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Skeletal Muscle Dysfunction in Lung Transplant Patients
by
Dmitry Rozenberg
A thesis submitted in conformity with the requirements
for the degree of Doctor in Philosophy
Institute of Medical Science
University of Toronto
© Copyright by Dmitry Rozenberg, 2017
II
Skeletal Muscle Dysfunction in Lung Transplant Patients
Dmitry Rozenberg
Doctor of Philosophy
Institute of Medical Science University of Toronto
2017
ABSTRACT:
Lung transplantation improves health-related quality of life (HRQL), daily function and survival
for individuals with advanced lung disease. However, lung transplantation is now offered to
older and more complex patients who are at a higher risk of skeletal muscle dysfunction; the
implications of which remain uncertain. The overall objective was to assess how elements of
muscle dysfunction (mass, strength and function) are associated with pre- and post-transplant
physical function, HRQL, and clinical outcomes. We hypothesized that pre-transplant skeletal
muscle dysfunction would be associated with impairments in pre-transplant HRQL, activities of
daily-living (ADL), six-minute walk distance (6MWD), and worse post-transplant functional
recovery with increased pre- and post-transplant mortality. Three studies targeting the pre- and
post-transplant periods were undertaken. In study 1, a novel method of muscle mass
quantification using computed tomography (CT) was retrospectively evaluated in 527 lung
transplant candidates. CT muscle cross-sectional area in transplant candidates was 10% lower
than age and sex-matched controls and independently associated with 6MWD, strength training
volumes and post-transplant hospital length of stay (LOS), but no association was observed
with pre- or post-transplant mortality. In study 2, muscle mass assessed with bio-electrical
impedance, quadriceps strength, and function (Short Physical Performance Battery, SPPB)
were prospectively evaluated in 50 lung transplant candidates. Quadriceps strength and SPPB
were associated with pre-transplant HRQL, ADL, and 6MWD. Number of muscle deficits (mass,
III
strength and/or function) was directly correlated with post-transplant hospital LOS, but not with
delisting/mortality or post-transplant 6MWD. In study 3, the impact of pre-transplant skeletal
muscle mass and function on post-transplant functional independence, HRQL, and 6MWD was
evaluated in a select group of lung transplant recipients with prolonged mechanical ventilation (≥
7 days). Age and intensive care unit (ICU) LOS were the only determinants of early post-
transplant functional recovery, highlighting the importance of ICU-acquired morbidity. In
summary, these studies demonstrate that skeletal muscle function is an important marker of
pre-transplant daily function and predicts post-transplant hospital LOS, but is not a significant
predictor of post-transplant function or mortality. Future studies should examine whether
targeted rehabilitation strategies in the pre-transplant period may improve daily function and
early post-transplant outcomes.
IV
ACKNOWLEDGEMENTS:
I would like to express my deepest gratitude to several groups of individuals without whom this
PhD thesis would not be possible. First, I would like to thank all the study participants who
dedicated their time, effort and provided valuable support for this graduate work.
Secondly, I would like to acknowledge the overwhelming support from my supervisors Dr.
Lianne Singer and Dr. Sunita Mathur who provided me with close guidance, writing support, and
ongoing mentorship throughout the PhD. Your strong dedication and passion for research is
extremely inspirational. I would also like to thank my PhD program advisory committee
members Dr. Margaret Herridge and Dr. Roger Goldstein for their generosity, time commitment,
and ongoing support. Dr. Herridge, thank you for allowing me to use the RECOVER dataset for
part of this thesis. Dr. Goldstein, I would like to express my gratitude for inspiring me to pursue
a research career in advanced lung disease and pulmonary rehabilitation.
I would like to acknowledge my funding sources for this graduate work that have provided me
with valuable salary support, which allowed me to focus on my graduate studies. This work
would not be possible without the support of the University of Toronto, Clinician Scientist
Training Program, Canadian Institute of Health Research Graduate Vanier and Master’s
Scholarships, and American Society of Transplant Fellowship.
It is a blessing to be a member of the Toronto Lung Transplant Program. I would like to thank all
my colleagues, volunteers and friends who provided me with valuable research support over the
last four years. Specifically, I would like to acknowledge Mrs. Noori Chowdhury and Sassan
Azad who have provided essential database support and assistance with patient recruitment.
Finally, I am thankful to my supporting parents, my caring wife Yulia, and my joyful daughter
Maya. I am truly blessed to have had such strong family support at each step along the way.
You have given me the inspiration and ongoing motivation to undertake this journey over the
last four years. Most importantly, you remind me of the critical importance of maintaining a
work-life balance.
V
STATEMENT OF CONTRIBUTIONS:
This thesis is presented in manuscript format and consists of six chapters. Chapter 1 is a
summary of the main problem and a review of the literature. My previously published
systematic review on this topic was utilized to help guide the literature review, overall objective
and hypothesis for this thesis. Chapter 2 provides a detailed framework of the thesis objectives
and hypotheses. Chapters 3 to 5 comprise three separate manuscripts of original investigation,
two of which have been published. Chapter 6 provides an overall discussion for the thesis and
outlines future research directions arising from this work.
Summary of Contributions Related to Thesis:
1. Rozenberg D, Wickerson L, Singer LG, Mathur S. Sarcopenia in lung transplantation: a
systematic review. J Heart Lung Transplant 2014; 33(12): 1203-12.
Contributions:
Contributed to conception and design (DR, LG.S, SM), selection of articles (DR, LW, SM),
analysis or interpretation of data (DR, LW, LG.S, SM), drafted the article (DR) and revised the
article critically for important intellectual content (DR, LW, LG.S, SM).
2. Rozenberg D, *Mathur S, Herridge M, Goldstein R, Schmidt H, Chowdhury NA, Mendes P,
*Singer LG. Thoracic Muscle Cross-Sectional Area is Associated with Hospital Length of Stay
Post Lung Transplantation. Transplant International 2017; July; 30(7): 713-724. E-pub May 26.
* Both authors contributed equally to this manuscript. (Study 1)
Contributions: DR, LG.S, MH, RG, and SM made substantial contributions to the conception and design of the
work. DR wrote the first draft of the manuscript and SM, MH, RG, HS, NA.C, PM, and LG.S
revised the manuscript for important intellectual content. All authors made substantial
contributions to the analysis or interpretation of data.
VI
3. Rozenberg D, Singer LG, Herridge M, Goldstein R, Wickerson L, Chowdhury NA, Mathur S.
Evaluation of Skeletal Muscle Function in Lung Transplant Candidates. Transplantation 2017;
E-pub ahead of Print April 3. (Study 2)
Contributions:
DR, LG.S, MH, RG, LW, NA.C and SM made substantial contributions to the conception and
design of the work. DR wrote the first draft of the manuscript and LG.S, MH, RG, LW, NA.C,
and SM revised the manuscript for important intellectual content. All authors made substantial
contributions to the analysis or interpretation of data.
4. Rozenberg D, Mathur S, Tomlinson G, Goldstein R, Robles P, Chu L, Chaparo C, Andrade B,
Burns S, Thomas C, Cameron J, Herridge M, Singer LG. In collaboration with the RECOVER
Program Investigators. Clinical Implications of Pre-Transplant Skeletal Muscle Mass, Strength
and Exercise Capacity on Functional Recovery in Lung Transplant Recipients after 7 or More
Days of Mechanical Ventilation. (Manuscript in Preparation). (Study 3)
Contributions:
DR, SM, GM, RG, MH, and LG.S made substantial contributions to the conception and design
of the work. DR wrote the first draft of the manuscript and DR, SM, RG, PR, CC, MH, and LG.S
revised the manuscript for important intellectual content. All authors made substantial
contributions to the analysis or interpretation of data.
VII
Financial Support:
DR receives salary support from the University of Toronto, Clinician Scientist Training program.
He has received Canadian Institutes of Health Research (CIHR) Master’s Award, Vanier
Graduate Scholarship and American Society of Transplant Fellowship for his graduate work.
Study 1:
This research was supported by grants from the Canadian Institutes of Health Research, the
Physicians’ Services Inc. Foundation, the Canadian Lung Transplant Study Group, the
University Health Network Multi-Organ Transplant Program, and the Ontario Lung Association -
Pfizer Canada.
Study 2:
This research was supported by a grant from the Ontario Thoracic Society.
Study 3:
The RECOVER Program was supported by Canadian Institute Health Research, Ministry of
Health Innovation Award, University of Toronto Integration Challenge Fund, John and Gail
Macnaughton Family Fund, Don and Jane Luck Family Fund and Jason Tham and Andrea
Chan Family Fund.
VIII
TABLE OF CONTENTS: Page
Acknowledgements …………………………………………………………………. IV Statement of Contributions …………………………………………………………… V Table of Contents ……………………………………………………………………... VIII List of Tables …………………………………………………………………………... XI List of Figures ………………………………………………………………………….. XII List of Appendices……………………………………………………………………… XIII Abbreviations …………………………………………………………………………… XIV CHAPTER 1 - Literature Review and Introduction ………….. ………………… 1 1.0 Statement of the Problem …………………………………………………………… 1 1.1 Overview of Lung Transplantation ………………………………………………… 3 1.1.2 Survival with Lung Transplantation ………………………………………………… 5 1.1.3 Risk Factors Associated with Lung Transplant Mortality …………………………... 6 1.1.4 Health Related Quality of Life …………………………………………………………. 9 1.1.5 Functional Outcomes …………………………………………………………………... 11 1.2 Evaluation of Skeletal Muscle Dysfunction in Chronic Lung Disease and Lung Transplant Patients ……………………………………………………………………… 18 1.2.1 Generic and Disease Specific Factors Related to Skeletal Muscle Dysfunction in Chronic Lung Disease and Transplant Recipients …………………………………… 18 1.2.2 Rationale for Measuring Muscle Mass, Strength and Function……………………... 25 1.2.3 Muscle Mass Measurements …………………………………………………………… 27 1.2.4 Peripheral and Respiratory Muscle Strength Measurements ……………………….. 33 1.2.5 Assessment of Physical Performance …………………………………………………. 37 1.3 Importance of Physical Fitness with Major Surgery and Solid-organ Transplantation 40 1.3.1 Physiologic Stress Response with Major Surgery …………………… ………………... 41 1.3.2 Skeletal Muscle Strength and Physical Performance with Major Surgery and Solid-Organ Transplantation ………………………………………………………… 42 1.3.3 Skeletal Muscle Mass with Major Surgery and Solid Organ Transplantation ……….. 44 1.3.4 Pre-Operative Exercise Training with Major Surgery and Solid-Organ Transplantation 47 1.4 Implications of Prolonged Mechanical Ventilation, Critical Care and Hospital Length of Stay……………………………………………………………………… 49 1.4.1 Intensive Care Unit Length of Stay and Clinical Implications …………………………... 50 1.4.2 Functional Status Prior to ICU Admission ………………………………………………… 52 1.4.3 Peri-operative ICU Management …………………………………………………………... 53
1.5 Recovery Beyond Hospital Admission in Lung Transplant Recipients ………………… 56
IX
1.5.1 Out-Patient Rehabilitation …………………………………………………………………... 56 1.5.2 Inpatient Rehabilitation Post-Transplant …………………………………………………... 57
1.6: Summary ……………………………………………………………………………………… 58
CHAPTER 2 – Thesis Overview ………………………………………………………… 60
2.1 Overall Aim and Hypothesis ………………………………………………………………... 60 2.2 Study Aims and Hypotheses ………………………………………………………………... 61 CHAPTER 3 - Thoracic Muscle Cross-Sectional Area is Associated with Hospital Length of Stay Post Lung Transplantation ………………………………………… 64
3.1 Abstract ………………………………………………………………………………………… 64
3.2 Introduction …………………………………………………………………………………….. 66
3.3 Methods ……………………………………………………………………………………… 67 3.3.1 Study Design and Participants………………………………………………………………. 67 3.3.2 Muscle Cross-Sectional Area Assessment ………………………………………………… 68 3.3.3 Clinical Variables ……………………………………………………………………………… 69 3.3.4 Statistical Analysis…………………………………………………………………………….. 71
3.4 Results ………………………………………………………………………………………… 72 3.4.1 Participants……………………………………………………………………………………. 72 3.4.2 Muscle CSA in Lung Transplant Candidates and Healthy Controls ……………………. 74 3.4.3 Six-Minute Walk Distance, Strength Training Volumes, and Quality of Life……………. 76 3.4.4 Pre-transplant Clinical Outcomes…………………………………………………………… 76 3.4.5 Post-transplant Clinical Outcomes …………………………………………………………. 78
3.5 Discussion …………………………………………………………………………………….. 81
3.6 Conclusion …………………………………………………………………………………….. 85 CHAPTER 4 - Evaluation of Skeletal Muscle Function in Lung Transplant Candidates …………………………………………………………………………………. 86
4.1 Abstract ………………………………………………………………………………………... 86
CHAPTER 5 - Clinical Implications of Pre-Transplant Skeletal Muscle Mass, Strength and Exercise Capacity on Functional Recovery in Lung Transplant Recipients after 7 or More Days of Mechanical Ventilation ……………………… 88
5.1 Abstract…………………………………………………………………………………….. 88
5.2 Introduction…………………………………………………………………………………… 90
5.3 Methods………………………………………………………………………………………. 92 5.3.1 Study Design and Participants……………………………………………………………... 92 5.3.2 Pre-Transplant Muscle Mass, Strength and Functional Capacity………………………. 92 5.3.3 Pre-Transplant Clinical Parameters………………………………………………………… 93
X
5.3.4 Peri-operative and Post-Transplant Outcomes……………………………………………. 94 5.3.5 Statistical Analysis …………………………………………………………………………… 95
5.4 Results………………………………………………………………………………………… 96 5.4.1 Pre-Transplant………………………………………………………………………………… 96 5.4.2 Post-Transplant …………………………………………………………………………….. 100
5.5 Discussion……………………………………………………………………………………… 103
5.6 Conclusion……………………………………………………………………………………... 108
CHAPTER 6 – Discussion and Conclusion …………………………………………… 110
6.1. Overview of Findings…………………………………………………………………………… 110
6.2: Assessment of Skeletal Muscle Dysfunction in Lung Transplant Candidates ………….. 111
6.3: Determinants of Skeletal Muscle Dysfunction in Lung Transplant Candidates ………… 119
6.4: Association of Skeletal Muscle Dysfunction with Post-transplant outcomes……………. 123
6.5: Clinical Implications of Skeletal Muscle Function Assessment…………………………….. 130
6.6 Limitations……………………………………………………………………………………….. 131
6.7 Conclusion………………………………………………………………………………………. 133
6.8 Future Directions……………………………………………………………………………….. 134
REFERENCES ...………………………………………………………………………… 139
APPENDIX 1 – Supplementary Tables and Figures ………………………………. 179
APPENDIX 2 - Ethics Approval Letters for Studies 1-3 …………………………… 182
APPENDIX 3 – Consent Form for Study 2 (Chapter 4) ……………..…………..…. 189
XI
LIST OF TABLES:
Table 1-1: Comparison of Factors Related to Skeletal Muscle Dysfunction in Chronic Lung Disease and Lung Transplant Recipients Table 3-1: Patient Characteristics and Associations with Muscle Cross-sectional Area Table 3-2: Associations between Thoracic Muscle Cross-sectional Area and Exercise Capacity, Strength Training Volumes, Quality of Life, and Pre-transplant Outcomes Table 3-3: Characteristics of Subjects by Availability of Health-related Quality of Life Data Table 3-4: Associations Between Muscle Cross-sectional Area and Post-Transplant Outcomes Table 5-1: Baseline Characteristics at Transplant (n=80) Table 5-2: Muscle CSA, Training Volumes, Exercise Capacity and Oxygen Requirements at Listing and Before Transplantation Table 5-3: Multivariate Association with Pre-Transplant Predictors and Motor Functional Independence Measure at 7 and 90 days Post-ICU. Table 5-4: Multivariate Association with Pre-Transplant Predictors and Post-Transplant Discharge Disposition (Inpatient Rehabilitation vs. Home). Table 5-5: Bivariate Association with Pre-Transplant Risk Factors and Post-Transplant Mortality Three Months Post-ICU Discharge (n=80)
XII
LIST OF FIGURES:
Figure 1-1: Skeletal Muscle Mass, Strength and Physical Performance Measures Figure 2-1: Conceptual Thesis Framework Figure 3-1: Representation of Cross-sectional Muscle Area using Slice-O-Matic Software Figure 3-2: Flow Diagram of Lung Transplant Candidates Included in the Study Figure 3-3A: Male Lung Transplant Candidates vs. Controls (Ages 50–69 years) Figure 3-3B: Female Lung Transplant Candidates vs. Controls (Ages 50-69 years) Figure 5-1: Flow Diagram of Study Participants Figure 6-1: Conceptual Framework of Risk Factors Affecting Skeletal Muscle Mass, Strength and Function
XIII
LIST OF APPENDICES:
Appendix 1 – Supplementary Tables and Figures
Appendix 2 - Ethics Approval Letters for Studies 1-3
Appendix 3 – Consent Form for Study 2 (Chapter 4)
XIV
ABBREVIATIONS:
ADL = Activities of Daily Living BIA = Bio-electrical Impedance BMI = Body Mass Index CI = Confidence Interval COPD = Chronic Obstructive Pulmonary Disease CSA = Cross-sectional Area CT = Computed Tomography D-XA = Dual Energy X-ray Absorptiometry ECLS = Extra-corporeal Life Support ECMO = Extra-corporeal Membrane Oxygenation FIM = Functional Independence Measure FFM = Fat free mass FFMI = Fat-free mass index HRQL = Health-related Quality of Life ICU = Intensive Care Unit ICUAW = Intensive Care Unit Acquired Weakness ILD = Interstitial Lung Disease LAS = Lung Allocation Score LCADL = London Chest Activity of Daily Living MIP = Maximal Inspiratory Pressure MEP = Maximal Expiratory Pressure MRC = Medical Research Council MV = Mechanical Ventilation PASE = Physical Activity Scale for the Elderly
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PCS = Physical Component Score PGD = Primary Graft Dysfunction SD = Standard Deviation SE = Standard Error SF-36 = Short-Form 36 SPPB = Short Physical Performance Battery 6MWD = Six-minute Walk Distance 6MWT = Six-Minute Walk Test SGRQ = St. George's Respiratory Questionnaire
1
CHAPTER 1
Literature Review and Introduction
1.0 Statement of the Problem
Chronic lung disease is a significant problem world-wide. It is estimated that hundreds of
millions of people are living with significant respiratory symptoms and approximately four
million people die from their chronic lung disease each year.1 Globally, chronic obstructive
pulmonary disease (COPD) is projected to be the third leading cause of morbidity and
mortality by 2020.2 Similarly, interstitial lung disease (ILD) is one of the most common
conditions referred for lung transplantation.3,4 Pulmonary arterial hypertension,5 cystic
fibrosis,6 and bronchiectasis7 also account for a significant degree of morbidity and mortality.
For many of these chronic lung diseases, lung transplantation remains the only life-saving
treatment strategy.8
Chronic lung disease is generally associated with a number of co-morbidities that can lead to
increased morbidity and mortality.9-11 A common extra-pulmonary manifestation of chronic
lung disease is skeletal muscle dysfunction.12,13 Skeletal muscle dysfunction is an
encompassing term that refers to the structural and functional changes observed in skeletal
muscles.14 The evaluation of skeletal muscle dysfunction can span the spectrum from
alterations in bioenergetics, contractility and structural integrity at the muscle fiber level to
non-invasive measures of muscle mass, strength and performance of functional activities.14,15
To date, the majority of research in the area of skeletal muscle dysfunction in chronic lung
disease has focused on patients with COPD, but there is increasing recognition of the
importance of this extra-parenchymal manifestation in other disease states such as ILD,12
pulmonary hypertension,16 cystic fibrosis,17 bronchiectasis18 and pre- and post-thoracic
surgery, including lung transplantation.19
2
Skeletal muscle dysfunction is prevalent in advanced lung disease. In COPD patients,
elements of skeletal muscle dysfunction including impaired muscle mass, strength, and
physical performance have been described.14 Decreased skeletal muscle strength has been
observed in other chronic respiratory conditions such as pulmonary fibrosis20 and cystic
fibrosis.17 In COPD, skeletal muscle dysfunction has been associated with reduced physical
activity, exercise capacity, health-related quality of life (HRQL), hospital length of stay and
survival.14 Important contributing factors to skeletal muscle dysfunction include physical
inactivity, deconditioning, hypoxemia, malnutrition, and use of corticosteroids.13 In other
chronic lung disease states, less is known about the clinical implications of skeletal muscle
dysfunction.21
Lung transplantation is a life-saving procedure for many individuals with advanced lung
disease. These patients undergo a comprehensive, multi-disciplinary evaluation of their
medical and psycho-social issues to determine their risks and benefits with lung
transplantation. Based on the international guidelines for selection of lung transplant
candidates, physical deconditioning is often emphasized as an absolute contraindication for
surgery.8 Routine physical measures in the pre-transplant period include assessment of body
mass index (BMI), six-minute walk distance (6MWD), pulmonary function and oxygen
requirements. It is well-established that exercise capacity pre-transplant is associated with
increased pre and post-transplant mortality.22,23 Similarly, lung transplant candidates who are
underweight (BMI < 18.5 kg/m2) or obese (BMI ≥ 30 kg/m2) have been observed to have
increased morbidity and mortality in the post-transplant period.24
Skeletal muscle mass and strength are significantly impaired in the pre- and post-transplant
period.21 However, the clinical implications of skeletal muscle dysfunction (muscle mass,
strength and function) have not been well described in lung transplantation with respect to its
association with HRQL, exercise capacity, activities of daily living (ADL), and pre- and post-
3
transplant clinical outcomes. A better understanding of skeletal muscle dysfunction and its
implications in the pre- and post-transplant period could potentially help with candidate
selection and rehabilitation strategies.
This thesis aims to characterize individual elements of skeletal muscle dysfunction (muscle
mass, strength and physical performance) in lung transplant candidates and assess their
association with pre- and post-transplant physical function, HRQL, and clinical outcomes. We
hypothesized that skeletal muscle dysfunction will independently be associated with pre-
transplant physical function and HRQL and with early post-transplant outcomes. This will be
evaluated through three complementary studies in lung transplant candidates and recipients
from a single transplant center. A detailed thesis framework is provided in Chapter 2.
The present introductory chapter will be comprised of five main sections. Section 1 will
review the current state of lung transplantation worldwide and outcomes commonly measured
in lung transplantation. Section 2 will outline the pathogenesis, diagnosis, and clinical
implications of skeletal muscle dysfunction in chronic lung disease, lung transplant candidates
and recipients. Section 3 will highlight the prognostic utility of pre-operative measures such
aerobic capacity and physical performance tests with major surgery and solid-organ
transplantation. Section 4 will outline the implications of prolonged mechanical ventilation,
critical care and hospital length of stay in patients undergoing major surgical procedures with
a focus on lung transplantation. Section 5 will review the rehabilitation strategies utilized in
the post-transplant period in lung transplant recipients.
1.1 Overview of Lung Transplantation
Lung transplantation is a life-saving procedure for many patients with advanced lung disease.
There have been many medical and surgical advances over the last 30 years since the first
successful lung transplantation, with significant improvement in survival. The number of lung
4
transplants performed annually continues to grow internationally. The latest report from the
International Society of Heart and Lung Transplant (ISHLT) Registry reported close to 4000
adult lung transplants performed in 2014 compared to approximately 2100 transplants in
2004.25 Based on the ISHLT registry data, the median survival after lung transplantation was
5.7 years.25 In addition to survival, lung transplantation confers a significant benefit with
respect to HRQL and functional capacity.26,27
The selection of lung transplant candidates has evolved over time to include patients who are
older, have increased co-morbidities, and potentially greater functional limitations.28,29 Based
on the recent ISHLT guidelines for selection of lung transplant candidates, a number of
relative contraindications were updated but the selection criteria remains fairly broad with the
greatest emphasis placed on potential life years gained.8 Generally, a comprehensive risk
assessment is recommended that includes medical comorbidities, functional status, psycho-
social elements and life expectancy with transplant. The ISHLT guidelines recommend
consideration of transplant for severe lung disease when medical therapy is ineffective,
mortality without transplantation is greater than 50% at two years, there is a reasonable
chance of survival beyond 90 days with transplant (> 80%), there is appropriate psychosocial
support, and absence of significant extra-parenchymal comorbidity that would limit five year
survival post-transplant.8
With improvement in survival, lung transplantation is no longer restricted to the youngest and
fittest patients. The median age of transplant recipients has gradually increased from 43 to 56
years from 1990 to 2011.30 Furthermore, the adoption of the Lung Allocation Score (LAS) in
the United States and Europe, which prioritizes patients with a high expected pre-transplant
mortality, has increased the average age and complexity of transplant recipients.31,32 As a
result of surgical advances, extra-corporeal membrane oxygenation (ECMO) is also gaining
recognition as a potential viable option for critically ill lung transplant candidates.8 ECMO
5
provides both cardiac and respiratory support through an external circuit to support patients
with cardiac or respiratory failure.33 Early outcomes with ECMO were generally poor with
about 40% one year survival, partly attributed to immobilization leading to critical care
myopathy.34-36 In the last several years, the outcomes with awake ECMO strategies that allow
mobilization due to reduced sedation have been favorable with one year survival being greater
than 80%.37,38 Thus, critically ill patients admitted to the ICU are more likely to be prioritized
for lung transplantation, but are at greater risk of pre-transplant mortality3 and post-transplant
morbidity and mortality.39,40
The sections that follow in this chapter describe the survival benefit of lung transplantation and
several prognostic factors. A detailed overview of the benefits in HRQL, ADL, exercise
capacity and physical activity will be summarized. The relationship between these functional
measures and skeletal muscle will be highlighted.
1.1.2 Survival with Lung Transplantation:
Survival in the first-year post-transplant has significantly improved over the last era compared
to eras preceding 2000, with unadjusted survival in the first year post-transplant being 80%.25
In the early post-transplant period, infection is the leading cause of morbidity and mortality in
lung transplant recipients.41,42 Infection can occur as a primary process or in association with
surgical complications (i.e. bleeding, airway complications) or primary graft dysfunction.
Beyond the first year, chronic allograft dysfunction is a significant risk factor for respiratory
infections and mortality.43 The risk of developing chronic allograft dysfunction is high with the
incidence approaching about 50 percent at 5 years after lung transplantation.30 Chronic
allograft dysfunction is also associated with significant functional decline and impairments in
HRQL.44,45 Unfortunately, there are no available treatment strategies for chronic allograft
dysfunction and this remains a major hurdle limiting long-term survival.
6
1.1.3 Risk Factors Associated with Lung Transplant Mortality
Recipient characteristics such as age, lung diagnosis, body composition, and disease severity
have been described to be important determinants of mortality as described below.25,46
Age:
Lung transplant candidates over the age of 65 years have usually been thought of as having a
relative contraindication for lung transplantation. Nevertheless, the number of lung transplant
recipients older than 65 years old has increased significantly in the United States approaching
about one third of recipients.47 Worldwide, a similar proportion of older lung transplant
recipients has been observed with about 40 percent being older than 60 years of age.30,48 At
our center, the proportion of older lung transplant recipients in 2016 was comparable to
international data with 61/142 (43%) being 60 years or older (Toronto Lung Transplant Clinical
Database). The unadjusted five-year survival based on the ISHLT registry (1990-2011) for
those over the age of 65 years old was 38%, 46% for those between 60-65 years old, and
52% to 57% across three age categories (50-59, 35-49 and 18-34 years old, respectively).30
However, it is important to highlight that these survival differences were not adjusted for type
of transplant, era or transplant indication, which are important contributing factors. It is not
surprising that older recipients have a shorter actuarial survival than younger patients, but the
shorter survival in older recipients is not solely attributable to actuarial differences.49 Genao et
al. recently demonstrated that the functional trajectory of older lung transplant recipients (≥ 65
years) compared to younger recipients was similar in the first 5 years post-transplant,
potentially supporting the benefit of transplantation in older patients.50 Furthermore, our group
has shown that lung transplant recipients derive a significant HRQL benefit with
transplantation, which does not differ significantly for older recipients.26
7
Diagnosis:
The most common indications for adult lung transplantation continue to evolve given
worldwide changes in lung allocation practices that have increased the proportion of ILD
candidates.8 This trend can be attributed to more liberal criteria which accepts older lung
transplant candidates and the widespread adoption of allocation systems that prioritize
transplantation based on disease severity, which favors ILD.8 Presently, ILD (28%) remains
the second most common indication for lung transplantation after COPD (36%) reported to the
ISHLT registry.25 Other common indications for lung transplantation include cystic fibrosis
(16%) and pulmonary arterial hypertension (4%). Lung transplant recipients with COPD are
known to have the best one-year survival compared to other diagnoses such as ILD and
pulmonary arterial hypertension that have the lowest one-year survival.25 ILD has also been
associated with the lowest 10-year survival with long term survival greatest for patients with
pulmonary arterial hypertension and cystic fibrosis. Unfortunately, ILD and in particular
idiopathic pulmonary fibrosis, is associated with the worst prognosis among the common
indications for lung transplantation.8
Body Composition:
The association between pre-transplant BMI and post-transplant outcomes has been
investigated in several studies. A number of single center studies have shown that pre-
transplant obesity (BMI ≥ 30 kg/m2) was associated with increased morbidity and mortality
post-transplantation.51-53 However, no association between increased BMI (30-34.9 kg/m2)
and one year mortality was observed in over 9000 lung transplant candidates who underwent
lung transplantation in the United States from 2005-2011, suggesting that it might not be the
best marker of body composition.54 Thus, the updated ISHLT guidelines recommend that
obesity (BMI ≥ 30 kg/m2) be considered a relative contraindication for transplantation.8
Similarly, the role of low BMI (< 18.5 kg/m2) and risk of mortality has been conflicting with
8
studies showing increased risk,53,54 whereas other studies did not find a significant
relationship.53,55 In a recent systematic review and meta-analysis of 13 studies, 7 of which
were included in the meta-analysis, there was an increased risk of mortality in lung transplant
candidates who were underweight (BMI < 18.5 kg/m2; RR: 1.36 95% CI 1.11-1.66) or obese
(BMI ≥ 30 kg/m2; RR: 1.90 95% CI 1.45-2.56).24
A potential reason for the variability in results with BMI and transplant outcomes is the fact
that BMI is a poor measure of body composition. Body mass index has been shown to
misclassify greater than one-third of healthy adults as non-obese when in fact their adipose
levels were significantly increased with gold standard tests of body composition such as Dual-
energy X-ray Absorptiometry (D-XA).56 Similarly in lung transplant candidates, Singer et al.
observed that BMI had a very poor sensitivity in discriminating clinically important adipose
tissues levels and sarcopenia (i.e. low muscle mass) measured with D-XA.54 Taken together,
these results suggest that BMI is helpful clinically but needs to be interpreted with caution
given the unmeasured loss of skeletal muscle mass and potential for increased visceral fat
distribution, which has been shown to be an important predictor of mortality in the general
population and in other solid organ transplant recipients.57,58
Lung Allocation Score and Canadian Listing Status:
One system that has been adopted in the United States and Europe is the lung allocation
score (LAS).59 The LAS is calculated using statistical modeling to estimate the risk of one
year mortality on the transplant list and the survival benefit with transplantation.60 A number of
demographic, physiological and clinical parameters are included: such as age, BMI, diagnosis,
presence of diabetes, pulmonary function, pulmonary pressures, 6MWD, oxygen
requirements, renal function and need for mechanical ventilation (MV) pre-transplant.60 A
score from 0 to 100 is derived based on statistical modeling and higher scores represent
increased transplant urgency and greater likelihood that a patient would derive early survival
9
benefit from lung transplantation. Since the implementation of the LAS in the United States,
there has been a significant reduction in waitlist mortality, increased number of transplants,
and a higher proportion of transplants performed for older recipients and those with ILD.31
In Canada, we utilize the listing transplant urgency which consists of two statuses: Status 1
(stable), and 2 (deteriorating). Our program has added a “Rapidly Deteriorating” status to
indicate patients with a very high mortality risk pre-transplant. The Canadian listing urgency
status is a subjective determination of disease severity predictive of waiting list survival.61
Whereas both the Canadian listing and the LAS attempt to balance the need for lung
transplantation and ability to survive the procedure, neither system considers important patient
reported outcomes such as HRQL or ADL in the pre-transplant period. In fact, the LAS has
been observed to be poorly associated with HRQL in a cohort of lung transplant candidates in
Japan62 and in our own patients.63 This is an important consideration as many candidates
undergo lung transplantation to derive benefits in HRQL and physical function, not solely
survival.
1.1.4 Health Related Quality of Life:
Health related quality of life is significantly improved with lung transplantation compared to
pre-transplant values.64,65 A number of generic and disease specific instruments have been
utilized in lung transplantation to study HRQL.66 The Short-Form 36 (SF-36) is the most
commonly used generic HRQL instrument in lung transplantation. It comprises eight health
domains and two summary scores, physical and mental component scores (PCS and MCS),
with higher scores denoting better HRQL. Each domain and summary score ranges from 0 to
100 with a standard deviation of 10, and a population normative score of 50, for the most
recent version of the SF-36 (version 2).67 A 5-point difference in the PCS or MCS is
considered clinically significant.68 The most common respiratory-specific HRQL instrument is
10
the St. George's Respiratory Questionnaire (SGRQ).69-71 The SGRQ was originally developed
to be used in COPD patients, but has been expanded to other respiratory disease states.72-74
The SGRQ consists of three domains (symptoms, activity and impacts) and total score. The
SGRQ has a range of scores from 0 to 100 with higher scores signifying worse HRQL. A
minimally important difference for the SGRQ has been described as 4 points.75
Health-related quality of life is significantly impaired in lung transplant candidates on both
generic and disease specific instruments and declines during the waitlist period. In a
prospective cohort study from our center of 430 lung transplant candidates, the mean SF-36
PCS score steadily declined leading up to transplant by about 15 points over a three year
period from a baseline score of 40 points.26 Similarly, the mean SGRQ total score was 45 at
initial assessment with greater impairments at the time closest to transplant (about a 20-point
worsening).26 Furthermore, HRQL impairments tend to be more pronounced in the physical
function domains compared to those of mental health pre-transplant.76,77
Lung transplant recipients experience significant improvements in the physical function,
physical role and general health domains in the first 6 months post-transplant with less
improvement observed beyond six-months.78,79 The improvements observed at 6 months
post-transplant were greater than 20 points in physical functioning and general health
domains.78 There is limited improvement in the mental HRQL domains with transplant given
the possibility of a ceiling effect, as these values have been comparable to population
normative values pre-transplant.80-82 With lung transplantation, there are also large and
significant improvements in the respiratory specific HRQL measures. Kugler et al. observed a
significant gradual improvement (ranging from 15-26 on the total SGRQ domain) first-year
post-transplant.78 Similarly, Singer et al from our center observed a dramatic improvement in
the SGRQ total domain of 47 points in a mixed model adjusted for age, sex, diagnosis and
time post-transplant.26
11
Several predictors of post-transplant HRQL have been described. The large observational
study (n=430) from our center demonstrated no clinically significant associations between
HRQL and age at the time of lung transplantation; however, ILD patients were noted to derive
less HRQL benefit than cystic fibrosis patients.26 With respect to gender differences, women
have been described to have less HRQL benefit with transplantation possibly due to increased
post-operative symptoms, but this has only been observed in a few studies.83,84 Other
predictors of post-transplant HRQL include chronic allograft dysfunction, side-effects of
immuno-suppression, and pain.44,45,85
1.1.5 Functional Outcomes
Activities of Daily Living:
Patients with advanced lung disease have decreased ability to perform ADL, which are
essential for every day well-being and independence.86 Activities of daily living can be
captured with the use of questionnaires, which provide information on the current functional
level.87 They can be characterized into three main categories based on the description by De
Vriendt et al.88 Basic ADL include behaviours such as bathing, dressing and self-grooming.
Instrumental ADL include daily tasks such as various house chores, shopping and financial
responsibilities. Advanced ADL are more complex activities that are often driven by personal
cultural experiences and motivation, but go beyond activities required for personal
independence such as working and hobbies.88,89
The primary limitation in carrying out ADL in chronic lung disease is dyspnea and individuals
with advanced disease often decrease their ADL and/or require assistance from a caregiver.
The degree of disability experienced by those living with advanced lung disease is not well
captured by measures of pulmonary function, thus standardized disability questionnaires can
be very helpful in assessing disease impact.90,91 The inability to perform ADL due to dyspnea
12
can often impair self-efficacy and HRQL.92 More importantly, limitations in ADL have been
associated with increased mortality in COPD.93,94
In lung transplant candidates, participation in ADL has not been well characterized. In a study
by Muller et al, the London Chest Activity of Daily Living (LCADL) scale was utilized in lung
transplant candidates.95 This scale assesses the impact of dyspnea on carrying out ADL in
four domains: self-care, house-hold activities, physical and leisure activity. Scores on the
LCADL were associated with exercise capacity pre-transplant, with the majority reporting their
ADL limitations due to dyspnea.95 Singer et al. recently established a 15-item Lung
Transplant Valued Life Activities disability scale that has been shown to be valid and
responsive to change.96 These two scales are promising in the field of lung transplantation as
previous assessments of disability were quite limited focusing mainly on basic ADL or whether
someone was employed.97,98 To our knowledge, an assessment of ADL in the early (< 3
months) or late post-transplant period has not been previously described and could help
provide greater insight into associations with HRQL and function.
The importance of independence with basic functioning in the pre-transplant period was
highlighted in a study of over 7800 lung transplant candidates utilizing data from the United
Network for Organ Sharing database. Greater pre-operative functional independence
measured by Karnofsky Performance Status Score was associated with lower mortality at one
year.99 Only about 12% required no assistance, whereas the remaining lung transplant
candidates required complete (30%) or partial assistance (58%) pre-operatively.99 In addition
to pre-transplant functional independence, other factors such as older age (> 60 years), pre-
transplant ICU admission with requirement for ECMO or mechanical ventilation were
associated with an increased one year mortality. Despite the case complexity in transplant
recipients, the Karnofsky Performance Score has been shown to be an independent predictor
of outcomes in solid-organ abdominal transplantation100 and lung re-transplantation.101
13
Exercise Capacity:
The 6MWT is a sub-maximal exercise test which is the most common functional assessment
of exercise capacity in advanced lung disease and lung transplant candidates.102 It was
originally developed to be used in COPD patients, but has been applied broadly in other
chronic respiratory conditions. The 6MWT has been shown to be a good marker of disease
severity, functional impairment, and aerobic capacity in lung transplant candidates,103 but has
some limitations given the variability observed between tests due to learning effects.104
However, other field walking tests such as incremental and endurance shuttle walk tests,
which are externally paced might be more sensitive to assess effects of interventions such as
exercise training105,106 or bronchodilator therapy.107 Furthermore, shuttle walk tests are less
vulnerable to testing variation (e.g. site or operator).102 However, the 6MWT is commonly
used in lung transplantation given its established prognostic value and incorporation into the
LAS.23,108
Most lung transplant candidates achieve less than 400 meters on the 6MWT with a distance of
45-55% predicted.22,109 In the largest study to-date of over 9500 lung transplant candidates,
the median 6MWD was 240 m IQR [137-330].23 The 6MWD has been observed to be
relatively preserved during the pre-transplant period (decline of 15 meters) in a select group of
lung transplant candidates from our center participating in outpatient pulmonary rehabilitation
with available rehabilitation data.110
Low 6MWD has been shown to be associated with pre-transplant delisting, mortality22,111 and
post-transplant outcomes such as hospital length of stay110 and survival.23,112 A low 6MWD in
the pre-transplant period has also been associated with increased risk of discharge to
inpatient rehabilitation post-transplant.113 Castleberry et al. demonstrated in over 9500 lung
transplant candidates that higher pre-transplant 6MWD was associated with higher peri-
operative (30 and 90 day) and one-year survival post-transplant.23 The results from their
14
study indicate that 6MWD is best incorporated as a continuous variable given no clear
dichotomous cut-offs for survival. The 6MWT provides a global assessment of physical
fitness, which has been described to be an important marker in predicting the physiological
stress response with surgery.114,115
In the post-transplant period, exercise capacity improves to 65-85% of predicted 6MWD within
3 to 4 months post-transplant.116,117 Ventilatory limitation is generally not a concern in lung
transplant recipients in the post-transplant period in the absence of complications such as
infection or chronic rejection.118 With cardiopulmonary exercise testing, most lung transplant
recipients have oxygen saturations above 90% on room air119,120 and the majority report
significant leg fatigue as opposed to dyspnea, as a major factor in stopping their exercise
test.121 Recovery in quadriceps strength has been implicated as a key contributor to the post-
transplant walk distance achieved.116,122 Thus, skeletal muscle dysfunction plays a critical role
in the exercise limitations observed post-transplant.27,121
Physical Activity:
Evaluation of physical activity in the pre-transplant period provides another avenue for
functional assessment. Physical activity levels can be evaluated using questionnaires,
pedometers or accelerometers.123 An assessment of physical activity in lung transplant
candidates can also assist with physical activity counselling and establishment of pulmonary
rehabilitation goals.
Lung transplant candidates have been observed to have reduced physical activity levels.124,125
A study from our center showed that lung transplant candidates with ILD had significantly
reduced daily step counts, which were higher on their rehabilitation days.125 However, even
on rehabilitation days, the daily step count of 3780 ± 2196 was significantly lower than the
average daily step count of 9500 and 8400 steps per day achieved by healthy Canadian men
15
and women, respectively.126 Similarly, Langer et al demonstrated in 96 lung transplant
candidates with COPD and ILD that they were significantly inactive with a total of 2928 ± 1796
steps achieved.124 Furthermore, they observed that lung transplant candidates had a lower
time walking daily by 23% compared to non-listed COPD patients at their center despite being
12 years younger.124 Patients with COPD actually have the lowest daily physically activity
levels (5319 steps) compared to other cardiopulmonary populations such as patients with
heart failure (7464 steps).127
Based on accelerometer data, Langer et al. also observed that their group of lung transplant
candidates spent only about 5% of their waking hours walking (34 ± 19 minutes) with the rest
of the time standing (26%) or sitting/lying down (69%).124 In comparison, the amount of time
spent in sedentary activity (less than 2 metabolic equivalents) for the general North American
population has been variable, ranging from 50-69%.126,128 Thus, lung transplant candidates
spend more time in sedentary activity; however, it is important to highlight that the general
North American population is quite sedentary with only 15% achieving the recommended
targets of 150 minutes of moderate-vigorous intensity activity per week.126
Physical activity levels have been characterized using the Physical Activity Questionnaire in
the Elderly (PASE), which is a validated 12-item self-administered questionnaire measuring
the amount of physical activity in the previous one week in those over the age of 65.129
Unfortunately, there is no readily available physical activity questionnaire that has routinely
been used in advanced lung disease; however, the PASE has been previously validated in
COPD patients using accelerometers to predict severe levels of physical inactivity.130 From
our center, Mendes et al observed that self-reported PASE scores were significantly lower in
ILD transplant candidates compared to healthy age and sex matched controls (81 ± 50 vs.
178 ± 120, p=0.03),131 and in fact the levels in these transplant candidates were noted to be
comparable to frail community dwelling elderly patients.132
16
Physical activity levels generally improve post-transplant beyond the first three months;109
however, are still reduced at the one year mark post-transplant compared to healthy
controls.133 Daily step count and time spent in moderate intensity activity was found to be
reduced by 42% and 66%, respectively, compared to controls at the one year mark post-
transplant.133 Physical activity levels one year post-transplant have been shown to be closely
associated with exercise capacity, quadriceps strength and HRQL.133 Rehabilitation in the first
3 months post-transplant has been demonstrated to lead to sustained improvement in
physical activity levels in lung transplant recipients at one year post-transplant.117 However,
physical activity levels beyond the first year post-transplant have not been described.134
Skeletal Muscle Dysfunction
Individual elements of skeletal muscle dysfunction such as muscle mass, strength, and
physical performance have been described in lung transplant patients using various non-
invasive modalities.21 Reduced skeletal muscle mass and lower extremity strength are
commonly observed in the pre-transplant period with persistence of skeletal muscle
dysfunction up to five years post-transplant.21 Kyle et al. noted in 37 lung transplant patients
that low fat-free mass with bio-electrical impedance (BIA) was observed in two-thirds of
transplant candidates and seen in one-third of patients two years post-transplant.135 Similarly,
quadriceps strength was impaired in the pre-transplant period (mean range 49-86%) with
persistence of quadriceps weakness beyond three-months post-transplant (58-101%) based
on a systematic review of 18 lung transplant studies.21 Bossenbroek et al. demonstrated that
the sit-to stand test, predominantly an assessment of lower extremity strength, was noted to
be significantly lower in candidates compared to lung transplant recipients on average 5-years
post-transplant (7.7 ± 2.5 versus 10 ± 4.4 repetitions in 30 seconds).136 Even though there
was significant recovery in lower extremity strength and function with the sit-to-stand test,
these values were still lower than healthy adults.137
Excerpts on Skeletal Muscle Dysfunction reproduced with permission from Elsevier. The article has been published in final form: Rozenberg D, et al. Sarcopenia in lung transplantation: a systematic review. J Heart and Lung Transplant. 2014 Dec; 33(12): 1203-12. DOI: 10.1016/j.healun.2014.06.003.
17
One important element of muscle function is endurance, which is the ability of the muscle to
sustain repeated contractions. There is evidence in COPD patients that the aerobic profile is
significantly impaired with reduction in the size of oxidative muscle fibers (type 1), oxidative
enzyme concentration, mitochondrial and capillary density.138,139 These changes in the
aerobic profile of muscle can contribute to impaired muscle endurance and activity tolerance,
as observed in COPD.140-142 Lands et al. observed in 19 lung transplant recipients low
exercise performance with cycling about 18 months post lung transplantation, partly attributed
to reduced leg muscle work capacity (i.e. endurance), independent of any ventilatory or
cardiac limitations.121
Individual elements of skeletal muscle dysfunction have been shown to be closely associated
with physical activity levels and exercise capacity in lung transplant candidates and recipients.
Quadriceps strength has moderate correlation with daily steps in lung transplant candidates
and recipients (r=0.51-0.66).125,133 Quadriceps strength has also been shown to correlate with
post-transplant 6MWD (r=0.41)143 and with peak oxygen uptake (r=0.71) in transplant
recipients.144 In lung transplant candidates, performance on the sit-to-stand test correlated
with physical activity levels characterized by daily steps (r=0.45).136 Thus, skeletal muscle
dysfunction has important systemic consequences on physical activity levels and exercise
capacity in the pre- and post-transplant periods.
The effects of skeletal muscle dysfunction on patient reported outcomes such as HRQL and
ADL in the pre- and post-transplant periods have not been investigated to-date.21 Skeletal
muscle evaluation may provide an additional assessment of daily function which may help
elucidate the limitations experienced by lung transplant candidates and recipients. This is an
important area of investigation in lung transplant candidates and recipients as skeletal muscle
function may prove to be modifiable with exercise training, ultimately affecting HRQL, daily
function and transplant outcomes.
18
1.2: Evaluation of Skeletal Muscle Dysfunction in Chronic Lung Disease and Lung Transplant Patients
Skeletal muscle dysfunction is multi-factorial with several factors described in chronic lung
disease and lung transplant recipients. A common contributing factor to skeletal muscle
dysfunction in chronic respiratory disease is muscle disuse (i.e. deconditioning) due to
physical inactivity.145 However, there are a myriad of additional factors that need to be
considered, including factors common to transplant recipients such as ongoing use of
corticosteroids, calcineurin inhibitors, inflammation and oxidative stress.
These factors can affect both the structure and function of skeletal muscle in chronic lung
disease and transplant recipients with changes in muscle fiber atrophy and fiber type
shift,138,146 and through changes in blood vessel capillarization,147 mitochondrial function and
bioenergetics as described in further detail below.148,149 Unlike chronic lung disease, the
mechanisms underlying skeletal muscle dysfunction in lung transplant recipients have not
been well characterized, as highlighted below.
This section presents an overview of the generic and disease specific factors (i.e. those that
are related to chronic lung disease and transplant recipients) that may contribute to skeletal
muscle dysfunction, summarized in Table 1-1. A discussion that follows reviews non-invasive
measurements of skeletal muscle mass, strength and function in chronic lung disease and
lung transplantation, including their clinical implications.
1.2.1: Generic and Disease Specific Factors Related to Skeletal Muscle Dysfunction in Chronic Lung Disease and Transplant Recipients
Aging:
Age is known to be a significant factor associated with a decline in skeletal muscle mass and
function.150,151 Aging is associated with the loss of motor neurons, especially the larger motor
units with the higher recruitment thresholds resulting in denervation, and as a consequence
19
leading to muscle fiber loss, atrophy, and function.152,153 The cross-sectional area (CSA) of
both type I (oxidative) and type II (glycolytic) fibers has been shown to be reduced in the
elderly compared to younger adults; however, the atrophy of fast twitch, glycolytic fibers
appears to be preferentially affected with aging.154,155 Furthermore, the capacity for motor
neurons to reinnervate neighbouring muscle fibers is also significantly impaired with aging.156
Rosenberg was the first to coin the term sarcopenia in 1989, mainly describing age-related
muscle mass loss.157 However, a recent consensus from the European Working Group on
Sarcopenia in the Elderly proposed that the definition of sarcopenia capture loss of strength or
physical function in addition to muscle mass loss.158 Unfortunately, to-date there has been no
well-established definition of sarcopenia in chronic lung disease; however, it is believed that
chronic lung disease accentuates many of the processes related to the development of
sarcopenia.159-161 Given that the age of lung transplant candidates continues to increase,
sarcopenia is certainly an important consideration both in the pre- and post-transplant period.
Muscle Disuse and Physical Inactivity:
Muscle disuse has been described as an important contributing factor for skeletal muscle
dysfunction. Disuse has been associated with muscle atrophy, weakness, decreased muscle
fiber cross-sectional area (CSA) and loss of oxidative muscle fibers (Type I) with a preferential
shift towards fast twitch muscle fibers (Type II).14,162 These changes in turn contribute to loss
of muscular endurance and activity tolerance, where the muscle energy requirements are
quickly depleted even at low exercise intensities.141,163 Muscle disuse is associated with
similar limb muscle changes as seen in COPD patients, which is in contrast to what is
observed with aging where there is a preferential loss of type II muscle fibers.14,164
Prolonged periods of bed rest from hospitalization can lead to accelerated losses in muscle
mass, strength and physical function.165 Loss of muscle mass due to inactivity tends to affect
20
the lower extremities and is more rapid in the early days of inactivity.166,167 Kortebein et al
observed that the loss of lower extremity muscle mass was more pronounced in older healthy
adults than younger patients after 10 days of bed rest.168 Similarly, Kortebein et al
demonstrated in healthy older adults that 10 days of bed rest with a stable diet resulted in
reductions in knee extensor strength (-13%), leg power (-14%), and aerobic capacity
(-12%).169 de Boer et al. observed that the lower extremity muscles affected with bedrest
were primarily the anti-gravity muscles (quadriceps and calf muscles) compared to the non-
antigravity muscles (hamstrings and tibiliais anterior).170 This highlights the importance of
muscle loading with everyday activity and the preferential loss of muscle in specific muscle
groups.
In chronic respiratory disease, physical inactivity is established to be an important contributing
factor for skeletal muscle dysfunction. Physical inactivity has been observed even in mild
COPD and is associated with impairments in quadriceps muscle size.171,172 In lung transplant
candidates with ILD, daily step count had moderate correlation with quadriceps strength.125
Similarly, Mendes et al. observed significant muscle atrophy and weakness of the lower limb
muscles compared to the upper extremity muscles in lung transplant candidates with ILD who
had low self-reported physical activity levels, providing indirect evidence of a pattern of
weakness associated with muscle disuse.131 In the post-transplant period, physical activity
levels remain reduced in the first-year post-transplant and quadriceps strength has been
observed to parallel the increase in physical activity levels.117,133
Smoking:
A number of mechanisms have been proposed for the effects of cigarette smoking on skeletal
muscle dysfunction, specifically affecting muscle atrophy.173 Some of the mechanisms
include: oxidative stress, decreased protein synthesis, and inflammation.174-176 Immunological
factors have also been suggested to be responsible for the persistence of the noxious
21
stimulus from smoking, which could have effects on skeletal muscle with inflammatory
cytokines reaching the muscle via the circulation.177-179 In lung transplant candidates, the
persistence of the immunological stimulus is probably less of a concern given most lung
transplant programs require smoking cessation for a minimum of 6 months duration,
consistent with our program requirements.
Inflammation and Oxidative Stress:
Systemic inflammation can lead to activation of cytokines which are responsible for local
muscle protein degradation or activation of proteolytic pathways.180-182 As described in several
reviews, cytokines can induce muscle atrophy through transcriptional activities via several
mechanisms including the ubiquitin-proteasome system, autophagy-lysosome system, and
apoptosis.183,184 In particular, tumor-necrosis factor alpha and interleukin-1 have been shown
to stimulate muscle specific proteins of the ubiquitin-proteasome system, which can impact
muscle catabolism and impair muscle contraction.185,186
Oxidative stress is another contributing factor that has been described to be related to
inflammation in chronic diseases such as COPD.187 Oxidative stress can induce a rise in
inflammatory cytokines, which could lead to some of the adverse effects on skeletal muscle
atrophy described above.187 Skeletal limb muscles have been observed to have a greater
degree of oxidative stress compared to the respiratory muscles in animal models.188,189
Oxidative stress is postulated as a contributing factor for muscle protein dysregulation
required for muscle structure and function, which in turn can lead to impairments in muscle
protein regeneration.190 In lung transplant recipients, the ability to combat oxidative stress has
been shown to be compromised up to one year post-transplant with low levels of anti-oxidant
markers observed in serum and bronchoalveolar lavage fluid in 19 transplant recipients.191
However, the direct effects of oxidative stress on skeletal muscle has not been described in
lung transplant recipients.
22
Generalized inflammation and oxidative stress can also have a significant effect on
mitochondrial density and bio-genesis,192 which have been associated with muscle atrophy,
weakness and loss of muscle endurance in patients with advanced lung disease and survivors
of critical illness. In COPD patients, mitochondrial density and biogenesis were significantly
reduced in the vastus lateralis muscles compared to healthy controls.148,193 Similarly,
mitochondrial function (ability to synthesize adenosine triphosphate, the energy currency of
the cell) was 50% lower in patients with ICU acquired weakness after two weeks of
mechanical ventilation compared to controls undergoing hip replacement surgery.194 Similarly,
lung transplant recipients have been shown to have a lower number of oxidative muscle fibers
(type 1) and decreased oxidative enzyme activity.149 In the post-transplant period,
mitochondrial function of skeletal muscle may be affected to a greater degree given the
chronic exposure to calcineurin inhibitors, which are known to hinder mitochondrial
biogenesis.195
Respiratory Failure:
Hypoxemia and hypercapnea have been observed in a number of chronic respiratory
conditions to contribute to skeletal muscle dysfunction, specifically reduced muscle strength
and endurance.196,197 Hypoxemia can affect energy storage, protein synthesis and impaired
muscle contractility.198-200 Hypercapnea through skeletal muscle acidosis can lead to
impairments in skeletal muscle protein synthesis in vitro, which could impair muscle size.201 In
lung transplant recipients, the effects of hypoxemia and hypercapnea on skeletal muscle
function have not been previously assessed and might be more applicable in transplant
candidates. Lung transplant recipients are generally not limited from a ventilatory stand-point
in the absence of acute or chronic allograft dysfunction.118
Nutritional Abnormalities:
Nutritional status can have a significant impact on skeletal muscle dysfunction. Malnutrition
23
has been associated with reduced muscle mass, lower proportion of oxidative muscle fibers,
and reduced physical function.202,203 The potential mechanism responsible for these changes
involve an imbalance between dietary intake (e.g. macro-nutrients like protein) and energy
expenditure (increased due to respiratory effort and systemic inflammation).190,204
In lung transplant candidates, malnutrition has been observed in about 10% of patients based
on pre-operative nutritional variables such as low BMI < 18.5 kg/m2, albumin, total protein,
immunoglobulins and total lymphocyte count.205 Malnourished lung transplant candidates
demonstrated worse one year survival post-transplant and increased risk for post-operative
infections.205
Corticosteroids and Immuno-Suppressive Medications
Corticosteroids are required for management of exacerbations and as part of maintenance
therapy in many inflammatory respiratory conditions, and are a mainstay of
immunosuppressive therapy post-transplant. Corticosteroids contribute to increased muscular
protein breakdown, which is supported by increased myostatin levels and reduced anabolic
hormones such as insulin-like growth factor 1 levels.206,207 Chronic corticosteroid use has
been observed to be associated with quadriceps muscle weakness in ILD patients, and
muscle strength had an inverse relationship with the total dose of corticosteroids received.208
A similar association between average daily dose of corticosteroids and quadriceps strength
was observed in cystic fibrosis patients.209 In the peri-operative post-transplant setting, Nava
et al demonstrated that 5 days of treatment with high dose corticosteroids for acute rejection
in lung transplant recipients was associated with generalized muscle weakness (respiratory
and quadriceps) in 45% of patients, which took up to 2 months to recover from.210
In addition to corticosteroids, lung transplant recipients are exposed to calcineurin inhibitors
which are believed to impair skeletal muscle function. Calcineurin inhibitors impair the ability
24
of blood vessels supplying muscle fibers to dilate thus reducing oxygen delivery to the
exercising muscle.211,212 In addition, calcineurin inhibitors have been shown to significantly
reduce mitochondrial oxidative capacity in animal studies.213 Taken together, calcineurin
inhibitors and corticosteroids are thought to have a significant effect on skeletal muscle
function in lung transplant patients. In other solid organ transplant recipients such as cardiac,
renal and liver, immunosuppressive medications have been implicated as a contributor to
skeletal muscle dysfunction, given a similar pattern of peripheral exercise limitation as seen in
lung transplant recipients.214-216
Table 1-1: Comparison of Factors Related to Skeletal Muscle Dysfunction in
Chronic Lung Disease and Lung Transplant Recipients
Factors Chronic Lung Disease
Lung Transplant Recipients
Aging
(152,153) (152,153)
Physical Inactivity
(131,162) (117,133)
Smoking
(173,174)
Inflammation
(181,185)
Oxidative Stress
(187,190) (191)
Hypoxemia
(196,198)
Hypercapnea (201)
Malnutrition
(202,203)
Medications: Corticosteroids Calcineurin Inhibitors
(206,207,208)
(210)
(211,212)
Note: Reference examples are provided in brackets.
25
1.2.2 Rationale for Measuring Muscle Mass, Strength and Function
Whereas the original definition of sarcopenia (i.e. loss of muscle mass) was meant to be
applied to the elderly, loss of muscle mass can occur with disuse, inflammation and
malnutrition; risk factors common to chronic lung disease as outlined above. These risk
factors could lead to alterations in protein synthesis, proteolysis, and impairments in
neuromuscular functioning.190 The European Working Group on Sarcopenia in Older People
(EWGSOP) defines sarcopenia as low muscle mass and one of low muscle function (strength
or performance).158
It was originally thought that skeletal muscle mass explained the loss of strength in older
adults. However, longitudinal studies have demonstrated that muscle mass and strength are
not necessarily concordant. A large prospective study in community dwelling elderly (Health,
Aging and Body Composition study) demonstrated that the decrease in quadriceps muscle
strength was significantly more rapid than muscle mass, suggesting that the decline in muscle
mass and strength can take on different trajectories.217 Similarly, in studies of muscle disuse
from bedrest or in survivors of critical illness the relationship of muscle mass with strength was
modest suggesting a more complex relationship between the two measures.218,219 In fact,
neurologic function and the intrinsic force-generating properties of skeletal muscle have been
proposed as significant contributing factors to muscle weakness, which can have a differential
effect with aging and in chronic disease.220 Thus, Clark and Manini coined the termed
dynapenia referring to the age-related loss of muscle strength and power, independent of
muscle mass.221 They proposed that loss of muscle strength and mass should be evaluated
independently and sarcopenia be reserved to describe the age-related loss of muscle mass.221
With aging, loss of muscle strength has been shown to be a stronger prognostic marker for
disability and death than loss of muscle mass.222,223
26
In chronic lung disease, there is no agreed upon definition of skeletal muscle dysfunction and
it is not known which elements of muscle dysfunction (muscle mass, strength and function)
are most closely associated with physical function, HRQL and clinical outcomes. In a large
cohort of COPD patients, Jones et al. observed sarcopenia using the EWGSOP definition in
15% of participants; however, quadriceps weakness was present in more than half of these
patients.159 This study illustrates a similar pattern of discordance of skeletal muscle mass and
strength in chronic lung disease as seen in community dwelling older adults,217 raising the
question of which skeletal muscle measures are most informative clinically.
A wide range of tools are available to measure skeletal muscle mass, strength and physical
performance. Some modalities are better suited for research compared to the clinical setting.
The availability, cost, and ease of measurement will often dictate use of these instruments.
The next three sections will review the wide range of modalities available for measurement of
skeletal muscle mass, strength and function and more importantly outline the skeletal muscle
impairments in chronic lung disease and lung transplant patients. The available measurement
modalities are outlined in Figure 1-1.
Figure 1-1: Skeletal Muscle Mass, Strength and Physical Performance Measures
27
1.2.3 Muscle Mass Measurements:
Muscle atrophy is recognized as an important extra-pulmonary manifestation of chronic lung
disease associated with physical disability,224 quality of life225 and mortality.226 A number of
anthropometric measurements and non-invasive modalities have been utilized to characterize
muscle mass, which include imaging modalities such as computed tomography (CT),
magnetic resonance imaging (MRI) and ultrasound (US), along with other modalities such as
bio-electrical impedance (BIA) and Dual-energy X-ray absorptiometry (D-XA).227,228 The
advantages and disadvantages of each technique are summarized below.
Anthropometric Measures:
Anthropometric measurements such as mid-arm circumference229 and sum of skin folds230
have been applied as estimates of fat-free mass using regression equations developed in
healthy populations; however, their predictive capabilities are inferior to non-invasive
modalities such as MRI231 and they have not been validated in lung transplant patients.
Furthermore, sarcopenia consensus guidelines in the elderly recommend against the use of
anthropometric measurements for estimation of fat-free mass given age-related changes in
tissue adiposity and skin elasticity, which can yield mixed results.158 Body mass index has
been the most common anthropometric measurement utilized in lung transplantation and
adopted by ISHLT guidelines. However, BMI is a relatively poor measure of low muscle mass
when compared to traditional measures such as D-XA. Singer et al. observed in a sub-cohort
of 142 lung transplant candidates with available D-XA, only 5% were observed to have low
BMI (< 18.5 kg/m2), whereas 46% were characterized as sarcopenic.54
Computed Tomography:
Computed tomography was one of the first imaging modalities that allowed whole-body and
regional quantification of skeletal muscle size.228 The analysis can be performed manually or
28
in a semi-automated manner with a number of software programs such as MATLAB, NIH
ImageJ or Slice-O-Matic that can identify linear attenuation coefficients, which correspond to
different body tissues.232,233 Skeletal muscle has a pre-defined coefficient of attenuation (-29
to 150 Hounsfield units), which allows it to be differentiated from fat tissue (-30 to -190
Hounsfield units) using the specialized software. Computed tomography is able to provide
quantification of intermuscular adipose tissue, which allows one to assess the amount of
muscle fat infiltration, which is associated with physical function.234 Computed tomography
has been applied across several disease states to characterize the trunk and limb muscles.
Computed tomography CSA from abdominal CT scans at the third lumbar vertebral level
(psoas, paraspinous or thigh muscles) has generally been used, as it has been shown to
approximate whole body skeletal muscle mass in healthy populations.235 Morphometric
techniques with abdominal CT have been well described in major surgery and liver
transplantation,236-238 but the application of CT for quantification of trunk muscle mass has only
recently been undertaken in chronic respiratory disease. Abdominal CT scans have been
utilized in lung transplant candidates as a measure of sarcopenia239,240 and the use of thoracic
CT scans has recently been described in non-listed COPD and lung transplant patients using
various protocols.241-244 Skeletal muscle mass has been quantified using the level of the aortic
arch241,242, twelfth thoracic vertebral level243 and in one study using the level of the carina.244
This is promising as thoracic CT scans are readily available in lung transplant candidates, but
have not been routinely utilized for estimation of skeletal muscle mass.
Computed tomography has generally been applied in chronic respiratory disease for
assessment of peripheral muscles. The most common CT protocol used is that of Bernard et
al. where muscle CSA is measured halfway between pubic symphysis and inferior femoral
condyle.245 With CT, a number of studies have demonstrated significant quadriceps muscle
atrophy of the lower extremity in COPD, cystic fibrosis and pulmonary arterial hypertension
29
compared to controls, ranging from 6-39%.180,246-248 In lung transplant recipients, Pinet et al.
demonstrated that CSA 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.144
Magnetic Resonance Imaging:
Magnetic resonance imaging is often regarded as the gold standard for assessment of
peripheral muscle size.249 It is able to provide detailed information on muscle size and
composition of the peripheral muscles. In addition, a single cross-sectional MRI slice at the
third lumbar vertebral level has been shown to have strong correlation with whole body
skeletal muscle mass volume assessed with MRI, suggesting a single slice estimate can
potentially be used.250 However, MRI is significantly more costly than other modalities (i.e.
CT, ultrasound), time consuming and requires additional expertise for analysis.228 It also has
several contraindications requiring exclusion of patients with pacemakers, defibrillators,
intracranial metallic clips or previous exposure to metallic bodies in the eye.251 Thus, MRI has
generally been reserved for assessment of peripheral muscle when detailed structural
information and composition has been required.
In chronic lung disease, MRI has been used to assess lower extremity muscle size in several
studies. COPD patients had approximately 20-25% lower quadriceps CSA and volume
compared to healthy controls.231,252,253 In lung transplant recipients, muscle size with MRI was
shown to be similar to COPD patients who had not undergone transplantation.254 Based on a
systematic review, there have been no other studies in lung transplant candidates or
recipients that have utilized MRI as an imaging modality for assessment of muscle size.21
Ultrasound:
Ultrasound has been used in patients with chronic respiratory disease to assess peripheral
30
skeletal muscle size and quality.131,255 Ultrasound is relatively inexpensive, portable, has no
radiation exposure and is relatively easy to perform in the clinical and laboratory setting.256
One limitation of ultrasound is the small field of view which limits the imaging to smaller
muscles, such as the rectus femoris of the quadriceps. However, muscle size of the limbs
from ultrasound has been shown to correlate closely with CT257 and MRI258 in COPD patients
and healthy individuals, respectively.
In COPD, quadriceps muscle atrophy has commonly been observed with ultrasound with
values generally 17-25% lower than that of healthy controls.172,257,259 A study from our center
by Mendes et al. demonstrated that lung transplant candidates with ILD had significant
quadriceps atrophy with ultrasound, with accompanying loss in strength of the knee extensors,
but no difference in size of the biceps muscles observed.131 Ultrasound has not been studied
in the post-transplant setting as an assessment of lower extremity atrophy, but holds a great
deal of promise given its portability and potential for clinical application in the critical care and
inpatient settings.256
Bioelectrical Impedance Analysis:
Bio-electrical impedance is one of the older forms of body composition assessment and was
developed in the 1950-1960s by Hoffer, Nyboer and Thomasset.260,261,262 It allows
quantification of fat-free mass and fat percentage for the entire body based on conductivity of
current (i.e. flow of energy). Bio-electrical impedance utilizes the differential conductivity of
tissues to differentiate highly conductive tissues (i.e. skeletal muscle) versus low-conductance
tissues such as fat and bone.260 As with other imaging modalities, BIA is also able to provide
muscle quality assessments using phase angle, which is the ratio of resistance (energy
dissipation) and reactance (energy storage).263 Phase angle assesses cellular integrity, which
carries prognostic information in chronic disease.263 Bio-electrical impedance is commonly
31
used today in assessment of body composition as it is readily available, inexpensive, and
results require limited analysis.
In advanced lung disease and lung transplantation, low fat free mass has been observed with
BIA.21,264 Fat-free mass is known to be reduced in the pre- and post-transplant periods.135,265
Kyle et al. demonstrated in 37 lung transplant candidates that low fat-free mass index was
prevalent in the pre-transplant period in two-thirds of patients compared to 5% of healthy
controls.135 Even though fat-free mass improved post-transplant, one-third of patients were
observed to have persistence of low fat-free mass index two years post-transplant.135
Dual-energy X-ray Absorptiometry:
Dual-energy x-ray absorptiometry is commonly utilized for assessment of skeletal muscle
mass and body composition. It has relatively low radiation exposure, modest cost, and is able
to characterize lean muscle mass, bone and fat tissue systemically and for various body
compartments.266,267 Given that the majority of lean soft tissue is found in the arms and legs,
the appendicular skeletal muscle mass is often used as a surrogate measure of skeletal
muscle mass.266 One drawback of D-XA measurement is its inability to characterize muscle
quality (i.e. fat infiltration), which the other imaging modalities are able to capture. The other
limitation is the lack of portability which makes it hard to apply clinically or in large population
studies.
In COPD patients, sarcopenia was present in 36/91 (40%) participants with low muscle mass,
defined using normative values for skeletal muscle index from D-XA (appendicular lean
mass/height2). Low muscle mass was strongly associated with the prognostic BODE Index
(score encompassing body mass index, airflow obstruction, dyspnea, and exercise capacity),
independent of age, sex, smoking status, and disease severity.268 In lung transplant
32
candidates, Singer et al. demonstrated the presence of sarcopenia with D-XA in 65/142 (46%)
patients was more commonly seen in those with low or normal weight (BMI < 25 kg/m2).54
Clinical Importance of Skeletal Muscle Mass
Irrespective of the modality utilized, the clinical implications of low skeletal muscle mass have
been described predominantly for people with COPD. Systemic measures of low muscle
mass with BIA264 and quadriceps atrophy226,269,270 have been observed to be associated with
increased mortality in patients with COPD independent of lung function. The association
between weight loss and reduced survival in COPD,271,272 cystic fibrosis273 and chronic heart
failure274 have been well described; however, anthropometric measures such as BMI are
unable to assess the importance of the various body composition compartments (i.e. muscle
mass versus fat). Skeletal muscle mass is known to be affected to a greater degree than fat
tissue in chronic respiratory disease.245,275 The pathogenesis of muscle mass loss is thought
to be related to increased protein catabolism, systemic inflammation, malnutrition, and chronic
inactivity. Loss of muscle mass can lead to increased risk of infection and difficulty coping
with major stressors such as critical illness.190,275 Skeletal muscle also constitutes the largest
insulin sensitive tissue in the body and is critical in regulating metabolism and body
composition.276 Thus, a more comprehensive evaluation of body composition and
assessment of skeletal muscle mass could potentially help predict pre- and post-transplant
outcomes.
The choice of imaging modality depends on the level of tissue differentiation required (muscle
versus fat), availability, cost, clinical setting, technical expertise and exposure to radiation or
other contraindications. Bio-electrical impedance analysis offers a validated measure of fat-
free mass quantification that is portable, reproducible and inexpensive. 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
33
concerns regarding radiation exposure with D-XA and CT.228 However, retrospective analysis
of thoracic CT scans, which are generally obtained for routine care, can provide a novel and
practical opportunity to quantify skeletal muscle mass in advanced lung disease and
transplantation with no added cost or radiation exposure.277
1.2.4 Peripheral and Respiratory Muscle Strength Measurements
Muscle strength is the ability of the muscle to generate maximal force, which is often
evaluated in the clinical and research setting.278 A number of methods to assess muscle
strength in advanced lung disease have been utilized such as manual muscle testing, hand-
held dynamometers, and computerized dynamometers.252 In the research setting,
computerized dynamometers have been the most common modality used in chronic lung
disease and lung transplantation given their reliability, accuracy and safety.21,252 However,
there are several limitations with computerized dynamometers such as their higher costs,
limited accessibility, training requirements, and time required for testing. Thus, a 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 testing279,280 and poor
reliability.281 Similarly, non-volitional methods such as muscle or nerve stimulation have been
used in an attempt to remove the motivational component of voluntary muscle strength
tests.14,252 However, non-volitional methods have not commonly been utilized due to some of
the expertise required and discomfort with electrical nerve stimulation, especially if repeated
measures are required.282 Over the last few years, novel techniques have been applied such
as magnetic stimulation of skeletal muscles which is relatively painless but requires additional
technical expertise.283,284 Thus, a number of techniques can be utilized in the clinical and
research settings to evaluate muscle strength. Standardized evaluation of muscle strength
34
allows identification of muscle weakness and prescription of resistance training in chronic
respiratory disease.
The majority of studies in advanced lung disease have examined strength in the lower
extremity using volitional tests demonstrating a reduction of 20 to 30% in quadriceps strength
compared to healthy controls.131,285-287 A similar pattern has been observed with non-volitional
tests such as magnetic femoral nerve stimulation.288,289 Given the quadriceps is one of the
major muscles involved with daily activity (i.e. walking, sit-to-stand) and is easily accessible, it
has been the focus of investigation in chronic respiratory disease.
The natural history of lower extremity muscle weakness in chronic respiratory disease is not
entirely clear but there is some suggestion that lower extremity weakness could have a
gradual decline accelerated by exacerbations.290 In one study, COPD patients were noted to
have an accelerated decline of about 4% over one year, where as a lower annual decline of 1-
2% in quadriceps strength was observed in another cohort of COPD patients, similar to what
is generally seen in a healthy elderly population.285,173
In lung transplantation, the quadriceps muscle has been the muscle most studied. Based on
our systematic review of 18 studies of lung transplant candidates and recipients, quadriceps
muscle strength in the pre-transplant period was significantly reduced (mean range of 49-86%
of predicted values), with a further reduction in the immediate post-transplant period (51-72%),
and with gradual improvement beyond 3-months post-transplant (58-101%).21 Generally,
lower extremity muscles have been shown to be weaker than the upper extremity muscles. In
the pre-transplant period, hand-grip force is generally greater than 80% predicted and
preserved throughout the post-transplant period.116,117,124 With hand-held dynamometry, both
biceps and triceps strength was greater than 80% in the pre- and post-transplant periods.143,291
The preservation of upper extremity strength could be partly explained by the fact that upper
35
extremity muscles are often involved in maintaining essential activities of daily living such as
self-care (i.e. brushing teeth, combing hair), where as physical activities that rely on lower
extremity muscles such as walking are often reduced.292
Clinical Implications of Peripheral Muscle Strength:
As in the general population,293 quadriceps muscle strength has been shown to be an
important independent predictor of survival in COPD.294 Swallow et al. demonstrated that
quadriceps muscle weakness was predictive of mortality in COPD patients, independent of
age, BMI, whole body fat-free mass index, and lung function.294 The prognostic implications of
lower extremity skeletal muscle dysfunction are further supported by findings by Marquis et al
who demonstrated that quadriceps muscle atrophy was associated with increased mortality in
COPD patients, independent of BMI.226 However, it remains unclear to what extent skeletal
muscle weakness is a systemic process or one that is confined to the lower extremities in
patients with chronic lung disease. Systemic factors outlined above such as inflammation,
hypoxemia, and nutrition may have an influence on local muscle factors (i.e. contractile
properties, blood flow) that can lead to muscle atrophy and weakness. These systemic
factors might be important mediators of clinical outcomes such as survival.
In lung transplantation, the association of pre-transplant skeletal muscle strength with post-
transplant outcomes remains unknown to-date and is an important area of research. In the
post-transplant period, Maury et al. observed that quadriceps weakness post-transplant was
associated with longer ICU length of stay, and quadriceps strength in the first three months
post-transplant was lower than pre-transplant values.116 The mechanisms underlying post-
transplant muscle weakness are not well understood and include elements of acute-
deconditioning and immuno-suppressive medications,116,117 but the contribution of other
factors such as oxidative stress, inflammation, and malnutrition have not been explored.21
36
Respiratory Muscle Strength:
Maximal respiratory pressures are often reduced in patients with COPD despite a training-like
effect from increased ventilatory load that makes these muscles more resistant to
fatigue.295,296 However, resistive loading of the diaphragm muscles has been shown to
actually accentuate diaphragm injury, through disruption of myofibrillar structure.297
Dysfunction of the respiratory muscles may worsen the chronic ventilatory failure observed in
COPD patients and has been shown to be a risk factor for hospital readmissions.298 In turn,
acute respiratory exacerbations can further impair respiratory muscle function.299 Lung
volume changes (i.e. dynamic hyperinflation) during respiratory exacerbations can create a
mechanical disadvantage for the diaphragm, rib cage and intercostal muscles potentially
imposing further functional deterioration.299, In addition to respiratory exacerbations, other key
contributing factors for respiratory muscle dysfunction include age and nutritional
abnormalities.296,300
To-date, respiratory muscle strength in lung transplant candidates or recipients in the early
post-transplant period has not been studied. Pinet et al compared diaphragmatic thickness
and non-volitional force measures in 12 lung transplant recipients, on average 48 months
post-transplant (range 8-95 months), to 12 matched healthy controls.301 They observed that
diaphragm muscles had preserved strength and thickness compared to controls, but
respiratory muscle strength in the early post-transplant period was not assessed. Respiratory
muscle structure and function in the peri-operative transplant period is an important area of
future investigation given that respiratory muscle strength, if impaired, can potentially be
amenable to inspiratory muscle training. In a recent systematic review and meta-analysis of
eight studies, inspiratory muscle training pre-operatively was shown to be associated with a
lower risk of combined pulmonary complications (RR: 0.48, 95% CI: 0.26 to 0.89) following
open cardiac, thoracic and upper abdominal surgery.302 Furthermore, pre-operative
37
inspiratory muscle training significantly improved respiratory muscle strength in the early post-
operative period.302
1.2.5 Assessment of Physical Performance:
A number of physical performance tests have been used in advanced lung disease that allow
for characterization of mobility, balance and physical function. The most common lower limb
performance tests utilized in advanced lung disease have included gait speed, sit-to-stand,
and the short-physical performance battery (SPPB).303 These simple performance based
functional tests may be more informative with respect to skeletal muscle function than an
assessment of exercise capacity using the six-minute walk test (6MWT). The 6MWT is
affected by multiple factors such as cardio-pulmonary limitations, dyspnea and fatigue, which
makes it hard to isolate lower extremity performance.102 Thus, functional tests can provide
information that is more specific to muscle function, which can assist with exercise
prescription, outcome assessment and mobility aid recommendations.
Gait Speed:
The most common gait speed assessment in COPD patients has been the 4 meter gait
speed.303 The 4 meter gait speed assessment has been shown to be a valid and reliable
measure in advanced lung disease. It correlates with measures of exercise capacity
(6MWT),304,305 HRQL as assessed by the SGRQ,304 and physical activity levels.305 There have
been a number of variations to the gait speed assessment which have included various
course durations (i.e. 10 meters)306 and various protocols (i.e. standing or walking start), which
could influence maximal gait speed achieved.303
Sit-to-Stand Test:
This assessment can be performed in several ways to assess number of repetitions in a
38
specific period of time (i.e. 30 or 60 seconds) or time period it takes to perform a certain
number of repetitions (i.e. five repetitions).303 In patients with advanced lung disease, the time
taken to perform five repetitions on the sit-to-stand test is commonly utilized.307-309 It has been
shown to be valid, reproducible and responsive with pulmonary rehabilitation.307 In one study,
the one minute sit-to-stand test was observed to be a strong predictor of two year mortality in
COPD patients.310
Timed Up and Go Test:
The test can be performed in a clinical setting and individuals are instructed to rise from a
chair, walk 3 meters, and return to the chair to sit down. The Timed Up and Go Test is able to
assess risk of falling311,312 and functional disabilities.312 The Timed Up and Go Test has been
described as a predictor of HRQL at one year follow-up in COPD patients.311 It has been
shown to be reliable with very good reproducibility.303 However, its performance
characteristics require further study in advanced lung disease, as evaluation has taken place
at both usual and fast speeds.303
Short-Physical Performance Battery:
The SPPB is a functional assessment of balance (tandem standing), five repetitions of the sit-
to-stand test and 4-meter gait speed, which has been utilized in community dwelling elderly
and populations with advanced lung disease.313,314 Each of these three measures is scored
from 0 to 4, with a total score out of 12. The SPPB is easy to perform, it has good validity and
reliability, and requires less than five minutes to complete.315 The SPPB has been shown to
be associated with exercise capacity (6MWD),316 quadriceps strength314 and future disability at
two year follow-up in COPD.317
Physical Performance Tests in Lung Transplantation:
In lung transplant candidates, there have only been a few studies utilizing physical
39
performance tests.21 In a systematic review of 18 studies, only two studies utilized the sit-to-
stand test to assess physical function in lung transplant candidates.136,265 Recently, Mendes
et al. demonstrated that the Timed Up and Go Test was significantly reduced in lung
transplant candidates with ILD compared to controls.131 In addition, the SPPB has been used
as a marker of physical frailty and shown to be associated with disability and pre-transplant
delisting and mortality.318 To our knowledge, the association of these physical performance
tests with HRQL, ADL and post-transplant outcomes have not been previously described in
lung transplantation.
Functional Independence Measure:
The functional independence measure (FIM) is an 18-item questionnaire that assesses the
level of assistance required by the patient. It has been applied in rehabilitation across a
diverse group of patients including critical care survivors and lung transplant recipients.319,320
The FIM consists of 2 main domains: motor (13 items; self-care, sphincter control, mobility,
and locomotion) and cognitive (5 items; communication and social cognition) with each item
given a score from 1 to 7.321 The total 18 items range from 18 to 126 with higher scores
signifying greater functional independence. Scores less than 40 reflect total assistance,
whereas a score of 50 represents moderate level of assistance. An accepted minimally
clinically important difference for the total FIM score is 20 and previous reports have
attempted to establish specific cut-offs for the minimally important difference in stroke
survivors: 22 and 17 points for the total FIM and motor domain, respectively.322 The motor
domain of the total FIM has been observed to be responsive to change in lung transplant
recipients undergoing inpatient rehabilitation.320 The FIM has been utilized at our center as a
research tool in ICU patients, some of whom had lung transplants. It provides a
comprehensive assessment of functioning, along with limitations in ADL, which is not always
practical to capture through physical assessment.
40
In summary, this section described the most common modalities utilized to evaluate skeletal
muscle mass, strength and function in advanced lung disease and lung transplant patients.
The next section will address the prognostic implications of these measurements and physical
fitness with major surgery and solid-organ transplantation, with a focus on lung
transplantation.
1.3: Importance of Physical Fitness with Major Surgery and Solid-organ
Transplantation
Thoracic-abdominal surgery and solid organ transplantation are major surgical procedures
that can result in increased peri-operative complications such as significant physical
deconditioning, prolonged hospital length of stay, and increased mortality compared to
intermediate or low risk surgery.323,324 A number of factors such as general anaesthesia,
prolonged surgical time, hemodynamic instability, high-dose corticosteroids in transplant
recipients and blood loss predispose patients to higher risk of peri-operative complications
with these procedures.325,326 A better understanding of patient risk factors for the upcoming
surgery could help inform patients, their families and the medical team of potential peri-
operative and long-term outcomes, which may help with transplant consent discussions. To-
date, risk stratification with major surgical procedures has often been a subjective assessment
of patient physiologic reserve, often described as the "eye-ball" test in surgery.327 However,
more robust and repeatable pre-operative assessments of physiologic reserve could help
inform rehabilitation strategies pre-operatively that could lead to improved outcomes.
The following section reviews pre-operative physiological risk factors with major surgery and
solid organ transplantation, with a focus on lung transplantation. A discussion of pre-operative
exercise training follows.
41
1.3.1 Physiological Stress Response with Major Surgery:
Physical fitness prior to thoraco-abdominal surgery has been associated with post-operative
outcomes. Surgery is a physical stressor and the recovery post-surgery often involves
periods of bed-rest and immobility. Periods of inactivity post-operatively have been related to
muscle atrophy, weakness, and pulmonary complications.328 In patients undergoing lung
resection, low pre-surgical aerobic capacity has been associated with post-operative
complications such as pneumonia, respiratory failure, and increased mortality.329,330 Similarly,
Szekely et al demonstrated that COPD patients with a 6MWD of less than 200 meters were
more likely to have a prolonged hospitalization (> 3 weeks) after lung volume reduction
surgery.331 In patients undergoing major abdominal oncological surgery, pre-operative self-
reported physical activity levels and measurements of physical fitness were associated with
post-operative length of stay and mortality.332 Thus, across a number of patient populations
and surgical interventions, pre-operative physical fitness and conditioning is often associated
with post-operative function, cardio-pulmonary complications, and hospital length of stay.
Functional decline with major surgery is multi-factorial. Surgery can lead to prolonged periods
of bedrest, which can result in increased physical deconditioning. The physiological stress
response from surgery can also act as a catabolic stimulus, hindering peripheral and
diaphragm muscle function, through increased protein breakdown.333 Furthermore, surgical
procedures near the diaphragm can induce respiratory muscular impairment through several
pathophysiological mechanisms including direct distortion of the respiratory muscles,
alteration in the thoraco-abdominal mechanics, and phrenic nerve reflex inhibition.334
Welvaart et al. demonstrated that patients undergoing a thoracotomy for a tumor in the right
lung were noted to have significant reductions in diaphragm force generation (about 35%) and
this force loss was more prominent in the fast twitch (type II) fibers after only 2 hours of
42
surgery.335 In addition to post-operative inactivity, the surgical stress response has been
observed to induce an increased inflammatory response (higher interleukin-6 levels), which
have been associated with reduced muscle endurance and self-reported fatigue levels, more
pronounced in older adults.336 Thus, many peri-operative factors such as surgical stress,
inflammation, muscle catabolism and physical inactivity can have significant effects on
peripheral and respiratory muscle function.
Most healthy individuals can respond appropriately to surgical stress and restore physiological
balance in the post-operative period.337 However, patients with chronic disease and poor
physical function pre-operatively have a harder time restoring this balance, which could hinder
post-operative recovery and lead to increased health care utilization.338 Thus, the ability to
identify pre-operative indicators of physical function such as skeletal muscle mass, strength
and physical performance can potentially help with prognostication, as described in the next
section.
1.3.2 Skeletal Muscle Strength and Physical Performance with Major
Surgery and Solid-Organ Transplantation:
There have only been a few studies that have assessed the clinical implications of functional
deficits (muscle strength and physical performance) in the pre-operative period. Afilalo et al,
demonstrated in elderly cardiovascular patients over the age of 70 years old that slow gait
speed over 5 meters was associated with the primary composite end point of in-hospital post-
operative mortality and major morbidity with cardiac surgery.339 Robinson et al. demonstrated
in patients over 65 years old undergoing colorectal and cardiac surgical procedures that
greater time required to complete the Timed Up and Go Test was associated with increased
post-operative complications such as requirement for discharge to another institution, 30-day
hospital readmission, and one year mortality.340 Irrespective of the procedure, the Timed Up
43
and Go Test had better performance operating characteristics than the standard surgical risk
calculators.340 Similarly, a history of one or more falls in the previous 6 months was
associated with lower likelihood of being discharged home, and an increased chance for 30-
day readmission to hospital with colorectal and cardiac surgical procedures in older adults.341
Functional assessments before major surgery have been mainly limited to the lower extremity
such as assessment of gait speed, Timed Up and Go Test, and falls history. Another
limitation is that pre-operative skeletal muscle function has been mainly assessed in the
elderly patient population.
In one study of 292 liver transplant candidates, the association of CT-based measures of
sarcopenia and functional measures was evaluated.342 Hand-grip strength and SPPB were
associated with pre-transplant mortality, whereas this relationship was not observed with
skeletal muscle mass quantified with abdominal CT.342 This highlights the prognostic
implications of functional deficits (muscle strength and physical performance) in the pre-
operative period, which have not been a major focus of investigation to-date in lung
transplantation.
In lung transplantation, a few studies have looked at pre-transplant functional status indirectly
to assess post-transplant outcomes. Grimm et al utilized the United Network for Organ
Sharing dataset to demonstrate that pre-operative performance status using the Karnofsky
Performance Status had a significant association with one year mortality post-transplant in
over 7800 lung transplant recipients.99 Wilson et al. assessed the impact of frailty, as a
marker of decreased physiologic reserve in 144 lung transplant candidates. A higher score on
the frailty deficit index was associated with increased one year mortality, but no association
was seen with ICU or hospital length of stay.343 To-date, associations between pre-transplant
muscle function (strength and performance) and post-transplant outcomes have not been
44
studied in lung transplant candidates, and may provide an objective measure of physiologic
reserve in this patient population.21
1.3.3 Skeletal Muscle Mass with Major Surgery and Solid Organ
Transplantation:
As a measure of sarcopenia (low muscle mass), the evaluation of total psoas muscle cross-
sectional area with CT morphometric techniques has been studied across several major
surgical procedures pre-operatively, as a means of risk stratification. With major elective
general or vascular surgery, lower psoas muscle size was associated with increased risk of
complications and one year mortality.344 A similar association with core muscle size was seen
with abdominal aortic repair and aortic valve replacement.238,345
In solid-organ transplantation, sarcopenia (low muscle mass) has been associated with
increased risk of morbidity and mortality post-transplant.28,277,344 Most of the literature on
sarcopenia in transplantation has come from liver transplant candidates with a few studies
from other solid organ transplants.277 Furthermore, sarcopenia has been defined by various
methodologies across the different organ groups.
Liver:
The importance of muscle mass was first demonstrated in liver transplantation by Englesbe et
al. who showed that total psoas muscle area on abdominal CT scan was associated with post-
transplant mortality.236 In a similar study, pre-transplant sarcopenia was associated with a
significantly increased risk of serious post-transplant infections and mortality among 207 liver
transplant recipients based on total psoas muscle area.346 Montano-Loza et al demonstrated
that sarcopenia was also associated with waitlist mortality in liver transplant candidates.347 In
a recent systemic review and meta-analysis of 19 studies in liver transplantation, low skeletal
muscle mass with abdominal CT was prevalent and ranged from 22 to 70% given various cut-
45
off values utilized between studies.348 However, irrespective of the definition, sarcopenia was
associated with increased risk of post-transplant infection and mortality in the pooled
analysis.348
Renal:
Low muscle mass pre-transplant was associated with worse outcomes in renal transplant
recipients. Muscle mass was calculated from a formula utilizing pre-transplant serum
creatinine in a large cohort of patients on dialysis awaiting transplantation. Low muscle mass
was associated with increased mortality post-transplant and a 2.2 fold increased risk of renal
graft loss.349 In a large observational study of over 14,500 renal transplant candidates,
Molznar et al observed there was increased mortality on the waiting list with lower muscle
mass, as measured by serum creatinine.350 In chronic kidney disease, the convention of
protein-energy wasting is often used as proposed by the International Society of Renal
Nutrition and Metabolism which requires 3 out of 4 criteria (serum chemistry, body mass
index, muscle mass, and dietary intake).351 Muscle mass comprises one of four criteria and is
defined by reduced mid-arm muscle circumference or creatinine levels.351 However, this
concept has been mainly limited to end-stage renal disease and not applied in other chronic
disease states.
Cardiac:
No studies to-date have examined the clinical implications of muscle wasting in cardiac
transplantation.277 However, the role of sarcopenia has been described in patients undergoing
aortic valve replacements. Low skeletal muscle cross-sectional area derived from abdominal
CT images at the third lumbar level was associated with longer hospital length of stay in
patients undergoing trans-catheter aortic valve replacements and was more prognostic than
functional measures (hand-grip strength and 5-meter gait speed).352 Similarly, Paknikar et al.
46
demonstrated that low psoas muscle size on abdominal CT was associated with increased
early morbidity, health-care utilization and decreased two-year survival in a large cohort of
patients undergoing open and trans-catheter aortic valve replacements.345
Lung:
In lung transplantation, quantification of muscle mass using abdominal CT scans at the third
lumbar vertebral level has recently been described, similar to the approach utilized in liver
transplant candidates. Muscle CSA in lung transplantation has been associated with post-
transplant outcomes such as ICU and hospital length of stay.239,240 However, the majority of
lung transplant programs including our center, perform mainly thoracic CT scans limiting the
applicability of abdominal CT scans. The clinical implications of muscle CSA from chest CT
has been recently described in one study of lung transplant candidates.244 Surprisingly, they
observed an increased one year mortality in the quartile with the highest muscle CSA, but this
analysis did not adjust for older age or higher proportion of ILD patients in this quartile. Thus,
the prognostic utility of skeletal muscle mass using thoracic CT in lung transplantation remains
poorly defined and its association with pre-transplant delisting, mortality and functional
outcomes has not been previously described.
Skeletal muscle mass in the pre-transplant period is emerging as an important risk factor in
solid-organ transplantation.277 Even though a number of techniques have been utilized in
solid-organ transplantation with varying cut-offs to define sarcopenia, there is clear evidence
that low muscle mass is a common problem and could provide prognostic value.
The clinical implications of muscle functional deficits, in addition to skeletal muscle mass,
require further investigation. It also remains unclear whether the prognostic implications of
skeletal muscle mass apply equally across the various surgical interventions.
47
1.3.4 Pre-Operative Exercise Training with Major Surgery and Solid-Organ
Transplantation
Exercise Training prior to Major Surgery
Exercise training has been shown to be beneficial in improving cardio-pulmonary and
musculoskeletal fitness across many chronic disease states, which are important markers of
peri-operative morbidity and mortality, as described above.353 Thus, pre-habilitation (aerobic,
strength and respiratory muscle training) has been utilized pre-operatively in preparation for
cardio-thoracic and abdominal surgical procedures.354-356 In patients undergoing cardiac
surgery, an inpatient cardio-pulmonary rehab program pre- and post-operatively has been
shown to be associated with shorter hospital length of stay and reduced post-operative cardio-
pulmonary complications (pleural effusions, atelectasis, pneumonia and arrhythmias).357 In a
study by Arthur et al of low risk cardiac patients awaiting elective coronary artery bypass
surgery, exercise training (aerobic and strength) combined with education resulted in a shorter
ICU and hospital length of stay compared to the usual care group encouraged to remain
physically active.358 Furthermore, exercise training improved HRQL in this group of patients,
which was maintained for up to 6 months post-operatively. In patients awaiting lung resection
for malignancy, pre-operative aerobic exercise training has been associated with increased
aerobic capacity355,359 and lower post-operative complications.329,330,360 In patients undergoing
colorectal surgery, both pre-rehabilitation programs (stationary cycling plus resistance training
or walking recommendations and breathing exercises) resulted in significant increases in
6MWD pre-operatively, and those with improvement in their functional capacity demonstrated
a faster recovery post-operatively in their functional capacity.361 Thus, exercise training prior
to major surgery has been shown to have a positive effect on cardio-pulmonary fitness and
peri-operative morbidity, but the effects on mortality require further study.362,363
48
Pre-Operative Exercise Training in Solid-Organ Transplantation:
In a recent systematic review of exercise training in solid-organ transplant candidates, only 11
studies including heart (n=6) and lung transplant (n=5) candidates were identified with no
studies in liver and renal transplant candidates.364 Adherence to rehabilitation was observed
to be very good in cardiac and lung transplant candidates, ranging from 82.5% to 100%.
Exercise training was well tolerated in this group of patients with no serious adverse events,
but it was difficult to ascertain the safety profile of exercise training due to the lack of reported
data.364 Mild side-effects such as myalgias, fatigue, pre-syncope and palpitations have been
previously described to affect fewer than 5% of training participants with advanced cardio-
pulmonary disease.365-367
There have been several studies in lung transplant candidates examining the benefits of
exercise training pre-transplant. In a small pilot study of 9 lung transplant candidates, lung
transplant patients were randomized to a 6-week rehabilitation program comprising of
education versus education plus exercise.368 In both groups, the walk distance and Quality of
Well-being scores increased with completion of the 6 week program but no difference was
seen between groups in this small group of patients.368 Florian et al. demonstrated that a
multi-disciplinary program consisting of 36 sessions pre-transplant had a significant effect on
exercise capacity and HRQL pre-transplant.369 Similarly, in 60 lung transplant candidates with
COPD, 6MWD was shown to have mild improvement (about 35 meters) in both the continuous
and interval training groups.370 Jastrzebski et al. examined the benefits of a 12 week Nordic
walking program in lung transplant candidates demonstrating improvements in 6MWD and
HRQL, without any adverse events. At our center, Li et al retrospectively examined 345 lung
transplant candidates over a five year period and found that pre-transplant exercise capacity
and muscle training volumes were preserved over a median duration of six months, whereas
HRQL scores declined.110 It is possible that the decline seen in HRQL with pulmonary
49
rehabilitation compared to other rehabilitation programs in the present study may be related to
disease severity and longer wait-time to transplantation (median of 6 months), compared to
other standard 12 week rehabilitation programs.371,372 Despite the decline in HRQL, lung
transplant candidates with a greater 6MWD pre-transplant had a shorter hospital length of
stay post-transplant.110 To date, the benefits of pre-transplant rehabilitation on post-transplant
functional recovery, HRQL, and clinical outcomes (ICU, hospital length of stay, and discharge
disposition) have not been evaluated.
At our center, pre-transplant outpatient pulmonary rehabilitation is standard of care with all
patients exercising three times per week for the entire time they are on the lung transplant
waiting listing. This is fairly unique among the solid organ transplant programs in Canada.373
Lung transplant candidates perform stretching, aerobic and resistance training with each
session lasting about 90 minutes in duration. Patients participate in the program until
transplantation and all exercise sessions are supervised by a physical therapist. The training
intensity is determined by the physical therapist and progressed accordingly based on rate of
perceived exertion, exercise capacity, heart rate and oxygen requirements. A more detailed
description of the Toronto Lung Transplant Rehabilitation program has been previously
published.374 Patients that are too ill to participate in pulmonary rehabilitation due to
admission to the hospital ward or ICU, participate in some form of rehabilitation guided by the
inpatient physical therapists. Stretching exercises, limited resistance and aerobic training are
incorporated into a daily routine as per patient tolerance.374
1.4: Implications of Prolonged Mechanical Ventilation, Critical Care and
Hospital Length of Stay
Lung transplant recipients are routinely admitted to the ICU post-transplant; however, the
post-operative period can be associated with several complications that can prolong ICU and
50
hospital length of stay. The typical range for ICU and hospital length of stay in lung transplant
recipients at our center has been 4-5 and 18-23 median days, respectively.109,110,113 Primary
graft dysfunction (PGD) is one of the leading causes of early morbidity and mortality in lung
transplant recipients.375,376 Infections, acute rejection, and non-pulmonary events such as
arrhythmias and delirium may also complicate the post-operative period.377 Treatment for
PGD is largely supportive with low volume mechanical ventilation for prevention of barotrauma
and application of extra-corporeal membrane oxygenation for refractory hypoxemia.378
Unfortunately, PGD can also lead to a protracted course of mechanical ventilation or extra-
corporeal life support, which can potentially result in a number of extra-pulmonary
complications as seen with other ICU survivors.379
1.4.1 Intensive Care Unit Length of Stay and Clinical Implications
Prolonged mechanical ventilation has been associated with poor functional outcomes and
increased health-care costs. A single center study by Unroe et al. of 126 medical and surgical
patients showed that 3 weeks of mechanical ventilation was associated with an overall one-
year mortality rate of 44%, with only 9% being functionally independent.380 Similarly, the one-
year mortality post-ICU was 48% in a multi-centered study of patients receiving 21 days of
mechanical ventilation.381 Herridge et al. demonstrated in a large, prospective multi-center
study that patients experienced significant morbidity and mortality after 7 or more days of
mechanical ventilation.319 Age and ICU length of stay were significant prognostic markers of
functional recovery and one year mortality in this group of patients. Younger patients (< 42
years old) and those that had an ICU length of stay of less than 2 weeks had the best
functional outcomes. More importantly, early functional recovery as measured by the 7-day
functional independence measure was an independent predictor of one-year mortality. Thus,
51
poor functional outcomes can result even after as little as 7 days of mechanical ventilation in a
medical and surgical ICU setting.
Patients that sustain a prolonged ICU course are susceptible to ICU acquired weakness
(ICUAW), which is characterized by clinically detected weakness in the setting of critical
illness when no other plausible etiology is identified.382 Factors associated with ICUAW
include multi-organ dysfunction, sepsis, prolonged period of mechanical ventilation or
immobilization.383 At least one quarter of patients are observed to have ICUAW after 5-7 days
of mechanical ventilation.384,385 In those ventilated for ≥ 10 days, ICUAW was seen in as
many as two-thirds of patients.386 ICUAW is a major determinant of functional impairment and
health care utilization.387 In non-transplant populations with acute lung injury, prolonged
mechanical ventilation (≥ 7 days) has been shown to be associated with impairments in
physical function and HRQL that persisted up to 5 years, despite complete normalization of
their lung function.388,389
Transplantation adds an extra level of complexity to the continuum of skeletal muscle
dysfunction given the interplay between pre-transplant factors related to chronic disease (e.g.
deteriorating clinical status) and post-transplant factors (e.g. reduced mobility or activity from
prolonged ICU stay, ongoing immune-suppression). Thus, skeletal muscle dysfunction in the
pre-transplant period may be an even greater concern in lung transplant recipients with
complex peri-operative courses due to factors such as PGD, infection, systemic organ failure,
and bleeding. This can potentially result in prolonged ICU length of stay and higher rates of
ICUAW.377
Even though it has not been well described in lung transplant recipients, prolonged
mechanical ventilation may lead to other significant extra-pulmonary manifestations such as
cognitive impairment and psychological sequalae (i.e. depression).390 Cognitive impairment
52
(global cognition and executive function) is an important manifestation of ICU survivors and
has been seen across ICU etiologies.391 In survivors of acute respiratory distress syndrome,
cognitive impairments were observed in 70-100% of patients at hospital discharge and 46-
80% at one year.392 In lung transplant recipients, Smith and colleagues observed that 57% of
participants had persistent cognitive impairment at three months post-transplant, with
cognitive performance worse in those experiencing delirium during hospitalization post-
transplant.393 In addition, psychological distress can result from numerous stressors
surrounding a complex ICU stay post-transplant given the underlying muscle weakness,
cognitive impairments, and potential strain on the caregiver.394,395 These factors may result in
increased health-care utilization and increased re-admission rates as seen in other ICU
populations,319,396 which may have significant effects on functional recovery and morbidity in
lung transplant recipients.
1.4.2 Functional Status Prior to ICU Admission
There have only been a few studies that looked at the importance of functional trajectories
prior to ICU admission, as most studies enrolled patients at the time of their ICU admission.
In a unique study by Ferrante et al utilizing a longitudinal database of community dwelling
elderly patients, those with higher levels of disability on 13 basic, instrumental, and mobility
activities prior to their ICU admission experienced significantly worse outcomes post-ICU
discharge.397 Pre-ICU functional trajectory groups with mild-moderate and severe disability
had double (HR: 2.41 95% CI 1.29-4.50) and triple (HR: 3.84 95% 1.84-8.03) the rates of one-
year mortality post ICU discharge, respectively. Similarly, Lone et al. demonstrated in a large
representative national database of 7656 ICU admitted patients across the United States in
2005, the number of previous hospital admissions (RR: 1.05 95% 1.04 – 1.05) and
comorbidities (RR (≥ 1 score on the Charlson index): 1.39 95% 1.29 -1.51) were independent
53
predictors of subsequent hospital admission over the next five years, whereas acute illness
severity or organ support (e.g. dialysis) at the time of ICU admission were not predictive of
subsequent health-care utilization.398 These studies illustrate the important impact of pre-ICU
comorbidities and functional independence on health-care utilization, morbidity, and mortality
post critical illness.
1.4.3 Peri-operative ICU Management
Mechanical Ventilation or Extra-Corporeal Life Support Pre-Transplant
Lung transplant candidates admitted to the ICU pre-transplant are at increased risk of
complications such as prolonged ICU stays pre- and post-transplant, increased risk of
infections, malnutrition, and skeletal muscle impairments.39 Even short periods of
immobilization of one week in the ICU have been shown to be associated with significant early
and rapid muscle atrophy, associated with decreased protein synthesis and significant ICU
acquired weakness,399 which can result in significant morbidity and mortality.319 Thus, lung
transplant patients requiring traditional non-ambulatory mechanical ventilation pre-transplant
are at risk of critical care myopathy and have a significantly lower one year survival compared
to those transplanted without any form of bridging life support.40
In the last several years, ECMO has been applied with minimal sedation which allows awake
patients to participate in physical activity and rehabilitation.400,401 The outcomes with awake
ECMO strategies compared to traditional non-ambulatory mechanical ventilation strategies
have been favorable. Feuhner et al demonstrated that survival at 6 months post-transplant in
the ECMO group (n=26) was 80% compared to 50% in the mechanically ventilated, non-
ambulatory historical control group (n=34).38 Furthermore, lung transplant patients requiring
ECMO pre-transplant compared to mechanically ventilated patients had a shorter period of
post-transplant mechanical ventilation (14 vs. 37 median days, p=0.04) and a trend towards
54
shorter hospital length of stay (38 vs. 67 median days, p=0.06).38 Similarly, Nosotti et al.
demonstrated in 11 patients a significant survival benefit at one year post-transplant in
patients bridged with ECMO (87.5%) compared to invasive mechanical ventilation (50%).37
Early ambulation of critically ill patients on ECMO has been undertaken by several centers
including our own,36,374,402 but most of the evidence for long term functional benefits with early
rehabilitation in the ICU comes from patients on mechanical ventilation as described below.
Even though the number of transplants bridged with ECMO has been small, ECMO is
emerging as a viable option for bridging critically ill, appropriately selected lung transplant
candidates to transplantation. This selection is critical given some of the potential physical
and cognitive morbidity that may result on ECMO with increased risk of bleeding, infection, or
renal failure and less common complications such as limb ischemia, stroke and air
emboli.403,404
Early Mobility During and After Mechanical Ventilation
In the critical care setting, early rehabilitation of mechanically ventilated patients has been
shown to be safe and effective. Early activity in the ICU setting has been associated with
reduced ICU and hospital length of stay and reduction in readmission rates and mortality in
the first year post ICU.405,406 Similarly, the functional status is significantly improved at the
time of hospital discharge in those undergoing physical and occupational therapy early on
during their ICU admission.407 Burtin et al. demonstrated in a clinical trial of 90 critically ill
survivors that early exercise training (starting from day 5) was associated with improved
6MWD, quadriceps strength and SF-36 Physical Functioning at hospital discharge compared
to the control group.408 With respect to exercise intensity, one well randomized controlled trial
demonstrated that physical function at 6 months post-ICU discharge was improved with both
intensive and standard physical therapy programs, but the benefit of a more intensive physical
therapy program was not observed.409 It is possible that the lack of benefit with the more
55
intensive physical therapy program may be related to the increased heterogeneity seen in
critical care populations with varying ages, comorbidities, and ICU durations. Thus, the
optimal rehabilitation program in the ICU and post-ICU discharge remains unclear and may
need to be tailored to the individual patient given the varying case complexity of critical care
survivors.
Despite good evidence for physical therapy in the ICU setting,410 there is significant variability
in mobility practices internationally for mechanically ventilated patients. In a large cohort of
ICU patients in Scotland and Australia, early mobilization was not commonly utilized
(Scotland: 41% vs. Australia: 16%).411 Several barriers were identified which included
sedation, mechanical ventilation and physiological instability.411 In another prospective, multi-
centered study across 12 ICUs in New Zealand and Australia of 194 patients, no mobilization
was observed in more than 80% of potential episodes for early mobility.412 More than half of
these patients went on to develop ICUAW, which was associated with increased mortality in
the first three months post ICU discharge.412 In North America, there was also significant
heterogeneity in the type and frequency of physiotherapy provided to ICU patients based on
the hospital and clinical scenario.413
Rehabilitation in the Intensive Care Unit for Lung Transplant Recipients
As with other critical care populations, early rehabilitation can help with functional capacity,
muscle strength and discharge from the critical care unit. In a study by Maury et al., the
deterioration in quadriceps muscle strength from pre-transplant levels was observed to be
related to ICU length of stay.116 The recovery in muscle strength in lung transplant recipients
is multi-factorial with significant contributing factors including high dose of
immunosuppression,210 prolonged bed rest,414 and impairments in oxidative capacity.149
56
Physical rehabilitation in the ICU setting should be started as early as possible focusing on
sitting and early mobilization.415,416 The same principles apply in lung transplantation as in
other critical care patients, in-order to offset the early onset of skeletal muscle wasting and
weakness.417 At our center, critical care patients participate in an early mobility program with
close supervision and tailored progression from the physical therapist.374 The program
progresses from passive and active bed exercises, transferring from bed to chair, standing or
marching on the spot, and ambulating with high wheeled walker up to 200 m. These set of
exercises can be performed in the ICU setting in patients on mechanical ventilation and extra-
corporeal life support, with appropriate modifications. There is good evidence to support the
safety and feasibility of early rehabilitation in critically ill patients.418 Furthermore, there is
significant benefit with respect to lower extremity strength, quality of life, decreased ICU and
hospital length of stay, and significant cost-savings, but these have not been assessed in lung
transplant recipients.410,419
1.5: Recovery Beyond Hospital Admission in Lung Transplant
Recipients
1.5.1 Out-Patient Rehabilitation:
The benefits of outpatient pulmonary rehabilitation beyond the immediate post-transplant
period have been described in several studies to-date. Langer et al. had examined 12 weeks
of supervised lower limb resistance and endurance training (three times per week) initiated
after hospital discharge compared to routine physical activity education. Six-minute walk
distance, quadriceps strength, physical activity levels and SF-36 physical functioning domain
were significantly increased after 12 weeks of exercise with differences between the two
groups persisting up to 12 months.117 Similarly, Maury et al. had previously demonstrated in
an observational study that three months of pulmonary rehabilitation post-transplant was
57
associated with improvements in exercise capacity (140 ± 91 m) and quadriceps strength (35
± 48%), but quadriceps strength still remained below pre-transplant levels at three months
post-transplant.116 Munro et al observed a similar pattern of improvement in exercise
capacity, lung function and all domains of the SF-36 in the first 3 months post-transplant with
a standard outpatient pulmonary rehabilitation program.420 However, the effects of the two
observational studies need to be interpreted with caution given the natural improvement
observed in the functional measures in the first year post-transplant.117 With the post-
transplant rehabilitation studies to-date, lung transplant recipients with complicated courses
post-transplant (i.e. prolonged periods of mechanical ventilation) were generally excluded
from these studies.
At our center, lung transplant recipients participate in outpatient pulmonary rehabilitation for
12-weeks post-transplant. The program is similar to the pre-transplant phase with stretching,
aerobic and resistance exercises performed three times weekly. The focus on improving
ambulation, exercise capacity and recovery of muscle strength and function are given during
this rehabilitation phase.374
1.5.2 Inpatient Rehabilitation Post-Transplant:
Whereas outpatient pulmonary rehabilitation is generally standard of care across most
Canadian lung transplant centers,373 some patients require an inpatient rehabilitation program
due to physical deconditioning resulting from a prolonged hospital stay. A number of medical
complications can arise such as major bleeding, pulmonary infections, PGD, hemodynamic
instability and requirement for hemodialysis, which can prolong discharge from the critical care
unit and hospital.377 At our center, lung transplant recipients that do not meet functional
requirements for a safe discharge home based on a multi-disciplinary assessment are referred
to an inpatient rehabilitation program.374 We have recently demonstrated that in addition to
58
total hospital length of stay, other independent predictors of discharge to inpatient
rehabilitation were age, last 6MWD pre-transplant and requirement for mechanical ventilation
pre-transplant.113
Inpatient rehabilitation programs for lung transplant recipients have been shown to be
effective allowing low intensity resistance, aerobic and balance training in a closely supervised
environment.320,421 The most common benefits with inpatient rehabilitation have been in the
physical domains noted on the functional independence measure associated with bathing,
dressing, walking, stair climbing and ability to perform transfers, which are affected to a
greater degree by proximal muscle weakness.421 Lung transplant recipients demonstrated
similar gains in FIM per day with rehabilitation similar to the benefits observed in other forms
of inpatient rehabilitation programs such as stroke.422 Thus, inpatient rehabilitation programs
allow for earlier discharge from acute care hospital beds and earlier functional recovery.320,421
However, close medical monitoring is required for this patient population given the risk of
infection and graft rejection that might warrant transfer back to the acute care facility.320,421
1.6: Summary
Lung transplantation is a life-saving therapy for patients with end-stage lung disease. Current
evidence demonstrates that skeletal muscle dysfunction is prevalent in advanced lung disease
and lung transplant candidates. There are a number of generic and disease specific factors
that contribute to impairments in skeletal muscle mass, strength and function, which can be
characterized using several non-invasive modalities. However, the clinical implications of
skeletal muscle impairments (muscle mass, strength and function) with respect to pre-
transplant exercise capacity, ADL and HRQL have not been well described. Furthermore, the
association of pre-operative skeletal muscle function with post-transplant functional recovery
and clinical outcomes remains unknown, especially in patients with a complicated course
59
post-transplant. Thus, utilization of readily available non-invasive measures to characterize
skeletal muscle dysfunction will provide an opportunity to better understand the importance of
pre-operative skeletal muscle mass, strength and physical function throughout the transplant
process.
A better understanding of the nature, prevalence and clinical implications of muscle
dysfunction could potentially lead to more informed transplant listing criteria and improved
clinical outcomes pre- and post-transplant. It can also help with targeted exercise training to
improve skeletal muscle health and potentially patient reported outcomes such as HRQL and
ADL. A comprehensive understanding of skeletal muscle dysfunction can be applied to other
high-risk populations such as the elderly, other solid organ transplant candidates, and those
with prolonged hospital or ICU stays.
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CHAPTER 2
Thesis Overview:
The proposed doctoral work provides an opportunity to better understand the manifestations
of skeletal muscle dysfunction and the clinical implications of muscle dysfunction in lung
transplant patients. Given the lack of agreement as to which definition of skeletal muscle
dysfunction should be utilized in chronic disease, the present doctoral work will examine
individual elements of skeletal muscle dysfunction (muscle mass, strength and physical
performance) and the combination of these parameters to improve our understanding of the
relationship between these measures. This will be accomplished through three
complementary studies, with different lung transplant cohorts, targeting both the pre- and
post-transplant periods, Figure 2-1.
2.1 Overall Aim and Hypothesis:
Overall Aim:
To characterize individual elements of skeletal muscle function (muscle mass, strength and
physical performance) in lung transplant candidates and assess their association with pre-
and post-transplant physical function, HRQL, and clinical outcomes.
Overall Hypothesis:
Skeletal muscle mass, strength and physical performance will be independently associated
with pre-transplant physical function and HRQL. Pre-operative skeletal muscle dysfunction
will help inform post-transplant functional recovery, HRQL, and clinical outcomes in the early
post-transplant period.
61
Figure 2-1: Conceptual Thesis Framework Abbreviations: CSA = Cross-sectional Area; CT = Computed Tomography; HRQL = Health-related
Quality of Life; LOS = Length of Stay; MV = Mechanical Ventilation; 6MWD = Six-minute Walk Distance
2.2 Study Aims and Hypotheses:
Study # 1 (Chapter 3)
Study one will retrospectively assess the utility of using thoracic computed tomography (CT)
scans in 527 lung transplant candidates (November 2003 to May 2009), as a measure of
skeletal muscle mass, with a subset of patients having HRQL and pulmonary rehabilitation
measures.
Aims:
1A) Compare thoracic muscle CSA in lung transplant candidates and controls.
1B) Assess the associations of thoracic muscle CSA with exercise capacity, muscle training
volumes, HRQL, pre- and post-transplant clinical outcomes.
Hypotheses:
1A) Lung transplant candidates will have lower muscle CSA than healthy controls.
62
1B) Low thoracic muscle CSA will be associated with reduced exercise capacity, HRQL, lower
muscle training volumes, longer hospital length of stay and increased peri-operative mortality
post-transplant.
Study # 2 (Chapter 4):
Study two is a prospective cohort study evaluating muscle mass, strength and physical
performance in 50 adult lung transplant candidates participating in pulmonary rehabilitation.
Aims:
2A) Characterize the distribution of skeletal muscle deficits (low muscle mass, strength and
physical performance) in lung transplant candidates.
2B) Assess the association of skeletal muscle deficits with pre-transplant exercise capacity,
activities of daily living and HRQL.
2C) As a secondary aim, assess the association between skeletal muscle deficits and pre-
and early post-transplant clinical outcomes.
Hypotheses:
2A) Lung transplant candidates will have significant overlap in skeletal muscle deficits with
impairments seen predominantly in lower extremity strength and physical performance.
2B) Quadriceps strength and physical performance will be associated with exercise capacity,
activities of daily living and HRQL pre-transplant.
2C) The combination of all three skeletal muscle deficits will be associated with increased
hospital length of stay and pre- and early post-transplant mortality.
Study # 3 (Chapter 5):
Study three will evaluate skeletal muscle dysfunction in the pre- transplant period in a group
of lung transplant recipients who are at high risk for long-term skeletal muscle dysfunction.
This will be a sub-analysis of a large prospective cohort study (RECOVER), which assessed
exercise capacity, HRQL, physical function and clinical outcomes up to 2 years post-ICU, in
63
survivors who required mechanical ventilation for at least 7 days.319 For all 80 lung transplant
recipients in this cohort, we will retrospectively collect rehabilitation data pertaining to pre-
transplant muscle mass, strength and exercise capacity to assess their clinical implications on
post-transplant outcomes three-months post-ICU discharge.
Aims:
3A) To assess the association of pre-transplant skeletal muscle mass, strength and exercise
capacity on functional independence 7-days post ICU discharge in lung transplant recipients
with prolonged mechanical ventilation (≥ 7 days).
3B) To evaluate the impact of pre-transplant muscle mass, strength and exercise capacity on
early post-transplant functional independence, exercise capacity (6MWD), HRQL (SF-36
PCS), and discharge disposition at 3 months post-ICU discharge.
Hypotheses:
3A) Pre-transplant functional deficits (muscle strength and exercise capacity) will be
independently associated with impaired functional independence at 7 days post-ICU
discharge.
3B) Pre-transplant functional deficits (muscle strength and exercise capacity) will be
associated with functional independence, HRQL and the change in exercise capacity from
pre-transplant values three months post-ICU discharge. Skeletal muscle mass and exercise
capacity will be important mediators of discharge disposition.
CHAPTER 3:
3.0 Thoracic Muscle Cross-Sectional Area is Associated with Hospital
Length of Stay Post Lung Transplantation
3.1 Abstract:
Background/Objectives: Low muscle mass is common in lung transplant candidates,
however, the clinical implications have not been well described. The study aims were to
compare skeletal muscle mass in lung transplant candidates with controls using thoracic
muscle cross-sectional area (CSA) from computed tomography and assess the association
with pre- and post-transplant clinical outcomes.
Methods: This was a retrospective, single centre cohort study of 527 lung transplant
candidates (median age: 55 IQR [42-62] years; 54% male). Thoracic muscle CSA was
compared to an age-and sex-matched control group. Associations between muscle CSA and
pre-transplant six-minute walk distance (6MWD), health-related quality of life (HRQL),
delisting/mortality, and post-transplant hospital outcomes and one-year mortality were
evaluated using multivariable regression analysis.
Results: Muscle CSA for lung transplant candidates was about 10% lower than controls
(n=38). Muscle CSA was associated with pre-transplant 6MWD, but not HRQL, delisting or
pre- or post-transplant mortality. Muscle CSA (per 10 cm2 difference) was associated with
shorter hospital stay [0.7 median days 95% CI (0.2-1.3), p=0.04], but did not predict discharge
to inpatient rehabilitation [OR: 0.85 95% (CI 0.71 to 1.02), p=0.07] after adjustment for age,
sex, diagnosis, height-squared and 6MWD.
64
65
Conclusion: Thoracic muscle CSA is a simple, readily available estimate of skeletal muscle
mass in lung transplant candidates predictive of hospital length of stay, but further study is
needed to evaluate the relative contribution of muscle mass versus functional deficits
(strength and performance) in predicting post-transplant outcomes.
Chapter reproduced with permission from John Wiley and Sons Inc. The article has been published in final form: Rozenberg D, et al. Thoracic Muscle Cross-Sectional Area is Associated with Hospital Length of Stay Post Lung Transplantation: A Retrospective Cohort Study. Transplant Int. 2017: 30 (7); 713-724. DOI: 10.1111/tri.12961.
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3.2 Introduction:
Lung transplantation provides a significant benefit with respect to HRQL,26 exercise capacity,27
and survival8,423 in people with advanced lung disease. However, optimal selection of lung
transplant candidates remains of critical priority given the morbidity and mortality associated
with transplantation. One fifth of lung transplant candidates die or are de-listed prior to
receiving a transplant and the mortality rate post-transplant is almost 20% in the first year.3,25
Despite improvements in medical management and surgical techniques, there is a growing
need for novel assessments of physical function and body composition that could aid with risk
stratification and management in this population.28
Sarcopenia, defined as age-related loss of muscle mass and function, is related to increased
physical disability, impairments in HRQL and death in older adults and is accelerated in
chronic disease states.424,425 Low muscle mass has been independently associated with
reduced post-transplant survival in liver and renal transplant recipients.236,349 In lung
transplant patients, low muscle mass has been observed to be prevalent using bio-electrical
impedance (BIA),426 however, measures of muscle mass have not been routinely utilized for
prognostication in lung transplantation.21
A simple, readily available measure of muscle mass is needed in lung transplantation. A
practical method for quantifying segmental muscle mass is computed tomography (CT), which
is considered a gold-standard for muscle size measurement.427,428 Muscle CSA taken from a
single axial slice from abdominal CT has been shown to be a good marker of total body
skeletal mass.235 In those undergoing major abdominal surgeries, low psoas muscle size from
abdominal CT has been associated with increased post-operative complications, health-care
costs and increased mortality.237,238,344 In a recent systematic review of 19 studies in liver
transplantation, low skeletal muscle mass (i.e. sarcopenia) quantified with abdominal CT was
67
observed to be prevalent (range 22-70%) and associated with waiting list and post-transplant
mortality.348 Similarly, in lung transplant patients muscle CSA from abdominal CT has been
associated with post-transplant outcomes such as intensive care unit (ICU)240 and hospital
length of stay.239 In COPD patients, muscle CSA from chest CT has been associated with
disease severity,241,243 exercise capacity,241 and mortality.243 We have recently shown that
measures of thoracic muscle CSA from a single axial slice of the chest correlated well with
accepted measures of muscle mass and were reproducible in lung transplant candidates.429
Chest CT muscle CSA could prove to be a valuable marker in risk stratification given the
availability of chest CT in clinical practice. To our knowledge, the clinical implications of
muscle CSA with respect to pre-transplant de-listing/mortality, HRQL, and strength training
volumes have not been previously described. Furthermore, the incremental utility of muscle
CSA to predict post-transplant outcomes compared to established parameters such as the
6MWD remains unknown.23,113
The aims of this study were to compare thoracic muscle CSA in lung transplant candidates
with controls and to assess the associations of thoracic muscle CSA with six-minute walk
distance (6MWD), strength training volumes, HRQL, pre- and post-transplant clinical
outcomes. The secondary aim was to evaluate the prognostic utility of muscle CSA as an
adjunct to pre-transplant 6MWD in predicting early post-transplant outcomes. We
hypothesized that muscle CSA would be significantly reduced in lung transplant candidates
and independently associated with functional capacity, pre-transplant de-listing/death, and
early post-transplant outcomes, independent of 6MWD.
3.3 Methods:
3.3.1 Study Design and Participants:
This was a retrospective cohort study of adult lung transplant candidates (age ≥ 18 years)
68
listed at University Health Network between November 1, 2003 and May 30, 2009. This
period was chosen due to an available set of exercise data from a prior study.110 For inclusion
in the current study, patients had to have a chest CT within 3 months of transplant listing.
Lung transplant patients who were listed for a re-transplant during the study period were
excluded. Research ethics approval was obtained from University Health Network (REB # 13-
6430-BE) and University of Toronto (REB # 30785).
The control group was comprised of 38 participants matched for age (≥ 50 years old) and sex
who underwent lung cancer screening with low dose CT, as part of a research study at
University Health Network.430 All participants had at least a 10 pack-year smoking history, had
generally good health, and no history of malignancy. The sample size was determined based
on the assumption that thoracic CSA would be 20% lower for lung transplant candidates than
controls (effect size=1.0, n=17 for each sex). Previous studies have demonstrated that
peripheral measures of muscle mass (i.e. quadriceps CSA) were about 20% lower in COPD
patients compared with controls.245,257
3.3.2 Muscle Cross-Sectional Area Assessment:
Thoracic CT (1-5 mm slices) were acquired on a Toshiba Aquillion scanner as part of routine
clinical evaluation for lung transplantation. The CT scan utilized for analysis was within three
months of transplant listing. Muscle CSA of the pectoralis major and minor, intercostals,
serratus anterior, paraspinal and latissimus dorsi muscles was quantified from CT using Slice-
O-matic software (Version 5.0, Tomovision, Montreal, Canada, Slice-O-Matic), Hounsfield unit
ranges of -29 to 150, Figure 3-1.431,432 The average of three slices, one at the carina level
and one slice above and below, were used to quantify muscle CSA. The same technique was
applied to the control group using low dose thoracic CT images (1-1.25 mm slices).
69
We have previously demonstrated that thoracic muscle CSA from a single axial CT slice
correlates strongly with thoracic muscle volume (r=0.89-0.91, p < 0.001) and has excellent
inter-rater reliability.429 The inter-rater reliability for this study was re-assessed in the first
twenty subjects, between two observers (D.R and P.M) at the carinal level, (ICC =0.998, 95%
CI 0.995 to 0.999). Given the high ICC values, muscle CSA for the remaining subjects was
assessed by one observer (D.R).
The construct validity of thoracic muscle CSA was also assessed using a separate lung
transplant cohort (n=50) from our center described in Chapter 4. Thoracic muscle CSA had a
strong association with fat-free mass index from BIA (r=0.71, p < 0.0001), Appendix-Figure
1A.
Figure 3-1: Representation of Cross-sectional Muscle Area using Slice-O-Matic Software Thoracic Muscles: Orange = Pectoralis; Green = Intercostal Muscles; Red = Para-Spinal Muscles;
Blue = Serratus Anterior and Latissimus Dorsi Muscles
3.3.3 Clinical Variables:
The following variables were abstracted from the medical records and Toronto Lung
Transplant clinical database at the time of transplant listing: Age (years), sex, anthropometric
70
measurements (weight (kg), height (cm), and body mass index (kg/m2)), diagnostic indication
for transplant, daily corticosteroid use, albumin (g/L), and need for bridging to lung
transplantation with mechanical ventilation or extra-corporeal life support. The listing urgency
status (Status 1, 2 and Rapidly deteriorating) was assessed at the time of transplant listing,
which is a subjective determination of disease severity predictive of waiting list survival.61
Exercise capacity was evaluated using the 6MWD (meters), which was routinely performed
within 4 weeks of transplant listing by a physical therapist as per American Thoracic Society
guidelines104,433 and reported as percent predicted.434 All lung transplant candidates at our
centre participate in a mandatory pulmonary rehabilitation program three times per week,
which is initiated at the time of listing and is ongoing for the waitlist duration.110,125 As a
surrogate of muscle strength, biceps and quadriceps strength training volumes at the start of
pulmonary rehabilitation (end of first week) were calculated from training logs on a subset of
patients as follows: [# repetitions * weight (pounds) * # sets].110 Training volumes were
calculated at the start of rehabilitation to reduce the influence of any training effect with
rehabilitation.
Short-Form 36 (SF-36) and St. George’s Respiratory Questionnaire (SGRQ) were available in
a subset of patients within three months of transplant listing from a completed prospective
study on HRQL.26 We included the SF-36 physical function domain, SF-36 physical
component score, and the activity domain of the SGRQ given their associations with physical
activity in lung transplant patients.109,117
Pre-transplant clinical outcomes assessed were medical delisting or death. We treated these
two as a composite outcome and patients were medically delisted if they were too ill to derive
benefit from lung transplantation. Post-transplant outcomes included: days of mechanical
ventilation, ICU days, hospital length of stay, mortality in hospital and at one year, and
71
development of grade 3 primary graft dysfunction (PGD) at 72 hours as per International
Society of Heart-Lung Transplant consensus definition (PaO2/FiO2 ratio of < 200 mmHg or
requirement for extra-corporeal membrane oxygenation or nitric oxide).435 Grade 3 PGD was
specifically evaluated as it is associated with post-transplant mortality.436 Discharge
disposition (home versus inpatient rehabilitation) was also documented. The standard
practice at our center is for lung transplant recipients to participate in an outpatient
rehabilitation program for at least 3-months post-transplant; however, recipients that are
unable to meet functional requirements for safe discharge home are referred to an inpatient
rehabilitation program.113 Pre- and post-transplant outcomes were abstracted from the
Toronto Lung Transplant clinical database.
3.3.4 Statistical Analysis:
Analysis was performed using Graph-Pad Prism (Version 7.0) and R (Version 3.32).
Continuous variables are described using mean ± standard deviation or median [interquartile
range 25-75%] with categorical variables described using frequencies. Visual inspection of
scatter plots, Kolmogorov-Smirnov and Pearson omnibus normality tests were used to assess
the distribution of data. Muscle CSA of lung transplant candidates aged 50-69 years versus
controls in the same age group were compared using an unpaired t-test with Welch’s
correction, stratified by sex.
Bivariate and multivariable associations between muscle CSA and 6MWD, strength training
volumes, HRQL, and pre-transplant medical delisting/death and post-transplant outcomes
were assessed using linear and logistic regression analyses. Covariates were selected based
on previously described associations with muscle mass (age, sex, height-squared (m2) and
diagnosis) with additional clinically relevant co-variates outlined in the results section. Logistic
regression analyses examined the association of muscle CSA with development of grade 3
PGD at 72 hours and mortality on the post-transplant admission and at one year. After
72
exclusion of patients who died during the hospitalization post-transplant, multivariable quantile
regression was used to assess the relationship of pre-transplant muscle CSA with median
time-based post-transplant outcomes (days of mechanical ventilation, ICU and hospital length
of stay). Discharge disposition (home versus inpatient rehabilitation) was assessed using
logistic regression. Pre-transplant 6MWD was included in post-transplant multivariable
regression models to assess the incremental utility of muscle CSA in prediction of early post-
transplant outcomes.
We performed model diagnostics examining plots of residuals to ensure assumptions of
independence, normality and constant variation of errors were met. A p value of < 0.05 was
considered significant for all analyses.
3.4 Results:
3.4.1 Participants:
There were 527 lung transplant candidates included in the study, Figure 3-2. Baseline
characteristics are described in Table 3-1. The mean muscle CSA for the lung transplant
cohort was 94 ± 25 cm2. Greater muscle CSA was associated with male sex, greater body
mass index, height, and a diagnosis of interstitial lung disease (ILD) or cystic fibrosis (CF),
Table 3-1. Muscle CSA was not associated with age, daily prednisone use, albumin levels, or
listing status (Table 3-1).
73
Figure 3-2: Flow Diagram of Lung Transplant Candidates Included in the Study
74
Table 3-1: Patient Characteristics and Associations with Muscle Cross-sectional Area
Parameter Cohort Summary (n=527)
Bivariate: Mean Difference in
muscle CSA
p value
Age (per 10 years) 55 IQR [42-62] -1.17 (-2.72 to 0.37) 0.14Male Sex 283 (54%) 33.4 (30.1 to 36.6) < 0.001 Diagnosis
ILD COPD
CF PAH Other
225 (43%) 123 (23%) 98 (19%) 21 (4%)
60 (11%)
Reference
-18.7 (-24.0 to -13.4) -0.95 (-6.7 to 4.8)
-12.3 (-23.1 to -1.5) -14.9 (-21.8 to -8.1)
-
< 0.001 0.74 0.05
<0.001Body Mass Index (per kg/m2), n=521 24.0 ± 4.4 1.77 (1.29 to 2.24) < 0.001
BMI Categories Normal Weight: 18.5-24.9 Underweight: BMI < 18.5
Overweight: 25.0-29.9 Obese: ≥ 30.0
223 (43%) 68 (13%)
188 (36%) 42 (8%)
Reference
-4.2 (-10.8 to 2.4) 9.9 (5.2 to 14.6)
22.3 (14.3 to 30.4)
-
0.28 0.01
<0.001Height (per cm), n=527 168 ± 10 1.45 (1.27 to 1.64) < 0.001
Albumin (per 1 g/L), n=472 39 ± 6 0.06 (-0.33 to 0.45) 0.76Daily Prednisone Use 192 (36%) -2.1 (-6.6 to 2.4) 0.36
Transplant Listing Status One (standard priority)
Two (high priority) Rapidly Deteriorating
260 (49%) 229 (44%)
38 (7%)
Reference
2.8 (-1.7 to 7.3) 4.7 (-4.0 to 13.3)
-
0.23 0.29
Data are presented as n (%), mean ± SD, or median [25-75% interquartile range]. Abbreviations: BMI = Body Mass Index; CSA = Cross-sectional area; COPD = Chronic Obstructive
Pulmonary Disease; CF = Cystic Fibrosis; ILD = Interstitial Lung Disease; PAH = Pulmonary Arterial
Hypertension.
3.4.2 Muscle CSA in Lung Transplant Candidates and Healthy Controls
When stratified by sex and age (50-69 years), lung transplant candidates had 10% lower
muscle CSA than controls with no significant difference in BMI (Figure 3). Muscle CSA was
as follows: [Males: Lung Transplant (n=183): 106 ± 20 vs. Controls (n=19) 117 ± 12 cm2,
p=0.002 and Females: Lung Transplant (n=131): 72 ± 15 vs. Controls (n=19): 80 ± 8 cm2,
p=0.001).
75
Figure 3-3A – Male Lung Transplant Candidates vs. Controls (Ages 50-69 years):
Age (Lung Transplant: 60.0 ± 5.1 vs. Controls 59.6 ± 5.4 years, p=0.78); BMI (Lung Transplant: 25.4 ±
4.0 kg/m2 vs. Controls: 25.7 ± 2.5 kg/m2, p=0.67).
Figure 3-3B - Female Lung Transplant Candidates vs. Controls (Ages 50-69 years):
Age (Lung Transplant: 59.7 ± 5.1 vs. Controls: 59.5 ± 5.3 years, p=0.89); BMI (Lung Transplant: 24.5 ±
4.1 kg/m2 vs. Controls: 26.1 ± 3.8 kg/m2, p=0.11)
Abbreviations: LTx = Lung Transplant; mCSA = Muscle Cross-Sectional Area
76
3.4.3 Six-Minute Walk Distance, Strength Training Volumes, and Quality of Life:
The lung transplant candidates had low 6MWD (46 ± 17 % predicted) and HRQL (SF-36 PCS:
27 ± 8 and SGRQ Activity Domain: 92 [79-92]). Six-minute walk distance, strength training
volumes and HRQL were associated with muscle CSA in the bivariate analysis (Table 3-2).
This relationship remained significant for 6MWD and strength training volumes when adjusted
for age, sex, height-squared and diagnosis, Table 3-2. For instance, for every 10 cm2
increase in muscle CSA, 6MWD increased by 9.3 m 95% CI (3.7-14.9), p= 0.001, R2=0.23.
The strength of the association with muscle CSA was stronger for biceps training volumes
than quadriceps (R2 0.21 vs. 0.10) after adjustment. There was no independent relationship
observed between available HRQL measures and muscle CSA after adjustment for covariates
(Table 3-2). Lung transplant candidates with available HRQL data (n=400) compared to those
without (n=127) had greater 6MWD and were more likely to be transplanted with no difference
in muscle CSA or demographics observed between the two groups (Table 3-3).
3.4.4 Pre-transplant Clinical Outcomes:
Of the 527 lung transplant candidates, n= 15 (3%) were medically delisted, n=67 (13 %) died,
and n=14 (3 %) taken off the transplant list due to clinical improvement with the remainder
being transplanted. There was no relationship observed between muscle CSA and medical
delisting or death (Table 3-2).
T
able
3-2
: A
ssoc
iatio
ns b
etw
een
Tho
raci
c M
uscl
e C
ross
-sec
tiona
l Are
a an
d E
xerc
ise
Cap
acity
, Str
engt
h T
rain
ing
Vol
umes
, Qua
lity
of L
ife, a
nd P
re-t
rans
plan
t Out
com
es
Dat
a ar
e pr
esen
ted
as m
ean
± S
D,
med
ian
[25-
75%
inte
rqua
rtile
ran
ge],
or m
ean
diffe
renc
e (9
5% c
onfid
ence
inte
rval
).
*Bic
eps
and
Qua
dric
eps
trai
ning
vol
umes
take
n at
initi
atio
n of
reh
abili
tatio
n.
** E
xclu
ded
due
to M
edic
al Im
prov
em
ent P
re-T
rans
plan
t (n=
14).
† M
ult
ivar
iate
Mea
n D
iffe
ren
ce f
or
mC
SA
fo
r P
hys
ical
Fu
nct
ion
an
d Q
ual
ity
of
Lif
e O
utc
om
es:
A
djus
ted
for
Age
, Sex
, H
eigh
t (m
2 ) a
nd D
iagn
osis
.
‡ M
ult
ivar
iate
Od
ds
Ra
tio
fo
r m
CS
A f
or
Del
isti
ng
/Mo
rtal
ity
vs. T
ran
sp
lan
ted
:
Adj
uste
d fo
r A
ge, S
ex,
Hei
ght (
m2 )
, Dia
gnos
is, a
nd P
rogr
am T
rans
plan
t Lis
ting
Sta
tus
Ab
bre
viat
ion
s: C
I: C
onfid
ence
Int
erva
l; m
CS
A =
Mus
cle
Cro
ss-s
ectio
nal a
rea;
SG
RQ
= S
t. G
eor
ge’s
Res
pira
tory
Que
stio
nnai
re;
O
R =
Odd
s R
atio
Ou
tco
me
Par
amet
ers
C
oh
ort
Su
mm
ary
Biv
aria
te:
Mea
n D
iffe
ren
ce f
or
ever
y 10
cm
2
in m
CS
A (
95
% C
I)
p v
alu
e
†Mu
ltiv
aria
te:
Mea
n D
iffe
ren
ce f
or
ever
y 10
cm
2
in
mC
SA
(9
5%
CI)
p v
alu
e
Ph
ysic
al F
un
ctio
n
S
ix-m
inut
e w
alk
dist
ance
(m
), n
=49
931
2 ±
123
10.9
(6.
7 to
15.
1)<
0.0
019.
3 (3
.7 t
o 14
.9)
0.00
1 *B
icep
s T
rain
ing
volu
me
(re
ps*l
bs),
n=
258
40 IQ
R [3
0-60
]5.
7 (4
.1 to
7.2
) <
0.0
014.
6 (2
.4 to
6.8
)<
0.0
01
*Qua
dric
eps
Tra
inin
g vo
lum
e (r
eps
*lbs
),
n=25
2 30
IQ
R [
20-4
5]
3.0
(1.8
to
4.3)
<
0.0
01
2.3
(0.4
to
4.2)
0.
02
Qu
alit
y o
f L
ife
(n=
400)
Sho
rt-F
orm
36
Phy
sica
l Fun
ctio
n D
omai
n15
IQR
[10-
32.5
]1.
3 (0
.6 t
o 2.
0)
0.00
10.
55 (
-0.4
to 1
.5)
0.26
S
hort
-For
m 3
6 P
hysi
cal C
ompo
nent
Sco
re27
± 8
0.5
(0.2
to 0
.8)
0.00
30.
3 (-
0.1
to 0
.8)
0.17
S
GR
Q A
ctiv
ity D
omai
n
92 IQ
R [7
9-92
]-0
.8(-
1.3
to -
0.3)
0.00
3-0
.14
(-0.
9 to
0.6
)0.
69
** C
linic
al O
utc
om
es (
n=
513)
Biv
aria
te:
OR
fo
r ev
ery
10 c
m2
in m
CS
A (
95
% C
I)
‡
Mu
ltiv
aria
te:
O
R f
or
ever
y 10
cm
2
in m
CS
A (
95
% C
I)
Del
istin
g/M
orta
lity
vs. T
rans
plan
ted
82
(16
%)
vs.
431
(84%
)0.
91 (
0.80
to 1
.01)
0.
08
0.96
(0.
78 to
1.1
1)
0.60
77
Table 3-3: Characteristics of Subjects by Availability of Health-related Quality of Life Data
Parameter Available HRQL (n=400)
No Available HRQL (n=127)
p value
Age, Median [IQR] years
55 IQR [43-62] 53 [40-62] 0.36
Male Sex
217 (54%) 66 (52%) 0.65
Diagnosis: Interstitial Lung Disease Chronic Obstructive Pulmonary Disease Cystic Fibrosis Pulmonary Arterial Hypertension Other
170 (42.5%) 102 (25.5%)
68 (17%) 17 (4%)
43 (11%)
55 (43%) 21 (17%) 30 (24%)
4 (3%) 17 (13%)
0.17
Muscle Cross-sectional Area (cm2)
94 ± 25 93 ± 26 0.57
Six-minute Walk Distance (m) (n=398/101)
322 ± 118 271 ± 133 0.01
Transplanted (n=431) Delisted/Died (n=82) Medically Improved (n=14)
337 (84%) 54 (14%)
9 (2%)
94 (74%) 28 (22%)
5 (4%)
0.03
Data are presented as mean ± SD or median [25-75% interquartile range].
Abbreviations: HRQL = Health-related Quality of Life
3.4.5 Post-transplant Clinical Outcomes:
A total of 431/527 (82%) were transplanted with the majority receiving a double lung
transplantation 359 (83%). Twenty-seven of 431 (6%) lung transplant recipients required
bridging with mechanical ventilation (n=19, 4%) or extra-corporeal life support (n=8, 2%) with a
median duration of 10 IQR [7-24] days in the ICU pre-transplant. No difference in muscle CSA
[-5.8 cm2 (-12.9 to 1.3), p=0.11)] was observed in those requiring bridging to transplantation
compared to those transplanted without bridging, adjusted for age, sex, height-squared and
diagnosis.
389 (90%) transplant recipients survived to hospital discharge with causes for in-hospital
mortality outlined in Figure 3-2. There was no observable difference in muscle CSA for hospital
discharge versus death for every 10 cm2, controlling for age, sex, height-squared and diagnosis
[OR: 1.13 95% (0.94-1.36), p=0.20]. Hospital mortality was increased in 51 lung transplant
78
79
recipients (12%) who developed grade 3 PGD [OR=4.8 95% (2.3-9.8, p < 0.001)], but no
independent association was observed between pre-transplant muscle CSA and development
of Grade 3 PGD [adjusted OR=0.91 95% (0.77-1.08, p=0.27) for every 10 cm2].
Of those surviving to hospital discharge, the adjusted OR of being discharged to inpatient rehab
versus home was 17% lower for every 10 cm2 increase in muscle CSA, Table 3-4. Muscle CSA
was no longer independently associated with discharge to inpatient rehabilitation when pre-
transplant 6MWD was incorporated into the model (Table 3-4) with 6MWD associated with a
reduced risk of being discharged to inpatient rehabilitation [OR = 0.74 95% CI (0.56-0.97,
p=0.03, n=372), for every 100 m increase. None of the other covariates (age, sex or height-
squared) were independently associated with discharge disposition except for a diagnosis of
COPD or CF, relative to ILD, who were less likely to be discharged to inpatient rehabilitation
(p=0.002).
After excluding patients who died during the transplant hospital admission, the median length of
stay in the intensive care unit (ICU) and hospital was 4 days IQR [2-11] and 20 days IQR [14-
35], respectively. Muscle CSA was independently associated with shorter hospital length of
stay [0.7 median days 95% (0.2 - 1.3), p=0.04] per 10 cm2 muscle CSA], even after adjustment
for pre-transplant 6MWD [- 1.3 median days 95% (-2.8 to -0.2, p=0.045, n=372) per 100 m
increase], Table 3-4. None of the other covariates were independently associated with hospital
length of stay. No independent relationship was observed between muscle CSA and
mechanical ventilation or ICU days post-transplant, Table 3-4.
A total of n=75 (17%) recipients died within one-year post-transplant. There was no
independent association found between muscle CSA and one-year all-cause mortality [OR=0.92
95% CI (0.80-1.06, p=0.26) for every 10 cm2], adjusted for age, sex, height-squared and
diagnosis.
T
able
3-4
: A
ssoc
iatio
ns B
etw
een
Mus
cle
Cro
ss-s
ectio
nal A
rea
and
Pos
t-T
rans
plan
t Out
com
es
Dat
a ar
e pr
esen
ted
as n
(%
), m
edia
n [2
5-75
% in
terq
uart
ile r
ange
], or
med
ian
diffe
renc
e (9
5% c
onfid
ence
inte
rval
).
*Out
com
es o
n n=
389
reci
pien
ts; e
xclu
ded
thos
e th
at d
ied
post
-tra
nspl
ant i
n ho
spita
l.
Mu
ltiv
aria
te M
edia
n D
iffe
ren
ce f
or
mC
SA
on
Da
ys o
f M
ech
anic
al V
enti
lati
on
, In
ten
sive
Car
e, a
nd
Ho
spit
al L
eng
th o
f S
tay
A
ND
M
ult
ivar
iate
Od
ds
Rat
io f
or
mC
SA
on
Dis
char
ge
Dis
po
siti
on
**
Mod
el 1
: Adj
uste
d fo
r A
ge, S
ex, H
eigh
t (m
2 ) a
nd D
iagn
osis
.
† M
odel
2:
Adj
uste
d fo
r A
ge, S
ex, H
eigh
t (m
2 ), D
iagn
osis
and
Six
-min
ute
Wal
k D
ista
nce
(n=
372)
. A
bb
revi
atio
ns:
CI:
Con
fiden
ce In
terv
al; m
CS
A =
mus
cle
cros
s-se
ctio
nal a
rea;
OR
= O
dds
Rat
io
*Ou
tco
mes
T
ran
spla
nte
d
Co
ho
rt
Su
mm
ary
(n=
389)
Biv
aria
te:
Med
ian
Dif
fere
nce
10
cm
2 in
mC
SA
(9
5%
CI)
p
** M
od
el 1
:
M
edia
n D
iffe
ren
ce
10 c
m2
in m
CS
A
(9
5%
CI)
M
ult
ivar
iate
p
† M
od
el 2
:
Med
ian
Dif
fere
nce
10
cm
2 in
mC
SA
(95
% C
I)
Mu
ltiv
aria
te
p
Day
s of
Mec
hani
cal V
entil
atio
n (n
=38
5)
2 IQ
R [1
-6]
-0.1
(-0
.14
to 0
.1)
0.10
0
(-0.
14 to
0)
1.0
0 (-
0.1
8 to
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80
3.5 Discussion:
This is the first study to provide evidence that muscle CSA was significantly reduced in lung
transplant candidates compared to a control group. Muscle CSA was independently associated
with 6MWD, strength training volumes, and post-transplant hospital length of stay. This
technique of measuring muscle CSA provides a valid surrogate for muscle mass with no added
cost or radiation exposure.241,437
Lung transplant candidates on average had a 10% lower thoracic CSA compared to age and
sex matched healthy controls. This difference is comparable to lung transplant studies using
bio-electrical impedance to characterize fat free mass.426 Sarcopenia, specifically low muscle
mass, has been described to be an important measure since it is a marker of increased
catabolic state and limited protein reserve, which is essential during periods of stress such as
major surgery, hospitalization or critical illness.438 In the present study, lower muscle CSA was
independently associated with greater hospital length of stay. These findings are consistent
with previous reports in patient populations undergoing major surgical procedures such as
general surgery, liver and renal transplantation where core muscle size from abdominal CT was
associated with longer hospital stay, higher rates of infection, and increased rates of post-
transplant mortality.236,344,348,349,439 In lung transplantation, pre-transplant abdominal muscle CSA
has been shown to be associated with ICU240 and hospital length of stay.239 Kelm et al.
observed that muscle CSA was associated with three-year survival in a selected sample of 36
lung transplant recipients with available abdominal CT scans.239 This is in contrast to the
present study and that of Weig et al. where muscle CSA was not related with hospital or one
year mortality.240 Thus, the relationship between muscle mass and post-transplant mortality
requires further study in lung transplantation.
81
82
We observed that muscle CSA was closely associated with 6MWD and accounted for 23% of
the variation in 6MWD after adjustment for confounders. This is consistent with previously
described relationships between 6MWD and measures of muscle mass assessed with bio-
electrical impedance 440,441 and quadriceps CSA.442 Six-minute walk distance is commonly
utilized by pulmonary rehabilitation programs as an assessment of cardiopulmonary
fitness.104,443 However, the effect of exercise training on body composition parameters such as
muscle mass is rarely evaluated due to practical limitations.444 There is evidence from COPD
patients that loss of lean muscle mass, irrespective of body weight, has significant implications
on exercise capacity and muscle strength.445 Thus, characterization of muscle CSA from
available CT scans could potentially be used as a surrogate measure of muscle mass in the
evaluation of patients for pulmonary rehabilitation.
Thoracic muscle CSA was also associated with biceps and quadriceps strength training
volumes. The close relationship between muscle size and strength has been mainly described
for the limb muscles in chronic lung disease.245,446 However, there is growing evidence that limb
muscle size is related to trunk muscle CSA.447,448 In the present study, a stronger association
between thoracic muscle CSA and biceps training volumes was observed compared to
quadriceps volumes, which could partly be explained by the proximity of the upper limb
(shoulder) muscles captured on the axial CT slices with the present technique. The differing
relationship could also be due to the fact that upper limb and core muscles might be less prone
to disuse related muscle atrophy than quadriceps muscles.131,170
We hypothesized that greater muscle CSA, a surrogate marker of muscle mass and therefore
overall physical fitness,441 would be associated with improved HRQL. Studies in patients with
moderate COPD have described the relationship between muscle mass and HRQL to be
mediated through levels of dyspnea225 and physical activity.449 However, we did not observe an
independent association between muscle CSA and HRQL physical domains. This could
83
possibly be explained by the fact that this relationship is mainly mediated by daily activity levels,
one of the main determinants of HRQL in lung transplant candidates.124,125 It is also possible
that those patients without available HRQL might have demonstrated a differing relationship
with muscle CSA, as this group was observed to have a lower exercise capacity and higher
likelihood of medical delisting or mortality pre-transplant.
Measurement of thoracic muscle CSA as a marker of muscle mass is an attractive method
given that sarcopenia is being recognized as an important prognostic and modifiable
determinant in advanced lung disease.28,159 However, thoracic muscle CSA might be better
incorporated as part of sarcopenia evaluation that includes both muscle mass and functional
deficits (muscle strength and physical function)158 given increasing evidence demonstrating that
these functional deficits have important clinical implications in advanced lung disease.
Quadriceps strength has been shown to be a significant predictor of mortality in COPD
patients.294 Low physical function assessed with the Short Physical Performance Battery has
been associated with pre-transplant delisting and mortality.318 In the present study, we
compared the utility of skeletal muscle mass to the 6MWT which is the most common measure
of cardiorespiratory fitness in advanced lung disease102 and has been shown to be a strong
prognostic marker of post-transplant outcomes.23,110 Skeletal muscle mass and 6MWD were
both independently associated with hospital length of stay; however, 6MWD was a stronger
predictor of discharge disposition. This is not entirely surprising as the 6MWT captures
limitations in the cardio-respiratory and musculo-skeletal systems, whereas skeletal muscle
mass characterizes only one element of the sarcopenia definition.158 We propose that a
comprehensive pre-transplant assessment of muscle mass, strength, functional performance,
and exercise capacity could provide further prognostic information in those recipients who are
more likely to sustain a longer hospital course and require discharge to inpatient rehabilitation.
Given the complex interaction between muscle mass, strength and physical function,223,425 future
84
studies exploring the prognostic implications of all three impairments as complementary
measures to 6MWD in lung transplantation are needed.
It is important to acknowledge several limitations in the present study. This was a single, centre
retrospective study with muscle CSA measured at the time of transplant listing. Muscle size
could potentially change while on the transplant list; however, previous studies using BIA have
described no significant change in muscle mass in the pre-transplant period.135 It also remains
unknown whether thoracic muscle CSA would change during an ICU admission pre-transplant;
a setting where the measurement of skeletal muscle mass remains a logistical challenge.450
Secondly, our control group was obtained from a cohort undergoing lung cancer screening who
were ≥ 50 years old and had at least a 10 pack-year smoking history. One can argue whether
this is an appropriate control group; however, the muscle CSA difference would likely be even
greater compared to control subjects without a history of smoking as it is known to be a risk
factor for muscle atrophy.451,452 It is also important to acknowledge that most cystic fibrosis
patients were not age-matched with this older control group. In addition, it is unknown whether
severe lung disease alters the geometry of the thoracic cavity, which could lead to differences in
thoracic muscle CSA attributable to variation in the distribution of the thoracic muscles rather
than muscle atrophy.241,243 However, in a previous study we observed that a single thoracic
axial CT slice was closely associated with thoracic muscle volume obtained from several slices
in lung transplant candidates.429 Furthermore, we did not observe an association between
muscle CSA and transplant listing urgency. Unfortunately, we are unable to comment on the
relationship between muscle CSA and Lung Allocation Score from the present study. Finally, all
lung transplant patients at our center participate in a structured rehabilitation program, which
could have an impact on the pre- and post-transplant clinical outcomes.
85
3.6 Conclusion:
In summary, thoracic muscle CSA can be applied as a novel, simple measure of skeletal muscle
mass and is independently associated with six-minute walk distance, strength training volumes
and post-transplant hospital length of stay. Further study is needed to assess the contribution
of functional deficits (strength and physical performance) in addition to muscle mass in the
evaluation of lung transplant candidates.
86
CHAPTER 4
4.0 Evaluation of Skeletal Muscle Function in Lung Transplant Candidates
4.1 Abstract:
Background/Objectives: Lung transplantation is offered to older and more complex patients
who may be at higher risk of skeletal muscle dysfunction, but the clinical implications of this
remain uncertain. The study aims were to characterize deficits in skeletal muscle mass,
strength and physical performance and examine the associations of these deficits with clinical
outcomes.
Methods: Fifty lung transplant candidates (58% male, 59 ± 9 years) were prospectively
evaluated for skeletal muscle deficits: muscle mass using bio-electrical impedance,
quadriceps, respiratory muscle and handgrip strength, and physical performance with the
Short Physical Performance Battery. Comparisons between number of muscle deficits (low
muscle mass, quadriceps strength and physical performance) and six-minute walk distance
(6MWD), London Chest Activity of Daily Living Questionnaire (LCADL), and quality of life were
assessed using one-way ANOVA. Associations with pre- and post-transplant
delisting/mortality, hospital duration, and three-month post-transplant 6MWD were evaluated
using Fisher's exact test and Spearman correlation.
Results: Deficits in quadriceps strength (n=27) and physical performance (n=24) were more
common than muscle mass (n=8). Lung transplant candidates with two or three muscle
deficits (42%) compared to those without any deficits (26%) had worse 6MWD=-109 m,
95%CI (-175 to -43), LCADL=18, 95%CI (7-30), and St. George's Activity Domain=12, 95%CI
87
(2-21). Number of muscle deficits was associated with post-transplant hospital stay (r=0.34,
p=0.04), but not with delisting/mortality or post-transplant 6MWD.
Conclusion: Deficits in quadriceps muscle strength and physical performance are common in
lung transplant candidates and further research is needed to assess whether modifying
muscle function pre-transplant can lead to improved clinical outcomes.
Contents of this chapter have been published in Transplantation:
Rozenberg D, et al. Evaluation of Skeletal Muscle Function in Lung Transplant
Candidates. Transplantation. 2017 April 3, DOI: 10.1097/TP.0000000000001754.
[E-pub ahead of print]
Please go the journal’s website to read the contents of Chapter 4.
http://journals.lww.com/transplantjournal/Abstract/onlinefirst/Evaluation_of_Skeletal_Muscle_F
unction_in_Lung.96962.aspx
CHAPTER 5
5.0 Clinical Implications of Pre-Transplant Skeletal Muscle Mass, Strength
and Exercise Capacity on Functional Recovery in Lung Transplant
Recipients after 7 or More Days of Mechanical Ventilation
5.1 Abstract:
Background/Objectives: Lung transplant patients are at risk of peri-operative complications
that can result in a prolonged course of mechanical ventilation (MV). Unlike other intensive care
unit (ICU) patients, all lung transplant recipients undergo rehabilitation prior to their transplant
and ICU stay with the goal of optimizing functional recovery after transplantation. We
hypothesized that greater pre-transplant skeletal muscle mass, strength and exercise capacity
would be associated with better post-transplant functional recovery in lung transplant recipients
requiring at least 7 days of MV.
Methods: Single center analysis of lung transplant recipients who required ≥ 7 days of MV peri-
operatively and participated in a prospective cohort study (RECOVER) evaluating post-ICU
recovery. Pre-transplant skeletal muscle mass (using thoracic computed tomography cross-
sectional area), strength (captured with muscle training volumes) and exercise capacity (6MWD)
were evaluated retrospectively. Post-transplant outcomes included the Functional
Independence Measure motor subscale (motor FIM, primary outcome at 7 days post-ICU) and
secondary outcomes included the Short-Form 36 Physical Component Score (SF-36 PCS),
change in 6MWD with transplant, and discharge disposition at 3 months post-ICU. Pre-
transplant predictors of recovery (age, sex, ICU length of stay (LOS), muscle mass, strength
and 6MWD) were assessed using multivariable regression.
88
89
Results: 80 lung transplant recipients (48% male; median age 57 IQR [44-64]) were included.
72 (90%) recipients survived to ICU discharge with a total median ICU LOS of 24 IQR [17-36]
days. At 7-days post-ICU, these participants required maximal-total assistance (motor FIM; 33
(SD) ± 19), with age being the only independent predictor (β= -5.2 ± 1.7, per 10 years). At
three-months post-ICU, lung transplant recipients had persistent functional limitations: motor
FIM (80 ± 17, minimal assistance), low 6MWD (63 ± 23 % predicted), SF-36 PCS (35 ± 10) and
high rates of discharge to inpatient rehabilitation (43%) versus home. At three-months post-
ICU, younger age and shorter ICU length of stay were the only independent predictors of better
post-transplant motor FIM, greater SF-36 PCS, and a higher likelihood of being discharged
home, whereas pre-transplant muscle mass, strength, and 6MWD were not significant.
Conclusions: In a select group of lung transplant recipients surviving 7 or more days of MV,
age and ICU LOS were significant determinants of early functional recovery and discharge
disposition. The lack of association between pre-transplant skeletal muscle function and post-
transplant outcomes highlights the importance of ICU acquired morbidity in this group of
patients. These findings may help facilitate discharge planning and discussions between the
health care team, patients, and their families about the clinical implications of ≥ 7 days of MV
peri-operatively.
90
5.2 Introduction:
Lung transplantation is offered to older and more medically complex patients that may have an
increased risk for a prolonged intensive care unit (ICU) and hospital course post-transplant.8,28
Critical illness can result in significant skeletal muscle atrophy and functional loss, which can
occur early in the first week of ICU.219,399 Furthermore, prolonged periods of immobility after
lung or heart-lung transplantation can result in deconditioning, which is known to be associated
with delayed functional recovery.116,453 Several studies have shown that physical conditioning
pre-operatively may mitigate the physical stress involved with major surgery and critical
illness.438,454-456
Early post-operative complications in lung transplant recipients such as primary graft
dysfunction (PGD), infection, systemic organ failure, and bleeding may result in a prolonged
course of mechanical ventilation (MV) and ICU stay.377 Prolonged MV is not uncommon in lung
transplant recipients, especially in the 10-30% recipients experiencing PGD,376,457 and could
potentially lead to an accelerated decline in physical function in the early post-transplant period.
A greater number of lung transplant recipients are also supported with MV or extra-corporeal life
support (ECLS) while awaiting transplantation, which may further contribute to ICU-acquired
weakness (ICUAW).458,459 The RECOVER program group has shown that medical and surgical
ICU survivors (excluding lung transplant recipients) who required at least 7 days of MV had
significantly increased morbidity and mortality based on risk strata determined by age and ICU
length of stay (LOS) and these predicted functional independence at one week through one
year after ICU discharge.319 In patients with acute lung injury, muscle weakness is common
after a prolonged ICU admission (≥ 7 days) and is associated with long-term impairments in
physical function and health-related quality of life (HRQL).388,389 These studies suggest that
91
early physical limitations from prolonged MV and immobilization may result in significant long-
term functional disability.
Unlike other critically ill patients with an unpredictable admission to the ICU, lung transplant
candidates generally perform pre-transplant pulmonary rehabilitation prior to their ICU
admission.373 We know that pulmonary rehabilitation helps preserve exercise capacity in lung
transplant candidates, even in the setting of progressive decline in lung function, and a greater
exercise capacity pre-transplant is associated with a shorter LOS post-transplant110 and a higher
likelihood of being discharged home.113 Low skeletal muscle mass (i.e. sarcopenia) pre-
transplant and lower extremity weakness post-transplant have been independently associated
with increased hospital length of stay and mortality after lung transplantation.23,116,239,240
However, no studies to date have assessed whether pre-transplant skeletal muscle parameters
and exercise capacity are associated with early post-transplant functional recovery in lung
transplant recipients, especially in those with prolonged periods of MV. We chose to investigate
early post-transplant outcomes (< 3 months post-ICU discharge) given evidence from the
RECOVER cohort319 and in lung transplant recipients51,460 that long-term outcomes were
influenced by early post-operative events.
The objectives of this study were to assess the association of pre-transplant skeletal muscle
mass, strength and exercise capacity with post-transplant Functional Independence Measure
motor subscale (primary outcome at 7 days post-ICU discharge) and secondary measures
including HRQL (Short-Form 36 Physical Component Score), change in 6MWD with
transplantation, discharge disposition, and mortality at 3 months post-ICU in lung transplant
recipients with ≥ 7 days of MV. We hypothesized that greater pre-transplant skeletal muscle
mass, strength and exercise capacity would be associated with better early post-transplant
functional recovery, greater HRQL, and a higher likelihood of being discharged home.
92
5.3 Methods:
5.3.1 Study Design and Participants:
This was an analysis of adult lung transplant recipients who participated in the RECOVER
Program study at the University Health Network (UHN) between October 1, 2009 to December
31, 2014, (NCT 00896220).319 Participants were included if they required a minimum of 7
consecutive days of MV pre- or post-transplant during the index transplant admission, Figure 1.
Research ethics approval was obtained from UHN (REB # 15-8858 BE) and University of
Toronto (REB #31637).
All lung transplant candidates were enrolled in an outpatient pulmonary rehabilitation program
comprised of stretching, aerobic and resistance training three times per week for the entire
waiting period, as previously described.110,374 Patients who were too ill to participate in
outpatient pulmonary rehabilitation (i.e. admitted to hospital or ICU) underwent an inpatient
rehabilitation program supervised by a physical therapist, if admitted at UHN.374 Corridor
ambulation, bedside cycling, and resistance exercises were continued as tolerated for ward
patients and early mobilization was undertaken for ICU patients.374
5.3.2 Pre-transplant Muscle Mass, Strength and Functional Capacity
Muscle Mass:
Thoracic muscle cross-sectional area (CSA) of the pectoralis major and minor, inter-costals,
latissimus dorsi and para-spinal muscles was quantified from computed tomography (CT)
scans, which were performed as part of routine clinical care. Muscle CSA was measured at two
time points pre-transplant: within 3 months of transplant listing and the last available
assessment pre-transplant. Muscle CSA was manually segmented using Slice-O-Matic
software (Tomovision, Montreal, Canada) with the Hounsfield unit ranges of -29 to 150, as
93
previously described.429 We have previously shown that CT muscle CSA has excellent intra and
inter-reliability429 and is a good surrogate marker of fat-free mass index assessed with bio-
electrical impedance (r=0.71, p < 0.0001) in lung transplant candidates, Appendix 1- Figure 3-
1A.
Muscle Strength:
The sum of biceps and quadriceps training volumes (number of repetitions multiplied by weight
lifted in pounds) were obtained from review of pre-transplant pulmonary rehabilitation records
and served as surrogate measures of upper and lower limb muscle strength.110 In the cohort of
50 lung transplant candidates described in Chapter 4, we observed moderate correlations
between biceps training volumes and hand-grip strength (r=0.68 p < 0.001) and quadriceps
training volumes and quadriceps peak torque (r=0.49, p<0.001), Appendix 1, Figure 5-1A and
5-2A). These correlations suggest that muscle training volumes may serve as indirect
measures of upper and lower limb strength. The biceps and quadriceps training volumes were
abstracted within four weeks of rehabilitation initiation and from the last available assessment
pre-transplant. Patients who were unable to perform resistance exercises against a training
load were assigned a score of zero.
Functional Capacity:
Functional capacity was assessed by a physical therapist or their assistant using the six minute
walk test (6MWT) in accordance with the American Thoracic Society (ATS) Guidelines.104,433
The 6MWT is repeated every three months as part of routine care at our centre. The six-minute
walk distance (6MWD) from the time of listing and the last available assessment before
transplantation were abstracted from the patient chart and requirement for supplemental oxygen
and walking aid during the 6MWT were also noted.
5.3.3 Pre-Transplant Clinical Parameters:
94
The following information was abstracted from the pre-transplant medical records: age, sex,
indication for transplant, body mass index, transplant listing urgency (Status 1, 2 and Rapidly
Deteriorating), requirement for hospital admission or ICU pre-transplant (including MV or ECLS),
daily corticosteroid use and median dose. Lung allocation score was calculated pre-transplant
using the United Network for Organ Sharing calculator.47,59
5.3.4 Peri-operative and Post-Transplant Outcomes:
The severity of illness was characterized by the Acute Physiology, Age and Chronic Health
Evaluation II score461 ascertained within 24 hours of ICU admission. The Multiple Organ
Dysfunction Score462 was calculated daily for the first week and the Multiple Organ Dysfunction
Score at day 7 was reported as it coincided with the minimum duration of MV required for this
study. Requirement for extracorporeal membrane oxygenation (ECMO), tracheostomy and
renal replacement therapy during the ICU stay were reported. Grade 3 PGD at 72 hours as per
International Society of Heart-Lung Transplant consensus definition (PaO2/FiO2 ratio of < 200
mmHg or requirement for ECMO or nitric oxide) was evaluated.435
The primary outcome measure was the motor subscale of the functional independence measure
(FIM) at 7-days post ICU discharge.321 The FIM consists of 2 main subscales: motor (4
categories including self-care, sphincter control, transfers and locomotion consisting of 13
items) and cognitive (2 categories: communication and social cognition with 5 items) with each
item given a score from 1 (total assistance) to 7 (complete independence).321 The motor
subscale (maximal score of 91) was used in the RECOVER program in a diverse group of
medical and surgical ICU patients,319 and observed to be responsive to change in lung
transplant recipients undergoing inpatient rehabilitation.320,421
Six-minute walk distance at three months post-ICU discharge was assessed in accordance with
the ATS Guidelines as part of routine clinical care and obtained from chart review.104,433 The
95
absolute change in 6MWD (meters) from pre-transplant to post-transplant values was
calculated. The change in 6MWD was chosen as it has been shown to be associated with the
recovery in quadriceps strength from pre-transplant baseline values, independent of graft
function.122
Health-related quality of life at 3 months post-ICU was evaluated with the Short-Form 36 (SF-
36). The SF-36 has been shown to be reliable, valid, and responsive in advanced lung disease
and after transplantation.26,76,463 The physical component score (PCS) was the primary HRQL
measure and has a minimal clinically important difference reported to be ≥ 4 units.464,
The Medical Research Council (MRC) score at 3 months post-ICU discharge was used to
evaluate strength. Six muscle groups were tested bilaterally (upper and lower body), each
scored 0 to 5 for a maximal score of 60.465 A total score of less than 48 out of 60 has been
shown to represent significant generalized muscle weakness and has been used as a criterion
to diagnose ICU acquired weakness (ICUAW).465 Even though this composite MRC score of <
48/60 (80%) is arbitrary, it has been shown to have excellent inter-rater reliability post-ICU
discharge in medical and surgical patients.466,467
Other outcomes assessed were pre- and post-transplant days of MV and ICU, post-transplant
hospital length of stay, discharge disposition (home or inpatient rehabilitation), mortality in
hospital and at 90 days post-ICU.
5.3.5 Statistical Analysis:
Analysis was performed using Graph-Pad Prism (Version 7.0) and R (Version. 3.32).
Continuous variables are described using mean ± standard deviation or median [interquartile
range 25-75%] with categorical variables described using frequencies. Visual inspection of
96
scatter plots, Kolmogorov-Smirnov and Pearson omnibus normality tests were used to assess
the distribution of data.
Transplant listing measures and the last available thoracic muscle CSA, training volumes, and
6MWD before transplantation were compared using paired t-tests. Multi-variable linear-
regression models assessed the association between the predictor variables age, sex, total ICU
length of stay (sum of pre- and post-transplant ICU days), last available muscle CSA, training
volumes, and 6MWD pre-transplant with the outcome variables: 7-day post-ICU motor FIM
(primary outcome) and secondary outcomes motor FIM, SF-36 PCS and change in 6MWD at
three-months post ICU. After excluding participants who died in ICU or hospital post-transplant,
the same independent co-variates were used to evaluate the association with discharge
disposition and mortality using logistic regression.
We performed model diagnostics examining plots of residuals to ensure assumptions of
independence, normality and constant variation of errors were met. A p value of < 0.05 was
considered significant for all analyses.
5.4 Results:
5.4.1 Pre-Transplant:
Eighty lung transplant recipients were included from the RECOVER Program study,319 Figure 5-
1. The lung transplant cohort comprised of 38 males (48%) with a median age of 57 IQR [44-
64] years. Baseline characteristics are shown in Table 5-1. The most common indications for
transplantation were interstitial lung disease (51%) and chronic obstructive pulmonary disease
(16%). The median lung allocation score was 38 [35-44] and 21 (27%) patients were admitted
to hospital or ICU pre-transplant. The median days in the ICU pre-transplant for the 15 lung
transplant candidates bridged to transplantation was 12 IQR [10-15] days.
97
Figure 5-1: Flow Diagram of Study Participants
98
Table 5-1: Baseline Characteristics at Transplant (n=80)
Parameter Value Age, Median IQR (years)
57 IQR [44-64]
Males (n, %)
38 (48%)
Body Mass Index (kg/m2)
24.2 ± 4.8
Diagnosis: Interstitial Lung Disease Chronic Obstructive Pulmonary Disease Cystic Fibrosis Pulmonary Arterial Hypertension *Other
41 (51%) 13 (16%) 8 (10%) 7 (9%)
11 (14%) Oral Corticosteroid therapy (n, median dose, mg)
41, 15 mg IQR [10-22.5]
Inpatient Prior to Transplant (n=21) Hospital Ward ICU (ECLS/Mechanical Ventilation)
6 (8%)
15 (19%) Lung Allocation Score Time of Transplant
38 [35-44]
Type of Transplant Single Double
8 (10%)
72 (90%) APACHE II Score, Median IQR
22 IQR [19-26]
*Other: Includes re-transplants (n=5, 6 %)
Abbreviations: APACHE = Acute Physiologic Assessment and Chronic Health Evaluation; ICU = Intensive Care Unit; ECLS = Extra-corporeal Life Support
Most lung transplant recipients (85%) participated in an outpatient pulmonary rehabilitation
program pre-transplant, on average attending 43 IQR [11-108] sessions with a median wait time
for transplant of 107 [33-251] days. Lung transplant candidates demonstrated small but
significant increases in their muscle training volumes during rehabilitation despite a decrease in
their 6MWD, Table 5-2. There was no significant change observed in muscle CSA pre-
transplant. Most lung transplant candidates required a high level of oxygen supplementation for
exertion (Table 5-2) and fifty percent (40/80) used a walker or cane.
T
able
5-2
: M
usc
le C
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, Tra
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and
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95%
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* p
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(cm
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92
± 2
4 (n
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) 86
± 2
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** B
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s T
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umes
(lb
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45 ±
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(n=
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54 ±
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(n=
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11
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), n
=69
0.00
2**
Qua
dric
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Tra
inin
g V
olum
es
(lbs*
reps
) 29
± 1
8 (n
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) 38
± 3
1 (n
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) 10
(4
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), n
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0.
001
** B
icep
s an
d Q
uadr
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s
T
rain
ing
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umes
(lb
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ps)
73 ±
46
(n=
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92 ±
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(n=
71)
21 (
10 to
32)
, n=
69
0.00
1
Six
-min
ute
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k D
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nce
(met
ers)
307
± 11
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At the time of transplant, 59 (74%) were participating in an outpatient pulmonary rehabilitation
program. There were no significant differences between the outpatient and inpatient
rehabilitation groups with respect to thoracic muscle CSA (88 ± 23 vs. 97 ± 25 cm2, p=0.18) or
6MWD (291 ± 108 vs. 246 ± 148 meters, p=0.21) based on the last assessment pre-
transplant. Muscle training volumes were significantly greater in those participating in the
outpatient compared to inpatient rehabilitation programs (114 ± 67 vs. 28 ± 62 reps*lbs,
n=53/18, p < 0.001).
5.4.2 Post-Transplant:
Intensive Care Unit Course:
Of the 80 lung transplant recipients requiring ≥ 7 days of MV, 23 (29%) developed Grade 3
PGD and 12 (15%) required ECMO support post-operatively. Seventy-two (90%) recipients
survived to ICU discharge with a total median ICU LOS of 24 IQR [17-36] days and total MV
duration of 21 IQR [12-31] days. The median Multiple Organ Dysfunction Score at 7 days of
MV was 7 IQR [5-7], with 16 (22%) requiring renal replacement therapy and 57 (79%)
receiving tracheostomy.
Functional Recovery at Seven Days Post Intensive Care Unit Discharge
The mean score for the motor FIM was 33 ± 19 representing moderate to total assistance at
7-days post ICU discharge. 21 of 53 (40%) were unable to walk to perform the 6MWT. Older
age (for every 10 years) was the only independent covariate associated with a 5-point
decrease in the motor FIM as shown in Table 5-3. The last available thoracic muscle CSA,
muscle training volumes, and 6MWD were not associated with the 7-day post ICU motor FIM.
Outcomes up to Three Months Post Intensive Care Unit Discharge
A total of 67 lung transplant recipients were discharged from hospital with 29 (43%)
100
101
transferred to inpatient rehabilitation and 38 (57%) discharged home. The median hospital
LOS was 58 IQR [38-83] days for this group of patients. Older age and ICU LOS were the
only two significant co-variates associated with discharge to inpatient rehabilitation, Table 5-4.
At three-months post-ICU discharge, there was significant improvement in the motor domain
of the FIM with the total score of 80 ± 17. Age at transplant and post-transplant ICU LOS
were the only significant determinants of FIM at three months with no association observed
between pre-transplant muscle CSA, muscle training volumes, or 6MWD, Table 5-3.
Approximately one-third (10/33) of lung transplant recipients had muscle weakness defined as
a total MRC strength score of < 48/60.
Table 5-3: Multivariate Association with Pre-Transplant Predictors and Motor Functional Independence Measure at 7 and 90 days Post-ICU.
Multivariate Parameters
Mean Effect ± SE on 7-Day Motor FIM (n=54)
Mean Effect ± SE on 3 Month Motor FIM (n=33)
Age, per 10 years
-5.2 ± 1.7 * -3.1 ± 0.8 *
Male Sex
3.3 ± 6.9 -0.3 ± 3.4
ICU LOS, per 10 days
-1.7 ± 0.8 -2.2 ± 0.4 *
Muscle CSA (10 cm2)
-0.2 ± 1.4 0.1 ± 0.7
Muscle Training Volumes (per 10 lbs*reps)
-0.03 ± 0.4 0.1 ± 0.2
6MWD (per 100 m)
-0.1 ± 2.5 0.8 ± 1.1
Adjusted R2
0.10 0.60
Data presented as mean effect ± standard error. * p value < 0.05 Abbreviations: CSA = Cross-sectional Area; FIM = Functional Independence Measure;
ICU = Intensive Care Unit; LOS = Length of Stay; SD = Standard Deviation; SE= Standard Error;
6MWD = Six-minute walk distance
102
Table 5-4: Multivariate Association with Pre-Transplant Predictors and Post-Transplant Discharge Disposition (Inpatient Rehabilitation vs. Home).
Multivariate Parameters
Rehab: Home (n=61) OR (95 % CI)
p value
Age, per 10 years
1.70 (1.03 – 2.82) 0.04
Male Sex
1.27 (0.24 – 6.77) 0.78
ICU LOS, per 10 days
1.49 (1.06 – 2.10) 0.02
Muscle CSA (10 cm2)
0.94 (0.66 – 1.33) 0.72
Muscle Training Volumes (per 10 lbs*reps)
0.98 (0.90 – 1.07) 0.65
6MWD (per 100 m)
1.25 (0.76 – 2.07) 0.38
C-statistic 0.74 - Data presented as odds ratio (95% confidence interval). Abbreviations: CI = Confidence Interval; CSA = Cross-sectional Area; ICU = Intensive Care Unit;
LAS = Lung Allocation Score; LOS = Length of Stay; OR = Odds Ratio;
6MWD = Six-minute walk distance
Exercise capacity was low at 3 months post-ICU discharge, 360 ± 134 meters (63 ± 23 %
predicted, n=53). A high proportion of participants used a walker or cane (22/53, 42%) to
perform the 6MWT, but only 4/53 (8%) required supplemental oxygen. In a multivariate
analysis, the last 6MWD pre-transplant (per 100 meters) was inversely associated with the
change from pre-transplant to post-transplant 6MWD (β = - 81 meters, SE ± 14.9, p < 0.001,
n=48). Other significant independent covariates of 6MWD change from pre-transplant values
were age (for every 10 years, β = -36 meters, SE ± 13, p = 0.01) and ICU LOS (every 10
days, β = -26 meters, SE ± 12, p = 0.03) with muscle CSA, training volumes and sex not
significant in the multivariate analysis.
The mean SF-36 PCS at 3 months post-ICU was 35 ± 10 (mean population score 50). Age
(for every 10 years, β = -2.9, SE ± 1.2, p = 0.02, n=30) and ICU LOS (for every 10 days, β =
-1.0, SE ± 0.48, p= 0.02, n=30) were independently associated with SF-36 PCS. None of the
103
other pre-transplant covariates (muscle CSA, training volumes, and 6MWD) were associated
with HRQL.
The overall mortality at three months post-ICU discharge was 13 (16%) with causes outlined
in Figure 5-1. No identifiable pre-transplant factors were found to be associated with post-
transplant mortality, Table 5-5.
Table 5-5: Bivariate Association with Pre-Transplant Risk Factors and Post-Transplant Mortality Three Months Post-ICU Discharge (n=80)
Parameters Bivariate Association with Mortality OR (95 % CI)
p value
Age, per 10 years 0.91 (0.60 – 1.36) 0.63 Male Sex 1.97 (0.58 – 6.7) 0.27
Hospital or ICU Admission Pre-Transplant
1.99 (0.57 – 7.0) 0.28
Lung Allocation Score 1.0 (0.70 – 1.42) 1.0 Muscle CSA (10 cm2) 1.07 (0.83 – 1.37) 0.62
Muscle Training Volumes (per 10 lbs*reps), n=71
0.98 (0.90 – 1.08) 0.76
6MWD (per 100 m) 1.32 (0.79 – 2.21) 0.28 Data presented as odds ratio (95% confidence interval). Abbreviations: CSA = Cross-sectional Area; ICU = Intensive Care Unit; LAS = Lung Allocation
Score; LOS = Length of Stay; 6MWD = Six-minute walk distance.
5.5 Discussion:
The present study is the first to assess the implications of pre-transplant skeletal muscle
parameters and exercise capacity on post-transplant functional outcomes in lung transplant
recipients surviving at least 7 days of MV and critical illness. Lung transplant recipients
discharged from the ICU had early impairments in functional recovery, HRQL, exercise
capacity and an increased proportion required discharge to inpatient rehabilitation. Older age
and ICU LOS were independent predictors of early post-transplant functional recovery, where
as no association with pre-transplant muscle CSA, muscle training volumes, and exercise
capacity was observed.
104
The finding that older age is associated with worse early functional recovery in the present
cohort of lung transplant recipients is consistent with the results of the multi-center RECOVER
study.319 In medical and surgical ICU survivors with at least 7 days of MV, age and ICU LOS
determined risk stratification groupings and one year mortality independent of ICU admitting
diagnosis or illness severity.319 Older age is particularly relevant in the current era given the
growing number of older lung transplant recipients, with over one-third being over the age of
65 years old.30 Whereas older patients have been shown to have reduced post-transplant
survival,8 Genao et al. demonstrated that the functional trajectory of older lung transplant
recipients (≥ 65 years) compared to younger recipients was similar post-transplant.50
Similarly, lung transplantation was shown to confer HRQL benefits beyond the first 3 months
post-transplant that were not significantly different in older recipients.26 This contrasts with the
present study that had demonstrated older age to have an inverse association with FIM,
HRQL, and exercise capacity in the first 3 months post-ICU discharge, highlighting the
importance of age as an important physiological marker in those sustaining a prolonged
course of MV. Older age is a risk factor for ICUAW and development of geriatric syndromes
(i.e. delirium, falls)383,468 which could potentially hinder recovery in functional independence
and exercise capacity in those experiencing complications post-transplant.469,470
ICU LOS was an important predictor of functional independence, HRQL and exercise capacity
in the present cohort of lung transplant recipients. Prolonged periods of bedrest and critical
illness can lead to significant muscle atrophy and ICUAW, resulting in decreased functional
mobility.419,471 Maury et al previously demonstrated that longer duration spent in the ICU was
associated with a moderate reduction in quadriceps muscle strength in lung transplant
recipients who had a median ICU stay of 6 days.116 In addition to prolonged immobility, other
risk factors for skeletal muscle dysfunction in lung transplant recipients include
hypoxemia,197,199 infection, and high dose corticosteroid use,206,210 which can all lead to
105
increased incidence of ICUAW.383 In addition to corticosteroid therapy, all lung transplant
recipients at our center are started on calcineurin inhibitors post-transplant which may
influence skeletal muscle recovery.195 However, a significant risk factor for early functional
impairments remains prolonged ICU duration with two weeks described as a risk factor for
development of critical illness neuropathy or myopathy.471 This is certainly an important
consideration in our cohort of lung transplant recipients who had a median ICU stay of 24
days.
The lung transplant recipients at 7 days post-ICU discharge had a mean motor FIM score of
33 ± 19, which represents total dependence on activities of daily living such as bathing,
dressing, transferring and walking. Forty percent of patients were unable to walk without
physical assistance at 7 days post-ICU discharge and therefore unable to perform the 6MWT.
As in the RECOVER study,319 we observed a gradient of disability measured with the motor
FIM that was associated with age and ICU LOS but independent of pre-transplant skeletal
muscle mass, strength or exercise capacity further highlighting the importance of ICU
acquired morbidity in this cohort of patients. Given the marked physical limitations observed
7-days post ICU discharge, it is not entirely surprising that the hospital length of stay and
discharge rates to inpatient rehabilitation were nearly 2.5 times of those described for our
program previously (usual median hospital stay of 22 days and discharge rates to inpatient
rehabilitation of 17%).113 We have previously shown that hospital LOS was an independent
predictor of discharge disposition113 as prolonged periods of bedrest and critical illness could
lead to further deconditioning and muscle atrophy through proteolysis.116,399,471 In the present
study, we observed that total ICU LOS was independently associated with discharge to
inpatient rehabilitation. Thus, transfer to a rehabilitation facility may be considered earlier in
the hospital course as it has been shown to be safe and associated with significant functional
recovery post-transplant.320,421 This information is critical as it can help guide discussions pre-
106
transplant with respect to discharge planning and assist with rehabilitation decisions in the
event of a protracted ICU course post-transplant.
Despite moderate-severe limitations within 7-days of ICU discharge, lung transplant recipients
demonstrated significant functional gains at 3 months post-ICU discharge requiring minimal
assistance (motor FIM score of 80), which was comparable to the non-transplant RECOVER
cohort.319 However, there was a significant degree of heterogeneity among this group of lung
transplant recipients with approximately one third having generalized muscle weakness with a
total MRC score < 48/60. This was not necessarily reflected by the 6MWD which was
reduced at around 63% predicted, but comparable to the non-transplant RECOVER cohort
and to other cohorts of lung transplant recipients at three months post-transplant.27,319 This
highlights the limitation of the 6MWT which is the most commonly used functional exercise
measure; however, is not able to specifically isolate muscular function and weakness.104 The
improvement in functional capacity at three months post-ICU is most likely a result of
significant alleviation of ventilatory limitation with transplantation, but persistent limitations in
exercise capacity have been shown to be related to musculoskeletal impairments.122 Other
clinical assessments of muscular function such as the Short-Physical Performance Battery
(SPPB) could help identify musculoskeletal and mobility impairments pre- and post-transplant
and serve as potential targets for rehabilitation.21
We hypothesized that greater pre-transplant skeletal muscle mass, strength and exercise
capacity would be associated with better post-transplant functional recovery in lung transplant
recipients requiring ≥ 7 days of MV. In lung transplant recipients with a standard duration of
MV (usually < 72 hours post-transplant),472 greater skeletal muscle mass and exercise
capacity have been previously shown to be associated with reduced hospital length of stay,110
lower likelihood of being discharged to inpatient rehabilitation113 and reduced mortality in lung
transplant recipients.239 The lack of association with pre-transplant skeletal muscle function
107
and post-transplant outcomes may be related to the high degree of case complexity observed
in these patients sustaining ≥ 7 days of MV. This was a cohort with declining pre-transplant
exercise capacity, a high proportion requiring bridging to transplantation, and post-transplant
had complications associated with high rates needing dialysis and tracheostomy.
Furthermore, the resulting case complexity in this lung transplant cohort was only partly
explained by Grade 3 PGD, which was observed in only one-third of the lung transplant
recipients. Other important sequela post ICU that need to be considered are cognitive
impairment and depression, which have been shown to be associated with physical function
post-transplant394 and also with short and long term functional outcomes in a broad group of
ICU survivors.319,473,474 Thus, the contribution of pre-transplant skeletal muscle function
comprises one of many elements of post-transplant functional recovery in a group with a high
degree of case complexity.
Our study has several limitations. First, skeletal muscle dysfunction in the pre-transplant
period was obtained from chart records using muscle training volumes, which did not allow us
to capture direct strength measures or physical performance, which may have been more
prognostic of post-transplant outcomes. We also used an estimate of whole body muscle
mass from thoracic CT, which was preserved in the pre-transplant period despite a significant
decline in functional capacity. It is possible that thoracic CT is not as sensitive as limb muscle
atrophy, which is known to be an important prognostic marker in advanced lung disease.226,269
We were also unable to comment on the influence of respiratory muscle dysfunction (i.e.
diaphragm atrophy and strength), which could have influenced some of the functional and
clinical outcomes in this group of patients, as previously described in non-transplant ICU
survivors.475 Furthermore, a large proportion of ICU survivors had missed outcome
assessments at three months due to medical illness or admission to inpatient rehabilitation at
other facilities. Bias in demographic characteristics and functional recovery may exist in those
108
who had missed evaluations. We chose the time-frame of up to three months post-ICU for
evaluation of post-transplant outcomes based on the RECOVER study which demonstrated
that early post-transplant outcomes were associated with long-term morbidity and mortality.319
However, it is important to highlight that muscle strength, exercise capacity and self-reported
physical function have been shown to have ongoing improvement up to one year post-
transplant.117 The association with pre-transplant skeletal muscle function may have been
different if assessments were taken at later time points post-transplant. Furthermore, lung
transplant recipients participate in rehabilitation up to three-months post-transplant in both
outpatient and inpatient programs as deemed appropriate by the transplant team. This
certainly could have had a differential effect on the three-month functional independence,
HRQL and exercise capacity in this group of patients. In addition, muscle strength measures
with the MRC scale were only performed at three months post-ICU discharge. Thus, we are
unable to comment on the relative contribution of ICU acquired weakness versus pre-
transplant skeletal muscle weakness in these patients. Furthermore, given the limitations of
sample size, we grouped the ICU LOS of the fifteen patients bridged to lung transplantation
with the rest of the transplant cohort, which may have underestimated the negative
consequences of pre-transplant ICU admission on post-transplant functional recovery. Lastly,
it is important to highlight the findings in this study apply to a select group of patients with a
prolonged ICU LOS and not to the entire pool of lung transplant recipients, most of whom do
not require ≥ 7 days of MV.
5.6 Conclusion:
Lung transplant recipients with a minimum of 7 days MV experienced significant morbidity and
impairments in early functional recovery resulting in a high proportion being discharged to
inpatient rehabilitation. Older age and prolonged ICU LOS were significant predictors of early
functional disability. Other pre-transplant factors such as skeletal muscle mass, training
109
volumes, and exercise capacity were not associated with post-transplant outcomes
highlighting the importance of ICU acquired morbidity in this group of patients. The findings
from this study could help facilitate advance care discussions among clinicians, patients and
their caregivers about the clinical implications of prolonged peri-operative MV. Future
investigations should aim to explore the implications of other pre-transplant markers such as
direct measures of peripheral muscle size and strength, functional capacity decline, and ECLS
support on post-transplant outcomes in recipients with complex peri-operative courses.
110
CHAPTER 6
6.0 Discussion:
6.1 Overview of Findings:
The findings from the three studies comprising this thesis highlight the importance of skeletal
muscle mass, strength and function on pre- and early post-transplant clinical outcomes in
three distinct, but complementary lung transplant cohorts from a single large lung transplant
center. The novel findings in this thesis are:
Chapter 3 (Study 1):
1) Thoracic muscle cross-sectional area (CSA), a novel surrogate marker of whole body
muscle mass was reduced in lung transplant candidates compared to controls.
2) Thoracic muscle CSA was independently associated with pre-transplant exercise
capacity, strength training volumes, but not health-related quality of life (HRQL).
3) Thoracic muscle CSA was independently associated with hospital length of stay post-
transplant, but not pre- or post-transplant mortality.
Chapter 4 (Study 2):
1) Skeletal muscle deficits (muscle mass, strength and physical function) were common
in the pre-transplant period and characterized mainly by reductions in quadriceps
strength and physical performance.
2) A greater number of skeletal muscle deficits was associated with lower exercise
capacity, greater impairments in activities of daily living (ADL), lower HRQL, and
longer post-transplant hospital length of stay.
111
Chapter 5 (Study 3):
1) Lung transplant recipients who required seven or more days of mechanical ventilation
had significant impairments in functional recovery, HRQL, exercise capacity, and high
rates of discharge to inpatient rehabilitation.
2) Older age and intensive care unit (ICU) duration were the strongest predictors of early
post-transplant functional recovery, whereas no association was observed for pre-
transplant thoracic muscle CSA, strength training volumes, or exercise capacity.
The findings in the present thesis highlight that evaluation of skeletal muscle dysfunction pre-
transplant was most informative in understanding the daily functional and exercise limitations
experienced by lung transplant candidates. Future studies should examine whether targeted
rehabilitation strategies in the pre-transplant period may improve daily function and early post-
transplant outcomes.
6.2: Assessment of Skeletal Muscle Dysfunction in Lung Transplant Candidates
In the present doctoral work, we began with the framework of sarcopenia (decreased muscle
mass and low peripheral muscle strength or physical function defined using the consensus
definition).158 Sarcopenia defined using the consensus definition has been shown to be
associated with an increased risk of adverse outcomes such as physical disability, poor HRQL
and death in community dwelling elderly.158,476,477 However in patients with advanced lung
disease, individual skeletal muscle impairments such as low quadriceps strength,294 mid-thigh
cross-sectional area,226 and fat free mass264 have been observed to be associated with
increased morbidity and mortality. Similarly, in liver and renal transplant candidates low
skeletal muscle mass has been related to increased post-transplant mortality.236,349 Individual
measures of sarcopenia (muscle mass, strength and function) have generally been evaluated
112
in lung transplant candidates, but their clinical implications not previously assessed.21 Thus,
we placed equal emphasis on all three measures due to the lack of agreement as to which
elements of muscle dysfunction were most relevant in chronic disease and transplant
candidates.478 We focused on the associations between individual elements of muscle
dysfunction pre-transplant and clinically relevant outcomes such as exercise capacity,
physical function, HRQL and pre- and post-transplant clinical outcomes.8 The individual
measures of skeletal muscle dysfunction are discussed below.
Muscle Mass Assessments:
Skeletal muscle mass was assessed using two modalities in the present thesis. Whole body
fat free mass was evaluated using bio-electrical impedance (BIA), which is an accurate and
valid technique that has been utilized in advanced lung disease and lung transplant
candidates.479,480 Whole body muscle mass was estimated using muscle CSA from thoracic
computed tomography (CT) in Chapters 3 and 5. Although thoracic muscle CSA is not the
standard method of skeletal muscle mass assessment, we demonstrated for the first time that
thoracic muscle CSA had a strong association with fat free mass index (obtained using BIA) in
50 lung transplant candidates. Lung transplant candidates were also noted to have lower
thoracic muscle CSA by 10% compared to control subjects, which is consistent with the
difference in fat free mass observed with BIA,426 further supporting the construct validity of this
measure. Unlike recently applied muscle CSA techniques using abdominal CT
measures,239,240 we used thoracic CT scans as they are readily available in all lung transplant
candidates without any additional cost or radiation exposure. The anatomical landmark for
thoracic CSA was the carina, which was chosen given the ease of clinical identification, and
previous evidence from our group demonstrating that any representative CSA slice in the mid
thoracic levels was closely associated with thoracic muscle volume.429 Thus, as
recommended by the sarcopenia consensus guidelines for assessment of whole body muscle
113
mass,158 we estimated skeletal muscle mass using two validated measures in lung transplant
candidates.
In Chapter 4, whole body muscle mass was observed to be relatively preserved in the majority
of lung transplant candidates, whereas impairments in lower extremity strength and physical
performance were more common. A similar pattern was recently observed in over 500 stable
outpatients with moderate to severe COPD (not listed for transplant) who had a high
prevalence of quadriceps weakness (57%), but less than 10% of these patients had
concomitant low muscle mass with BIA before initiation of pulmonary rehabilitation.159 In
community dwelling older adults, the loss of lower extremity strength has been shown to occur
more rapidly than the accompanying loss of quadriceps muscle mass with aging.425 Several
factors have been proposed that can contribute to the differential loss of muscle function
relative to muscle mass including reduction in intrinsic force generating properties, muscle
quality (i.e. fat infiltration), and neuromuscular changes in voluntary control.481,482 Thus, as
observed in Chapter 4, functional deficits (reduced strength and physical performance, also
referred to as dynapenia)222 might be more informative with respect to physical disability in
advanced lung disease and may be more predictive of post-transplant outcomes compared to
whole body muscle mass measures.
It is important to highlight that the present thesis does not allow us to comment on site specific
muscle atrophy in lung transplant candidates. In previous work, our lab has previously
demonstrated moderate to strong associations between thoracic muscle CSA and both
quadriceps muscle thickness and rectus femoris CSA assessed with B-mode ultrasound.429 It
is possible that estimates of whole body muscle mass might underestimate regional changes
in limb muscle atrophy observed in lung transplant candidates,131 as lower extremity muscles
have been shown to have increased vulnerability for muscle atrophy compared to other
muscle groups.245 Measurement of localized muscle atrophy (i.e. quadriceps CSA) has
114
important functional consequences given the moderate-strong association between
quadriceps muscle size, strength and physical performance.172,257 Furthermore, regional
muscle measurements with non-invasive imaging modalities (computed tomography,
magnetic resonance imaging, or ultrasound) may also be used to evaluate muscle quality (i.e.
fat infiltration), which has been shown to be an important mediator of physical function and
disability, independent of muscle size.483 Thus, the consensus definition of sarcopenia
proposed in community dwelling elderly which presently integrates whole-body muscle
mass,158 might not be as applicable in chronic lung disease, given evidence for preferential
lower extremity muscle atrophy, weakness, and functional deficits compared to loss of whole
body muscle mass.
Muscle Strength Assessments:
Skeletal muscle strength was assessed using various methods in the three studies:
computerized dynamometer (Biodex; gold standard tool), hand-held and hand grip
dynamometers, and muscle training volumes obtained from exercise training logs, all of which
have been previously utilized at our center.110,125,131 Whereas computerized dynamometers
are considered the gold standard and the most common tool used in the research setting to
evaluate peripheral muscle strength, their utilization in the clinical setting has been limited due
to higher cost, accessibility, training and time required for testing.252 Hand-held
dynamometers offer a good alternative in the clinical setting for assessment of muscle
strength given their portability, low cost and ability to evaluate any peripheral muscle group.
However, hand-held dynamometers have their limitations, especially when testing larger
muscle groups such as knee extensors given their lower accuracy and reliability, as stronger
individuals can potentially break the opposing force of the tester.280,281 In the cohort of lung
transplant candidates described in Chapter 4, we observed that there was moderate
agreement between traditional measures of hand-grip strength and quadriceps strength
115
(isometric peak torque) from Biodex with biceps and quadriceps muscle training volumes
obtained from pulmonary rehabilitation, respectively. This is promising as upper and lower
extremity muscle training volumes are routinely used at our center for resistance training in
pulmonary rehabilitation and offer a potential surrogate measure of muscle strength that may
be utilized clinically, when standard strength testing is not feasible in a busy clinical setting.
However, there are a few limitations that arise when using training volumes to estimate
muscle strength given patients are not usually trained to their peak muscle capacity and the
resistance exercises are generally progressed by a specific incremental load.
The pattern of muscle weakness with predominance of lower extremity dysfunction
(quadriceps weakness and low score on the SPPB) compared to upper extremity weakness
(hand-grip strength), as observed in Chapter 4, is in keeping with general disuse and
deconditioning.166,170 Quadriceps weakness (greater than one standard deviation) was seen in
over half of the lung transplant candidates compared to low hand-grip strength seen in about
one-third of candidates. In Chapters 3 and 5, strength training volumes of the biceps were
generally about 30% greater than the quadriceps training volumes. This pattern has been
previously described in advanced lung disease patients given the relative preservation of
upper extremity strength with greater reliance on these muscles to carry out ADL (i.e. food
preparation and self-care), whereas tasks such as daily walking that rely on muscles of the
lower extremities are often reduced in the pre-transplant period.124,125,292 Even though
quadriceps strength was more commonly reduced and had a stronger association with HRQL
and ADL than hand grip strength, we are unable to comment on the contribution of the
proximal muscles of the shoulder girdle (i.e. trapezius, deltoids). More importantly, the
proximal upper extremity muscles have been observed to be weaker than the distal muscles
in COPD,286 which could have had a differential effect on HRQL and ADL. Also, future
assessment of upper extremity endurance, which has been shown to correlate with proximal
116
upper extremity exercise capacity, strength and performance of ADL,131,484 might provide
additional insight into the daily functional limitations experienced by lung transplant
candidates.
Assessment of Lower Extremity Function
In Chapter 4, we observed significant impairments in the total score of the SPPB in lung
transplant candidates within 4 weeks of transplant listing. We used a cut-off score of less than
10 points (out of 12) which has previously been shown to be associated with muscle atrophy
and lower extremity dysfunction in COPD.485 We observed that 48% of lung transplant
candidates had low scores on the SPPB, which was consistent with the proportion observed in
another study from our center examining skeletal muscle dysfunction in twenty-six transplant
candidates with ILD.131 The impairments in SPPB were predominantly in gait speed and the
sit-to-stand test with only a few patients demonstrating impairments in balance (tandem
stance). Singer et al. in a large cohort of lung transplant candidates (n=262) observed a
similar pattern in SPPB scores, with balance instability observed in only 8% of participants.318
In addition to preservation of balance, we observed a low percentage of self-reported falls
(12%) in the previous year in our lung transplant cohort. This contrasts with findings in COPD
where 46% of patients had a self-reported fall in the preceding year and standard balance
screening tests could discriminate fallers from non-fallers.312 There are several possibilities
for the decreased prevalence of falls observed in our lung transplant cohort. First, the low
prevalence of balance instability and falls observed could be due to the highly-selected nature
of lung transplant candidates, as compared to the larger population of patients with advanced
lung disease. Second, the prevalence of self-reported falls may have been lower in our cohort
of lung transplant candidates in Chapter 4, given the high proportion of ILD participants.
Individuals with ILD may have fewer balance deficits than people with COPD given differences
in co-morbidities and corticosteroid use, which are known to affect balance.486 However,
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further verification of falls risk in non-COPD patients is needed given the high morbidity
associated with falling in community dwelling elderly.487,488
Pre-transplant Exercise Capacity: Six-minute Walk Test
The 6MWD is one of the most important known predictors of pre- and post-transplant mortality
and is commonly utilized as a measure of exercise capacity in lung transplantation.22,23,104
However, the 6MWT is unable to isolate the contribution of peripheral limitations (i.e. muscle)
to exercise from central limitations (ventilatory or cardiovascular).104 In Chapter 4, we
observed low to moderate correlations between 6MWD and quadriceps strength or SPPB,
respectively. The lower associations in our cohort could be related to disease severity,
highlighting the greater contribution of ventilatory limitations to exercise capacity in lung
transplant candidates compared to non-listed COPD and ILD patients. In our cohort, the
FEV1 for obstructive lung disease was 21 ± 7 % and the FVC for restrictive lung disease was
46 ± 16 %. Gosselink et al. in their cohort of non-transplant COPD patients (FEV1 43 ± 19 %)
observed a moderate association (r=0.63) between quadriceps force and 6MWD.489
Similarly, Nishiyama et al. noted that quadriceps force was associated with aerobic capacity
(r=0.62) in a group of mild IPF patients with a FVC (77 ± 17 %).20 Our findings are in line with
Singer et al. who observed a moderate association between SPPB and 6MWD (r=-0.54),
where as no significant association was observed by Van der Woude et al. between
quadriceps strength and 6MWD (r-value not reported) in their cohort of lung transplant
candidates.291,318 Thus, it is important to recognize that the contribution of lower extremity
muscle strength to exercise capacity will vary depending on disease severity and population
studied. Furthermore, physical performance tests that integrate balance and lower extremity
strength are potentially more informative than exercise capacity in highlighting the daily
functional limitations experienced by community dwelling elderly 490 and those with advanced
lung disease.303 Future investigations are needed to understand the contribution of lower
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extremity endurance (i.e. leg fatigue) to daily function, as endurance has been described to be
an important factor limiting functional capacity, especially in the presence of hypoxemia.197
Assessment of Patient Reported Outcomes Pre-Transplant:
We used standard, validated measures of HRQL evaluation (Short Form-36 and St. George’s
Respiratory Questionnaire) and ADL (London Chest Questionnaire) in lung transplant
candidates.26,95 The degree of impairment in HRQL measures was consistent with other
studies from our center that had assessed HRQL in stable outpatients.109 We observed that
functional deficits (strength and physical performance) had moderate associations with HRQL
and ADL (Chapter 4), where as no independent association was observed with muscle mass
(Chapters 3 and 4). This is in keeping with the literature as the degree of disability
experienced by those living with advanced lung disease is not captured well with static
measures such as lung function, and functional measures (strength and performance) are
potentially more informative in understanding limitations in daily function.90,91
We suspect the lack of association between skeletal muscle mass and HRQL in the present
thesis could be related to the fact that we utilized a measure of whole body muscle mass in
both studies. The association between muscle mass and HRQL would likely have been
stronger if lower extremity muscle size was assessed, as quadriceps size provides a better
reflection of physical activity levels.172 Physical activity has been shown to be a strong
determinant of HRQL in lung transplant candidates.109,124 The lack of association between
skeletal muscle mass and HRQL could also be due to the fact that HRQL measurements were
obtained from stable outpatients participating in pulmonary rehabilitation. Mostert et al.
observed that the loss of fat free mass in COPD patients had a stronger relationship with the
St. George’s Respiratory questionnaire and functional measures than muscle mass evaluated
at a single time point. Loss of fat-free mass is more likely to be seen in patients requiring
hospitalization or those unable to participate in pulmonary rehabilitation.445 Thus, it is possible
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the relationship in Chapter 3 between skeletal muscle mass and HRQL could have been
stronger in those unable to complete HRQL assessments, as those without these
assessments were observed to have lower exercise capacity and were more likely to be
delisted or die pre-transplant.
Whereas we observed a moderate association with functional muscle deficits and pre-
transplant HRQL and ADL in Chapter 4, no association was seen in Chapters 4 and 5
between skeletal muscle dysfunction and Lung Allocation score (LAS). It is important to
highlight that the LAS was designed to optimize survival over the first-year post-transplant, but
does not factor elements such as skeletal muscle dysfunction, HRQL, ADL and post-
transplant function.32 The significant differences in HRQL and ADL across skeletal muscle
deficits (Chapter 4) suggests that skeletal muscle dysfunction provides greater insight into
pre-transplant HRQL and disability, which are not captured with the LAS.61,62 A better
understanding of the physical factors that influence daily function could help inform the optimal
timing of transplant listing as many candidates pursue transplantation to derive benefit in
HRQL and ADL, not just survival.
6.3: Determinants of Skeletal Muscle Dysfunction in Lung Transplant Candidates
There are multiple factors which can contribute to skeletal muscle dysfunction in people with
advanced lung disease such as hypoxemia, malnutrition, physical inactivity/disuse,
corticosteroids, and systemic inflammation.12,14 The lung transplant candidates in all three
studies had multiple factors which could have contributed to skeletal muscle dysfunction as
outlined in the conceptual framework in Figure 6-1. Most study participants (> 90%) were
using long-term oxygen therapy for exertion and about one third were taking daily oral
corticosteroids. In addition, unintentional weight loss ≥ 10 pounds in the year prior was
observed in about one quarter of our study participants in Chapter 4, which could be related to
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imbalance of protein synthesis and degradation pathways as previously described in
cardiopulmonary disease.491 We can infer from Chapters 4 and 5 that one contributing factor
for skeletal muscle dysfunction was muscle disuse, given a higher proportion of transplant
candidates with preferential weakness of the lower extremity muscles relative to the upper
extremities. In addition, a large proportion of patients in Chapter 4 had low self-reported
physical activity levels, as previously described in lung transplant candidates.131
Unfortunately, given the cross-sectional nature of the thesis studies we are unable to
comment on the direct contribution of each of these factors, but several key associations are
highlighted below.
Figure 6-1: Conceptual Framework of Factors Affecting Skeletal Muscle Mass, Strength and
Function. Legend: Studies assessing risk factors outlined in brackets. Study 1 = Chapter 3,
Study 2 = Chapter 4, and Study 3 = Chapter 5.
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Malnutrition/Weight Loss:
In Chapter 4, we noted that COPD patients were more likely to have unintentional weight loss
in the year preceding transplant listing compared to ILD patients, and the weight loss was
associated with reduced skeletal muscle mass assessed with BIA. In chapter 3, lung
transplant candidates with COPD were also observed to have lower skeletal muscle mass
compared to ILD patients based on thoracic muscle CSA, independent of age and sex. It is
possible that disease duration could have had an influence on muscle mass, as ILD patients
are generally referred for lung transplantation earlier in their disease course, which could
mitigate some of the muscle mass loss with respiratory exacerbations, disease progression
and corticosteroid therapy.492 The lower skeletal muscle mass observed in COPD patients is
an important consideration as it is a marker of increased catabolic state and reduced protein
reserve, which is essential during periods of major surgery such as transplantation and critical
illness.438 In addition, weight loss has been shown to affect diaphragm bulk which could have
significant effects on respiratory muscle function in the post-transplant period.493
Hypoxemia:
Most study participants (> 90%) required long-term oxygen therapy for exertion at the time of
transplant listing. There was a progressive increase in oxygen requirements while on the lung
transplant list as observed in Chapter 5 and consistent with previous work from our center.110
Even though we are unable to comment on the direct effect of hypoxemia on skeletal muscle
dysfunction, chronic hypoxia is known to have a significant effect on skeletal muscle mass in
humans.494 Chronic respiratory disease patients with low arterial oxygen levels have been
shown to have significantly reduced body weight and muscle mass.187,495,496 This muscle
atrophy is thought to be mediated through hypoxemia induced oxidative stress and
inflammation.197,497 In addition, chronic hypoxemia can result in decreased muscle strength
and endurance, with a shift towards type II (fast-twitch fibers).196
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Corticosteroids:
We did not observe an association between elements of skeletal muscle dysfunction and
corticosteroid use in any of the three studies assessing thoracic muscle CSA or
peripheral muscles. This contrasts with previous reports in COPD and ILD that have
described steroid myopathy as a significant contributor to hand-grip strength and
quadriceps weakness.208,498,499 However, there are several important differences that
should be highlighted. First, the cross-sectional nature of the studies did not allow us to
capture the cumulative dose of corticosteroids in the preceding six months, which was
the main determinant assessed in previous studies.498,499 Secondly, the pattern of
steroid use in lung transplant candidates may be different from non-listed patients given
that prescribers might be more conscientious of the metabolic consequences such as
weight gain, osteoporosis and diabetes in transplant candidates.500,501 Thirdly, the
pattern of steroid use in Chapter 4 assessing peripheral muscles may have been
different in this recent ILD predominant cohort given the known harmful effects of chronic
prednisone therapy in IPF patients.502 Finally, we had assessed the impact of
corticosteroids on thoracic muscle CSA in two out of the three studies, which potentially
would be less affected than the peripheral muscles.503
One important question that remains unanswered in advanced lung disease is to what
extent skeletal muscle dysfunction is a result of years of muscle disuse and physical
inactivity versus an underlying myopathy from multiple factors such as hypoxemia,
corticosteroids, malnutrition and inflammation. To try to differentiate disuse versus
myopathy, it will be important to match patients with chronic lung disease and controls
with a similar level of physical activity followed longitudinally for several years. This is an
ongoing challenge in many other chronic disease states as well, including congestive
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heart failure and diabetes, given the significant overlap in musculoskeletal risk
factors.504,505
6.4: Association of Skeletal Muscle Dysfunction with Post-transplant Outcomes
Given the established impairments in skeletal muscle function in the pre-transplant period,21
the prognostic utility of pre-transplant muscle mass, strength and function in predicting
clinically important post-transplant outcomes was evaluated in this thesis.
Hospital Length of Stay:
Pre-transplant thoracic muscle CSA and total number of skeletal muscle deficits were
associated with post-transplant hospital length of stay in Chapters 3 and 4, where as no
association with pre-transplant muscle mass and function was observed in Chapter 5 in a
group of lung transplant patients with a prolonged course of MV (≥ 7 days). The findings in
Chapters 3 and 4 are consistent with previous studies that have demonstrated that better
physical function and conditioning prior to surgery hastens hospital recovery.332,506,507 We
have also previously shown that pulmonary rehabilitation pre-transplant generally preserves
exercise capacity (6MWD), and a greater 6MWD pre-transplant was associated with reduced
post-transplant hospital length of stay.110 This faster recovery potentially allows for early
participation in supervised rehabilitation post-transplant and reduces the negative
consequences of bed-rest that could result in significant deconditioning.508,509 To our
knowledge, Chapter 5 is the first study to demonstrate that any pre-transplant conditioning
achieved with rehabilitation was significantly mitigated by 7 or more days of MV. However, it
is important to highlight in this study a high proportion (26%) of lung transplant candidates
were admitted to hospital or ICU pre-transplant, which could have certainly limited some of the
musculoskeletal gains which occurred with pre-transplant pulmonary rehabilitation. In fact,
this group of patients showed less increase in their muscle training volumes and had a
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significant decrease in their exercise capacity pre-transplant compared to patients with
standard peri-operative courses at our center.110
Discharge Disposition:
Lung transplant recipients with a prolonged hospital length of stay had high rates of discharge
to inpatient rehabilitation compared to discharge home. In fact, discharge to inpatient
rehabilitation was independently associated with total peri-operative ICU length of stay in
Chapter 5, which may help with earlier discharge planning. A long stay in the critical care unit
and hospital can result in decreased functional capacity, mobility, and skeletal muscle
dysfunction, which in turn can lead to prolonged hospitalization and increased rehabilitation
requirements.510 In a previous study from our center by Tang M et al, total hospital length of
stay was found to be an independent predictor of discharge disposition.113 This is consistent
with the findings in the present thesis illustrating lung transplant recipients with a prolonged
hospitalization (median stay of 58 days) had higher rates of discharge to inpatient
rehabilitation (43%), than the discharge rates observed in Chapters 3 and 4 (11-17%) with
typical post-transplant hospital stays (median range; 20-23 days). The standard practice at
our center is for lung transplant recipients to participate in outpatient rehabilitation for at least
3-months post-transplant; however, recipients that are unable to meet functional requirements
for safe discharge home are referred to an inpatient rehabilitation program. The decision to
discharge patients to inpatient rehabilitation is complex and could potentially be initiated early
in the post-transplant period. There are multiple factors that need to be considered in the
post-transplant period that could necessitate discharge to inpatient rehabilitation such as
medical requirements (i.e. dialysis), ability to exercise, motivation, social circumstances, and
transplant team perception.374 In addition, early discharge to inpatient rehabilitation is a
promising cost-saving strategy as it optimizes functional recovery and reduces the number of
days that lung transplant recipients occupy acute care hospital beds.320 Inpatient rehabilitation
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focuses on increasing functional independence through low intensity resistance, balance and
aerobic training that is more individualized and progressed more gradually than the outpatient
program, which is a feasible option for patients with low baseline function at the time of
hospital discharge.374
Functional Independence Post-transplant:
The Functional Independence Measure (FIM) applied in the early post-transplant period
provides a multi-dimensional patient centered approach to evaluating the level of assistance
required for performance of ADL.321 The FIM has been previously applied across several
medical and surgical disease states, including cardio-pulmonary transplantation.319,421 Lung
transplant recipients with a prolonged course of MV (Chapter 5) were observed to have
severe limitations in the motor FIM at 7-days post ICU discharge, representing maximal to
total assistance. The greatest limitations were with toileting, transfers, dressing and
locomotion. Importantly, 40% of lung transplant recipients were unable to walk at 7 days post-
ICU discharge and therefore unable to perform the 6MWT. This highlights the utility of the
FIM measure over the 6MWT in the early post-transplant period. By three months post-ICU
discharge, lung transplant recipients demonstrated significant functional gains demonstrating
moderate independence with the FIM. The recovery in physical function observed in lung
transplant recipients at 7 days and 3 months post-ICU discharge was comparable to the main
multi-center RECOVER cohort with mixed diagnoses.319 In chapter 5, age and ICU length of
stay were consistently shown to be the two most important determinants of functional
recovery, independent of pre-transplant skeletal muscle mass, strength training volumes, and
exercise capacity. Furthermore, these results in lung transplant recipients are consistent with
previous findings demonstrating that functional recovery post-ICU is independent of admitting
disease severity, medical or surgical intervention.319
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Improvement in Functional Capacity Post-Transplant:
Exercise capacity at three-months post-transplant improved by 96 meters in Chapter 4 and by
104 m in Chapter 5. This is comparable to other observational studies demonstrating
increases in 6MWD ranging from 92 to 152 meters, primarily due to alleviation of ventilatory
limitations with transplantation.116,122,420 The variability in recovery in 6MWD with
transplantation could possibly be attributed to multiple factors such as ICU and hospital length
of stay, demographics (age and diagnosis), and differences in rehabilitation practices across
studies. Despite a prolonged ICU course, the patient cohort studied in Chapter 5 showed an
improvement in exercise capacity at 3 months post-ICU that was comparable to cohorts with a
more typical course post-transplant as observed in the literature and Chapter 4.116,122,420 This
indicates there is rehabilitation potential with respect to functional capacity in lung transplant
recipients experiencing a complex post-operative course.
In Chapter 5, lung transplant recipients with lower pre-transplant exercise capacity
demonstrated a greater potential for improvement in their exercise capacity post-transplant
despite a complicated hospital course. A similar relationship was observed by Walsh et al.
where post-transplant exercise capacity was inversely associated with pre-transplant 6MWD
and quadriceps muscle strength recovery was a stronger determinant of exercise capacity
than graft function up to 26 weeks post-transplant.122 Similarly, Wickerson et al. noted that
lower pre-transplant 6MWD was associated with a greater improvement in daily physical
activity levels three-months post-transplant independent of lung function.109 These studies
demonstrate that lung transplant recipients with lower pre-transplant exercise capacity have a
greater potential to improve their post-transplant functional capacity as a result of significant
alleviation of ventilatory limitation with transplantation, but limitations in exercise capacity
persist mainly due to musculoskeletal impairments.122 In Chapter 5, exercise capacity at 3
months post-ICU was reduced at 63% predicted with approximately one-third of lung
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transplant recipients (10/33) having generalized muscle weakness based on the Medical
Research Council scale.465 It is important to highlight that recovery in exercise capacity post-
transplant is complex and multiple other factors need to be considered such as muscle
endurance, oxidative capacity, and the use of walking aids, which could have a significant
contribution on walk distance.511,512
Health-Related Quality of Life after Lung Transplantation:
Self-perceived physical function in the post-transplant period was captured with the SF-36
Physical Component Score (PCS). We observed that the post-transplant SF-36 PCS (35 ±
10) at three months post-ICU discharge remained below population normative values (score
of 50), but was comparable to the HRQL observed in other studies of lung transplant
recipients and other critically ill patients (RECOVER).109,117,319 In fact, age and ICU length of
stay were the only significant determinants of post-transplant HRQL, independent of pre-
transplant skeletal muscle mass, strength training volumes or exercise capacity. As in the
larger RECOVER cohort, the SF-36 PCS had a moderate to strong association with the motor
FIM at three-months post ICU discharge,319 highlighting the importance of post-transplant
function on HRQL physical domains after transplant. Wickerson et al. in an observational
cohort study at our centre observed that increased physical activity levels paralleled the
improvement in HRQL up to 6 months post-transplant.109 In addition to increasing functional
independence and physical activity levels, the improvement in HRQL in the early post-
transplant period is multi-factorial with other contributing factors including alleviation of
ventilatory limitations, liberation from oxygen therapy, improvement in post-operative pain and
potentially rehabilitation.109,117
It is difficult to separate the effect of rehabilitation from the natural recovery of HRQL in lung
transplant recipients, as all lung transplant patients at our center undergo post-transplant
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rehabilitation. However, Langer et al in a randomized control trial demonstrated no difference
in any of the SF-36 domains after 3 months of outpatient rehabilitation compared to the control
group (encouraged to be physically active) after hospital discharge.117 It is possible that the
lack of a difference in HRQL observed in their study could be related to the significant
immediate improvement in HRQL with transplantation. The effect of post-transplant
rehabilitation on HRQL might be more pronounced in lung transplant recipients with a complex
hospital course; however, a randomized clinical trial to assess this would not be ethical given
the known positive benefits of rehabilitation in this group of patients.
Post-transplant Mortality:
In this thesis, the association of skeletal muscle dysfunction with standard peri-operative and
early post-transplant outcomes, including mortality was evaluated. We chose to investigate
early post-transplant outcomes given previous studies demonstrating that long-term outcomes
were significantly influenced by early post-operative events in lung transplant
recipients.51,457,460 Similarly, in the general medical and surgical ICU setting, functional
independence at 7 days post-ICU discharge was prognostic of one year mortality.319
We hypothesized that low skeletal muscle mass would be associated with increased morbidity
and mortality post-transplant given that skeletal muscle mass is an important marker of
physiologic and protein reserve, which is essential during periods of critical illness and major
surgery such as transplantation.438 However, we observed no association between pre-
transplant skeletal muscle mass and peri-operative hospital and one-year mortality (Chapter
3). Similarly, no association was observed between skeletal muscle deficits and early post-
transplant mortality (3 months) in Chapters 4 and 5, but it is important to highlight that we
were not statistically powered for this analysis in the latter two studies. To our knowledge,
there have been a total of three studies recently published in lung transplant candidates that
examined the association between skeletal muscle mass and post-transplant mortality. Kelm
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et al. demonstrated that low pre-transplant abdominal muscle CSA was associated with one
and three-year survival in a select group of lung transplant candidates (n=36) mainly with
COPD.239 This is in contrast with the findings in Chapter 3 and those of Weig et al. who found
no association between low skeletal muscle mass and post-transplant mortality in hospital and
at one year.240 Interestingly, Lee et al. utilizing a similar technique as our group for quantifying
thoracic muscle CSA at the carina observed that lung transplant candidates in the largest
muscle CSA quartile had the lowest one year survival, however, their analysis was not
adjusted for older age or higher proportion of ILD patients which could have biased their
results.244 Thus, the differences between the studies could be related to measurement
techniques, thresholds used to define sarcopenia, rehabilitation practices, and transplant
indication, as ILD patients are known to have the worst post-transplant survival compared to
other diagnostic groups.423 It is also possible that measurement of whole body muscle mass
might not be an ideal prognostic marker of mortality in this group of patients given that
selection of lung transplant candidates is dependent on their body weight and nutritional
status. Thus, evaluation of muscle atrophy of the lower extremities might prove to be more
prognostic in future investigations given increased vulnerability for regional, lower limb muscle
atrophy compared to whole body muscle mass measurements in chronic lung disease.245,513
The peri-operative hospital mortality rate was similar across all three studies in this thesis
ranging from 10-16%, with the greatest mortality observed in lung transplant recipients with
prolonged mechanical ventilation (Chapter 5). Given that primary graft dysfunction (PGD) is
one of the most common causes of peri-operative mortality in lung transplant recipients and
associated with body composition,376,514 we evaluated the association of PGD with skeletal
muscle mass. In Chapters 3 and 5, we did not observe an association between skeletal
muscle mass and development of PGD. This is interesting as increased pre-transplant BMI
has been described as an important determinant of PGD, which lends further support that
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perhaps increased adipose tissue is a stronger contributor to development of PGD than
muscle mass in lung transplant recipients, and could be mediated through higher plasma
leptin levels.460 Furthermore, a similar relationship between adiposity and delayed graft
function and graft survival has been observed in renal transplant recipients.515,516 Whereas we
did not assess tissue adiposity in the present work, future studies exploring the mechanisms
underlying changes in skeletal muscle mass and adipose tissue could help advance our
understanding of the risks associated with obesity and PGD in lung transplant recipients.
6.5: Clinical Implications of Skeletal Muscle Function Assessment
The present thesis examined several measures of skeletal muscle dysfunction (muscle mass,
strength and function) individually and in combination. We observed that whole body muscle
mass assessed with thoracic muscle CSA was independently associated with post-transplant
hospital length of stay, but not with pre-transplant HRQL. Similarly, the total number of
skeletal muscle deficits pre-transplant (muscle mass, strength or low physical performance)
was associated with post-transplant hospital length of stay, but functional deficits (strength
and performance) were more informative of patient reported outcomes and exercise capacity
pre-transplant. It is important to highlight that the skeletal muscle measures in the present
thesis did not predict functional recovery or mortality post-transplant.
The utility of these non-invasive muscle measures is gaining recognition in lung
transplantation, as they have recently been shown to be good prognostic markers of pre- and
post-transplant morbidity and mortality in several studies, although outcomes have been
variable across studies and measurement modalities.239,240,318 It is possible the variability
observed with transplant outcomes could be related to the phenotypic heterogeneity of
skeletal muscle dysfunction in lung transplant candidates and recipients.21 Skeletal muscle
dysfunction might prove to be more informative in transplant recipients with typical peri-
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operative ICU courses than those with complex and prolonged ICU stays who may have a
high degree of ICUAW and functional disability, not necessarily predicted by pre-transplant
skeletal muscle dysfunction as observed in Chapter 5.
As evidence in the field emerges, standardization of muscle measurement techniques and
establishment of valid cut-offs for low muscle mass and function could potentially assist with
transplant candidacy evaluation and prognostication. It is possible that lung transplant
candidates who have lower muscle mass, strength and physical function could benefit from
lung transplant prioritization as individual elements of skeletal muscle dysfunction have been
shown to be amenable to rehabilitation.159 Interestingly, lung transplant recipients in Chapter
5 who had skeletal muscle impairments pre-transplant demonstrated functional improvements
post-transplant even in the setting of a complex peri-operative course demonstrating
rehabilitation potential. A better understanding of risk factors (i.e. malnutrition, physical
inactivity, corticosteroids) and heterogeneity in skeletal muscle dysfunction (muscle mass,
strength and function) could help guide rehabilitation strategies and inform the degree of
reversibility in the pre- and post-transplant periods.
6.6 Limitations
Several limitations should be considered when interpreting the findings of this thesis. First,
the studies in the present work did not capture individuals who were assessed for lung
transplantation and deemed unsuitable for transplant listing. Patients with advanced lung
disease declined for transplant listing could have been sicker and have a greater prevalence
of skeletal muscle dysfunction than those who were listed. Thus, this could have
underestimated the effect of skeletal muscle dysfunction on HRQL and functional outcomes in
patients with advanced lung disease. Secondly, the cross-sectional study design of two of the
studies limits our ability to comment on the influence of risk factors or the natural progression
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of skeletal muscle dysfunction in patients with advanced lung disease. Whereas we
considered common factors affecting muscle such as age, sex, diagnosis, body stature, and
corticosteroid use, skeletal muscle function could be influenced by other determinants pre-
and post-transplant such as respiratory exacerbations, comorbidities, nutritional status and
physical activity levels which were not assessed across all studies.12,517 Thirdly, there were
some limitations with our muscle mass and strength measures that need to be highlighted.
We evaluated whole body muscle mass using BIA or estimated muscle mass using thoracic
muscle CSA and thus are unable to comment on regional atrophy (such as that of the lower
limb muscles) or muscle composition, which could certainly have had a differential effect on
HRQL and ADL measures. Furthermore, we used non-invasive, volitional measures of
skeletal muscle function (muscle strength and physical performance) in the present thesis.
Volitional measures are influenced by factors such as neuromuscular factors (e.g. central
activation), motivation and cooperation, which may underestimate the actual contractile
capacity of the muscle despite standardization of strength measurement techniques.
Furthermore, volitional measures do not allow for isolation of the central (i.e. motor cortex,
nerve conduction) from peripheral factors (i.e. neuro-muscular junction and muscle fibers)
associated with muscle force contraction. It is also important to highlight that muscle strength
was the predominant functional deficit assessed as we did not capture muscle endurance or
lower extremity muscle power, which have been shown to be stronger prognostic markers of
mobility and disability in older adults compared to muscle strength.518-520
Another important limitation is that the patient cohorts studied in all three studies were drawn
from a single, large tertiary center. The Toronto Lung Transplant program requires all lung
transplant candidates to participate in a standard pulmonary rehabilitation program while
awaiting lung transplantation. Certainly, the clinical implications of pre-transplant skeletal
muscle dysfunction could be very different at other transplant centers without a mandatory
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pulmonary rehabilitation program or in centers with smaller transplant volumes.521 The
present thesis also did not assess certain environmental and patient factors that could have
had an influence on hospital length of stay and discharge disposition, such as caregiver
support. Even though all lung transplant candidates in our program are required to have a
pre-arranged support person with appropriate living arrangements, factors such as availability
of inpatient rehabilitation beds, relocation distance, caregiver support, and neuropsychological
sequelae post-transplant could have had an influential effect on discharge disposition.
Furthermore, all ICU and hospital ward patients post-transplant participate in a mobility
program and perform light exercises as prescribed and supervised by a physiotherapist.
However, the recovery during the peri-operative period and discharge disposition could be
affected by participation in hospital rehabilitation. Thus, future prospective studies should aim
to record these environmental and patient factors to assess their influence on discharge
disposition.
6.7: Conclusion:
This thesis provides new evidence highlighting the clinical implications of skeletal muscle
dysfunction in lung transplant patients. Skeletal muscle dysfunction in lung transplant
candidates was associated with HRQL, ADL, and exercise capacity and associated with post-
transplant hospital length of stay. In a select group of lung transplant recipients who required
≥ 7 days of MV, age and ICU duration were the only significant determinants of post-
transplant functional outcomes and this highlights the importance of ICU acquired morbidity in
these patients. Given the changing demographics with lung transplant candidates being older
and presenting with greater complexity, the findings of this thesis may help facilitate
discussion and informed consent among patients, families, and the health-care team about
potential outcomes peri-operatively. Future work will need to help clarify whether targeted
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rehabilitation strategies in the pre-transplant period may improve daily function and early post-
transplant outcomes.
6.8 Future Directions:
There are several areas of future investigation that arise from this work on skeletal muscle
dysfunction in lung transplant candidates. Future studies will need to focus on non-listed
chronic lung disease patients both in the inpatient and outpatient settings, across various
disease states, given the phenotypic heterogeneity in skeletal muscle dysfunction observed in
the present thesis. The ability to capture patients earlier in their disease course even prior to
transplant listing and ability to monitor the change in skeletal muscle mass, strength and
function across various disease states could provide a better understanding of certain skeletal
muscle determinants (i.e. corticosteroids, hypoxemia, malnutrition). To-date, it remains
unclear whether changes in skeletal muscle mass and function (strength and physical
performance) occur rapidly with exacerbations, if the decline is step-wise over time or if
individuals with chronic respiratory disease actually have an accelerated decline in lower
extremity muscle strength above the 1-2% per year experienced by the aging population.522,523
Thus, future studies should aim to study a number of chronic lung disease cohorts over longer
periods of follow-up, which could help understand the change in skeletal muscle structure and
function over time with respiratory exacerbations and between disease states.
Future investigations should aim to characterize muscle specific atrophy and composition, as
whole-body measures could underestimate the presence of muscle atrophy, particularly of the
lower extremity muscles. One promising modality is B-mode ultrasound,131 which offers a
portable, reliable, low-cost imaging modality that can be utilized across a variety of clinical
settings including hospitalized and critically ill patients.256 In addition to skeletal muscle
atrophy, it is possible to assess muscle quality (i.e. fibrous or muscle fat infiltration) with
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ultrasound using echo intensity.524,525 Future studies could focus on whether low muscle
quality is more predictive of clinical outcomes than muscle atrophy or weakness in advanced
lung disease and lung transplant candidates.
In the present thesis, we observed relative preservation of respiratory muscle strength in the
majority of lung transplant candidates using traditional, volitional measures (i.e. maximal
inspiratory and expiratory pressures). We suspect that non-volitional measures of diaphragm
function might be a more sensitive marker of respiratory muscle dysfunction in advanced lung
disease. Future study could utilize non-volitional measures such as B-mode ultrasound to
assess diaphragm thickness and inspiratory capacity from measures of diaphragm thickening
in patients admitted with an exacerbation.526 The hypothesis is that high inspiratory effort
during an exacerbation can result in diaphragm injury and dysfunction. To-date, the
association of diaphragm dysfunction with HRQL, exercise capacity, duration of
hospitalization, rates of respiratory failure and mortality have not been previously described in
advanced lung disease or transplant patients, and could prove to be an important prognostic
marker. Also, evaluation of inspiratory muscle training in lung transplant candidates with
respiratory muscle dysfunction may prove to be beneficial, especially in those experiencing a
complex peri-operative ICU course.
Given the increasing prevalence of obesity in pulmonary disease,527 characterization of body
composition beyond traditional anthropometric measures such as BMI will be important, as
BMI is a poor surrogate marker for skeletal muscle mass and adiposity. Patients with
sarcopenia (low muscle mass) and obesity can present a phenotype that is associated with
greater inflammation and increased physical disability.528 Body composition assessment can
help with prognostication in COPD and ILD.529,530 Similarly, increased levels of adiposity in
lung transplant recipients have been linked with higher rates of PGD and mortality.460
Presently, body composition is evaluated clinically using D-XA or BIA, which allow systemic
136
and segmental characterization of fat free mass and tissue adiposity but is not always
practical in the clinical setting.531 One promising modality that can be applied in future studies
is the use of thoracic CT, which in addition to estimates of skeletal muscle mass can allow for
characterization of adiposity levels.228,532 The application of thoracic CT for body composition
assessment is promising given its readily availability in patients with advanced lung disease,
but CT requires further validation in representative cohorts.
From the present thesis, low skeletal muscle mass was observed to be associated with
unintentional weight loss in the preceding year. Adequate nutritional support is required in
chronic respiratory disease for preservation of body weight, muscle mass, respiratory and limb
muscle strength.533 Unfortunately, most of the literature on nutritional supplementation comes
from COPD where supplementation is effective when combined with exercise training in
patients with low body weight.534,535 However, the effects of nutritional supplementation on
patients with ILD remains unclear. Also, the benefits of dietary modification on skeletal
muscle function in patients with normal weight or those with sarcopenic obesity have not been
well established, and is an important area of future investigation given the increasing
prevalence of obesity in advanced lung disease. Future studies should explore the application
of novel modalities such as phase angle with bioelectrical impedance263 and automated, self-
administered 24-hour dietary recalls,536,537 which can provide additional insight into nutritional
status pre- and post-transplant in a variety of clinical settings.
Recently, the construct of frailty which encompasses an individual’s ability to deal with
physiological stressors has been shown to be predictive of pre-transplant delisting/mortality318
and post-transplant survival.343 Frailty allows for a holistic assessment of the individual taking
into account psycho-social, cognitive and physical factors,538 which have been shown to be
intertwined and may be protective against functional impairments post-transplant.394 It is
possible that the prognostic utility of frailty measures might be improved with incorporation of
137
musculoskeletal measures, which have been demonstrated to be amenable to rehabilitation
and may prove to be objective measures of functional gain.159 If frailty and skeletal muscle
measures are going to be routinely applied in the clinical setting for transplant candidacy
evaluation, factors such as time, feasibility, and costs associated with these functional
measures will need to be evaluated in future studies.
The extent that muscle mass, strength and function are modifiable with exercise training in the
pre- and post-transplant period is an important area of future investigation. Skeletal muscle
dysfunction is known to be present in the pre-transplant period with limitations persisting post-
transplant.21 In fact, quadriceps strength has been observed to be lower than pre-transplant
values in the early post-transplant period even after exercise training suggesting that lower
extremity weakness and function is not solely related to acute muscle deconditioning from
hospitalization.116 However, factors in the post-transplant period hindering recovery of skeletal
muscle function have not been well described. The role of chronic corticosteroids and
calcineurin inhibitors on skeletal muscle mass, composition (i.e. fat infiltration)539 and oxidative
capacity540 may help inform some of the underlying mechanisms of skeletal muscle
dysfunction post-transplant. Fat infiltration and oxidative capacity can be evaluated using
non-invasive imaging modalities (ultrasound, CT, or MRI)255,539,541 and near-infrared
spectroscopy,542 respectively. It is possible that a subset of lung transplant recipients who
sustain periods of critical illness with hospitalizations along their journey to transplantation
could have difficulty with muscle anabolism and not necessarily proteolysis, as shown in non-
transplant critical care survivors.219 This could account for some of the phenotypic
heterogeneity observed in skeletal muscle function pre- and post-transplant,21 but future
studies utilizing molecular analysis of atrophy and hypertrophy pathways may be informative.
The findings in the present thesis were limited to the pre-transplant period and early post-
transplant period within the first three-months post-transplant. Future investigations should
138
aim to further understand the implications of declining pre-transplant functional capacity and
peri-operative ICU support on skeletal muscle function beyond the early post-transplant
period. Given the ongoing exposure to immunosuppression, infection and chronic rejection,
progressive skeletal muscle impairments may play a significant role in the post-transplant
period and can have a significant effect on ADL, HRQL, functional capacity, and metabolic
consequences such as diabetes and hypertension.117,543,544 Future studies should assess
whether educational strategies targeting an active, healthy lifestyle pertaining to nutrition and
physical activity will allow lung transplant recipients to derive a greater and sustained HRQL
and functional benefit with transplantation.
139
REFERENCES: 1 Ferkol T, Schraufnagel D. The global burden of respiratory disease. Ann Am Thorac Soc
2014; 11:404-406
2 Chapman KR, Mannino DM, Soriano JB, et al. Epidemiology and costs of chronic obstructive
pulmonary disease. Eur Respir J 2006; 27:188-207
3 Valapour M, Skeans MA, Heubner BM, et al. OPTN/SRTR 2012 Annual Data Report: lung.
Am J Transplant 2014; 14 Suppl 1:139-165
4 Gibson GJ, Loddenkemper R, Lundback B, et al. Respiratory health and disease in Europe:
the new European Lung White Book. Eur Respir J 2013; 42:559-563
5 Papathanasiou A, Nakos G. Why there is a need to discuss pulmonary hypertension other
than pulmonary arterial hypertension? World J Crit Care Med 2015; 4:274-277
6 Spoonhower KA, Davis PB. Epidemiology of Cystic Fibrosis. Clin Chest Med 2016; 37:1-8
7 Barker AF. Bronchiectasis. N Engl J Med 2002; 346:1383-1393
8 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
9 Kreuter M, Ehlers-Tenenbaum S, Palmowski K, et al. Impact of Comorbidities on Mortality in
Patients with Idiopathic Pulmonary Fibrosis. PLoS One 2016; 11:e0151425
10 Vanfleteren LE, Spruit MA, Groenen M, et al. Clusters of comorbidities based on validated
objective measurements and systemic inflammation in patients with chronic obstructive
pulmonary disease. Am J Respir Crit Care Med 2013; 187:728-735
11 Negewo NA, McDonald VM, Gibson PG. Comorbidity in chronic obstructive pulmonary
disease. Respir Investig 2015; 53:249-258
12 Panagiotou M, Polychronopoulos V, Strange C. Respiratory and lower limb muscle function
in interstitial lung disease. Chron Respir Dis 2016; 13:162-172
13 Barreiro E, Gea J. Respiratory and Limb Muscle Dysfunction in COPD. COPD 2015;
12:413-426
14 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:e15-62
15 Mador MJ, Bozkanat E. Skeletal muscle dysfunction in chronic obstructive pulmonary
disease. Respir Res 2001; 2:216-224
140
16 Panagiotou M, Peacock AJ, Johnson MK. Respiratory and limb muscle dysfunction in
pulmonary arterial hypertension: a role for exercise training? Pulm Circ 2015; 5:424-
434
17 Troosters T, Langer D, Vrijsen B, et al. Skeletal muscle weakness, exercise tolerance and
physical activity in adults with cystic fibrosis. Eur Respir J 2009; 33:99-106
18 Gale NS, Bolton CE, Duckers JM, et al. Systemic comorbidities in bronchiectasis. Chron
Respir Dis 2012; 9:231-238
19 Osadnik CR, Rodrigues FM, Camillo CA, et al. Principles of rehabilitation and reactivation.
Respiration 2015; 89:2-11
20 Nishiyama O, Taniguchi H, Kondoh Y, et al. Quadriceps weakness is related to exercise
capacity in idiopathic pulmonary fibrosis. Chest 2005; 127:2028-2033
21 Rozenberg D, Wickerson L, Singer LG, et al. Sarcopenia in lung transplantation: a
systematic review. J Heart Lung Transplant 2014; 33:1203-1212
22 Martinu T, Babyak MA, O'Connell CF, et al. Baseline 6-min walk distance predicts survival
in lung transplant candidates. Am J Transplant 2008; 8:1498-1505
23 Castleberry AW, Englum BR, Snyder LD, et al. The utility of preoperative six-minute-walk
distance in lung transplantation. Am J Respir Crit Care Med 2015; 192:843-852
24 Upala S, Panichsillapakit T, Wijarnpreecha K, et al. Underweight and obesity increase the
risk of mortality after lung transplantation: a systematic review and meta-analysis.
Transpl Int 2016; 29:285-296
25 Yusen RD, Edwards LB, Kucheryavaya AY, et al. The Registry of the International Society
for Heart and Lung Transplantation: Thirty-second Official Adult Lung and Heart-Lung
Transplantation Report--2015; Focus Theme: Early Graft Failure. J Heart Lung
Transplant 2015; 34:1264-1277
26 Singer LG, Chowdhury NA, Faughnan ME, et al. Effects of Recipient Age and Diagnosis on
Health-related Quality-of-Life Benefit of Lung Transplantation. Am J Respir Crit Care
Med 2015; 192:965-973
27 Wickerson L, Mathur S, Brooks D. Exercise training after lung transplantation: a systematic
review. J Heart Lung Transplant 2010; 29:497-503
28 Hook JL, Lederer DJ. Selecting lung transplant candidates: where do current guidelines fall
short? Expert Rev Respir Med 2012; 6:51-61
29 Nathan SD. The future of lung transplantation. Chest 2015; 147:309-316
141
30 Yusen RD, Christie JD, Edwards LB, et al. The Registry of the International Society for
Heart and Lung Transplantation: Thirtieth Adult Lung and Heart-Lung Transplant
Report--2013; focus theme: age. J Heart Lung Transplant 2013; 32:965-978
31 Egan TM, Edwards LB. Effect of the lung allocation score on lung transplantation in the
United States. J Heart Lung Transplant 2016; 35:433-439
32 Lehr CJ, Zaas DW. Candidacy for lung transplant and lung allocation. Thorac Surg Clin
2015; 25:1-15
33 Makdisi G, Wang IW. Extra Corporeal Membrane Oxygenation (ECMO) review of a
lifesaving technology. J Thorac Dis 2015; 7:E166-176
34 Jurmann MJ, Haverich A, Demertzis S, et al. Extracorporeal membrane oxygenation as a
bridge to lung transplantation. Eur J Cardiothorac Surg 1991; 5:94-97; discussion 98
35 Jackson A, Cropper J, Pye R, et al. Use of extracorporeal membrane oxygenation as a
bridge to primary lung transplant: 3 consecutive, successful cases and a review of the
literature. J Heart Lung Transplant 2008; 27:348-352
36 Garcia JP, Kon ZN, Evans C, et al. Ambulatory veno-venous extracorporeal membrane
oxygenation: innovation and pitfalls. J Thorac Cardiovasc Surg 2011; 142:755-761
37 Nosotti M, Rosso L, Tosi D, et al. Extracorporeal membrane oxygenation with spontaneous
breathing as a bridge to lung transplantation. Interact Cardiovasc Thorac Surg 2013;
16:55-59
38 Fuehner T, Kuehn C, Hadem J, et al. Extracorporeal membrane oxygenation in awake
patients as bridge to lung transplantation. Am J Respir Crit Care Med 2012; 185:763-
768
39 Lehr CJ, Zaas DW, Cheifetz IM, et al. Ambulatory extracorporeal membrane oxygenation
as a bridge to lung transplantation: walking while waiting. Chest 2015; 147:1213-1218
40 Griffiths RD, Hall JB. Intensive care unit-acquired weakness. Crit Care Med 2010; 38:779-
787
41 Zaas AK, Alexander BD. New developments in the diagnosis and treatment of infections in
lung transplant recipients. Respir Care Clin N Am 2004; 10:531-547
42 Burguete SR, Maselli DJ, Fernandez JF, et al. Lung transplant infection. Respirology 2013;
18:22-38
43 Boehler A, Estenne M. Post-transplant bronchiolitis obliterans. Eur Respir J 2003; 22:1007-
1018
44 Kugler C, Fischer S, Gottlieb J, et al. Health-related quality of life in two hundred-eighty lung
transplant recipients. J Heart Lung Transplant 2005; 24:2262-2268
142
45 Vermeulen KM, Ouwens JP, van der Bij W, et al. Long-term quality of life in patients
surviving at least 55 months after lung transplantation. Gen Hosp Psychiatry 2003;
25:95-102
46 Liu V, Zamora MR, Dhillon GS, et al. Increasing lung allocation scores predict worsened
survival among lung transplant recipients. Am J Transplant 2010; 10:915-920
47 Organ Procurement and Transplantation Network.
https://optn.transplant.hrsa.gov/resources/allocationcalculators/ (Last accessed on July
31, 2017).
48 Whitson BA, Hayes D, Jr. Indications and outcomes in adult lung transplantation. J Thorac
Dis 2014; 6:1018-1023
49 Gutierrez C, Al-Faifi S, Chaparro C, et al. The effect of recipient's age on lung transplant
outcome. Am J Transplant 2007; 7:1271-1277
50 Genao L, Whitson HE, Zaas D, et al. Functional status after lung transplantation in older
adults in the post-allocation score era. Am J Transplant 2013; 13:157-166
51 Allen JG, Arnaoutakis GJ, Weiss ES, et al. The impact of recipient body mass index on
survival after lung transplantation. J Heart Lung Transplant 2010; 29:1026-1033
52 Lederer DJ, Wilt JS, D'Ovidio F, et al. Obesity and underweight are associated with an
increased risk of death after lung transplantation. Am J Respir Crit Care Med 2009;
180:887-895
53 Kanasky WF, Jr., Anton SD, Rodrigue JR, et al. Impact of body weight on long-term survival
after lung transplantation. Chest 2002; 121:401-406
54 Singer JP, Peterson ER, Snyder ME, et al. Body composition and mortality after adult lung
transplantation in the United States. Am J Respir Crit Care Med 2014; 190:1012-1021
55 Ruttens D, Verleden SE, Vandermeulen E, et al. Body mass index in lung transplant
candidates: a contra-indication to transplant or not? Transplant Proc 2014; 46:1506-
1510
56 Shah NR, Braverman ER. Measuring adiposity in patients: the utility of body mass index
(BMI), percent body fat, and leptin. PLoS One 2012; 7:e33308
57 Reis JP, Macera CA, Araneta MR, et al. Comparison of overall obesity and body fat
distribution in predicting risk of mortality. Obesity (Silver Spring) 2009; 17:1232-1239
58 Kovesdy CP, Czira ME, Rudas A, et al. Body mass index, waist circumference and mortality
in kidney transplant recipients. Am J Transplant 2010; 10:2644-2651
59 McShane PJ, Garrity ER, Jr. Impact of the lung allocation score. Semin Respir Crit Care
Med 2013; 34:275-280
143
60 Eberlein M, Garrity ER, Orens JB. Lung allocation in the United States. Clin Chest Med
2011; 32:213-222
61 Hirji A, Zhao H, Lien DC, et al. Clinical judgment versus lung allocation score in predicting
waitlist mortality. J Heart Lung Transplant 2015. 34(4S): S245.
62 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
63 Gurau AJ, Chowdhury N, Singer LG. Lung Allocation Score is not associated with Health-
related Quality of Life in Lung Transplant Candidates. J Heart Lung Transplant 2007;
26: S160.
64 Finlen Copeland CA, Vock DM, Pieper K, et al. Impact of lung transplantation on recipient
quality of life: a serial, prospective, multicenter analysis through the first posttransplant
year. Chest 2013; 143:744-750
65 Gerbase MW, Spiliopoulos A, Rochat T, et al. Health-related quality of life following single
or bilateral lung transplantation: a 7-year comparison to functional outcome. Chest
2005; 128:1371-1378
66 Singer JP, Singer LG. Quality of life in lung transplantation. Semin Respir Crit Care Med
2013; 34:421-430
67 Ware JE, Jr., Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I.
Conceptual framework and item selection. Med Care 1992; 30:473-483
68 Swigris JJ, Brown KK, Behr J, et al. The SF-36 and SGRQ: validity and first look at
minimum important differences in IPF. Respir Med 2010; 104:296-304
69 Eskander A, Waddell TK, Faughnan ME, et al. BODE index and quality of life in advanced
chronic obstructive pulmonary disease before and after lung transplantation. J Heart
Lung Transplant 2011; 30:1334-1341
70 Lutogniewska W, Jastrzebski D, Wyrwol J, et al. Dyspnea and quality of life in patients
referred for lung transplantation. Eur J Med Res 2010; 15 Suppl 2:76-78
71 Smeritschnig B, Jaksch P, Kocher A, et al. Quality of life after lung transplantation: a cross-
sectional study. J Heart Lung Transplant 2005; 24:474-480
72 Yorke J, Jones PW, Swigris JJ. Development and validity testing of an IPF-specific version
of the St George's Respiratory Questionnaire. Thorax 2010; 65:921-926
73 Swigris JJ, Lee HS, Cohen M, et al. St. George's Respiratory Questionnaire has
longitudinal construct validity in lymphangioleiomyomatosis. Chest 2013; 143:1671-
1678
144
74 Wallace B, Kafaja S, Furst DE, et al. Reliability, validity and responsiveness to change of
the Saint George's Respiratory Questionnaire in early diffuse cutaneous systemic
sclerosis. Rheumatology (Oxford) 2015; 54:1369-1379
75 Jones PW. Interpreting thresholds for a clinically significant change in health status in
asthma and COPD. Eur Respir J 2002; 19:398-404
76 Vasiliadis HM, Collet JP, Poirier C. Health-related quality-of-life determinants in lung
transplantation. J Heart Lung Transplant 2006; 25:226-233
77 Stavem K, Bjortuft O, Lund MB, et al. Health-related quality of life in lung transplant
candidates and recipients. Respiration 2000; 67:159-165
78 Kugler C, Strueber M, Tegtbur U, et al. Quality of life 1 year after lung transplantation. Prog
Transplant 2004; 14:331-336
79 Myaskovsky L, Dew MA, McNulty ML, et al. Trajectories of change in quality of life in 12-
month survivors of lung or heart transplant. Am J Transplant 2006; 6:1939-1947
80 Ricotti S, Vitulo P, Petrucci L, et al. Determinants of quality of life after lung transplant: an
Italian collaborative study. Monaldi Arch Chest Dis 2006; 65:5-12
81 MacNaughton KL, Rodrigue JR, Cicale M, et al. Health-related quality of life and symptom
frequency before and after lung transplantation. Clin Transplant 1998; 12:320-323
82 Kugler C, Tegtbur U, Gottlieb J, et al. Health-related quality of life in long-term survivors
after heart and lung transplantation: a prospective cohort study. Transplantation 2010;
90:451-457
83 Rodrigue JR, Baz MA. Are there sex differences in health-related quality of life after lung
transplantation for chronic obstructive pulmonary disease? J Heart Lung Transplant
2006; 25:120-125
84 Limbos MM, Chan CK, Kesten S. Quality of life in female lung transplant candidates and
recipients. Chest 1997; 112:1165-1174
85 Santana MJ, Feeny D, Ghosh S, et al. Patient-reported outcome 2 years after lung
transplantation: does the underlying diagnosis matter? Patient Relat Outcome Meas
2012; 3:79-84
86 Vogiatzis I, Zakynthinos S. Factors limiting exercise tolerance in chronic lung diseases.
Compr Physiol 2012; 2:1779-1817
87 Monjazebi F, Dalvandi A, Ebadi A, et al. Functional Status Assessment of COPD Based on
Ability to Perform Daily Living Activities: A Systematic Review of Paper and Pencil
Instruments. Glob J Health Sci 2016; 8:210-223
145
88 De Vriendt P, Gorus E, Cornelis E, et al. The process of decline in advanced activities of
daily living: a qualitative explorative study in mild cognitive impairment. Int
Psychogeriatr 2012; 24:974-986
89 Reuben DB, Laliberte L, Hiris J, et al. A hierarchical exercise scale to measure function at
the Advanced Activities of Daily Living (AADL) level. J Am Geriatr Soc 1990; 38:855-
861
90 Reilly CC, Bausewein C, Garrod R, et al. Breathlessness during daily activity: The
psychometric properties of the London Chest Activity of Daily Living Scale in patients
with advanced disease and refractory breathlessness. Palliat Med 2016
91 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
92 Hajiro T, Nishimura K, Tsukino M, et al. A comparison of the level of dyspnea vs disease
severity in indicating the health-related quality of life of patients with COPD. Chest
1999; 116:1632-1637
93 Yohannes AM, Baldwin RC, Connolly M. Mortality predictors in disabling chronic obstructive
pulmonary disease in old age. Age Ageing 2002; 31:137-140
94 Yohannes AM, Baldwin RC, Connolly MJ. Predictors of 1-year mortality in patients
discharged from hospital following acute exacerbation of chronic obstructive pulmonary
disease. Age Ageing 2005; 34:491-496
95 Muller JP, Goncalves 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
96 Singer JP, Blanc PD, Dean YM, et al. Development and validation of a lung transplant-
specific disability questionnaire. Thorax 2014; 69:437-442
97 Christie JD, Edwards LB, Kucheryavaya AY, et al. The Registry of the International Society
for Heart and Lung Transplantation: 29th adult lung and heart-lung transplant report-
2012. J Heart Lung Transplant 2012; 31:1073-1086
98 Paris W, Diercks M, Bright J, et al. Return to work after lung transplantation. J Heart Lung
Transplant 1998; 17:430-436
99 Grimm JC, Valero V, 3rd, Kilic A, et al. Preoperative performance status impacts
perioperative morbidity and mortality after lung transplantation. Ann Thorac Surg 2015;
99:482-489
146
100 Dolgin NH, Martins PN, Movahedi B, et al. Functional status predicts postoperative
mortality after liver transplantation. Clin Transplant 2016
101 Kilic A, Beaty CA, Merlo CA, et al. Functional status is highly predictive of outcomes after
redo lung transplantation: an analysis of 390 cases in the modern era. Ann Thorac
Surg 2013; 96:1804-1811; discussion 1811
102 Holland AE, Spruit MA, Troosters T, et al. An official European Respiratory
Society/American Thoracic Society technical standard: field walking tests in chronic
respiratory disease. Eur Respir J 2014; 44:1428-1446
103 Cahalin L, Pappagianopoulos P, Prevost S, et al. The relationship of the 6-min walk test to
maximal oxygen consumption in transplant candidates with end-stage lung disease.
Chest 1995; 108:452-459
104 Singh SJ, Puhan MA, Andrianopoulos V, et al. An official systematic review of the
European Respiratory Society/American Thoracic Society: measurement properties of
field walking tests in chronic respiratory disease. Eur Respir J 2014; 44:1447-1478
105 Eaton T, Young P, Nicol K, et al. The endurance shuttle walking test: a responsive
measure in pulmonary rehabilitation for COPD patients. Chron Respir Dis 2006; 3:3-9
106 McNamara RJ, McKeough ZJ, McKenzie DK, et al. Water-based exercise in COPD with
physical comorbidities: a randomised controlled trial. Eur Respir J 2013; 41:1284-1291
107 Pepin V, Brodeur J, Lacasse Y, et al. Six-minute walking versus shuttle walking:
responsiveness to bronchodilation in chronic obstructive pulmonary disease. Thorax
2007; 62:291-298
108 Dudley KA, El-Chemaly S. Cardiopulmonary exercise testing in lung transplantation: a
review. Pulm Med 2012; 2012:237852
109 Wickerson L, Mathur S, Singer LG, et al. Physical activity levels early after lung
transplantation. Phys Ther 2015; 95:517-525
110 Li M, Mathur S, Chowdhury NA, et al. Pulmonary rehabilitation in lung transplant
candidates. J Heart Lung Transplant 2013; 32:626-632
111 Lederer DJ, Arcasoy SM, Wilt JS, et al. Six-minute-walk distance predicts waiting list
survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2006; 174:659-664
112 Armstrong HF, Garber CE, Bartels MN. Exercise testing parameters associated with post
lung transplant mortality. Respir Physiol Neurobiol 2012; 181:118-122
113 Tang M, Mawji N, Chung S, et al. Factors affecting discharge destination following lung
transplantation. Clin Transplant 2015; 29:581-587
147
114 Older P, Hall A, Hader R. Cardiopulmonary exercise testing as a screening test for
perioperative management of major surgery in the elderly. Chest 1999; 116:355-362
115 Ridgway ZA, Howell SJ. Cardiopulmonary exercise testing: a review of methods and
applications in surgical patients. Eur J Anaesthesiol 2010; 27:858-865
116 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
117 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
118 Sciurba FC, Owens GR, Sanders MH, et al. The effect of obliterative bronchiolitis on
breathing pattern during exercise in recipients of heart-lung transplants. Am Rev Respir
Dis 1991; 144:131-135
119 Williams TJ, Patterson GA, McClean PA, et al. Maximal exercise testing in single and
double lung transplant recipients. Am Rev Respir Dis 1992; 145:101-105
120 Miyoshi S, Trulock EP, Schaefers HJ, et al. Cardiopulmonary exercise testing after single
and double lung transplantation. Chest 1990; 97:1130-1136
121 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
122 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:E504-511
123 Trost SG, O'Neil M. Clinical use of objective measures of physical activity. Br J Sports
Med 2014; 48:178-181
124 Langer D, Cebria 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
125 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
126 Colley RC, Garriguet D, Janssen I, et al. Physical activity of Canadian adults:
accelerometer results from the 2007 to 2009 Canadian Health Measures Survey.
Health Rep 2011; 22:7-14
127 Nguyen HQ, Steele BG, Dougherty CM, et al. Physical activity patterns of patients with
cardiopulmonary illnesses. Arch Phys Med Rehabil 2012; 93:2360-2366
148
128 Tudor-Locke C, Brashear MM, Johnson WD, et al. Accelerometer profiles of physical
activity and inactivity in normal weight, overweight, and obese U.S. men and women.
Int J Behav Nutr Phys Act 2010; 7:60
129 Washburn RA, Smith KW, Jette AM, et al. The Physical Activity Scale for the Elderly
(PASE): development and evaluation. J Clin Epidemiol 1993; 46:153-162
130 DePew ZS, Garofoli AC, Novotny PJ, et al. Screening for severe physical inactivity in
chronic obstructive pulmonary disease: the value of simple measures and the validation
of two physical activity questionnaires. Chron Respir Dis 2013; 10:19-27
131 Mendes P, Wickerson L, Helm D, et al. Skeletal muscle atrophy in advanced interstitial
lung disease. Respirology 2015; 20:953-959
132 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
133 Langer D, Gosselink R, Pitta F, et al. Physical activity in daily life 1 year after lung
transplantation. J Heart Lung Transplant 2009; 28:572-578
134 Langer D. Rehabilitation in Patients before and after Lung Transplantation. Respiration
2015; 89:353-362
135 Kyle UG, Nicod L, Raguso C, et al. Prevalence of low fat-free mass index and high and
very high body fat mass index following lung transplantation. Acta Diabetol 2003; 40
Suppl 1:S258-260
136 Bossenbroek L, ten Hacken NH, van der Bij W, et al. Cross-sectional assessment of daily
physical activity in chronic obstructive pulmonary disease lung transplant patients. J
Heart Lung Transplant 2009; 28:149-155
137 Jones CJ, Rikli RE, Beam WC. A 30-s chair-stand test as a measure of lower body
strength in community-residing older adults. Res Q Exerc Sport 1999; 70:113-119
138 Whittom F, Jobin J, Simard PM, et al. Histochemical and morphological characteristics of
the vastus lateralis muscle in patients with chronic obstructive pulmonary disease. Med
Sci Sports Exerc 1998; 30:1467-1474
139 Gosker HR, Zeegers MP, Wouters EF, et al. Muscle fibre type shifting in the vastus
lateralis of patients with COPD is associated with disease severity: a systematic review
and meta-analysis. Thorax 2007; 62:944-949
140 Maltais F, LeBlanc P, Whittom F, et al. Oxidative enzyme activities of the vastus lateralis
muscle and the functional status in patients with COPD. Thorax 2000; 55:848-853
141 Butcher SJ, Lagerquist O, Marciniuk DD, et al. Relationship between ventilatory constraint
and muscle fatigue during exercise in COPD. Eur Respir J 2009; 33:763-770
149
142 Evans RA, Kaplovitch E, Beauchamp MK, et al. Is quadriceps endurance reduced in
COPD?: a systematic review. Chest 2015; 147:673-684
143 Reinsma GD, ten Hacken NH, Grevink RG, et al. Limiting factors of exercise performance
1 year after lung transplantation. J Heart Lung Transplant 2006; 25:1310-1316
144 Pinet C, Scillia P, Cassart M, et al. Preferential reduction of quadriceps over respiratory
muscle strength and bulk after lung transplantation for cystic fibrosis. Thorax 2004;
59:783-789
145 Gea J, Casadevall C, Pascual S, et al. Respiratory diseases and muscle dysfunction.
Expert Rev Respir Med 2012; 6:75-90
146 Gosker HR, van Mameren H, van Dijk PJ, et al. Skeletal muscle fibre-type shifting and
metabolic profile in patients with chronic obstructive pulmonary disease. Eur Respir J
2002; 19:617-625
147 Jobin J, Maltais F, Doyon JF, et al. Chronic obstructive pulmonary disease: capillarity and
fiber-type characteristics of skeletal muscle. J Cardiopulm Rehabil 1998; 18:432-437
148 Gosker HR, Hesselink MK, Duimel H, et al. Reduced mitochondrial density in the vastus
lateralis muscle of patients with COPD. Eur Respir J 2007; 30:73-79
149 Wang XN, Williams TJ, McKenna MJ, et al. Skeletal muscle oxidative capacity, fiber type,
and metabolites after lung transplantation. Am J Respir Crit Care Med 1999; 160:57-63
150 Doherty TJ. Invited review: Aging and sarcopenia. J Appl Physiol (1985) 2003; 95:1717-
1727
151 Doherty TJ. The influence of aging and sex on skeletal muscle mass and strength. Curr
Opin Clin Nutr Metab Care 2001; 4:503-508
152 Lexell J. Human aging, muscle mass, and fiber type composition. J Gerontol A Biol Sci
Med Sci 1995; 50 Spec No:11-16
153 Faulkner JA, Larkin LM, Claflin DR, et al. Age-related changes in the structure and
function of skeletal muscles. Clin Exp Pharmacol Physiol 2007; 34:1091-1096
154 Vandervoort AA. Aging of the human neuromuscular system. Muscle a d Nerve 2002;
25:17-25
155 Deschenes MR. Effects of aging on muscle fibre type and size. Sports Med 2004; 34:809-
824
156 Luff AR. Age-associated changes in the innervation of muscle fibers and changes in the
mechanical properties of motor units. Ann N Y Acad Sci 1998; 854:92-101
157 Rosenberg IH. Sarcopenia: origins and clinical relevance. J Nutr 1997; 127:990S-991S
150
158 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
159 Jones SE, Maddocks M, Kon SS, et al. Sarcopenia in COPD: prevalence, clinical
correlates and response to pulmonary rehabilitation. Thorax 2015; 70:213-218
160 Dasarathy S. Cause and management of muscle wasting in chronic liver disease. Curr
Opin Gastroenterol 2016; 32:159-165
161 Yoshida T, Delafontaine P. Mechanisms of Cachexia in Chronic Disease States. Am J
Med Sci 2015; 350:250-256
162 Booth FW, Gollnick PD. Effects of disuse on the structure and function of skeletal muscle.
Med Sci Sports Exerc 1983; 15:415-420
163 Steiner MC, Evans R, Deacon SJ, et al. Adenine nucleotide loss in the skeletal muscles
during exercise in chronic obstructive pulmonary disease. Thorax 2005; 60:932-936
164 Polkey MI, Moxham J. Attacking the disease spiral in chronic obstructive pulmonary
disease. Clin Med (Lond) 2006; 6:190-196
165 English KL, Paddon-Jones D. Protecting muscle mass and function in older adults during
bed rest. Curr Opin Clin Nutr Metab Care 2010; 13:34-39
166 LeBlanc AD, Schneider VS, Evans HJ, et al. Regional changes in muscle mass following
17 weeks of bed rest. J Appl Physiol (1985) 1992; 73:2172-2178
167 Ferrando AA, Lane HW, Stuart CA, et al. Prolonged bed rest decreases skeletal muscle
and whole body protein synthesis. Am J Physiol 1996; 270:E627-633
168 Kortebein P, Ferrando A, Lombeida J, et al. Effect of 10 days of bed rest on skeletal
muscle in healthy older adults. JAMA 2007; 297:1772-1774
169 Kortebein P, Symons TB, Ferrando A, et al. Functional impact of 10 days of bed rest in
healthy older adults. J Gerontol A Biol Sci Med Sci 2008; 63:1076-1081
170 de Boer MD, Seynnes OR, di Prampero PE, et al. Effect of 5 weeks horizontal bed rest on
human muscle thickness and architecture of weight bearing and non-weight bearing
muscles. Eur J Appl Physiol 2008; 104:401-407
171 Watz H, Waschki B, Meyer T, et al. Physical activity in patients with COPD. Eur Respir J
2009; 33:262-272
172 Shrikrishna D, Patel M, Tanner RJ, et al. Quadriceps wasting and physical inactivity in
patients with COPD. Eur Respir J 2012; 40:1115-1122
173 van den Borst B, Koster A, Yu B, et al. Is age-related decline in lean mass and physical
function accelerated by obstructive lung disease or smoking? Thorax 2011; 66:961-969
151
174 Zhang J, Liu Y, Shi J, et al. Side-stream cigarette smoke induces dose-response in
systemic inflammatory cytokine production and oxidative stress. Exp Biol Med
(Maywood) 2002; 227:823-829
175 Petersen AM, Magkos F, Atherton P, et al. Smoking impairs muscle protein synthesis and
increases the expression of myostatin and MAFbx in muscle. Am J Physiol Endocrinol
Metab 2007; 293:E843-848
176 Montes de Oca M, Loeb E, Torres SH, et al. Peripheral muscle alterations in non-COPD
smokers. Chest 2008; 133:13-18
177 Gan WQ, Man SF, Senthilselvan A, et al. Association between chronic obstructive
pulmonary disease and systemic inflammation: a systematic review and a meta-
analysis. Thorax 2004; 59:574-580
178 Nordskog BK, Fields WR, Hellmann GM. Kinetic analysis of cytokine response to cigarette
smoke condensate by human endothelial and monocytic cells. Toxicology 2005;
212:87-97
179 Borchers MT, Wesselkamper SC, Curull V, et al. Sustained CTL activation by murine
pulmonary epithelial cells promotes the development of COPD-like disease. J Clin
Invest 2009; 119:636-649
180 Plant PJ, Brooks D, Faughnan M, et al. Cellular markers of muscle atrophy in chronic
obstructive pulmonary disease. Am J Respir Cell Mol Biol 2010; 42:461-471
181 Doucet M, Russell AP, Leger B, et al. Muscle atrophy and hypertrophy signaling in
patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007;
176:261-269
182 Barreiro E, Schols AM, Polkey MI, et al. Cytokine profile in quadriceps muscles of patients
with severe COPD. Thorax 2008; 63:100-107
183 Spate U, Schulze PC. Proinflammatory cytokines and skeletal muscle. Curr Opin Clin Nutr
Metab Care 2004; 7:265-269
184 Fanzani A, Conraads VM, Penna F, et al. Molecular and cellular mechanisms of skeletal
muscle atrophy: an update. J Cachexia Sarcopenia Muscle 2012; 3:163-179
185 Reid MB, Lannergren J, Westerblad H. Respiratory and limb muscle weakness induced by
tumor necrosis factor-alpha: involvement of muscle myofilaments. Am J Respir Crit
Care Med 2002; 166:479-484
186 Li W, Moylan JS, Chambers MA, et al. Interleukin-1 stimulates catabolism in C2C12
myotubes. Am J Physiol Cell Physiol 2009; 297:C706-714
152
187 Moylan JS, Reid MB. Oxidative stress, chronic disease, and muscle wasting. Muscle a d
Nerve 2007; 35:411-429
188 Barreiro E, de la Puente B, Minguella J, et al. Oxidative stress and respiratory muscle
dysfunction in severe chronic obstructive pulmonary disease. Am J Respir Crit Care
Med 2005; 171:1116-1124
189 Barreiro E, Gea J, Corominas JM, et al. Nitric oxide synthases and protein oxidation in the
quadriceps femoris of patients with chronic obstructive pulmonary disease. Am J Respir
Cell Mol Biol 2003; 29:771-778
190 Remels AH, Gosker HR, Langen RC, et al. The mechanisms of cachexia underlying
muscle dysfunction in COPD. J Appl Physiol (1985) 2013; 114:1253-1262
191 Williams A, Riise GC, Anderson BA, et al. Compromised antioxidant status and persistent
oxidative stress in lung transplant recipients. Free Radic Res 1999; 30:383-393
192 Poderoso JJ, Boveris A, Cadenas E. Mitochondrial oxidative stress: a self-propagating
process with implications for signaling cascades. Biofactors 2000; 11:43-45
193 Puente-Maestu L, Perez-Parra J, Godoy R, et al. Abnormal mitochondrial function in
locomotor and respiratory muscles of COPD patients. Eur Respir J 2009; 33:1045-1052
194 Jiroutkova K, Krajcova A, Ziak J, et al. Mitochondrial function in skeletal muscle of patients
with protracted critical illness and ICU-acquired weakness. Crit Care 2015; 19:448
195 Keller C, Hellsten Y, Steensberg A, et al. Differential regulation of IL-6 and TNF-alpha via
calcineurin in human skeletal muscle cells. Cytokine 2006; 36:141-147
196 Kent BD, Mitchell PD, McNicholas WT. Hypoxemia in patients with COPD: cause, effects,
and disease progression. Int J Chron Obstruct Pulmon Dis 2011; 6:199-208
197 Koechlin C, Maltais F, Saey D, et al. Hypoxaemia enhances peripheral muscle oxidative
stress in chronic obstructive pulmonary disease. Thorax 2005; 60:834-841
198 Pastoris O, Dossena M, Foppa P, et al. Modifications by chronic intermittent hypoxia and
drug treatment on skeletal muscle metabolism. Neurochem Res 1995; 20:143-150
199 Romer LM, Haverkamp HC, Amann M, et al. Effect of acute severe hypoxia on peripheral
fatigue and endurance capacity in healthy humans. Am J Physiol Regul Integr Comp
Physiol 2007; 292:R598-606
200 Caron MA, Theriault ME, Pare ME, et al. Hypoxia alters contractile protein homeostasis in
L6 myotubes. FEBS Lett 2009; 583:1528-1534
201 England BK, Chastain JL, Mitch WE. Abnormalities in protein synthesis and degradation
induced by extracellular pH in BC3H1 myocytes. Am J Physiol 1991; 260:C277-282
153
202 Kelsen SG, Ference M, Kapoor S. Effects of prolonged undernutrition on structure and
function of the diaphragm. J Appl Physiol (1985) 1985; 58:1354-1359
203 Lopes J, Russell DM, Whitwell J, et al. Skeletal muscle function in malnutrition. Am J Clin
Nutr 1982; 36:602-610
204 Goris AH, Vermeeren MA, Wouters EF, et al. Energy balance in depleted ambulatory
patients with chronic obstructive pulmonary disease: the effect of physical activity and
oral nutritional supplementation. Br J Nutr 2003; 89:725-731
205 Chamogeorgakis T, Mason DP, Murthy SC, et al. Impact of nutritional state on lung
transplant outcomes. J Heart Lung Transplant 2013; 32:693-700
206 Decramer M, de Bock V, Dom R. Functional and histologic picture of steroid-induced
myopathy in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1996;
153:1958-1964
207 Schakman O, Gilson H, Kalista S, et al. Mechanisms of muscle atrophy induced by
glucocorticoids. Horm Res 2009; 72 Suppl 1:36-41
208 Hanada M, Sakamoto N, Ishimatsu Y, et al. Effect of long-term treatment with
corticosteroids on skeletal muscle strength, functional exercise capacity and health
status in patients with interstitial lung disease. Respirology 2016; 21:1088-1093
209 Barry SC, Gallagher CG. Corticosteroids and skeletal muscle function in cystic fibrosis. J
Appl Physiol (1985) 2003; 95:1379-1384
210 Nava S, Fracchia C, Callegari G, et al. Weakness of respiratory and skeletal muscles after
a short course of steroids in patients with acute lung rejection. Eur Respir J 2002;
20:497-499
211 Evans AB, Al-Himyary AJ, Hrovat MI, et al. Abnormal skeletal muscle oxidative capacity
after lung transplantation by 31P-MRS. Am J Respir Crit Care Med 1997; 155:615-621
212 Sinoway LI, Minotti JR, Davis D, et al. Delayed reversal of impaired vasodilation in
congestive heart failure after heart transplantation. Am J Cardiol 1988; 61:1076-1079
213 Mercier JG, Hokanson JF, Brooks GA. Effects of cyclosporine A on skeletal muscle
mitochondrial respiration and endurance time in rats. Am J Respir Crit Care Med 1995;
151:1532-1536
214 Kavanagh T, Yacoub MH, Mertens DJ, et al. Cardiorespiratory responses to exercise
training after orthotopic cardiac transplantation. Circulation 1988; 77:162-171
215 Kempeneers G, Noakes TD, van Zyl-Smit R, et al. Skeletal muscle limits the exercise
tolerance of renal transplant recipients: effects of a graded exercise training program.
Am J Kidney Dis 1990; 16:57-65
154
216 Stephenson AL, Yoshida EM, Abboud RT, et al. Impaired exercise performance after
successful liver transplantation. Transplantation 2001; 72:1161-1164
217 Delmonico MJ, Harris TB, Visser M, et al. Longitudinal study of muscle strength, quality,
and adipose tissue infiltration. Am J Clin Nutr 2009; 90:1579-1585
218 Kawakami Y, Akima H, Kubo K, et al. Changes in muscle size, architecture, and neural
activation after 20 days of bed rest with and without resistance exercise. Eur J Appl
Physiol 2001; 84:7-12
219 Dos Santos C, Hussain SN, Mathur S, et al. Mechanisms of Chronic Muscle Wasting and
Dysfunction after an Intensive Care Unit Stay. A Pilot Study. Am J Respir Crit Care
Med 2016; 194:821-830
220 Clark BC, Manini TM, Bolanowski SJ, et al. Adaptations in human neuromuscular function
following prolonged unweighting: II. Neurological properties and motor imagery
efficacy. J Appl Physiol (1985) 2006; 101:264-272
221 Clark BC, Manini TM. Sarcopenia =/= dynapenia. J Gerontol A Biol Sci Med Sci 2008;
63:829-834
222 Manini TM, Clark BC. Dynapenia and aging: an update. J Gerontol A Biol Sci Med Sci
2012; 67:28-40
223 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
224 Spruit MA, Pennings HJ, Janssen PP, et al. Extra-pulmonary features in COPD patients
entering rehabilitation after stratification for MRC dyspnea grade. Respir Med 2007;
101:2454-2463
225 Shoup R, Dalsky G, Warner S, et al. Body composition and health-related quality of life in
patients with obstructive airways disease. Eur Respir J 1997; 10:1576-1580
226 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
227 Heymsfield SB, Adamek M, Gonzalez MC, et al. Assessing skeletal muscle mass:
historical overview and state of the art. J Cachexia Sarcopenia Muscle 2014; 5:9-18
228 Heymsfield SB, Gonzalez MC, Lu J, et al. Skeletal muscle mass and quality: evolution of
modern measurement concepts in the context of sarcopenia. Proc Nutr Soc 2015;
74:355-366
155
229 Soler-Cataluna JJ, Sanchez-Sanchez L, Martinez-Garcia MA, et al. Mid-arm muscle area
is a better predictor of mortality than body mass index in COPD. Chest 2005; 128:2108-
2115
230 Hronek M, Kovarik M, Aimova P, et al. Skinfold anthropometry--the accurate method for
fat free mass measurement in COPD. COPD 2013; 10:597-603
231 Mathur S, Takai KP, Macintyre DL, et al. Estimation of thigh muscle mass with magnetic
resonance imaging in older adults and people with chronic obstructive pulmonary
disease. Phys Ther 2008; 88:219-230
232 Friedman J, Lussiez A, Sullivan J, et al. Implications of sarcopenia in major surgery. Nutr
Clin Pract 2015; 30:175-179
233 Irving BA, Weltman JY, Brock DW, et al. NIH ImageJ and Slice-O-Matic computed
tomography imaging software to quantify soft tissue. Obesity (Silver Spring) 2007;
15:370-376
234 Addison O, Marcus RL, Lastayo PC, et al. Intermuscular fat: a review of the consequences
and causes. Int J Endocrinol 2014; 2014:309570
235 Shen W, Punyanitya M, Wang Z, et al. Total body skeletal muscle and adipose tissue
volumes: estimation from a single abdominal cross-sectional image. J Appl Physiol
(1985) 2004; 97:2333-2338
236 Englesbe MJ, Patel SP, He K, et al. Sarcopenia and mortality after liver transplantation. J
Am Coll Surg 2010; 211:271-278
237 Sheetz KH, Waits SA, Terjimanian MN, et al. Cost of major surgery in the sarcopenic
patient. J Am Coll Surg 2013; 217:813-818
238 Lee JS, He K, Harbaugh CM, et al. Frailty, core muscle size, and mortality in patients
undergoing open abdominal aortic aneurysm repair. J Vasc Surg 2011; 53:912-917
239 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
240 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
241 McDonald ML, Diaz AA, Ross JC, et al. Quantitative computed tomography measures of
pectoralis muscle area and disease severity in chronic obstructive pulmonary disease.
A cross-sectional study. Ann Am Thorac Soc 2014; 11:326-334
156
242 Hoang V, Li GW, Kao CC, et al. Determinants of pre-transplantation pectoralis muscle
area (PMA) and post-transplantation change in PMA in lung transplant recipients. Clin
Transplant 2016
243 Tanimura K, Sato S, Fuseya Y, et al. Quantitative Assessment of Erector Spinae Muscles
in Patients with Chronic Obstructive Pulmonary Disease. Novel Chest Computed
Tomography-derived Index for Prognosis. Ann Am Thorac Soc 2016; 13:334-341
244 Lee S, Paik HC, Haam SJ, et al. Sarcopenia of thoracic muscle mass is not a risk factor
for survival in lung transplant recipients. J Thorac Dis 2016; 8:2011-2017
245 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
246 Dufresne V, Knoop C, Van Muylem A, et al. Effect of systemic inflammation on inspiratory
and limb muscle strength and bulk in cystic fibrosis. Am J Respir Crit Care Med 2009;
180:153-158
247 Batt J, Ahmed SS, Correa J, et al. Skeletal muscle dysfunction in idiopathic pulmonary
arterial hypertension. Am J Respir Cell Mol Biol 2014; 50:74-86
248 Guo Y, Gosker HR, Schols AM, et al. Autophagy in locomotor muscles of patients with
chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2013; 188:1313-
1320
249 Prado CM, Heymsfield SB. Lean tissue imaging: a new era for nutritional assessment and
intervention. JPEN J Parenter Enteral Nutr 2014; 38:940-953
250 Schweitzer L, Geisler C, Pourhassan M, et al. What is the best reference site for a single
MRI slice to assess whole-body skeletal muscle and adipose tissue volumes in healthy
adults? Am J Clin Nutr 2015; 102:58-65
251 Dill T. Contraindications to magnetic resonance imaging: non-invasive imaging. Heart
2008; 94:943-948
252 Robles PG, Mathur S, Janaudis-Fereira T, et al. Measurement of peripheral muscle
strength in individuals with chronic obstructive pulmonary disease: a systematic review.
J Cardiopulm Rehabil Prev 2011; 31:11-24
253 Shields GS, Coissi GS, Jimenez-Royo P, et al. Bioenergetics and intermuscular fat in
chronic obstructive pulmonary disease-associated quadriceps weakness. Muscle a d
Nerve 2015; 51:214-221
254 Mathur S, Levy RD, Reid WD. Skeletal muscle strength and endurance in recipients of
lung transplants. Cardiopulm Phys Ther J 2008; 19:84-93
157
255 Maddocks M, Jones M, Snell T, et al. Ankle dorsiflexor muscle size, composition and force
with ageing and chronic obstructive pulmonary disease. Exp Physiol 2014; 99:1078-
1088
256 Connolly B, MacBean V, Crowley C, et al. Ultrasound for the assessment of peripheral
skeletal muscle architecture in critical illness: a systematic review. Crit Care Med 2015;
43:897-905
257 Seymour JM, Ward K, Sidhu PS, et al. Ultrasound measurement of rectus femoris cross-
sectional area and the relationship with quadriceps strength in COPD. Thorax 2009;
64:418-423
258 Reeves ND, Maganaris CN, Narici MV. Ultrasonographic assessment of human skeletal
muscle size. Eur J Appl Physiol 2004; 91:116-118
259 Seymour JM, Ward K, Raffique A, et al. Quadriceps and ankle dorsiflexor strength in
chronic obstructive pulmonary disease. Muscle Nerve 2012; 46:548-554
260 Hoffer EC, Meador CK, Simpson DC. Correlation of whole-body impedance with total body
water volume. J Appl Physiol 1969; 27:531-534
261 Nyboer J. Workable volume and flow concepts of bio-segments by electrical impedance
plethysmography. TIT J Life Sci 1972; 2:1-13
262 Thomasset A. Bioelectrical properties of tissue impedance measurements. Lyon Med
1962; 94: 107–118.
263 Norman K, Stobaus N, Pirlich M, et al. Bioelectrical phase angle and impedance vector
analysis--clinical relevance and applicability of impedance parameters. Clin Nutr 2012;
31:854-861
264 Slinde F, Gronberg A, Engstrom CP, et al. Body composition by bioelectrical impedance
predicts mortality in chronic obstructive pulmonary disease patients. Respir Med 2005;
99:1004-1009
265 Bossenbroek L, den Ouden ME, de Greef MH, et al. Determinants of overweight and
obesity in lung transplant recipients. Respiration 2011; 82:28-35
266 Heymsfield SB, Smith R, Aulet M, et al. Appendicular skeletal muscle mass: measurement
by dual-photon absorptiometry. Am J Clin Nutr 1990; 52:214-218
267 Kim J, Wang Z, Heymsfield SB, et al. Total-body skeletal muscle mass: estimation by a
new dual-energy X-ray absorptiometry method. Am J Clin Nutr 2002; 76:378-383
268 Costa TM, Costa FM, Moreira CA, et al. Sarcopenia in COPD: relationship with COPD
severity and prognosis. J Bras Pneumol 2015; 41:415-421
158
269 Greening NJ, Harvey-Dunstan TC, Chaplin EJ, et al. Bedside assessment of quadriceps
muscle by ultrasound after admission for acute exacerbations of chronic respiratory
disease. Am J Respir Crit Care Med 2015; 192:810-816
270 Galesanu RG, Bernard S, Marquis K, et al. Obesity in chronic obstructive pulmonary
disease: is fatter really better? Can Respir J 2014; 21:297-301
271 Wilson DO, Rogers RM, Wright EC, et al. Body weight in chronic obstructive pulmonary
disease. The National Institutes of Health Intermittent Positive-Pressure Breathing Trial.
Am Rev Respir Dis 1989; 139:1435-1438
272 Schols AM, Slangen J, Volovics L, et al. Weight loss is a reversible factor in the prognosis
of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998; 157:1791-
1797
273 Ionescu AA, Nixon LS, Evans WD, et al. Bone density, body composition, and
inflammatory status in cystic fibrosis. Am J Respir Crit Care Med 2000; 162:789-794
274 Anker SD, Ponikowski P, Varney S, et al. Wasting as independent risk factor for mortality
in chronic heart failure. Lancet 1997; 349:1050-1053
275 Pouw EM, Schols AM, Deutz NE, et al. Plasma and muscle amino acid levels in relation to
resting energy expenditure and inflammation in stable chronic obstructive pulmonary
disease. Am J Respir Crit Care Med 1998; 158:797-801
276 Stump CS, Henriksen EJ, Wei Y, et al. The metabolic syndrome: role of skeletal muscle
metabolism. Ann Med 2006; 38:389-402
277 Carey EJ. Sarcopenia in solid organ transplantation. Nutr Clin Pract 2014; 29:159-170
278 Fitts RH, McDonald KS, Schluter JM. The determinants of skeletal muscle force and
power: their adaptability with changes in activity pattern. J Biomech 1991; 24 Suppl
1:111-122
279 Kelln BM, McKeon PO, Gontkof LM, et al. Hand-held dynamometry: reliability of lower
extremity muscle testing in healthy, physically active,young adults. J Sport Rehabil
2008; 17:160-170
280 Martin HJ, Yule V, Syddall HE, et al. Is hand-held dynamometry useful for the
measurement of quadriceps strength in older people? A comparison with the gold
standard Bodex dynamometry. Gerontology 2006; 52:154-159
281 Lu YM, Lin JH, Hsiao SF, et al. The relative and absolute reliability of leg muscle strength
testing by a handheld dynamometer. J Strength Cond Res 2011; 25:1065-1071
282 Man WD, Moxham J, Polkey MI. Magnetic stimulation for the measurement of respiratory
and skeletal muscle function. Eur Respir J 2004; 24:846-860
159
283 Allen GM, Gandevia SC, McKenzie DK. Reliability of measurements of muscle strength
and voluntary activation using twitch interpolation. Muscle a d Nerve 1995; 18:593-600
284 Polkey MI, Kyroussis D, Hamnegard CH, et al. Quadriceps strength and fatigue assessed
by magnetic stimulation of the femoral nerve in man. Muscle a d Nerve 1996; 19:549-
555
285 Hopkinson NS, Tennant RC, Dayer MJ, et al. A prospective study of decline in fat free
mass and skeletal muscle strength in chronic obstructive pulmonary disease. Respir
Res 2007; 8:25
286 Gosselink R, Troosters T, Decramer M. Distribution of muscle weakness in patients with
stable chronic obstructive pulmonary disease. J Cardiopulm Rehabil 2000; 20:353-360
287 Franssen FM, Broekhuizen R, Janssen PP, et al. Limb muscle dysfunction in COPD:
effects of muscle wasting and exercise training. Med Sci Sports Exerc 2005; 37:2-9
288 Man WD, Soliman MG, Nikoletou D, et al. Non-volitional assessment of skeletal muscle
strength in patients with chronic obstructive pulmonary disease. Thorax 2003; 58:665-
669
289 Vivodtzev I, Flore P, Levy P, et al. Voluntary activation during knee extensions in severely
deconditioned patients with chronic obstructive pulmonary disease: benefit of
endurance training. Muscle Nerve 2008; 37:27-35
290 Spruit MA, Gosselink R, Troosters T, et al. Muscle force during an acute exacerbation in
hospitalised patients with COPD and its relationship with CXCL8 and IGF-I. Thorax
2003; 58:752-756
291 Van Der Woude BT, Kropmans TJ, Douma KW, et al. Peripheral muscle force and
exercise capacity in lung transplant candidates. Int J Rehabil Res 2002; 25:351-355
292 Gea J, Orozco-Levi M, Barreiro E, et al. Structural and functional changes in the skeletal
muscles of COPD patients: the "compartments" theory. Monaldi Archives for Chest
isease 2001; 56:214-224
293 Newman AB, Kupelian V, Visser M, et al. Strength, but not muscle mass, is associated
with mortality in the health, aging and body composition study cohort. J Gerontol A Biol
Sci Med Sci 2006; 61:72-77
294 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
295 Gea J, Agusti A, Roca J. Pathophysiology of muscle dysfunction in COPD. J Appl Physiol
(1985) 2013; 114:1222-1234
160
296 Levine S, Bashir MH, Clanton TL, et al. COPD elicits remodeling of the diaphragm and
vastus lateralis muscles in humans. J Appl Physiol (1985) 2013; 114:1235-1245
297 Reid WD, Huang J, Bryson S, et al. Diaphragm injury and myofibrillar structure induced by
resistive loading. J Appl Physiol (1985) 1994; 76:176-184
298 Vilaro J, Ramirez-Sarmiento A, Martinez-Llorens JM, et al. Global muscle dysfunction as a
risk factor of readmission to hospital due to COPD exacerbations. Respir Med 2010;
104:1896-1902
299 Gayan-Ramirez G, Decramer M. Mechanisms of striated muscle dysfunction during acute
exacerbations of COPD. J Appl Physiol (1985) 2013; 114:1291-1299
300 Gea J, Martinez-Llorens J, Barreiro E. [Nutritional abnormalities in chronic obstructive
pulmonary disease]. Med Clin (Barc) 2014; 143:78-84
301 Pinet C, Cassart M, Scillia P, et al. Function and bulk of respiratory and limb muscles in
patients with cystic fibrosis. Am J Respir Crit Care Med 2003; 168:989-994
302 Mans CM, Reeve JC, Elkins MR. Postoperative outcomes following preoperative
inspiratory muscle training in patients undergoing cardiothoracic or upper abdominal
surgery: a systematic review and meta analysis. Clin Rehabil 2015; 29:426-438
303 Bisca GW, Morita AA, Hernandes NA, et al. Simple Lower Limb Functional Tests in
Patients With Chronic Obstructive Pulmonary Disease: A Systematic Review. Arch
Phys Med Rehabil 2015; 96:2221-2230
304 Kon SS, Patel MS, Canavan JL, et al. Reliability and validity of 4-metre gait speed in
COPD. Eur Respir J 2013; 42:333-340
305 Karpman C, DePew ZS, LeBrasseur NK, et al. Determinants of gait speed in COPD.
Chest 2014; 146:104-110
306 Karpman C, Lebrasseur NK, Depew ZS, et al. Measuring gait speed in the out-patient
clinic: methodology and feasibility. Respir Care 2014; 59:531-537
307 Jones SE, Kon SS, Canavan JL, et al. The five-repetition sit-to-stand test as a functional
outcome measure in COPD. Thorax 2013; 68:1015-1020
308 Roig M, Eng JJ, MacIntyre DL, et al. Deficits in muscle strength, mass, quality, and
mobility in people with chronic obstructive pulmonary disease. J Cardiopulm Rehabil
Prev 2011; 31:120-124
309 Janssens L, Brumagne S, McConnell AK, et al. Impaired postural control reduces sit-to-
stand-to-sit performance in individuals with chronic obstructive pulmonary disease.
PLoS One 2014; 9:e88247
161
310 Puhan MA, Siebeling L, Zoller M, et al. Simple functional performance tests and mortality
in COPD. Eur Respir J 2013; 42:956-963
311 Wilke S, Spruit MA, Wouters EF, et al. Determinants of 1-year changes in disease-specific
health status in patients with advanced chronic obstructive pulmonary disease: A 1-
year observational study. Int J Nurs Pract 2015; 21:239-248
312 Beauchamp MK, Hill K, Goldstein RS, et al. Impairments in balance discriminate fallers
from non-fallers in COPD. Respir Med 2009; 103:1885-1891
313 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
314 Singer J, Yelin EH, Katz PP, et al. Respiratory and skeletal muscle strength in chronic
obstructive pulmonary disease: impact on exercise capacity and lower extremity
function. J Cardiopulm Rehabil Prev 2011; 31:111-119
315 Puthoff ML. Outcome measures in cardiopulmonary physical therapy: short physical
performance battery. Cardiopulm Phys Ther J 2008; 19:17-22
316 Eisner MD, Iribarren C, Yelin EH, et al. Pulmonary function and the risk of functional
limitation in chronic obstructive pulmonary disease. Am J Epidemiol 2008; 167:1090-
1101
317 Eisner MD, Iribarren C, Blanc PD, et al. Development of disability in chronic obstructive
pulmonary disease: beyond lung function. Thorax 2011; 66:108-114
318 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
319 Herridge MS, Chu LM, Matte A, et al. The RECOVER Program: Disability Risk Groups and
1-Year Outcome after 7 or More Days of Mechanical Ventilation. Am J Respir Crit Care
Med 2016; 194:831-844
320 Patcai JT, Disotto-Monastero MP, Gomez M, et al. Inpatient rehabilitation outcomes in
solid organ transplantation: Results of a unique partnership between the rehabilitation
hospital and the multi-organ transplant unit in an acute hospital. Open Journal of
Therapy and Rehabilitation 2013; 1(2): 52-61.
321 Linacre JM, Heinemann AW, Wright BD, et al. The structure and stability of the Functional
Independence Measure. Arch Phys Med Rehabil 1994; 75:127-132
162
322 Beninato M, Gill-Body KM, Salles S, et al. Determination of the minimal clinically important
difference in the FIM instrument in patients with stroke. Arch Phys Med Rehabil 2006;
87:32-39
323 Vonlanthen R, Slankamenac K, Breitenstein S, et al. The impact of complications on costs
of major surgical procedures: a cost analysis of 1200 patients. Ann Surg 2011;
254:907-913
324 Handy JR, Jr., Denniston K, Grunkemeier GL, et al. What is the inpatient cost of hospital
complications or death after lobectomy or pneumonectomy? Ann Thorac Surg 2011;
91:234-238
325 Zeyneloglu P. Respiratory complications after solid-organ transplantation. Exp Clin
Transplant 2015; 13:115-125
326 De Gasperi A, Feltracco P, Ceravola E, et al. Pulmonary complications in patients
receiving a solid-organ transplant. Curr Opin Crit Care 2014; 20:411-419
327 Jain R, Duval S, Adabag S. How accurate is the eyeball test?: a comparison of physician's
subjective assessment versus statistical methods in estimating mortality risk after
cardiac surgery. Circ Cardiovasc Qual Outcomes 2014; 7:151-156
328 Farhan H, Moreno-Duarte I, Latronico N, et al. Acquired Muscle Weakness in the Surgical
Intensive Care Unit: Nosology, Epidemiology, Diagnosis, and Prevention.
Anesthesiology 2016; 124:207-234
329 Bayram AS, Candan T, Gebitekin C. Preoperative maximal exercise oxygen consumption
test predicts postoperative pulmonary morbidity following major lung resection.
Respirology 2007; 12:505-510
330 Loewen GM, Watson D, Kohman L, et al. Preoperative exercise Vo2 measurement for
lung resection candidates: results of Cancer and Leukemia Group B Protocol 9238. J
Thorac Oncol 2007; 2:619-625
331 Szekely LA, Oelberg DA, Wright C, et al. Preoperative predictors of operative morbidity
and mortality in COPD patients undergoing bilateral lung volume reduction surgery.
Chest 1997; 111:550-558
332 Dronkers JJ, Chorus AM, van Meeteren NL, et al. The association of pre-operative
physical fitness and physical activity with outcome after scheduled major abdominal
surgery. Anaesthesia 2013; 68:67-73
333 Paddon-Jones D, Sheffield-Moore M, Cree MG, et al. Atrophy and impaired muscle
protein synthesis during prolonged inactivity and stress. J Clin Endocrinol Metab 2006;
91:4836-4841
163
334 Siafakas NM, Mitrouska I, Bouros D, et al. Surgery and the respiratory muscles. Thorax
1999; 54:458-465
335 Welvaart WN, Paul MA, Stienen GJ, et al. Selective diaphragm muscle weakness after
contractile inactivity during thoracic surgery. Ann Surg 2011; 254:1044-1049
336 Bautmans I, Njemini R, De Backer J, et al. Surgery-induced inflammation in relation to
age, muscle endurance, and self-perceived fatigue. J Gerontol A Biol Sci Med Sci
2010; 65:266-273
337 McEwen BS. Physiology and neurobiology of stress and adaptation: central role of the
brain. Physiol Rev 2007; 87:873-904
338 Hoogeboom TJ, Dronkers JJ, Hulzebos EH, et al. Merits of exercise therapy before and
after major surgery. Curr Opin Anaesthesiol 2014; 27:161-166
339 Afilalo J, Eisenberg MJ, Morin JF, et al. Gait speed as an incremental predictor of mortality
and major morbidity in elderly patients undergoing cardiac surgery. J Am Coll Cardiol
2010; 56:1668-1676
340 Robinson TN, Wu DS, Sauaia A, et al. Slower walking speed forecasts increased
postoperative morbidity and 1-year mortality across surgical specialties. Ann Surg
2013; 258:582-588; discussion 588-590
341 Jones TS, Dunn CL, Wu DS, et al. Relationship between asking an older adult about falls
and surgical outcomes. JAMA Surg 2013; 148:1132-1138
342 Wang CW, Feng S, Covinsky KE, et al. A Comparison of Muscle Function, Mass, and
Quality in Liver Transplant Candidates: Results From the Functional Assessment in
Liver Transplantation Study. Transplantation 2016; 100:1692-1698
343 Wilson ME, Vakil AP, Kandel P, et al. Pretransplant frailty is associated with decreased
survival after lung transplantation. J Heart Lung Transplant 2016; 35:173-178
344 Englesbe MJ, Lee JS, He K, et al. Analytic morphomics, core muscle size, and surgical
outcomes. Ann Surg 2012; 256:255-261
345 Paknikar R, Friedman J, Cron D, et al. Psoas muscle size as a frailty measure for open
and transcatheter aortic valve replacement. J Thorac Cardiovasc Surg 2016; 151:745-
750
346 Krell RW, Kaul DR, Martin AR, et al. Association between sarcopenia and the risk of
serious infection among adults undergoing liver transplantation. Liver Transpl 2013;
19:1396-1402
164
347 Montano-Loza AJ, Meza-Junco J, Prado CM, et al. Muscle wasting is associated with
mortality in patients with cirrhosis. Clin Gastroenterol Hepatol 2012; 10:166-173, 173
e161
348 van Vugt JL, Levolger S, de Bruin RW, et al. Systematic Review and Meta-Analysis of the
Impact of Computed Tomography-Assessed Skeletal Muscle Mass on Outcome in
Patients Awaiting or Undergoing Liver Transplantation. Am J Transplant 2016;
16:2277-2292
349 Streja E, Molnar MZ, Kovesdy CP, et al. Associations of pretransplant weight and muscle
mass with mortality in renal transplant recipients. Clin J Am Soc Nephrol 2011; 6:1463-
1473
350 Molnar MZ, Streja E, Kovesdy CP, et al. Associations of body mass index and weight loss
with mortality in transplant-waitlisted maintenance hemodialysis patients. Am J
Transplant 2011; 11:725-736
351 Fouque D, Kalantar-Zadeh K, Kopple J, et al. A proposed nomenclature and diagnostic
criteria for protein-energy wasting in acute and chronic kidney disease. Kidney Int
2008; 73:391-398
352 Dahya V, Xiao J, Prado CM, et al. Computed tomography-derived skeletal muscle index: A
novel predictor of frailty and hospital length of stay after transcatheter aortic valve
replacement. Am Heart J 2016; 182:21-27
353 Kemi OJ, Wisloff U. High-intensity aerobic exercise training improves the heart in health
and disease. J Cardiopulm Rehabil Prev 2010; 30:2-11
354 O'Doherty AF, West M, Jack S, et al. Preoperative aerobic exercise training in elective
intra-cavity surgery: a systematic review. Br J Anaesth 2013; 110:679-689
355 Jones LW, Peddle CJ, Eves ND, et al. Effects of presurgical exercise training on
cardiorespiratory fitness among patients undergoing thoracic surgery for malignant lung
lesions. Cancer 2007; 110:590-598
356 Carli F, Charlebois P, Stein B, et al. Randomized clinical trial of prehabilitation in colorectal
surgery. Br J Surg 2010; 97:1187-1197
357 Herdy AH, Marcchi PL, Vila A, et al. Pre- and postoperative cardiopulmonary rehabilitation
in hospitalized patients undergoing coronary artery bypass surgery: a randomized
controlled trial. Am J Phys Med Rehabil 2008; 87:714-719
358 Arthur HM, Daniels C, McKelvie R, et al. Effect of a preoperative intervention on
preoperative and postoperative outcomes in low-risk patients awaiting elective coronary
165
artery bypass graft surgery. A randomized, controlled trial. Ann Intern Med 2000;
133:253-262
359 Bobbio A, Chetta A, Ampollini L, et al. Preoperative pulmonary rehabilitation in patients
undergoing lung resection for non-small cell lung cancer. Eur J Cardiothorac Surg
2008; 33:95-98
360 Nagamatsu Y, Shima I, Yamana H, et al. Preoperative evaluation of cardiopulmonary
reserve with the use of expired gas analysis during exercise testing in patients with
squamous cell carcinoma of the thoracic esophagus. J Thorac Cardiovasc Surg 2001;
121:1064-1068
361 Mayo NE, Feldman L, Scott S, et al. Impact of preoperative change in physical function on
postoperative recovery: argument supporting prehabilitation for colorectal surgery.
Surgery 2011; 150:505-514
362 Jack S, West M, Grocott MP. Perioperative exercise training in elderly subjects. Best Pract
Res Clin Anaesthesiol 2011; 25:461-472
363 Hulzebos EH, Smit Y, Helders PP, et al. Preoperative physical therapy for elective cardiac
surgery patients. Cochrane Database Syst Rev 2012; 11:CD010118
364 Wallen MP, Skinner TL, Pavey TG, et al. Safety, adherence and efficacy of exercise
training in solid-organ transplant candidates: A systematic review. Transplant Rev
(Orlando) 2016
365 O'Connor CM, Whellan DJ, Lee KL, et al. Efficacy and safety of exercise training in
patients with chronic heart failure: HF-ACTION randomized controlled trial. JAMA 2009;
301:1439-1450
366 Pandey A, Garg S, Khunger M, et al. Efficacy and Safety of Exercise Training in Chronic
Pulmonary Hypertension: Systematic Review and Meta-Analysis. Circ Heart Fail 2015;
8:1032-1043
367 He M, Yu S, Wang L, et al. Efficiency and safety of pulmonary rehabilitation in acute
exacerbation of chronic obstructive pulmonary disease. Med Sci Monit 2015; 21:806-
812
368 Manzetti JD, Hoffman LA, Sereika SM, et al. Exercise, education, and quality of life in lung
transplant candidates. J Heart Lung Transplant 1994; 13:297-305
369 Florian J, Rubin A, Mattiello R, et al. Impact of pulmonary rehabilitation on quality of life
and functional capacity in patients on waiting lists for lung transplantation. J Bras
Pneumol 2013; 39:349-356
166
370 Gloeckl R, Halle M, Kenn K. Interval versus continuous training in lung transplant
candidates: a randomized trial. J Heart Lung Transplant 2012; 31:934-941
371 Ries AL, Kaplan RM, Limberg TM, et al. Effects of pulmonary rehabilitation on physiologic
and psychosocial outcomes in patients with chronic obstructive pulmonary disease.
Ann Intern Med 1995; 122:823-832
372 Naji NA, Connor MC, Donnelly SC, et al. Effectiveness of pulmonary rehabilitation in
restrictive lung disease. J Cardiopulm Rehabil 2006; 26:237-243
373 Trojetto T, Elliott RJ, Rashid S, et al. Availability, characteristics, and barriers of
rehabilitation programs in organ transplant populations across Canada. Clin Transplant
2011; 25:E571-578
374 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
375 Porteous MK, Diamond JM, Christie JD. Primary graft dysfunction: lessons learned about
the first 72 h after lung transplantation. Curr Opin Organ Transplant 2015; 20:506-514
376 Diamond JM, Lee JC, Kawut SM, et al. Clinical risk factors for primary graft dysfunction
after lung transplantation. Am J Respir Crit Care Med 2013; 187:527-534
377 Fuehner T, Kuehn C, Welte T, et al. ICU Care Before and After Lung Transplantation.
Chest 2016; 150:442-450
378 Lee JC, Christie JD. Primary graft dysfunction. Proc Am Thorac Soc 2009; 6:39-46
379 Herridge MS, Moss M, Hough CL, et al. Recovery and outcomes after the acute
respiratory distress syndrome (ARDS) in patients and their family caregivers. Intensive
Care Med 2016; 42:725-738
380 Unroe M, Kahn JM, Carson SS, et al. One-year trajectories of care and resource utilization
for recipients of prolonged mechanical ventilation: a cohort study. Ann Intern Med 2010;
153:167-175
381 Carson SS, Kahn JM, Hough CL, et al. A multicenter mortality prediction model for
patients receiving prolonged mechanical ventilation. Crit Care Med 2012; 40:1171-1176
382 Fan E, Cheek F, Chlan L, et al. An official American Thoracic Society Clinical Practice
guideline: the diagnosis of intensive care unit-acquired weakness in adults. Am J
Respir Crit Care Med 2014; 190:1437-1446
383 Hermans G, Van den Berghe G. Clinical review: intensive care unit acquired weakness.
Crit Care 2015; 19:274
167
384 Ali NA, O'Brien JM, Jr., Hoffmann SP, et al. Acquired weakness, handgrip strength, and
mortality in critically ill patients. Am J Respir Crit Care Med 2008; 178:261-268
385 Sharshar T, Bastuji-Garin S, Stevens RD, et al. Presence and severity of intensive care
unit-acquired paresis at time of awakening are associated with increased intensive care
unit and hospital mortality. Crit Care Med 2009; 37:3047-3053
386 Mirzakhani H, Williams JN, Mello J, et al. Muscle weakness predicts pharyngeal
dysfunction and symptomatic aspiration in long-term ventilated patients.
Anesthesiology 2013; 119:389-397
387 Hermans G, Van Mechelen H, Clerckx B, et al. Acute outcomes and 1-year mortality of
intensive care unit-acquired weakness. A cohort study and propensity-matched
analysis. Am J Respir Crit Care Med 2014; 190:410-420
388 Fan E, Dowdy DW, Colantuoni E, et al. Physical complications in acute lung injury
survivors: a two-year longitudinal prospective study. Crit Care Med 2014; 42:849-859
389 Herridge MS, Tansey CM, Matte A, et al. Functional disability 5 years after acute
respiratory distress syndrome. N Engl J Med 2011; 364:1293-1304
390 Jackson JC, Pandharipande PP, Girard TD, et al. Depression, post-traumatic stress
disorder, and functional disability in survivors of critical illness in the BRAIN-ICU study:
a longitudinal cohort study. Lancet Respir Med 2014; 2:369-379
391 Pandharipande PP, Girard TD, Jackson JC, et al. Long-term cognitive impairment after
critical illness. N Engl J Med 2013; 369:1306-1316
392 Wilcox ME, Brummel NE, Archer K, et al. Cognitive dysfunction in ICU patients: risk
factors, predictors, and rehabilitation interventions. Crit Care Med 2013; 41:S81-98
393 Smith PJ, Rivelli S, Waters A, et al. Neurocognitive changes after lung transplantation.
Ann Am Thorac Soc 2014; 11:1520-1527
394 Cohen DG, Christie JD, Anderson BJ, et al. Cognitive function, mental health, and health-
related quality of life after lung transplantation. Ann Am Thorac Soc 2014; 11:522-530
395 Cameron JI, Chu LM, Matte A, et al. One-Year Outcomes in Caregivers of Critically Ill
Patients. N Engl J Med 2016; 374:1831-1841
396 Kramer AA, Higgins TL, Zimmerman JE. Intensive care unit readmissions in U.S.
hospitals: patient characteristics, risk factors, and outcomes. Crit Care Med 2012; 40:3-
10
397 Ferrante LE, Pisani MA, Murphy TE, et al. Functional trajectories among older persons
before and after critical illness. JAMA Intern Med 2015; 175:523-529
168
398 Lone NI, Gillies MA, Haddow C, et al. Five-Year Mortality and Hospital Costs Associated
with Surviving Intensive Care. Am J Respir Crit Care Med 2016; 194:198-208
399 Puthucheary ZA, Rawal J, McPhail M, et al. Acute skeletal muscle wasting in critical
illness. JAMA 2013; 310:1591-1600
400 Turner DA, Cheifetz IM, Rehder KJ, et al. Active rehabilitation and physical therapy during
extracorporeal membrane oxygenation while awaiting lung transplantation: a practical
approach. Crit Care Med 2011; 39:2593-2598
401 Rehder KJ, Turner DA, Hartwig MG, et al. Active rehabilitation during extracorporeal
membrane oxygenation as a bridge to lung transplantation. Respir Care 2013; 58:1291-
1298
402 Mangi AA, Mason DP, Yun JJ, et al. Bridge to lung transplantation using short-term
ambulatory extracorporeal membrane oxygenation. J Thorac Cardiovasc Surg 2010;
140:713-715
403 Lafc G, Budak AB, Yener AU, et al. Use of extracorporeal membrane oxygenation in
adults. Heart Lung Circ 2014; 23:10-23
404 Mols G, Loop T, Geiger K, et al. Extracorporeal membrane oxygenation: a ten-year
experience. Am J Surg 2000; 180:144-154
405 Morris PE. Moving our critically ill patients: mobility barriers and benefits. Crit Care Clin
2007; 23:1-20
406 Morris PE, Griffin L, Berry M, et al. Receiving early mobility during an intensive care unit
admission is a predictor of improved outcomes in acute respiratory failure. Am J Med
Sci 2011; 341:373-377
407 Schweickert WD, Pohlman MC, Pohlman AS, et al. Early physical and occupational
therapy in mechanically ventilated, critically ill patients: a randomised controlled trial.
Lancet 2009; 373:1874-1882
408 Burtin C, Clerckx B, Robbeets C, et al. Early exercise in critically ill patients enhances
short-term functional recovery. Crit Care Med 2009; 37:2499-2505
409 Moss M, Nordon-Craft A, Malone D, et al. A Randomized Trial of an Intensive Physical
Therapy Program for Patients with Acute Respiratory Failure. Am J Respir Crit Care
Med 2016; 193:1101-1110
410 Kayambu G, Boots R, Paratz J. Physical therapy for the critically ill in the ICU: a
systematic review and meta-analysis. Crit Care Med 2013; 41:1543-1554
169
411 Harrold ME, Salisbury LG, Webb SA, et al. Early mobilisation in intensive care units in
Australia and Scotland: a prospective, observational cohort study examining
mobilisation practises and barriers. Crit Care 2015; 19:336
412 Investigators TS, Hodgson C, Bellomo R, et al. Early mobilization and recovery in
mechanically ventilated patients in the ICU: a bi-national, multi-centre, prospective
cohort study. Crit Care 2015; 19:81
413 Hodgin KE, Nordon-Craft A, McFann KK, et al. Physical therapy utilization in intensive
care units: results from a national survey. Crit Care Med 2009; 37:561-566; quiz 566-
568
414 Hashem MD, Nelliot A, Needham DM. Early Mobilization and Rehabilitation in the ICU:
Moving Back to the Future. Respir Care 2016; 61:971-979
415 Schuurmans MM, Benden C, Inci I. Practical approach to early postoperative management
of lung transplant recipients. Swiss Med Wkly 2013; 143:w13773
416 Leal S, Sacanell J, Riera J, et al. Early postoperative management of lung transplantation.
Minerva Anestesiol 2014; 80:1234-1245
417 Kress JP, Hall JB. ICU-acquired weakness and recovery from critical illness. N Engl J Med
2014; 370:1626-1635
418 Adler J, Malone D. Early mobilization in the intensive care unit: a systematic review.
Cardiopulm Phys Ther J 2012; 23:5-13
419 Hunter A, Johnson L, Coustasse A. Reduction of intensive care unit length of stay: the
case of early mobilization. Health Care Manag (Frederick) 2014; 33:128-135
420 Munro PE, Holland AE, Bailey M, et al. Pulmonary rehabilitation following lung
transplantation. Transplant Proc 2009; 41:292-295
421 Bowman M, Faux S. Outcomes of an inpatient rehabilitation program following
complicated cardio-pulmonary transplantation. Int J Phys Med Rehabil 2013; 1:1-6.
422 Scrutinio D, Monitillo V, Guida P, et al. Functional Gain After Inpatient Stroke
Rehabilitation: Correlates and Impact on Long-Term Survival. Stroke 2015; 46:2976-
2980
423 Titman A, Rogers CA, Bonser RS, et al. Disease-specific survival benefit of lung
transplantation in adults: a national cohort study. Am J Transplant 2009; 9:1640-1649
424 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
170
425 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
426 Kyle UG, Nicod L, Romand JA, et al. Four-year follow-up of body compostion in lung
transplant patients. Transplantation 2003; 75:821-828
427 Goodpaster BH, Thaete FL, Kelley DE. Composition of skeletal muscle evaluated with
computed tomography. Ann N Y Acad Sci 2000; 904:18-24
428 Lee RC, Wang ZM, Heymsfield SB. Skeletal muscle mass and aging: regional and whole-
body measurement methods. Can J Appl Physiol 2001; 26:102-122
429 Mathur S, Rodrigues N, Mendes P, et al. Computed tomography derived thoracic muscle
size as an indicator of sarcopenia in people with advanced lung disease.
Cardiopulmonary Physical Therapy Journal 2017; 28(3): 99-105.
430 Menezes RJ, Roberts HC, Paul NS, et al. Lung cancer screening using low-dose
computed tomography in at-risk individuals: the Toronto experience. Lung Cancer
2010; 67:177-183
431 Slice-O-Matic Software, http://www.tomovision.com/products/sliceomatic.html, Last
accessed May 1, 2017.
432 Heymsfield SB, Wang Z, Baumgartner RN, et al. Human body composition: advances in
models and methods. Annu Rev Nutr 1997; 17:527-558
433 Laboratories ATSCoPSfCPF. ATS statement: guidelines for the six-minute walk test. Am J
Respir Crit Care Med 2002; 166:111-117
434 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
435 Christie JD, Carby M, Bag R, et al. Report of the ISHLT Working Group on Primary Lung
Graft Dysfunction part II: definition. A consensus statement of the International Society
for Heart and Lung Transplantation. J Heart Lung Transplant 2005; 24:1454-1459
436 Christie JD, Bellamy S, Ware LB, et al. Construct validity of the definition of primary graft
dysfunction after lung transplantation. J Heart Lung Transplant 2010; 29:1231-1239
437 Kim YS, Kim EY, Kang SM, et al. Single cross-sectional area of pectoralis muscle by
computed tomography - correlation with bioelectrical impedance based skeletal muscle
mass in healthy subjects. Clin Physiol Funct Imaging 2015
438 Kotler DP. Cachexia. Ann Intern Med 2000; 133:622-634
171
439 Montano-Loza AJ, Meza-Junco J, Baracos VE, et al. Severe muscle depletion predicts
postoperative length of stay but is not associated with survival after liver
transplantation. Liver Transpl 2014; 20:640-648
440 Eisner MD, Blanc PD, Sidney S, et al. Body composition and functional limitation in
COPD. Respir Res 2007; 8:7
441 Schols AM, Soeters PB, Dingemans AM, et al. Prevalence and characteristics of
nutritional depletion in patients with stable COPD eligible for pulmonary rehabilitation.
Am Rev Respir Dis 1993; 147:1151-1156
442 Diaz AA, Morales A, Diaz JC, et al. CT and physiologic determinants of dyspnea and
exercise capacity during the six-minute walk test in mild COPD. Respir Med 2013;
107:570-579
443 van Gestel AJ, Baty F, Rausch-Osthof AK, et al. Cardiopulmonary and gas-exchange
responses during the six-minute walk test in patients with chronic obstructive
pulmonary disease. Respiration 2014; 88:307-314
444 Nyberg A, Saey D, Maltais F. Why and How Limb Muscle Mass and Function Should Be
Measured in Patients with Chronic Obstructive Pulmonary Disease. Ann Am Thorac
Soc 2015; 12:1269-1277
445 Mostert R, Goris A, Weling-Scheepers C, et al. Tissue depletion and health related quality
of life in patients with chronic obstructive pulmonary disease. Respir Med 2000; 94:859-
867
446 Sanchez FF, Faganello MM, Tanni SE, et al. Anthropometric midarm measurements can
detect systemic fat-free mass depletion in patients with chronic obstructive pulmonary
disease. Braz J Med Biol Res 2011; 44:453-459
447 Kuk JL, Church TS, Blair SN, et al. Associations between changes in abdominal and thigh
muscle quantity and quality. Med Sci Sports Exerc 2008; 40:1277-1281
448 Lee SJ, Janssen I, Heymsfield SB, et al. Relation between whole-body and regional
measures of human skeletal muscle. Am J Clin Nutr 2004; 80:1215-1221
449 Waschki B, Kirsten AM, Holz O, et al. Disease Progression and Changes in Physical
Activity in Patients with Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care
Med 2015; 192:295-306
450 Chlan LL. Feasibility of Bioelectric Impedance as a Measure of Muscle Mass in
Mechanically Ventilated ICU Patients. Open J Nurs 2014; 4:51-56
451 Martinez BP, Batista AK, Gomes IB, et al. Frequency of sarcopenia and associated factors
among hospitalized elderly patients. BMC Musculoskelet Disord 2015; 16:108
172
452 Nedergaard A, Henriksen K, Karsdal MA, et al. Musculoskeletal ageing and primary
prevention. Best Pract Res Clin Obstet Gynaecol 2013; 27:673-688
453 Ambrosino N, Bruschi C, Callegari G, et al. Time course of exercise capacity, skeletal and
respiratory muscle performance after heart-lung transplantation. Eur Respir J 1996;
9:1508-1514
454 Santa Mina D, Scheede-Bergdahl C, Gillis C, et al. Optimization of surgical outcomes with
prehabilitation. Appl Physiol Nutr Metab 2015; 40:966-969
455 Cook JW, Pierson LM, Herbert WG, et al. The influence of patient strength, aerobic
capacity and body composition upon outcomes after coronary artery bypass grafting.
Thorac Cardiovasc Surg 2001; 49:89-93
456 Gillis C, Li C, Lee L, et al. Prehabilitation versus rehabilitation: a randomized control trial in
patients undergoing colorectal resection for cancer. Anesthesiology 2014; 121:937-947
457 Christie JD, Kotloff RM, Ahya VN, et al. The effect of primary graft dysfunction on survival
after lung transplantation. Am J Respir Crit Care Med 2005; 171:1312-1316
458 Rajagopal K, Hoeper MM. State of the Art: Bridging to lung transplantation using artificial
organ support technologies. J Heart Lung Transplant 2016; 35:1385-1398
459 Jolley SE, Bunnell AE, Hough CL. ICU-Acquired Weakness. Chest 2016; 150:1129-1140
460 Lederer DJ, Kawut SM, Wickersham N, et al. Obesity and primary graft dysfunction after
lung transplantation: the Lung Transplant Outcomes Group Obesity Study. Am J Respir
Crit Care Med 2011; 184:1055-1061
461 Knaus WA, Draper EA, Wagner DP, et al. APACHE II: a severity of disease classification
system. Crit Care Med 1985; 13:818-829
462 Marshall JC, Cook DJ, Christou NV, et al. Multiple organ dysfunction score: a reliable
descriptor of a complex clinical outcome. Crit Care Med 1995; 23:1638-1652
463 Chang JA, Curtis JR, Patrick DL, et al. Assessment of health-related quality of life in
patients with interstitial lung disease. Chest 1999; 116:1175-1182
464 Wyrwich KW, Fihn SD, Tierney WM, et al. Clinically important changes in health-related
quality of life for patients with chronic obstructive pulmonary disease: an expert
consensus panel report. J Gen Intern Med 2003; 18:196-202
465 Stevens RD, Marshall SA, Cornblath DR, et al. A framework for diagnosing and classifying
intensive care unit-acquired weakness. Crit Care Med 2009; 37:S299-308
466 Hough CL, Lieu BK, Caldwell ES. Manual muscle strength testing of critically ill patients:
feasibility and interobserver agreement. Crit Care 2011; 15:R43
173
467 Fan E, Ciesla ND, Truong AD, et al. Inter-rater reliability of manual muscle strength testing
in ICU survivors and simulated patients. Intensive Care Med 2010; 36:1038-1043
468 Sacanella E, Perez-Castejon JM, Nicolas JM, et al. Functional status and quality of life 12
months after discharge from a medical ICU in healthy elderly patients: a prospective
observational study. Crit Care 2011; 15:R105
469 Tomaszek SC, Fibla JJ, Dierkhising RA, et al. Outcome of lung transplantation in elderly
recipients. Eur J Cardiothorac Surg 2011; 39:726-731
470 Vadnerkar A, Toyoda Y, Crespo M, et al. Age-specific complications among lung
transplant recipients 60 years and older. J Heart Lung Transplant 2011; 30:273-281
471 Lipshutz AK, Gropper MA. Acquired neuromuscular weakness and early mobilization in
the intensive care unit. Anesthesiology 2013; 118:202-215
472 Beer A, Reed RM, Bolukbas S, et al. Mechanical ventilation after lung transplantation. An
international survey of practices and preferences. Ann Am Thorac Soc 2014; 11:546-
553
473 Fletcher SN, Kennedy DD, Ghosh IR, et al. Persistent neuromuscular and
neurophysiologic abnormalities in long-term survivors of prolonged critical illness. Crit
Care Med 2003; 31:1012-1016
474 Jackson JC, Girard TD, Gordon SM, et al. Long-term cognitive and psychological
outcomes in the awakening and breathing controlled trial. Am J Respir Crit Care Med
2010; 182:183-191
475 Medrinal C, Prieur G, Frenoy E, et al. Respiratory weakness after mechanical ventilation is
associated with one-year mortality - a prospective study. Crit Care 2016; 20:231
476 Landi F, Liperoti R, Russo A, et al. Sarcopenia as a risk factor for falls in elderly
individuals: results from the ilSIRENTE study. Clin Nutr 2012; 31:652-658
477 Landi F, Cruz-Jentoft AJ, Liperoti R, et al. Sarcopenia and mortality risk in frail older
persons aged 80 years and older: results from ilSIRENTE study. Age Ageing 2013;
42:203-209
478 Correa-de-Araujo R, Hadley E. Skeletal muscle function deficit: a new terminology to
embrace the evolving concepts of sarcopenia and age-related muscle dysfunction. J
Gerontol A Biol Sci Med Sci 2014; 69:591-594
479 Lerario MC, Sachs A, Lazaretti-Castro M, et al. Body composition in patients with chronic
obstructive pulmonary disease: which method to use in clinical practice? Br J Nutr
2006; 96:86-92
174
480 Kyle UG, Genton L, Hans D, et al. Validation of a bioelectrical impedance analysis
equation to predict appendicular skeletal muscle mass (ASMM). Clin Nutr 2003;
22:537-543
481 Clark BC, Taylor JL. Age-related changes in motor cortical properties and voluntary
activation of skeletal muscle. Curr Aging Sci 2011; 4:192-199
482 Delbono O. Expression and regulation of excitation-contraction coupling proteins in aging
skeletal muscle. Curr Aging Sci 2011; 4:248-259
483 Marcus RL, Addison O, Dibble LE, et al. Intramuscular adipose tissue, sarcopenia, and
mobility function in older individuals. J Aging Res 2012; 2012:629637
484 Calik-Kutukcu E, Arikan H, Saglam M, et al. Arm strength training improves activities of
daily living and occupational performance in patients with COPD. Clin Respir J 2015
485 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
486 Crisan AF, Oancea C, Timar B, et al. Balance impairment in patients with COPD. PLoS
One 2015; 10:e0120573
487 Muir SW, Berg K, Chesworth B, et al. Quantifying the magnitude of risk for balance
impairment on falls in community-dwelling older adults: a systematic review and meta-
analysis. J Clin Epidemiol 2010; 63:389-406
488 O'Loughlin JL, Robitaille Y, Boivin JF, et al. Incidence of and risk factors for falls and
injurious falls among the community-dwelling elderly. Am J Epidemiol 1993; 137:342-
354
489 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
490 Judge JO, Schechtman K, Cress E. The relationship between physical performance
measures and independence in instrumental activities of daily living. The FICSIT
Group. Frailty and Injury: Cooperative Studies of Intervention Trials. J Am Geriatr Soc
1996; 44:1332-1341
491 Bouras EP, Lange SM, Scolapio JS. Rational approach to patients with unintentional
weight loss. Mayo Clin Proc 2001; 76:923-929
492 Brown AW, Kaya H, Nathan SD. Lung transplantation in IIP: A review. Respirology 2016;
21:1173-1184
175
493 Arora NS, Rochester DF. Effect of body weight and muscularity on human diaphragm
muscle mass, thickness, and area. J Appl Physiol Respir Environ Exerc Physiol 1982;
52:64-70
494 Hoppeler H, Kleinert E, Schlegel C, et al. Morphological adaptations of human skeletal
muscle to chronic hypoxia. Int J Sports Med 1990; 11 Suppl 1:S3-9
495 Takabatake N, Nakamura H, Abe S, et al. The relationship between chronic hypoxemia
and activation of the tumor necrosis factor-alpha system in patients with chronic
obstructive pulmonary disease. Am J Respir Crit Care Med 2000; 161:1179-1184
496 Pitsiou G, Kyriazis G, Hatzizisi O, et al. Tumor necrosis factor-alpha serum levels, weight
loss and tissue oxygenation in chronic obstructive pulmonary disease. Respir Med
2002; 96:594-598
497 Payen JF, Wuyam B, Levy P, et al. Muscular metabolism during oxygen supplementation
in patients with chronic hypoxemia. Am Rev Respir Dis 1993; 147:592-598
498 Decramer M, Lacquet LM, Fagard R, et al. Corticosteroids contribute to muscle weakness
in chronic airflow obstruction. Am J Respir Crit Care Med 1994; 150:11-16
499 Kozu R, Senjyu H, Jenkins SC, et al. Differences in response to pulmonary rehabilitation
in idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease. Respiration
2011; 81:196-205
500 Meyer KC. Immunosuppressive agents and interstitial lung disease: what are the risks?
Expert Rev Respir Med 2014; 8:263-266
501 Walters JA, Walters EH, Wood-Baker R. Oral corticosteroids for stable chronic obstructive
pulmonary disease. Cochrane Database Syst Rev 2005:CD005374
502 Idiopathic Pulmonary Fibrosis Clinical Research N, Raghu G, Anstrom KJ, et al.
Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N Engl J Med
2012; 366:1968-1977
503 Dekhuijzen PN, Decramer M. Steroid-induced myopathy and its significance to respiratory
disease: a known disease rediscovered. Eur Respir J 1992; 5:997-1003
504 Middlekauff HR. Making the case for skeletal myopathy as the major limitation of exercise
capacity in heart failure. Circ Heart Fail 2010; 3:537-546
505 D'Souza DM, Al-Sajee D, Hawke TJ. Diabetic myopathy: impact of diabetes mellitus on
skeletal muscle progenitor cells. Front Physiol 2013; 4:379
506 Hadj A, Esmore D, Rowland M, et al. Pre-operative preparation for cardiac surgery
utilising a combination of metabolic, physical and mental therapy. Heart Lung Circ
2006; 15:172-181
176
507 Robinson TN, Eiseman B, Wallace JI, et al. Redefining geriatric preoperative assessment
using frailty, disability and co-morbidity. Ann Surg 2009; 250:449-455
508 Kaneda H, Saito Y, Okamoto M, et al. Early postoperative mobilization with walking at 4
hours after lobectomy in lung cancer patients. Gen Thorac Cardiovasc Surg 2007;
55:493-498
509 Lipsitz LA. Dynamics of stability: the physiologic basis of functional health and frailty. J
Gerontol A Biol Sci Med Sci 2002; 57:B115-125
510 Berry MJ, Morris PE. Early exercise rehabilitation of muscle weakness in acute respiratory
failure patients. Exerc Sport Sci Rev 2013; 41:208-215
511 Vaes AW, Annegarn J, Meijer K, et al. The effects of a "new" walking aid on exercise
performance in patients with COPD: a randomized crossover trial. Chest 2012;
141:1224-1232
512 Probst VS, Troosters T, Coosemans I, et al. Mechanisms of improvement in exercise
capacity using a rollator in patients with COPD. Chest 2004; 126:1102-1107
513 Engelen MP, Schols AM, Does JD, et al. Skeletal muscle weakness is associated with
wasting of extremity fat-free mass but not with airflow obstruction in patients with
chronic obstructive pulmonary disease. Am J Clin Nutr 2000; 71:733-738
514 Thabut G, Christie JD, Ravaud P, et al. Survival after bilateral versus single-lung
transplantation for idiopathic pulmonary fibrosis. Ann Intern Med 2009; 151:767-774
515 Bardonnaud N, Pillot P, Lillaz J, et al. Outcomes of renal transplantation in obese
recipients. Transplant Proc 2012; 44:2787-2791
516 Cannon RM, Jones CM, Hughes MG, et al. The impact of recipient obesity on outcomes
after renal transplantation. Ann Surg 2013; 257:978-984
517 Gea J, Pascual S, Casadevall C, et al. Muscle dysfunction in chronic obstructive
pulmonary disease: update on causes and biological findings. J Thorac Dis 2015;
7:E418-438
518 Roshanravan B, Patel KV, Fried LF, et al. Association of Muscle Endurance, Fatigability,
and Strength With Functional Limitation and Mortality in the Health Aging and Body
Composition Study. J Gerontol A Biol Sci Med Sci 2017; 72:284-291
519 Puthoff ML, Nielsen DH. Relationships among impairments in lower-extremity strength and
power, functional limitations, and disability in older adults. Phys Ther 2007; 87:1334-
1347
520 Reid KF, Fielding RA. Skeletal muscle power: a critical determinant of physical functioning
in older adults. Exerc Sport Sci Rev 2012; 40:4-12
177
521 Thabut G, Christie JD, Kremers WK, et al. Survival differences following lung
transplantation among US transplant centers. JAMA 2010; 304:53-60
522 Frontera WR, Hughes VA, Fielding RA, et al. Aging of skeletal muscle: a 12-yr longitudinal
study. J Appl Physiol (1985) 2000; 88:1321-1326
523 Ferrucci L, Penninx BW, Volpato S, et al. Change in muscle strength explains accelerated
decline of physical function in older women with high interleukin-6 serum levels. J Am
Geriatr Soc 2002; 50:1947-1954
524 Fukumoto Y, Ikezoe T, Yamada Y, et al. Skeletal muscle quality assessed from echo
intensity is associated with muscle strength of middle-aged and elderly persons. Eur J
Appl Physiol 2012; 112:1519-1525
525 Cadore EL, Izquierdo M, Conceicao M, et al. Echo intensity is associated with skeletal
muscle power and cardiovascular performance in elderly men. Exp Gerontol 2012;
47:473-478
526 Sferrazza Papa GF, Pellegrino GM, Di Marco F, et al. A Review of the Ultrasound
Assessment of Diaphragmatic Function in Clinical Practice. Respiration 2016; 91:403-
411
527 McClean KM, Kee F, Young IS, et al. Obesity and the lung: 1. Epidemiology. Thorax 2008;
63:649-654
528 Joppa P, Tkacova R, Franssen FM, et al. Sarcopenic Obesity, Functional Outcomes, and
Systemic Inflammation in Patients With Chronic Obstructive Pulmonary Disease. J Am
Med Dir Assoc 2016; 17:712-718
529 Rutten EP, Calverley PM, Casaburi R, et al. Changes in body composition in patients with
chronic obstructive pulmonary disease: do they influence patient-related outcomes?
Ann Nutr Metab 2013; 63:239-247
530 Simon-Blancal V, Freynet O, Nunes H, et al. Acute exacerbation of idiopathic pulmonary
fibrosis: outcome and prognostic factors. Respiration 2012; 83:28-35
531 Duren DL, Sherwood RJ, Czerwinski SA, et al. Body composition methods: comparisons
and interpretation. J Diabetes Sci Technol 2008; 2:1139-1146
532 Tong Y, Udupa JK, Torigian DA, et al. Chest Fat Quantification via CT Based on
Standardized Anatomy Space in Adult Lung Transplant Candidates. PLoS One 2017;
12:e0168932
533 Collins PF, Elia M, Stratton RJ. Nutritional support and functional capacity in chronic
obstructive pulmonary disease: a systematic review and meta-analysis. Respirology
2013; 18:616-629
178
534 Creutzberg EC, Wouters EF, Mostert R, et al. Efficacy of nutritional supplementation
therapy in depleted patients with chronic obstructive pulmonary disease. Nutrition 2003;
19:120-127
535 Ferreira IM, Brooks D, White J, et al. Nutritional supplementation for stable chronic
obstructive pulmonary disease. Cochrane Database Syst Rev 2012; 12:CD000998
536 Kirkpatrick SI, Subar AF, Douglass D, et al. Performance of the Automated Self-
Administered 24-hour Recall relative to a measure of true intakes and to an interviewer-
administered 24-h recall. Am J Clin Nutr 2014; 100:233-240
537 Thompson FE, Dixit-Joshi S, Potischman N, et al. Comparison of Interviewer-Administered
and Automated Self-Administered 24-Hour Dietary Recalls in 3 Diverse Integrated
Health Systems. Am J Epidemiol 2015; 181:970-978
538 Gobbens RJ, Luijkx KG, Wijnen-Sponselee MT, et al. In search of an integral conceptual
definition of frailty: opinions of experts. J Am Med Dir Assoc 2010; 11:338-343
539 Maddocks M, Shrikrishna D, Vitoriano S, et al. Skeletal muscle adiposity is associated with
physical activity, exercise capacity and fibre shift in COPD. Eur Respir J 2014;
44:1188-1198
540 Zoll J, N'Guessan B, Ribera F, et al. Preserved response of mitochondrial function to
short-term endurance training in skeletal muscle of heart transplant recipients. J Am
Coll Cardiol 2003; 42:126-132
541 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
542 Okamoto T, Kanazawa H, Hirata K, et al. Evaluation of oxygen uptake kinetics and oxygen
kinetics of peripheral skeletal muscle during recovery from exercise in patients with
chronic obstructive pulmonary disease. Clin Physiol Funct Imaging 2003; 23:257-262
543 Ollech JE, Kramer MR, Peled N, et al. Post-transplant diabetes mellitus in lung transplant
recipients: incidence and risk factors. Eur J Cardiothorac Surg 2008; 33:844-848
544 Forli L, Bollerslev J, Simonsen S, et al. Disturbed energy metabolism after lung and heart
transplantation. Clin Transplant 2011; 25:E136-143
179
APPENDIX 1: Supplementary Tables and Figures
Chapter 3:
0 5 10 15 20 250
50
100
150
Fat-free Mass Index (kg/m2)
Th
ora
cic
Mu
scle
CS
A (
cm2 )
r=0.71,p<0.0001
Figure 3-1A: Thoracic Muscle Cross-Sectional Area vs. Whole Body Muscle Mass with Bio-electrical Impedance Abbreviations: CSA= Cross-Sectional Area
180
Chapter 4:
Table 4-1A: Daily Corticosteroid Use and Skeletal Muscle Mass and Strength Differences
Parameter Daily Oral Corticosteroids
(n=18)
No Daily Use (n=32)
p value
Age (years) 57 ± 11 61 ± 8 0.18Male Sex 11 (61%) 18 (56%) 0.77Diagnosis: Interstitial Lung Disease Chronic Obstructive Lung Disease Pulmonary Hypertension Cystic Fibrosis
16 (89%)
1 (5.5%) 0 %
1 (5.5%)
16 (50%) 11 (34%) 4 (13%) 1 (3%)
0.03
Fat-Free Mass Index (kg/m2) 18.4 ± 2.7 18.2 ± 2.8 0.80Hand-Grip Strength (% Predicted) 87 ± 19 88 ± 19 0.99Quadriceps Strength (% Predicted) 82 ± 19 77 ± 20 0.36Maximal Inspiratory Pressure (% Predicted) (n=17/26)
101 ± 34 101 ± 39 0.99
Maximal Expiratory Pressure (% Predicted) (n=17/26)
131 ± 46 131 ± 46 1.0
Results presented as mean ± SD and Proportion, n (%).
181
Chapter 5:
Bic
eps
Tra
inin
g V
olu
me
s (
lbs
* r
eps
)
Figure 5-1A: Biceps Training Volumes in Pulmonary Rehabilitation vs Hand-Grip Strength (n=49) at 4 weeks after transplant listing. Abbreviations: lbs = Pounds; Reps = Repetitions
Figure 5-2A: Quadriceps Training Volumes in Pulmonary Rehabilitation vs Quadriceps Strength from Biodex (n=49) at 4 weeks after transplant listing. Abbreviations: lbs = Pounds; Reps = Repetitions
182
APPENDIX 2: Ethics Approval Letters for Studies 1 to 3
183
PROTOCOL REFERENCE # 30785
September 29, 2014
Dr. Lianne Singer and Dr. Sunita MathurDEPT OF MEDICINEFACULTY OF MEDICINE
Dr. Dmitry RozenbergDEPT OF MEDICINEFACULTY OF MEDICINE
Dear Dr. Lianne Singer, Dr. Sunita Mathur and Dr. Dmitry Rozenberg,
Re: Administrative Approval of your research protocol entitled, "Retrospective review of frailty inadvanced lung disease"
We are writing to advise you that the Office of Research Ethics (ORE) has granted administrativeapproval to the above-named research protocol. The level of approval is based on the following role(s)of the University of Toronto (University), as you have identified with your submission and administeredunder the terms and conditions of the affiliation agreement between the University and the associatedTAHSN hospital:
Graduate Student research - hospital-based onlyStorage or analysis of De-identified Personal Information (data)
This approval does not substitute for ethics approval, which has been obtained from your hospitalResearch Ethics Board (REB). Please note that you do not need to submit Annual Renewals, StudyCompletion Reports or Amendments to the ORE unless the involvement of the University changes sothat ethics review is required. Please contact the ORE to determine whether a particular change to theUniversity's involvement requires ethics review.
Best wishes for the successful completion of your research.
Yours sincerely,
Dario KuzmanovicREB Manager
OFFICE OF RESEARCH ETHICSMcMurrich Building, 12 Queen's Park Crescent West, 2nd Floor, Toronto, ON M5S 1S8 CanadaTel: +1 416 946-3273 Fax: +1 416 946-5763 [email protected] http://www.research.utoronto.ca/for-researchers-administrators/ethics/
184
NOTIFICATION OF REB RENEWAL APPROVAL
Date: February 10, 2017
To: Lianne G SingerRoom 134; Floor 11, Room 134, PMB, New ClinicalServices Building; Toronto General Hospital; 585University Avenue, M5G 2N2; Toronto, Ontario,Canada
Re: 13-6696Evaluation of Frailty and Sarcopenia in AdvancedLung Disease
REB Review Type: DelegatedREB Initial Approval Date: February 21, 2014REB Renewal Approval Effective Date: February 21, 2017Lapse In REB Approval: N/AREB Expiry Date: February 21, 2018
The University Health Network Research Ethics Board has reviewed and approved the Renewal (13-6696.4)for the above mentioned study.
Best wishes on the successful completion of your project.
Sincerely,Svetlana TzvetkovaEthics Coordinator, University Health Network Research Ethics Board
For: Alan BaroletCo-Chair, University Health Network Research Ethics Board
The UHN Research Ethics Board operates in compliance with the Tri-Council Policy Statement; ICHGuideline for Good Clinical Practice E6(R1); Ontario Personal Health Information Protection Act (2004); PartC Division 5 of the Food and Drug Regulations; Part 4 of the Natural Health Products Regulations and theMedical Devices Regulations of Health Canada.
May/1/2017 12:28 pm Page 1/1
185
PROTOCOL REFERENCE # 30045
March 13, 2017
Dr. Sunita MathurDEPT OF PHYSICAL THERAPYFACULTY OF MEDICINE
Dr. Dmitry RozenbergDEPT OF PHYSICAL THERAPYFACULTY OF MEDICINE
Dear Dr. Mathur and Dr. Dmitry Rozenberg,
Re: Your research protocol entitled, "Evaluation of frailty and sarcopenia in advanced lung disease"
ETHICS APPROVAL Original Approval Date: March 24, 2014Expiry Date: March 23, 2018Continuing Review Level: 1Renewal: Data Analysis Only
We are writing to advise you that you have been granted annual renewal of ethics approval to theabove-referenced research protocol through the Research Ethics Board (REB) delegated process.Please note that all protocols involving ongoing data collection or interaction with human participants aresubject to re-evaluation after 5 years. Ongoing research under this protocol must be renewed prior tothe expiry date.
Any changes to the approved protocol or consent materials must be reviewed and approvedthrough the amendment process prior to its implementation. Any adverse or unanticipatedevents should be reported to the Research Oversight and Compliance - Human Research EthicsProgram as soon as possible. If your research is funded by a third party, please contact theassigned Research Funding Officer in Research Services to ensure that your funds are released.
Please ensure that you submit an Ethics Renewal Form or a Study Completion/Closure Report15 to 30 days prior to the expiry date of your protocol. Note that ethics renewals for studiescannot be accepted more than 30 days prior to the date of expiry as per our guidelines.
Please note, all approved research studies are eligible for a routine Post-Approval Review (PAR) sitevisit. If chosen, you will receive a notification letter from our office. For information on PAR, please seehttp://www.research.utoronto.ca/wp-content/uploads/documents/2014/09/PAR-Program-Description-1.pdf.
Best wishes for the successful completion of your research.
Yours sincerely,
Elizabeth Peter, Ph.D.REB Chair
Research Oversight and Compliance Office - Human Research Ethics ProgramMcMurrich Building, 12 Queen's Park Crescent West, 2nd Floor, Toronto, ON M5S 1S8 CanadaTel: +1 416 946-3273 Fax: +1 416 946-5763 [email protected] http://www.research.utoronto.ca/for-researchers-administrators/ethics/
186
NOTIFICATION OF REB RENEWAL APPROVAL
Date: March 13, 2017
To: Lianne G SingerRoom 134; Floor 11, Room 134, PMB, New ClinicalServices Building; Toronto General Hospital; 585University Avenue, M5G 2N2; Toronto, Ontario,Canada
Re: 15-8858Clinical Implications of Sarcopenia in Lung TransplantPatients
REB Review Type: DelegatedREB Initial Approval Date: March 26, 2015REB Renewal Approval Effective Date: March 26, 2017Lapse In REB Approval: N/AREB Expiry Date: March 26, 2018
The University Health Network Research Ethics Board has reviewed and approved the Renewal (15-8858.3)for the above mentioned study.
Best wishes on the successful completion of your project.
Sincerely,Marina MikhailEthics Coordinator, University Health Network Research Ethics Board
For: Alan BaroletCo-Chair, University Health Network Research Ethics Board
The UHN Research Ethics Board operates in compliance with the Tri-Council Policy Statement; ICHGuideline for Good Clinical Practice E6(R1); Ontario Personal Health Information Protection Act (2004); PartC Division 5 of the Food and Drug Regulations; Part 4 of the Natural Health Products Regulations and theMedical Devices Regulations of Health Canada.
May/1/2017 12:32 pm Page 1/1
187
PROTOCOL REFERENCE # 31637
May 12, 2015
Dr. Lianne Singer and Dr. Sunita MathurDEPT OF MEDICINEFACULTY OF MEDICINE
Dr. Dmitry RozenbergDEPT OF MEDICINEFACULTY OF MEDICINE
Dear Dr. Lianne Singer, Dr. Sunita Mathur and Dr. Dmitry Rozenberg,
Re: Administrative Approval of your research protocol entitled, "Clinical implications of sarcopenia inlung transplant patients"
We are writing to advise you that the Office of Research Ethics (ORE) has granted administrativeapproval to the above-named research protocol. The level of approval is based on the following role(s)of the University of Toronto (University), as you have identified with your submission and administeredunder the terms and conditions of the affiliation agreement between the University and the associatedTAHSN hospital:
Graduate Student research - hospital-based onlyStorage or analysis of De-identified Personal Information (data)
This approval does not substitute for ethics approval, which has been obtained from your hospitalResearch Ethics Board (REB). Please note that you do not need to submit Annual Renewals, StudyCompletion Reports or Amendments to the ORE unless the involvement of the University changes sothat ethics review is required. Please contact the ORE to determine whether a particular change to theUniversity's involvement requires ethics review.
Best wishes for the successful completion of your research.
Yours sincerely,
Dario KuzmanovicREB Manager
OFFICE OF RESEARCH ETHICSMcMurrich Building, 12 Queen's Park Crescent West, 2nd Floor, Toronto, ON M5S 1S8 CanadaTel: +1 416 946-3273 Fax: +1 416 946-5763 [email protected] http://www.research.utoronto.ca/for-researchers-administrators/ethics/
188
189
APPENDIX 3: Consent Form for Study 2 (Chapter 4)
Patient Consent Form – 02-21-2014, V.S. 1.2
1
CONSENT TO PARTICIPATE IN A RESEARCH STUDY
Title Evaluation of Frailty and Sarcopenia in Advanced Lung Disease
Investigator Dr. Lianne Singer, MD
Phone Number: 416-340-4800 ext. 4996
Co-Investigators Dr. Sunita Mathur, PT, PhD Lisa Wickerson, BSc (PT), MSc Dr. Dmitry Rozenberg, MD
Funder Ontario Thoracic Society
Introduction
You are being asked to take part in a research study. Please read this explanation about the study and its risks and benefits before you decide if you would like to take part. You should take as much time as you need to make your decision. You should ask the study doctor or study staff to explain anything that you do not understand and make sure that all of your questions have been answered before signing this consent form. Before you make your decision, feel free to talk about this study with anyone you wish. Participation in this study is voluntary.
Background and Purpose You have been asked to take part in this research study because you have been placed on the lung transplant waiting list at the University Health Network (UHN). While we know that lung transplant outcomes are often dependent on factors like age and make-up (fat and muscle), it is unclear whether there are other processes such as frailty – in other words, the ability of the body to withstand physical stress that may play a key role.
Some of the factors that may tell us that a person can withstand a physical stress, such as surgery are the amount of muscle the person has, their physical strength and their ability to walk or balance. These factors tend to be decreased in people with advanced lung disease. However, the effect of muscular health and ability to tolerate physical stress on quality of life, health care use, and transplant outcomes has not been previously studied in patients awaiting lung transplantation. This study will give us a preliminary assessment of the importance of being able to deal with physical stress and the impact of muscle health on clinical outcomes. About 50 participants
190
Patient Consent Form – 02-21-2014, V.S. 1.2
2
from the lung transplant program at UHN (Toronto General Hospital) will be included this study.
Study Design This is a longitudinal study. This means that assessments will be take place over a period of time. There will be one major testing session at the initial visit and then some brief testing sessions every 3 months until your receive your lung transplant. The following testing sessions will be scheduled around times you are at UHN for rehabilitation or other medical appointments.
Study Visits and Procedures The initial testing session will take place at the University of Toronto, Muscle Function Lab approximately 4 weeks into the start of pulmonary rehabilitation. The following testing sessions will take place at Toronto General Hospital.
Testing at University of Toronto, Muscle Function & Performance Lab (~1.5 hours):
Muscle Mass – your body composition (amount of muscle and fat) will be calculated using a special commercial machine (bioelectrical impedance device). We will have you lie down comfortably and attach two small leads (one to your hand and foot). By passing an electrical current, the machine will be able to assess the various compartments of your body (muscle, fat, and water). The entire measurement will take less than 5 minutes and has no side effects. You will not feel the electrical current since it is very low intensity.
Muscle Strength testing – you will be seated on a machine that is used to test your leg muscle strength. You will be asked to push against a pad as hard as you can to determine your maximal muscle strength. Similarly, the study investigator will use a hand held device to test the strength of your handgrip and thigh muscles.
Short Performance Physical Battery (SPPB) – this is a test of walking and balance. You will be asked to stand in one position holding your balance, rise from a chair 5 times and walk for 4 metres while being timed.
Quality of Life Measures – we will ask you to complete several questionnaires that have patient, community, general and respiratory disease-specific questions that will be done through an Internet-site, with an average completion time of 25 minutes. This will be done during your first visit on the muscle lab computer with no personal health information recorded and all answers stored safely in a database using a password.
Physical Activitiy Questionnaires - you will also be asked to complete two brief physical activity questionnaires to assess your level of activity in the last week.
Testing at Toronto General Hospital after initial testing (~ additional 10 minutes)
6 Minute Walk Test – you will be asked to walk in a hallway for 6 minutes and we will measure how far you walk. You will be able to take a rest if needed. This test is part of
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the routine care at UHN for people awaiting lung transplant and is usually done every 3 months.
Muscle Strength testing – Similar to your first visit, the study investigator will use a hand held device to test the strength of your thigh muscles only.
One page questionnaire – this will assess your physical activity level, a question related to your grip strength, your energy level, and your ability to cope with physical stress. It will also examine any recent visits to the emergency department, admissions to hospital or use of any antibiotics and/or steroids for respiratory infections.
Calendar of Visits: Boxes marked with an X show what will happen at each visit:
Visit Initial Test (4 weeks)
3 months 6 months 9 months Every 3 Months
Time
U of T procedures:
Muscle Mass X 10 min
Muscle Strength X 15 min
SPPB X 10 min
Quality of Life X 25 min
Physical Activity Questionnaires
X 15 min
TGH procedures:
*6 MWT X X X X X 10 min
One Page Questionnaire
X X X X X 5 min
Thigh Muscle Strength
X X X X X 5 min
*6 MWT will be routinely done every 3 months as part of normal care.
Reminders
It is important to remember the following things during this study:
Wear comfortable clothing for exercise during the study visits. Ask your study team about anything that worries you. Tell study staff anything about your health that has changed. Tell your study team if you change your mind about being in this study.
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For the muscle mass measurement performed on your initial visit,we ask you kindly not to do strenuous exercise (i.e. walking fast, liftingobjects > 5 kg) for 12 hours prior to testing and avoid having anything toeat or drink 2 hours prior to the test. You may have a light breakfast thatmorning.
Risks Related to Being in the Study The possible risks from participating in this study are:
Muscle fatigue and soreness - It is common to feel that your muscles are sore or tired after the strength testing and functional testing (occurs in about 20% of people). The tiredness should go away after a few hours and the soreness should go away after 1 to 2 days. If your muscle soreness lasts for more than 48 hours, please call the study team to let them know.
There are no known risks to bioelectrical impedance but please notify our team if you have a heart device (i.e. pacemaker or defibrillator) or you may be pregnant as the device has not been studied in these populations.
Benefits to Being in the Study You may receive potential benefit from being in the study by finding out more about your muscle health and ability to cope with physical stress while awaiting lung transplantation.
Voluntary Participation Your participation in this study is voluntary. You may decide not to be in this study, or to be in the study now and then change your mind later. You may leave the study at any time without affecting your care. You may refuse to answer any questions you do not want to answer, or not answer an interview question by saying “pass”.
Confidentiality
If you agree to join this study, the study doctor and his/her study team will look at your personal health information and collect only the information they need for the study. Personal health information is any information that could be used to identify you and includes your:
name age new or existing medical records, that includes types, dates and results of medical
tests or procedures.
The information that is collected for the study will be kept in a locked and secure area by the study doctor for 10 years. Only the study team or the people or groups listed above (page 1) will be allowed to look at your records. Your participation in this study also may be recorded in your medical record at this hospital.
Representatives of the University Health Network Research Ethics Board may look at the study records and at your personal health information to check that the information
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collected for the study is correct and to make sure the study followed proper laws and guidelines.
All information collected during this study, including your personal health information, will be kept confidential and will not be shared with anyone outside the study unless required by law. You will not be named in any reports, publications, or presentations that may come from this study.
If you decide to leave the study, the information about you that was collected before you leave the study will still be used in order to help answer the research question. No new information will be collected without your permission.
In Case You Are Harmed in the Study
If you are harmed as a direct result of taking part in this study, all necessary medical treatment will be made available to you at no cost. By signing this form you do not give up any of your legal rights against the investigators, sponsor or involved institutions for compensation, nor does this form relieve the investigators, sponsor or involved institutions of their legal and professional responsibilities.
Expenses Associated with Participating in the Study
You will not have to pay for any of the testing procedures involved with this study. You will be given $10 for your initial visit to the University of Toronto, Muscle function lab to assist with parking costs.
Conflict of Interest The study team has an interest in completing this study. Their interests should not effect your decision to participate in this study. You should not feel pressured to join this study.
Questions about the Study
If you have any questions, concerns or would like to speak to the study team for any reason, please call: Dr. Dmitry Rozenberg at 416-946-0418 or page him at 416-790-4732. You can also call: Dr. Lianne Singer at 416-340-4800 x 4996 or Dr. Sunita Mathur at 416-978-7761.
If you have any questions about your rights as a research participant or have concerns about this study, call the Chair of the University Health Network Research Ethics Board (REB) or the Research Ethics office number at 416-581-7849. The REB is a group of people who oversee the ethical conduct of research studies.These people are not part of the study team. Everything that you discuss will be kept confidential.
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Consent This study has been explained to me and any questions I had have been answered. I know that I may leave the study at any time. I agree to take part in this study.
Print Study Participant’s Name Signature Date
(You will be given a signed copy of this consent form)
My signature means that I have explained the study to the participant named above. I have answered all questions.
Print Name of Person Obtaining Consent Signature Date
The consent form was read to the participant. The person signing below agrees that the study as set out in this form was properly explained to the participant and he/she has had all questions answered.
Print Name of Witness Signature Date
Relationship to Participant
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Appendix H: Patient Instructions Form, 12‐15‐2013, V.S. 1.0
**Instructions:
Thank you for agreeing to participate in this research study titled:
Evaluation of Frailty and Sarcopenia in Advanced Lung Disease
Your initial testing session will be at the University of Toronto, Muscle Function and Performance Lab on: __________________________________.
Address: 500 University Avenue, Toronto, ON, M5G 1V7. You will be greeted on the main level and brought down to the muscle lab.
** Reminders:
Please wear comfortable clothing and shoes suitable for exercise
Muscle Mass Measurement: In order to ensure accurate results, we ask youkindly not to do any strenuous exercise for 12 hours prior to testing andavoid having anything to eat or drink 2 hours prior to your test.
You may have a light breakfast that morning.
If you have any questions, concerns or unable to attend for any reason, please do not hesitate to page Dr. Dmitry Rozenberg at (416) 790-4732.
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