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

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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.

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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.

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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.

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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.

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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

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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

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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

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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

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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.

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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.

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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

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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

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plan

t Out

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es

 

Dat

a ar

e pr

esen

ted

as m

ean

± S

D,

med

ian

[25-

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inte

rqua

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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

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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.

  

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99 

  

  

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

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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

135  

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  

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532 Tong Y, Udupa JK, Torigian DA, et al. Chest Fat Quantification via CT Based on

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533 Collins PF, Elia M, Stratton RJ. Nutritional support and functional capacity in chronic

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535 Ferreira IM, Brooks D, White J, et al. Nutritional supplementation for stable chronic

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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

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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 ethics.review@utoronto.ca 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 ethics.review@utoronto.ca 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 ethics.review@utoronto.ca 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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