unintentional weight loss.
Mayo Clin Proc. 2001;76:923–929.
53. Nishiyama O, Taniguchi H, Kondoh Y, et al. Health-related quality of life in patients with idiopathic pulmonary fibrosis. What is the main contributing factor?
Respir Med. 2005;99:408–414.
54. Mainguy V, Maltais F, Saey D, et al. Peripheral muscle dysfunction in idiopathic pulmonary arterial hypertension.
Thorax. 2010;65:113–117.
55. Singer JP, Katz PP, Iribarren C, et al. Both pulmonary and extra-pulmonary factors predict the development of disability in chronic obstructive pulmonary disease.
Respiration. 2013;85:375–383.
56. Chen F, Oga T, Yamada T, et al. Lung allocation score and health-related quality of life in Japanese candidates for lung transplantation.
Interact Cardiovasc Thorac Surg. 2015;21:28–33.
57. Wijkstra PJ, TenVergert EM, van der Mark TW, et al. Relation of lung function, maximal inspiratory pressure, dyspnoea, and quality of life with exercise capacity in patients with chronic obstructive pulmonary disease.
Thorax. 1994;49:468–472.
58. Tsukino M, Nishimura K, Ikeda A, et al. Physiologic factors that determine the health-related quality of life in patients with COPD.
Chest. 1996;110:896–903.
59. Swigris JJ, Kuschner WG, Jacobs SS, et al. Health-related quality of life in patients with idiopathic pulmonary fibrosis: a systematic review.
Thorax. 2005;60:588–594.
60. Shrikrishna D, Patel M, Tanner RJ, et al. Quadriceps wasting and physical inactivity in patients with COPD.
Eur Respir J. 2012;40:1115–1122.
61. Guerrero K, Wuyam B, Mezin P, et al. Functional coupling of adenine nucleotide translocase and mitochondrial creatine kinase is enhanced after exercise training in lung transplant skeletal muscle.
Am J Physiol Regul Integr Comp Physiol. 2005;289:R1144–R1154.
62. Lands LC, Smountas AA, Mesiano G, et al. Maximal exercise capacity and peripheral skeletal muscle function following lung transplantation.
J Heart Lung Transplant. 1999;18:113–120.
63. Langer D, Cebrià i Iranzo MA, Burtin C, et al. Determinants of physical activity in daily life in candidates for lung transplantation.
Respir Med. 2012;106:747–754.
64. Puthucheary ZA, Rawal J, McPhail M, et al. Acute skeletal muscle wasting in critical illness.
JAMA. 2013;310:1591–1600.
65. Maury G, Langer D, Verleden G, et al. Skeletal muscle force and functional exercise tolerance before and after lung transplantation: a cohort study.
Am J Transplant. 2008;8:1275–1281.
66. Walsh JR, Chambers DC, Davis RJ, et al. Impaired exercise capacity after lung transplantation is related to delayed recovery of muscle strength.
Clin Transplant. 2013;27:E504–E511.
67. Guralnik JM, Ferrucci L, Simonsick EM, et al. Lower-extremity function in persons over the age of 70 years as a predictor of subsequent disability.
N Engl J Med. 1995;332:556–561.
68. Robles PG, Sussman MS, Naraghi A, et al. Intramuscular fat infiltration contributes to impaired muscle function in COPD.
Med Sci Sports Exerc. 2015;47:1334–1341.
69. Bernard S, LeBlanc P, Whittom F, et al. Peripheral muscle weakness in patients with chronic obstructive pulmonary disease.
Am J Respir Crit Care Med. 1998;158:629–634.
70. Kistler KD, Nalysnyk L, Rotella P, et al. Lung transplantation in idiopathic pulmonary fibrosis: a systematic review of the literature.
BMC Pulm Med. 2014;14:139.
