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Sarcopenia in Lung Transplantation: A Systematic Review Dmitry Rozenberg MD, Lisa Wickerson MSc, BScPT, Lianne G. Singer MD, Sunita Mathur PhD

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S1053-2498(14)01157-7 http://dx.doi.org/10.1016/j.healun.2014.06.003 HEALUN5790

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J Heart Lung Transplant

Cite this article as: Dmitry Rozenberg MD, Lisa Wickerson MSc, BScPT, Lianne G. Singer MD, Sunita Mathur PhD, Sarcopenia in Lung Transplantation: A Systematic Review, J Heart Lung Transplant, http://dx.doi.org/10.1016/j.healun.2014.06.003 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Word count (Abstract): 250 (Body): 2861 Title: Sarcopenia in Lung Transplantation: A Systematic Review

Running head: Sarcopenia in Lung Transplant

Dmitry Rozenberg, MD; 1,2,3 Lisa Wickerson MSc, BScPT,,3,4 Lianne G Singer, MD;1,2,3, Sunita Mathur, PhD4

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Division of Respirology, Department of Medicine, University of Toronto, 2 Department of Respirology and 3Toronto Lung Transplant Program, Toronto General Hospital; 4 Department of Physical Therapy, University of Toronto, Toronto, Canada.

Corresponding author:Dr. Dmitry Rozenberg Toronto General Hospital 11C-1196- 585 University Avenue Toronto, ON M5G 2N2 Tel: (416)-340-4996 Fax: (416) 340-3609

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Contributions: *Dmitry Rozenberg (D.R): Contributed to conception and design, selection of articles, analysis and interpretation of data, drafted the article and revised the article critically for important intellectual content. Lisa Wickerson (L.W.): Contributed to selection of articles, analysis and interpretation of data and revised the article critically for important intellectual content. Lianne G Singer (L.S): Contributed to conception, design of the study, interpretation of data and revised the article critically for important intellectual content. Sunita Mathur (S.M): Contributed to conception, design of the study, selection of articles, data interpretation and revision of the article critically for important intellectual content. *D. Rozenberg receives salary support from the University of Toronto, Clinician Scientist Training program. There is no other financial support or conflicts that exist for any of the authors.

Key Words: Sarcopenia, Lung Transplantation, Skeletal muscle

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Abstract: Background: Lung transplant candidates and recipients have significant impairments in skeletal muscle mass, strength and function – individual measures of sarcopenia. Skeletal muscle dysfunction has been observed in the pre- and post-transplant period and could have an important effect on transplant outcomes. Methods: A systematic review was performed to characterize the techniques used to study sarcopenia and assess the level of impairment throughout the transplant process. Electronic databases were searched (inception to July 2013) for prospective studies measuring at least one element of sarcopenia (muscle mass, strength or function) in lung transplant patients. Eighteen studies were included and study quality was assessed using the Downs and Black scale. Results: A variety of measurements were used to evaluate sarcopenia in 694 lung transplant patients. Muscle mass was assessed in seven studies, using bioelectrical impedance (n=4), computed tomography or magnetic resonance imaging (n=2), or skin folds (n=1) and found to be significantly reduced. Quadriceps strength (QS) was examined in 14 studies with computerized dynamometer (n=10) and hand-held dynamometer (n=4). QS was reduced in the pre-transplant period (mean range, 49-86% predicted, n=455 patients), further reduced immediately post-transplant (51-72%, n= 126), and improved beyond 3 months post-transplant (58-101%, n= 164). Lower extremity function (sit-to-stand) was measured in only two studies. Conclusion: A multitude of measurement techniques have been used to assess individual measures of sarcopenia with reduced muscle mass and QS observed in the pre- and posttransplant period. Further standardization of measurement techniques is needed to assess the clinical impact of sarcopenia in lung transplantation.

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Abbreviations: BIA

= Bio-electrical impedance analysis

CT

= Computed tomography

D-XA = Dual-energy x-ray absorptiometry MRI

= Magnetic Resonance Imaging

RCT

= Randomized Controlled Trial

6MWT = Six minute walk test

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Introduction: Lung transplantation is known to improve quality of life,1 exercise capacity2 and survival3 but the majority of patients have impairments in skeletal muscle mass and strength pre- and post-transplant.4-7 Given these skeletal muscle impairments, the construct of sarcopenia has been suggested as a potential risk factor for morbidity in lung transplantation and could prove to be an important modifiable risk factor in optimizing transplant outcomes.8 Sarcopenia has been defined using the consensus definition of decreased muscle mass and at least one of low peripheral muscle strength or function.9 It portends an increased risk for adverse outcomes such as physical disability, poor quality of life and death in elderly patients.10,11 In liver and renal transplant recipients, sarcopenia has been associated with decreased post-transplant survival.12,13 In COPD patients, various individual measures of sarcopenia such as muscle strength,14 mid-thigh cross-sectional area,15 and fat-free mass16 have been linked to mortality. In lung transplant patients, the prevalence and clinical impact of sarcopenia using the consensus definition has not been studied, even though low muscle mass4 and muscle weakness17,18 have been observed independently. A number of modalities have been used to assess muscle mass, strength or function in the elderly and in patients with lung disease.9,19

Muscle mass has been assessed with

computed tomography (CT)15 and magnetic resonance imaging (MRI),20 bio-electrical impedance (BIA), dual-energy x-ray absorptiometry (D-XA) and anthropometry.4,16,21 Muscle strength has included measures of hand-grip strength and quadriceps strength using hand-held and computerized dynamometry.4,18 Functional tests used in the elderly include: short physical performance battery, usual gait speed, and Timed Up and Go test.4,22,23 In advanced lung disease, the 6 minute walk test (6MWT) has been the most commonly used functional exercise measure,24 but it does not specifically isolate muscle function as part of the sarcopenia consensus definition.9 5

Given the number of available methods in measuring individual elements of sarcopenia, this systematic review was undertaken to address two main objectives: 1) to systemically describe the non-invasive techniques used to study muscle mass, strength or function; and 2) assess the level of skeletal muscle impairment in lung transplant patients.

Methods: Search Strategy: The following electronic databases were searched: MEDLINE, PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Physiotherapy Evidence Database (PEDro), Excerpta Medica Database (EMBASE), including Cochrane Central Registrar of Controlled Trials. The search included studies from inception to July 2013. Searches were performed by one author (D.R) based on the strategy developed for PubMed (Table 1) but modified accordingly for each database. Study Selection: Two authors (D.R) and (L.W) independently reviewed the titles and abstracts from all databases to determine if the studies met inclusion criteria. A third investigator (S.M) resolved any disagreements. For inclusion, the articles had to pertain to adult lung transplant patients (age ≥ 18 years) either listed or transplanted. Only English-language publications and studies on humans were included. The articles were considered relevant if at least one element of the consensus definition of sarcopenia was measured as the primary or secondary outcome: muscle mass, strength or function.9 Given the limited number of studies with a non-transplant control group, this was not a prerequisite for study inclusion. Studies with a retrospective design or case series were excluded. Data Extraction: Two reviewers (D.R plus L.W or S.M) independently extracted the data and any discrepancies were resolved by consensus. A standardized data extraction form was used to collect: publication type, sample size, pre-transplant lung disease, type of transplant, measures 6

of muscle mass, strength or function, clinical outcomes and occurrence of any adverse events. The measurement tools used to assess muscle mass, strength and function were recorded. Throughout this review, the term “function” refers to physical tests that were able to specifically assess muscular performance. Strength measurements were further characterized based on type of muscle contraction: static (isometric) and dynamic (isotonic or isokinetic). Further detail on limb position, muscle group and side tested, number of trials, rest period, and instructions were recorded. The impact of exercise training on sarcopenia and the clinical correlates with low muscle mass, strength or function were assessed. Mean ranges (% predicted) for quadriceps strength using computerized and hand-held dynamometers were established between studies. Quality Assessment: The Downs and Black scale was used to assess the methodological quality of the papers. The checklist has five sub-scales that evaluate: reporting, external validity, bias, confounding, and power.25 A modified single question on power was used in the present review.26 The quality of the studies was assessed independently by two reviewers (D.R plus L.W or S.M) and discrepancies resolved by consensus.

No studies were excluded based on

study quality.

Results: Of the 617 unique abstracts retrieved electronically, 29 full-text articles were assessed for eligibility and 18 articles met criteria for study inclusion (see Figure 1).5-7,17,18,20,27-38 There were a variety of study designs and sarcopenia measures (muscle mass, strength or function) as outlined in Table 2. A total of 694 lung transplant candidates or recipients were included. The mean age of study participants ranged from 34 to 63 years. The most common pre-transplant conditions were: COPD (58%), interstitial lung disease (18%), cystic fibrosis (14%), pulmonary hypertension (6%), and other (4%). In the 11 studies that addressed transplant type, double 7

lung transplant was performed in the majority of patients (70%), single lung in 28%, and multiorgan in 2%. Quality assessment: The overall quality of the studies (Table 3) was fair to moderate given that most studies were cross-sectional or lacked a control group. The reporting sub-scale score in most of the studies was moderately-high. The external validity scores were low as many studies excluded older patients or those with complex co-morbidities. The internal validity components (bias and confounding) scores were low given they are more applicable to RCTs. A sample size calculation was provided in two studies,18,20 but most studies received a full score on the power sub-scale due to the primary outcome being significant. Muscle Mass Measurements: Four studies30,31,33,35 measured fat-free mass using BIA at a frequency of 50 kHz, as previously described.39 Imaging was used to estimate the muscle volume of thigh muscles and cross-sectional area of quadriceps in two studies; each one respectively using MRI20 and CT34. In another study, lean mass was estimated using sum of skin folds from the biceps, triceps, supra-iliac and sub-scapular regions.6 Muscle Strength Measurements: The strength measurements are summarized in Table 4. A total of 15 studies had at least one measure of muscular strength: quadriceps (n=14), hamstring (n=2), hand-grip (n=4) and biceps/triceps (n=2). Two–thirds (n=10) of the studies assessed strength isometrically5,7,17,18,27-30,32,36 with the remaining studies using isokinetic measurements.6,20,34,37,38 A computerized dynamometer was the most common measurement tool used to assess quadriceps or hamstring strength (n=10) with the remaining studies using hand-held dynamometers.

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The limb tested for strength varied among the studies: bilateral (n=4), dominant (n=6), or unspecified (n=5). The contraction duration was specified in only one study27 and no studies mentioned familiarization of the patients to the testing protocol. Muscular Function Lower body function was assessed in only two studies using the sit-to-stand test31,33 with no studies assessing upper extremity function. Impact of Lung Transplantation on Fat Free Mass: Fat-free mass was observed to be decreased in the pre- and post-transplant period. Kyle et al. demonstrated in 37 lung transplant patients that low fat-free mass index was prevalent in the pre-transplant period in two-thirds of patients and was found in one-third of patients at 2 years post-transplant.35 Similarly, Vivodtzev et al. found that fat-free mass was significantly lower in 12 lung transplant recipients (mean duration post-transplant about 3 years) compared to healthy age-matched controls with no change after 3 months of home based exercise.30 Pinet et al. demonstrated that cross-sectional area of the quadriceps measured with CT was reduced by 30% in 12 cystic fibrosis patients post-transplant (median 48 months) compared to healthy age-matched controls.34 Impact of Lung Transplantation on Muscle Strength: With combined analysis, quadriceps strength was reduced in the pre-transplant period (mean range 49-86 % predicted, n = 455) with a further reduction in the immediate posttransplant period (51-72%, n = 126). Quadriceps strength was improved (58-101 %, n = 164) beyond 3 months post-transplant. Langer et al. demonstrated that lower extremity exercise in the post-transplant period helped improve the 15-20% loss in quadriceps muscle force compared to pre-transplant values.18

Maury et. al. similarly found that quadriceps force

increased by about 35 ± 48% compared to values in the immediate post-transplant period prior to rehabilitation.17 Hand-grip force was less affected than quadriceps force in several studies being > 80% 9

predicted in the pre-transplant period17,18,29 and only reduced in the immediate post-transplant period (63 ± 20%)16 and preserved beyond 3 month post-transplant. 16,18,32 Similarly, upper extremity strength of the biceps and triceps measured with a hand-held dynamometer was greater than 80% predicted.5,36 Correlates of Sarcopenia Measures with Clinical and Physical Activity Outcomes A moderate correlation was found between quadriceps strength and intensive care unit (ICU) duration post-transplant (r=0.41).17 Similarly, quadriceps strength correlated with several physical activity measures: daily steps (r= 0.51-0.66),28,32 body mass index (r=0.43)36, exercise capacity (r=0.41)5, and peak oxygen uptake (r=0.77)34. Lower body function (i.e. sit to stand test) correlated with daily steps (r=0.45); a measure of physical activity.33 Upper extremity strength was examined in only one study where triceps strength had moderate correlation with BMI (r=0.43)36 in transplant candidates with cystic fibrosis. Safety of Sarcopenia Measurements: Only one study27 reported assessing any adverse events as part of their testing protocol for muscle mass, strength, or function. Walsh et al. had described that one patient was excluded from the study due to musculoskeletal injury; however, it was difficult to ascertain whether this occurred as part of routine testing.27

Discussion: The current review highlights the multitude of modalities that have been used to study muscle mass, strength, and function in lung transplant patients, individual measures of sarcopenia. However, no lung transplant study to date has characterized sarcopenia using the consensus definition.9 Fat-free mass and quadriceps strength were both reduced in the pre- and post-transplant period with significant improvements in quadriceps strength observed beyond 3 months post-transplant with routine exercise training17,18,27,38 and natural recovery.5 The strength in the lower extremities was affected more than the upper extremities. Quadriceps

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strength had a moderately-strong correlation with ICU duration, exercise capacity and oxygen uptake. BIA was the most common tool used to assess fat-free mass in lung transplant patients. BIA is easy to use, portable, reproducible, inexpensive, and has been validated in lung transplant patients.39 Alternative methods for determining muscle mass such as D-XA or muscle size using CT or MRI have been used primarily in research settings given the higher cost, difficulty with equipment access, and concerns regarding radiation exposure with D-XA and CT. Anthropometric measurements such as mid-arm circumference21 and skin folds40 have been applied as estimates of fat-free mass; however, their predictive capabilities are inferior to MRI41 and they have not been validated in lung transplant patients. Furthermore, sarcopenia consensus guidelines in the elderly recommend against the use of anthropometric measurements.9 Muscle strength testing of the lower limb using a computerized dynamometer was the most common modality of peripheral muscle strength measurement with a few studies using hand-held dynamometers. Computerized dynamometers have been used in a variety of patient populations with good test reliability, accuracy and safety.19 The limitations of computerized dynamometers are their higher costs, accessibility, training, and time required for testing. Thus, hand-held dynamometer might be a good alternative for measuring muscle strength clinically where time and availability are limited but greater caution should be taken when testing large muscle groups (i.e. knee extension) given the mechanical difficulty of testing42,43 and poor reliability.44 In the present review, lower body strength and function were noted to be reduced more than the upper extremities in keeping with previous studies.45,46 One possible explanation could be the fact that physical activities such as walking, that rely on lower body muscles are often reduced in the pre-transplant period,28,29,33 whereas activities of daily living that use the arms are more likely to be maintained. Lower body strength was also noted to be decreased in the 11

immediate post-transplant period with recovery above pre-transplant levels by 3 months.18,27,38 However, the recovery observed in quadriceps strength was still lower than in healthy adults and is most likely multi-factorial given the prolonged hospital course, malnutrition, and immunosuppressive medications in lung transplant recipients. Although the pathophysiology underlying sarcopenia has not been studied specifically in lung transplant patients, the mechanisms thought to be responsible for reduced muscle mass with aging and chronic disease are a result of an imbalance between protein synthesis and increased protein breakdown, leading to muscle atrophy. As outlined in several recent reviews,47,48 the three main mechanisms leading to increased protein degradation are: (1) ubiquitin-proteasome system, (2) autophagy-lysosome system and (3) apoptosis. In COPD patients, low muscle mass has been linked to excess protein degradation by the ubiquitinproteasome system, one of the primary pathways, which has been associated with loss of quadriceps cross-sectional area and muscle strength.49,50 The mechanisms underlying impairments of muscle strength and function in lung transplant recipients have not been well characterized. In fact, there has been an emphasis on studying muscular oxidative capacity in this population to help explain the observed exercise limitations.51,52 The impairments in muscular oxidative capacity include a lower proportion of slow-twitch muscle fibers (type 1) and reduced mitochondrial enzymatic activity.53 Decreased peripheral oxygen utilization has been implicated as another limitation to muscle oxidative capacity.54,55 Unfortunately, the cellular adaptations underlying the clinical measurements of sarcopenia (muscle mass, strength, and function), such as muscle fiber cross-sectional area, and single fiber contractile properties have not been described in lung transplant patients as in other solid organ transplants. In renal transplant recipients, significant reduction in muscle fiber cross-sectional area and ultra-structural fiber changes (lower myofibrillar volume, increased lipid deposition and mitochondria) have been suggested as possible contributors of muscle weakness.56 In another study by Horber et al., the total number of thigh muscle fibers, 12

myofibrillar volume and capillary density in renal transplant recipients were significantly lower than age-matched controls; however, no differences were found in intracellular lipids and mitochondria.57

Similarly, cardiac transplant patients had no ultra-structural muscle fiber

differences compared to controls, apart from reduced capillary density, which could contribute to impaired muscle oxidative capacity.58 Thus, the cellular mechanisms underlying posttransplant sarcopenia, especially in lung transplantation, remain undefined. In the present review, only one study examined the relationship of quadriceps strength with clinical outcomes.

Maury et al. had shown that there was a significant negative correlation with

quadriceps strength and ICU duration post-transplant.17 In other lung transplant patients, quadriceps strength had moderately-strong correlation with physical activity level,28,32 exercise capacity5 and oxygen uptake.34 Unlike in COPD where various individual measures of sarcopenia have been linked to mortality using direct strength testing,14 mid-thigh crosssectional area,15 and fat-free mass16, the clinical implications of these measures have not been studied in lung transplant patients. It is unclear to what extent exercise training mitigates the recovery of muscle mass and strength in lung transplant recipients. There has been only one RCT that demonstrated 3 months of exercise training helped improve quadriceps force, 6MWT, and daily walking to a greater extent than natural recovery observed at 3 months and 1 year post-transplant.18

Kyle

et al. had observed in their cohort of 37 lung transplant patients that weight and fat-free mass naturally recovered in the majority of patients at 2 years post-transplant.4 Vivodtzev et al. found no significant change in fat-free mass with 12 weeks of home based exercise training, but noted a significant increase in muscle strength, exercise duration, and proportion of type 1 fibers.30 Additional RCT studies are needed to determine if exercise training can improve muscle dysfunction above its natural recovery.

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Limitations: The limitations of this review include the difficulty in pooling data given the variability in the literature in muscle assessment protocols, study designs and exercise interventions. The studies reviewed had populations that varied in age, lung disease, and period of testing pre- and post-transplant, which made it difficult to make quantitative comparisons.

Conclusions and Clinical Implications for Future Research: A number of measurement techniques have been used to assess skeletal muscle mass, strength, and function, individual measures of sarcopenia. Fat free mass and quadriceps strength were consistently shown to be reduced in the pre-transplant period with a significant improvement in quadriceps strength by three months post-transplant with various rehabilitation strategies. No studies to date have examined the prevalence of sarcopenia using the consensus definition or its impact on clinical outcomes such as hospital duration or mortality in the pre- and post-transplant period. Given that sarcopenia is more prevalent with aging, this is an important area of research as lung transplantation is being increasingly provided to patients with older age, increased co-morbidities and functional limitations.3

Furthermore, the majority

of the studies to-date excluded patients with any complex co-morbidities, myopathies, or prolonged hospitalizations – potentially the most sarcopenic patients. Additional studies examining prevalence of sarcopenia with standardization of measurement techniques, rehabilitation strategies and incorporation of clinical outcomes are required. Also, the muscle fiber properties and molecular pathways underlying sarcopenia will be important in advancing our understanding of this clinical entity in lung transplant patients. Ultimately, sarcopenia may prove to be an important modifiable risk factor in predicting outcomes in lung transplantation.

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Conflicts of Interest and Funding Sources: The authors would like to acknowledge Carla Hagstrom from the University of Toronto, Gerstein library for her assistance with the electronic search of articles. D. Rozenberg receives salary support from the University of Toronto, Clinician Scientist Training program. There is no other financial support or conflicts that exist for any of the authors.

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Tables: Table 1: Keywords used in the literature search Table 2: Summary of studies included in systematic review with sarcopenia measures Table 3: Downs and Black Quality Assessment Scores for all Studies Table 4: Description of Strength Measurements

Figures: Figure 1: Study Selection Flow Diagram

23

Table 1 – Keywords used in the literature search Disease Related Terms Lung Transplant

Sarcopenia Related Terms AND

Skeletal muscle

Measure Related Terms AND

Strength Test

Others Related Terms AND

Training

OR

OR

OR

OR

Pulmonary Transplant

Peripheral Muscle

Function Test

Exercise

Muscle Strength

OR

OR

OR

Measurement

Program

Muscle Force

OR

OR

Muscle Function

Evaluation

Weight Training

Muscle Dysfunction

OR

OR

Muscle Weakness

Assessment

Rehabilitation

Muscle Endurance

OR

OR

Muscle Fatigue

Body Composition

Physical Activity

OR

OR

OR

Fat Free Mass

Test

Training

Lean Mass

OR

OR

OR

Exam

Activity

Physical Function

OR Function

24

Table 2: Summary of studies included in systematic review with sarcopenia measures Author

Walsh

Yea r

27

28

Wickerson

Age

Study Design

2013

42 ± 13

Prospective Cohort

2013

62 [5365]

Crosssectional

Randomized Controlled Trial

Langer

18

2012

59 ± 4

Langer

29

2012

55 ± 7

Crosssectional

2011

47 ± 13

Prospective Cohort (healthy controls)

2011

56 ± 5

Crosssectional

Vivodtzev

30

Bossenbrock 31

[Exercise Training (ET) vs.Control:Usu al Care]

Sampl e Size

50

24

Transpla nt Status

Outcome Measure(s)

Pre & Post

Quadriceps Force (QF)

Pre

Quadriceps Torque (QT)

40

Pre & Post

Quadriceps Force (QF) Hand-grip force (HF)

96

Pre

Quadriceps Force (QF) Hand-grip force (HF)

12

Post

Fat Free Mass Index(FFMI) Quadriceps Force (QF)

42

Post

Fat Free Mass (FFMI) Sit to Stand Test

25

Findings Pre-tx QF = 86 ± 6%; QS declined in first 2 weeks posttx but improved above pre-tx levels (100 ± 7%) at 26 weeks (p=0.03) Pre-tx QT: 120 ± 36 Nm (81 ± 23%) Pre-tx QF: ET (78 ± 22%) vs. Control (75 ± 25 %), p=NS; 1 year posttx QF: ET (92 ± 21%) vs. Control (71 ± 20%), p=0.001; 1 year posttx HF: ET (94 ± 22%) vs. Control (91 ± 18%), p=0.18. Pre-tx QF= 74 ± 19%; Pre-tx HF= 86 ± 19% Post-tx FFMI: LTR (27 ± 3 2 kg/m ) vs. Control (31 2 ± 4 kg/m ), p=0.05; QF: LTR (5.4 ± 3.2 kg) vs. Control (10.5 ± 4.6 kg), p=0.02 Pre-tx FFMI: Overweight (17 ± 3 2 kg/m ) vs.

Langer

32

Bossenbrock 33

Mathur

20

Author

2009

59 ± 5

Crosssectional (healthy controls)

2009

55 ± 5

Crosssectional

2008

63 ± 5

Crosssectional (COPD controls)

Yea r

Age

Study Design

22

Post

Quadriceps Torque (QT) Hand-grip force (HF)

62

Pre & Post

Fat Free Mass Index (FFMI) Sit to Stand Test

6

Post

Quadriceps/Hamstrin gs Volume Quadriceps Torque (QT)

Sampl e Size

Transpla nt Status

Outcome Measures

26

Normal (19 2 ± 2 kg/m ), p < 0.05; Sit-to-stand (n): Overweight (10 ± 4 times) vs. Normal (11 ± 2 times), p=NS. Post-tx QT= LTR (102 ± 36 Nm) vs. Control (155 ± 35 Nm), p

Sarcopenia in lung transplantation: a systematic review.

Lung transplant candidates and recipients have significant impairments in skeletal muscle mass, strength and function--individual measures of sarcopen...
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