Domiciliary ambulatory oxygen in chronic obstructive ...

Domiciliary ambulatory oxygen in

chronic obstructive pulmonary disease

Rosemary Patricia Moore

B App Sc (Phty)

Grad Dip Physio (Cardiothoracic)

M Physio (Research)

Student number: 19981

Submitted in total fulfillment of the requirements of the degree of

Doctor of Philosophy

Melbourne Physiotherapy School

Faculty of Medicine, Dentistry and Health Sciences

The University of Melbourne

July 2010

ii

Dedication

This thesis is dedicated to my late husband, Russell Curwood, who also made

sacrifices in order that this work could take place, but was unable to share the

pleasure and satisfaction of its completion.

iii

Abstract

Ambulatory oxygen, able to be transported during activity, has been available

since early last century. There is confusion regarding which breathless patients

should receive domiciliary ambulatory oxygen. Chronic obstructive pulmonary

disease (COPD) is a major cause of breathlessness and disability. It is

characterised by reduced airflow and is associated with hypoxaemia (in its later

stages), functional impairment and reduced quality of life. Besides ceasing

smoking, oxygen therapy, used for at least 15 hours per day, is the only

intervention shown to improve survival in people with COPD and severe resting

hypoxaemia.

Many people with COPD who are not severely hypoxaemic at rest experience

disabling exertional breathlessness. Ambulatory oxygen is often prescribed in

this circumstance despite a lack of supportive evidence. This research project

aimed to determine whether such people benefit from domiciliary ambulatory

oxygen and to examine factors with may be associated with benefit. The thesis

describes three areas of work. Firstly, suitable tools for measuring physical

activity were examined. Secondly, acute resting ventilatory responses to

hyperoxia were assessed as possible predictive factors for benefit from

domiciliary ambulatory oxygen. Thirdly, a randomised, controlled trial of

domiciliary ambulatory oxygen was conducted.

As physical activity is limited in COPD, this is an important research outcome.

However, no precise, inexpensive tool for its measurement has been developed

for use in this population. Self-report diaries have been used in many

populations and the pedometer is widely recognised as a valid, reliable, objective

measurement tool but has not been well-tested in COPD. Pilot studies were

conducted to develop a suitable diary and the relationship between seven-day

data from the diary and a pedometer were compared. It was concluded that the

diary was more reliably completed of the two, offers greater promise as a tool for

measuring activity in COPD and that representative activity data may be collected

over fewer than seven consecutive days in this population.

iv

The second area of work in this thesis assessed the acute effects of hyperoxia

upon resting levels of hyperinflation, ventilation and dyspnoea in patients with

COPD of varying disease severity. The aim was to characterise patients

responsive to hyperoxia, as it was hypothesised that factors defining such

individuals might be predictive of benefit from domiciliary ambulatory oxygen.

This study found that hyperoxia improves dyspnoea but induces no significant

reduction in resting pulmonary hyperinflation in COPD. However, pulmonary

volume response was greater in participants with moderate to severe airflow

obstruction.

The main study in the thesis is a 12-week, double-blinded trial comparing

ambulatory cylinder air with oxygen in patients with COPD and exertional

dyspnoea, but without severe resting hypoxaemia. No benefits from ambulatory

oxygen were found in any outcomes of dyspnoea, health-related quality of life,

mood disturbance, function or cylinder utilisation. Six factors were selected to

define subgroups which might benefit differentially from domiciliary ambulatory

oxygen and no benefit was found in any subgroup. It was concluded that

domiciliary ambulatory cylinder oxygen provides no improvement in dyspnoea,

health-related quality of life or function in this group of people with COPD.

v

Declaration

This is to certify that:

i) the thesis comprises only my original work towards the PhD;

ii) due acknowledgement has been made in the text to all other material

used;

iii) the thesis is less than 100,000 words in length, exclusive of tables,

references and appendices.

Rosemary Moore

July 2010

vi

Glossary of abbreviations and symbols

ANCOVA

ANOVA

BMI

cm

cmH2O

CO2

COPD

COT

CRQ

DH

DLCO

EELV

EFL

ERV

fB

fC

FEV1

FiO2

FRC

FVC

HADS

HRQL

IC

IRV

ITL

kPa

L

ml

mg

mm

mmHg

MID

MRC

analysis of covariance

analysis of variance

body mass index

centimetre/s

centimetres of water

carbon dioxide

chronic obstructive pulmonary disease

continuous oxygen therapy

Chronic Respiratory Disease Questionnaire

dynamic hyperinflation

diffusing capacity for carbon monoxide

end expiratory lung volume

expiratory flow limitation

expiratory reserve volume

breathing frequency (respiratory rate per minute)

cardiac frequency (heart rate per minute)

forced expiratory volume in one second

fraction of inspired oxygen

functional residual capacity

forced vital capacity

Hospital Anxiety and Depression Scale

health-related quality of life

inspiratory capacity

inspiratory reserve volume

inspiratory threshold loading

kilopascal/s

litre/s

millilitre/s

milligram/s

millimetre/s

millimetres of mercury

minimal important difference

Medical Research Council

vii

NOTT

O2

PaCO2

PaO2

PEEPi

RV

SD

SEM

SpO2

TLC

TLCO

VAS

VE

VT

VO2

V/Q

VC

6MWD

6MWT

%pred

Nocturnal Oxygen Therapy Trial

oxygen

arterial partial pressure of carbon dioxide

arterial partial pressure of oxygen

intrinsic positive end expiratory pressure

residual volume

standard deviation

standard error of the mean

oxyhaemoglobin saturation measured by pulse oximetry

total lung capacity

transfer factor for carbon monoxide

visual analogue scale

minute ventilation

tidal volume

total body oxygen uptake

ventilation/perfusion

vital capacity

six minute walk distance

six minute walk test

percentage of predicted value

viii

Acknowledgements

A project of this magnitude could not be achieved or even contemplated without

the generous assistance of many individuals. A large number of patients,

colleagues and friends have contributed their time and their skills to this project.

In addition, many people have supported me through this journey in many other

ways.

Firstly, I would like to thank my supervisors, Professor Christine McDonald, Dr.

David Berlowitz, Associate Professor Linda Denehy and Dr. Bruce Jackson for

their professional and personal support and encouragement, for generously

sharing their wealth of knowledge with me, for all the time they have given me

and for their tremendous patience over the time of my candidature.

Next, I would also like to acknowledge the very special contributions of research

assistants, Chrissie Risteski and Nadia Gagliardi, who are the two main reasons

that our study participant attrition rate, notoriously poor in this study group, was

so low. Other assistants who I would like to thank are Jeremy Friedman and

Anthony D‟Aloisio, also Patty Barry for the wonderful job she did to pull together

and format my thesis.

Many colleagues at both study sites, the Austin and Northern Hospitals, have

also contributed to this project. In particular, the respiratory scientists provided

me with a space in which to work and valuable advice in addition to contributing

their professional skills. All of the following deserve special thanks: Jeff Pretto,

Danny Brazzale, Sherine Yousef, Soula Tzitzivakos, Sue Jones and Faiyaz

Tambuwala. The medical libraries at both study sites have been wonderful

resources and I feel privileged to have access to them. I would like to thank

librarians Anne McLean, her staff at Austin Health and Ilana Jackson at the

Northern Hospital for all the assistance they have given me, which has always

been so willingly provided.

I would also like to acknowledge the contribution made to this project by the late

Professor Rob Pierce, former Director of the Department of Respiratory and

Sleep Medicine at Austin Health. Although not directly involved in this project, his

interest, advice and the support he gave me were greatly appreciated. Whilst his

legacy remains, his passing has left a great void within the department and

ix

beyond, and his enthusiasm, wisdom and care are missed by colleagues and

patients alike.

A major challenge for this project was participant recruitment. Many

physiotherapists and respiratory physicians, both within and outside the study

sites, generously provided their assistance with this. I would particularly like to

thank colleagues in the Austin Hospital‟s physiotherapy department and the

Department of Respiratory and Sleep Medicine for their help in this regard. I

would also like to acknowledge the gracious assistance of the reception staff in

the relevant departments at both study sites, in particular, Cynthia Stojanovic in

the Respiratory Laboratory at the Austin Hospital. Thanks also to staff of Austin

Health‟s Department of Corporate Affairs who provided invaluable assistance

with promoting the study.

Other colleagues who I would like to thank are Simon Higgins, Associate

Professors Sue Jenkins and Anne Holland, Drs. Fergal O‟Donoghue and

Annemarie Lee and Professors Glenn Bowes and Jo Douglass for their support,

encouragement and advice at various stages along the way. In addition, I am

very grateful for the statistical advice of Professor Ian Gordon and Dr. Ken

Sharpe and for the assistance of my friend, Philippa Younger, who helped to

develop the lay documents for this project. I would also like to thank Professsor

Rik Gosselink and Drs. Fabbio Pitta and Donald Mahler, as I feel honoured that

they took the time to answer emails requesting advice from a stranger on the

other side of the world.

This project could not have taken place without the funding which was provided

by a number of sponsors. I was very fortunate to be supported by scholarships

from The Northern Clinical Research Centre, the National Health and Medical

Research Council (Dora Lush Biomedical Postgraduate Scholarship), Northern

Health and the Institute for Breathing and Sleep, Austin Health. In addition, the

project was generously supported by a grant-in-aid from Air Liquide Limited,

which supplied and delivered all gas cylinders and related apparatus to our

participants. The management, technical and administrative staff of Air Liquide

were always a pleasure to work with and I am most grateful to them. Other

grants to support the project were provided by Boehringer Ingelheim Limited, the

Austin Medical Research Foundation and the Finkel Foundation.

x

There are many extremely knowledgeable professionals with whom I have had

the honour to work during my career as a physiotherapist and who have

contributed to my professional development. I would particularly like to

acknowledge two people who initially kindled my interest in research. Firstly, Dr.

Margaret Smith, Respiratory Physician (Alfred Hospital, Melbourne), who

inspired my interest in oxygen therapy and our first poster presentation, titled

“Oxygen requirements during exercise in hypoxic cystic fibrosis subjects” (Moore

et al 1988). Secondly, Dr Joseph Milic-Emili, who inspired my interest in

pulmonary mechanics with a presentation in Melbourne during the 1980‟s on

intrinsic PEEP, which I not only understood, but also found fascinating. In

addition, a special friend and colleague, the late Jill Nosworthy, encouraged me

to accept the opportunity I was given to undertake this project and made me

believe that I could do it.

A further thank you is to the partners and staff of Accru Danby Bland Provan,

Chartered Accountants and Business Advisors, for all of their personal support

and assistance and in particular, for allowing me to print my thesis in their offices.

A special thank you also goes to everyone at “Mario‟s”, Hawthorn, for their

friendship and support and for allowing me and my laptop to occupy a corner of

their café for many hours. Some of my “best work” has been achieved there,

inspired by their wonderful coffee.

From a personal perspective, I would like to thank my family, especially my

father, and many friends for the kindness and support that they have given me

and my son, Tim, during my candidature. Importantly, I would like to thank Tim

for his patience. His mother has been writing a thesis for all but four of his fifteen

years! I hope that he also will be inspired to take on big challenges and enjoy the

rewards of their accomplishment. I also hope that being an observant to his

mother‟s work will not discourage any interest in this regard!

Last, but far from least, I would like to thank the people who generously gave

their time to participate in the studies in this thesis, including members of the

Hawthorn Huffers Respiratory Support group who participated in the pilot studies.

Such studies can not take place without these volunteers, many of whom face

considerable challenges with their health on a daily basis. I hope that the results

of these studies will provide a useful contribution to the understanding of their

lung disease and its management, from which they and others may benefit.

xi

Publications

Moore RP, Berlowitz DJ, Pretto JJ, Brazzale DJ, Denehy L, Jackson B,

McDonald CF (2009): Acute effects of hyperoxia upon resting pattern of

ventilation and dyspnoea in chronic obstructive pulmonary disease. Respirology;

14 (4): 545-550.

Moore RP, Berlowitz DJ, Denehy L, Jackson B, McDonald CF (2009): Use of

pedometer and daily diary for measurement of physical activity in COPD. Journal

of Cardiopulmonary Rehabilitation and Prevention; 29: 57-61.

Moore RP, Berlowitz DJ, Pretto JJ, Brazzale DJ, Denehy L, Sharpe K, Jackson B,

McDonald CF (2010): Domiciliary ambulatory oxygen is not beneficial in patients

with COPD but without resting hypoxaemia. Thorax; In press

xii

Presentations

Moore R, Berlowitz D, Pretto J, Brazzale D, Denehy L, Jackson B, McDonald C:

Acute effects of hyperoxia upon resting pattern of ventilation and

dyspnoea in chronic obstructive pulmonary disease.

Respirology 12 (Suppl 1): A50.

(Poster presentation at the Annual Scientific Meeting of the Thoracic

Society of Australia and New Zealand, Auckland, March, 2007.)

In: Proceedings of The American Thoracic Society International

Conference 2007. New York: American Thoracic Society: A609.

(Poster presentation at the Annual Scientific Meeting of the American

Thoracic Society, San Francisco, October, 2007.)


(Poster presentation at the Asia Pacific Society of Respirology 2007

Congress, Surfers Paradise, November, 2007.)

Moore R, Berlowitz D, Denehy L, Jackson B, McDonald C: Use of pedometer and

daily diary for measurement of physical activity in COPD.


(Poster presentation at the Annual Scientific Meeting of the Thoracic

Society of Australia and New Zealand, Auckland, March 2007.)


(Poster presentation at the Asia Pacific Society of Respirology 2007

Congress. Surfers Paradise, November 2007.)

xiii

Moore R, Berlowitz D, Denehy L, Sharpe K, Jackson B, McDonald C (2009):

Double blind, randomised controlled trial of ambulatory oxygen versus air

in COPD.

Respirology (2009) 14 (Suppl 1): A29.

(Oral presentation at the Annual Scientific Meeting of the Thoracic Society

of Australia and New Zealand, Darwin, April 2009.)

The e-Australian Journal of Physiotherapy (2009) 55 (4) Supplement: 18

(Oral presentation at the Australian Physiotherapy Conference, Sydney,

October 2009.)

Moore RP, Berlowitz DJ, Pretto JJ, Brazzale DJ, Denehy L, Sharpe K, Jackson B,

McDonald CF (2010): Domiciliary ambulatory oxygen is not beneficial in

patients with COPD but without resting hypoxaemia.

American Journal of Respiratory and Critical Care Medicine (2010) May 1;

181: A5418.

(Poster presentation at the American Thoracic Society 2010 International

Conference, New Orleans, May 2010.)

xiv

Awards

Oral Presentation Prizes

2009: Thoracic Society of Australia and New Zealand/Boehringer Ingelheim Prize

for the best presentation on Chronic Obstructive Pulmonary Disease

related issues.

Moore R, Berlowitz D, Denehy L, Sharpe K, Jackson B, McDonald C:


in COPD.

2009: Cardiorespiratory Physiotherapy Group, Australian Physiotherapy

Association - award for excellence in research.

Moore R, Berlowitz D, Denehy L, Sharpe K, Jackson B, McDonald C:


in COPD.

Poster Prizes

2007: Thoracic Society of Australia and New Zealand.

Moore R, Berlowitz D, Pretto J, Brazzale D, Denehy L, Jackson B,

McDonald C: Acute effects of hyperoxia upon resting pattern of

ventilation and dyspnoea in chronic obstructive pulmonary disease.

2007: Northern Health Research Week.

Moore R, Berlowitz D, Denehy L, Jackson B, McDonald C: Use of

pedometer and daily diary for measurement of physical activity in COPD.

2009: Austin Health Research Week - Allied Health Prize.

Moore RP, Berlowitz DJ, Pretto JJ, Brazzale DJ, Denehy L, Sharpe K,

Jackson B, McDonald CF: Domiciliary ambulatory oxygen is not

beneficial in patients with COPD and mild resting hypoxaemia.

xv

Table of Contents

Dedication ....................................................................................................... ii

Abstract .......................................................................................................... iii

Declaration ...................................................................................................... v

Glossary of abbreviations and symbols ...................................................... vi

Acknowledgements ..................................................................................... viii

Publications ................................................................................................... xi

Presentations ................................................................................................ xii

Awards ......................................................................................................... xiv

Table of Contents ......................................................................................... xv

List of Appendices ....................................................................................... xix

List of Tables ................................................................................................ xx

List of Figures ............................................................................................. xxii

Chapter 1: Introduction .................................................................................. 1

1.1 Introduction to the topic ..................................................................... 1 1.2 Statement of the problem .................................................................. 2 1.3 Research aims .................................................................................. 3 1.4 Overview of the thesis ....................................................................... 4

Chapter 2: Oxygen therapy ............................................................................ 7

2.1 Introduction ....................................................................................... 7 2.2 Historical perspectives ...................................................................... 9

2.2.1 Physiology ........................................................................... 9 2.2.2 Therapeutic uses of oxygen ............................................... 10

2.3 Domiciliary oxygen systems ............................................................ 12 2.3.1 Supply devices .................................................................. 12 2.3.2 Delivery systems ............................................................... 13 2.3.3 Conservation devices ........................................................ 13 2.3.4 Current domiciliary oxygen systems .................................. 13

2.4 Ventilatory control ........................................................................... 14 2.4.1 Overview ........................................................................... 14 2.4.2 Central controllers ............................................................. 15 2.4.3 Sensors ............................................................................. 15 2.4.4 Oxygen and carbon dioxide transport ................................ 16 2.4.5 Control of the ventilatory system ........................................ 17 2.4.6 Hazards of oxygen therapy ................................................ 19

xvi

2.5 Domiciliary oxygen therapy ............................................................. 21 2.5.1 Definitions .......................................................................... 21 2.5.2 Oxygen prescription guidelines .......................................... 23 2.5.3 Evidence for oxygen prescription guidelines ...................... 25 2.5.4 Prescription of domiciliary ambulatory oxygen in COPD .... 31 2.5.5 Evidence for use of domiciliary ambulatory oxygen ............ 32

2.6 Conclusions ..................................................................................... 42

Chapter 3: COPD ........................................................................................... 43

3.1 Introduction ..................................................................................... 43 3.2 History ............................................................................................. 44 3.3 Definition ......................................................................................... 46 3.4 Disease severity classifications ....................................................... 48 3.5 Epidemiology and risk factors .......................................................... 49 3.6 Mortality .......................................................................................... 51 3.7 Pathology ........................................................................................ 52

3.7.1 Inflammatory responses ..................................................... 52 3.7.2 Airways .............................................................................. 53 3.7.3 Lung parenchyma .............................................................. 54 3.7.4 Pulmonary vasculature ...................................................... 55

3.8 Pathophysiology .............................................................................. 55 3.8.1 Introduction ........................................................................ 55 3.8.2 Airflow limitation ................................................................. 56 3.8.3 The respiratory pump ......................................................... 59 3.8.4 Dynamic hyperinflation....................................................... 63 3.8.5 Cardiovascular effects ....................................................... 69 3.8.6 Gas exchange abnormalities ............................................. 70 3.8.7 Systemic and other effects ................................................. 72

3.9 Clinical features ............................................................................... 74 3.9.1 Dyspnoea .......................................................................... 74 3.9.2 Cough and sputum ............................................................ 77

3.10 Management ................................................................................... 77 3.10.1 Overview ........................................................................... 77 3.10.2 Oxygen therapy in COPD .................................................. 79

3.11 Conclusions ..................................................................................... 80

Chapter 4: Outcome measures in COPD ..................................................... 81

4.1 Overview ......................................................................................... 81 4.2 Dyspnoea ........................................................................................ 83

4.2.1 Introduction ........................................................................ 83 4.2.2 The Medical Research Council Dyspnoea Scale ............... 84 4.2.3 Dyspnoea domain of the Chronic Respiratory Disease

Questionnaire .................................................................... 86 4.2.4 Baseline and Transition Dyspnoea Index ........................... 87 4.2.5 The Borg Scale .................................................................. 89 4.2.6 Summary of measures of dyspnoea .................................. 91

4.3 Health-related quality of life ............................................................. 92 4.3.1 Generic measures ............................................................. 92 4.3.2 Disease specific measures ................................................ 94

4.4 Mood disturbance ............................................................................ 96 4.5 Functional status ............................................................................. 98

4.5.1 Exercise capacity ............................................................... 99 4.5.2 Physical activity ............................................................... 103

4.6 Summary ....................................................................................... 108

xvii

Chapter 5: Pilot of the activity diary .......................................................... 111

5.1 Introduction ................................................................................... 111 5.2 Aims .............................................................................................. 111 5.3 Pilot 1 Method ............................................................................... 112 5.4 Pilot 1 Results ............................................................................... 113 5.5 Pilot 1 Conclusions ........................................................................ 114 5.6 Pilot 2 Method ............................................................................... 114 5.7 Pilot 2 Results ............................................................................... 115 5.8 Pilot 2 Conclusions ........................................................................ 116 5.9 Outcome of pilot studies ................................................................ 116

Chapter 6: Comparison of pedometer and activity diary in COPD .......... 119

6.1 Introduction ................................................................................... 119 6.2 Aims .............................................................................................. 120 6.3 Method .......................................................................................... 120

6.3.1 Participants ...................................................................... 120 6.3.2 Procedure ........................................................................ 120 6.3.3 Data management ........................................................... 122

6.4 Results .......................................................................................... 122 6.5 Discussion ..................................................................................... 126 6.6 Conclusions................................................................................... 131

Chapter 7: Acute effects of hyperoxia on resting pattern ........................ 133

7.1 Introduction ................................................................................... 133 7.2 Inspiratory capacity as a measure of hyperinflation ....................... 134

7.2.1 Background ..................................................................... 134 7.2.2 Measurement technique .................................................. 136 7.2.3 Baseline end expiratory lung volume ............................... 137 7.2.4 Technical acceptability ..................................................... 138 7.2.5 Validity of inspiratory capacity measurement ................... 139 7.2.6 Reproducibility of inspiratory capacity measurement ....... 140 7.2.7 Responsiveness of inspiratory capacity measurement ..... 141 7.2.8 Interpretation of inspiratory capacity values ..................... 141 7.2.9 Summary ......................................................................... 144

7.3 Ventilatory responses to hyperoxia in COPD ................................. 145 7.3.1 Responses during exercise .............................................. 145 7.3.2 Responses at rest ............................................................ 149 7.3.3 Variability in response to hyperoxia ................................. 150 7.3.4 Ventilatory response to hyperoxia: summary ................... 150

7.4 Study aims .................................................................................... 150 7.5 Materials and methods .................................................................. 151

7.5.1 Participants ...................................................................... 151 7.5.2 Study design .................................................................... 151 7.5.3 Procedures ...................................................................... 151 7.5.4 Analysis ........................................................................... 153

7.6 Results .......................................................................................... 153 7.6.1 Participants ...................................................................... 153 7.6.2 Response to hyperoxia .................................................... 154

7.7 Discussion ..................................................................................... 158

Chapter 8: Effects of domiciliary ambulatory oxygen in COPD............... 161

8.1 Introduction ................................................................................... 161 8.2 Study aims .................................................................................... 163

xviii

8.3 Study hypotheses .......................................................................... 163 8.4 Materials and method .................................................................... 164

8.4.1 Study design .................................................................... 164 8.4.2 Study sample size ............................................................ 165 8.4.3 Participants ...................................................................... 168 8.4.4 Study group allocation ..................................................... 170 8.4.5 Assessment procedure .................................................... 170 8.4.6 Measurements ................................................................. 173 8.4.7 Intervention procedures ................................................... 181 8.4.8 Data management ........................................................... 183

8.5 Results .......................................................................................... 184 8.5.1 Baseline data ................................................................... 184 8.5.2 Outcomes for air and oxygen groups ............................... 191 8.5.3 Subgroup analyses .......................................................... 192

8.6 Discussion ..................................................................................... 201

Chapter 9: Conclusions and future directions .......................................... 207

9.1 Introduction ................................................................................... 207 9.2 Major findings and future directions ............................................... 207 9.3 Strengths and limitations of this research ...................................... 209 9.4 Conclusions ................................................................................... 211

References .................................................................................................. 213

xix

List of Appendices

Appendix I Baseline/Transition Dyspnoea Index Worksheet ................. 261

Appendix II Baseline/Transition Dyspnoea Index Scoring Sheets .......... 263

Appendix III The Assessment of Quality of Life Instrument ..................... 267

Appendix IV The Chronic Respiratory Disease Questionnaire ................ 273

Appendix V The Hospital Anxiety and Depression Scale........................ 287

Appendix VI Six Minute Walk Test Protocol ............................................ 291

Appendix VII Pilot 1 Activity Diary ............................................................ 299

Appendix VIII Activity Diary Pilot Questionnaire ........................................ 303

Appendix IX Pilot 2 Activity Diary ............................................................ 305

Appendix X Activity Diary ....................................................................... 307

Appendix XI Inspiratory Capacity Measurement Worksheet 1 ................. 311

Appendix XII Inspiratory Capacity Measurement Worksheet 2 ................. 313

Appendix XIII Study Information Sheet ..................................................... 315

Appendix XIV Study Promotion Flyer ........................................................ 317

Appendix XV Study Referral Form ............................................................ 319

Appendix XVI Study Protocol Summary .................................................... 321

Appendix XVII Study Promotion Covering Letter ........................................ 323

Appendix XVIII Participant Information and Consent Form .......................... 325

Appendix XIX Participant Data Sheet ........................................................ 337

Appendix XX Additional Information Sheet ............................................... 341

Appendix XXI Chronic Respiratory Disease Questionnaire Response

Sheet .................................................................................. 343

Appendix XXII Assessment of Quality of Life Index Response Sheet ......... 345

Appendix XXIII Six Minute Walk Test Worksheet ........................................ 347

Appendix XXIV Cylinder Company Referral Form ........................................ 349

Appendix XXV Preferences and Opinions Survey ....................................... 351

Appendix XXVI Study Checklist ................................................................... 353

Appendix XXVII Medical Research Council Dyspnoea Scale ........................ 355

xx

List of Tables

Table 2.1 Summary of Cochrane Collaboration reviews of domiciliary

oxygen therapy ................................................................................. 8

Table 2.2 Summary of terms describing different forms of oxygen therapy ..... 22

Table 2.3 Summary of prescription guidelines for continuous, nocturnal

and domiciliary ambulatory oxygen from Australasia ...................... 24

Table 2.4 Summary of the Nocturnal Oxygen Therapy Trial ........................... 25

Table 2.5 Summary of randomised controlled trials of domiciliary

ambulatory oxygen ......................................................................... 34

Table 3.1 Classification systems for disease severity in COPD ...................... 49

Table 3.2 Summary of the causes of airflow limitation in COPD. .................... 57

Table 4.1 Definitions of outcome measure criteria .......................................... 83

Table 4.2 Categories of dyspnoea measures .................................................. 84

Table 4.3 The Medical Research Council Dyspnoea Scale ............................. 85

Table 4.4 The Medical Research Council (MRC) Dyspnoea Scale ................. 86

Table 4.5 Summary of Baseline and Transition Dyspnoea Index scores ......... 88

Table 4.6 The modified Borg Scale or CR10................................................... 90

Table 4.7 Chronic Respiratory Disease Questionnaire (CRQ) dimension

scores the minimal important difference (MID) in scores ................. 96

Table 5.1 Daily time periods and activity categories for first pilot activity

diary.............................................................................................. 112

Table 6.1 Demographic data of included participants: mean (standard

deviation) and comparisons of means between males and

females (t tests) ............................................................................ 124

Table 6.2 Pedometer count and time spent for activity categories over

seven days ................................................................................... 125

Table 7.1 Assessment of degree of pulmonary hyperinflation using

inspiratory capacity ....................................................................... 144

Table 7.2 Summary of results of three studies which have compared the

effects of breathing room air and hyperoxia, at rest and with

exercise, in COPD ........................................................................ 146

Table 7.3 Demographic data of study participants (n = 51) ........................... 154

Table 7.4 Results after 5 minutes of breathing air and 44% oxygen for all

participants ................................................................................... 156

xxi

Table 7.5 Mean change (hyperoxia minus air values) in inspiratory

capacity (IC), dyspnoea ................................................................ 157

Table 8.1 Study outcomes and measures used. ........................................... 165

Table 8.2 Study inclusion and exclusion criteria ........................................... 168

Table 8.3 Characteristics of subgroups examined ........................................ 184

Table 8.4 Participant recruitment data by study site ..................................... 185

Table 8.5 Demographic data of the 17 participants who did not proceed to

randomisation. .............................................................................. 185

Table 8.6 Baseline data for air and oxygen groups and results of t tests to

compare groups ............................................................................ 187

Table 8.7 Outcome measures and t tests to compare air and oxygen

groups at baseline. ....................................................................... 189

Table 8.8 Results of quality of life and mood disturbance outcomes; group

comparisons using repeated measures analysis of variance ........ 193

Table 8.9 Results of functional capacity ....................................................... 195

Table 8.10 Transition Dyspnoea Index (TDI) focal scores at weeks 4 and

12 post randomisation .................................................................. 197

Table 8.11 Number and proportion (%) of participants with a TDI focal

score ............................................................................................ 197

Table 8.12 Gas cylinder usage in participants overall and comparing air

and oxygen groups ....................................................................... 199

Table 8.13 Results of subgroup analyses using analysis of covariance

(ANCOVA) and estimates of the mean differences in Chronic

Respiratory Disease ..................................................................... 200

xxii

List of Figures

Figure 2.1 The oxyhaemoglobin dissociation curve ........................................ 17

Figure 3.1 Venn diagram illustrating the overlap of chronic bronchitis,

emphysema and asthma within COPD .......................................... 47

Figure 3.2 Time course of COPD ................................................................... 50

Figure 3.3 Diagram illustrating the causes of airflow obstruction in COPD ..... 56

Figure 3.4 Flow volume loops in COPD and health ........................................ 59

Figure 3.5 Frontal section of the chest wall at full expiration showing the

zone of apposition ......................................................................... 60

Figure 3.6 Typical length-tension curve for a skeletal muscle (solid curve)..... 63

Figure 3.7 Changes in lung function with exercise in a) normal individuals

and b) patients with COPD ............................................................ 65

Figure 3.8 Changes in operating lung volumes leading to restrictive

constraints upon tidal volume ........................................................ 66

Figure 3.9 Relaxation Pressure (P) – volume (V) relationships of the total

respiratory system a) in health and b) in COPD ............................ 68

Figure 3.10 Diagram illustrating the many sensory sources of breathing

discomfort contributing to and modifying the intensity of

dyspnoea ...................................................................................... 75

Figure 4.1 Model of functional status .............................................................. 98

Figure 6.1 Flow of participants through the study ......................................... 123

Figure 6.2 Correlations (Pearson coefficient) between standing/walking

time and pedometer activity count ............................................... 126

Figure 7.1 Lung volumes and subdivisions ................................................... 136

Figure 7.2 Tracing of tidal breathing ............................................................. 137

Figure 7.3 Study procedures ........................................................................ 152

Figure 7.4 Correlations (Pearson co-efficient) between change in

inspiratory capacity and disease severity .................................... 157

Figure 8.1 Study flowchart ............................................................................ 167

Figure 8.2 Exercise testing procedure .......................................................... 179

Figure 8.3 Labels used for domiciliary study cylinders .................................. 182

Figure 8.4 Flow of participants through the study ......................................... 186

xxiii

Figure 8.5 Graphs of air and oxygen group scores in the three outcome

measures which demonstrated a main effect for time over the

12 weeks of the study ................................................................. 196

Figure 8.6 Histogram depicting cylinder utilisation over the 12 weeks of

the study by participants overall .................................................. 198

Chapter 1: Introduction 1

There are known knowns; there are things we know we know. We also know there are known unknowns, that is to say we know there are some things we do not know. But there are also unknown unknowns - the ones we don't know we don't know. Donald Rumsfeld (2002)

Introduction

1.1 Introduction to the topic ..................................................................... 1 1.2 Statement of the problem .................................................................. 2 1.3 Research aims .................................................................................. 3 1.4 Overview of the thesis ....................................................................... 4

1.1 Introduction to the topic

Oxygen is a colourless, odourless, tasteless, transparent, non-flammable gas

(Saposnick and Hess 2002). It is a by-product of photosynthesis and the basis

for respiration in plants and animals. Oxygen is the most abundant element in

the earth's crust constituting approximately 50% by weight (Nunn 2005). Prior to

the advent of living organisms, the earth‟s atmosphere contained no free oxygen

(Cotes 1993). Over millions of years the atmospheric concentration of oxygen

has gradually increased to stabilise at the current level of approximately 21% by

volume (Nunn 2005, Saposnick and Hess 2002). However, it is anticipated that

this will change in the future as a result of human activities (Cotes 1993, Nunn

2005).

Although oxygen and its importance for sustaining life were identified over 230

years ago (Chinard 1995), there are still many questions regarding how it should

be used therapeutically. Initial interest in its domiciliary use for patients with

chronic lung disease was in relation to portable or ambulatory delivery systems

which had become available early last century to support military aviators and

mountaineers. From the 1950‟s, a number of small, mostly uncontrolled trials

were suggestive of benefits from domiciliary supplemental oxygen. However, it

was not until the early 1980‟s that convincing evidence was published from the

results of two landmark, randomised controlled trials, known as the Nocturnal

Oxygen Therapy trial (NOTT) (Nocturnal Oxygen Therapy Trial Group 1980) and

1 Chapter


Medical Research Council (MRC) trial (Medical Research Council Working Party

1981, Nocturnal Oxygen Therapy Trial Group 1980). Together, these trials

demonstrated survival benefits from using continuous oxygen therapy (COT) for

at least 15 hours per day in people with chronic obstructive pulmonary disease

(COPD) and severe resting hypoxaemia. The use of COT for this patient group is

now widely accepted. Since the 1980‟s, however, relatively little research has

been conducted to further investigate the effects of domiciliary oxygen,

particularly the intermittent use of ambulatory oxygen, and there remains

confusion throughout the world about which patients should receive this

treatment.

1.2 Statement of the problem

COPD is a leading cause of disease and disability globally, for which there is no

cure (Rodriguez-Roisin et al 2008). COPD refers to a group of disorders

including chronic bronchitis and emphysema and is characterised by reduction in

airflow which is not fully reversible. It is associated with progressive, disabling

dyspnoea and reductions in function and quality of life. People with COPD

commonly develop hypoxaemia as their condition advances (Rodriguez-Roisin et

al 2008). Treatment options for COPD remain limited (Rodriguez-Roisin et al

2008) and domiciliary oxygen has a major role in its management (Cranston et al

2005).

Long-term COT, when used for at least 15 hours per day, is the only intervention

known to increase life expectancy in people with COPD who are severely

hypoxaemic at rest (Medical Research Council Working Party 1981, Nocturnal

Oxygen Therapy Trial Group 1980). Extrapolation of the results of the NOTT and

MRC trials might suggest that the use of ambulatory oxygen would maximise the

time spent on oxygen over 24 hours and ought therefore to maximise the benefits

seen. However, there is a lack of evidence to support this notion (Ram and

Wedzicha 2003). Whilst international guidelines for domiciliary oxygen vary on

this issue, domiciliary ambulatory oxygen is funded in many centres for patients

qualifying to receive COT.

Many people with COPD are not severely hypoxaemic at rest but experience

significant exertional dyspnoea, which may or may not be associated with oxygen

desaturation. Several studies have demonstrated acute improvements in exercise


capacity and/or dyspnoea during laboratory-based exercise testing while

breathing oxygen-enriched gas compared with breathing air in people with COPD

(Snider 2002). This suggests that the longer-term use of ambulatory oxygen

during exertion might also be beneficial in this circumstance. However, the three

previous studies designed to answer this question have not satisfactorily

demonstrated a role for ambulatory oxygen for these patients (Eaton et al 2002,

McDonald et al 1995, Nonoyama et al 2007a). These studies were limited by

small sample sizes assessed over relatively short periods and by using gas flow

rates which may have been insufficient to induce a benefit (Snider 2002).

Nevertheless, domiciliary ambulatory oxygen is also provided in some centres for

people with COPD who do not have severe resting hypoxaemia.

Domiciliary ambulatory oxygen is expensive and is cumbersome and difficult for

many people to use. It is therefore important to know whether there are any

clinically relevant benefits to be derived from its application.

1.3 Research aims

The variability in prescription of domiciliary ambulatory oxygen reflects the lack of

evidence from well-designed research with sufficient power to detect an effect if

present. The research within this thesis attempts to address this gap in evidence,

specifically to examine whether or not domiciliary ambulatory oxygen benefits

patients with COPD who have exertional dyspnoea but do not have severe

resting hypoxaemia and do not qualify to receive COT.

In order to explore the possibility that response to ambulatory oxygen in COPD

may be associated with factors other than the relief of hypoxaemia, people with

and without exertional desaturation were studied. Other factors examined were

severity of dyspnoea, level of airflow obstruction and oxygen-induced

improvement in exercise capacity. In addition, gender differences were

examined as there is some evidence that gender may influence disease severity

and response to some therapies (de Torres et al 2006, Katsura et al 2007). A

further factor which was assessed was pulmonary volume response as one

theory which explains the improvements found with supplemental oxygen during

exercise in COPD relates to improvements in operating lung volumes (O'Donnell

et al 2001a). During exercise the lungs become increasingly hyperinflated, over

and above resting levels (dynamic hyperinflation) due to increased ventilatory


demand and reduced expiratory time. Dynamic hyperinflation is believed to be a

major factor contributing to perceived respiratory discomfort (dyspnoea) and

exercise limitation (O'Donnell and Webb 2008). It has been shown that the

application of supplemental oxygen during exercise reduces ventilatory demand

and consequently delays the onset of dynamic hyperinflation and dyspnoea

(O'Donnell et al 2001a).

1.4 Overview of the thesis

Chapter 2 of this thesis describes historical aspects leading to the current

therapeutic uses of oxygen. The control of ventilation and how this relates to

oxygen therapy, domiciliary delivery systems and criteria for domiciliary oxygen

prescription are also outlined.

Chapter 3 provides an overview of the pathology and pathophysiology of COPD.

Mechanisms of altered pulmonary mechanics and gas exchange and other

abnormalities are also described.

Chapter 4 describes the outcome measures commonly used in COPD to

measure dyspnoea, quality of life and function. The measures chosen for use in

this research and the rationale for these choices are outlined.

Chapters 5 and 6 cover the development of measures to assess functional

performance or physical activity for use in this research. Whilst the gold standard

for measurement of daily physical activity is the accelerometer, the complexity

and expense of such a device renders it impractical for use in large scale

research. Pilot studies to develop an activity diary are described in Chapter 5. In

Chapter 6, data from the diary developed were correlated and compared with

those of a simple, waist-mounted pedometer.

Chapter 7 describes a study which assessed the acute effects of supplemental

oxygen (hyperoxia) upon resting levels of lung inflation and ventilation in patients

with COPD. Whilst hyperoxia-induced volume responses have been

demonstrated during exercise, little is known about such responses at rest.

Volume responses were assessed by measuring inspiratory capacity and the

rationale and method used is described. It was hypothesised that if a resting

volume response to hyperoxia was present in some people with COPD, those


demonstrating this response may be more responsive to domiciliary ambulatory

oxygen.

Chapter 8 describes the main study of this thesis. This was a 12-week, double-

blinded, randomised controlled trial of ambulatory oxygen compared with

ambulatory air in patients with COPD but without resting hypoxaemia. The main

outcome measured was dyspnoea. Secondary measures included health-related

quality of life, mood disturbance, function and gas cylinder utilisation. Subgroup

analyses of factors potentially predictive of benefit were also performed including

exertional desaturation, exercise and volume response to hyperoxia, severity of

dyspnoea and airflow obstruction and gender.

Chapter 9 summarises the findings of this research and their significance.

Chapter 2: Oxygen therapy 7

No natural phenomenon can be adequately studied in itself alone, but to be understood must be considered as it stands connected with all of nature. Sir Francis Bacon (1561-1626)

Oxygen therapy

2.1 Introduction ....................................................................................... 7 2.2 Historical perspectives ...................................................................... 9

2.2.1 Physiology ........................................................................... 9 2.2.2 Therapeutic uses of oxygen ............................................... 10

2.3 Domiciliary oxygen systems ............................................................ 12 2.3.1 Supply devices .................................................................. 12 2.3.2 Delivery systems ............................................................... 13 2.3.3 Conservation devices ........................................................ 13 2.3.4 Current domiciliary oxygen systems .................................. 13

2.4 Ventilatory control ........................................................................... 14 2.4.1 Overview ........................................................................... 14 2.4.2 Central controllers ............................................................. 15 2.4.3 Sensors ............................................................................. 15 2.4.4 Oxygen and carbon dioxide transport ................................ 16 2.4.5 Control of the ventilatory system ........................................ 17 2.4.6 Hazards of oxygen therapy ................................................ 19

2.5 Domiciliary oxygen therapy ............................................................. 21 2.5.1 Definitions .......................................................................... 21 2.5.2 Oxygen prescription guidelines .......................................... 23 2.5.3 Evidence for oxygen prescription guidelines ...................... 25 2.5.4 Prescription of domiciliary ambulatory oxygen in COPD .... 31 2.5.5 Evidence for use of domiciliary ambulatory oxygen............ 32

2.6 Conclusions..................................................................................... 42

2.1 Introduction

Domiciliary oxygen has become one of the major forms of treatment for patients

with COPD (Cranston et al 2005) since the publication of two landmark studies

which demonstrated improved survival with long-term oxygen in patients with

COPD and severe hypoxaemia (Medical Research Council Working Party 1981,

Nocturnal Oxygen Therapy Trial Group 1980). Patients with COPD form the

majority of users of this therapy (McDonald et al 2005, Rees and Dudley 1998a).

Accordingly, the majority of oxygen research studies have investigated its use in

COPD, although few randomised controlled trials have been published (Table

2.1). Results of studies of COPD patients have been extrapolated to support the

use of supplemental oxygen for other causes of hypoxaemia, for example cystic

2 Chapter


fibrosis and interstitial lung disease (Ringbaek 2005), despite less evidence of

benefit in these groups. Similarly, there is little evidence to support the long-term,

domiciliary use of oxygen during exertion, when it might be anticipated to provide

significant benefit. Despite the wide-spread use of domiciliary oxygen in the

management of COPD, remarkably little progress has been made to extend the

findings of the two landmark studies since their publication over 25 years ago

(Croxton and Bailey 2006).

Table 2.1 Summary of Cochrane Collaboration reviews of domiciliary oxygen

therapy

Year

Title

Studies

included/ identified

Results

2003 (Ram and Wedzicha 2003)

Ambulatory oxygen for COPD

2/90 COPD with and without severe resting hypoxaemia: no clear effects upon dyspnoea, quality of life, function.

2005 (Cranston et al 2005)

Domiciliary oxygen for COPD

4/6 COT: improves survival in COPD with severe hypoxaemia but not with mild to moderate hypoxaemia or nocturnal desaturation only.

2005 (Bradley and O'Neill 2005)

Short-term ambulatory oxygen for COPD

31/60 Laboratory assessment of exercise capacity in moderate to severe COPD: strong evidence of improvement.

2005 (Crockett et al 2001)

Domiciliary oxygen for ILD

1 (unpublished)

/2

COT: no evidence of improved survival.

2005 (Mallory et al 2005)

Oxygen therapy for CF

9/10 Intermittent oxygen therapy during sleep: no survival or symptom benefit. May improve oxygenation. Improvements in exercise duration and peak performance.

2007 (Nonoyama et al 2007b)

Oxygen therapy for exercise training in COPD

5/216 Insufficient evidence of long-term benefits from training oxygen.

COPD, Chronic obstructive pulmonary disease; COT, continuous oxygen

therapy; ILD, intersitital lung disease; CF, cystic fibrosis


This chapter outlines the milestones in the evolution of oxygen as a therapeutic

modality in the domiciliary setting. Discussion includes historical perspectives

and the medical literature which have combined to influence its current use in the

management of exertional breathlessness in patients with COPD. The outcome

measures referred to in this chapter are discussed in Chapter 4.

2.2 Historical perspectives

2.2.1 Physiology

It has long been known, even to primitive man, that breathing is necessary to

support life and that its cessation results in death (Proctor 1995a). Hippocrates

(460-370 BC) proposed that inspired air contained something which entered the

heart and spread throughout the body and Aristotle (384-322 BC) showed that

animals would not survive in air-tight boxes. The early suggestion that the breath

served to cool the fires of the heart and the blood was an accepted theory for

more than 2000 years until the 17th century AD (Proctor 1995a). The foundation

for the understanding of the function of breathing was provided by Harvey (1578-

1657) with the landmark discovery of the circulation of the blood reported in 1616

(Permutt 1995).

Mayow published the first detailed description of the mechanics of breathing in

1674 (Proctor 1995b). At this time it was appreciated that the blood derived

something from the air while it was in the lungs, identified by Mayow to be "nitro-

aerial spirit" (Fitzgerald 1995). Also during the 17th century Baptiste van Helmont

identified "gas sylvestre", now known as carbon dioxide (Fitzgerald 1995). It was

almost a century later that Black identified the role of carbon dioxide in respiration

(Fitzgerald 1995).

In 1774 Priestly (1733-1804) generated "dephlogisticated" or "pure" air (Priestly

1775, cited in Chinard 1995). Lavoisier (1743-1794) named this gas oxygen in

the following year, the name being derived from the Greek, meaning "acid

producer" (Attia et al 2004). While Priestly is credited with discovering oxygen,

Lavoisier identified the function of the respiratory gases and the role of the lungs

in the major functions of breathing in 1777 (Chinard 1995, West 2004).


2.2.2 Therapeutic uses of oxygen

When Priestly reported his discovery of “dephlogisticated” air, he commented

upon its “superior goodness” and predicted that it might become "a fashionable

article in luxury” (Priestly 1775, cited in Chinard 1995). The popularity of the

Japanese "oxygen bars" over 200 years later may be considered testament to the

accuracy of this prediction! Oxygen soon became used therapeutically for many

ailments, including infertility and hysteria (Block 1982). In 1886 it was promoted

for use intravenously, subcutaneously, via the stomach, uterus and vagina and as

an enema to treat liver and intestinal diseases (Attia et al 2004). By the end of

the 19th century, the widespread, indiscriminate use of oxygen had resulted in it

falling into disrepute as a therapeutic modality (Block 1982).

One of the first documented therapeutic uses of oxygen for respiratory conditions

was for treatment of acute bacterial pneumonia in 1885 (Petty 2000b). However,

it was not until the early 20th century that its therapeutic value became better

understood, with the evolving knowledge of the physiological and clinical

consequences of reduction in oxygen availability. In 1917 an English physician,

Haldane, described the use of oxygen as a therapy for gas poisoning in World

War I (Haldane 1917). Two years later he published a detailed discussion of the

physiological basis for "anoxaemia" and predicted that oxygen would soon be

used in hospitals (Haldane 1919). In 1920, another English physician described

positive outcomes with the use of oxygen for pneumonia and concluded that the

"anoxaemia", which may be present in certain respiratory diseases, may be

relieved by effective oxygen administration (Meakins 1920). The first report of

systematic use of oxygen in American hospitals was in 1922, for the treatment of

bacterial pneumonia (Barach 1922).

Interest in the use of supplemental oxygen outside the hospital setting developed

during the 1950‟s. The development of suitable portable apparatus had been

driven by the requirements of mountaineers (the first successful ascent of Mount

Everest took place in 1953) and the aviators in the world wars (Cotes and Gilson

1956). A famous runner, Roger Bannister reported subjective improvement in

breathlessness during heavy exercise with hyperoxia in an unblinded study of

four healthy subjects including the authors (Bannister and Cunningham 1954).

The clinical application of domiciliary oxygen commenced with the use of portable

systems during exertion. Pioneers in this area were Cotes in the United


Kingdom, Barach in New York and Thomas Petty (1932–2009) in Denver,

Colorado. Cotes reported increased walking time and improved arterial

saturation in 22 of 29 patients with chronic lung disease and severe

breathlessness when using transportable high-pressure cylinders (Cotes and

Gilson 1956). Barach described the use of small, transfillable oxygen cylinders

able to be carried during exercise (Barach 1959). Petty's group provided a

rationale for prescribing oxygen according to arterial blood gas targets rather than

arbitrarily chosen flow rates and reported improvements in exercise capacity and

cost-benefits in a study of six patients with chronic lung disease (Levine et al

1967). The Denver group was one of the first to report improvement in cardiac

symptoms and haematocrit with continuous oxygen, including portable cylinders,

in a study of 20 patients with advanced COPD over 12 months (Petty and Finigan

1968). A study from England also reported improvements in exercise tolerance

although formal assessment of exercise capacity and the degree to which

ambulation was supported by portable systems were not reported (Abraham et al

1968). Additionally, an early report of reduced recovery time after oxygen-

supported exercise was published around this time (Pierce et al 1965).

Following on from these initial studies, researchers in the United Kingdom

investigated the daily requirements of oxygen, provided by a stationary source, to

reverse pulmonary hypertension and suggested improvements in pulmonary

artery pressure with 12, 15 and 18 hours per day of supplemental oxygen (Stark

et al 1972, Stark et al 1973). It was additionally reported by these authors that 15

to 18 hours per day was superior to 12 hours (Stark et al 1972, Stark et al 1973).

Around this time, the Denver group published evidence to suggest a survival

benefit from long-term use of supplemental oxygen in patients with COPD and

cor pulmonale but not in patients without cor pulmonale (Neff and Petty 1970).

Other studies from this period also suggested walking endurance was

significantly increased with the administration of supplemental oxygen in patients

with COPD and severe hypoxaemia (Bradley et al 1978, Leggett and Flenley

1977, Lilker et al 1975).

The first double-blinded randomised controlled trial to assess the effects of

portable oxygen included nine patients with COPD and severe hypoxaemia

(Lilker et al 1975). Portable cylinders containing air or oxygen were provided for

continuous use during waking hours, over a five week period, in randomised,

crossover fashion with a 10-day washout between the periods (Lilker et al 1975).


This study demonstrated a statistically significant increase in PaO2 both at rest

and at maximal exercise, after oxygen compared with air (measured 4 to 24

hours after cessation of study gas use) and it was concluded that oxygen

provided more than placebo benefits. However, no differences in dyspnoea or

functional activity levels were found (Lilker et al 1975).

Thus, by the 1970's a number of small, mostly uncontrolled studies had been

published to suggest acute and long-term benefits from hyperoxia in chronic lung

disease with severe hypoxaemia. These studies stimulated interest in domiciliary

oxygen therapy on both sides of the Atlantic and the commencement of two

relatively large, randomised controlled trials of long term domiciliary oxygen

(Medical Research Council Working Party 1981, Nocturnal Oxygen Therapy Trial

Group 1980) which is discussed in Section 2.5.3.

2.3 Domiciliary oxygen systems

2.3.1 Supply devices

Priestly first produced oxygen by heating mercuric oxide but it was not until 1895

that relatively large quantities of oxygen were first produced inexpensively by

fractional distillation of liquefied air (Weilacher 2002). The first oxygen systems

to become available for domiciliary use in the 1950's consisted of large, high-

pressure, compressed gas cylinders with a means to transfill to small, portable

cylinders (Petty and Flenley 1986). Liquid transfillable systems later became

available in the United States in 1965 (Petty 2000b). The latter became

increasingly popular in that country for continuous oxygen administration, while in

the UK, where less continuous supply was initially recommended (average 15

hours per day), compressed gas cylinders were used (Petty and Flenley 1986).

Electrically powered concentrator systems using a molecular sieve to separate

room air from oxygen were first developed in the UK (Petty 2000b) and

introduced for domiciliary use in 1974 (Kacmarek 2000). These devices, in

combination with transportable compressed gas cylinders have become the most

commonly used method of providing continuous domiciliary oxygen in developed

countries (Kacmarek 2000). Whilst the standard concentrator is moveable, it is

essentially a stationary device and requires mains electricity. Also in use are

liquid oxygen systems combining a large stationary unit from which small,

portable canisters may be transfilled (Nasilowski et al 2008). A smaller


concentrator has been developed to run off a 12-volt car battery (Rees and

Dudley 1998b) and light-weight portable devices which have rechargeable

batteries are now available (Kacmarek 2000, Nasilowski et al 2008) but are

expensive. Concentrators capable of refilling gas cylinders in the home have

been recently developed (Nasilowski et al 2008) and whilst promoted as an

economical alternative for very ambulant patients, are not yet widely used

(McCoy 2002).

2.3.2 Delivery systems

Early delivery systems included the nasal catheter which appeared in 1904 (Attia

et al 2004) and a mask with a reservoir bag attached via a non-rebreathing valve,

serving as a conservation device (Haldane 1919). Barach developed an oxygen

tent in 1922 (Barach 1922) but it was not until the early 1960's that the double

nasal cannulae became available which, in modified form, remains the most

common oxygen delivery apparatus used in the domiciliary setting today (Petty

1995).

2.3.3 Conservation devices

Since the 1980's, a variety of conservation devices have been developed to

extend the duration of cylinder oxygen supply (Saposnick and Hess 2002).

These include two types of reservoir cannulae, the pendant and the "moustache",

which have small reservoirs which fill during expiration and the transtracheal

catheter, a small-diameter catheter inserted surgically into the trachea between

the second and third tracheal rings, delivering oxygen directly into the midtrachea

(Saposnick and Hess 2002). Far better accepted, however, have been the

demand oxygen delivery systems (DODS) which became available in 1984

(Saposnick and Hess 2002). These devices are placed between the supply and

delivery device, provide a flow of oxygen on demand at the initiation of inspiration

and are available for use with stationary liquid oxygen reservoirs, liquid portable

cylinders and compressed gas oxygen cylinders (McCoy 2002).

2.3.4 Current domiciliary oxygen systems

In summary, domiciliary oxygen may now be supplied via concentrators,

compressed gas cylinders or, less commonly, liquid oxygen systems. Portable

concentrators are now available but have limitations of weight, short battery life

and expense. The most common apparatus used world-side for providing


supplemental oxygen during acitivity is the compressed gas cylinder (Kacmarek

2000) using the double nasal cannulae, often in combination with a DODS.

2.4 Ventilatory control

2.4.1 Overview

The importance of the ventilatory system is well summarised by Haldane‟s

description of the role of oxygen in supporting life as “…..peculiar, since the body

has practically no storage capacity for oxygen, but depends from moment to

moment for its supply from the air” (Haldane 1919). Priestly noted that mice

deprived of "dephlogisicated" air would die and that a candle burnt faster in

"dephlogisicated" air than in common air (Priestly 1775 cited in Chinard 1995).

These observations suggested to him that "humans might live out too fast, and

the animal powers be too soon exhausted in this pure kind of air". Further, he

postulated that the air provided by nature is "as good as we deserve" (Priestly

1775 cited in Chinard 1995), alluding to the importance that fraction of inspired

oxygen (FiO2) plays in the equilibrium required for normal cell function.

The ventilatory system is comprised of the central control areas, the sensors and

the effectors (respiratory muscles) (West 2005). Respiratory motor command

emanates primarily in response to signals from chemoreceptors which, in turn,

respond to changes in chemical composition of the blood or other fluids

surrounding them (Ganong 2003, West 2005). Additional, non-chemical

influences upon ventilation are provided by the mechanoreceptors which located

in a number of areas. Despite variable demands for oxygen uptake and CO2

elimination, normally breathing is able to be regulated to maintain sufficient

exchange of oxygen and carbon dioxide (CO2) and therefore normal levels of

these gases in arterial blood and normal acid-base status (pH between 7.35 and

7.45) (American Thoracic Society 1999a).

This section describes the ventilatory controllers and sensors and how ventilation

is controlled in health. The respiratory muscles, (the effectors) and the

mechanisms by which ventilatory control and respiratory muscle function are

altered in COPD will be described in Chapter 3.


2.4.2 Central controllers

The respiratory muscles are under the influence of both automatic and voluntary

control, making them unique amongst skeletal muscles (Manning and

Schwartzstein 1998). The automatic process of breathing is regulated by

impulses originating from the brain stem, particularly the pons and medulla, which

are collectively termed the respiratory centre. When required, for example during

speech, these impulses may be overridden to some extent by the voluntary

system which is located in the cortex (Ganong 2003, Lumb 2005). Other parts of

the brain such as the limbic system and hypothalamus also alter breathing, for

example, during periods of rage and fear (West 2005).

2.4.3 Sensors

The respiratory chemoreceptors are situated centrally and peripherally. The

central chemoreceptors, located in the medulla, respond to changes in the

hydrogen ion concentration in the brain extracellular fluid surrounding them,

mediated by changes in pH and carbon dioxide (CO2). The composition of the

extracellular fluid around these receptors is determined mostly by the

cerebrospinal fluid (CSF) and also by local blood flow and local metabolism

(Lumb 2005).

Peripheral chemoreceptors are located in the carotid bodies at the bifurcation of

the common carotid arteries and in the aortic bodies above and below the aortic

arch (West 2005). In addition to changes in CO2 and pH, the peripheral

chemoreceptors also respond to changes in PaO2 and hypoperfusion which may

result from severe hypotension (Lumb 2005). In humans the peripheral

chemoreceptors are the main receptors capable of influencing the respiratory

centre in response to arterial hypoxaemia (West 2005) although this response

also involves multiple pathways and organs, including the brain, which act to

modify carotid body signals (Cherniack 2004).

Mechanoreceptors located in the lung and chest wall feed afferent information to

the brainstem regarding mechanical aspects of function. Afferents from

pulmonary mechanoreceptors are mostly carried via the vagus nerve, although

some may be carried via sympathetic nerves (Lumb 2005). Three main types of

pulmonary sensory receptors have been identified, pulmonary stretch receptors,

irritant receptors and J receptors (Manning and Schwartzstein 1998, West 2005).

The pulmonary stretch receptors, which are located predominantly in the airways,


respond to increases in lung volume. The irritant receptors, found in the airway

epithelium, respond to stimulation of the bronchial mucosa by a variety of

mechanical and chemical stimuli, including noxious gases, dusts, cold air, high air

flow rates, large changes in lung volume and increases in bronchial smooth

muscle tone. Juxtapulmonary or J receptors are located in the alveolar walls

throughout the airways and lung parenchyma, close to the capillaries. These

receptors respond to mechanical stimuli such as increases in pulmonary

interstitial and capillary pressure, by initiating rapid, shallow breathing (American

Thoracic Society 1999a, Lumb 2005, Manning and Schwartzstein 1998).

In addition to the above, breathing is also influenced by afferent stimuli from

proprioceptors in the joints, muscles and tendons of the chest wall, baroreceptors

(located in the carotid sinuses, aortic arch, atria and ventricles) and afferent

nerves responding to pain and temperature (Ganong 2003, Lumb 2005, Manning

and Schwartzstein 1998).

2.4.4 Oxygen and carbon dioxide transport

Oxygen is carried by the blood in two ways: in solution in the plasma (a small

amount) and in red blood cells in chemical combination with haemoglobin cells

(West 2005). The latter is expressed as a percentage of the maximal amount

that haemoglobin can carry (oxyhaemoglobin saturation). The relationship

between oxygen concentration in the blood (mmHg) and oxyhaemoglobin

saturation (%), or the affinity of haemoglobin for oxygen, is described by the

oxyhaemoglobin dissociation curve (Figure 2.1) (West 2005).

The upper, flat portion of the curve ensures that arterial oxygen concentration

remains high if PaO2 decreases to approximately 50 to 60 mmHg. A decrease in

affinity of haemoglobin for oxygen occurs when temperature or PaCO2 are

increased or pH is reduced (the curve moves to the right). This assists the

unloading of oxygen to the muscles. Conversely, the curve moves to the left

when these measures change in opposite directions (Lumb 2005, West 2005).


Figure 2.1 The oxyhaemoglobin dissociation curve. Changes in temperature,

pH, and organic phosphates, for example, 2,3-Diphosphoglycerated (DPG)

directly affect the dissociation of oxygen (Dorcas 2008).

PO2, (arterial) partial pressure of oxygen; mmHg, millimeters of mercury

CO2 is the end-product of aerobic metabolism and is mostly produced in the

mitochondria. It is carried in the blood in three ways: dissolved, as carbonic acid

and as bicarbonate, the largest proportion being the latter (Lumb 2005).

Elimination of CO2 from the lungs has an important influence upon acid-base

status. The volume of CO2 in the blood is relatively high, almost 100 times that of

the volume of oxygen (Lumb 2005). Therefore CO2 levels change slowly in

response to altered ventilation, in contrast to oxygen levels which change rapidly.

PaCO2 is a measure of the respiratory component of acid-base status while

bicarbonate level defines its metabolic component (West 2005).

2.4.5 Control of the ventilatory system

Response to carbon dioxide

Under normal circumstances, the most important factor controlling ventilation is

PaCO2, mainly due to its influence upon pH of the CSF (West 2005). CO2

diffuses readily across the blood-brain barrier separating the CSF from the


cerebral blood vessels. When PaCO2 rises, diffusion increases, liberating

hydrogen ions and reducing the pH of the CSF This increases ventilation, minute

volume and therefore pulmonary excretion of CO2 (Ganong 2003). This

mechanism is normally very sensitive, maintaining PaCO2 within 40 ±3 mmHg

during non-sleeping hours (West 2005). Increased PaCO2 is also accompanied

by cerebral vasodilation which enhances diffusion of CO2 into the CSF and brain

extracellular fluid, further driving a reduction in CO2 (West 2005).

However, if ventilation is compromised and unable to increase sufficiently to meet

metabolic demand, alveolar PCO2 rises, making elimination of CO2 from the body

difficult. Hypercapnia may rapidly result, depressing the central nervous system

including the respiratory centre and producing headache, confusion and

eventually coma (CO2 narcosis) (Ganong 2003, Lumb 2005).

Response to oxygen

Reduction in alveolar PO2 also stimulates ventilation but this effect is not usually

marked until alveolar PO2 decreases to approximately 50 to 60 mmHg (Ganong

2003, West 2005). Therefore, the role of hypoxic stimulus to ventilation in health

is usually small, an exception being ascent to altitude (Ganong 2003, West

2005).

Response to pH

The stimulation of ventilation in response to the reduction in arterial pH has been

discussed in relation to elevation in PaCO2. Reduction in arterial pH may also

occur independently of a rise in PaCO2, although these changes usually occur

concurrently (West 2005).

Response to exercise

In response to increasing workload, the cardiovascular system is called upon to

deliver increasingly higher amounts of oxygen and eliminate increasingly higher

amounts of CO2. At higher levels of exercise, anaerobic metabolism begins to

take place within exercising muscle cells as oxygen delivery is no longer able to

meet aerobic metabolic demands and lactic acid production results (MacIntyre

2000, West 2005). The cardiovascular response is to increase cardiac output,

initially by increasing stroke volume and then heart rate. In health, cardiac output

may increase five-fold, achieved by near doubling of stroke volume and an

increase of heart rate to approximately 220 minus the subject's age (West 2005).


Normally, it is the cardiovascular system which is the limiting factor to exercise as

the ventilatory system has greater reserve (MacIntyre 2000, West 2005). The

ventilatory response to exercise is primarily determined by pH (West 2005) and is

a bi-phasic response, with an initial rise to clear excess CO2 from aerobic

metabolism and a subsequent more rapid rise to clear additional CO2 from

anaerobic metabolism (MacIntyre 2000, West 2005). The point of changeover

between phases is termed the "anaerobic threshold" (MacIntyre 2000, West

2005).

During exercise in health, the relationship between alveolar ventilation and

pulmonary blood flow (V/Q ratio) becomes more non-uniform (Hammond et al

1986) and the difference in partial pressure of oxygen between alveolar gas and

arterial blood (PA-a02) increases (Havercamp et al 2005). Increased pulmonary

perfusion decreases the time for exposure of haemoglobin to alveolar gas (transit

time), although this is not usually sufficient to impact upon gas transfer when the

alveolar-capillary interface is normal (MacIntyre 2000). However, with increasing

intensity of exercise, alveolar ventilation increases out of proportion to perfusion,

thus counteracting these mechanisms (Havercamp et al 2005). The net result is

that in health, PaCO2 remains constant and PaO2 increases slightly during

moderate exercise. However, at very high workloads, PaCO2 and PaO2 may fall

and pH may also fall due to liberation of lactic acid as a consequence of

anaerobic glycolysis (West 2005).

Of interest, a number of reports of improved exercise performance when

breathing supplemental oxygen in healthy individuals appeared in the early

1900‟s, including that of a famous runner, Roger Bannister in 1953 (MacIntyre

2000). Although not fully understood, more recent work has suggested that the

mechanisms behind this improvement may include reduced ventilatory drive,

reduced ventilatory muscle work and therefore reduced metabolic demand

(MacIntyre 2000, West 2005).

2.4.6 Hazards of oxygen therapy

Physiological hazards

Although the use of supplemental oxygen may be beneficial, high levels of

hyperoxia may also have toxic effects at the cellular level (Lumb 2005). The lung

is the most susceptible organ to oxygen toxicity as the lungs have the highest

tissue partial pressure of oxygen. Oxygen administered at a concentration of


100% over long periods may damage the capillary endothelium, causing

increased capillary permeability and interstitial and alveolar oedema. A

combination of interstitial fluid accumulation and substitution of alveolar type I

cells for type II cells results in thickening of the alveolar/capillary membrane

(Lumb 2005) and ultimately may cause haemorrhage and atelectasis, consistent

with the adult respiratory distress syndrome (Block 1982, Lumb 2005).

Oxygen toxicity may also be manifested by tracheobronchial irritation, depressed

tracheobronchial mucus transport and tracheobronchitis (Block 1982). In

addition, oxygen toxicity is understood to be a major factor in the development of

the pulmonary abnormalities (bronchopulmonary dysplasia) (Block 1982) and of

retrolental fibroplasia (Lumb 2005) seen in newborns who have had severe

respiratory distress syndrome treated with hyperoxia. Breathing 100% oxygen

also accelerates absorption atelectasis due to the reduction of alveolar nitrogen

concentration (Lumb 2005, West 2005). Absorption atelectasis refers to the

absorption into the blood of alveolar gas which is trapped beyond airways which

are partially or completely obstructed which may be due to secretions, tumour,

bronchospasm, mucosal oedema or airway closure during anaesthesia (Lumb

2005).

Further discussion of the adverse effects of breathing high concentrations of

oxygen is beyond the scope of this thesis as domiciliary ambulatory oxygen is

generally provided using low flow systems. In the main study of this research,

study gases (cylinder oxygen or air) were provided at a flow of 6 L/min via nasal

cannulae (in the case of those receiving oxygen, estimated concentration = 44%)

(McCoy 2000, Shapiro and Peruzzi 1994). However, it of note that pulmonary

cellular, exudative and fibrotic lesions, consistent with the changes described

above in relation to oxygen toxicity, have been reported in some patients

receiving continuous oxygen at a flow of 1 to 4 L/min for several years, although

at clinically insignificant levels (Block 1982).

Additional issues regarding the provision of supplemental oxygen to patients with

COPD are discussed in Section 3.10.2.

Practical problems

While oxygen does not explode, it does support combustion (Block 1982, Cusick

2001). Therefore, oxygen should not be used in the presence of open flames


(Cusick 2001), combustible materials such as petroleum based oils, lotions and

sprays or equipment capable of creating a spark such as electrical appliances

(Findeisen 2001, Tamir et al 2007). Whilst some fires have been reported in

association with domiciliary oxygen therapy, these have been generally as a

result of carelessness on the part of the patient (Block 1982). In particular,

smoking while using domiciliary oxygen has resulted in facial burns, inhalation

injuries and even death (Chang et al 2001, Lacasse et al 2006, Maxwell et al

1993).

2.5 Domiciliary oxygen therapy

2.5.1 Definitions

The terms used to categorise domiciliary oxygen therapy are confusing (Table

2.2). This issue was highlighted at an American "Consensus conference for long

term oxygen therapy” where consensus regarding terminology was unable to be

reached (Doherty and Petty 2006)! In this thesis, domiciliary oxygen therapy will

be described according to the three classifications used in Australasian

prescription guidelines: continuous (COT), nocturnal and intermittent (McDonald

et al 2005).

COT is defined as that used long-term, on a daily basis, for ≥15 hours per day

(including the night hours), for domiciliary treatment of chronic hypoxaemia

(McDonald et al 2005) and is generally provided via an oxygen concentrator.

This has traditionally been termed long term oxygen therapy (LTOT) (American

Association for Respiratory Care 2007, Royal College of Physicians 1999),

however confusion arises as oxygen may also be prescribed for long term use

during exercise, at rest and/or during sleep (American Thoracic Society 1995b,

Croxton and Bailey 2006, Doherty and Petty 2006), thus encompassing all three

classifications.


Table 2.2 Summary of terms describing different forms of oxygen therapy

Classification

Definition and subcategories

Continuous oxygen therapy (COT)

≥ 15 hours per day, via concentrator ± transportable apparatus: – Long-term COT (also "Long-term oxygen

therapy", LTOT) – Short-term COT (STOT)

Nocturnal oxygen therapy (NOT)

During sleep, via concentrator

Intermittent oxygen therapy

Via transportable apparatus: – In conjunction with COT – Emergency or stand-by – Air-travel – Palliative (often via stationary device) – Training oxygen – Short burst oxygen therapy (SBOT) – Short-term ambulatory oxygen (laboratory

assessment) – Domiciliary (long-term) ambulatory oxygen

Short term oxygen therapy (STOT) is a term used to describe the prescription of

COT for patients who are hypoxaemic upon discharge from hospital (Eaton et al

2001). It is recommended that arterial blood gases be retested, as once clinical

stability has been reached, many patients who previously did not qualify for COT

will return to their previous status. The suggested time for retesting varies from

one to three months (American Thoracic Society 1995b, Eaton et al 2001, Royal

College of Physicians 1999). Nocturnal oxygen therapy (NOT) is prescribed for

use during sleep only and is generally provided by an oxygen concentrator

(McDonald et al 2005).

Intermittent oxygen therapy is provided in a number of circumstances. Cylinder

oxygen may be provided for use in conjunction with COT. It is occasionally

provided for emergency, “stand-by” use by patients who live in isolated areas and

suffer life-threatening hypoxaemic episodes, for example, during acute asthma

(McDonald et al 2005, O'Donoghue 1995). Supplemental oxygen may also be

recommended during air-travel for patients who are known to become severely

hypoxic in this circumstance (Johnson 2003, McDonald et al 2005, Stoller 2000)

and for palliative use, to relieve intractable dyspnoea in patients with a terminal

illness (McDonald et al 2005).


Perhaps the most controversial application of intermittent oxygen is that used in

relation to exertional activities, for patients who do not qualify for COT, NOT or

other intermittent oxygen therapy. Four categories of such use have been found

in the literature, training oxygen, short burst oxygen therapy (SBOT) and

exertional oxygen provided for short-term (laboratory-based) and long-term

(domiciliary) use. Training oxygen refers to use during specific exercise, for

example pulmonary rehabilitation programs (Young 2005) and SBOT, mainly

prescribed in the United Kingdom, is used for pre-oxygenation before exertion,

during recovery after exertion or at rest (Royal College of Physicians 1999).

Short-term ambulatory oxygen is a term used to describe application during

laboratory-based assessments of exercise capacity (Bradley and O'Neill 2005).

Responses to supplementary oxygen (hyperoxia) in this circumstance are

commonly referred to as acute responses, and this term will be referred to in this

thesis.

The focus of this thesis is the longer-term, domiciliary provision of ambulatory

oxygen, able to be transported by the patient, provided for use during exertional

activities. This will be referred to as domiciliary ambulatory oxygen.

2.5.2 Oxygen prescription guidelines

Specific guideline documents for domiciliary oxygen prescription have been

published in the medical literature by groups from Australasia, America, Britain

and Europe and Canada (American Association for Respiratory Care 2007,

European Society of Pneumonology 1989, McDonald et al 2005, Ontario Ministry

of Health and Long Term Care Assistive Devices Program 2005, Royal College of

Physicians 1999). The full guideline document of the British Royal College of

Physicians is not readily available, but a summary has been published in its

journal (Wedzicha 1999). Oxygen prescription guidelines have also been

summarised as part of COPD management guidelines by Australasian,

American, British and European groups (American Thoracic Society 1995b, Celli

and MacNee 2004b, McKenzie et al 2003, Pauwels et al 2001, Siafakas et al

1995). Australasian, British, American, European and Canadian specific

guideline documents for COT, NOT and domiciliary ambulatory oxygen

prescription are summarised in Table 2.3.

24

Table 2.3 Summary of prescription guidelines for continuous, nocturnal and domiciliary ambulatory oxygen from Australasia (McDonald et al

2005), United States of America (American Association for Respiratory Care 2007), United Kingdom (Royal College of Physicians 1999) and

Canada (Ontario Ministry of Health and Long Term Care Assistive Devices Program 2005).

Australasia

United States

United Kingdom

Canada

Continuous PaO2mmHg (kPa) at rest

≤ 55 (≤ 7.3) or 56–59 (7.4-7.8) + hypoxic organ damage

≤ 55 (≤ 7.3) or SpO2 ≤88% or 56-59 (7.4-7.8), SpO2 ≤89% + hypoxic organ damage

< 55 (< 7.3) or 55-59 (7.3-7.8) + hypoxic organ damage

≤ 55 (≤ 7.3), or SpO2 ≤88% or 56-59 (7.4-7.8), SpO2 89-90% + hypoxic organ damage

Goal PaO2 > 60 mmHg (8 kPa)

PaO2 > 60 mmHg (8 kPa)

Nocturnal < 55 mmHg

or SpO2 <88% >⅓ of night

Lung disease + sleep apnoea + nocturnal desaturation PaO2 ≤55 mmHg

7.3-7.8 kPa + nocturnal hypoxaemia

Formal sleep study required to assess for sleep disordered breathing treatable by other means

Domiciliary Ambulatory Determined by exercise test/s

SpO2 ≤ 88% on air + improvement in exercise capacity or dyspnoea on O2

PaO2 ≤ 55 mmHg (≤ 7.3 kPa), SpO2 ≤88% on air

SpO2 ≤ 4% to reach < 90% on air + ≥10% walk distance or ≥10% dyspnoea on O2

MRC Dyspnoea score ≥4 + SpO2 <80% on walking or SpO2 ≤88% + Borg score ≥1 unit + 25% walk distance or 2 min walking time + Borg score ≥1 unit

PaO2, arterial partial pressure of oxygen; mmHg, millimeters of mercury; kPa, kilopascals; SpO2 oxyhaemoglobin saturation; MRC, Medical

Research Council


2.5.3 Evidence for oxygen prescription guidelines

Continuous oxygen therapy

Evidence to support the use of COT was provided by two landmark randomised

controlled trials published in the early 1980's, the North American NOTT

(Nocturnal Oxygen Therapy Trial Group 1980) and the British MRC trial (Medical

Research Council Working Party 1981). Both studies included patients with

advanced COPD (Table 2.4).

Table 2.4 Summary of the Nocturnal Oxygen Therapy Trial (NOTT) (Nocturnal

Oxygen Therapy Trial Group 1980) and The Medical Research Council (MRC)

trial (Medical Research Council Working Party 1981)

n

Inclusion criteria

Intervention

Outcome

NOTT 203 PaO2 ≤55 mmHg or ≤59 mmHg + hypoxic organ damage

Nocturnal vs continuous O2

Flow: 1-4 L/min to achieve PaO2 60-80 mmHg + 1L/min for exercise, sleep Duration: 1-2 years

Mean O2 use 11.8 vs 17.8 hrs/day

survival, HRQL, neuropsychological function

MRC trial

87

PaO2 40–60 mmHg on air at rest; at least one recorded episode of heart failure with ankle oedema

O2 ≥15 hours per day vs nil Flow: 2 L/min or to achieve PaO2 ≥60 mmHg Duration: 3 years

survival @ 500 days

red cell mass

rise in PVR

mmHg, millimeters of mercury; L/min, litres per minute; O2, oxygen; HRQL,

health-related quality of life; mmHg, millimeters of mercury; PVR, peripheral

vascular resistance

The NOTT compared continuous use (as close to 24 hours per day as possible)

with nocturnal use (approximately 12 hours per day) (Nocturnal Oxygen Therapy

Trial Group 1980). Continuous use significantly improved survival at 24 and 36

months (Nocturnal Oxygen Therapy Trial Group 1980). The MRC trial compared

the use of oxygen for approximately 15 hours per day with no oxygen and found

significant improvements in survival with oxygen at three, four and five years

(Medical Research Council Working Party 1981).


As inclusion criteria for the two studies were similar, their results have been

considered to collectively indicate that in COPD with severe hypoxaemia, survival

is poor with no oxygen therapy, increasingly improved with 12 and 15 hour per

day of supplemental oxygen and greatest with more continuous oxygen (Petty

and Flenley 1986). These trials therefore demonstrated a relationship between

survival and the average daily duration of oxygen use and provided the evidence

base for recommending that oxygen therapy be provided long term in the

circumstance of severe hypoxaemia (Table 2.3).

Although the conclusions drawn from the NOTT and MRC studies are widely

accepted, the two studies have some limitations (Medical Research Council

Working Party 1981, Nocturnal Oxygen Therapy Trial Group 1980). Firstly, both

focused upon the indications for COT in terms of hypoxaemia only. The

usefulness of other measures of disease severity and symptoms for predicting a

benefit from COT therefore remains unknown, raising the question of whether

there are patients without severe resting hypoxaemia who may benefit from this

therapy. Secondly, the recommendations for COT prescription derived from the

NOTT and MRC studies are derived from arterial oxygen levels chosen a priori as

study inclusion criteria, rather than retrospectively from the studies‟ results. The

recommendations are, to some extent, supported by two randomised controlled

trials of COT in patients with COPD and moderate resting hypoxaemia (n= 135

and 76) which found no survival benefits (Chaouat et al 1999, Gorecka et al

1997). Whilst these two studies may have been underpowered to determine an

absence of survival benefit, the similarity of their results add further support to

their findings and to the conclusions of the NOTT and MRC studies that patients

with severe resting hypoxaemia will derive a benefit (Croxton and Bailey 2006).

Retrospective analysis of the NOTT data was performed to explore the reasons

that COT was found to confer a greater survival benefit than nocturnal oxygen, in

particular, whether this was related to baseline exercise capacity or to the

duration of oxygen administration (Petty 2000a). Patients receiving nocturnal

oxygen were provided with a stationary source only, whereas those receiving

COT had also been provided with portable apparatus to encourage oxygen use

for as many hours per day as possible. During a three-week stabilisation period,

daily distance walked was recorded using a pedometer. As a surrogate marker

of exercise capacity, Petty and Bliss used pedometer data to determine the

distance walked per day during the third of these weeks. Using a cut-off of 3,590


feet per day (median walking distance), the group was divided into 18 pairs of low

and high walkers having received COT and 22 pairs of low and high walkers

having received nocturnal oxygen, matched for age, gender and disease severity

(Petty 2000a). A significant improvement in survival was found in the high

walkers who received COT compared with low walkers who received nocturnal

oxygen. When comparing the two low walking groups, survival was significantly

greater in those who received COT than in those who received nocturnal oxygen.

(Statistical comparison of the two high-walking groups was not reported.) These

authors concluded that differences found in survival could be due to either or both

the duration of oxygen use per day or the method with which it was provided

(stationary versus ambulatory source) (Petty 2000a). These findings would also

suggest that the provision of ambulatory oxygen equipment, which might

enhance activity, might confer a survival benefit.

Approaches to the prescription of COT vary internationally (Table 2.3) (Wijkstra et

al 2001). Variations include the use of pulse oximetry rather than blood gas

analysis to determine eligibility (MacNee 2005) and the requirement for this to be

assessed during a period of clinical stability (Guyatt et al 2000, MacNee 2005,

Wijkstra et al 2001). Participants in the NOTT were required to meet the PaO2

inclusion criterion at least twice during a three week period. The British Royal

College of Physicians prescription guidelines specify this requirement for COT,

whereas others require clinical stability but do not define this further (MacNee

2005). Adherence to guidelines is also variable, particularly with regard to this

issue (MacNee 2005).

Variations also exist regarding target blood oxygen levels for COT (Table 2.3). In

addition, the American and Australasian guidelines (American Thoracic Society

1995b, McDonald et al 2005) suggest that an increase in flow of 1L/min may be

required during sleep, exercise and air travel, although this recommendation has

been challenged (Nisbet et al 2006) as there is no clear evidence base for it. The

optimal number of hours for use per day and timing of use over 24 hours also

remains uncertain.

Nocturnal oxygen

Nocturnal oxygen is recommended for patients who do not qualify for COT

according to the abovementioned criteria, but exhibit isolated episodes of

hypoxaemia during sleep (McDonald et al 2005). Whether or not this is beneficial


remains unclear (Chaouat et al 1999, Cranston et al 2005, Folgering 1999).

Australasian guidelines specifically define nocturnal desaturation in contrast to

others (Table 2.3) (Folgering 1999).

The recommendation for nocturnal oxygen is based upon a double-blinded,

randomised controlled trial of 38 patients with COPD, daytime saturation of

90% and nocturnal desaturation defined as oxyhaemoglobin saturation (SpO2) <

90% for ≥ 5 minutes and a nadir of ≤ 85% (Fletcher et al 1992). It was concluded

that nocturnal oxygen at a flow rate of 3 L/min resulted in a reduction in

pulmonary artery pressure (Fletcher et al 1992). However, these findings have

since been challenged (Chaouat et al 1999, Folgering 1999). One randomised

controlled trial compared nocturnal oxygen (to achieve SpO2 >90%) with no

oxygen in 76 patients with COPD, mild to moderate hypoxaemia (daytime PaO2

56-69 mmHg) and nocturnal hypoxaemia (SpO2 <90% for ≥30% of the night)

(Chaouat et al 1999). Over a two-year follow-up, nocturnal oxygen was found

neither to alter pulmonary haemodynamics (there was a small, non-significant

increase in pulmonary artery pressure in both groups) nor to delay the onset of

daytime severe hypoxaemia (qualifying to receive COT). In addition, no survival

benefit was found, although the sample size studied may have been too small to

have found a difference (Chaouat et al 1999).

Intermittent oxygen therapy

1. Short burst oxygen therapy

The British oxygen therapy guidelines recommend the use of SBOT for relief of

dyspnoea in COPD, interstitial fibrosis, heart failure and palliative care, but it is

acknowledged that the use of SBOT is not evidence-based and assessment

criteria are not provided (Royal College of Physicians 1999). The use of SBOT

appears to be based upon a double blinded, crossover study of 10 patients with

COPD, mean PaO2 = 72.4 mmHg and at least moderate exertional dyspnoea

(Woodcock et al 1981). These authors measured exercise capacity (incremental

treadmill exercise test and six minute walk test, 6MWT) and exertional

breathlessness (visual analogue scale at 75% of maximal distance on the

treadmill test and end 6MWT) after one, five and fifteen minutes of pre-dosing

with cylinder oxygen compared with cylinder air (flow-rate of 4 L/min) (Woodcock

et al 1981). No difference was found after one minute but after five minutes of

oxygen pre-dosing, statistically significant (but clinically small) improvements

were found in both tests of exercise capacity and there was a significant


reduction in breathlessness. No further improvements were found after 15

minutes of oxygen pre-dosing compared with five minutes of oxygen pre-dosing.

These authors concluded that oxygen pre-dosing for one minute was insufficient

to provide a benefit, for five minutes was significantly better and that no further

benefit was obtained from 15 minutes of pre-dosing (Woodcock et al 1981).

One theory proposed to explain the benefit reported by some patients from SBOT

is that reflexes may be associated with the cooling effect of gas flowing onto the

face or may stimulate nasal receptors (Liss and Grant 1988, Schwartzstein et al

1987, Spence et al 1993). However, a study designed to test this hypothesis

found no reduction in breathlessness or recovery times after exercise when

patients with COPD were administered oxygen or air via a mask or when

breathing air from an electric fan compared with no intervention (Mckinlay et al

2007, O'Driscoll 2008). It has further been suggested that the benefits reported

from SBOT may relate to a placebo effect or improvement in condition over time

(O'Driscoll 2008).

A review which included the study of Woodcock et al (1981) and nine additional

studies examined the use of SBOT using pre-dosing, post-dosing and oxygen at

rest in patients with COPD (O'Neill et al 2006). No overall benefits were found in

breathlessness or a range of other outcome measures and it was concluded that

the use of SBOT is not evidence-based and should not continue unless a

scientific rationale for it becomes evident (O'Neill et al 2006).

Other studies and a more recent review of the literature (O'Driscoll 2008) have

also failed to provide evidence to support the use of SBOT. Quantrill et al

published a small randomised, double-blinded study of 22 patients who had

already reported benefit from SBOT. No significant differences in recovery time

(objective and patient-reported) were found between breathing oxygen at

previously prescribed flow rates compared with air, after performing two self-

selected activities (Quantrill et al 2007). Although subjective recovery time was

found to be shorter on oxygen, this was of doubtful clinical significance. A

limitation of this study was that it may have been underpowered (n=22), as the

sample size was based upon power calculations for an outcome measure

(breathlessness using a VAS) not included in the results. In addition, the

activities used in the assessment and their duration were not standardised

(Quantrill et al 2007). Eaton et al also found no support for long-term SBOT in a


six-month, double-blinded, randomised controlled trial to assess the effects of

oxygen (2 L/min), used as necessary for distressing or disabling breathlessness

(Eaton et al 2006). Included were 78 subjects being discharged from hospital

after an acute exacerbation of COPD, with a resting PaO2 >8 kPa (60 mmHg)

and therefore not qualifying for COT. Participants were randomly allocated into

one of three study groups, those receiving cylinder oxygen, cylinder air or usual

care. No significant differences were found between the groups for health-related

quality of life (HRQL) (using the Chronic Respiratory Disease Questionnaire,

CRQ and the Short Form-36, SF-36), mood disturbance (Hospital anxiety and

depression scale, HADS) or health care utilisation with the exception of the

emotion domain of the CRQ, where the greatest improvement occurred in the

usual care group (Eaton et al 2006).

2. Short-term ambulatory oxygen

A number of studies have demonstrated that hyperoxia, provided during

laboratory-based exercise assessment, improved exercise capacity and

dyspnoea in many patients with COPD, including those without exercise

desaturation (Albert and Calverley 2008, Bradley and O'Neill 2005, Snider 2002).

One mechanism thought to underly these benefits is an oxygen-induced

reduction in ventilatory demand which reduces or delays the onset of exercise

induced dynamic pulmonary hyperinflation thereby improving operational lung

volumes (Albert and Calverley 2008, Cooper 2006, Cukier et al 2007, O'Donnell

and Laveneziana 2006c). This appears to occur in a dose-dependent fashion, up

to FiO2 0.5 or a flow of 6 L/min of 100% oxygen delivered via nasal cannulae

(Snider 2002, Somfay et al 2001). Reduction of lactate production in exercising

muscle by enhancement of oxygen delivery to the tissues is also thought to have

an important role (Albert and Calverley 2008).

3. Training oxygen

Knowledge of the potential acute benefits achieved with hyperoxia has promoted

interest in the use of oxygen supplementation during exercise training (“training

oxygen”) (Young 2005), despite the lack of conclusive evidence of any long-term

benefit (Nonoyama et al 2007b). Small, randomised, controlled studies of oxygen

provided during relatively low exercise intensities in rehabilitation settings have

failed to show improved outcomes (Garrod et al 2000, Rooyackers et al 1997).

Conversely, one double-blinded study of 29 patients with COPD who did not have

exercise desaturation demonstrated greater training intensity and improvement in


exercise endurance when trained on oxygen compared with air (both delivered

via nasal cannulae at 3 L/min) (Emtner et al 2003). Statistically significant

differences in some measures of HRQL (CRQ, SF-36) were reported between

groups, however, these differences did not appear to be clinically significant

(Emtner et al 2003). Despite a lack of supporting evidence, training oxygen has

been recommended by the British Royal College of Physicians (Royal College of

Physicians 1999) and prescription guidelines have been proposed by one New

Zealand author (Young 2005).

4. Intermittent oxygen therapy – other.

Although classified as intermittent therapy, transportable cylinders are

recommended in conjunction with COT. Extrapolation from the NOTT and MRC

studies led to the anticipation that providing transportable oxygen in this

circumstance would encourage maintenance of activity whilst adhering to the

recommendation for COT of ≥15 hours of supplemental oxygen per day, thus

conferring the same benefits as COT (McDonald et al 2005). However, this has

not been supported in the one trial (a double-blinded, randomised, crossover trial)

designed to test this hypothesis (Lacasse et al 2005).

Similarly, there is no evidence to support the other domiciliary uses of intermittent

oxygen therapy listed in Table 2.2. Although oxygen for air travel is becoming

more commonly used, assessment methods and prescription criteria vary widely

(Johnson 2003, McDonald et al 2005, Stoller 2000). A large, international,

double-blinded, randomised controlled trial to evaluate the effects of palliative

oxygen for patients having intractable dyspnoea without severe hypoxaemia has

shown a small improvement over seven days with both air and oxygen delivered

via a concentrator, suggestive of a placebo effect (Abernathy et al 2009).

2.5.4 Prescription of domiciliary ambulatory oxygen in COPD

Prescription guidelines for domiciliary ambulatory oxygen have been set

arbitrarily, by extrapolation from those for COT and are variable (Table 2.3).

Prescription is currently based primarily upon demonstration of exertional

desaturation and secondarily upon an acute response to supplemental oxygen

during an exercise test, usually the 6MWT or Incremental Shuttle Walk Test

(ISWT) (Wedzicha 2000).


The relevance of these criteria to any potential longer term benefits remains

unknown. The primary criterion of exertional desaturation appears to be based

upon the commonly held assumption that exertional breathlessness, reduced

exercise tolerance and hypoxaemia are closely associated (O'Driscoll 2008).

Whilst many acutely ill patients may be concurrently breathless and hypoxaemic,

in many other situations hypoxaemia may exist without breathlessness and vice

versa, both in health and disease (O'Driscoll 2008).

All four guideline documents in Table 2.3 state the need for formal exercise

testing, but only one defines this further (Royal College of Physicians 1999). The

British guidelines require a practice test followed by two tests breathing air or

cylinder oxygen at a flow of 2 L/min, in randomised order (Royal College of

Physicians 1999). The Canadian guidelines require a test of maximal walking

time breathing room air and cylinder oxygen (Ontario Ministry of Health and Long

Term Care Assistive Devices Program 2005). Significant improvement in

exercise capacity or dyspnoea with exertional oxygen is a requirement in the

Australasian, British and Canadian guidelines (McDonald et al 2005, Ontario

Ministry of Health and Long Term Care Assistive Devices Program 2005, Royal

College of Physicians 1999). Improvement is defined further in the British and

Canadian guidelines (Ontario Ministry of Health and Long Term Care Assistive

Devices Program 2005, Royal College of Physicians 1999). However, the levels

chosen for improvement in exercise capacity and dyspnoea appear to be

arbitrary (Lock et al 1991). Some authors (Eaton et al 2002) have determned

significant improvement in exercise capacity to be 54 metres, consistent with the

minimal important difference (MID) in six minute walk distance (6MWD) initially

proposed (Redelmeier et al 1997). However, this determination of the MID has

since been challenged (Holland et al 2010, Puhan et al 2008, Solway et al 2001)

and is discussed in Section 4.5.1. An increase in exercise tolerance of 50%

and/or reduction in symptoms limiting exercise has been suggested by other

authors (Dean et al 1992), although this definition also appears to be arbitrary.

2.5.5 Evidence for use of domiciliary ambulatory oxygen

The results of studies to date have not answered the question of whether

domiciliary ambulatory oxygen has a role in the treatment of patients with COPD

who are breathless on exertion and have a resting PaO2 which precludes them

from receiving COT (Table 2.5). The acute benefits of hyperoxia upon exercise


capacity and dyspnoea and the recognised benefits of long-term COT appear to

be major factors contributing to an ongoing interest in this area.

A Cochrane review published in 2003 found only two double-blinded, randomised

controlled trials designed to examine this question (Lilker et al 1975, McDonald et

al 1995). The earlier of these (Lilker et al 1975) was performed prior to the NOTT

and MRC studies in nine patients who would now qualify to receive COT and has

been discussed in Section 2.2.2. A further, more recent trial of long-term

domiciliary exertional oxygen in patients qualifying to receive COT failed to

demonstrate any benefits upon HRQL or exercise tolerance (Lacasse et al 2005).

This was a one-year, blinded, randomised, crossover study (n=24) with three

periods of three months during which participants received, in randomised order:

standard therapy (domiciliary oxygen via a concentrator), standard therapy plus

cylinder oxygen and standard therapy plus cylinder air (Lacasse et al 2005).

Four further relevant studies have been published. The first double-blinded,

randomised controlled trial to investigate this question in patients without severe

resting hypoxaemia was a 2x6 week, randomised, crossover study (McDonald et

al 1995). The study was completed by 26 (36 enrolled) patients with COPD,

resting PaO2 >60mmHg (some with exertional desaturation) and exertional

dyspnoea sufficient to interfere with daily activities (McDonald et al 1995).

Participants were non-smokers, clinically stable, receiving optimal medical

therapy, with no significant cardiac dysfunction or locomotor disability. Cylinders

containing air or oxygen, of identical appearance, weighing 5 kg were provided

with a trolley and a conserving DODS (flow rate 4 L/min), for use during

exertional activities. Outcomes were exercise capacity (6MWT and step test) and

HRQL (Chronic Respiratory Disease Questionnaire, CRQ) recorded at baseline

and after each six week period, respiratory symptom scores recorded twice daily

and gas cylinder use for each six week period (McDonald et al 1995).

34

Table 2.5 Summary of randomised controlled trials of domiciliary ambulatory oxygen

n Participants Study design Study results Conclusions

Lilker et al 1975

9 COPD, PaO2 <60 + cor pulmonale

Randomised, 2x5/52 crossover: cylinder air vs O2.

Significant ↑ in PaO2 at rest and at maximal exercise post O2 c/w post air.

Portable O2 of > placebo value.

McDonald et al 1995

26 COPD, PaO2 >60 + exertional dyspnoea

Randomised, 2x6/52 crossover: cylinder air vs O2 @ 4L/min.

No differences between O2 and air periods for 6MWD, step test, CRQ domains.

Acute benefit, but not predictive of improved function or HRQL.

Eaton et al 2005

41 COPD, resting PaO2 ≥7.3 kPa (55mmHg) + SpO2 ≤88% on exertion + exertional dyspnoea

Randomised, 2x6/52 crossover: cylinder air vs O2 @ 4L/min.

No difference between air and oxygen periods in 6MWD. Statistically significant but clinically small differences between O2 and air in CRQ and HAD domains. Similarly for 4/8 domains of SF-36.

Significant improvements in QOL, but not predicted by acute response.

Lacasse et al 2005

24 COPD, receiving COT: resting PaO2 ≤7.3 kPa (55mmHg) or SpO2 ≤88% or PaO2 ≤7.8kPa (59mmHg) + hypoxic organ damage

Randomised, 3x3/12 crossover: concentrator alone, + cylinder air, + cylinder O2. Flow → PaO2 >60mmHg (>8kPa).

No difference between the 3 treatments for any CRQ domain or 6MWD. Few cylinders used, average 30 mins/day.

No placebo or real benefit of cylinders as an adjunct to COT.

(Nonoyama et al 2007a)

27 COPD, SpO2 ≤88% for 2 mins during 6MWT

Series of N-of-1 RCT‟s, 3x4/52 pairs of 2/52 oxygen + 2/52 placebo in random order. Flow 1-3 L/min → SpO2 ≥90% on exertion.

Small, significant ↑ in no of steps in 5 min walk test, no statistical or clinical differences between O2 and placebo for CRQ and SGRQ.

No support for general application in this group.

35

n Participants Study design Study results Conclusions

Sandland et al 2008

20 Severe hypoxaemia at rest (n=7) or exercise desaturation >4% below 90%, MRC Dyspnoea score >3.

Parallel RCT, 8/52 O2 or air. Flow 2 L/min.

No significant change in exercise capacity, endurance, domestic activity, CRQ or SF-36 scores for either group over time. No difference between groups for CRQ scores. No interaction for cylinder usage (self-report) or time spent away from home. Significantly more oxygen cylinders used over 8/52.

No improvement in physical activity, QoL or time spent away from home.

COPD, chronic obstructive pulmonary disease; PaO2, arterial partial pressure of oxygen; O2, oxygen; L/min, litres per minute; 6MWD, Six

Minute Walk Distance; CRQ, Chronic Respiratory Disease Questionnaire; HRQL, Health-related quality of life; kPa, kilopascals; HAD, Hospital

Anxiety and Depression Scale; SF36, Short Form 36 questionnaire; 6MWT, Six Minute Walk Test; RCT, randomised controlled trial; SRGQ, St.

George‟s Respiratory Questionnaire; MRC, Medical Research Council


These authors reported an acute benefit in exercise capacity (breathing oxygen

compared with air), with statistically significant increases in mean 6MWT and

number of steps at all three assessments (McDonald et al 1995). However, the

differences in mean scores were clinically small (range 11 - 21 metres and 4 - 5

steps or 12 - 17% respectively).

With regard to longer term benefits, a significant difference in 6MWD was found

after six weeks of domiciliary oxygen compared with domiciliary air. Whilst

6MWD was greater after oxygen, the difference was clinically small (14 metres).

No differences were found after six weeks of domiciliary air compared with six

weeks of domiciliary oxygen in step tests, end-test breathlessness (Borg scores),

degree of desaturation during exercise tests, any domains of the CRQ or number

of cylinders used. Symptom scores from diary cards were significantly higher

(that is, worse symptoms) after home oxygen compared with home air periods.

When asked their preferred six-week period, 50% of participants chose either the

period using air cylinders or had no preference. These authors concluded that

acute laboratory-based improvement in exercise capacity with hyperoxia does not

translate into a useful improvement in quality of life or daily function in this group

and should not be used as a basis for oxygen prescription (McDonald et al 1995).

Eaton et al (2002) conducted a similar 2x6 week, double-blinded, randomised

cross-over study to that of McDonald et al (1995) in patients with COPD without

severe resting hypoxaemia (PaO2 ≥7.3mmHg, 55kPa). Inclusion criteria were

otherwise similar to those of McDonald et al (1995) with the added requirements

of demonstrated exertional desaturation (SpO2 ≤88%) and completion of a formal

pulmonary rehabilitation program. Light weight (2.04 kg) cylinders of identical

appearance were provided, for use during exertional activities, with a backpack or

shoulder bag, using the same flow-rate and DODS as those of McDonald et al

(1995). Data of 41 participants (enrolled=50) were analysed from assessments

at baseline and after both 6-week periods. Outcomes measured were HRQL

(CRQ and SF-36), mood disturbance (HADS), exercise capacity (6MWD,

breathing room air, cylinder air and cylinder oxygen) and cylinder use, which was

calculated from cylinder weight before and after use and from self-reported data

(Eaton et al 2002).

Eaton et al (2002) also reported an acute response to ambulatory oxygen

compared with breathing room air at baseline. Although clinically small,


statistically significant improvements in 6MWT distance and post-test

breathlessness (Borg score) were found in the group overall, 28 participants

(68%) were deemed acute responders, defined as improvement of at least the

MID in 6MWT distance (54 metres) (Redelmeier et al 1997) or decrease in post-

test Borg score (1 unit) (Mahler and Witek 2005d).

Statistically significant differences in all domains of the CRQ and HADS and four

of the eight domains of the SF-36 were reported after domiciliary oxygen

compared with domiciliary air. However, the mean differences in scores were

small and for CRQ domains did not reach clinical significance (Jaeschke et al

1989). Response to domiciliary oxygen, defined as improvement in any of the

four domains of the CRQ of at least the MID in scores (Jaeschke et al 1989), was

found in 23 (56%) of participants. There were no differences in 6MWD or post-

test breathlessness after domiciliary oxygen compared with domiciliary air (Eaton

et al 2002).

A significant treatment order effect for cylinder use was reported, with those

randomised to receive oxygen first having a higher weekly use (12.25 cylinders

compared with 6.95 cylinders), but no change in the pattern of usage over the

time of the study. No other cylinder use data were reported. Of the 34

participants who demonstrated a response acutely or after six weeks of

domiciliary oxygen, 14 (41%) did not wish to be considered for ongoing

domiciliary oxygen. Neither acute exercise response nor any baseline

characteristics were predictive of benefit from domiciliary oxygen (Eaton et al

2002).

Together, these studies may be considered suggestive that domiciliary oxygen,

provided at a flow of 4 L/min, may provide quality of life benefits. However, both

studies have a number of limitations. Both were of short duration and, as only

small populations were assessed (combined n=67), may potentially have been

underpowered to show an effect. Neither study design allowed for a washout

period between oxygen and air interventions, resulting in a potential bias either

way from carry-over effects (Eaton et al 2002, McDonald et al 1995). In the

McDonald study, carry-over effect was tested for and not found. Apart from an

order effect found for cylinder use, it is unclear whether this issue was further

examined by Eaton et al (2002). Both studies used gas flow rates of 4 L/min.

which, although greater than that commonly used in clinical practice (2 L/min), is


less than that believed to be necessary (6 L/min) to achieve a maximal clinical

benefit in some patients (Snider 2002, Somfay et al 2001). It is of interest that in

both studies (Eaton et al 2002, McDonald et al 1995), a large number of

participants chose not to continue with domiciliary cylinders, indicating that the

small quality of life benefit measured did not outweigh the disadvantages or

perceived negative aspects of using cylinders in the long term.

The third relevant study was a double-blinded, N-of-1, randomised controlled trial

of 27 patients with COPD, dyspnoea limiting daily activities, not qualifying to

receive COT but with exertional desaturation (defined as SpO2 ≤88% for two

minutes during a 6MWT breathing room air) (Nonoyama et al 2007a). All

participants undertook three pairs of two-week treatment periods with ambulatory

oxygen and placebo gas mixture. Study gases were supplied from identical

cylinders or concentrators. Oxygen flow was titrated to maintain SpO2 ≥92%

(flow rate 1-3 L/min). The placebo mixture was 24% oxygen delivered at a flow

rate of 2 L/min, which was estimated to deliver an average FiO2 of 0.212.

Participants were requested to use the gas provided for at least one hour per day

during activities which made them breathless.

Participants were assessed in the home at the end of each two-week period.

Outcomes were HRQL using the CRQ and the St. George's Respiratory

Questionnaire (SGRQ) and function using a five minute walk test. The latter was

conducted breathing the gas mixture provided over the preceding two weeks.

Participants were instructed to walk at a comfortable pace such as they would

use on a day-to-day basis and to rest as required. Pre and post-test modified

Borg scores for breathlessness (zero to 10 scale) and number of steps were

recorded. Gas use was calculated by determining differences in gas cylinder

pressure or concentrator time recorded between the start and end of the

treatment period.

These authors (Nonoyama et al 2007a) reported an acute benefit with hyperoxia

at baseline, demonstrated by a statistically significant increase in exercise

endurance time (mean 4.6 to 7.0 minutes, p=0.003) assessed using a constant-

power, laboratory-based exercise test. However, hyperoxia did not influence

dyspnoea or leg fatigue (measured using a modified Borg Scale) or end-exercise

ventilation (method of measurement not stated).


These authors reported a significant improvement in number of steps and

decrease in dyspnoea at completion of 5-minute walk tests breathing oxygen

compared with placebo gas (p=0.04 in both instances). However, these

differences were clinically small as the difference in mean number of steps was

15 (4%) and between mean dyspnoea scores was 0.4 units. There were no

statistically or clinically significant differences between oxygen and placebo

periods for any HRQL domains. Statistically significant differences in CRQ

dyspnoea and mastery scores were found over time, (that is, unrelated to the gas

mixture used) but it was acknowledged that these differences were small. There

were no significant differences for gas usage between oxygen and placebo

mixture (Nonoyama et al 2007a).

Response to domiciliary oxygen was defined as a higher CRQ dyspnoea score

during the exertional oxygen period in all three treatment pairs and a difference of

≥0.5 in at least two of the pairs. Two participants were deemed responders

according to these criteria, but no similar responses in the remaining domains of

the CRQ, the SGRQ or the walk test were found for these responders

(Nonoyama et al 2007a).

This trial does have some important limitations. An N-of-1 trial design assumes

that treatment effects will be of rapid onset and offset with no carry-over effects

between treatments (Drummond and Wise 2007). This assumption may be valid

for demonstration of acute effects of hyperoxia upon exercise capacity, however

training effects which may result from an increase in general activity or exercise

may take weeks or months to occur or dissipate (Drummond and Wise 2007).

The authors argue that an N-of-1 trial does, however, allow observation of

individual responses to an intervention which might otherwise not be reported in a

group analysis (Drummond and Wise 2007, Nonoyama et al 2007a). Individual

variability in response to hyperoxia during exercise in this population has been

observed by a number of other authors (Calverley 2006, Peters et al 2006, Snider

2002, Somfay et al 2001), adding weight to the merits of this method. The

authors (Nonoyama et al 2007a) contend that establishing criteria which define a

response to treatment a priori adds strength to any inferences made from results.

However, it is unclear why a difference in CRQ dyspnoea score of 0.5 units was

chosen, as the MID for this domain of the questionnaire is 2.5 units (Jaeschke et

al 1989). It is noteworthy that only two participants were deemed responders to


domiciliary oxygen, despite the clinically small difference in scores required to

qualify.

It has been suggested that an N-of-1 study design mitigates the need for larger

trials to define responses on a population basis (Guyatt et al 1990). If this is the

case, such studies would be preferable in this patient group given the difficulties

encountered with recruitment reported by these and a number of authors

(Nonoyama et al 2007a), and indeed encountered in conducting the main study in

Chapter 8 of this thesis. Based upon power calculations, Nonoyama and

colleagues (2007a) had a target sample size of 40 and although results from only

27 participants were analysed, these authors contend that enrollment of

additional participants would have been most unlikely to have altered their

conclusions. The authors support this contention by acknowledging that the

trends in favour of benefits from oxygen in dyspnoea and fatigue were weak and

confidence intervals excluded mean differences above the MID in scores in both

cases.

The authors state that participants and outcome assessors were blinded to the

gas mixture provided. However, true double-blinding to study gases is

questionable as oxygen flows were titrated to achieve a saturation of ≥92% whilst

the placebo gas was delivered at 2 L/min. Some participants may have been

aware that the differences occurred as a result of titration of oxygen and it would

be anticipated assessors would also have been aware of this issue.

There is one further, small randomised controlled trial, which is the first to have

objectively assessed the effects of exertional oxygen upon physical activity in

patients with COPD (n=20) (Sandland et al 2008). However, this study included

three patients who qualified to receive COT and four who had otherwise qualified

to receive oxygen concentrators for intermittent use (not further defined).

Participants not receiving COT all demonstrated exertional desaturation, defined

as SpO2 more than 4% below 90%, which the authors state is consistent with the

British Royal College of Physicians Guidelines (Table 2.3). Participants were

requested to use their cylinders while performing activities of daily living and

walking outside their homes. No improvements were found in HRQL, functional

performance or dyspnoea after eight weeks of cylinder oxygen compared with

cylinder air (Sandland et al 2008). Study gases were delivered in light weight

cylinders carried in a back-pack, at a flow rate of 2 L/min. Seven-day activity was


measured using an accelerometer and time outside the house was recorded

using a stop-watch, at baseline and during the study period. HRQL was

measured using the CRQ and SF-36 and dyspnoea using that domain of the

CRQ.

This study also has some limitations. The authors claim that the study was

double-blinded. However, this is questionable as the air and oxygen cylinders

were colour-coded, and participants were visited at home on a number of

occasions to change cylinders and aid with adherence (Sandland et al 2008).

Further, nine of 30 patients randomised did not complete the study, some

(number not stated) due to non-acceptance of the cylinders. This is an important

factor in interpreting results as these patients‟ data were not included in the

analysis (that is, intention-to-treat analysis was not performed) and may have

influenced the outcome. In addition, it was reported that there was a worsening

in dyspnoea for the air group with a mean change of 0.6 units from pre to post

intervention. However, no statistical analysis of this data was provided and this

change in score fails to reach clinical significance (Sandland et al 2008).

Nevertheless, the negative findings of study are consistent with others in the

literature.

To summarise, despite its use in many centres, there is no robust evidence to

support the use of domiciliary ambulatory oxygen in patients with COPD but who

do not have severe resting hypoxaemia. There have been six small, randomised

controlled trials of domiciliary, ambulatory oxygen published in the literature

(Eaton et al 2002, Lacasse et al 2005, Lilker et al 1975, McDonald et al 1995,

Nonoyama et al 2007a, Sandland et al 2008). Two of these studies were in

patients with severe resting hypoxaemia who would qualify for COT according to

current guidelines and therefore may receive cylinder oxygen as part of that

therapy (Lacasse et al 2005, Lilker et al 1975) and one included some patients

who were severely hypoxaemic at rest (Sandland et al 2008).

The three studies relevant to this research have examined small populations, with

relatively short durations of gas use and reported conflicting results. Two used a

six-week, blinded, crossover design (Eaton et al 2002, McDonald et al 1995) and

suggested very modest improvements in HRQL (measured by the CRQ) with

exertional oxygen in 26 and 41 patients respectively. An N-of-1 study of 27

participants with exertional desaturation found no benefits in HRQL or exercise


capacity (Nonoyama et al 2007a) and a further small trial including some patients

who did not have severe resting hypoxaemia also failed to show any benefits in

quality of life or activity (Sandland et al 2008).

2.6 Conclusions

Early studies of domiciliary oxygen from the 1950's focused upon its use during

activity. Two landmark trials published in the 1980's provided confirmation that a

survival benefit is conferred when supplementary oxygen is used long term and

continuously during rest and sleep over 24 hours in patients with COPD and

severe resting hypoxaemia (Medical Research Council Working Party 1981,

Nocturnal Oxygen Therapy Trial Group 1980). The combined results of these

two studies have provided the basis for internationally recognised guidelines for

its prescription in this circumstance (Medical Research Council Working Party

1981, Nocturnal Oxygen Therapy Trial Group 1980).

Hyperoxia has been shown to provide acute, laboratory-based benefits in

exercise capacity and breathlessness in patients with COPD (Bradley and O'Neill

2005, Ram and Wedzicha 2003, Snider 2002). The reasons for these

improvements are thought to be multifactorial and not solely dependent upon the

relief of hypoxaemia. Whilst it might be anticipated that the long-term use of

supplemental oxygen during exertion might also be beneficial, the few small

studies designed to assess its effects have failed to provide evidence to support

this notion. Despite this, domiciliary ambulatory oxygen is provided in many

countries for use during exertion in patients who do not qualify for COT but

desaturate upon exertion. Whether or not it is beneficial for such patients

remains unknown. The focus of the research in thesis was to explore the effects

of domiciliary ambulatory oxygen in patients with COPD who do not have severe

resting hypoxaemia.

Chapter 3 describes the pathophysiology and clinical features of COPD.

Mechanisms of altered gas exchange and aspects of supplemental oxygen

administration in COPD will also be discussed.

Chapter 3: COPD 43

Whoever invented cigarettes ought to be disgusted with themselves. Oisin Darcy (2006 - aged 11 years)

Chronic obstructive pulmonary disease

3.1 Introduction ..................................................................................... 43 3.2 History ............................................................................................. 44 3.3 Definition ......................................................................................... 46 3.4 Disease severity classifications ....................................................... 48 3.5 Epidemiology and risk factors .......................................................... 49 3.6 Mortality .......................................................................................... 51 3.7 Pathology ........................................................................................ 52

3.7.1 Inflammatory responses .................................................... 52 3.7.2 Airways .............................................................................. 53 3.7.3 Lung parenchyma .............................................................. 54 3.7.4 Pulmonary vasculature ...................................................... 55

3.8 Pathophysiology .............................................................................. 55 3.8.1 Introduction ........................................................................ 55 3.8.2 Airflow limitation ................................................................. 56 3.8.3 The respiratory pump ......................................................... 59 3.8.4 Dynamic hyperinflation ...................................................... 63 3.8.5 Cardiovascular effects ....................................................... 69 3.8.6 Gas exchange abnormalities ............................................. 70 3.8.7 Systemic and other effects ................................................. 72

3.9 Clinical features ............................................................................... 74 3.9.1 Dyspnoea .......................................................................... 74 3.9.2 Cough and sputum ............................................................ 77

3.10 Management ................................................................................... 77 3.10.1 Overview ........................................................................... 77 3.10.2 Oxygen therapy in COPD .................................................. 79

3.11 Conclusions..................................................................................... 80

3.1 Introduction

Chronic obstructive pulmonary disease (COPD) is a leading cause of disability

and premature death (Rodriguez-Roisin et al 2008). It has been estimated to

have affected 44 million people in 1990 and to have killed almost three million

people world-wide in 2000 (Lomas 2002). It is anticipated that by 2020 it will rank

fifth for burden of disease and be the third most common cause of mortality

(Lopez et al 2006, Murray and Lopez 1996, Murray and Lopez 1997). Cigarette

smoking is the most important risk factor for developing COPD but interactions

between host factors and other environmental exposures may also contribute

3 Chapter

Chapter 3: COPD 44

(McKenzie et al 2003). Alarmingly, it has been reported that COPD is the only

leading cause of death which is increasing in prevalence, despite being

essentially preventable (Hurd 2000).

The precise prevalence of COPD remains unknown. It is believed that more than

half a million Australians suffer from moderate to severe COPD and it is ranked

fourth among the common causes of disease for men and sixth for women in

Australia (McKenzie et al 2009). Thus, COPD imposes a huge economic burden

and, when allowing for hidden costs such as those related to carer burden,

absenteeism and early retirement, has been estimated to be costing the

Australian community well over $1 billion per annum (Access Economics Pty

Limited 2008).

The characteristic symptoms of COPD are cough, sputum production and

dyspnoea upon exertion and the common presentation is with a productive cough

or an acute respiratory illness (Pauwels et al 2001). The onset of chronic

symptoms is insidious. Whilst dyspnoea does not tend to be a feature of the

illness until the sixth or seventh decade of life (American Thoracic Society

1995b), symptoms may also present much earlier in life (Access Economics Pty

Limited 2008).

3.2 History

Laennec, who invented the stethoscope in 1819, is credited with presenting one

of the earliest descriptions of emphysema, which was based upon observations

of postmortem specimens of air-dried, inflated human lungs (Hogg 2004a). In his

treatise on diseases of the chest published in 1835, he observed that air was

slower to escape from emphysematous lungs than from normal lungs and

postulated that reduced expiratory airflow may be due to reduced elasticity within

the lung (cited in (Petty 1985).

Early descriptions of chronic bronchitis came from the British literature with the

recognition of this as being a serious and disabling disorder by Badham in 1808

(cited in Petty 2002). Chronic bronchitis was used for many years in the British

literature to describe symptoms now considered to be characteristic of COPD

(Fletcher et al 1959), whilst North American physicians used the term

emphysema (Burrows et al 1966).

Chapter 3: COPD 45

Some clarification of terminology came as a result of two landmark conferences,

The CIBA (Company for Chemical Industry Basel) Guest Symposium held in

Britain (Ciba 1959) and a symposium of The American Thoracic Society

(American Thoracic Society 1962) and it was eventually concluded that the

chronic bronchitis patients of Britain and the emphysema patients of the United

States shared common features (Burrows et al 1966).

Although over half a century has elapsed since the CIBA Symposium, the

definitions of chronic bronchitis and emphysema established then are still

recognised today (McKenzie et al 2009). Chronic bronchitis is defined clinically,

as chronic mucus production occurring on most days for at least three months in

the year for at least two successive years. Emphysema is defined in anatomical

terms, as a permanent increase of airspaces distal to the terminal bronchioles,

due to dilatation or destruction of their walls (Ciba 1959). This definition is

dependent upon knowledge of normal airspace size, including during lung

inflation, and was initially only able to be determined by examination of

pathological specimens of inflated lung tissue. However, the development of

computerised axial tomography (CT) in the 1980‟s provided a means to quantify

distal airspace enlargement in living patients (Hayhurst et al 1984) and it is now

accepted that CT may be used to reliably determine severity and distribution of

emphysema (Hogg 2004a, Siafakas et al 1995). A definition of asthma was also

proposed at the CIBA symposium where it was described as widespread

narrowing of the bronchial airways which changes over a short period of time in

response to therapy or spontaneously (Ciba 1959). The degree of reversibility of

airflow obstruction which denotes asthma was not defined then and remains

unresolved.

The term “chronic non-specific lung disease” was proposed to encompass all

three disease entities, chronic bronchitis, emphysema and asthma (Ciba 1959).

Other terms such as COAD (chronic obstructive airway disease) and COLD

(chronic obstructive lung disease) appeared as it became apparent that

expiratory obstruction to airflow was the major cause of disability in such patients.

Subsequently, it became understood that flow could be limited by airway

narrowing due to disease within the lumen or its walls, or by loss of elastic recoil

(Mead et al 1976) and the terms chronic airflow limitation or obstruction (CAL or

CAO) were devised.

Chapter 3: COPD 46

After many decades, a consensus has been reached internationally denoting

COPD as the preferred term. COPD is now considered to encompass the many

clinical labels which have been used in the past including emphysema, chronic

bronchitis, chronic obstructive bronchitis, CAL, CAO, COAD and COLD (British

Thoracic Society 1997). COPD is also accepted as including some cases of

chronic asthma (American Thoracic Society 1995b, McKenzie et al 2009,

National Institute for Clinical Excellence 2004). Over recent decades, clinical

practice guidelines for the management of COPD have been published by a

number of groups around the world. These include statements from respiratory

societies such as the American Thoracic Society (American Thoracic Society

1995b), the European Respiratory Society (Siafakas et al 1995), updated

conjointly in 2004 (Celli and MacNee 2004b), the British Thoracic Society (British

Thoracic Society 1997), the Global Initiative for COPD (a collaboration of the

World Health Organisation and the National Heart, Lung and Blood Institute of

America) (Rodriguez-Roisin et al 2008), the Thoracic Society of Australia and

New Zealand (McKenzie et al 2009) and the National Institute for Clinical

Excellence in Britain (National Institute for Clinical Excellence 2004). These

guidelines have the common aim of promoting the prevention of and

improvement in management and outcomes in COPD.

3.3 Definition

COPD is described as a preventable and treatable disease which can include

significant pulmonary and extrapulmonary effects. Its pulmonary manifestations

are characterised by airflow obstruction that is usually progressive, not fully

reversible and associated with an abnormal inflammatory response to gases or

noxious particles (Rodriguez-Roisin et al 2008). The underlying disease process

further involves decreased gas transfer due to the parenchymal destruction of

emphysema (Rodriguez-Roisin et al 2008).

Common to the COPD management guideline documents is recognition of a

degree overlap between chronic bronchitis, emphysema and asthma within

COPD and the understanding that COPD and asthma may co-exist (Celli and

MacNee 2004b, McKenzie et al 2009, National Institute for Clinical Excellence

2004, Rodriguez-Roisin et al 2008) (Figure 6.1). The differential diagnosis of

asthma and COPD remains problematical (Jenkins 2003) as long-standing or

poorly controlled asthma may lead to chronic, irreversible airway narrowing in the

Chapter 3: COPD 47

absence of exposure to the recognised risk factors for COPD (McKenzie et al

2009).

Figure 3.1 Venn diagram illustrating the overlap of chronic bronchitis,

emphysema and asthma within COPD (McKenzie et al 2009, p S10).

It is recommended that a diagnosis of COPD be based upon physical

examination, a history of smoking or exposure to other noxious agents and may

be confirmed by spirometric demonstration of airflow limitation (FEV1/FVC<0.7

post-bronchodilator) which is not fully reversible (McKenzie et al 2009,

Rodriguez-Roisin et al 2008). Reversibility is determined by change in FEV1

subsequent to the administration of a short-acting bronchodilator. However, the

degree of change representing clinical significance has been arbitrarily chosen

and consequently, specific spirometric definitions vary (Gross 2003, National

Institute for Clinical Excellence 2004).

The classic symptoms of COPD, cough, excess sputum production and

breathlessness (McKenzie et al 2009) are well recognised. However, the

presenting symptoms can be quite variable and tend to develop insidiously

(National Institute for Clinical Excellence 2004), making a diagnosis difficult.

chronic bronchitis without airflow

obstruction

other causes of airflow

obstruction

emphysema without airflow

obstruction

Chapter 3: COPD 48

Cough and sputum production can precede the development of airflow limitation

by years but some patients develop significant airflow limitation and

breathlessness without cough and excess sputum production (Rodriguez-Roisin

et al 2008).

The definition of COPD used for the studies described in this thesis is in

accordance with the Australasian COPDX guidelines (McKenzie et al 2009).

Participants had a clinical diagnosis of COPD, supported by baseline spirometric

measurements (FEV1 <80% of predicted value and FEV1/FVC <0.70%).

3.4 Disease severity classifications

COPD is defined on the basis of airflow limitation, using the most well-recognised

test of expiratory flow, FEV1 (Rodriguez-Roisin et al 2008). FEV1 is recognised

as a useful indicator as it is reproducible, reliable and relatively easily measured

and due to its association with mortality and degree of dyspnoea (McKenzie et al

2009). However, the classifications used for disease severity vary internationally

(Table 3.1) and levels of demarcation have been arbitrarily chosen (Rodriguez-

Roisin et al 2008). A further limitation of these classifications is that a single

measure may be unable to provide an adequate assessment of the true severity

of COPD the impact of COPD not only upon the degree of airflow limitation but

also on severity of its extra-pulmonary manifestations (Rodriguez-Roisin et al

2008). In this research, it was elected to use spirometric classifications of airflow

obstruction recommenced jointly by the American Thoracic and European

Respiratory Societies Respiratory Societies, which are outlined in Section 7.6.1

(Pellegrino et al 2005).

Chapter 3: COPD 49

Table 3.1 Classification systems for disease severity in COPD

Mild

Moderate

Severe

FEV1/ FVC%

FEV1

% pred FEV1/ FVC%

FEV1

% pred FEV1/ FVC%

FEV1

% pred

*ATS/ERS

≤70

≥ 80

≤70

50-80

≤70

30-50

Very severe: <30

*COPD_X

<70

60-80

<70

40-59

<70

<40

*GOLD

<70

≥ 80

<70

<80-50

<70

<50-30

Very severe: Respiratory failure ± <30

NICE

50-80

30-49

<30

* = post bronchodilator,

ATS/ERS, American Thoracic Society/ European Respiratory Society (Celli &

MacNee, 2004b); COPD-X, Thoracic Society of Australia and New Zealand

(McKenzie et al 2009); GOLD, Global Initiative for COPD (Rodriguez-Roisin et al

2008); NICE, National Institute for Clinical Excellence (National Institute for

Clinical Excellence 2004)

3.5 Epidemiology and risk factors

Accurate determination of COPD prevalence, morbidity and mortality in

populations is problematic (Hurd 2000), in part due to variability in disease

definitions severity classifications. COPD runs an insidious course over years

and is often not diagnosed in its initial phase (Celli and MacNee 2004b). It has a

variable natural history and not all individuals follow the same course (Celli and

MacNee 2004b). COPD is often not diagnosed until clinical signs are apparent

and the disease process is at least moderately advanced (Celli and MacNee

2004b, Rodriguez-Roisin et al 2008). Breathlessness which is sufficient to lead

to an initial medical consultation may occur when FEV1 is already less than 50%

of predicted value (Fletcher and Peto 1977). Mortality data is thought to

underestimate the extent to which COPD causes death as it is more likely to be

cited as a contributory factor (Rodriguez-Roisin et al 2008). At the time of writing,

most of the epidemiological data available on COPD comes from developed

Chapter 3: COPD 50

countries only for this and the above reasons, and must be interpreted with

caution (Hurd 2000).

It is estimated that cigarette smoke accounts for more than 90% of cases of

COPD in developed countries (Calverley and Walker 2003). It is commonly

believed that only a minority of smokers develop clinically significant COPD, with

estimates ranging from 15 to 20% (Barnes 2004, Celli and MacNee 2004b).

However, all smokers are thought to develop lung inflammation (Hogg 2004a).

The association between cigarette smoking and degree of airflow obstruction was

initially described some decades ago in an eight-year study of 792 men initially

aged 30 to 59 years (Fletcher and Peto 1977) (Figure 6.1). These authors

described a gradual, but clinically insignificant, decline in predicted value of FEV1

(FEV1 %pred) from the age of 25 years. However, the rate of decline was greater

in susceptible smokers and greater in those smoking ≥15 cigarettes per day than

in those smoking >15 per day. Further, their results indicated that whilst the rate

of loss of FEV1 %pred reverted to normal in those who ceased smoking. It was

concluded that these results highlighted the importance of smoking cessation

(Fletcher and Peto 1977).

Figure 3.2 Time course of COPD, adapted from findings of Fletcher and Petto

in 1977 (McKenzie et al 2009, p S11).

Chapter 3: COPD 51

The study of Fletcher and Peto (1977) has since been extended to a larger cohort

(n=5124) including females (n=2270) (Kohansal et al 2009). This study also

found that smoking increased the rate of decline in lung function, although never-

smoker females had a lower rate of decline than males. In addition, it was found

that decline in lung function was equivalent between never-smokers and those

who ceased smoking before 30 years of age. However the rate of lung function

decline did not differ between those ceasing to smoke after 40 years of age and

continuing smokers, suggesting that early cessation is beneficial (Kohansal et al

2009).

Additional environmental factors which may contribute to the development of

COPD include heavy occupational dust and chemical exposure and air pollution

(Rodriguez-Roisin et al 2008). Inhalation of biomass fuels is also an important

cause, particularly among women who cook in poorly ventilated homes as is the

case in many third world countries (Calverley and Walker 2003). The host factor

which is most commonly associated with COPD is the rare hereditary deficiency

of 1-antitrypsin, but it is believed that other genetic factors may be involved

(McKenzie et al 2009, Rodriguez-Roisin et al 2008). It is also been suggested

that gender-related factors may contribute to the development of COPD

(Rodriguez-Roisin et al 2008), although these remain undetermined.

3.6 Mortality

The classic epidemiological studies of Fletcher and Peto described above also

demonstrated an association between increased mortality and smoking-related

lung disease (Figure 3.2) (Fletcher and Peto 1977). Whilst FEV1 has been

described as the most important single predictor of mortality (Peto et al 1983)

other indices may also useful. These include the degree of pulmonary

hyperinflation (measured by the ratio of inspiratory capacity to total lung capacity

(IC/TLC) (Casanova et al 2005), peak oxygen consumption during a

cardiopulmonary exercise test, 6MWD, degree of dyspnoea (measured using the

Medical Research Council dyspnoea scale) and body mass index (BMI)

(McKenzie et al 2009). The latter three indices have been combined with FEV1

into a multidimensional grading system, the BODE index, which has been found

to strongly predict mortality (Celli et al 2004a). The development of hypoxaemic

respiratory failure has been identified as an independent predictor of mortality,

associated with a three-year survival of approximately 40% (Medical Research

Chapter 3: COPD 52

Council Working Party 1981) and admission to hospital with an infective

exacerbation and hypercapnic respiratory failure is also associated with a poor

prognosis (Connors et al 1996).

As discussed in Chapter 2, the only intervention which has been shown to

improve survival in COPD, besides ceasing smoking, is the provision of long-

term, COT (Medical Research Council Working Party 1981, Nocturnal Oxygen

Therapy Trial Group 1980).

3.7 Pathology

3.7.1 Inflammatory responses

COPD is a product of acceleration of the normal inflammatory responses to long-

term exposure to inhaled noxious particles and gases, particularly within the

respiratory tract (Calverley and Walker 2003, Rodriguez-Roisin et al 2008). An

increase in inflammatory cells, in particular neutrophils, macrophages and T

lymphocytes, is characteristic of COPD (Calverley and Walker 2003, Rodriguez-

Roisin et al 2008). Inflammatory cells release a number of mediators which are

responsible for sustaining neutrophilic inflammation and ongoing structural

damage to the airways and lung parenchyma (Rodriguez-Roisin et al 2008).

Lung damage is thought to occur due to an imbalance between the release of

proteases, which may degrade elastin and are derived from inflammatory and

epithelial cells, and antiprotease enzymes which are able to reduce elastin

degradation and thus protect against this process (Calverley and Walker 2003,

Rodriguez-Roisin et al 2008). Elastin is an important structural protein of the lung

(West 2003). Some proteinases are also thought to be responsible for inducing

mucus secretion and producing mucus gland hyperplasia. The serum protein

alpha-1 antitrypsin is one antiproteinase understood to be involved in COPD and

it has been known for some decades that the hereditary deficiency of this protein

is responsible for an increased risk of developing emphysema (Laurell and

Eriksson 1963).

Proteinase/antiproteinase imbalance may result from increased production or

activity of proteases and/or decreased antiprotease activity due to oxidative

stress (Rodriguez-Roisin et al 2008). Oxidative stress is thought to occur due to

an imbalance between oxidants and antioxidants, in favour of the former

Chapter 3: COPD 53

(Rodriguez-Roisin et al 2008) and is understood to be an important component in

accelerating the inflammatory process in COPD airways (Calverley and Walker

2003, O'Reilly and Bailey 2007, Rodriguez-Roisin et al 2008). Markers of

oxidative stress, for example hydrogen peroxide and nitric oxide, have been

found in the epithelial lining, breath, sputum and urine of patients with COPD

(Calverley and Walker 2003, Rodriguez-Roisin et al 2008). In addition to

inactivation of antiproteinases, oxidants may react with some biological markers

to result in cell dysfunction or death and damage to the lung extracellular matrix

(Rodriguez-Roisin et al 2008).

The inflammatory responses described above result in damage to large and small

conducting airways, alveolar and parenchymal structures and the pulmonary

vasculature (Petty 2003, Rodriguez-Roisin et al 2008). The destruction and

alterations to lung architecture which occur will be outlined in the following

sections.

3.7.2 Airways

Inflammatory cells infiltrate the surface epithelium of the larger, more central

airways which have cartilage in their walls, that is, the trachea, bronchi and

bronchioles of greater than 2 to 4 mm in internal diameter (Petty 2003,

Rodriguez-Roisin et al 2008, Thurlbeck 1997). Chronic inflammation in the larger

airways is associated with metaplasia of epithelial goblet and squamous cells,

hypertrophy of submucosal mucus-secreting glands and mucus hypersecretion

(Rodriguez-Roisin et al 2008). Dysfunction or destruction of cilia, an increase in

the amount of smooth muscle and connective tissue in the airway wall and

degeneration of airway cartilage also occurs (Rodriguez-Roisin et al 2008). The

pathological changes in the central airways may result in increased cough, with

or without sputum and may be present alone or in combination with the changes

in the smaller airways and lung parenchyma described below (Calverley and

Walker 2003).

The major contribution to the airflow limitation in COPD arises from the non-

cartilagenous smaller airways, defined as those which are less than 2 mm in

internal diameter, located from the fourth to 12th generation of airway branching

in the lung (Hogg et al 2004b). Airflow limitation primarily occurs as a result of

chronic inflammation and infiltration by inflammatory cells, repeated cycles of

injury and repair to the airway wall, structural remodelling and increased airway

thickness (Hogg et al 2004b). The remodelling processes include fibrosis which

Chapter 3: COPD 54

is characterised by accumulation of mesenchyma cells and extracellular

connective tissue matrix, and deposition of collagen and scar tissue under the

epithelium and within the outer part of the airway wall (Hogg et al 2004b). The

presence of lymphoid follicles has also been observed, contributing to increased

thickness of the small airway walls (Hogg et al 2004b). It is postulated that these

follicles develop due to the organisation of lymphocytes which are increased in

number due to an adaptive immune response to colonisation and infection of the

smaller airways (Hogg et al 2004b).

Chronic inflammation in the smaller airways is also associated with infiltration by

inflammatory exudate, goblet cell metaplasia, mucus hypersecretion and cilial

dysfunction (Pauwels et al 2001). Whilst occlusion of the lumen of the smaller

airways results from intraluminal oedema and mucus hypersecretion, these

factors are thought to make a less significant contribution to airflow limitation than

the structural changes to the walls of the smaller airways (Barnes 2004, Pauwels

et al 2001). This hypothesis is supported by the demonstration of a significant

association between thickness of the walls of the smaller airways and disease

severity based upon percent of predicted value of FEV1 (Hogg et al 2004b).

3.7.3 Lung parenchyma

The lung parenchyma includes the respiratory bronchioles, the alveoli (the gas

exchanging surface) and the pulmonary capillary system. The parenchymal

destruction of COPD (emphysema) most commonly involves destruction of

alveolar walls and enlargement of gas-exchanging airspaces, but is not

characterised by excess fibrosis (Pauwels et al 2001). Dilatation and destruction

of the respiratory bronchioles (which contain both bronchiolar epithelium and

alveoli in their walls) is known as centrilobular emphysema (Hogg and Senior

2002, Rodriguez-Roisin et al 2008) or centriacinar emphysema (West 2003) and

generally occurs more severely in upper zones of the lungs (Hogg and Senior

2002, Thurlbeck 1997). Destruction extending throughout the acinus or gas

exchanging part of the lung (respiratory bronchioles, alveolar ducts and sacs) is

termed panacinar emphysema, tends to occur mainly in the lower zones of the

lungs and is classically associated with alpha-1 protease deficiency (Rodriguez-

Roisin et al 2008, Thurlbeck 1997, West 2003).

A third type of emphysema, distal acinar or paraseptal emphysema, has also

been described, where the destructive process involves distal airways, alveolar

Chapter 3: COPD 55

ducts and sacs located adjacent to fibrous septa or the pleura (American

Thoracic Society 1995b). This may result in large apical bullae which may

rupture causing a pneumothorax or may severely compress other lung tissue,

frequently in the context of well-preserved airflow (American Thoracic Society

1995b).

3.7.4 Pulmonary vasculature

Damage to the pulmonary vasculature commences early in the natural history of

COPD (Pauwels et al 2001). Changes include an increase in vascular smooth

muscle, thickening of the vessel walls and infiltration of the vessel wall by

inflammatory cells. Endothelial dysfunction occurs in the pulmonary arteries

affecting regulation of vascular tone and cell proliferation (Pauwels et al 2001).

Increased pulmonary vascular pressure develops with reduction in the vessel

lumen diameter, causing further smooth muscle hypertrophy, deposition of

proteoglycans and collagen, and destruction of the pulmonary capillary bed

(Pauwels et al 2001).

3.8 Pathophysiology

3.8.1 Introduction

The respiratory system has two major components, the lung which is the gas-

exchanging organ and the respiratory pump which ventilates the lung (Roussos

and Koutsoukou 2003). The respiratory pump is comprised of the chest wall (the

rib cage and respiratory muscles) and its controlling system (the central nervous

system and its connecting pathways). The work required to move the lung and

chest wall is termed work of breathing and may be represented as a product of

pressure (intrapleural pressure in cmH2O) and change in volume (above FRC in

litres) (Lumb 2005, West 2005). In COPD, abnormalities of the lung, in particular

the airways (resistive load) and chest wall (elastic load) combine to increase the

work of breathing. Damage to the lung parenchyma and vasculature further

compromises the function of the respiratory system as the disease progresses.

Other interrelated abnormalities include pulmonary hyperinflation, altered gas

exchange, pulmonary hypertension and cor pulmonale, which tend to develop in

that order (Rodriguez-Roisin et al 2008).

In the early stages of the disease, the majority of people with COPD are able to

maintain ventilation sufficient to sustain normal PaO2 and PaCO2, despite the

Chapter 3: COPD 56

mechanical disadvantage at which the respiratory muscles are working (Miller

and Dempsey 2004). However, with advancing disease severity, the respiratory

system becomes increasingly unable to meet the demands placed upon it.

Failure may occur in one or both parts of the respiratory system, in ventilation

due to abnormalities of the ventilatory pump or in gas exchange due to

abnormalities within the lungs. The mechanisms by which the respiratory system

is compromised in COPD will be described in the following sections.

3.8.2 Airflow limitation

Flow of air in a system is a function of pressure applied and resistance

encountered as follows (Thurlbeck 1997):

When this relationship is applied to the respiratory system, airway resistance

(Raw) may be defined as the ratio between driving pressure and rate of airflow

(V), where driving pressure is the difference between alveolar pressure (Palv)

and pressure at the airway opening (Pao) (Netter 1996):

Figure 3.3 Diagram illustrating the causes of airflow obstruction in COPD

(Barnes 2000, p 270).

pressure

resistance flow =

Palv – Pao

V Raw =

Chapter 3: COPD 57

COPD is characterised by expiratory flow limitation (EFL), while inspiratory flow

may be relatively well preserved, even in severe COPD (Rodarte 2004). The

ability to expel air may be compromised in forced and quiet expiration and in

severe COPD expiratory flow during tidal breathing at rest is often equivalent to

the flow achievable with maximal effort (Calverley and Walker 2003, Milic-Emili

1998).

EFL occurs over time due to a combination of factors which influence airflow

resistance and driving pressure, both intrinsic and extrinsic to the airways, the

most significant of which are irreversible (Figure 3.3) (O'Donnell and Webb 2005,

Pauwels et al 2001) (Table 3.2). Intrinsic factors have been discussed above.

Extrinsic factors include reduced airway tethering (or radial traction) due to

destruction of lung parenchyma (emphysema) and regional extra-luminal airway

compression from adjacent overinflated alveolar units (Pride and Macklem 1986,

West 2003). Parenchymal destruction also contributes to reduced airflow by

reducing elastic lung recoil and therefore driving pressure for expiratory flow

(O'Donnell and Webb 2005, Pauwels et al 2001).

Table 3.2 Summary of the causes of airflow limitation in COPD.

Irreversible Structural changes to the airway walls

Loss of elastic recoil due to alveolar destruction

Destruction of alveolar support which maintains small airway patency

Reversible Accumulation of inflammatory cells, mucus and plasma exudate

Smooth muscle contraction in peripheral and central airways

Dynamic hyperinflation during exercise

In health, the normal, end expiratory lung volume (EELV) at rest (= functional

residual capacity, FRC) corresponds to the relaxation volume of the respiratory

system, at a point when the elastic recoil pressure of the respiratory system is

zero (atmospheric pressure) (Milic-Emili 1998). It occurs at a point of equilibrium

where the elastic recoil of the lung is balanced by the normal tendency for the

chest wall to expand (Lumb 2005, Tantucci et al 1998, West 2005).

In COPD, airflow limitation alters the balance of forces between the lung and

chest wall (Roussos and Koutsoukou 2003). When EFL reaches a critical level,

Chapter 3: COPD 58

lung emptying becomes incomplete during tidal breathing as alveolar units with

slow or large time constants (measured by the product of compliance and

resistance) are continuing to empty after the onset of the next inspiratory effort

(O'Donnell and Webb 2005, West 2003). The result is that end-expiratory lung

volume (EELV) is permanently increased above normal elastic equilibrium

volume (that is, above true FRC) and the lungs are chronically hyperinflated

(Calverley and Walker 2003, O'Donnell and Webb 2005, Pride and Macklem

1986). Pulmonary hyperinflation is defined as an increase in EELV above the

predicted normal value (Milic-Emili 1998, Roussos and Koutsoukou 2003) and

conventionally is recognised as existing when TLC is >120% of predicted value

(O'Donnell and Laveneziana 2006d). In advanced COPD, resting EELV may be

above the normal tidal breathing range (Rodarte 2004).

The gold-standard for measuring EFL has involved assessment of the

relationship between flow and transpulmonary pressure, a complex and invasive

method requiring the passing of an oesophageal balloon (Calverley and Koulouris

2005). However, EFL may also be assessed by superimposing the flow-volume

loop of tidal breath within a maximum flow-volume curve (Hyatt 1961). In

advanced COPD, the flow-volume loop, particularly the expiratory loop may be

quite abnormal (Figure 3.4). Maximal flow at any volume above residual volume

(RV) is reduced and total lung capacity (TLC) is increased (Rodarte 2004).

Maximal inspiration and expiration typically begin and end at abnormally high

lung volumes (Rodarte 2004, West 2003), that is, the curve is shifted to the left

along the horizontal volume axis. As expiratory flow rates are reduced overall,

the curve is lower than normal on the vertical, flow axis (Rodarte 2004) and after

an initial, brief period of relatively greater flow, the remainder of the expiratory

loop generally is concave to the horizontal axis (Pierce et al 2005, West 2003).

EFL is present when resting tidal volume (VT) curves are not below or inside the

maximum expiratory flow-volume curve or envelope (Calverley and Koulouris

2005). Further, the degree of encroachment of the tidal expiratory flow loop upon

the maximal expiratory flow envelope is a measure of the extent of EFL

(O'Donnell and Webb 2004). This approach to measurement of EFL has

broadened understanding of altered respiratory dynamics, but has theoretical and

practical limitations (Calverley and Koulouris 2005, Milic-Emili 2000, Tantucci et

al 2008). It is ideally performed using a body plethysmograph and requires an

upright sitting position and patient co-operation. In addition, the maximal

Chapter 3: COPD 59

expiratory flows which can be achieved are dependent upon the volume and time

history of the preceding inspiration, which differ between tidal and maximal FVC

manoeuvres. Respiratory mechanics and time-constant inequalities also differ

between the two manoeuvres, making comparisons of the two curves problematic

(Calverley and Koulouris 2005, Milic-Emili 2000, Tantucci et al 2008).

Nevertheless, this remains the commonly used method in clinical practice

(Calverley and Koulouris 2005, Milic-Emili 2000, Tantucci et al 2008).

Figure 3.4 Flow volume loops in COPD and health, at peak exercise in COPD

compared with exercise at a comparable metabolic load in an age-matched

person. The outer loops represent the maximal limits of flow and volume. The

smallest loops represent the resting tidal volumes. The thicker loops represent

the increased tidal volumes and flows seen with exercise. The dotted lines

represent the inspiratory capacity manoeuvre to total lung capacity (O'Donnell

2001c, p S648).

3.8.3 The respiratory pump

EFL and chronic elevation of EELV have profound effects upon the respiratory

pump, particularly the respiratory muscles. The most important muscle of

inspiration, the diaphragm, is a skeletal muscle, supplied by the phrenic nerves

via cervical segments 3, 4 and 5. In health, the level of the diaphragm moves by

approximately 1 cm during tidal breathing, but may move up to approximately 10

centimetres during forced breathing (West 2005).

Chapter 3: COPD 60

The Zone of Apposition

At the end of normal, relaxed tidal expiration, the costal fibres of the diaphragm

are vertically aligned and abut or are apposed to the internal aspect of the lower,

lateral ribs, over an area known as the zone of apposition (Figure 3.5) (Crane

1992, Lumb 2005, Roussos and Koutsoukou 2003).

Figure 3.5 Frontal section of the chest wall at full expiration showing the zone

of apposition (Crane 1992, p 6).

Normally, as the contracting diaphragm descends, abdominal pressure increases

and the abdominal contents are displaced down (caudally) and forward.

Resistance to this movement, provided by the abdominal contents, serves to fix

or anchor the dome of the diaphragm. As the costal fibres of the diaphragm

continue to contract, the lower ribs are drawn upward and outward due to the

vertical alignment of the costal fibres. A combination of this action and

contraction of the intercostal muscles serves to increase the lateral diameter of

the thorax via “bucket handle” movement of the ribs (Crane 1992, West 2005). In

health, the co-ordinated contraction of the diaphragm, the intercostal muscles

and other muscles of the rib cage such as the scalene muscles, efficiently

achieves a level of ventilation which is adequate to meet metabolic demands

(Crane 1992).

Chapter 3: COPD 61

In COPD, increased EFL and hyperinflation result in flattening of the diaphragm

and decrease of the zone of apposition, such that the costal fibes are no longer

vertically aligned. In severe cases, these fibres may be perpendicular to the

chest wall, thus pulling the lower ribs inward during inspiration (Hoover‟s sign)

(Crane 1992, Roussos and Koutsoukou 2003).

Laplace’s law

Laplace‟s law states that pressure the diaphragm is able to exert upon the

abdomen is inversely proportional to the radius of its curvature as follows:

where Pdi is transdiaphragmatic pressure, Tdi is tension generated by the

diaphragm and Rdi is the radius of curvature of the diaphragm (Roussos and

Koutsoukou 2003). The radius of the curvature of the diaphragm is increased

towards infinity when it is flattened in a hyperinflated state, making it less efficient

with regard to converting tension into transdiaphragmatic pressure (Crane 1992,

Roussos and Koutsoukou 2003, West 2005).

The length-tension relationship

A characteristic of skeletal muscles is that the force which they are able to

generate is dependent upon initial length (Decramer 1997) and there is an

optimal length at which maximal force may be generated (Roussos and

Koutsoukou 2003). This concept is known as the length-tension relationship

(Campbell and Howell 1963) (Figure 4.5). The optimal length for the muscles of

the respiratory system is when the lungs are approximately at normal predicted

value of FRC (Roussos and Macklem 1982). The hyperinflated resting position of

the rib cage seen in COPD prevents the diaphragm and other inspiratory muscles

from adopting their normal resting length and places them in shortened positions,

thus reducing their efficiency (Roussos and Macklem 1982).

Inspiratory muscle threshold loading

The mechanical disadvantages of pulmonary hyperinflation are compounded by

inspiratory muscle threshold loading, defined as the load which must be

overcome for inspiratory flow to commence (O'Donnell and Webb 2003, Pride

and Macklem 1986). This is contributed to by the combined inward or expiratory

Tdi

Rdi

Pdi = 2

Chapter 3: COPD 62

recoil of the lung and chest wall which is present at higher lung volumes,

particularly those greater than 70% of TLC (Miller and Dempsey 2004). In

addition, the reduced lung emptying (gas trapping) which occurs with flow

limitation is typically associated with positive alveolar pressure at the end of

relaxed expiration. This phenomenon is referred to as intrinsic positive end

expiratory pressure (PEEPi) or autoPEEP (Milic-Emili 1998, Miller and Dempsey

2004, O'Donnell and Webb 2003, Pepe and Marini 1982, Tantucci et al 1998).

When PEEPi is present, inspiratory flow does not commence at the onset of

inspiratory muscle activity. The inspiratory muscles must develop sufficient

pressure to overcome PEEPi as only then will alveolar pressure become sub-

atmospheric. It has been estimated that in stable COPD, PEEPi may amount to

7 to 9 cmH2O, with values of up to 13 cmH20 with spontaneous breathing in acute

respiratory failure secondary to an exacerbation of COPD (Milic-Emili 1998).

Compensatory mechanisms

Despite the mechanical disadvantages against which the respiratory muscles are

working in advanced COPD, it is believed that inspiratory muscle contractile

fatigue is not a major factor in exercise limitation (O'Donnell and Webb 2003).

Further, it is believed that, in chronic airflow limitation, adaptations to the

diaphragm may occur which enable it to become resistant to fatigue. It has been

observed in animal models of emphysema that “sarcomere dropout” may occur in

the diaphragm, resulting in a reduction in the optimal length for force generation

(Figure 3.6) (Farkas and Roussos 1983). Other adaptations include increased

proportion of Type I slow twitch fibres (compared with Type II fast twitch fibres)

(Morton et al) and increased mitochondrial concentration (improving oxidative

capacity) (O'Donnell and Webb 2003).

Chapter 3: COPD 63

Figure 3.6 Typical length-tension curve for a skeletal muscle (solid curve).

Maximal active tension changes depending on initial muscle length. Point A is

optimal initial length (LO) at which maximal possible tension (PO) can be

generated. At point B myosin (m) and actin (a) filaments in individual sarcomeres

are already overlapped at starting length. The dashed curve represents the

length-tension relationship after „sarcomere dropout‟. At the same starting length

as at point B myosin and actin filaments in the remaining sarcomeres are placed

in optimal configuration (Point C) (Decramer 1997, p 936).

3.8.4 Dynamic hyperinflation

Despite the disadvantages against which the respiratory system is working, the

functional impact of many of the physiological changes found in COPD initially

only becomes evident upon exertion (Calverley and Walker 2003). During

exercise, tissue oxygen consumption and carbon dioxide (CO2) production rise in

proportion to power output. These rises must be accompanied by increases in

Chapter 3: COPD 64

alveolar ventilation in order to maintain sufficient gas exchange to meet

demands.

The maximum capacity of the pulmonary system is rarely approached in health

even during high intensity exercise (Miller and Dempsey 2004). Several

physiological mechanisms allow ventilation to be increased during exertion, whilst

minimising work of breathing and its associated oxygen cost (Haverkamp et al

2005, O'Donnell and Webb 2003). Increased alveolar ventilation occurs by

increasing minute ventilation (VE), initially by raising both VT and breathing

frequency (Figure 3.7), whilst maintaining or increasing inspiratory capacity.

Increased VT is achieved by increases in end-inspiratory lung volume (EILV) and

a reduction in EELV to below the normal relaxation volume of the respiratory

system. The latter is the result of progressive, active recruitment of expiratory

muscles (O'Donnell and Webb 2003), in proportion to exercise intensity

(Haverkamp et al 2005). Average reductions in EELV of between 0.3 L and 1.0 L

have been described (O'Donnell and Webb 2003). Reduction in EELV serves to

place the diaphragm at a more optimal point of its length-tension relationship and

reduces inspiratory work as the rib cage at lower lung volume is subject to

outward recoil at the onset of the ensuing inspiration. At higher intensities of

exercise, VT reaches a plateau and further increases in minute volume are

achieved by increases in frequency alone, with resultant decreases in both

inspiratory and expiratory time (Haverkamp et al 2005).

During exercise in health, increases in resistive loads may also be minimised by

the use of mouth breathing (instead of nasal breathing), activation of upper

airway abductor muscles and airway bronchodilatation via circulating

catecholamines. Physiological dead space is reduced by up to approximately

30% of baseline value, and in healthy, young people may represent

approximately 13% of total ventilation at maximal exercise (O'Donnell and Webb

2003). Normal subjects do not experience EFL even at maximal exercise

(Calverley and Koulouris 2005, O'Donnell and Webb 2003). However, very

highly trained athletes may demonstrate flow-limitation at extremely high levels of

exercise (Rodman et al 2002).

Chapter 3: COPD 65

Figure 3.7 Changes in lung function with exercise in a) normal individuals and

b) patients with COPD (O'Donnell 2006a, p 38).

TLC, total lung capacity; VC, vital capacity; RV, residual volume; EELV, end-

expiratory lung volume; IC, inspiratory capacity

In contrast, in COPD EELV during exercise becomes increasingly compromised

(Figures 3.7, 3.8). EELV is a dynamic variable, which is influenced by the extent

of EFL, time-constant abnormalities and the breathing pattern for a given level of

ventilation (O'Donnell and Laveneziana 2006d). During exercise, the increased

intrathoracic pressure which occurs during active expiration further predisposes

the airways to premature collapse (due to reduced lung elastic recoil and airway

tethering), thus increasing EFL (Miller and Dempsey 2004). Exertional

tachypnoea (exacerbated by gas exchange abnormalities) results in the available

expiratory time becoming increasingly insufficient to allow EELV to return to its

usual relaxation volume (O'Donnell and Laveneziana 2006d). Therefore lung

emptying is further reduced and this temporary increase of EELV above its

baseline value (acute on chronic hyperinflation) is termed dynamic hyperinflation

(DH) (O'Donnell and Laveneziana 2006d). The degree of DH which occurs

during exercise in COPD is variable and is proportional to the extent of EFL and

ventilatory demand (O'Donnell and Laveneziana 2006d). Dynamic changes in

EELV (DH) may be conveniently and reliably assessed by measurement of

Chapter 3: COPD 66

inspiratory capacity (IC), (Calverley and Koulouris 2005, O'Donnell et al 2007)

which will be discussed in Chapter 7.

Figure 3.8 Changes in operating lung volumes leading to restrictive constraints

upon tidal volume (VT - ) with increasing ventilation during exercise in a) age-

matched normal subjects b) COPD subjects. In COPD, VT is limited from below

(reduced inspiratory capacity (IC) and above (minimal inspiratory reserve volume

(IRV - ) (O'Donnell and Laveneziana 2006c, p 221).

VC, vital capacity; EELV, end-expiratory lung volume; EILV, end-inspiratory lung

volume; TLC, total lung capacity.

The efficiency of the respiratory system during exercise may be illustrated by the

relaxation pressure volume (P-V) curve of the lung and chest wall (Figure 3.9).

Elastic recoil pressure of the respiratory system (the sum of recoil pressures of

the lung and chest wall) is plotted against pulmonary volume during inspiration

and expiration. Pressure is measured by occluding inspiration or expiration with

Chapter 3: COPD 67

the subject relaxing the respiratory muscles. The P-V curve is sigmoidal in shape

and demonstrates the pressure production required for a given change in lung

volume.

In health, operating lung volumes are usually maintained within the linear portion

of this curve, approximately between 20% and 80% of vital capacity (O'Donnell

and Webb 2003, Rodman et al 2002). At these levels, the pressure production

required for a given change in lung volume is relatively less than at the alinear

extremes of the curve where pulmonary compliance is significantly reduced. As

the respiratory system is operating in the area which avoids the extremes of the

curve, efficiency is maximised.

In COPD, exercise VT encroaches on the upper, alinear extreme of the P–V curve

where there is increased elastic loading. The ability to further expand VT is

reduced, that is, inspiratory reserve volume (IRV) is diminished (O'Donnell and

Webb 2003). In contrast to health, the combined recoil pressure of the lungs and

chest wall in hyperinflated patients with COPD is inwardly directed during both

rest and exercise, contributing to the inspiratory threshold load on the inspiratory

muscles (O'Donnell and Laveneziana 2006d).

In this circumstance, expiratory flow can only be increased by breathing at higher

lung volume. Movement of VT towards TLC is therefore regarded as a

compensatory mechanism (O'Donnell and Webb 2004, Rodarte 2004, Tantucci et

al 1998). It is believed that this is due to distension or “splinting” open of

narrowed airways (Macklem 1984). It has been estimated that a patient with an

FEV1 of approximately 30% of predicted value and a TLC of 125% predicted may

be able to generate almost no expiratory flow at a volume corresponding to 100%

of predicted value of TLC (Rodarte 2004). Factors which determine the extent to

which TLC may increase remain unclear but it has been proposed that decreased

lung elastic recoil and chest wall remodeling may be involved (Rodarte 2004).

Chapter 3: COPD 68

Figure 3.9 Relaxation Pressure (P) – volume (V) relationships of the total

respiratory system a) in health and b) in COPD. Tidal P–V curves at rest ( ) and

during exercise ( ) are shown (O'Donnell and Laveneziana 2006c, p 221).

RV, residual volume; TLC, total lung capacity; IRV, inspiratory reserve volume;

EELV, end expiratory lung volume

Whilst DH attenuates EFL and maximises expiratory flow rates early in exercise,

this advantage is quickly negated through further mechanical restriction

(O'Donnell and Webb 2004). The inspiratory muscles, in particular the

diaphragm, become increasingly disadvantaged further compromising their ability

to generate pressure (Miller and Dempsey 2004, O'Donnell and Webb 2003). DH

also results in encroachment of VT on the upper, alinear extreme of the

respiratory system‟s P-V curve, where pulmonary compliance is reduced and the

inspiratory threshold load is therefore greatly increased (Figure 3.9) (O'Donnell

and Webb 2005). As lung volume increases, a given change in diaphragm length

results in less caudal diaphragm displacement. Consequently, a much greater

force of contraction and therefore central motor output is required to maintain a

given VT and accessory muscles of inspiration are frequently recruited (Miller and

Dempsey 2004). The inefficiency of operating at high lung volumes is believed to

Chapter 3: COPD 69

lead to a mismatch between inspiratory effort and inhaled volume, known as

neuromechanical uncoupling (Haverkamp et al 2005) or dissociation (American

Thoracic Society 1999a). This concept and its association with dyspnoea was

initially described over a decade ago (O'Donnell and Webb 1993) and is further

discussed in Section 3.9.1.

Eventually, the level of ventilation required to maintain normal resting CO2

content cannot be sustained (Rodarte 2004). In these patients, failure of the

ventilatory pump or Type II respiratory failure develops, defined as chronic

elevation of PaCO2 (Roussos and Koutsoukou 2003).

3.8.5 Cardiovascular effects

A major cardiovascular complication of COPD is pulmonary hypertension, which

tends to develop late in the course of the disease and after the onset of severe

hypoxaemia (Rodriguez-Roisin et al 2008). Pulmonary hypertension in COPD

has traditionally been explained as an effect of hypoxaemia (Section 3.8.6),

however there is evidence that other mechanisms also contribute (Christensen et

al 2004). These include destruction of the pulmonary capillary bed due to

emphysema a vascular inflammatory response similar to that seen in the airways

(Rodriguez-Roisin et al 2008). Vessel lumen diameter is reduced both by intimal

hyperplasia and smooth muscle hypertrophy leading to vessel wall remodelling

and thickening (Rodriguez-Roisin et al 2008). It has also been proposed that

repeated episodes of hypoxaemia, for example during exercise, may promote

pulmonary vasoconstriction and lead to remodelling of the pulmonary arteries

such that this process is no longer reversible (Weitzenblum 1994).

The pulmonary circulation may be further compromised by venous stasis and

pulmonary embolism due to right heart failure (Pauwels et al 2001). Increased

blood viscosity may also occur due to secondary polycythaemia (West 2005).

Altitude studies have long identified secondary polycythaemia as a physiological

adaptation to chronic hypoxaemia (Lumb 2005) and it has similarly been

observed in hypoxaemia related to COPD (Benowitz and Brunetta 2005).

Increased pulmonary vascular resistance and blood viscosity combine to

increase the pressure required to perfuse the pulmonary vascular bed and

therefore increase right ventricular afterload (O'Donnell and Webb 2003).

Elevation of pulmonary artery pressure is generally modest at rest, but may be

Chapter 3: COPD 70

more marked upon exercise (Pauwels et al 2001). Some patients with COPD

develop cor pulmonale, defined as hypertrophy of the right ventricle which is

secondary to diseases affecting pulmonary function and/or structure, in the

absence of diseases primarily affecting left heart function (Pauwels et al 2001). It

results in fluid retention, characterised by dependent oedema and engorged neck

veins.

COPD may have other effects upon cardiac performance which may become

more apparent during exercise. Severe hyperinflation and expiratory muscle

activity are understood to impede venous return and reduce right ventricular pre-

load (O'Donnell and Webb 2003, Rodarte 2004). Further, DH and elevated

airway resistance result in very negative pleural pressures during inspiration,

increasing left-ventricular afterload (Rodarte 2004). When compared with healthy

subjects, patients with COPD generally have a lower stroke volume and a

correspondingly higher heart rate for a given total body oxygen uptake (VO2)

(O'Donnell and Webb 2003). Emphysema has also been shown to be linearly

related to impaired left ventricular filling and reduced cardiac output, without

changes in the ejection fraction (Barr et al 2010). In some patients, limited

cardiac output may be the main factor causing a fall of PO2, which, in the

presence of V/Q inequality, exaggerates hypoxaemia (West 2003).

An association between COPD and an increased risk of cardiovascular disease

has also been noted. Endothelial function in pulmonary and renal circulations is

abnormal in people with COPD (Augusti et al 2003). Whilst these diseases share

the common risk factors of cigarette smoking, increasing age and inactivity, it is

hypothesised that the persistent, low-grade systemic inflammation present in

COPD may contribute to cardiovascular changes (Augusti et al 2003).

3.8.6 Gas exchange abnormalities

At rest, patients with COPD usually have a lower than normal PaO2 and a normal

or higher than normal PaCO2 (Barbera 2000, West 2003). During exercise, PaO2

may decrease, remain constant or may occasionally increase, and PaCO2 may

remain stable or increase (Barbera 2000). In advanced disease, some patients

with COPD may have severe hypoxaemia with PaO2 between 50 and 40 mmHg,

due to gas exchange impairment and increased oxygen consumption (West

2003).

Chapter 3: COPD 71

The main determinant of the gas exchange abnormalities found in COPD is V/Q

inequality or mismatch (Rodriguez-Roisin et al 2009) which results from altered

ventilation and perfusion. Gas exchange units with wasted ventilation

(physiological dead space) occur due to destruction of portions of the alveolar-

capillary bed and changes within the pulmonary vessels. Gas exchange units

with wasted perfusion (venous admixture or shunt) occur as a result of reduced

ventilation due to abnormal airflow resistance and lung compliance (Lumb 2005).

These pulmonary abnormalities are inhomogenous (Pauwels et al 2001).

Consequently, areas representing V/Q ratios from infinity to zero are present

(Cooper and Celli 2008, Rodarte 2004, West 2003). Significant V/Q mismatch

may occur early in the disease process, when spirometrically determined airflow

limitation is minimal (Rodriguez-Roisin et al 2009). Despite the reduction in lung

surface area available for gas diffusion due to the destructive processes of the

disease, diffusion impairment is believed not to be the mechanism underlying

hypoxaemia in COPD, either at rest or during exercise (Wagner et al 1977).

V/Q inequality may be partially compensated for by localised hypoxic pulmonary

vasoconstriction which occurs in poorly ventilated regions. This response to

hypoxia is primarily mediated by reduced alveolar partial pressure of oxygen, but

also by mixed venous (pulmonary arterial) pressure of oxygen (Lumb 2005).

This diverts pulmonary blood flow away from areas where oxygen tension is low

and thus reduces the regional degree of V/Q inequality and minimises arterial

hypoxaemia (Lumb 2005). Whilst this response is initially reversible, for example,

with the provision of supplemental oxygen, the degree of reversibility reduces

over time with chronic hypoxia and advancing pulmonary vessel wall damage

(Pauwels et al 2001), contributing to the development of secondary pulmonary

hypertension (Lumb 2005). A further compensatory mechanism which serves to

reduce the adverse effects of airflow limitation is collateral ventilation. This refers

to ventilation through communicating channels which exist between adjacent

alveoli and between neighbouring small airways (West 2003).

Despite these compensatory mechanisms, hypoxaemia eventually occurs,

(Rodriguez-Roisin et al 2009, West 2003), initially only during exercise, but

ultimately at rest (Pauwels et al 2001). Mechanical inefficiency and increased

load upon the respiratory muscles combine to cause an inadequate VT,

particularly at elevated breathing frequencies where inspiratory and expiratory

times are reduced. In addition, increased work of breathing may result in a

Chapter 3: COPD 72

marked increase in the O2 cost of breathing (oxygen consumed by the respiratory

muscles) (West 2003). The latter is estimated to be less than 5% of the total

resting oxygen consumption during normal, quiet breathing (West 2005), but may

rise to 50% of whole body oxygen uptake in COPD (Aliverti and Macklem 2001).

Chronic hypercapnia may also develop as COPD progresses and ventilation to

the gas exchanging surfaces becomes insufficient to meet demand (Pauwels et

al 2001, West 2003). One theory proposed to explain this is that the oxygen cost

of breathing is so high that increased ventilation is avoided at the expense of an

elevation in CO2 (West 2003). As PaCO2 rises, pH falls, resulting in respiratory

acidosis. In patients with chronic hypercapnia, the pH of the brain extracellular

fluid may be returned to near normal by renal retention of bicarbonate

(compensated respiratory acidosis) (Lumb 2005) which may take five to seven

days to reach maximal levels (Netter 1996). For these patients, the sensitivity of

the respiratory centre to rises in PaCO2 may be reduced or lost (Lumb 2005) and

stimulation of the peripheral chemoreceptors by arterial hypoxaemia becomes the

main factor influencing ventilation (West 2003). This has important implications

for provision of oxygen therapy to these patients (Section 3.10.2).

3.8.7 Systemic and other effects

COPD is associated with other significant, extrapulmonary abnormalities affecting

nutrition and the cardiovascular, nervous and musculoskeletal systems and bone

marrow (Augusti et al 2003). The mechanisms underlying these effects are not

clear. However, systemic inflammation, tissue hypoxia, oxidative stress and

reduced activity and deconditioning are believed to contribute (Augusti et al 2003,

O'Donnell and Webb 2003). Similar markers of inflammatory changes to those

found in the lungs have also been detected in the systemic circulation, in addition

to the presence of circulating inflammatory cells and evidence of oxidative stress

(Augusti et al 2003, Pauwels et al 2001).

Nervous system abnormalities include altered bioenergetic metabolism of the

brain and reduced cognitive performance (Augusti et al 2003, Leisker et al 2004).

A high prevalence of depression has been reported in COPD patients (Augusti et

al 2003) as have anxiety disorders including generalised anxiety and panic

disorders (Brenes 2003).

Chapter 3: COPD 73

Nutritional abnormalities include alterations in caloric intake, basal metabolic rate

and body composition (Augusti et al 2003). Weight loss and low body mass

index (BMI) are prevalent, particularly in patients with severe COPD (Augusti et al

2003, Calverley and Walker 2003). Loss of skeletal muscle mass is the major

cause of weight loss, with a lesser contribution from lost fat mass contributes

(Augusti et al 2003). The prevalence of osteoporosis is increased in COPD,

possibly caused by one or a combination of the above factors in addition to

corticosteroid therapy (Augusti et al 2003, Calverley and Walker 2003).

Skeletal muscle abnormalities and dysfunction are common in patients with

COPD (American Thoracic Society/European Respiratory Society 1999, Augusti

et al 2003) and are believed to contribute to exercise intolerance (Debigare and

Maltais 2008). Changes include altered fibre type composition and atrophy

(Augusti et al 2003), loss of muscle mass and mitochondrial (aerobic) potential

and compromised oxidative phoshorylation with an elevated demand upon

anaerobic glycolysis (Casaburi 2001, O'Donnell and Webb 2003). An excess

accumulation of metabolic byproducts, particularly lactate has been

demonstrated (Casaburi 2001, Casaburi et al 1991, O'Donnell and Webb 2003).

These changes impair contractility, result in a loss of strength and endurance and

predispose to fatigue (O'Donnell and Webb 2003). Leg fatigue has been shown

to be as important as breathlessness in limiting peak exercise performance

(Jones 2005).

Peripheral skeletal muscle function is also compromised by the development of

hypercapnia and hypoxaemia which reduce delivery of oxygen to the working

muscles and reduce pH (Aliverti and Macklem 2008, Pauwels et al 2001). Early

metabolic acidosis during exercise is thought to stimulate ventilation (due to

increased CO2 via acid buffering effects), thus hastening the ventilatory limitation

of exercise (Casaburi et al 1991). Further contributing factors to skeletal muscle

dysfunction are malnutrition, low circulating levels of anabolic hormones and

myopathic changes, particularly in relation to corticosteroid therapy (Augusti et al

2003, Calverley and Walker 2003, Casaburi 2001, O'Donnell and Webb 2003).

However, despite these multiple inhibitory factors, a number of studies have

demonstrated that exercise training can improve peripheral muscle strength and

endurance (Casaburi 2001, O'Donnell and Webb 2003).

Chapter 3: COPD 74

3.9 Clinical features

3.9.1 Dyspnoea

Definition

Dyspnoea is the most common symptom experienced by patients with COPD

(O'Donnell and Webb 2005). It is associated with functional limitation and

reduced quality of life and tends to be progressive and inexorable with advancing

disease (O'Donnell et al 2007, O'Donnell and Webb 2005).

Dyspnoea is derived from the Greek words “dys” meaning painful, difficult or

disordered and “pnoia” meaning breathing. Dyspnoea is defined as a perceived

difficulty with breathing, an unpleasant urge to breathe (O'Donnell et al 2007), or

a subjective experience of breathing discomfort, consisting of distinct sensations

which vary in intensity (American Thoracic Society 1999a). Qualitative

descriptors of the sensations evoked by dyspnoea have been identified, including

sensations of “air hunger‟ (an uncomfortable urge to breathe), increased

inspiratory work or effort, chest tightness and unsatisfied inspiration (O'Donnell et

al 2007, Williams et al 2009).

Mechanisms of dyspnoea

The mechanisms of dyspnoea are multifactorial and not yet fully understood

(O'Donnell et al 2007). Whilst individuals have some voluntary control over

breathing, sensations arising from the input of the chemo- and mechanoreceptors

as a result of respiratory activity may also influence the perception of dyspnoea

and therefore rate and pattern of breathing (American Thoracic Society 1999a).

In addition, a number of peripheral receptors, situated in the upper and lower

airways, lung parenchyma and respiratory muscles, are associated with

generating sensations of dyspnoea. It is further proposed that specialised

mechanoreceptors in skin, joints and muscles may also provide important

proprioceptive input (O'Donnell et al 2007).

Afferent signals from these receptors to the brainstem respiratory centre are

thought also to be fed to the sensory cortex, resulting in an awareness of the

outgoing motor stimuli to the ventilatory muscles (American Thoracic Society

1999a), that is, a cognitive awareness of breathing (O'Donnell et al 2007).

Processing of these signals and the complex interaction of psychological, social,

cultural and environmental factors and the context in which such sensations

Chapter 3: COPD 75

occur, combine to influence an individual‟s response and induce secondary

physiological responses (American Thoracic Society 1999a, O'Donnell and Webb

2005) Figure 3.10). This processing of afferent signals has been further

described as an assessment of the emotional and threat-related consequences of

the stimuli which produce the signals, which is modified by attention, experience,

learning and affective state (O'Donnell et al 2007).

Figure 3.10 Diagram illustrating the many sensory sources of breathing

discomfort contributing to and modifying the intensity of dyspnoea (Manning and

Schwartzstein 1995, p 1552).

Dyspnoea is regarded as a reflection of an imbalance or a perceived disparity

between achieved and required ventilation (Hill et al 2004, O'Donnell et al 2007).

One theory proposed to explain dyspnoea in COPD relates to the length-tension

relationship of the respiratory muscles. As a consequence of DH, the respiratory

muscles become increasingly shortened during exercise, placing them at a

greater mechanical disadvantage (Campbell and Howell 1963).

Neuromechanical disassociation is a more recently proposed explanation for

dyspnoea and also relates to respiratory muscle dysfunction (American Thoracic

Society 1999a, O'Donnell et al 2007). This is defined as a disequilibrium

between efferent respiratory motor command (driving inspiratory activity) and

Chapter 3: COPD 76

afferent feedback from receptors (American Thoracic Society 1999a, O'Donnell et

al 2007). Dyspnoea arises when there is a disparity between the effort expended

and the anticipated mechanical consequences, those being changes in

intrathoracic pressure, respiratory muscle length and chest wall or lung

movement (American Thoracic Society 1999a, Ferrari et al 1997, Hill et al 2004,

Manning and Schwartzstein 1998, O'Donnell et al 2007). This is thought to give

rise to sensations of unsatisfied respiratory effort (O'Donnell et al 2007).

DH has an important role in neuromechanical dissociation due to the constraints

it places upon VT expansion during periods of increased demand. With DH, VT

becomes positioned on the upper, noncompliant extreme of the P-V curve (Figure

3.9) where elastic loading upon the respiratory muscles is increased. It has been

shown that as DH increases, VT becomes fixed at a critical, threshold level where

IRV is approximately 0.5L below TLC. At this point dyspnoea rises abruptly to

become intolerable (O'Donnell et al 2007).

Neuromechanical dissociation may be quantified by measuring the ratio of effort

(tidal oesophageal pressure swings relative to maximal inspiratory pressure) and

thoracic displacement (VT expressed as a percentage of predicted vital capacity)

(O'Donnell et al 2007). Whilst this quantification of neuromechanical dissociation

may be crude, effort-displacement ratios have been shown to correlate highly

with dyspnoea and degree of DH and also to rise precipitously once this

threshold point is reached (O'Donnell and Webb 2005). This theory is further

supported by the fact that the degree of dyspnoea experienced by patients with

COPD correlates more closely with the extent of hyperinflation than FEV1

(O'Donnell et al 1999, O'Donnell and Webb 1993). Further, degree of DH is a

predictive factor for dyspnoea during exercise in COPD (O'Donnell and Webb

1993).

At the limit of exercise tolerance in COPD, when dyspnoea has also reached

intolerable levels, the respiratory muscle fibres are significantly shortened. The

respiratory muscles are possibly fatigued and working at near maximal contractile

effort against heightened inspiratory and expiratory resistance, and the oxygen

cost of breathing is greatly elevated. Further expansion of VT is constrained in

the setting of strong chemical drive from metabolic acidosis and, in some cases,

severe hypoxaemia or hypercapnia and decreased gas exchange efficiency

(Loring et al 2009). There are other factors which may limit ventilation, for

Chapter 3: COPD 77

example obesity or the presence of a non-ventilated emphysematous bulla

(Loring et al 2009). However, these are beyond the scope of this thesis and will

not be further discussed.

Responses to dyspnoea

The physiological alterations or disturbances described above may be

compounded by behavioral style and emotional state (American Thoracic Society

1999a). Responses vary between individuals, but may generate strong

emotional reactions of fear and distress which precipitate conditioned behavioral

responses. These may include pursed-lips breathing, adoption of supported

leaning positions which augment the recruitment of accessory muscles of

breathing, cessation and avoidance of activity and social withdrawal (O'Donnell et

al 2007). For some patients, these strategies are not beneficial and feelings of

lack of control and panic may ensue. Fear and anxiety can trigger further

responses via the sympathetic nervous system, which can further amplify

discomfort and distress (O'Donnell et al 2007).

3.9.2 Cough and sputum

Increased cough and sputum production often precede the development of

airflow obstruction in COPD by many years (American Thoracic Society 1995b).

However, not all individuals who experience the symptoms of mucus

hypersecretion and ciliary dysfunction develop all the changes of COPD and

conversely, some patients develop significant airflow obstruction without chronic

cough and sputum (Pauwels et al 2001). The onset of sputum production tends

to occur insidiously and daily expectorated volume rarely exceeds 60 mls.

Sputum is usually mucoid, but becomes purulent during exacerbations and is

mostly expectorated in the mornings (American Thoracic Society 1995b).

3.10 Management

3.10.1 Overview

Until the 1960's, therapies for COPD were limited to inpatient treatment of acute

episodes, which included antibiotics, mucolytic agents, ephedrine and

theophylline (Petty 2002). Corticosteroids were not used, exercise was

prohibited due to concerns of straining the right heart and oxygen therapy was

contraindicated (Petty 2002).

Chapter 3: COPD 78

Since that time, various COPD guideline documents have been developed to

summarise diagnosis, monitoring and management strategies and these contain

many similarities. As discussed previously, all provide a definition of COPD and

stress the importance of considering this as a diagnosis in any patient presenting

with its common symptoms, cough, sputum production or dyspnoea, or with a

history of exposure to risk factors for the disease. Diagnostic procedures are

also outlined.

Cigarette smoking is regarded as addictive and as a chronic relapsing disorder

(Celli and MacNee 2004b) and risk management includes addressing this and

other relevant issues. The management of stable COPD includes

pharmacotherapy, in particular bronchodilators and glucocorticoids. Also

recommended are formal pulmonary rehabilitation programs, nutritional

interventions, assessment for the possibility of sleep disorders and, in selected

cases, surgery including bullectomy, lung volume reduction surgery or

transplantation. Consideration of oxygen therapy according to recognised

oxygen therapy guidelines is advised (Table 2.3). Advice regarding air travel is

also covered in oxygen therapy guidelines. Additional issues regarding oxygen

therapy in COPD are discussed in Section 3.10.2.

Exacerbations of COPD have been defined as a change from baseline in a

patient‟s dyspnoea, cough and/or sputum, beyond day-to-day variability and

necessitating a change in management (Celli and MacNee 2004b).

Recommended management includes adjustment of pharmacological agents

used for stable disease, with the possible addition of systemic glucocorticoids

and/or antibiotics. Indications for hospitalisation, appropriate investigations,

implementation and/or adjustment of oxygen therapy and assisted ventilation and

palliative care issues are also highlighted.

Of note, the definitions, staging and prognosis of COPD promoted by the various

societies has previously focussed on the lungs and therapy has been targeted at

pulmonary variables such as FEV1 and PaO2. As COPD is no longer considered

to be a disease affecting the lungs alone, assessment and management of its

significant extrapulmonary manifestations are now more widely appreciated.

New therapeutic strategies have been developed which aim to improve function

and quality of life, the most important of these being pulmonary rehabilitation

programs (American Thoracic Society 1999b, British Thoracic Society 2001).

Chapter 3: COPD 79

3.10.2 Oxygen therapy in COPD

Whilst the use of oxygen therapy for patients with advanced COPD is well-

established, there are issues which warrant further consideration. Of particular

concern is its use for patients with severe COPD and chronic hypercapnia.

These patients may develop worsening hypercapnia due to the relief of

hypoxaemia by hyperoxia (hyperoxic hypercapnia) (Lumb 2005). Minute

ventilation is reduced as a consequence of diminished hypoxic drive to breathe in

the setting of reduced chemoreceptor sensitivity to carbon dioxide (Lumb 2005,

West 2003). The narcotic effect of increasing hypercapnia then further amplifies

this effect in susceptible patients (Young 2007).

It has been proposed that a further contribution to oxygen-induced hypercapnia in

such patients is the release of hypoxic vasoconstriction, resulting in increased

dead-space ventilation and ventilation-perfusion mismatch (Lumb 2005).

However, this response has also been demonstrated in patients with COPD who

do not have oxygen-induced hypercapnia (Robinson et al 2000). It is also

proposed that the increase in alveolar dead-space observed with oxygen-induced

hypercapnia may be related to carbon dioxide mediated bronchodilatation

(Robinson et al, 2000).

For patients with COPD, low concentrations of oxygen are recommended with

measurement of PaO2 and PaCO2 after 15 to 20 minutes to ensure that PaCO2

has not risen by more than a few mmHg and monitoring to ensure that the patient

has remained alert (Lumb 2005, West 2005). The issue of emergency

administration of oxygen therapy for this patient group during acute

exacerbations remains controversial due to the potential for oxygen-induced CO2

narcosis balanced against the need to avoid the more acute risk of inadequate

oxygenation (Dent et al 2007, Joosten et al 2007, Levetown 2002, Thomson et al

2002, Young 2007).

Intermittent oxygen therapy may also be particularly hazardous in patients with

hyperoxic hypercapnia, a situation which Haldane likened to bringing a drowning

man to the surface occasionally (Gibson 2004). The rationale for this is that upon

cessation of hyperoxia, subsequent hypoxaemia may be more severe than prior

to its administration as increased alveolar partial pressure of CO2 will reduce

alveolar and therefore arterial partial pressure of oxygen. A higher PaCO2 is

Chapter 3: COPD 80

likely to remain for some minutes in this situation as body stores slowly wash out

(West 2003).

Further, there is some evidence that oxygen therapy may exacerbate the

inflammatory component of COPD due to increased oxidative stress

(Carpagnano et al 2004). Markers of oxidative stress in plasma (interlukine-6)

and airways (exhaled 8-isoporstane) have been shown to increase after short-

term exposure to hyperoxia (one hour at 28% via facemask) in normal subjects

and those with COPD (Carpagnano et al 2004). However, the clinical relevance

of this finding is not yet clear (Troosters 2004b) and long-term effects are

unknown (Carpagnano et al 2004, O'Reilly and Bailey 2007).

3.11 Conclusions

COPD is an umbrella term used to describe a complex, multi-system disorder.

This chapter has discussed the pathological and physiological manifestations of

the disease, particularly its effects upon the respiratory system. The mechanisms

by which these factors interact to result in dyspnoea and reduced quality of life

and functional status are also described.

The next chapter outlines the measures which have been used in COPD

populations to assess the effectiveness of interventions upon these outcomes of

the disease.

Chapter 4: Outcome measures in COPD 81

It is more important to know what sort of person has a disease, than to know what sort of disease a person has. Hippocrates (460BC – 370BC)

Outcome measures in chronic obstructive pulmonary disease

4.1 Overview ......................................................................................... 81 4.2 Dyspnoea ........................................................................................ 83

4.2.1 Introduction ........................................................................ 83 4.2.2 The Medical Research Council Dyspnoea Scale ............... 84 4.2.3 Dyspnoea domain of the Chronic Respiratory Disease

Questionnaire .................................................................... 86 4.2.4 Baseline and Transition Dyspnoea Index ........................... 87 4.2.5 The Borg Scale .................................................................. 89 4.2.6 Summary of measures of dyspnoea .................................. 91

4.3 Health-related quality of life ............................................................. 92 4.3.1 Generic measures ............................................................. 92 4.3.2 Disease specific measures ................................................ 94

4.4 Mood disturbance ............................................................................ 96 4.5 Functional status ............................................................................. 98

4.5.1 Exercise capacity ............................................................... 99 4.5.2 Physical activity ............................................................... 103

4.6 Summary ....................................................................................... 108

4.1 Overview

The significant medical and economic burdens imposed by COPD have promoted

global interest in the development of strategies to improve outcomes for patients

with COPD and instruments with which to evaluate these strategies.

Despite the non-reversibility of airflow limitation being a feature of this disease,

the traditional approach to evaluating efficacy of therapies in COPD has been to

measure lung function, particularly FEV1, which reflects the abnormalities of lung

architecture in COPD (Mahler 2005a). Unfortunately, measures of lung function

are poorly responsive and do not correlate well with the symptoms, psychosocial

manifestations and other clinical features of COPD (Sullivan et al 2003). These

factors may be examined in the context of health status, which encompasses

4

Chapter


health-related quality of life (HRQL) and functional status (Curtis and Patrick

2003).

Measures of health status have, in contrast, been shown to be responsive to

interventions in COPD, one notable example being pulmonary rehabilitation

programs. There is strong evidence that pulmonary rehabilitation programs result

in decreased breathlessness and health care utilisation, as well as improved

quality of life and exercise capacity (American Thoracic Society 1999b, British

Thoracic Society 2001), despite no change in conventional pulmonary function

measures. It is fortunate that symptoms, quality of life and functional status, the

issues which are of primary importance to patients with COPD (ZuWallack 2000),

are now readily able to be measured using tools which have been well examined

and are widely recognised.

Outcome measures may be defined according to three categories: discriminative

(able to discriminate between subjects at a single point in time), evaluative (those

which evaluate change over time, for example, in response to an intervention)

and those designed to predict prognosis (Curtis et al 1994). They may be further

described according to the criteria outlined in Table 4.1. This chapter describes

the evaluative measures used in this project with reference to these criteria and,

where possible, the minimal important difference (MID) in scores. The MID is

defined as the smallest difference in scores which informed patients or proxies

perceive to be important and which may lead a patient or clinician to consider

changing management (Schunemann and Guyatt 2005b). The discriminative

measures of dyspnoea which were used will also be discussed. Tests of

respiratory function used as discriminatory measures in this project will not be

further described in this thesis, with the exception of inspiratory capacity (IC).

Change in IC was used to assess the effects of hyperoxia upon degree of resting

hyperinflation, and is described in Chapter 7.


Table 4.1 Definitions of outcome measure criteria (Mahler 2005a, Mahler et al

1998, Polgar and Thomas 1998).

Criterion

Definition

Validity

Examines whether an instrument measures what

it is intended to measure; extent of correlation

with other instruments which evaluate the same

measure.

Reliability

Test-retest (includes intra-rater)

Inter-rater

Reproducibility of results

Extent of agreement (correlation) between tests

Extent of agreement (correlation) between

assessors

Responsiveness Ability to detect change even when small

(evaluative instruments)

Interpretability

Clinical importance of specific changes in scores

(evaluative instruments). Is related to the

minimal important difference in scores (MID).

4.2 Dyspnoea

4.2.1 Introduction

Dyspnoea is the main reason that patients with COPD seek medical care . The

discrepancy between the severity of lung disease measured in physiological

terms and the severity of dyspnoea is well-recognised. Consequently, a number

of widely-accepted, validated instruments, both discriminative and evaluative,

have been developed in order to measure dyspnoea in research and clinical

settings (Mahler 2005a). These instruments may be further categorised as

clinical, exertional and quality of life instruments (Table 4.2) (Hajiro et al 1998,

Meek and Lareau 2003). As the primary focus of this research was to evaluate

the effects of ambulatory oxygen upon dyspnoea in patients who identified

themselves as being significantly limited by it, instruments from each of these

categories were used.


Table 4.2 Categories of dyspnoea measures (Hajiro, et al., 1998; Meek &

Lareau, 2003)

Category

Association

Examples

Clinical

Activities, particularly

activities of daily living

Medical Research Council Dyspnoea Scale

Baseline and Transition Dyspnoea Indices

Oxygen Cost Diagram

Exertional Symptoms during

exercise, exercise

testing

Borg Scale

Visual Analogue Scale

Quality of

life

Health related quality of

life, functional status

Chronic Respiratory Disease Questionnaire

Saint George Respiratory Questionnaire

University of San Diego Shortness of Breath

Questionnaire

4.2.2 The Medical Research Council Dyspnoea Scale

As dyspnoea frequently results in an inability to perform activities of daily life, one

of the first questionnaires designed to measure dyspnoea was a five-point clinical

scale, based upon the magnitude of activities or tasks evoking breathlessness

(Fletcher 1952). This scale rated degree of dyspnoea while walking distances on

level surfaces or climbing and was initially used to assess patients with

pneumoconiosis. It was further developed for use in the diagnosis of chronic

bronchitis (Table 4.3) (Fletcher 1959) under the auspices of the British Medical

Research Council (MRC) and became known at the MRC Dyspnoea Scale

(Medical Research Council 1960). The same instrument has been termed the

Modified Medical Research Council (MMRC) Dyspnoea Scale by some authors

(Nishimura et al 2002) and other modifications have been published (Mahler and

Wells 1988, Sahebjami and Sathianpitayakul 2000). The terms MRC and MMRC

Dyspnoea Scale appear to have been used interchangeably in the literature.


Table 4.3 The Medical Research Council Dyspnoea Scale (Fletcher et al 1959)

Grade 1 Are you ever troubled by breathlessness except on strenuous

exertion?

Grade 2 (If yes) Are you short of breath when hurrying on the level or

walking up a slight hill?

Grade 3 (If yes) Do you have to walk slower than most people on the level?

Do you have to stop after a mile or so (or after one-quarter hour)

on the level at your own pace?

Grade 4 (If yes to either) Do you have to stop for breath after walking about

100 yards (or after a few minutes) on the level?

Grade 5 (If yes) Are you too breathless to leave the house or breathless

after undressing?

In 1999, Bestall et al reviewed a simplified but very similar version to that

originally proposed (Table 4.4), with the aim of determining its validity as a

measure of disability in COPD. Termed the MRC Dyspnoea Scale by these

authors, this is also an interval scale, with which patients grade themselves

according to five statements relating to function, specifically walking. A single

score is generated, with a higher grade representing more severe dyspnoea.

These authors (Bestall et al 1999) found significant associations between scores

from this version of the MRC scale (Table 4.4) and a number of well-recognised

variables used to measure severity and impact of COPD including measures of

functional capacity (Incremental Shuttle Walking Test), disease-specific quality of

life (the St George‟s Respiratory Questionnaire and the Chronic Respiratory

Disease Questionnaire), mood status (the Hospital Anxiety and Depression

Scale) and general activity (the Nottingham Extended Activities of Daily Living

score). However, neither version of the scale (Tables 4.3, 4.4) is considered to

be sufficiently sensitive (able to detect rapid change in response to an

intervention) for use as an evaluative instrument (American Thoracic Society

1999a, Mahler et al 1984, Meek 2004), possibly due to a lack of clear boundaries

between each level (American Thoracic Society 1999a).


The MRC scale described by Bestall et al (1999) (Table 4.4) was used as a

discriminative tool to assess suitability for inclusion in the main study of this

thesis (Chapter 8). It was chosen due to it being a simple, validated and well-

recognised instrument for assessing dyspnoea in relation to function in COPD

populations (Wedzicha et al 1998). A grading of three or greater was required for

inclusion, representing moderate to severe dyspnoea (Bestall et al 1999).

Table 4.4 The Medical Research Council (MRC) Dyspnoea Scale (Bestall et al

1999)

4.2.3 Dyspnoea domain of the Chronic Respiratory Disease Questionnaire

The Chronic Respiratory Disease Questionnaire (CRQ) was developed in 1987

as a disease-specific health-related quality of life (HRQL) questionnaire (Guyatt

et al 1987). Dyspnoea is one of four domains included in the CRQ and is

assessed by asking subjects to identify five activities which are important,

performed frequently in daily life and which have caused breathlessness over the

previous two weeks. The degree of dyspnoea experienced with each activity is

graded by the subject, according to a seven-point Likert scale, with scores

ranging from one (extremely short of breath) to seven (not at all short of breath).

The five scores are summed to provide an overall dyspnoea rating (range 5 to

35) with higher scores representing less dyspnoea. A difference of 0.5 per item

(activity), equivalent to 2.5 in overall dyspnoea score, is accepted as representing

the MID in dyspnoea scores (Jaeschke et al 1989). Serial applications of the

questionnaire are performed using the same five activities to measure changes in

scores.

Grade 1 I only get breathless with strenuous exercise

Grade 2 I get short of breath when hurrying on the level or up a slight hill

Grade 3 I walk slower than most people of the same age on the level

because of breathlessness or have to stop for breath when

walking at my own pace on the level

Grade 4 I stop for breath after walking 100 yards or after a few minutes

on the level

Grade 5 I am too breathless to leave the house


One limitation of the dyspnoea domain of the CRQ is that by allowing patients to

choose activities, the questionnaire is not standardised (Jones 1991). However,

this questionnaire was developed as an evaluative (rather than a discriminative)

tool to measure changes over time (Mahler 2004) and, by tailoring of the

dyspnoea evaluation to the individual, has the advantage of increasing sensitivity

to small change over time (Curtis and Patrick 2003). The CRQ remains well

recognised and has been used extensively in clinical and research settings both

to measure dyspnoea in COPD populations and for assessment of HRQL overall

(American Thoracic Society 1999a, Cazzola et al 2008, Troosters 2005). For

these reasons, the dyspnoea domain of the CRQ was chosen as the primary

outcome measure for the main study of this research. The CRQ is further

discussed as a disease-specific measure of HRQL (Section 4.3.2).

4.2.4 Baseline and Transition Dyspnoea Index

In 1984, the Baseline and Transition Dyspnoea Index (BDI/TDI) was proposed as

a more comprehensive and inclusive measure of dyspnoea (Mahler et al 1984).

In contrast to the MRC dyspnoea scale which focuses on a single dimension, the

magnitude of task provoking dyspnoea, the BDI/TDI examines two further

dimensions influencing dyspnoea, functional impairment and magnitude of effort

(Mahler et al 1984). Functional impairment is defined as the degree of

impairment in usual activities, including the requirements of daily living,

maintenance of residence and garden, work and shopping (Mahler et al 1984).

Magnitude of effort relates to the fact that degree of breathlessness experienced

in the performance of a given task may be altered by reducing the associated

effort, for example, by resting or performing the task more slowly (Mahler et al

1984). The initial version of the BDI/TDI is scored by an interviewer (Table 4.5),

using a worksheet to guide open-ended questions exploring the patient‟s

experience of breathlessness (Appendix I) and a response sheet (Appendix II)

(Mahler et al 1984).


Table 4.5 Summary of Baseline and Transition Dyspnoea Index scores (Mahler

et al 1998)

The BDI is a discriminative instrument which rates severity of dyspnoea at a

single point in time according to the three dimensions. The three dimension

scores are summed to provide the BDI focal score with higher scores

representing less dyspnoea (Mahler 2004). The TDI is an evaluative instrument

designed to measure changes from baseline state (BDI scores) (Mahler 2004).

The TDI is scored with reference to the subject‟s comments recorded on the

worksheet during administration of the BDI and by reminding him/her of these

comments. For each dimension, TDI grades range from -3 (major deterioration),

to zero (no change) to +3 (major improvement) and these scores are summed to

provide a TDI focal score (Mahler et al 1984). Scoring takes approximately five

minutes to complete.

The reliability and validity of BDI/TDI have been reported by a number of authors

(Mahler 2005a, Mahler et al 1984, Witek and Mahler 2003). BDI scores have

been significantly correlated with other relevant discriminative measures including

the MRC scale and the Oxygen Cost Diagram (described below) (Mahler et al

1998). The TDI has also been shown to be sensitive to change in randomised

controlled trials of a variety of pharmacological and non-pharmacological

Grades

Components

Baseline Dyspnoea Index (BDI): dyspnoea at baseline

0 to 4

0 to 4

0 to 4

0 to 12

Functional impairment: performance of daily activities and occupation

Magnitude of task: difficulty of activities causing breathlessness

Magnitude of effort: degree of effort able to be exerted

BDI focal score

Transition Dyspnoea Index (TDI): changes from baseline state

-3 to +3

-3 to +3

-3 to +3

-9 to +9

Change in functional impairment

Change in magnitude of task

Change in magnitude of effort

TDI focal score


interventions in COPD including pulmonary rehabilitation, inspiratory muscle

training and bronchodilator medications (Mahler et al 1998, Witek and Mahler

2003) and has been used to track progressive dyspnoea in COPD over a two

year period (Mahler et al 1995). There is evidence to suggest that a TDI score of

one unit represents a clinically significant change (improvement or deterioration)

in comparison with baseline (Witek and Mahler 2003).

Although the authors who developed the instrument have reported satisfactory

inter-rater reliability of the BDI/TDI (Mahler et al 1984), a possible limitation of this

instrument is that questions are not standardised. This limitation is addressed by

the authors‟ suggestion that for each subject, the questionnaire is administered

by the same interviewer on every occasion and with use of a standardised

worksheet (Appendix I) developed according to the published instructions (Mahler

et al 1998). A self-administered and computerised version of the instrument has

been developed to provide more standardised measuring criteria (Mahler et al

2005c), however this was not available at the time of commencement of this

research.

The BDI/TDI was chosen as an additional outcome measure of dyspnoea in this

research because it is comprehensive, includes three dimensions of dyspnoea,

and has been widely used in COPD research including in an Australian

population (Brusaco et al 2003). To minimise the issue of inter-rater variability,

the BDI and TDI were administered by one trained interviewer only for the

duration of that study.

4.2.5 The Borg Scale

The Borg scale is commonly used as a direct, point-in-time measurement of

breathlessness during exercise in COPD (American Thoracic Society 1999a,

British Thoracic Society 2001, Cazzola et al 2008, Hill et al 2004, ZuWallack

2000). This scale was first introduced by the psychologist Gunnar Borg in the

late 1960‟s as a means of quantifying an individual‟s perception of exertion during

physical work (Borg 1970) and became known as the Rating of Perceived

Exertion (RPE) scale (Borg 1982). The RPE scale was a category or ordinal

scale, ranging from 6 to 20, which was designed to represent heart rates of 60 to

200 beats per minute (Borg 1982). This scale was subsequently modified to

range from zero to 10 (Borg 1982) and became known as the Modified Borg

Scale or the CR-10 scale due to it being a category scale with ratio properties


(Table 4.6) . Some numbers on the scale are anchored by verbal descriptors of

intensity. Patients may select an intervening number or fraction or a number

greater than 10 if intensity exceeds previous experiences (Borg 1982). Borg

(1982) recommended use of the original RPE scale for rating exertion in exercise

testing and rehabilitation settings and the modified scale for rating other

subjective symptoms such as breathlessness. Whilst this approach has been

taken in some centres, others have used the modified scale (Table 4.6) for rating

both (American Thoracic Society 2002).

Table 4.6 The modified Borg Scale or CR10 (Borg 1982)

0

0.5

1

2

3

4

5

6

7

8

9

10

*

Nothing at all

Very, very weak (just noticeable)

Very weak

Weak (light)

Moderate

Somewhat strong

Strong (heavy)

Very strong

Very, very strong (almost max)

Maximal

A potential limitation of the Borg scale is a lack of standardised instructions for

use (Ambrosino and Scano 2001b). This limitation has recently been addressed

with the publication of the following instructions for its use:

Notwithstanding this limitation, a number of authors have demonstrated Borg

Scale ratings to be reliable and valid (American Thoracic Society 1999a, Grant et

al 1999, Mahler and Horowitz 1994). It is proposed that a difference of one unit

on the Borg scale represents the MID in scores (Solway et al 2002).

This is a scale for rating breathlessness. The number zero represents no breathlessness. The number ten represents the strongest or greatest breathlessness that you have ever experienced (Mahler and Horowitz 1994 p 1079).


An alternative and also well-described scale for use for a direct, point-in-time

measurement of breathlessness is the Visual Analogue Scale (VAS) (American

Thoracic Society 1999a, British Thoracic Society 2001, Cazzola et al 2008).

This consists of a line, usually 100 mm in length, with descriptors indicating

extremes of breathlessness (no breathlessness and greatest breathlessness).

Subjects are instructed to place a mark on the line corresponding to symptom

severity. As the line is of a standardised length, the location of the mark is

recognised as a measure of the patient‟s dyspnoea (Ambrosino and Porta

2001a). Reliability and validity of the VAS for assessment of breathlessness

have been demonstrated (ATS dyspnoea 1999).

The VAS has been used in an Oxygen Cost Diagram (OCD) which consists of 13

activities, ranked along a 100 mm line according to their associated oxygen cost

(American Thoracic Society 1999a, Simon and Weiss 1989). The activities range

from sleeping to brisk walking uphill and the subject is asked to mark the line at

the point above which activity would be ceased due to breathlessness. The

score for the OCD is calculated by measuring the distance from the bottom of the

line to the mark selected (Ambrosino and Porta 2001a, Mahler et al 1995). A

limitation of the OCD is that the activities listed may not be relevant to all subjects

(Ambrosino and Porta 2001a, American Thoracic Society 1999a).

Of the two scales for point-of-time assessment of breathlessness, the Modified

Borg Scale was chosen for use in the studies of this thesis as it has a number of

theoretical advantages. Firstly, it has been suggested that some subjects may

have difficulty using the VAS due to inability to see the line and/or remember how

it is oriented (American Thoracic Society 1999a). It has also been proposed that

the “ceiling” score of the VAS is disadvantageous when compared with the open-

ended Borg scale where a score of >10 may be selected . A further limitation of

the VAS in a research setting is that direct comparisons between individuals are

not possible due to the absence of descriptors other than those at the extremes

of the scale .

4.2.6 Summary of measures of dyspnoea

The primary focus of this research was to determine the effects of ambulatory

oxygen primarily upon dyspnoea. In order to comprehensively assess dyspnoea,

four measures were chosen, at least one from each category described in Table

4.2. The MRC dyspnoea scale was chosen determine suitability for inclusion.


The dyspnoea domain of the CRQ was chosen to assess dyspnoea in the context

of HRQL. The BDI/TDI was chosen as an additional measure of dyspnoea due to

it being a comprehensive, inclusive measure. The Modified Borg Scale was used

as a point-of-time measure during exercise and pulmonary function testing.

4.3 Health-related quality of life

Quality of life is a broad term describing the gap between that which is desired in

life and that which is achieved (ZuWallack 2000) or perceived level of satisfaction

with issues important to the individual (Curtis and Patrick 2003). In addition to

health condition and health care, quality of life may be influenced by many

interrelated factors including financial status, freedom, housing, employment,

social support, spiritual fulfillment and other factors related to quality of the

environment.

Health-related quality of life (HRQL) refers to the subjective aspects of quality of

life which are affected by health status, taking into account physiological

dysfunction, symptoms and the ability to perform and enjoy the activities of daily

life (Cazzola et al 2008, Jones 2001, ZuWallack 2000). HRQL is now well

established as in important outcome in COPD research. This recognises

patients‟ primary concerns about their level of day to day function and symptoms,

factors which are not reflected in physiological measures or survival. HRQL

instruments measure the impact of disease upon daily life, health and well-being,

providing an estimate of the primary and secondary effects of disease (Cazzola

et al 2008, Curtis and Patrick 2003).

There are two main categories of HRQL measures, generic measures which are

designed to assess the impact of any disease upon overall health status and

those which are disease-specific (Cazzola et al 2008, Curtis and Patrick 2003).

The use of both types of measures is generally recommended for research

purposes (Cazzola et al 2008, Curtis and Patrick 2003).

4.3.1 Generic measures

Generic measures include health status measures which assess many important

aspects of HRQL and utility or preference-based measures, which rank the

preferences of patients for treatment process and outcome. Utility measures

summarise HRQL as a single number (health state) along a continuum,

commonly from 0.0 representing death to 1.0 representing full health or an


asymptomatic condition where physical and social activity are optimal and

mobility is not limited (Jones and Kaplan 2003, Mahler 2000). Utility weights may

then be applied to obtain an index (utility score) of the strength of an individual‟s

preference for this health state compared with full health and death (Hawthorne

et al 2001). Utility scores may be used for cost-benefit analyses (Jones 2005,

Mahler 2000), for example, when expressed as quality-adjusted life years

(QALY‟s) to reflect survival in terms of quality of that survival (Curtis and Patrick

2003).

As generic instruments assess a diversity of issues and provide standardised

health scores, they have the additional advantages of allowing comparisons to be

made between subjects, across widely disparate patient and study populations or

medical interventions (Curtis and Patrick 2003) and between study samples and

population norms (Hawthorne and Osborne 2005). It has been suggested that

they may provide a better overall assessment, thus revealing unexpected impacts

of treatment which are not closely related to respiratory health (Curtis and Patrick

2003). However, they may be less sensitive to small changes in response to an

intervention (Guyatt et al 1993, Mahler 2000).

The Quality of Well Being Index (Kaplan et al 1984) was one of the earliest utility

measures developed and has been used in COPD research. Examples of other

generic instruments which have been used in this population include the Medical

Outcomes Study Short-form 36 Item (SF-36) questionnaire (Ware and

Sherbourne 1992), the Sickness Impact Profile (Bergner et al 1981) and the

Nottingham Health Profile (Hunt et al 1986).

The generic HRQL instrument chosen for use in this research was the

Assessment of Quality of Life (AQoL) utility instrument, (Hawthorne et al 2001,

Hawthorne et al 1999). This instrument is a multi-attribute utility instrument,

designed to evaluate health care interventions in public health and acute settings.

The AQoL was developed using a time trade-off method and was based upon the

preferences of an Australian population. It was therefore considered to be

uniquely suitable for use in this research. Validity and sensitivity have been

demonstrated in relation to other HRQL instruments (Hawthorne et al 2001). The

instrument consists of 15 questions which measure five dimensions: illness,

independent living, social relationships, physical senses and psychological

wellbeing. Each dimension has three items (questions) for which the respondent


chooses from one of four answers. Items are scored from zero to three (range

zero to nine per dimension or zero to 45 for total score), with a lower score

representing a “better” quality of life. The AQoL may be used as a profile health

status measure in which each dimension is reported separately (Hawthorne and

Osborne 2005). However, it is most commonly used as a utility measure in which

scores range from 1.00 (best health state) to -0.04 (state worse than death)

where 0.00 is a death-equivalent state.

The AQoL has been used in a variety of settings including studies of outcomes

after stroke, influenza and co-ordinated care programs and the use of cochlear

implants (Osborne et al 2003). Further work has been published regarding

population norms and the MID in scores has been estimated to be 0.06 utility

points (95% confidence interval 0.03-0.08) (Hawthorne and Osborne 2005).

Two versions of the AQoL have been devised, Version 1A which was designed to

be self-administered with all items written in the first person (Hawthorne et al

1999) and Version 1B which was designed to be interviewer-administered and is

presented in the third person (Appendix III). In Version 1B, written, standardised

cues are provided in italics for the interviewer, should the respondent ask for

clarification of an item. An additional reason for choosing this generic measure of

HRQL for use in this research was its availability in an interviewer-administered

version. The questionnaire relates to recall over the previous week and takes

approximately eight minutes to complete.

4.3.2 Disease specific measures

Generic measures provide valuable information regarding HRQL across

populations but may be less sensitive to change within specific patient groups.

Disease specific measures have been developed to address this issue by

including only those aspects of HRQL which are important and relevant to the

patient group being studied (Curtis and Patrick 2003, Guyatt et al 1993, Jones et

al 1991, Mahler 2000).

Two of the most commonly used and well-recognised COPD specific measures

are the CRQ (Guyatt et al 1987) and The St George‟s Respiratory Questionnaire

(Jones et al 1992). The St George‟s Respiratory Questionnaire is a 76 item, self-

administered questionnaire and comprises questions regarding symptoms over

the previous year and current symptoms, medications and activities. The number


of response options per question varies from two to five and responses are

weighted. Three component scores (symptoms, activity and impact upon daily

life) and a total score are calculated by summing the weighted scores from each

response (maximum possible 3989.4 units), dividing the summed weights by the

maximum score for that component and expressing the result as a percentage

(0% = best possible score) (Jones 2002). .

The CRQ was the first quality of life measure developed specifically for COPD

and was designed to be an evaluative instrument (Curtis and Patrick 2003, Singh

et al 2001b). It was initially designed as an interviewer-administered instrument,

which has been shown to be valid, reliable (Guyatt et al 1989, Guyatt et al 1987,

Wijkstra et al 1994) and responsive (Guyatt et al 1989, Guyatt et al 1987, Harper

et al 1997, Mahler et al 1998). A self-administered version has since been

developed and validated against the original (Schunemann et al 2005a).

The CRQ is comprised of 20 items, scored from one to seven, on a seven-point

Likert scale and includes four domains, dyspnoea (described above), fatigue,

emotional function and mastery (sense of control over the disease). The fatigue

and mastery domains each have four items and emotional function has seven

items which rate energy levels, frustration, depression, anxiety, fear and panic

with dyspnoea. Scores are summed for each domain and to provide a total score

and the MID in scores has been determined to be 0.5 units per item (Table 4.7).

Furthermore, it is suggested that a change in score of approximately 1.0 unit per

item represents a moderate clinical effect and of more than 1.0 unit per item, a

large clinical effect (Guyatt et al 1993, Jaeschke et al 1989). The questionnaire

relates to recall over the previous two weeks and takes approximately 20 minutes

to complete on the first occasion and approximately 10 minutes subsequently

(Curtis and Patrick 2003).


Table 4.7 Chronic Respiratory Disease Questionnaire (CRQ) dimension scores

the minimal important difference (MID) in scores (Jaeschke et al 1989).

Domain

Number of items

(questions)

Range of scores

MID

dyspnoea 5 5-35 2.5

fatigue 4 4-28 2.0

emotional function 7 7-49 3.5

mastery 4 4-28 2.0

total score 20 20-140 10

It was elected to use the CRQ for this research (Appendix IV). The St George‟s

Respiratory Questionnaire is also well-supported (Cazzola et al 2008, Curtis and

Patrick 2003). However, the CRQ has the further advantages of having an

interviewer-administered version, being less complex to administer and score,

and encompassing a domain for specific measurement of dyspnoea.

4.4 Mood disturbance

Psychosocial and mood disturbances, particularly anxiety and depression, are

more prevalent in COPD than in general populations (Brenes 2003, Kim et al

2000, Lacasse et al 2001). Many questionnaires assessing mood status are

heavily biased towards levels of activity and somatic factors such as energy

levels, sleep and eating patterns (American Thoracic Society 1999b). Such

questionnaires are unsuitable for assessment of mood disturbance in COPD as

these factors may be physical indicators of the underlying disease process and

are therefore more likely to return false positive results (Hermann 1997). It is

therefore recommended that assessment of anxiety and depression in these

patients should be performed using questionnaires which rely primarily on

cognitive changes rather than physical indicators of psychological distress

(American Thoracic Society 1999b).

The Hospital Depression and Anxiety scale (HAD) (Zigmund and Snaith 1983)

was chosen for use in this research for this reason and its additional advantages


of ease of administration and scoring (Appendix V). It has been demonstrated to

be a reliable and valid measure for assessing clinically significant anxiety and

depression in general medical outpatients (Hermann 1997, Zigmund and Snaith

1983) and has been commonly used in chronic lung disease (American Thoracic

Society 1999b), particularly COPD. It has been translated (from English) into a

number of languages and further validated and extensively used in its translated

versions (Hermann 1997). The scale has been shown to be sensitive to change

in disease states and to be responsive to interventions whilst not over-

responsive to transient fluctuations (Hermann 1997). It is considered appropriate

for use in an outpatient setting in chronic disease as severe psychopathological

symptoms are not included, thus making the scale more sensitive to milder forms

of psychiatric disorder by avoiding a “floor effect” (Hermann 1997).

The scale is self-administered, can be completed in two to six minutes, and

consists of 14 questions, seven each (alternating) to score depression and

anxiety. Questions are scored on a four-point scale from zero to three (range of

zero to 21 for each dimension) with higher scores representing more severe

symptoms. Participants are asked to underline the response which best

describes their feelings over the previous week. The scale may be used as a

single measure of emotional distress or as a two-dimensional instrument, given

that anxiety and depression have differing clinical characteristics (Johnston et al

2000). The latter approach was used for this research.

The issue of placement of the HAD within a series of questionnaires has been

raised by some authors with the suggestion that HAD scores may be higher if the

questionnaire is administered after other questionnaires relating to distressing

issues rather than before (Johnston et al 2000). For this reason, all assessments

were administered in the same sequence in the main study of this research

(Chapter 8).

A difference in scores representing the MID has not been determined. However,

Zigmond and Snaith (1983) proposed that a score of seven or eight represents

possible anxiety or depression and 10 or 11 represents probable anxiety or

depression. On this basis, it is proposed that a score of ≥10 in either dimension

represents symptoms of clinical significance (Johnston et al 2000).


4.5 Functional status

Functional status refers to the extent to which behaviours and activities normally

undertaken in the course of daily life can be performed (Leidy and Haase 1996).

Functional status has been further defined using a multidimensional model

(Figure 4.1) compromising functional capacity (maximal potential) and functional

performance (activities chosen to perform). The model also defines functional

reserve (the difference between capacity and performance) and capacity

utilisation (the extent to which functional capacity is called upon (Leidy 1994,

Leidy and Haase 1996, ZuWallack 2003).

Figure 4.1 Model of functional status (ZuWallack 2003, p 230).

Instruments designed to broadly assess overall functional status exist, for

example, the Functional Status and Dyspnoea Questionnaire, which relates to

episodes of severe breathlessness over the previous month (Lareau et al 1998).

However, the sensitivity of such instruments is questionable (British Thoracic

Society 2001). In addition, functional performance and/or functional capacity may

change within an individual, independently of one another (Drummond and Wise

2007, Leidy 1994). For these reasons, both of these dimensions of functional

status should be examined when assessing the effects of an intervention upon

functional status. This is achieved by using surrogate markers of functional

status, with tests of exercise capacity as indicators of functional capacity and

Functional reserve

Influenced by symptoms, particularly dyspnoea and

fatigue in COPD

Functional capacity

Functional performance

Functional capacity utilisation


physical activity measures as markers of functional performance (British Thoracic

Society 2001). Factors relating to functional performance are also included in

disease specific HRQL measures (British Thoracic Society 2001).

4.5.1 Exercise capacity

Functional or exercise capacity has been defined as the activity level which is

achievable but not able to be maintained (Leidy 1995, ZuWallack 2003). It has

long been evaluated in young, healthy individuals by means of timed or maximal

exercise testing (Steele 1996). As patients with chronic lung disease often

present with reduced exercise tolerance, objective tests of exercise capacity have

gained popularity in recent decades as a means of assessing response to

therapeutic interventions in this population.

Laboratory-based, maximal exercise tests, using progressive, incremental

protocols performed on a cycle ergometer or treadmill, remain the gold standard

tests of exercise capacity (Steele 1996, Turner et al 2004). Cardiac and

ventilatory parameters are monitored, enabling measurement of maximal aerobic

capacity and comparisons with predicted values. Such tests may also be of

diagnostic value, differentiating between cardiac and pulmonary limitation to

exercise (Steele 1996). The disadvantage of these laboratory-based tests is that

they are expensive and may be difficult to access (Steele 1996).

Field walking tests have, more recently, gained wide acceptance as valid,

practical alternatives due to being relatively simple and requiring less technical

expertise and equipment (American Thoracic Society 1999b, British Thoracic

Society 2001, Solway et al 2001, Steele 1996, Troosters 2005). As they measure

an activity performed as part of daily living, field walking tests have the additional

advantage of evaluating more functional aspects of exercise capacity (Carter et al

2003, Enright et al 2003, Solway et al 2001).

Fixed-time field walking tests, measuring the maximal distance walked during a

specified time, have been derived from the twelve minute running test of Kenneth

Cooper, the American fitness enthusiast (Cooper 1968). The twelve minute

running test was developed for assessment of physical fitness in healthy

individuals and was shown to correlate well with maximal oxygen uptake

measured on a treadmill (Cooper 1968). The first walking test to be used in

clinical practice was the twelve minute walking test, which was shown to be


reproducible and to correlate well with maximum oxygen uptake and ventilation

achieved during maximal, incremental ergometer cycle testing chronic bronchitis

(McGavin et al 1976).

Subsequently, the use of two, six and twelve minute walking tests was compared

to explore the use of shorter, less exhausting walking tests (Butland et al 1982).

All three tests were found to be highly reproducible and correlated well with one

another, but it was concluded that shorter tests may be less discriminatory

(Butland et al 1982). A test of six minutes‟ duration was recommended as a

“sensible compromise” (Butland et al 1982, p 1608) and the 6MWT remains one

of the most commonly used measures of exercise capacity in chronic lung

disease (American Thoracic Society 2002, Carter et al 2003, de Torres et al

2002, Stevens et al 1999, Turner et al 2004). .

Studies have shown the 6MWD to be reliable and valid for use in patients with

COPD when compared with other relevant measures (Solway et al 2001),

including cycle ergometry (Bernstein et al 1994, Guyatt et al 1985, Wijkstra et al

1994) and the 12 minute walk test (Butland et al 1982). It has also been shown

to be responsive to change in COPD (Bernstein et al 1994, Guyatt et al 1984).

Another commonly used clinical test of exercise capacity which was developed

for use in COPD is the incremental shuttle walk test (ISWT) (Singh et al 1992).

This test is based upon the twenty metre shuttle run test, used to assess exercise

capacity in normal populations (Leger and Lambert 1982). In contrast to the

fixed-time 6MWT which allows self-pacing and resting if required, the shuttle walk

test is externally-paced and requires an incremental increase in walking speed.

Speed is increased every minute by 0.17 milliseconds and is indicated by audio

signals played from a cassette or compact disc. Twelve increments or levels of

speed have been included to accommodate patients with a wide range of

function. The test is conducted along a 10 metre course and the test is

terminated when the participant is unable to maintain the required speed (Singh

et al 1992). Whilst the properties of the ISWT have been less extensively

examined than those of the 6MWT (Solway et al 2001), it has been shown to

correlate with both 6MWD (Singh et al 1992) and incremental treadmill exercise

testing (Singh et al 1994). Repeatability has been demonstrated after one

practice walk in COPD (Revill et al 1999) and it has been demonstrated that the

MID for the ISWT is 47.5 metres (Singh et al 2008).


It has previously been accepted that both the 6MWT and the ISWT are sub-

maximal in nature (American Thoracic Society 2002, Steele 1996) and that the

ISWT provides greater cardiopulmonary stress due to being externally paced

(Steele 1996). However, strong correlations have been demonstrated between

ISWT distance and maximal oxygen uptake (VO2max) measured on treadmill

testing (Singh et al 1994) and moderately strong correlations between 6MWD,

VO2max and maximal work capacity measured during cycle ergometry

(Bernstein et al 1994, Guyatt et al 1985, Wijkstra et al 1994). In addition, it has

been demonstrated that the 6MWD, the ISWT and incremental cycle ergometer

testing elicit similar peak heart rate and dyspnoea levels and that peak VO2

achieved on cycle ergometer testing has been strongly correlated with distance

achieved in both tests (Turner et al 2004). Thus, it is now suggested that both

field walking tests can challenge patients to similar levels of cardiovascular and

respiratory stress to that achieved with incremental cycle ergometer testing

(Turner et al 2004).

The 6MWT was chosen to measure functional exercise capacity in this research

(Chapter 8) for a number of reasons. Firstly, due relative ease of administration,

requiring less equipment than the ISWT and being less complex for participants

to understand, it was considered to be the more practical of the two tests.

Secondly, it was deemed to better reflect activities of daily living due to it being

self-paced (Solway et al 2001) and of a duration which is comparable to that of

many activities of daily living which require exertion (Steele 1996).

With regard to interpretation of 6MWT results, it has been widely accepted that

the MID for 6MWD scores is 54 metres (Redelmeier et al 1997). However, others

have proposed that percentage of predicted values would be a more appropriate

measure of MID for 6MWD, as a single figure may not be representative of the

MID across a range of disease severity and that (Solway et al 2001). A recent

analysis of pooled data from nine prospective studies suggested a significant

change was 35 metres or about 10% change from baseline 6MWD (Puhan et al

2008), whilst another recent study suggested a MID of 25 metres and found this

absolute change to be a more sensitive indicator than percentage change from

baseline (Holland et al 2010). Normal values for the 6MWT have been

investigated in healthy adults (Camarri et al 2006, Enright and Sherrill 1998,

Troosters et al 2002a) but such values are yet to be established in COPD.


A criticism of the 6MWT has been lack of standardisation in its administration

(Troosters et al 2002a). Whilst a comprehensive guideline document to address

this issue has been published (American Thoracic Society 2002), a few issues

remain unresolved. Firstly, there is no consensus regarding optimal track length.

This is an important factor as additional effort and time are required to achieve a

given distance on a shorter track due to a greater number of turns (Scurbia et al

2003). The guideline document recommends a track length of 100 feet (30

metres) on the basis that this has been used in the majority of studies (American

Thoracic Society 2002) but provides no further evidence for this recommendation.

Nonetheless, there is some evidence to suggest that track length does not affect

outcome, provided a minimum length of 50 feet (15.2 metres) is used (Scurbia et

al 2003). This proposal is based upon retrospective comparisons of 6MWD

measured across 14 centres as part of a multicentre trial. Bivariate and

multivariate analyses adjusting for age, sex, height and FEV1 %predicted found

no significant difference in mean 6MWD using tracks ranging in length from 50 to

164 feet (15.2 to 50 metres) (Scurbia et al 2003). The main study of this thesis

(Chapter 8) was conducted across two study sites. In order to address this issue

and provide consistency and comparable results, a 25 metre track was used at

both cites, this being the longest track available at both.

Secondly, a learning effect with repeated testing has been demonstrated by a

number of authors, raising the question of the need for practice tests. An

increase 6MWD has been reported with a second test (Gibbons et al 2001,

Troosters et al 2002a), and over three consecutive days and four consecutive

months (Butland et al 1982, Knox et al 1988). The American Thoracic Society

guideline document (American Thoracic Society 2002) suggests that a practice

walk is not usually necessary, but should be considered. Others have

recommended one practice walk (Troosters et al 2002a), two practice walks

(Guyatt et al 1984, Solway et al 2001) and at least five practice walks (Knox et al

1988). In this research (Chapter 8), two test walks were required at each

assessment (one each breathing cylinder air and cylinder oxygen). Therefore, it

was elected to use one practice walk (a total of three walks) in order to control for

learning effects, and limit fatigue.

Thirdly, there is also no consensus with regard to duration of rest time between

tests when more than one test is to be performed. A variety of approaches have

been reported, including 15 minutes or until heart rate returns to normal (Poulain


et al 2003), 20 minutes (Guyatt et al 1984), 30 minutes (Gibbons et al 2001,

Turner et al 2004), 30 minutes or until heart rate returned to normal (Steffen et al

2002) or repeating tests on separate days (Butland et al 1982, Redelmeier et al

1997, Roomi et al 1998, Stevens et al 1999). The guideline document (American

Thoracic Society 2002) suggests that a 10 minute rest should take place prior to

commencement of the first test. Other work suggests that this is sufficient time

for the physiological effects of breathing a study gas to occur (Alvisi et al 2003).

In this research, it was elected to allow at least a 10 minute rest period and

sufficient time for return to stable baseline measures prior to and between walks.

Standardisation of encouragement during tests is a further important factor for

consideration (Steffen et al 2002). An improvement of 30.5 metres in scores has

been demonstrated with the provision of encouraging phrases at 30 second

intervals compared with no encouragement (Guyatt et al 1984). The guideline

document (American Thoracic Society 2002), which specifies scripted

encouragement and statement of time remaining at one minute intervals, was

followed in this research. In addition, the instructions for performance of the

tests, based upon these guidelines, were read to all participants at each

assessment time (Appendix VI).

In conclusion, 6MWD was used in this research to assess functional capacity due

to its practicality, likely responsiveness to change and relative simplicity.

Standardised instructions and encouragement were provided, which were based

upon published guidelines (American Thoracic Society 2002). Other aspects of

the test protocol used are described in Section 8.4.6.

4.5.2 Physical activity

Functional performance or physical activity is defined as voluntary, free-living

movement, produced by the skeletal muscles, resulting in energy expenditure

and includes exercise, sport, recreation, occupational activity and household

tasks (Belza et al 2001, Shephard 2003, Steele et al 2000, Vanhees et al 2005).

Exercise is considered a subset of physical activity, defined as structured,

deliberately performed activity, with a specific aim such as preparation for athletic

competition or sport, or improvement or maintenance of some aspect of health

(Shephard 2003, Steele et al 2003a).


Interest in practical, inexpensive tools with which to measure physical activity has

evolved with advances in technology and in response to the needs of both

healthy and clinical populations. Inactivity is a known major risk factor for a

number of illnesses resulting in recommendations promoting regular physical

activity, particularly walking, in general populations. Examples include the

recommendations of taking 10,000 steps per day for prevention of cardiovascular

disease (Hatano 1993) and walking 2,000 to 2,500 extra steps per day to control

weight (Hill et al 2003). In pulmonary disease, the relationship between

dyspnoea, inactivity and functional decline is well recognised (Steele et al 2000).

As inactivity is both a cause and an effect of declining function in COPD (Belza et

al 2001) the assessment of physical activity is important when evaluating the

effects of interventions in this population.

Physical activity may be quantified in four ways, by direct observation, calculation

of energy expenditure, objectively using motion sensors and subjectively, using

self-report measures (Pitta et al 2006a, Tudor-Locke and Myers 2001b). Direct

observation involves watching or videotaping by observers and although it may

be regarded as the gold standard (Vanhees et al 2005), is intrusive, time-

consuming and impractical in a free-living setting (Steele et al 2000). Methods

for quantifying energy expenditure, for example calorimetry and the double-

labelled water technique, are costly and less direct markers of physical activity

(Pitta et al 2006a, Tudor-Locke and Myers 2001b, Vanhees et al 2005). Of these

four methods, objective measurement using motion sensors and self-report

measures appear more practical for use in large research studies.

No accepted gold standard measurement tool exists for use in COPD populations

where practical, inexpensive methods are required on a large scale (Hill and

Goldstein 2007, Pitta et al 2006a, Shephard 2003, Vanhees et al 2005). For this

research it was elected to concurrently use one objective measurement tool, the

pedometer, and one subjective measurement tool, an Activity Diary. The

following sections discuss the rationale for tools selected. Chapter 5 describes a

pilot study for development of a relevant, practical diary for use and Chapter 6

further describes the two tools used for activity measurement in this research and

compares their use.


Objective measurement

Objective monitoring of physical activity is still a relatively new science and no

gold standard exists for its measurement under free-living conditions (Schneider

et al 2004). Body-worn motion sensors, capable of detecting body movement,

recording the number of steps taken over a period of time and estimating

distance covered and energy expenditure, have been developed for use in

research and general populations (Crouter et al 2003). There are two main types

of body-worn motion sensors, the accelerometer and the pedometer. Both have

been used to measure free-living physical activity in a variety of populations (Le

Masurier et al 2004, Steele et al 2003a, Tudor-Locke and Myers 2001a, Tudor-

Locke et al 2002, Tudor-Locke et al 2004b, Vanhees et al 2005).

The accelerometer is the more complex of the two devices and electronically

measures accelerations or changes in velocity over time which are produced as a

specific body segment or limb part moves (Bjornson and Belza 2004).

Accelerations are detected and converted into digital signals by piezoelectric

transducers and microprocessors (Vanhees et al 2005). Signals are downloaded

into computer software and recorded as events or steps (Bjornson and Belza

2004) which may be analysed to determine frequency, intensity and duration of

activity (Bjornson and Belza 2004, Tudor-Locke and Myers 2001b, Vanhees et al

2005). Accelerometers have been designed to detect movement in a single,

vertical plane (uniaxial) or in two or three dimensions (bi- or triaxial

accelerometers (Bjornson and Belza 2004). Whilst accelerometers have

significant memory capacity and are recognised by some authors as the superior

method for assessing free-living activity (Le Masurier et al 2004, Pitta et al

2005a), cost and the additional technical expertise required often render them

impractical for use (Tudor-Locke and Myers 2001b).

The simple pedometer is a cheaper and less complex device (Pitta et al 2006a,

Steele et al 2003a, Tudor-Locke and Bassett 2004a, Vanhees et al 2005) which

is worn clipped to a belt or waist-band. The pedometer was originally a gear-

driven mechanical device, but newer pedometers are electronic, battery operated

and more accurate (Bassett et al 2000b, Bjornson and Belza 2004). The

pedometer contains a spring-suspended horizontal lever arm which responds to

vertical accelerations during walking (Bassett et al 2000b, Bjornson and Belza

2004, Schneider et al 2004). Movement of the lever closes an electrical circuit to

register events or steps, the sum of which is digitally displayed (Bjornson and


Belza 2004, Schneider et al 2004). An estimate of distance walked may be

derived by inputting average stride length and estimated energy expenditure

(kilocalories per minute, from an assumed value of energy consumption per step)

by inputting stride length, height and age (Bassett et al 2000b, Tudor-Locke and

Myers 2001a). The pedometer has generally performed well against other

objective tools for measuring activity including accelerometers and direct

observation under controlled conditions (Le Masurier et al 2004, Steele et al

2003a, Tudor-Locke and Myers 2001a, Tudor-Locke et al 2002, Tudor-Locke et

al 2004b).

The pedometer is regarded as an acceptably valid, accurate, low-cost monitoring

tool for use in clinical research (Bassett 2000a, Le Masurier et al 2004,

Schonhofer et al 1997, Steele et al 2003a, Tudor-Locke and Myers 2001b, Tudor-

Locke et al 2002, Tudor-Locke et al 2004b, Welk et al 2000) and is promoted as

the more practical of the two motion sensors (Le Masurier and Tudor-Locke

2003).

Very few studies have examined the use of motion sensors in COPD (Coronado

et al 2003, Pitta et al 2006a, Sandland et al 2005, Schonhofer et al 1997, Steele

et al 2003b). The only study reporting pedometer use in COPD found it to be

reliable over one month in 25 clinically stable patients (Schonhofer et al 1997). It

was also found to be sensitive to change after institution of nocturnal nasal

mechanical ventilation in 25 patients with chronic respiratory failure and a range

of respiratory diseases, including six patients with COPD (Schonhofer et al 1997).

It was elected to use a standard pedometer for objective measurement of daily

activity in this research due to its availability, simplicity, low cost, ease of use and

it having acceptable accuracy for step counting, consistent with the needs of this

research. Number of steps or pedometer count was used (rather than distance

or energy expenditure) in keeping with findings of greater accuracy in this

measure in pedometers (Crouter et al 2003) and the research objectives. The

pedometer used is further described and compared with a subjective, self-report

daily diary in Chapter 6.

Subjective measurement

Subjective, self-report methods for assessing physical activity are frequently used

in research settings due to their practical advantages (Pitta et al 2006a,


Shephard 2003, Speck and Looney 2006, Vanhees et al 2005). Self-report

instruments include retrospective recall questionnaires or surveys and diaries or

logs completed daily or more frequently (Pitta et al 2006a, Shephard 2003).

Questionnaires mostly assess general patterns of habitual, higher level activity

(Kriska and Caspersen 1997). They are of limited value in capturing

spontaneous, light to moderate intensity activity, particularly walking, which is

characteristic of COPD and other sedentary populations and are therefore

subject to floor effects (Karabulut et al 2005, Melanson et al 2004, Shephard

2003, Tudor-Locke and Myers 2001b). In addition, questionnaires rely on recall

over periods ranging from a week to a year or lifetime (Karabulut et al 2005,

Melanson et al 2004, Shephard 2003, Tudor-Locke and Myers 2001b), rendering

them less precise, less sensitive to change and subject to recall bias (Tudor-

Locke and Myers 2001b) particularly in elderly and cognitively impaired

populations such as those with COPD (Leisker et al 2004). Some questionnaires

used to assess physical activity include a combination of additional dimensions,

also limiting their precision (Leidy 1995).

Activity questionnaires which have been used in COPD include the Modified

Activity Recall Questionnaire which assesses activity recalled over a four day

period (Belza et al 2001), the Activity Self-Efficacy Questionnaire which relates to

perceived distances walked over a given time (Kaplan et al 1994, Steele et al

2003a), the Minnesota Leisure Time Physical Activity Questionnaire which

assesses frequency and intensity of activities performed over the previous month

(Taylor et al 1978) and the Nottingham Extended Activities of Daily Living scale

which rates activities over the previous week, chosen from a list of 22 items

(Lincoln and Gladman 1992).

It would be anticipated that a diary or log of activity, completed over a short time

frame, would be less subject to recall bias (Kriska and Caspersen 1997,

Shephard 2003) and better able to capture ubiquitous, low level activity. Despite

these potential advantages, very few daily activity diaries have been described in

the literature and only two have been found in publications assessing COPD

populations (Pitta et al 2005a, Singh and Morgan 2001a). The validity, reliability

and responsiveness of these instruments have also not been determined in a

COPD population.


With little information available regarding the use of either objective or subjective

monitoring of physical activity in COPD research, it was elected to use a daily

diary record as a subjective measure, concurrently with the pedometer. It was

believed that a daily diary would be more responsive than the generalised activity

questionnaires described above and therefore more appropriate for use in this

research. No activity diary validated for use in COPD was found in the literature,

so it was elected to develop a diary which would fulfill the needs of the research.

A pilot study conducted to develop the Activity Diary used is described in Chapter

4. The methodology for its use and comparisons of its results with those of the

pedometer are described in Chapter 5.

Duration of physical activity monitoring

The main aim of this research was to assess the effects of domiciliary ambulatory

oxygen provided for 12 weeks. Outcomes were to be assessed at baseline and

four and 12 weeks after receiving domiciliary cylinders (randomisation). It was

deemed that physical activity should be monitored for a seven-day time period at

each assessment time. This is consistent with recommendations found in the

literature, allowing for any day-of-the-week effects upon physical activity which

has been observed in adult and younger populations (Bassett et al 2000c,

Matthews et al 2002, Trost et al 2000, Tudor-Locke et al 2004b). Rather than

recording physical activity over the duration of the study period, and in keeping

with the study protocol, the two methods of assessing physical activity (activity

diary and pedometer) were used concurrently for three periods of seven

consecutive days, during baseline and just prior to the assessments at weeks

four and 12 of the intervention phase.

4.6 Summary

The primary structural and mechanical effects of COPD upon the lungs and its

secondary effects upon multiple organs often result in severe symptoms,

disability and handicap, impacting upon the ability of the individual to interact with

the environment (Jenkins 2000, Jones and Kaplan 2003). A number of

instruments are now available for quantifying the effects of COPD upon the

individual in terms of symptoms, particularly dyspnoea, HRQoL and functional

status. This chapter has provided a framework to define these concepts and to

categorise relevant outcome measures. Some outcome measures commonly


used in COPD populations, those chosen for use in this research and the

rationale for their choice were described.

A valid, reliable instrument for measurement of daily physical activity, which was

practical yet inexpensive, was required for the large study population examined in

this research. However, no such instrument was identified from the literature.

Chapter 5 outlines the procedures undertaken to develop a self-report activity

diary. Chapter 6 describes a study comparing data from the diary with that from

a simple pedometer.

Chapter 5: Activity measurement in COPD: Pilot of Activity Diary 111

Measure what can be measured, make measurable what cannot be measured. Gallileo Galilei (1569–1642)

Activity measurement in chronic obstructive pulmonary disease: pilot of an Activity Diary

5.1 Introduction ................................................................................... 111 5.2 Aims .............................................................................................. 111 5.3 Pilot 1 Method ............................................................................... 112 5.4 Pilot 1 Results ............................................................................... 113 5.5 Pilot 1 Conclusions ........................................................................ 114 5.6 Pilot 2 Method ............................................................................... 114 5.7 Pilot 2 Results ............................................................................... 115 5.8 Pilot 2 Conclusions ........................................................................ 116 5.9 Outcome of pilot studies ................................................................ 116

5.1 Introduction

No gold standard exists with which to measure free-living physical activity in

large-scale research in COPD. A diary of daily activity, completed over a short

time frame has the potential advantages of being less subject to recall bias, whilst

capturing the low-level activity which is typical of patients with moderate to severe

COPD. Despite these potential advantages, no such diary has been validated for

use in COPD populations and only two have been described in the literature

(Pitta, et al., 2005a; S. Singh & Morgan, 2001a). This chapter describes the pilot

studies of various activity diaries which were conducted in order to provide a

suitable diary for this research.

5.2 Aims

The aims of this pilot study of the activity diary were to:

1. design a diary suitable for use

2. test the diary for acceptability and relevance to potential study participants

3. determine the practicality of this method of data collection

4. assess the quality of the data which could be collected from the diary

5. determine a method by which diary data could be quantified.

5 Chapter


5.3 Pilot 1 Method

The first pilot activity diary was based upon that first described for use in a COPD

population (Singh and Morgan 2001a). It consisted of seven sheets of "A4" size

(29.5 cm x 21 cm), one for each consecutive 24 hour period, a cover page and an

instruction page (Appendix VII). Only written instructions were provided. Each

diary page contained ten rows relating to categories of activity (McMurray et al

1998, Singh and Morgan 2001a) and five columns relating to time periods over

24 hours (McMurray et al 1998) (Table 5.1). In the study reported by Singh et al

(2001a), participants were requested to record change in activity to the nearest

minute. It was elected to include columns representing time periods (McMurray

et al 1998) to prompt completion of the diary and recall of activities. Subjects

were asked to fill in the actual time which each of the time periods represented,

for example, waking to breakfast - 6.00 to 9.30 am and to record the duration of

activities performed to the nearest minute in the box provided, as described

previously (Singh and Morgan 2001a).

Table 5.1 Daily time periods and activity categories for first pilot activity diary

Time periods

Activity categories

1 waking to breakfast

2 breakfast to

lunchtime

3 lunch to dinner time

4 dinner to bedtime

5 bedtime to waking.

1 lying

2 sitting, for example reading, watching television

3 sitting activity, eg. performing a seated exercise program

4 standing

5 standing activity, eg. preparing meals, performing an

exercise program

6 personal, for example showering, cleaning

7 walking (slow/intermittent)

8 walking (brisk/for exercise)

9 driving

10 comments

11 outings, that is total time spent outside the home for that

day

With two exceptions, the activity categories used for the first pilot study were

identical to those previously used to examine the ability of an accelerometer to

discriminate between different activities of daily living in COPD (Singh and


Morgan 2001a). One category was omitted from the previous version (shopping)

and a category recording outings, defined as time spent outside the home, was

included. This measure of behaviour has been proposed as a simple but useful

indicator for monitoring progress in COPD populations, sensitive to change and

able to be reliably collected over a number of years (Donaldson et al 2005).

Whilst acknowledged that time spent outside a person‟s home may be spent

indoors elsewhere, there is evidence that this measure is responsive to transient

events (for example, exacerbations) and has an influence upon HRQL

(Donaldson et al 2005). A further addition to the questionnaire was the request

that subjects who were using domiciliary oxygen cylinders indicate activities

during which the cylinders were used with a tick (√).

Participants in the pilot study were also provided with a covering letter and

questionnaire about aspects of the diary` (Appendix VIII). Participants were

primarily recruited from a Respiratory Support Group in the Melbourne

metropolitan area, with one additional participant of a similar age group to that

anticipated to take part in the main study recruited from the general community.

5.4 Pilot 1 Results

Seven participants (six females) with ages ranging from 60 to 82 years took part

in the first pilot study. All with the exception of one had a diagnosis of chronic

lung disease and had completed a pulmonary rehabilitation course. Diagnoses

included asthma (two participants), COPD (two participants), bronchiectasis (two

participants). One participant had been prescribed long term oxygen therapy and

was using portable cylinders for exertion. Six participants returned their diary

sheets and questionnaires; the seventh package of diary sheets was initially

mislaid, was not completed and ultimately not returned as that participant

subsequently died.

Of the six participants who returned diary sheets, all had attempted to complete

all sheets and had completed at least part of the questionnaire. Four participants

had dated every diary sheet. Only one participant had specified the times at

which each time period started and finished across the top of the table, but two

other participants had filled in the times of each activity in such a way that the

time periods could be deduced. The data from the diaries of the two latter

participants was complete with each time period accounted for. Data from the


remaining four participants was incomplete, with many time periods being

unaccounted for. The participant who had been prescribed portable oxygen

placed a tick against exertional activities and many other activities, which was

interpreted as total oxygen usage (via concentrator and portable cylinders) rather

than cylinders alone. None of the participants completed the section for

recording time spent during outings.

The six participants who returned their diary sheets completed all or most of the

questions on the questionnaire. Five expressed difficulty in understanding how to

complete the diary. These five participants reported finding problems

distinguishing between the classifications of activities, for example, sitting and

sitting/activity, standing and standing/activity, walking/intermittent and

walking/brisk. No participants had further suggestions in relation to the design of

the diary, and all felt that the font size (11 point) was sufficiently large. None

reported that the diary had taken too long to complete each day, but two

expressed concerns with remembering the activities which had taken place

during each time period, particularly if the diary was not completed at the end of

each day. One expressed concerns regarding the accuracy of the information

she provided.

5.5 Pilot 1 Conclusions

It was concluded that first piloted activity diary was too complex and difficult for

participants to understand. Of particular concern were the difficulties in

understanding the activity classifications. In addition, the requirements regarding

recording of time periods and outings were not clear, resulting in a significant

amount of missing data.

As a result of these findings, the first diary piloted was abandoned and a second

activity diary was designed for assessment.

5.6 Pilot 2 Method

The second diary piloted was presented as seven sheets, one for each of seven

consecutive days (Appendix IX). Each sheet was "A4" size, printed on both

sides. On the front of the sheet were instructions for use and on the reverse side

was the table for data entry.


Activity categories were simplified, as it was thought this would make the diary

easier to complete, and enhance accuracy of the data. Across the top of the data

entry table were three activity categories, lying, sitting and standing. Down the

left hand side of the diary sheet were 18 rows representing hourly time periods

from 6.00 am to midnight, with three additional rows for midnight to 6.00 am and

one for total time spent during outings (outside the home and garden) for the day

and any comments. Subjects with oxygen cylinders were asked to indicate

usage by circling the activity or describing its use in a fourth column labelled

"other".

Instructions for completion of the diary sheets were again written only (Appendix

IX). Participants again received a covering letter and a questionnaire regarding

ease of diary use. The questionnaire was identical to that provided for Pilot 1, but

with the addition of one question as follows:

Participants were primarily recruited from the same respiratory support group as

for the first pilot study, with an additional participant of a similar age group

recruited from the general community.

5.7 Pilot 2 Results

Eight participants (three females) with ages ranging from 60 to 82 years

participated in the second pilot study of the activity diary. Seven had been

diagnosed with chronic lung disease and six had completed a pulmonary

rehabilitation course. Diagnoses included COPD (four participants),

bronchiectasis (two participants) and asthma (one participant).

All eight subjects who agreed to participate in the study completed and returned

their diary sheets and questionnaires. Diary sheets were filled in for every hour

by six participants. However there were six hours of missing data in one case

and three hours of missing data in another. Outings were recorded as requested

by six participants.

One participant expressed difficulty understanding how to complete the diary,

which she felt was related to her diagnosis of early Alzheimer‟s disease. Despite

“Should the diary consist of seven separate sheets, or should the sheets

be joined into one document?”


the remaining seven participants reporting no difficulties in understanding the

requirements for using the diary, only two participants filled in the activity/ies

performed in every time period, as requested. Common difficulties were

recording only one activity for every one hour period (four participants) and the

use of a tick or the description of an activity rather than providing the duration of

time for which a type of activity (lying, sitting or standing) was performed for that

hour.

No participants had further suggestions in relation to the design of the diary, and

all felt that the font size (11) was sufficiently large. None reported that the diary

had taken too long to complete each day, but two expressed concerns in

remembering the activities which had taken place during each time period (one of

these two being the participant who had been diagnosed with Alzheimer‟s

disease). In answer to the question regarding a preference for seven separate

sheets or one document for seven days of diary data, four participants preferred

the seven diary sheets to remain separate, one would have preferred a single

document and the remainder expressed no preference.

5.8 Pilot 2 Conclusions

It was concluded that the broader categories of activities were easier for

participants to understand. However, it appeared that written instructions alone

were insufficient. It was concluded that an example of a correctly completed

diary sheet should be provided, in addition to specific verbal instructions with

regard to the following:

1. how to fill in the squares for each time period

2. how to record when portable cylinders were used

3. the need to record duration of outings (outside the house and garden)

4. guidelines as to when/how often each day the diaries should be filled in.

Positive outcomes of the pilot studies were that separate diary sheets for each

day were preferred and that the font size used was sufficiently large.

5.9 Outcome of pilot studies

The outcome of the pilot studies was identification of the need to develop a third

version of the activity diary. The third version was developed from that used in a


study of patients experiencing chronic pain (Follick et al 1984) which, since the

time of this pilot study, has been used in an adapted form in a COPD population

(Pitta et al 2005a).

The third version again used one diary sheet to cover 24 hours. Each sheet was

of “A3” size, folded in half, with instructions for use on the front sheet (Appendix

X, page 1). An example of a completed diary was also provided and the diary

data table covered both of the inside sheets (Appendix X). Four columns were

provided for the following activity categories: lying, sitting, standing/walking and

sleeping. A further column was provided for recording of portable cylinder use.

This diary was organised into rows representing half hour blocks. Participants

were instructed to complete their diaries at least three times over a 24 hour

period: at midday, 5 pm and prior to retiring for the evening. They were asked to

record the one activity which undertaken for the majority of each half hour block,

that is for 15 minutes or more, by placing a tick in the appropriate box. If

uncertain, they were requested to describe their activities for the half hour block.

Portable cylinder usage for 15 minutes or more during any half hour block was to

be recorded by placing a tick in the sixth column.

A record of total time of outings for the day (outside the house and garden) was

again requested. Additional data requested was the recording of times the

pedometer was put on and taken off each day. All participants received

standardised verbal instructions in addition to the written instructions provided on

each diary sheet. Emphasis was placed upon the need to:

1. fill in activity for every half hour time period

2. record when portable cylinders were used in the appropriate column

3. complete the diary at least three times per day

4. record duration of outings (outside the house and garden)

5. record the time the pedometer was put on in the morning and removed at

night.

Analysis of the data provided by the diaries was also based upon the method of

Follick et al (1984). Ticks recorded for each of the four activity categories were

summed on each diary sheet with each tick accorded a value of 0.5 units (total =

24 units.) Similarly, the ticks denoting use of portable cylinders and hours

recorded for outings were also summed.


This third version of the Activity Diary (Appendix X) was used for the main study

of this research (Chapter 8). An assessment of diaries completed by the first 10

study participants indicated that no difficulties were experienced with their use,

either during the run-in phase or the intervention phase when records of cylinder

use data were also requested. The analysis of the Activity Diary data is further

described and compared with that of pedometer data in Chapter 6, the next

chapter of this thesis.

Chapter 6: Comparison of pedometer and activity diary in COPD 119

An experiment is a question which science poses to Nature, and a measurement is the recording of Nature's answer. Max Planck (1949)

Comparison of pedometer and activity diary for measurement of physical activity in COPD

6.1 Introduction ................................................................................... 119 6.2 Aims .............................................................................................. 120 6.3 Method .......................................................................................... 120

6.3.1 Participants ...................................................................... 120 6.3.2 Procedure ........................................................................ 120 6.3.3 Data management ........................................................... 122

6.4 Results .......................................................................................... 122 6.5 Discussion ..................................................................................... 126 6.6 Conclusions................................................................................... 131

6.1 Introduction

A number of well-validated tools exist for measuring dyspnoea and HRQoL in

COPD populations (Celli et al 2004a). However, the optimal method for

measuring functional status is less clear. One dimension of functional status,

functional capacity, may be assessed by measuring exercise capacity. However,

no gold standard exists for measurement of the other dimension of functional

status which is functional performance or free-living physical activity. This

particularly applies to the needs in large-scale research settings in a COPD

population as was the case in this research project.

The potential advantages of measuring physical activity subjectively with a daily

diary and objectively with a simple pedometer have been discussed in Chapter 4.

Pilot studies to develop a suitable diary with which to measure physical activity in

a COPD population were described in Chapter 5. This chapter describes and

compares the concurrent use of an activity diary and a pedometer in a population

of patients with moderate to severe COPD and significant functional impairment

associated with exertional dyspnoea.

6 Chapter


6.2 Aims

The aims of this study were to 1) assess free-living physical activity in patients

with COPD by objective measurement using a simple pedometer and subjective

measurement using a self-report daily diary, 2) determine the strength of the

relationship between these two methods and 3) determine whether any baseline,

demographic characteristics were suggestive of a differential response.

6.3 Method

6.3.1 Participants

This was a prospective observational study. Included in the study were the first

80 subjects enrolled in the main study of domiciliary ambulatory oxygen (Chapter

8). Participants had a clinical diagnosis of COPD, moderate to severe

breathlessness, determined by Medical Research Council (MRC) dyspnoea score

of at least three (Table 4.4), (Bestall et al 1999) but were not severely

hypoxaemic at rest (resting PaO2 >55mmHg or 7.3kPa). Excluded were those

with severe locomotor disability or other condition significantly limiting activity.

6.3.2 Procedure

Physical activity was recorded for seven consecutive days using a pedometer

and an activity diary concurrently. Written and verbal instructions for the use of

both methods were provided at an initial visit to one of the study sites. Data were

collected between this and the subsequent visit day in order to eliminate activity

on an assessment day which was considered unlikely to be representative of

usual activity (Donaldson et al 2005). Telephone contact was made at the

beginning and end of the seven day assessment period.

The pedometer used was the Yamax Digiwalker SW-700 (Yamax Corporation,

Tokyo, Japan). Of the large number of commercially available pedometers, the

Yamax pedometer has received the most scientific attention and has consistently

been shown to be among the most accurate in several brand-comparison studies

of controlled and free-living conditions (Le Masurier et al 2004). It is suggested

that the precision of the Yamax pedometer may be due to a high quality control in

manufacturing as the Japanese industrial standards recommend a maximal

permissible rate of step miscounting of 0.3% or three steps in 1000 (Hatano

1993). This recommendation is less likely to be applied in other countries

(Crouter et al 2003).


The results of the first published brand-comparison study (Bassett et al 1996)

reported that the Yamax pedometer available at the time was the most accurate

for step counting of the five devices compared. More recent studies have

demonstrated the Yamax Digi-Walker SW-701 pedometer to be among the most

accurate and reliable when compared with nine others in controlled conditions

(Crouter et al 2003, Schneider et al 2003) and 12 others in free-living conditions

(Schneider et al 2004). This model differs from the one used in this research

project only in that it measures distance in miles rather than in meters. Additional

advantages of Yamax Digiwalker SW-700 were availability, low cost, a more

robust design of its clip and a plastic cover to reduce the likelihood of tampering

with or inadvertent resetting of the control buttons.

Participants were requested to attach the pedometer to a firm belt or waistband,

anterior to the hip, aligned with the patella, while dressed. The cumulative seven-

day reading was recorded by a study assessor at the subsequent study visit.

Each participant used the same pedometer for all three assessment periods to

reduce the likelihood of variability between devices as a source of error

(Schonhofer et al 1997, Steele et al 2003a).

Self reported activity was assessed using the method of Follick et al (Follick et al

1984) in combination with the findings of the pilot studies reported in Chapter 5.

Time spent performing four categories of activity: lying, sitting, standing/walking

and sleeping were recorded in 0.5 hour blocks over 24 hours (Appendix X).

Participants were instructed to complete this diary at least three times over a 24

hour period: at midday, 5 pm and prior to retiring for the evening. The activity

undertaken for the majority of each half hour block, that is, for 15 minutes or

more, was recorded by placing a tick in the appropriate box. In addition, total

daily hours of pedometer wear and outings (Donaldson et al 2005) were

recorded, the latter defined as travel beyond the boundary of their homes.

Missing diary data were completed at the subsequent assessment visit by

participant recall or by determination of the activity most commonly performed

over the other days of assessment for each 0.5 hour block. However, if greater

than three consecutive hours of diary data were missing, or if the pedometer was

reportedly worn on incorrect days, the participant was asked to repeat the seven

day assessment period. If either pedometer or diary data was again incomplete,

that participant‟s data were excluded from further analysis.


Pulmonary function tests were performed according to American Thoracic

Society guidelines (American Thoracic Society 1995c). Spirometry (flow-volume

curves) was performed using The SensorMedics Vmax Series. Predicted values

used were those of Knudson et al for spirometry (Knudson et al 1976) and Roca

et al for transfer factor of carbon monoxide (TLCO) (Roca et al 1990).

6.3.3 Data management

All data was entered into a specifically designed data base, data verification was

undertaken and data was analysed using the Statistical Package for Social

Sciences (Version 14.0, SPSS Inc, Chicago, USA). Comparisons of group

means were conducted using t-tests and strength of relationship was assessed

using the Pearson correlation coefficient. A one-way analysis of variance

(ANOVA) was used to assess for day of the week difference in standing/walking

time. A between-groups one-way analysis of covariance (ANCOVA) was used to

explore the effects of baseline characteristics (independent variables) upon the

relationship between pedometer count (dependent variable) and standing/walking

time (co-variate). The level of statistical significance was set at p <0.05.

6.4 Results

From a group of 80 participants, 76 complete data sets were analysed (Figure 2).

The four participants whose data were not included were all male, had a mean

age of 65.8 years, mean FEV1 of 31% predicted, FEV1/FVC of 30% and mean

PaO2 of 71.5 mmHg. There were 15 incomplete data sets initially. In 14 cases

(18%) the pedometer was worn for an incorrect number of days (<7 days by 6

participants, >7 days by 8 participants) and diary data was incomplete for four

participants (5%).


Figure 6.1 Flow of participants through the study

Demographic data of the 76 participants with complete data sets is summarised

in Table 6.1. Males outnumbered females (51:25), had significantly worse airflow

obstruction (FEV1/FVC%, p=0.035), a trend towards higher TLCO (p=0.051) but

did not differ significantly from females with regard to other demographic

measures. One participant (female) was a lifelong non-smoker and had a history

of asthma.

80 participants

1st attempt:

65 complete

15 initially incomplete: pedometer = 11

diary = 1 both = 3

2nd attempt:

11 complete

2 incomplete: pedometer = 1

diary = 1

2 withdrew consent

13 repeated

76 complete data sets

available for analysis


Table 6.1 Demographic data of included participants: mean (standard

deviation) and comparisons of means between males and females (t tests)

Total n = 76

Males n = 51

Females

n = 25

p value

Age (years)

71.1 (9.6)

72.4 (8.6)

68.5 (11.0)

0.096

FEV1 (litres) 1.34 (0.48) 1.78 (0.54) 1.06 (0.34) 0.330

FEV1 % predicted 46.3 (18.5) 43.5 (18.9) 51.8 (16.6) 0.066

FEV1 /FVC (%) 41.7 (13.1) 39.5 (12.8) 46.2 (12.8) 0.035

TLCO (ml/min/mmHg) 11.6 (4.1) 12.3 (4.28) 10.3 (3.6) 0.051

BMI (kg/m2) 28.2 (6.7) 27.7 (6.7) 29.0 (6.6) 0.425

PaO2 (mmHg) 72.7 (8.8) 72.2 (7.8) 73.6 (10.7) 0.535

FEV1, forced expiratory volume in one second; FVC, forced vital capacity; TLCO,

transfer factor for carbon monoxide; BMI, body mass index; PaO2, arterial partial

pressure of oxygen

Study results are summarised in Table 6.2. Mean pedometer count over seven

days was 23,129 (range 1,725 to 66,454 counts) and mean standing/walking time

was 35.5 hours (range 0.5 to 75 hours). There was a moderate, statistically

significant correlation between these measures (r=0.374, p=0.001). There were

also significant correlations between outings time and pedometer count and

outings time and standing/walking time for all participants. There was no

significant difference in standing/walking time over different days of the week

(p=0.25).


Table 6.2 Pedometer count and time spent for activity categories over seven

days (mean, standard error of the mean, SEM) and results of correlations

(Pearson coefficient, r value) between these measures.

Mean (SEM)

r value

p value

All participants n = 76

Pedometer count vs Standing/walking time (hours)

23,128.8 (1,959.5) 35.5 (1.9)

0.374

0.001

Pedometer count vs Sit + standing/walking time (hours)

98.9 (1.2)

0.236

0.04

Pedometer count vs Sleep time (hours)

57.0 (1.4)

0.001

0.99

Pedometer count vs Outings time (hours)

17.3 (1.2)

0.359

0.001

Standing/walking time (hours) vs Outings time (hours)

0.285

0.01

Males n = 51


23,406.2 (2,545.1) 34.3 (2.5)

0.357

0.010


100.3 (1.4)

0.279

0.047


56.9 (1.7)

0.035

0.808


17.3 (1.6)

0.336

0.016


0.277

0.049

Females n = 25


22,562.9 (2988.1) 38.1 (2.6)

0.456

0.022


96.2 (2.0)

0.127

0.544


57.4 (2.5)

-0.081

0.700


17.4 (1.5)

0.461

0.020


0.333

0.104

There was a stronger correlation between standing/walking time and pedometer

count in females than males (r=0.456 and 0.357 respectively) (Figure 3). There

was no significant gender difference for pedometer count (p=0.546) with 5% of

variance in pedometer count explained by gender. However, a significant gender


difference was found for standing/walking time (F [1,73] =12.24, p=0.001, partial

eta squared=0.144). Therefore, gender explained 14.4% of variance in

standing/walking time.

Figure 6.2 Correlations (Pearson coefficient) between standing/walking time

and pedometer activity count for seven days in males (n=51, r=0.456) and

females (n=25, r=0.357).

6.5 Discussion

This study demonstrated modest, statistically significant correlations between

activity measured by pedometer readings and diary records over seven days.

The findings suggest that, in patients with moderate to severe COPD, a diary or a

pedometer may adequately assess activity, but that a daily diary appears to be

completed more reliably.

Each method of assessing physical activity has known limitations which may

result in under or overestimation of activity levels. Despite the relative simplicity


of the pedometer, failure to use it as requested was reported by 14 participants

(18%) at the initial assessment (compared with 5% with incomplete initial diary

data). Problems included forgetting to wear the device (n=6) and wearing the

device in excess of seven days (n=8). These findings are consistent with those

of other studies reporting failure to adhere to instructions for pedometer use in

17% of patients with chronic respiratory failure (Schonhofer et al 1997). Similarly,

adherence difficulties with accelerometer use have been reported in 19% of

elderly subjects with COPD, including placement problems and technical issues

such as battery problems (Pitta et al 2006a).

A further limitation of the pedometer is potential loss of data due to the device

unknowingly falling off (Tudor-Locke and Myers 2001a) and battery failure or

dislodgement as a consequence of being dropped, problems which may also

occur with accelerometers (Pitta et al 2006a). In addition, duration of use is of

necessity self-reported as the device does not have time-sampling capabilities

(Bassett 2000a, Karabulut et al 2005, Pitta et al 2006a, Welk et al 2000). It was

elected to record a seven-day cumulative count as it was felt that daily recording

by participants would be too onerous. However, it is possible that adherence to

instructions for use may have improved if participants had been required to

record their pedometer data at the completion of use each day and this may also

have assisted in detecting device malfunction. Other authors have reported that

participants between 40 and 80 years of age may successfully record a total daily

count and reset the device (Tudor-Locke and Myers 2001a).

Memory capacity of the pedometer may also be a potential source of error when

recording a cumulative seven-day count as the capacity for the pedometer used

in this study is 99,999 counts. However, a review of 23 publications (Tudor-

Locke and Myers 2001a) suggested that normal values for activity counts range

between 6,000 to 8500 per day in healthy older adults and 3500 to 5500 in

individuals with disabilities or chronic diseases. The mean weekly activity count

for participants in this study (23,129 counts) is consistent with this estimation and

indicative that the memory capacity was unlikely to have been exceeded.

Pedometers have been reported to underestimate steps at very low walking

speeds (≤54 m/min or 2 mph), suggesting limited accuracy in frail populations or

those with shuffling gait (Bassett et al 1996, Crouter et al 2003, Cyarto et al 2004,

Le Masurier et al 2004, Le Masurier and Tudor-Locke 2003, Melanson et al 2004,


Steele et al 2003a, Tudor-Locke et al 2002). Pedometers may also under-predict

activity levels during more vigorous activities such as running, upper limb work,

strength training, cycling and using other fitness equipment (Bassett 2000a,

Shephard 2003, Steele et al 2003a, Welk et al 2000). However, these activities

are unlikely to have been a source of error in this study, being rarely performed in

sedentary populations (Tudor-Locke and Myers 2001b). Incorrect positioning of

the device, obesity or a loose waistband may prevent maintenance of the vertical

orientation of the device which is necessary for its function (Steele et al 2003a,

Tudor-Locke and Myers 2001a). Twenty-eight (37%) of participants in this study

were obese (BMI ≥30 kg/m2) which may have influenced results. Specific

instructions were provided to all participants regarding positioning of the device to

minimise this potential source of error, however it cannot be excluded.

In addition to steps taken, pedometers detect vertical motion at the waist as a

result of other activity, which may also be regarded as a source of

overestimation. However, in this study, pedometer data was interpreted as

“activity count” rather than step count, reflecting overall activity (Singh and

Morgan 2001a). This approach is consistent with that of other authors

(Schonhofer et al 1997) and with the aim in this study being to assess free-living

activity rather than distance walked or energy expenditure in absolute units. A

further potential source of overestimation of pedometer activity count is motorised

transport (Melanson et al 2004, Schonhofer et al 1997, Tudor-Locke and Myers

2001a). However, only minimal mean activity counts have been reported from

this source, ranging from 3.1 counts when traveling 6.4 k (Karabulut et al 2005)

to 15 counts when traveling 32.6 k (Le Masurier and Tudor-Locke 2003).

Motorised transport may in itself also be regarded as a form of activity in this

sedentary population.

Collection of pedometer data within the participants‟ homes was not possible and

participants were requested to carry the devices to and from assessment visits in

a container, provided to minimise jarring during transit as a source of erroneous

increase in activity count. The use of wheelchairs and electric scooters may also

be problematic (Steele et al 2003a) but only one participant in this study

frequently used a wheelchair and one occasionally used a motorized scooter,

both of which may also be regarded as forms of activity.


Self-report of activity also has known limitations including recall bias and other

misreporting of activity levels (Pitta et al 2006a, Pitta et al 2005a, Shephard 2003,

Tudor-Locke et al 2004b). Although a patient‟s perspective of activity levels is of

interest (Pitta et al 2006a), it may not be accurate. Follick‟s diary (Follick et al

1984) was chosen for use owing to its relevance to a COPD population, being the

less complex of the two previously used in COPD studies and requiring recall

over a relatively short time span. These factors were considered likely to

enhance completion of the diary over a period of days, as was the requirement

for this research. The other included nine activity categories, recorded to the

nearest minute and was used to confirm the ability of an accelerometer to

distinguish brisk walking from other low-level activity over 48 hours (Singh and

Morgan 2001a).

Follick‟s diary was initially reported to be reliable and valid for measurement of

activity in patients with chronic pain (Follick et al 1984). Patient diary records

were shown to correlate strongly with those of a spouse or carer in 20 subjects

over four periods of four hours (r =0.83 for lying time and 0.93 for

standing/walking time) and with measurement of lying time using a motion sensor

in eight subjects (r =0.94) (Follick et al 1984). When used by Pitta et al (2005a)

in a COPD population, poor agreement was found between self-report and both

an accelerometer (over one hour and 12 hours) and direct observation (over one

hour). However, in that study (Pitta et al 2005a), Follick‟s diary was adapted to

record the minutes spent in each of five activity categories including cycling which

may have compromised its accuracy.

Conversely, the approach of the present study of averaging activities performed

over 0.5 hour blocks, whilst having the advantage of simplicity, may also have

compromised accuracy of the data. In addition, it is possible that participants

found that completion of the diary at least three times per day for a seven day

period was onerous, contributing to misreporting. A seven day study period was

chosen to allow for possible day-of-the-week effects upon physical activity which

have been observed in other populations (Bassett et al 2000c, Gretebeck and

Montoye 1992, Matthews et al 2002, Trost et al 2000, Tudor-Locke et al 2005).

The finding in the present study of no significant day-of-the-week difference is

consistent with that of other COPD studies (Pitta et al 2005b, Sandland et al

2005, Steele et al 2000). This is an important finding as it suggests that

representative activity data may be collected over fewer than seven days, which


might improve adherence and accuracy of data collection for both self-report and

objective methods (Trost et al 2005).

The moderate, significant correlations demonstrated between mean time spent

outside the home and both pedometer count and standing/walking time are of

interest. In the present study, a mean outing time of 2.48 hours per day was

reported. This is consistent with a mean outing time of 2.74 hours per day found

in a similar COPD population (mean age 67.6 years, FEV1/FVC 44%) (Donaldson

et al 2005), adding support to the proposal that outing time is a useful indicator in

COPD populations.

It might be anticipated that the use of a combination of objective and self-report

methods may overcome the relative disadvantages of both methods and allow

physical activity to be interpreted from multiple perspectives (Tudor-Locke and

Myers 2001b). A review of 11 publications investigating this combined approach

in clinical and healthy populations which found variable correlations between self-

report and pedometer data with a median value of r =0.33, range 0.2 to 0.94

(Tudor-Locke et al 2002). Two further publications reported moderate

correlations between the two methods (Spearman‟s rho =0.607, r =0.43) (Speck

and Looney 2006, Stel et al 2004). Comparison of the results of the present

study and this range of findings may reflect a variety of self report methods used

but also supports the notion that the different methods may be assessing different

aspects of activity (Pitta et al 2005a, Schonhofer et al 1997).

This study also found a gender difference in self-reported activity, with females

reporting significantly greater standing/walking time but returning a slightly lower

mean pedometer count. Despite the increasing incidence of COPD in females

and evidence of greater disease severity and susceptibility to COPD in females,

this group is significantly underrepresented in COPD research. Indeed, males

outnumbered females by 2:1 in this study, possibly resulting in a type II error.

Some studies have suggested that after correcting for degree of airflow

obstruction, females with COPD have a poorer quality of life and experience

greater dyspnoea (de Torres et al 2005, de Torres et al 2006, Katsura et al

2007). It is possible that these factors may influence perceptions of activity and

result in over-reporting of activity levels in females. A further explanation may be

that the females in this study had a higher mean BMI. Although not significantly


different, this may have influenced the accuracy of the pedometer data, resulting

in it being under-reported.

6.6 Conclusions

Reliable, economical methods for assessing physical activity in sedentary

populations such as those with COPD are warranted. A variety of self-report and

objective methods are available, but few have been assessed in COPD

populations in free-living circumstances. This is the first study to assess the

combined use of a simple pedometer and activity diary in a large COPD

population. Findings indicate that the daily diary is the more reliably completed of

the two methods and that representative activity data may be collected over

fewer than seven consecutive days in this population. Inclusion of time spent

outside the home may be useful to explore in further research in this patient

population.

The activity diary used in our study appears to offer greater promise than the

pedometer as an inexpensive, practical assessment tool for measuring free-living

daily activity in a COPD population. Further investigation of these two methods is

required to determine their precision as discriminative, evaluative and predictive

tools.

Chapter 7: Acute effects of hyperoxia on ventilation and dyspnoea 133

The important thing in science is not so much to obtain new facts as to discover new ways of thinking about them. William Lawrence Bragg

Acute effects of hyperoxia on resting pattern of ventilation and dyspnoea in COPD.

7.1 Introduction ................................................................................... 133 7.2 Inspiratory capacity as a measure of hyperinflation ....................... 134

7.2.1 Background ..................................................................... 134 7.2.2 Measurement technique .................................................. 136 7.2.3 Baseline end expiratory lung volume ............................... 137 7.2.4 Technical acceptability ..................................................... 138 7.2.5 Validity of inspiratory capacity measurement ................... 139 7.2.6 Reproducibility of inspiratory capacity measurement ....... 140 7.2.7 Responsiveness of inspiratory capacity measurement ..... 141 7.2.8 Interpretation of inspiratory capacity values ..................... 141 7.2.9 Summary ......................................................................... 144

7.3 Ventilatory responses to hyperoxia in COPD ................................. 145 7.3.1 Responses during exercise .............................................. 145 7.3.2 Responses at rest ............................................................ 149 7.3.3 Variability in response to hyperoxia ................................. 150 7.3.4 Ventilatory response to hyperoxia: summary ................... 150

7.4 Study aims .................................................................................... 150 7.5 Materials and methods .................................................................. 151

7.5.1 Participants ...................................................................... 151 7.5.2 Study design .................................................................... 151 7.5.3 Procedures ...................................................................... 151 7.5.4 Analysis ........................................................................... 153

7.6 Results .......................................................................................... 153 7.6.1 Participants ...................................................................... 153 7.6.2 Response to hyperoxia .................................................... 154

7.7 Discussion ..................................................................................... 158

7.1 Introduction

Hyperoxia is defined as partial pressure of oxygen greater than that at sea level

(Cain 1987). Hyperoxia has been shown to improve exertional dyspnoea and

exercise performance in many patients with COPD, including some with

insignificant exertional desaturation (Cukier et al 2007, O'Donnell and

Laveneziana 2006c, Peters et al 2006). Whilst the mechanisms underlying these

improvements in exercise capacity and breathlessness are not fully understood, a

7 Chapter


significant contributing factor is believed to be an oxygen-induced reduction in

ventilatory demand, which allows for improved operational lung volumes by

slowing the onset of dynamic hyperinflation (Cooper 2006, O'Donnell and

Laveneziana 2006c). Previous studies suggest that this may occur in a dose-

dependent fashion, up to a fraction of inspired oxygen (FiO2) of 0.5 or a flow of 6

L/min of 100% oxygen delivered via nasal cannulae (Snider 2002, Somfay et al

2001).

The degree of volume response to hyperoxia at rest in COPD patients is unclear

and studies reporting this and other resting physiological responses are very few

in number, have examined small sample sizes and have reported contradictory

findings (Alvisi et al 2003, O'Donnell et al 1997a, O'Donnell and Laveneziana

2006c, Peters et al 2006). This chapter describes a study which aimed to assess

ventilatory and dyspnoea responses to hyperoxia at rest in a large group of

patients with COPD of varying disease severity. Pulmonary hyperinflation was

assessed by measuring inspiratory capacity (IC) spirometrically and the rationale

for using this method and the technique of measurement are also described.

It was anticipated that individuals would vary in their response to hyperoxia at

rest. In addition, it was anticipated that characterising those patients who did

demonstrated a response, particularly a pulmonary volume response, would be

possible by examining a large group of patients with COPD with a wide range of

disease severity. It was hypothesized that individuals responding acutely to

hyperoxia at rest might also be responders to domiciliary ambulatory oxygen. If

this were the case, assessment of ventilatory parameters at rest, including IC,

might be useful for prescribing domiciliary ambulatory oxygen in COPD patients

who do not qualify to receive it as part of COT.

7.2 Inspiratory capacity as a measure of hyperinflation

7.2.1 Background

The traditional method for measuring pulmonary hyperinflation has involved

calculation of total lung capacity (TLC), residual volume (RV) and functional

residual capacity (FRC) or end expiratory lung volume (EELV) (Figure 7.1) using

the complex and expensive body plethysmograph (Calverley and Koulouris 2005,

Duranti et al 2002). However, spirometric measurement of IC has gained

popularity over the past few decades as a valid, relatively simple alternative


(Duranti et al 2002, O'Donnell and Webb 1993, Pierce et al 2005). IC is defined

as the difference between TLC and EELV (Figure 7.1) or the maximal amount of

air which can be inhaled from EELV when taking a slow, full inspiration with no

hesitation (Miller et al 2005, Tantucci et al 2006). Thus, IC measurement

provides an indirect estimate of degree of lung hyperinflation (Miller et al 2005)

and a reduction in IC represents an increase in pulmonary hyperinflation

(O'Donnell and Webb 1993). Resting IC may be reliably measured using a

spirometer of the type commonly available in many respiratory laboratories

(Calverley and Koulouris 2005) and may also be reliably measured during

exercise using some computerised cardiopulmonary exercise systems (O'Donnell

et al 2009).

In COPD patients, IC measurement was initially used to demonstrate the role of

dynamic hyperinflation (DH) in exercise limitation (Calverley 2006, O'Donnell and

Webb 1993). By using serial measurement of IC, hyperoxia been shown to delay

the onset of dynamic hyperinflation during exercise in a number of studies (Alvisi

et al 2003, O'Donnell et al 1997a, O'Donnell and Laveneziana 2006c, Peters et al

2006, Somfay et al 2001, Stevenson and Calverley 2004). IC measurement has

also been used in many studies to assess the influence of various

pharmacological agents (bronchodilators) upon lung mechanics, and has

generally indicated that such medications can reduce degree of hyperinflation

(Calverley 2006). However, few studies have reported the use of IC

measurement to assess responses to these interventions at rest (Alvisi et al

2003, O'Donnell et al 1997a, O'Donnell et al 2001a, Peters et al 2006).


Figure 7.1 Lung volumes and subdivisions (Wanger et al 2005 p 512).

IRV, inspiratory reserve volume; VT, tidal volume; ERV, expiratory reserve

volume; IVC, inspiratory vital capacity; RV, residual volume; IC, inspiratory

capacity; FRC, functional residual capacity; TLC, total lung capacity.

7.2.2 Measurement technique

Various techniques for measuring IC have been reported in the literature,

reflecting recent interest in its use to assess degree of hyperinflation and a

growing availability of suitable equipment with which to measure it. Essentially,

the subject is instructed to take regular, relaxed breaths then to inspire deeply to

TLC, in a relaxed manner, except near end-inspiration (Miller et al 2005), where a

maximal effort is required (Somfay et al 2001) (Figure 7.2). No recognised,

standardised measurement technique exists, limiting comparability of studies

which have used this measure an outcome. Relatively recently and since

commencement of this research, some guidelines for spirometric measurement

of IC have been published (Miller et al 2005) but these are not comprehensive.

This section outlines important issues for consideration when measuring IC. The

measurement technique used in the studies of this thesis is described in Section

7.5.3.


Figure 7.2 Tracing of tidal breathing followed by an inspiratory manoeuvre from

functional residual capacity (FRC) or end expiratory lung volume to total lung

capacity (TLC) to record inspiratory capacity (IC) (Miller et al 2005, p 329).

EVC, expiratory vital capacity; RV, residual volume.

7.2.3 Baseline end expiratory lung volume

An accurate baseline value for EELV against which IC may be measured is

important (Dolmage and Goldstein 2002) and can be problematic as EELV is

dynamically regulated, including at rest. Various methods for establishing

baseline EELV have been described, including observation of several

reproducible readings of VT (Celli et al 2003), of four to six consistent end-

expiratory levels (Marin et al 2001) and observation of breathing pattern only

(O'Donnell and Webb 1993). Other authors have used the mean of the six

breaths preceding the IC prompt (Dolmage and Goldstein 2002) and the mean

EELV of three preceding breaths (Calverley and Koulouris 2005, Tantucci et al

2006). The published guidelines require a stable EELV, stating that this usually

requires at least three breaths at VT, but do not define this further (M. Miller, et

al., 2005; Tantucci, et al., 2006).

Apparent change or drift in baseline EELV has been problematic in the past due

possible differences in temperature, gas density and/or humidity between expired

gas and ambient or calibration gas. However, current equipment has the


capacity to correct for this potential source of error (Calverley and Koulouris

2005, Dolmage and Goldstein 2002, Puente-Maestu et al 2005).

The importance of timing of the IC prompt has been highlighted by some authors,

as errors may occur if inspiration begins before stable baseline EELV is achieved

(Calverley and Koulouris 2005). One group reported using the following

instructions: “at the end of the next normal expiration, take a deep breath all the

way in” (Somfay et al 2001, p 79). However, publications using IC measurement

generally provide no details regarding this aspect of measurement technique and

it is not mentioned in the published guidelines (Miller et al 2005, Tantucci et al

2006). This aspect of measurement technique was standardised in the current

research (Section 7.5.3).

7.2.4 Technical acceptability

Little information is available with regard to technical acceptability of the maximal

inspiratory IC manoeuvres. Guidelines emphasise the importance of patient

position (seated with shoulders relaxed), use of a nose clip, and the need for an

unforced but maximal inspiration without hesitation or obstruction of the

mouthpiece (Miller et al 2005, Tantucci et al 2006). As this is an effort-dependent

test, verbal encouragement is required to achieve a maximal effort on top of a

maximal inspiration before relaxing (Somfay et al 2001) and acceptability is

determined largely by observation of a trained technician.

During incremental exercise testing, recording of a single IC manoeuvre at each

workload is usual practice (Calverley and Koulouris 2005, O'Donnell and Webb

1993, Puente-Maestu et al 2005), but at rest no recognised standard practice

exists. Approaches include recording the mean of the best two of three

reproducible manoeuvres, defined as peak inspiratory plateau volume within

±10% (Somfay et al 2001), the better of two manoeuvres from at least three

acceptable trials agreeing to within 5% or 60 ml (Marin et al 2001) and the

highest of two (Murciano et al 2000) or at least two (Tantucci et al 2006)

acceptable manoeuvres. Others have stated a requirement of three reproducible

efforts within 5% but have not stated which effort is taken as the result (O'Donnell

et al 2001a). The guidelines for IC measurement suggest that the average of at

least three acceptable manoeuvres be reported, allowing for a variability of up to

5% (Miller et al 2005).


7.2.5 Validity of inspiratory capacity measurement

Serial measurement of IC has been used to track changes in EELV during

exercise in COPD over the last few decades (O'Donnell and Webb 2003). This

approach to measurement of DH is dependent upon the assumption that TLC

and the elastic properties of the respiratory system remain essentially unaltered

during exercise, a view which is widely accepted (Calverley and Koulouris 2005,

Casanova et al 2005, Gelb et al 2004, Murciano et al 2000, O'Donnell and Webb

2003).

This assumption was initially based upon studies using an electrically braked

cycle ergometer within a specifically adapted body plethysmograph (Stubbing et

al 1980a). Studies of 12 normal males (Stubbing et al 1980a) and six males with

COPD (mean FEV1 39.2% of predicted value) (Stubbing et al 1980b) found no

significant change between resting values of TLC and those recorded during

submaximal, steady state exercise. In addition, TLC (measured at rest using

body plethysmography) has been found to remain unchanged in a study of 20

patients with COPD after recovery from an acute exacerbation (Parker et al

2005).

However, contradictory findings regarding the stability of TLC have been reported

from one large study of 957 patients with airflow obstruction (FEV1/FVC <85%

predicted and hyperinflation (TLC >115% predicted), measured before and after

administration of salbutamol (Newton et al 2002). A statistically significant

reduction in mean TLC (in litres) was reported, which represented a reduction of

2.5% compared with pre-bronchodilator levels. A methodological limitation of this

study was that participants were included on the basis of respiratory function

parameters only and specific clinical information was not considered. Previous

studies have demonstrated that in asthma, TLC may change in response to

bronchodilator (Holmes et al 1978) and after induced airway narrowing (Kirby et

al 1986) and although such responses are variable, inclusion of patients with

asthma may have confounded the results of this study (Newton et al 2002).

A further issue when interpreting TLC values that with severe airflow limitation,

lung volume may be overestimated by using the body plethysmography due to

poor transmission of alveolar pressure to the mouth through flow-limited airways

(Rodenstein et al 1982, Stanescu et al 1982). To overcome this limitation,

optoelectronic plethysmography has also been used to assess TLC in COPD.


This system involves the use of infrared light to detect changes in absolute lung

volumes by monitoring the three-dimensional movements of reflective markers

placed upon the chest and abdominal walls (Calverley and Koulouris 2005,

Duranti et al 2002). Using this method, IC was found to increase after a single

dose of a bronchodilator in 13 subjects with COPD (mean FEV1 of 45% of

predicted value) but TLC did not vary, thus confirming the validity of IC

measurement for assessing changes in EELV and therefore degree of

hyperinflation (Duranti et al 2002).

7.2.6 Reproducibility of inspiratory capacity measurement

Reproducibility (or repeatability) is defined as a closeness of agreement of

successive measurements of a variable performed on the same individual under

the same conditions (Dolmage and Goldstein 2002). In addition to the above

considerations, reproducibility of IC measurement is based upon the assumption

that patients are able to generate a peak, maximal inspired volume with each IC

effort which is equivalent to the volume of TLC at rest or baseline. It has been

hypothesised that in COPD, increased elastic load placed upon the respiratory

muscles when VT is positioned closer to the alinear extreme of the pressure-

volume curve might result in inability to generate a maximal inspiratory effort to

TLC (Yan et al 1997), particularly during incremental exercise to exhaustion.

This issue has been addressed by measuring oesophageal pressure via an

oesophageal balloon, as a marker of pleural pressure and therefore inspiratory

effort. Oesophageal pressure was found to be constant when measuring IC at

rest and at the end of incremental, exhaustive exercise in two studies of patients

with COPD (n=15 and 12 respectively) (O'Donnell et al 1997b, Yan et al 1997).

Other studies have shown that IC measurements are reproducible at rest and for

equivalent exercise workloads in the same patients over three different occasions

of testing (O'Donnell and Webb 1993), at peak symptom-limited exercise

(O'Donnell et al 1998) and in pooled data of large patient numbers (n=463).

Pooled data of large multi-centre, multi-national trials (n=463) has also

demonstrated high reproducibility of IC measures performed at run-in visits at

rest, isotime and peak exercise with high ICC‟s (R≥0.87) (O'Donnell et al 2009).

The question of within-session reproducibility of IC measurements has been

examined by recording the greater of at least two acceptable IC manoeuvres and

calculating the difference between the highest and second highest


measurements (Tantucci et al 2006). These two measurements were within 200

ml or <9% of each other in 90% of subjects. This was concluded to acceptable

reproducibility (Tantucci et al 2006) as the difference found was within the

recommendations of the American Thoracic Society for spirometry which require

a difference of <200 ml for FEV1 and FVC in adults .

7.2.7 Responsiveness of inspiratory capacity measurement

The role of serial IC measurement in tracking increases in hyperinflation during

exercise in COPD is well established (O'Donnell et al 1997a, O'Donnell et al

1997b, O'Donnell and Webb 1993). IC values have also been shown to correlate

well with changes in exertional dyspnoea measured using the Borg Scale

(O'Donnell et al 1998). Serial IC measurement has also been used to assess

response to pharmacological agents, in particular bronchodilators. Agents

studied include albuterol (Belman et al 1996, Duranti et al 2002), iprotropium

(O'Donnell et al 1999), tiotropium (Celli 2003, Dusser et al 2006, O'Donnell

2004), salbutamol (O'Donnell et al 2001d, Pellegrino et al 1998, Tantucci et al

1998) and salmetorol (Man et al 2004). A combination of ipratropium and

salbutamol has been examined in two studies (Cukier et al 2007, Peters et al

2006) and the effects of different bronchodilators have also been compared using

this measure (Di Marco et al 2003, Van Noord et al 2006). These studies have

generally shown reductions in exercise-related dynamic hyperinflation (Calverley

2006) whilst demonstrating that IC is responsive to change after administration of

bronchodilator therapy in the setting of apparently non-reversible spirometric

measures, particularly FEV1. This also supports the notion that both

measurements should be considered as complimentary when assessing

response to therapies in COPD (Calverley and Koulouris 2005).

IC measurement has been used in a number of studies to assess volume

response to hyperoxia during exercise. However, little is known about volume

response to hyperoxia at rest. The few studies which have assessed the latter

are described below.

7.2.8 Interpretation of inspiratory capacity values

At the time of writing there is no consensus regarding normal values of IC or the

minimal important difference (MID) (Schunemann and Guyatt 2005b) in IC

values. IC is often reported as a raw value in litres, but a variety of approaches

has been used (Table 7.1). Predicted value of IC (IC% predicted) has been


calculated by subtracting predicted value of FRC from predicted value of TLC

(Newton et al 2002, O'Donnell et al 2001b). IC% predicted, when estimated in

this manner, has been found be highly predictive of exercise tolerance in flow-

limited subjects with COPD (Diaz et al 2000). Whilst it has been proposed that

normal IC has a value of ≥80% predicted (Di Marco et al 2003, Diaz et al 2000).

Use of the above method for calculation of IC% predicted has been challenged

(Tantucci et al 2006) due to lack of currency of published predicted values and

the use of younger populations in their calculation (American Thoracic Society

1995c, Quanjer et al 1993, Tantucci et al 2006). This issue has been addressed

in a multicentre Italian study of 429 non-obese, healthy subjects aged 65 to 85

with no previous diagnosis of respiratory disease or other major co-morbidity

(Tantucci et al 2006). Multiple regression analyses determined that age, height

and body mass index provided a better model for prediction of IC (r2=0.34 and

0.36 for males and females respectively) than age and height only (r2=0.24 and

0.34). From this study, equations for providing reference values were derived,

which the authors concluded were reliable for application in elderly southern

European caucasian populations (Tantucci et al 2006). In addition, these authors

found that values thus obtained were lower than those predicted from commonly

used reference values (Quanjer et al 1993) and acknowledged that the predictive

equations required testing and validation in other, larger population samples

(Tantucci et al 2006).

An increase IC of 10% in predicted value or 0.3L has been proposed as the MID

in IC, due to its association with important improvements in dyspnoea (reduction

of 0.5 Borg scale units) and increases in exercise endurance time (25%)

(O'Donnell 2006b, O'Donnell et al 1999, O'Donnell and Laveneziana 2006c,

Parker et al 2005), related to increased ability to expand VT during exercise.

Further, it has been suggested that a change of 10% in predicted value

represents statistical significance, based upon the lower 95% confidence interval

for response to ipratropium bromide in 29 patients with moderate to severe

COPD (O'Donnell et al 1999). Other authors have assessed the 95% confidence

interval for variability in repeated measures in patients with airflow obstruction

(asthma and COPD) to correspond to 220 mls or 9% of predicted value of IC

(Pellegrino et al 1998). Newton et al (2002) determined that a clinically

significant change in IC would be 200 ml and 10% of predicted value, based upon

the findings of these two groups (O'Donnell et al 1999, Pellegrino et al 1998) and


their own study (Newton et al 2002) described above. In the studies of this

thesis, the value accepted as representative of the MID for IC was 10% of

predicted value.

The ratio of IC to TLC (IC/TLC) has been found to be a predictive factor for

mortality in COPD (Casanova et al 2005). Further to the finding of this

association, it has been proposed that IC should be expressed as a percentage

of TLC and, in keeping with the concept of left ventricular ejection fraction, be

termed “inspiratory fraction” (Casanova et al 2005). IC %predicted, determined

from the predictive equations previously referred to (Tantucci et al 2006), has

also been found to be a strong predictor of mortality, as well as exacerbation-

related hospital admissions in patients with COPD (Tantucci et al 2008).


Table 7.1 Assessment of degree of pulmonary hyperinflation using inspiratory

capacity (IC) measurement and values derived from IC which have been reported

in the literature.

EELV (litres) (TLC - IC) (Murciano et al 2000)

(O'Donnell and Webb 1993)

(O'Donnell et al 2001a)

EELV/TLC% (EELV = TLC - IC) (Belman et al 1996)

(Man et al 2004)

(O'Donnell and Webb 1993)

(Peters et al 2006)

(Somfay et al 2001)

(Spahija et al 2005)

IRV/TLC% (IRV = IC - VT)

EILV/TLC% (EILV = TLC - IRV)

(Man et al 2004)

(O'Donnell et al 2001a)

(Somfay et al 2001)

IC/TLC% (Casanova et al 2005)

(Marin et al 2001)

IC% predicted value

(TLC% predicted - FRC% predicted)

(Diaz et al 2000)

(Di Marco et al 2003)

(Mahler et al 2005b)

(Murciano et al 2000)

(Newton et al 2002)

(O'Donnell et al 1998)

(O'Donnell et al 2001b)

(Peters et al 2006)

(Tantucci et al 1998)

EELV, end expiratory lung volume; TLC, total lung capacity; IC, inspiratory

capacity; IRV, inspiratory reserve volume; VT, tidal volume; EILV, end inspiratory

lung volume; FRC, functional residual capacity

7.2.9 Summary

In COPD, spirometric IC measurement provides a relatively simple means with

which to assess important changes in lung function which may be missed by

measurement of FEV1 alone (Celli et al 2003, O'Donnell and Laveneziana 2006c,


Pellegrino et al 1998). A number of studies have demonstrated validity, reliability

and responsiveness of this measure in COPD although further work is required to

establish normal values and the change in value which represents clinical

significance.

7.3 Ventilatory responses to hyperoxia in COPD

7.3.1 Responses during exercise

It is generally accepted that dynamic hyperinflation has an important role in the

limitation of exercise in COPD (O'Donnell and Webb 2008). Further, it is known

that hyperoxia can improve exercise tolerance and dyspnoea in COPD. Although

multifactorial, one mechanism to explain this improvement is hyperoxia-induced

slowing of the onset of exercise-induced dynamic hyperinflation (O'Donnell and

Laveneziana 2006c).

Two important studies which have assessed the effects of hyperoxia during

exercise are summarised in Table 7.2 (O'Donnell et al 1997a, O'Donnell et al

2001a). The earlier of these studies assessed 11 patients with COPD and mild

hypoxaemia and found no significant changes in IC or minute ventilation (VE) at

exercise isotime between breathing room air and 60% hyperoxia. However,

hyperoxia significantly increased endurance time and reduced breathlessness

(measured using the Modified Borg scale) at exercise isotime. When Borg

breathlessness and leg fatigue scores were plotted against time (Borg/time

slope), there were significant reductions in rate of increase with hyperoxia and an

association was found between reduction in Borg scores, VE and blood lactate

levels. The authors concluded that hyperoxia can improve exercise endurance in

patients who have COPD but do not have severe hypoxaemia by ameliorating

breathlessness, which occurs in relation to reduced ventilatory demand and blood

lactate levels (O'Donnell et al 1997a).


Table 7.2 Summary of results of three studies which have compared the effects

of breathing room air and hyperoxia, at rest and with exercise, in COPD

O’Donnell et al

(1997a)

Hyperoxia 60%

O’Donnell et al

(2001a)

Hyperoxia 60%

Peters et al

(2006)

Hyperoxia 50%

Participants

Hypoxaemia

Resting PaO2

n=11

Mild

Mean 74mmHg

n=11

Moderate -

severe

≤60mmHg

Exercise SpO2

<88%

n=16

Normoxic

>65mmHg

Exercise SpO2

≥88%

At rest

Dyspnoea NS NS NS

fB NS NS -

fC NS ↓ p<0.05 -

VE NS NS -

IC NS NS NS

Exercise endurance time

↑ p<0.01 ↑ p<0.01 ↑ p<0.05

Exercise isotime (100% room air endurance time)

Dyspnoea ↓ p=0.020 ↓ p<0.05 ↓ p<0.05

Leg fatigue NS ↓ p<0.05 ↓ p<0.05

fB NS ↓ p<0.05 ↓ p<0.05

VE NS ↓ p<0.05 ↓ p<0.05

IC

Difference

NS p=0.068

In means: +0.14L

↑ p<0.05

Mean: +0.29L

NS

In means: +0.03L

PaO2, arterial partial pressure of oxygen; mmHg, millimeters of mercury; SpO2,

oxyhaemoglobin saturation; dyspnoea, Borg score; NS, non-significant; B,

breathing frequency; C, cardiac frequency; VE, minute ventilation; IC,

inspiratory capacity: L, litres

A similar study of 11 patients with more severe hypoxaemia also found a

significant increase in exercise endurance time and a significant reduction in Borg


ratings of breathlessness at exercise isotime with hyperoxia compared with room

air (O'Donnell et al 2001a). In this group, however, there were also significant

reductions in leg fatigue, respiratory rate (fB), VE and IC. The authors concluded

that the improvements found in exercise tolerance were related, in part, to a

combination of reduced ventilatory drive and improved operational lung volumes

and reduction in dyspnoea (O'Donnell et al 2001a).

Similar assessments were conducted by Peters et al (2005) in a study of the

combined effects of bronchodilators and 50% hyperoxia in 16 patients with

“normoxic” COPD and significant exertional breathlessness (Table 7.2). These

authors also found an increase in exercise endurance time and a reduction in

dyspnoea at exercise isotime, but no change in IC at exercise isotime in the

group overall, although responses were variable (Peters et al 2006). This study

is further discussed below.

It has been suggested that hyperoxia-induced improvements in endurance and

exertional symptoms may be dose dependent, up to an inspired oxygen fraction

(FiO2) of 0.5 or a flow of 100% oxygen of 6L/min (Snider 2002, Somfay et al

2001). A study of ten patients with COPD without severe hypoxaemia (SpO2

>92% at rest and >88% during exercise), found a significant improvement in

endurance time on a symptom-limited exercise test (at 75% of maximal work rate

achieved when breathing room air) with FiO2 0.3 compared with air. A further

significant improvement with FiO2 0.5 was found, but there were no additional

improvements with FiO2 0.75 or 1.0 (Somfay et al 2001). When breathing FiO2

0.3 at isotime (the time at which the room air test ended) there were also

significant reductions in dyspnoea (measured using the Modified Borg scale),

heart rate (fC) and VE and significant increases in IC (difference in means=0.2L)

and IRV (Somfay et al 2001). These authors concluded that their findings

supported the hypothesis that hyperoxia reduces ventilatory drive, thus lowering

respiratory rate and prolonging expiratory time to allow for a fuller expiration and

improvement in operational lung volumes.

The effect of hyperoxia (40%) during recovery from symptom-limited maximal

exercise has been investigated in 18 patients with moderate to severe COPD

who did not qualify for long term oxygen therapy and did not desaturate (SpO2

≥88%) during exercise (Stevenson and Calverley 2004). Time taken for

resolution of DH was significantly shorter (mean difference 6.6 minutes, p=0.001)


with hyperoxia compared with air. However, perception of breathlessness during

recovery and time taken to return to baseline dyspnoea scores (measured using

the Modified Borg Scale) were not reduced by oxygen (Stevenson and Calverley

2004).

As mentioned, there has been recent interest in the combined effects of

hyperoxia and bronchodilators during exercise in COPD. The study of Peters et

al (2006) was a double-blind, crossover study comparing the effects of 50%

hyperoxia with breathing room air, after inhaling nebulised bronchodilators

(iprotropium 0.5mg + salbutamol 2.5mg) or placebo (Peters et al 2006). Findings

suggested that the two interventions had different effects. Bronchodilator

treatment was associated with increased IC at rest (difference in mean IC 0.32L,

p<0.05) and during exercise, allowing greater VT expansion and therefore VE

throughout exercise. Hyperoxia was associated with reduced VE as a result of

reduced fB, minimal change in VT and no significant change in IC at rest or during

exercise for the group as a whole, although volume response was variable.

Dyspnoea (Modified Borg Score) was decreased and endurance time increased

with all interventions, but these changes were greatest with the combined

interventions. The authors concluded that these effects were synergistic and

occurred as a result of reduced hyperinflation with bronchodilator therapy and

reduced ventilatory drive with oxygen therapy (Peters et al 2006).

The findings of the above study were supported by those of a similar study of 28

patients with more severe COPD (SpO2 ≤89% at rest or on exercise) (Cukier et al

2007). This study assessed the effects of hyperoxia (3L/min via nasal prongs)

and breathing cylinder air with nebulised bronchodilators (iprotropium 500μg +

salbutamol 5mg) compared with nebulised placebo solution upon 6MWD (Cukier

et al 2007). Mean 6MWD increased significantly after bronchodilators+air

compared with placebo+air (p=0.047). There was further improvement with

placebo+hyperoxia compared with bronchodilator+air (p=0.011). However, the

greatest improvements were demonstrated after bronchodilators+hyperoxia,

when compared with placebo+air (p<0.0001), bronchodilators+air (p<0.0001) and

placebo+oxygen (p=0.014). After bronchodilator, five individuals showed a

change exceeding the MID in 6MWD (Redelmeier et al 1997), after hyperoxia 13

patients achieved this improvement and after combined therapy, 19 (68%)

achieved this. In addition, end-test dyspnoea scores (Modified Borg Score) were


significantly lower with brochodilators+hyperoxia than the other three conditions

(Cukier et al 2007).

Together, these acute studies indicate that in patients with COPD, the combined

effects of bronchodilator and oxygen therapies provide useful benefits which are

greater than those provided by each therapy alone (Cukier et al 2007, Peters et

al 2006). These benefits are apparent in patients with and without significant

hypoxaemia and are particularly observed in dyspnoea and exercise tolerance.

Bronchodilators increased exercise endurance by reducing EELV before and at

any given time during exercise and oxygen reduced the rate of increase of

exercise-induced EELV (that is DH) (Cukier et al 2007), by suppression of

chemoreceptor activity (Peters et al 2006, Somfay et al 2002).

7.3.2 Responses at rest

Physiological responses to hyperoxia at rest in COPD, including effects upon

degree of hyperinflation, are uncertain. Although EELV is also dynamically

regulated at rest, its variability in COPD has mainly been examined in the context

of exercise (Calverley 2006). In addition to volume responses, other responses

to hyperoxia at rest have received little attention and have been assessed in few,

small studies and have reported conflicting findings.

One study has assessed resting response to 30% hyperoxia in nine patients with

COPD and one with bronchiectasis (Alvisi et al 2003). All participants were had

severe hypoxaemia, defined as PaO2 ≤55 mmHg at rest or during exercise or

resting PaO2 56-60 mmHg with concurrent cor pulmonale. After five minutes of

hyperoxia, a statistically significant increase in IC and statistically significant

reductions in VT, mean inspiratory flow and dyspnoea (VAS score) were found.

These authors concluded that hyperoxia-induced reductions in dyspnoea

occurred due to reduced ventilation and degree of hyperinflation, as a result of

reduced hypoxic inspiratory drive (Alvisi et al 2003).

These findings are in contrast to the resting responses to hyperoxia reported in

the three studies (O'Donnell et al 1997a, O'Donnell et al 2001a, Peters et al

2006) described above (Table 7.2). These studies found no significant changes

in dyspnoea or IC in patients with mild hypoxaemia (O'Donnell et al 1997a),

moderate to severe hypoxaemia (O'Donnell et al 2001a) or normoxia (Peters et al


2006). In addition, no changes in fB or VE were found in the two studies reporting

these measures (O'Donnell et al 1997a, O'Donnell et al 2001a).

7.3.3 Variability in response to hyperoxia

A number of authors have reported inter-patient variability in responses to

hyperoxia both at rest (Alvisi et al 2003, Snider 2002) and during exercise

(O'Donnell et al 1997a, O'Donnell et al 2001b, Peters et al 2006, Snider 2002,

Somfay et al 2001). Variability in degree of hyperinflation has given rise to the

notion of volume “responders” and “non-responders” to hyperoxia (Calverley

2006, Peters et al 2006). For example, although Peters et al (2006) found no

significant change in mean IC overall with hyperoxia at exercise isotime, seven of

their 16 subjects demonstrated increased IC at exercise isotime. These volume

responders were noted to have more severe airflow limitation than non-

responders (FEV1/FVC 39% and 48% respectively, p=0.009), significantly worse

dyspnoea scores, poorer exercise endurance and more significant changes in

ventilatory response than non-responders (Peters et al 2006).

7.3.4 Ventilatory response to hyperoxia: summary

Hyperoxia has been shown to increase exercise endurance and reduce

dyspnoea acutely during laboratory-based exercise in patients with moderate to

severe COPD. Studies have suggested that these benefits are associated with

reduced ventilatory demand, increased expiratory time and therefore reduction in

exercise-induced dynamic pulmonary hyperinflation, although it is likely that other

factors are involved. The few small studies which have investigated these

responses at rest have reported conflicting findings. In addition, inter-patient

variability in both resting and exercise responses has been reported. This raises

the questions of how responders to hyperoxia may be identified and whether an

acute response might be predictive of benefit from hyperoxia in the longer term,

domiciliary setting.

7.4 Study aims

The aim of this study was to characterise ventilatory and dyspnoea responses to

hyperoxia at rest, in a large group of patients with COPD of varying severity. It

was hypothesised that responses would vary and that characterisation of patients

as oxygen responders or non-responders at rest might assist in determining

those patients with COPD who may be likely to respond to supplemental oxygen

during exertion.


7.5 Materials and methods

7.5.1 Participants

Patients with a clinical diagnosis of COPD attending the respiratory laboratory for

routine breathing tests were invited to participate in the study. Patients had

refrained from using bronchodilators for at least four hours and had not received

supplemental oxygen for at least 20 minutes prior to testing.

7.5.2 Study design

This was a prospective, double-blinded, randomised controlled trial. All subjects

provided written, informed consent prior to participation. Ethical approval to

conduct the study was obtained from the Hospital Research Ethics Committee.

7.5.3 Procedures

Participants were assessed at baseline whilst breathing room air and after

breathing each of the two study gases, 44% oxygen and air, in randomised order,

through a closed breathing circuit (Figure 7.3). Assessments were undertaken at

three time points: 1) after breathing room air at rest for at least five minutes, 2)

after breathing the first study gas for at least five minutes and 3) after breathing

the second study gas for at least five minutes. Participants breathed room air for

at least three minutes between completion of testing on the first study gas and

commencement of breathing the second study gas.

The breathing circuit included a 100L Douglas bag, a Hans Rudolf wide bore,

non-rebreathing valve (Model 2700, Hans Rudolf, Kansas City, MO, USA) and a

pneumotachograph, connected to a SensorMedics Vmax Series spirometer

(SensorMedics Corporation, Yorba Linda, California). The study gases were

delivered to the Douglas bag from cylinders of identical appearance.

Four variables were recorded at the three measurement points: B, cardiac

frequency ( C) and oxygen saturation (SpO2) using a Masimo Radical Signal

Extraction pulse oximeter (Masimo Corporation, Irvine, California) and dyspnoea

using the modified, 10 point Borg Scale (American Thoracic Society 2002) and

standardised descriptor (Section 4.2.5).


Figure 7.3 Study procedures.

B, breathing frequency; C, cardiac frequency; SpO2, oxyhaemoglobin

saturation; dyspnoea, Borg score; IC, inspiratory capacity

After 5 minutes of breathing the first study gas, IC was measured by an additional

assessor (a respiratory scientist trained in the measurement technique).

Readings were recorded on two worksheets in order to maintain blinding to the

study gases (Appendices XI and XII). The subject breathed at VT until a stable

EELV was indicated on the spirometer display screen (mean of three consecutive

breaths within 100 mls of each other).

The IC prompt was given just after stable EELV was achieved, nearing the end of

the next expiration. A maximal inspiratory effort was encouraged, followed by

normal expiration. A minimum of three technically acceptable trials were

performed and the average of two volumes within 200 ml of each other was taken

as the result. These procedures were repeated after breathing the second study

gas for at least five minutes. The IC measurement procedures took

approximately 30 minutes to complete.

Room air ≥ 5 minutes Baseline

RANDOMISATION

Air

Hyperoxia

Hyperoxia

Air B, fC, SpO2,

dyspnoea,

IC

B, fC, SpO2, dyspnoea

B, fC, SpO2, dyspnoea, IC

Gas 1 5 minutes

Gas 2 5 minutes

3 minutes room air


VE and VT were calculated from resting breathing immediately prior to the IC

efforts. The average of two or three measures was taken as the result. When

only one measure was recorded on either study gas, results for that variable were

excluded from the analysis. Other pulmonary function tests were performed

according to American Thoracic Society guidelines. Predicted values used were

those of Knudson et al for spirometry (Knudson et al 1976) and Goldman and

Becklake for lung volumes, from which IC %pred was determined (Goldman and

Becklake 1959).

7.5.4 Analysis

Data were entered into a specifically designed data base and data verification

was performed. The Statistical Package for Social Sciences (Version 14, SPSS

Inc, Chicago) was used for data analysis. Group means and effect of gas order

were analyzed using paired samples t tests and correlations were performed

using Pearson correlation coefficients. Linear regression models were created to

further examine the relationships between the relevant variables. The level of

statistical significance (alpha) was set at 0.05.

7.6 Results

7.6.1 Participants

Fifty-two participants with a clinical diagnosis of COPD were enrolled in the study

(Table 7.3). One subject who did not have airflow obstruction consistent with

COPD (FEV1/FVC <70%) (Pauwels et al 2001) was excluded from subsequent

analyses. Of the 51 participants included in the analyses, 40 were males and

nine had severe hypoxaemia and qualified to receive COT according to Thoracic

Society of Australia and New Zealand guidelines for oxygen prescription

(McDonald et al 2005). Three participants who had never smoked were included

in the analysis on the basis of their poorly reversible airflow obstruction, six were

current smokers and 42 were ex-smokers. Twelve participants (24%) had mild

airflow obstruction (FEV1 >70% predicted), 16 (31%) had moderate airflow

obstruction (FEV1 50-69 % pred) and 23 (45%) had severe airflow obstruction

(FEV1 ≤ 35 % pred) (Pellegrino et al 2005).


Table 7.3 Demographic data of study participants (n = 51)

Mean (SD)

Range

Age (years)

72.6 (9.7)

48 – 85

FEV1 (litres) 1.40 (0.78) 0.46 – 3.36

FEV1% predicted 54.7 (24.9) 17 – 122

FVC (litres) 2.82 (1.03) 1.41 – 5.47

FVC % predicted 86.3 (21.0) 52 – 139

IC (litres) 2.05 (0.79) 0.73 – 4.97

IC % predicted 74.9 (22.3) 20.8 – 122.5

FEV1/FVC (%) 44.0 (14.5) 22 – 68

SpO2 (%) 94.6 (3.2) 85 – 100

Pack/years 48.8 (34.8) 0 – 161

SD, standard deviation; FEV1, forced expiratory volume in one second; FVC,

forced vital capacity; IC, inspiratory capacity; SpO2, oxyhaemoglobin saturation

7.6.2 Response to hyperoxia

Results of measures taken after five minute periods of breathing air and 44%

hyperoxia at rest are summarised in Tables 7.4 and 7.5. The mean increase in

SpO2 was 3.8% (standard error of the mean, SEM 0.4), p <0.0001. There was no

significant increase in IC during hyperoxia (mean +0.4L, SEM 0.02, p =0.069)

and considerable intra-patient variability in response was observed. A total of 42

data sets of VE measures and 49 sets of VT measures were included in the

analysis. There were no significant changes in ventilatory measures (VE and VT).

There were statistically significant reductions in dyspnoea score and heart rate

during hyperoxia. No gas order effect was observed for IC (p=0.172), but an

order effect was apparent for C (p=0.002) and dyspnoea (p=0.041) with these

measures both being lower whilst breathing the second study gas.

In the subgroup qualifying to receive COT, a significant increase in SpO2 was

demonstrated but no significant changes were found in the other measures. No

significant correlation was found between change in IC and degree of airflow

obstruction (FEV1% predicted) in the 51 participants (r=0.16, p=0.25, Figure 7.4).


However, when this analysis was confined to the 39 participants with at least

moderate airflow obstruction (FEV1 <70 %pred) (Pellegrino et al 2005), a

significant correlation was demonstrated (r=0.39, p=0.015) (Figure 7.4). No

correlation was found between change in dyspnoea and change in IC for the

group overall (r= -0.144, p=0.312), for those with moderate to severe disease (r=

-0.073, p=0.657) or for those who qualified to receive LTOT (r=0.304, p=0.427).


Table 7.4 Results after 5 minutes of breathing air and 44% oxygen for all

participants, those with moderate to severe airflow obstruction and those who

qualified to receive long term oxygen therapy

Air

mean (± SD) SEM 44% Oxygen

mean (± SD) SEM t

value df

p value

All participants n = 51

SpO2 (%) 94.1 (4.1) 0.6 98.4 (2.1) 0.3 8.043 50 <0.000

1 IC (litres) 2.05 (0.79) 0.1 2.09 (0.76) 0.11 1.875 50 0.069

IC (% predicted) 74.9 (22.3) 3.1 76.4 (21.3) 3.0 -1.951 50 0.057

VE (L/min) n = 42 13.1 (3.7) 0.6 13.2 (2.9) 0.4 0.278 41 0.783

VT (litres) n = 49 0.79 (0.22) 0.03 0.81 (22) 0.03 0.892 48 0.377

B (/min) 18.4 (6.0) 0.8 18.0 (5.6) 0.8 -1.021 50 0.312

C (/min) 78.0 (13.2) 1.8 76.5 (12.9) 1.8 -2.880 50 0.006

Dyspnoea 1.3 (1.2) 0.2 1.2 (1.1) 0.2 -2.099 50 0.041

FEV1 <70% n = 39, mean 43.3 (±13.7)%

SpO2 (%) 94.0 (4.4) 0.7 98.5 (1.7) 0.3 6.649 38 0.000

IC (litres) 1.85 (0.7) 0.1 1.89 (0.7) 0.10 1.608 38 0.116

IC (% predicted) 70.1 (20.7) 3.3 71.6 (18.5) 3.0 -1.717 38 0.094

VE (L/min) n = 31 13.1 (3.7) 0.7 13.4 (3.1) 0.6 0.605 30 0.550

VT (litres) n = 38 0.8 (0.2) 0.04 0.8 (0.2) 0.03 1.756 37 0.087

B (/min) 19.0 (6.1) 1.0 18.2 (5.8) 0.9 -1.883 38 0.075

C (/min) 78.9 (13.5) 2.2 77.7 (12.6) 2.0 -1.979 38 0.055

Dyspnoea 1.4 (1.2) 0.2 1.2 (1.0) 0.7 -2.337 38 0.025

LTOT n = 9

SpO2 (%) 89.9 (6.4) 2.1 98.2 (1.6) 0.5 4.530 8 0.002

IC (litres) 1.88 (0.667) 0.2 1.93 (0.571) 0.2 .972 8 0.359

IC (% predicted) 63.5 (19.5) 6.5 65.6 (16.6) 5.5 -1.095 8 0.305

VE (L/min) n = 6 16.4 (3.9) 1.6 14.9 (3.0) 1.2 -1.564 5 0.179

VT (litres) n = 8 0.86 (0.27) .10 0.82 (0.28) 0.1 -.855 7 0.421

B (/min) 20.2 (9.4) 3.1 21.3 (8.9) 3.0 1.890 8 0.095

C (/min) 87.2 (8.2) 2.7 85.6 (5.9) 2.0 -1.021 8 0.337

Dyspnoea 1.6 (1.3) 0.4 1.5 (1.3) 0.4 -1.000 8 0.347

SD, standard deviation; SEM, standard error of the mean; SpO2, oxyhaemoglobin

saturation; IC, inspiratory capacity; VE, minute ventilation; L/min, litres per minute;

VT, tidal volume; B, breathing frequency; dyspnoea, Borg score; C, cardiac

frequency.


Table 7.5 Mean change (hyperoxia minus air values) in inspiratory capacity

(IC), dyspnoea (Borg score) and arterial saturation (SpO2)

Mean ∆ IC in litres (SEM)

range

Mean ∆ IC % predicted (SEM)

range

Mean ∆ dyspnoea

(SEM)

Mean ∆ SpO2% (SEM)

All participants

0.04 (0.02)

-0.44 to +0.43

1.5 (0.8)

-15.7 to +12.3

-0.2 (0.1)

3.8 (0.4)

FEV1 < 70%

predicted

0.04 (0.02)

-0.44 to +0.43

1.5 (0.9)

-15.7 to +12.3

-0.2 (0.1) 4.1 (0.5)

Qualified to

receive LTOT

0.05 (0.05)

-0.22 to +0.27

2.2 (2.0)

-7.4 to 10.3

-0.1 (0.1) 7.0 (1.2)

IC, inspiratory capacity; SEM, standard error of the mean; SpO2, oxyhaemoglobin

saturation; FEV1, forced expiratory volume in one second; LTOT, long term

oxygen therapy

Figure 7.4 Correlations (Pearson co-efficient) between change in inspiratory

capacity and disease severity (FEV1% predicted) for all participants and those

with moderate to severe airflow limitation.

IC, inspiratory capacity; FEV1, forced expiratory volume in one second; L, litres

FEV1 (% predicted)

10 30 50 70 90 110 130

Ch

an

ge

in

IC

wit

h h

yp

ero

xia

(L

)

-0.50

-0.25

0.00

0.25

0.50

Moderate and severeairflow obstruction

r=0.39, p=0.015

All participants r=0.16, p=0.25


7.7 Discussion

The results of this study indicate that in patients with COPD and a range of

disease severity, hyperoxia at rest induces significant reductions in heart rate and

dyspnoea, but no significant reduction in resting lung volumes or ventilation. The

finding of a significant association between change in IC and degree of airflow

obstruction in patients with moderate to severe airflow obstruction suggests that

in this subgroup, resting lung volumes are more likely to be improved with

hyperoxia. In patients with moderate to severe airflow obstruction, the reduction

in IC was best predicted by resting IC expressed as a percentage of predicted

value.

This study was successful in its aim of extending previous investigations of

hyperoxia at rest in COPD to include a larger group of patients with a wide range

of disease severity. The hyperoxia-induced change in IC has been shown to be

an important determinant of improvement in exercise limitation in obstructive lung

disease (O'Donnell et al 2001a, O'Donnell and Laveneziana 2006c, Snider 2002,

Somfay et al 2002). A level of 44% hyperoxia was selected in this study as this is

estimated to correspond with breathing 100% oxygen via nasal prongs at a flow

of 6 litres per minute (McCoy 2000, Shapiro and Peruzzi 1994), the highest flow

delivered by commercially available domiciliary delivery systems.

Alvisi et al reported that hyperoxia reduced IC at rest in patients with COPD and

severe hypoxaemia (Alvisi et al 2003). These findings were not replicated in a

comparable subgroup in the present study, despite the use of a higher inspired

oxygen concentration (44% compared with 30%). Further, with the exception of

dyspnoea score, the results of this study are consistent with those reported by

O‟Donnell et al in patients with severe hypoxaemia (O'Donnell et al 2001a) where

IC and other ventilatory measures were assessed at rest prior to incremental

exercise. These authors also reported no significant changes in IC, VE, fB, a

significant reduction in C and significant increase in SpO2 with 60% hyperoxia

(O'Donnell et al 2001a). Additionally, findings of the present study of no resting

volume response to hyperoxia were consistent with those of Peters et al (2006)

and O‟Donnell et al (1997a) referred to previously.

From the available data, the subset of nine patients with severe hypoxaemia in

current study was comparable with those in the studies of Alvisi et al (2003) and


O‟Donnell et al (2001a). There were no significant differences in patient

demographics (IC% predicted, FEV1% predicted, FEV1/FVC) between the 10

participants in the study of Alvisi et al (2003) and this subset of patients who

qualified to receive COT (p =0.23, 0.40 and 0.06 respectively). Such

comparisons with the cohort of O‟Donnell et al (2001a) are not possible from the

information published. However, mean FEV1% predicted was similar and

suggestive of severe airflow limitation (Pellegrino et al 2005) in all three groups

(31% for O‟Donnell et al 2001a, 30% for Alvisi et al 2003 and 34% for this

subset).

Although the patients were comparable across the three trials, the methods used

to measure dyspnoea may explain some of the differences found in results.

Alvisi et al (2003) used a visual analogue scale (VAS, zero to 10 cm) to measure

dyspnoea, whilst the Modified Borg scale was used in the present study and by

O‟Donnell et al (2001a). The Borg scale has been widely used to quantify

dyspnoea in COPD during exercise but may be less suitable for use at rest, less

sensitive to change than the VAS and subject to a floor effect. The mean Borg

score was low at baseline for our subgroup who qualified for LTOT (1.6 units) and

even lower in the group of O‟Donnell et al (2001a) (0.8 units), compared with a

baseline mean of 2.5 cm on the VAS in the participants of Alvisi et al (2003).

Interpretation of the results of the present study is complicated by the finding

suggestive of a gas order effect for dyspnoea score and heart rate. In both

instances, values were lower while breathing the second study gas. This was

interpreted as indicative of a degree of familiarity with the study procedures.

Importantly, there was no gas order effect for IC, indicating that any differences

found in IC were observed irrespective of study gas order. By way of

comparison, O‟Donnell et al (2001a) reported no gas order effect for symptom,

ventilation or metabolic responses to exercise in their group with severe

hypoxaemia, and the strong similarity of the results of the two studies would

suggest that gas order did not influence the findings of the present study.

Although Alvisi et al found a statistically significant increase in IC after five

minutes of hyperoxia, increase in mean IC was only 90mls, (Alvisi et al 2003)

considerably less than the value which is believed to represent the MID in IC

(O'Donnell and Laveneziana 2006). The increase in mean IC reported by

O‟Donnell et al (2001a) was 130 ml (9.8%), and that of the present study was 40


ml (2.0%). During hyperoxia, two of the 10 patients assessed by Alvisi et al had

no increase in IC, compared with four of our nine patients who qualified for COT,

further highlighting the variability in response observed between participants in

other studies (O'Donnell and Laveneziana 2006). These differing findings may

be explained by variation in measurement technique and the absence of a

standardised protocol for spirometric measurement of IC. In addition, the small

sizes of the three study samples raises the possibility that all three were

underpowered to detect a true effect of hyperoxia at rest in patients with severe

hypoxaemia group. A meta-analysis across these studies may resolve this

question.

The significant relationship observed between change in IC and FEV1% predicted

in patients with at least moderate airflow limitation suggests that those with more

severe airflow limitation may have a greater volume response to hyperoxia. This

relationship between more severe airflow obstruction and change in IC with

hyperoxia has been observed during exercise in normoxic patients with COPD

(Peters et al 2006). Further, the results of the present study suggest that IC%

predicted may also be an important predictor of volume response to hyperoxia at

rest. Peters et al (2006) also found that that this measure was an important

predictor of improvement in dyspnoea during exercise.

Collectively, the results of these various studies highlight the complexity of the

relationships between hyperoxia, lung volume and airflow obstruction in COPD,

and challenge the use of PaO2 or SpO2 as the primary criterion for oxygen

prescription (Table 2.3). Further research will require many more participants to

better characterise volume responders to hyperoxia at rest, to determine whether

such improvements correlate with improvements in exertional dyspnoea and/or

exercise tolerance.

In conclusion, this study indicates that hyperoxia at rest does not improve resting

lung volume in patients with COPD of varying disease severity. This is in

contrast to previous findings in COPD patients with severe hypoxaemia (Alvisi et

al 2003). However, the finding of a relationship between airflow obstruction and

improvement in resting hyperinflation during hyperoxia (irrespective of the

presence of hypoxaemia) raises the interesting possibility that oxygen therapy is

potentially of benefit in non-hypoxaemic patients with COPD.

Chapter 8: Effects of domiciliary ambulatory oxygen in COPD 161

When you can’t breathe, nothing else matters. The Australian Lung Foundation

The effects of domiciliary ambulatory oxygen in chronic obstructive pulmonary disease

8.1 Introduction ................................................................................... 161 8.2 Study aims .................................................................................... 163 8.3 Study hypotheses .......................................................................... 163 8.4 Materials and method .................................................................... 164

8.4.1 Study design .................................................................... 164 8.4.2 Study sample size ........................................................... 165 8.4.3 Participants ...................................................................... 168 8.4.4 Study group allocation ..................................................... 170 8.4.5 Assessment procedure .................................................... 170 8.4.6 Measurements ................................................................. 173 8.4.7 Intervention procedures ................................................... 181 8.4.8 Data management ........................................................... 183

8.5 Results .......................................................................................... 184 8.5.1 Baseline data ................................................................... 184 8.5.2 Outcomes for air and oxygen groups ............................... 191 8.5.3 Subgroup analyses .......................................................... 192

8.6 Discussion ..................................................................................... 201

8.1 Introduction

Confusion exists regarding which breathless patients should receive ambulatory

oxygen. COPD is a leading cause of disability and death globally, characterised

by progressive airflow limitation, dyspnoea, loss of function and, in its later

stages, chronic hypoxaemia. Treatment options are limited and, besides ceasing

smoking, long-term, COT is the only intervention known to increase life

expectancy in patients with COPD who are severely hypoxaemic at rest. Based

upon evidence provided by the NOTT and MRC trials (Nocturnal Oxygen Therapy

Trial Group 1980), COT is prescribed internationally for patients who have PaO2

≤55 mmHg or <60mmHg with hypoxic organ damage (American Association for

Respiratory Care 2007, McDonald et al 2005, Royal College of Physicians 1999).

Extrapolation from the results of these studies (Nocturnal Oxygen Therapy Trial

8 Chapter


Group 1980) would suggest that the use of ambulatory oxygen may supplement

the benefits of COT, but there are few data to support this (Lacasse et al 2005).

Many people with COPD are not severely hypoxaemic at rest, but experience

significant exertional dyspnoea, which may or may not be associated with oxygen

desaturation. This dyspnoea limits exercise tolerance and contributes to

progressive physical deconditioning and decline in general function. Several

studies of such people with COPD have demonstrated acute improvements in

exercise capacity and/or dyspnoea during laboratory exercise testing while

breathing oxygen-enriched gas (hyperoxia) compared with breathing air (Bradley

and O'Neill 2005, Snider 2002). This suggests that ambulatory oxygen, provided

long-term in the domiciliary setting, would have a role in the treatment of patients

with COPD who are breathless on exertion but who have a resting PaO2 which

precludes their receiving COT. However, only three previous studies have

addressed this question in this patient group and have failed to provide

convincing evidence of benefit.

McDonald et al examined 26 patients, some with exertional desaturation, in a

2x6-week crossover trial and reported a significant but clinically small

improvement in exercise capacity after ambulatory oxygen compared with

ambulatory air and no difference in quality of life (McDonald et al 1995). In a

similar study of 41 patients with COPD and exertional desaturation, Eaton et al

reported no difference in exercise capacity or end-exercise dyspnoea after

oxygen compared with air and statistically significant but clinically small

improvements in quality of life, anxiety and depression (Eaton et al 2002).

Nonoyama et al reported no improvement in quality of life after using ambulatory

oxygen compared with placebo in an N-of-1 study of 27 patients with COPD and

exertional desaturation over three pairs of two-week treatments (Nonoyama et al

2007a).

Although effort-related hypoxaemia may be one mechanism underpinning the

development of exertional breathlessness in patients with COPD, response to

hyperoxia during exertion is not solely dependent upon relief of hypoxaemia

(O'Donnell and Webb 2005). Another theory proposed to explain hyperoxia-

induced acute benefits in exercise capacity and dyspnoea relates to the

ventilatory constraints resulting from DH during exercise (Cooper 2006,

O'Donnell and Laveneziana 2006d). Hyperoxia is believed to attenuate DH by


reducing ventilatory demand, allowing improved time for lung emptying and

therefore improved operational lung volumes. Previous studies suggest that this

may occur in a dose-dependent fashion, up to a FiO2 0.5 or a flow of 6 L/min of

100% oxygen delivered via nasal cannulae (Snider 2002, Somfay et al 2001).

However, inter-patient variability in response has been noted (Calverley 2006,

Peters et al 2006, Snider 2002, Somfay et al 2002), giving rise to the notion of

volume “responders” and “non-responders” to hyperoxia (Peters et al 2006).

Other factors which may contribute to a response to hyperoxia remain unclear.

To summarise, there is evidence that ambulatory oxygen provides acute benefits

for patients with COPD, including those who are not hypoxaemic at rest or during

exertion. However, the longer-term effects of ambulatory oxygen remain unclear

and those patients most likely to benefit, if any, remain undefined.

8.2 Study aims

The primary aim of this study was to determine the effects of domiciliary

ambulatory oxygen, used during exertion, in people with COPD who experience

exertional dyspnoea but who do not have severe resting hypoxaemia and do not

fulfill the requirements to receive COT.

The primary outcome measure was dyspnoea. Secondary outcomes were

quality of life, mood disturbance and function. Gas cylinder utilisation was also

examined. A secondary aim of the study was to explore predictive factors for any

benefits found.

8.3 Study hypotheses

The following hypotheses were examined.

Hypothesis 1: Longer term, domiciliary use of ambulatory oxygen during exertion

improves dyspnoea, quality of life and function in people with COPD who are not

severely hypoxaemic at rest, but experience limiting exertional dyspnoea.

Hypothesis 2: The effectiveness of domiciliary ambulatory oxygen is associated

with exertional desaturation, pulmonary volume or exercise response to

hyperoxia, degree of airflow obstruction or dyspnoea and/or gender.


8.4 Materials and method

8.4.1 Study design

This study was a prospective, double-blinded, randomised, controlled trial (Figure

8.1) comparing domiciliary ambulatory cylinder oxygen with cylinder air. There

were two independent variables, time and group. Time was a repeated measure

with three assessment occasions, at baseline, four weeks after randomisation

(the commencement of the treatment phase) and 12 weeks after randomisation.

Participants were randomly allocated to one of two groups, those receiving

domiciliary cylinder air (control group) or cylinder oxygen (treatment group).

Allocation to the treatment or control group was blinded to all study assessors

and participants. The main outcome and secondary outcomes measured are

listed in Table 8.1. With the exception of cylinder utilisation and a survey of

participant preferences, these measures were assessed on the three assessment

occasions.


Table 8.1 Study outcomes and measures used.

Outcomes Measures used

Dyspnoea

CRQ – dyspnoea score*

TDI Focal Score

Quality of Life CRQ – fatigue score

CRQ – emotional function score

CRQ – mastery score

CRQ – total score

AQoL – utility score

Mood disturbance HADS – anxiety score

HADS – depression score

Functional capacity 6MWD – breathing cylinder air

Functional performance 7-day Stand/walk time (hours)

7-day Pedometer count

7-day Outings time (hours)

Cylinder utilisation Total number used (over 12 weeks)

7-day diary reported hours of cylinder use

(weeks 4 and 12)

Survey Preference to continue or cease using cylinders

(upon study completion)

*Primary outcome measure

CRQ, Chronic Respiratory Disease Questionnaire; TDI, Transition Dyspnoea

Index; AQoL, Assessment of Quality of Life Questionnaire; HADS, Hospital

Anxiety and Depression Scale; 6MWD, Six Minute Walk Distance

8.4.2 Study sample size

The study sample size was based upon the numbers required to demonstrate a

difference representing clinical significance (minimal important difference, MID) in

the three major outcome measures, CRQ dyspnoea score, health-related quality

of life (CRQ total score) and exercise capacity (6MWD). Power calculations were

made with hypothesis testing using a 2-sample t-test and data from previous


studies involving a comparable COPD population and these outcome measures.

Calculations were based upon a power of 80% to detect the MID in these

measures, assuming an alpha of 0.05.

For the CRQ dyspnoea score, 64 participants per group were required, based

upon mean ±standard deviation (SD) 14 ±5 (McDonald et al 1995) and MID of 2.5

units (Jaeschke et al 1989). Allowing for an attrition rate of 20%, a target of 154

was determined. Similarly, a target of 57 participants per group was determined

to detect the MID in CRQ total score (10 units), using mean ±SD of 77 units ±17

(Eaton et al 2002), requiring a target of 142 when allowing for a 20% attrition rate.

For 6MWD, using a mean score mean ± SD of 326 metres mean ± 97 (McDonald

et al 1995) and an MID of 54 metres (American Thoracic Society 2002), 52

participants per group were required, or a target of 130 participants when

allowing for an attrition rate of 20%.


Figure 8.1 Study flowchart. MRC, Medical Research Council; BDI, Baseline Dyspnoea Index; PFT‟s,

pulmonary function tests; IC, inspiratory capacity; ABG‟s, arterial blood gas

analysis; CRQ, Chronic Respiratory Disease Questionnaire; AQoL, Assessment of

Quality of Life Questionnaire; HADS, Hospital Anxiety and Depression Scale; TDI,

Transition Dyspnoea Index.

Visit 1 (Week 0) Enrolment MRC Dyspnoea Score BDI ABG's PFT's including IC

Visit 2 (Week 2) CRQ, AQoL, HADS Activity diary check Pedometer reading Exercise Tests

Visit 3 (Week 6) TDI + Visit 2 assessments

Visit 4 (Week 14) TDI + Visit 2 assessments Survey

Run in

2 weeks

Cylinder oxygen

12

weeks

Cylinder air

12

weeks

OR

Activity diary + pedometer 3 x 7 days during week prior to Visits 2, 3,and 4

Randomisation


8.4.3 Participants

Inclusion and exclusion criteria

Study inclusion and exclusion criteria are summarised in Table 8.2. Participants

had a clinical diagnosis of COPD and reported significant exertional dyspnoea.

An MRC Dyspnoea Scale grade of 3 is defined as walking slower than most

people of the same age on the level or needing to stop during self-paced walking

on the level due to breathlessness. Higher scores denote more severe dyspnoea

(Table 4.4). A resting PaO2 >55 mmHg breathing room air was chosen to include

only those participants who did not qualify to receive COT (McDonald et al 2005).

Participants may previously have used domiciliary oxygen therapy or have

attended a formal pulmonary rehabilitation program, but not within four weeks of

enrolment. Attendance at a pulmonary rehabilitation maintenance program

during the study was acceptable. Participation of culturally and linguistically

diverse patients was encouraged, but communication sufficient to complete

diaries and questionnaires was required.

Smoking history was assessed prior to attendance for Visit 1. If smoking status

remained questionable at Visit 1, carbon monoxide levels were assessed (after

consent was obtained). The dangers of smoking (or presence of other naked

flame) in the vicinity of gas cylinders was emphasised to all study participants by

the study investigators and upon delivery of cylinders.

Table 8.2 Study inclusion and exclusion criteria

Inclusion criteria

Exclusion criteria

Diagnosis of COPD

MRC Dyspnoea Scale grade of 3

PaO2 >55 mmHg at rest, breathing room air

Not currently receiving domiciliary oxygen therapy

Not attending a Pulmonary Rehabilitation Program

Non-smoker ≥2 weeks prior to enrolment

No exacerbation of COPD previous 4 weeks

Significant locomotor

disability or other severe

disabling condition

COPD, chronic obstructive pulmonary disease; MRC, Medical Research Council;

PaO2, arterial partial pressure of oxygen; mmHg, millimetres of mercury

An exacerbation was defined as a sustained worsening of condition from stable

state and beyond normal day-to-day variations, necessitating a change in regular


medications (Rodriguez-Roisin 2000). Worsening of condition was defined as an

increase in two of the three following major symptoms: dyspnoea, sputum

volume, sputum purulence or one of the above three plus one of the following

minor symptoms: cough, wheeze, sore throat, fever or a symptom of an upper

respiratory tract infection (nasal discharge or congestion) (Anthonisen et al 1987,

Donaldson et al 2003).

Exclusion criteria included a locomotor disability which significantly limited ability

to perform the exercise tests, more so than breathlessness. Similarly, people

with medical conditions other than COPD which more significantly affected quality

of life or exercise tolerance or were the primary cause of exertional

breathlessness were excluded.

Participants were free to withdraw from the study at any time. Participation was

otherwise continued on the basis of “intention to treat”, including if a hospital

admission was required, during which oxygen may have been utilised.

Recruitment procedure

Participants were recruited from the Northern and Austin Hospitals, Melbourne,

and from the catchment areas of these two centres. The study was promoted to

relevant respiratory physicians, hospital resident medical officers, allied health

and nursing staff via promotional information sheets (Appendix XIII) and to

patients by means of a flyer (Appendix XIV). The study was also promoted by

mail to respiratory physicians within public and private health systems, general

practitioners and staff involved in running pulmonary rehabilitation and pulmonary

rehabilitation maintenance programs in the catchment areas of the study sites.

These health professionals were sent packages containing study information

sheets, flyers, referral forms (Appendix XV), self-addressed envelopes, a

summary of the study protocol (Appendix XVI) and a covering letter (Appendix

XVII). Presentations (in lecture format) were made to medical and allied health

staff at both study centres and some other major treatment centres in Melbourne.

The study was further promoted by means of a public announcement in local and

Melbourne newspapers and as a television news item.

Subjects referred for inclusion in the study were contacted by telephone. The

study requirements were explained, including the need to remain in the

Melbourne metropolitan area during enrolment, and subjects were asked about


their dyspnoea (to determine their rating on the MRC Dyspnoea Scale) and their

smoking history. If agreeable and appearing to fulfill the study criteria, a study

information and consent form (Appendix XVIII) was sent by mail. Subjects

referring themselves for inclusion in the study were also asked about their

respiratory condition and if necessary, their doctor was contacted (with the

subject's consent) to confirm a diagnosis of COPD. Telephone contact was

made approximately one week after mailing the study information and, if willing to

participate, an appointment time was then made for the first assessment visit.

The study was approved by the Human Research Ethics Committee at both study

centres prior to its commencement. Formal, written consent to participate was

obtained from all participants prior to enrolment.

8.4.4 Study group allocation

Participants were randomly allocated to receive cylinder air or oxygen by means

of a computer-generated list of random numbers. Assignment to the study group

was made by the gas cylinder company, on the basis of consecutive study

numbers being allocated an odd or even number from this list. The list was held

by the gas cylinder company and a copy of this list was held in a sealed envelope

at The Northern Clinical Research Centre.

Study numbers were assigned to each study centre in blocks of 10 consecutive

numbers (that is, numbers 1 to 10 assigned to The Northern Hospital; numbers

11 to 20 assigned to The Austin Hospital, and so forth). Participants were

assigned a study number consecutively in order of enrolment at each study

centre.

8.4.5 Assessment procedure

Scheduling

Participants were required to attend The Austin or the Northern Hospital on four

occasions of up to three hours duration over the 14 week study period. Visit

dates were able to be scheduled up to seven days prior or after the required

dates. The procedures performed during the study are summarised in Figure 8.1

and described below.


Visit 1

At the initial visit, the subject was asked if there were any further questions

regarding the study procedures. If willing to proceed, MRC Dyspnoea Score was

confirmed and formal consent to participate in the study (witnessed signature of

the consent form) was obtained (see Appendix XVIII).

A general assessment was completed (see Appendix XIX) prior to the

assessments shown in Figure 8.1, in the order indicated. Instructions for the use

of the Activity Diary (Appendix X) and pedometer device were provided.

Appointment dates were made for Visits 2, 3 and 4 and dates for use of the

Activity Diary and the pedometer device were confirmed.

Participants were requested to wear a "Talisman SOS" device during the

intervention phase of the study. These water-tight devices contain the wearer's

contact and medical details for use in an emergency, written in waterproof ink, on

paper strip which is sealed inside the device. For the purposes of the study, it

was also recorded that the wearer was a participant in a research trial and that

the green study cylinders may contain air or oxygen and must not be used in an

emergency. Four device options were offered: a wrist (chain) bracelet in one of

two link sizes, a nylon wrist strap or a pendant/neck chain. The device was

prepared for use between Visits 1 and 2.

At the Austin Hospital all Visit 1 assessments were performed in the Respiratory

Laboratory. At The Northern Hospital initial assessment and BDI scoring was

performed in a private conference room, arterial blood sampling was performed in

the outpatient pathology department and analysed in the hospital Pathology

Laboratory and pulmonary function testing was performed in the Respiratory

Laboratory.

Visit 2

Changes in condition, medications and the reading on the pedometer were

recorded (see Appendix XX). The assessments indicated in Figure 8.1 were

administered in the order shown and results were recorded on the relevant

response sheets (Appendices XXI, XXII, V and XXIII respectively). The

appointment date for Visit 3 and the dates for completion of the Activity Diary and

the pedometer were confirmed. The information recorded for storage in the

"Talisman SOS" device was reviewed by the participant prior to it being sealed in


the device and given to the participant. The participant was informed that the gas

cylinder company would be in contact to arrange a time for delivery of cylinders

and related apparatus. All participants were requested to use their cylinders as

much as possible, during any activity which caused shortness of breath, but not

at rest and were told that the number of cylinders able to be supplied was not

limited.

The sponsoring gas cylinder company was then informed of the participant‟s

contact details and study number (Appendix XXIV). Four cylinders, a

trolley/stroller, conservation device and nasal prongs were delivered to the

participant's home on the next business day or as soon as practicable. At the

time of delivery, instruction regarding the function and management of the

cylinders were provided in detail by a specifically-trained company

representative, as occurs in usual practice. Participants were asked to order

replacement cylinders through the company and the procedure for this was also

explained.

Visit 3

After noting any changes in medications during the intervening period, the

Transitional Dyspnoea Index was administered, followed by the same procedures

as for Visit 2, in the same order.

Visit 4

At the final study visit, the same assessments as for Visit 3 were completed. In

addition, participants were asked to rate their MRC Dyspnoea Score (after the

TDI had been administered) and were asked to complete a survey of their

preferences and opinions of cylinder use (Appendix XXV).

At this time, participants were given the opportunity to attend or re-attend a

formal Pulmonary Rehabilitation program if appropriate. In addition, those

individuals who appeared to possibly qualify for domiciliary ambulatory according

to the current Australian Guidelines (McDonald et al 2005) were offered a referral

to the oxygen therapist at either of the study centres and/or a letter was written to

the treating physician outlining the exercise test results.

Extended run-in

The run-in period (usually two weeks from Visit 1 to Visit 2) was extended if the

participant reported experiencing an exacerbation (as defined above) during the


initial two weeks of participation. The seven day period for completion of the

Activity Diary and use of pedometer was postponed until four weeks after an

exacerbation was deemed by the participant and the investigator to have

resolved and after cessation of unusual antibiotic and/or corticosteroid therapy.

Visit 2 then took place approximately five weeks after resolution of an

exacerbation.

Run-in was also extended if there were significant changes to relevant

medications, for example, introduction of a new inhaled medication or other

respiratory or non-respiratory illness. In this circumstance, Visit 1 assessments

were repeated four weeks after the change took place, followed by the usual

procedures. No greater than 12 weeks was to elapse between the first two

assessment visits. After that time, it was considered that assessments

conducted at Visit 1 were longer applicable and participants were requested to

repeat those assessments.

Follow-up during participation

During the two weeks between Visits 1 and 2, participants received at least one

telephone phone call to assess general condition and confirm dates for Visit 2

and of commencement of use of the Activity Diary and pedometer. For

participants requiring an extended run-in period, additional telephone calls were

made as required. Participants received at least one telephone call between

Visits 2 and 3 and between Visits 3 and 4 to ensure that study cylinders had been

delivered and no problems had been encountered with their use. In addition,

calls were made to confirm appointment times for Visits 3 and 4 a few days prior

to these visits. Dates and outcome of calls were documented.

Additional documentation

A study checklist was completed at the conclusion of each Visit (Appendix XXVI).

Telephone calls made between visits were also recorded on this sheet.

Documentation of any exacerbations, adverse events or other relevant issues

was also recorded as necessary (Appendix XX).

8.4.6 Measurements

With the exception of the pulmonary function tests and arterial blood gas

analysis, all assessments were performed by the author or one of two research

assistants specifically trained in the administration of the study procedures.


The MRC Dyspnoea Score

Participants were asked to rate their level of breathlessness at Visit 1 using the

MRC Dyspnoea Scale. This was printed on laminated card, using Arial font, size

14 (Appendix XXVII).

The Baseline and Transitional Dyspnoea Index (BDI/TDI)

These assessments were administered according to The BDI-TDI Training Video

(produced in 2004 by D. Mahler in conjunction with GlaxoSmithKline Group of

Companies, Philadelphia, USA). The author administered all BDI and TDI

assessments throughout the study in order to maximise reliability of

assessments. The BDI was administered prior to all but the MRC Dyspnoea

Scale at Visit 1 and prior to all other assessments at Visits 3 and 4.

Arterial blood gas analysis

At the Austin Hospital, the blood sample for ABG analysis was taken by a

qualified Respiratory Scientist, specifically trained in this procedure and analysed

within the respiratory laboratory. At the Northern Hospital, the blood sample for

ABG analysis was taken in the outpatient pathology department by nurses

specifically trained in this procedure and analysed at that hospital‟s pathology

laboratory.

Anthropometric measurements

Anthropometric measurements were made by the respiratory scientists

immediately prior to pulmonary function testing. Participants were weighed using

a Seca Digital Column Weight Scale (Davco Weight Scales Inc, Hamburg,

Germany) at The Austin Hospital and using Colonial Bathroom Scales Model

1650 (Colonial Weighing Australia Pty Ltd, Sunshine Victoria) at The Northern

Hospital. Measurements were recorded to the nearest 0.1 kilogram, with

subjects wearing light clothing. Height was measured to the nearest 0.01 metre

using a wall mounted tape and measuring stick. Height and weight data were

then used to calculate BMI (weight in kilograms divided by the square of height in

metres, kg/m2).

Pulmonary function testing

Pulmonary function testing was performed at Visit 1 after completion of the initial

assessment, administration of the BDI and arterial blood gas analysis. Testing

was performed by qualified respiratory scientists and was conducted in the


following order: flow volume curves, diffusion capacity, body plethysmography

(Austin Hospital only), inspiratory capacity (IC) measurement.

Subjects were asked to withhold administration of bronchodilators where

prescribed, for at least four hours prior to testing. At the Austin Hospital, the

same spirometer was used for the first three sets of measurements, requiring the

subject to move once to a different room in the laboratory for IC measurement.

At The Northern Hospital, the same spirometer was used for all tests. Procedure

for performance of the four pulmonary function tests is described below.

1. Flow volume curves

Standard spirometry using flow volume curves was conducted according to

published guidelines (American Thoracic Society 1995c) and predicted values

(Knudson et al 1976). The SensorMedics Vmax Series spirometer and

computerised testing system (SensorMedics Corporation, Yorba Linda,

California) was used at both study sites.

Flow-volume curves were used to derive the following measures: forced vital

capacity (FVC), forced expiratory volume in one second (FEV1) and the ratio of

these two volumes (FEV1/VC) (Pierce et al 2005). The standard measurement

protocol includes the recording of at least three technically acceptable,

repeatable efforts. The subject is asked to inspire maximally, then to exhale

forcefully and completely using maximal effort, then to inhale with the mouthpiece

in situ. Technical acceptance is determined by the assessor and repeatability is

defined as the best FEV1, FVC and VC measurements having at least one other

value within 100 mls or 10%, which ever was smaller. The higher or highest is

accepted as the test result for each of these values. This procedure takes an

average of 10 minutes to complete.

2. Gas Transfer Factor

Gas transfer was assessed by measurement of carbon monoxide diffusing

capacity (TLCO), expressed in ml/min/mmHg. TLCO is defined as the rate of

transfer of carbon monoxide from inspired gas to pulmonary capillary blood

(Pierce et al 2005). TLCO was measured using the single breath transfer factor

technique, according to published guidelines (American Thoracic Society 1995a)

and predicted values (Roca et al 1990).


Using this technique, TLCO is derived from a representative sample of alveolar

gas, taken after dead space gas has been washed out. A gas mixture containing

nitrogen plus 0.3% carbon monoxide and 0.3% methane is inhaled during the

following manoeuvres: tidal breathing, maximal expiration, maximal inspiration, a

breath hold of approximately 10 seconds against a closed shutter, then relaxed,

full expiration. A minimum of two technically acceptable and repeatable

measurements is required. Technical acceptance is determined by the assessor

and repeatability is defined as two measurements being within 10% of each

other. The mean of these two measurements is accepted as the test result. This

procedure takes an average of five minutes to complete.

3. Body plethysmography

Standard measures of thoracic gas volume were taken using a constant volume,

variable pressure type body plethysmograph (the SensorMedics VS63J Autobox,

SensorMedics Corporation, Yorba Linda, California) and the SensorMedics Vmax

Series spirometer. Measurements of total lung capacity (TLC), functional

residual capacity (FRC) and residual volume (RV) were taken according to

published guidelines (DuBois et al 1956, SensorMedics Corporation 1996) and

predicted values (Goldman and Becklake 1959). This procedure was performed

at the Austin Hospital site only, as the required equipment was not available at

The Northern Hospital.

The plethysmograph consists of a large chamber in which the subject sits. The

door of the chamber remains closed during testing, creating a seal to the

atmosphere. The subject breathes through a mouthpiece connected to a

breathing circuit. After an equilibration period of 30-60 seconds and when the

subject is deemed to be breathing at a stable FRC, the circuit is occluded by a

shutter for approximately one second. The subject is then required to make a

few gentle inspiratory and expiratory ("panting") efforts against the occlusion.

The shutter is released when a technically acceptable manoeuvre has been

completed. The subject is then required to inspire maximally and expire

maximally but without force and then come off the mouthpiece. After a rest to

allow return to stable state, the procedure is repeated at least twice, until three

technically acceptable and repeatable manoeuvres have taken place.

Repeatability is defined as three sets of FRC and TLC measurements matching

to within 10%.


As pressure measured at the mouth is reflective of alveolar pressure, pressure

changes within the plethysmograph during the above manoeuvres reflect

changes in thoracic gas volume. By plotting the mouth pressure against the box

pressure, and applying Boyle‟s Law (P1V1 = P2V2 where P = pressure and V =

volume), the volume of gas in the thorax is calculated and lung volumes are

derived. For FRC and TLC, the mean of the acceptable measurements is taken

as the test result. RV is calculated by subtracting VC from mean TLC. The

higher of VC or FVC measurements from this test or spirometry was accepted as

VC for this calculation. This procedure takes an average of 10 minutes to

complete.

4. Inspiratory capacity

The method used for IC measurement was identical to that described in Chapter

7.

Quality of life and mood disturbance assessments

Interviewer-administered versions of two quality of life questionnaires, the CRQ

(Appendix IV) and the AQoL (Appendix III) were used. Both have been described

in Chapter 4. These questionnaires were administered in a standardised manner

by one of three trained interviewers (the author or an assistant), in a private

room.

For administration of the CRQ, coloured answer cards were laminated, printed

with upper case letters in “arial” font, size 26. For administration of the AQoL, the

participant was also provided with a copy of the questionnaire to read

concurrently, printed in “arial” font, size 12. For measurement of mood

disturbance, the HADS was self-administered. The question sheets were printed

in “arial” font, size 14. Answer sheets were checked to ensure all questions had

been answered.

Exercise testing

A standardised 6MWT was used to assess functional capacity. A specific

protocol for testing was devised (Appendix VI), based upon published guidelines

(American Thoracic Society 2002). Three, 6MWT‟s were performed by each

participant at Visits 2, 3 and 4. At both study sites, the tests were performed

indoors on a hard surface, along a 25-metre flat, straight track. Preparation

included positioning of turning points, marked by placing two strips of adhesive


tape (2 cm x approximately 25 cm) on the floor in the shape of a cross, 24 metres

apart. A starting line, 0.5 metre behind one cross, was marked by a line of

adhesive tape on the floor and line of tape was similarly placed at the other end

of the track. A chair was placed near the starting line.

Testing was performed at a similar time of day. Participants wore comfortable

clothing and suitable shoes and were not to have exercised vigorously within two

hours prior to testing. Medications were taken as usual and inhaled medications

taken on the day of testing were recorded. The recommended contraindications

to testing (American Thoracic Society 2002) were adhered to, including unstable

angina or a myocardial infarction during the previous month (absolute

contraindication). The study exclusion criteria were in accordance with these

contraindications. In addition, testing was to be stopped should the participant

display chest pain, intolerable dyspnoea, leg cramps, staggering, diaphoresis, or

a pale or ashen appearance.

The testing procedure is summarised in Figure 8.2. The apparatus and flow

rates used were the same as those provided in the domiciliary setting. Two study

CH size cylinders, labeled cylinder X and cylinder Y but otherwise identical, were

used in random order on each occasion of testing. One cylinder contained

compressed air (control) and the other contained compressed oxygen

(treatment). The subject was blinded to the contents of each cylinder.

Randomisation was performed by allocation of a random number from a

computer-generated list, to each consecutive participant visit. If the random

number assigned was odd, cylinder X was used first, and vice versa. Gas flow

was set at 6 L/min on Mode A, via the “Impulse Elite” demand delivery

conservation device (AirSep Corporation, Buffalo, New York). During testing,

cylinders were transported by participants in a trolley/stroller.


Figure 8.2 Exercise testing procedure

L/min, litres per minute

Familiarisation with the gas cylinders and related equipment took place at Visit 2,

prior to the first (practice) test. This procedure included explanation of the

function of cylinders and the conservation device, the intermittent nature of flow

and how it is triggered. The participant then selected the preferred hand for

holding the cylinder trolley. This was recorded on the worksheet and the same

hand was subsequently used for all tests. Direction of travel and turns was

determined such that the cylinder traveled around on the outside of turns.

Alternatively, participants requiring a four-wheel frame used a basket attached to

the frame in which to carry their cylinders and walked in an anticlockwise

direction on each occasion of testing. Participants were shown how to turn

around the crosses and performed a least one practice turn.

Standardised instructions (Appendix VI), based on published guidelines

(American Thoracic Society 2002) were read to the participant prior to the first

test walk on all three occasions of testing. Each time the participant returned to

the starting line the lap counter was clicked once. Upon completion of the test

the assessor recorded the number of laps completed, as indicated on the

counter, and additional distance covered by using the wall markers (Austin

Hospital) or measuring wheel (Northern Hospital). Total distance walked was

calculated, rounding to the nearest metre.

If the participant stopped walking during the test and needed a rest, standardised

encouragement was provided at one minute intervals during the rest period. In

addition, the participant was told how many minutes remained at minutely

intervals. The number and duration of any rest periods was noted on the

worksheet.

Preparation

Instructions

Cylinder familiarisation

Visit 2 only

Test 1 Practice Test

1st cylinder

No gas flow

Test 2 1

st cylinder

6 L/min flow

Test 3 2

nd cylinder

6 L/min flow


The subject rested for at least 10 minutes prior to Test 1 and a period of at least

10 minutes elapsed between Tests 2 and 3, allowing sufficient time for

measurements to return to baseline and to breathe the following test gas for 10

minutes at rest. Measurements recorded at the beginning and end of each test

were fB, fC, SpO2 and Borg scores for dyspnoea and fatigue were recorded. At

both study sites, SpO2 and fC were measured using a Masimo Radical Signal

Extraction (SET) pulse oximeter, (Masimo Corporation, Irvine, California) at both

study sites. SpO2 was also recorded minutely during each test and subsequently

until return to baseline. The pulse oximeter was attached to the cylinder trolley.

Apart from taking minutely oximeter readings, the assessor stood near the mid-

point of the track during each test and did not walk with the participant.

The Modified Borg Scale (American Thoracic Society 2002) was used to measure

breathlessness and fatigue, especially leg fatigue. This was printed on laminated

card, using Arial font, size 20. Standardised instructions for use of the scale were

provided as follows:

The same procedures for exercise testing were followed at Visits 3 and 4,

omitting the familiarisation procedure.

Functional performance measurement

Three measures of functional performance were assessed on three occasions

over seven days. These were hours spent standing or walking and on outings

according to diary records (Appendix X) and pedometer count. The Activity Diary

sheets, a pedometer and written and verbal instructions for their use were

provided at Visits 1, 2 and 3. Participants were provided with the same

pedometer for the duration of the study. Pedometer counts were recorded by a

study assessor at Visits 2, 3 and 4 and the device was reset to zero at this time.

Protocols for use of these measurement tools and the rationale for their selection

are described in Chapter 6.

This is a scale for rating breathlessness and fatigue, especially leg fatigue. The number zero represents no breathlessness or fatigue. The number ten represents the strongest or greatest breathlessness or fatigue that you have ever experienced. Before and after each test you will be asked to point to the number which represents your perceived level of breathlessness or fatigue, especially leg fatigue.


Gas utilisation

Gas cylinder utilisation was calculated from the gas cylinder company records of

the number of cylinders delivered to each participant. In addition, gas pressure

was recorded for each cylinder upon return, enabling calculation of partial

cylinder use. Seven day study gas utilisation was also assessed using self-

report in the Activity Dairy (Appendix X). These records provided an estimate of

gas use in hours.

Participant survey

At the final visit, participants were asked to complete a survey (Appendix XXV).

Questions assessed preference to continue or cease cylinder use, the perceived

benefits and disadvantages of their use and practical difficulties encountered.

General comments were also invited.

8.4.7 Intervention procedures

Apparatus

Study gases were provided in transportable CH size (470 L) cylinders. These

cylinders were 55 cm in height and weighed approximately 4.2 kg when filled. Air

and oxygen-containing cylinders were identical in appearance and were labeled

Study Gas 1 or 2 (Figure 8.4). The coding for cylinder labels was blinded to

study assessors and participants for the duration of the study.

For all participants, pulsed gas flow was delivered via the ImPulse Elite electronic

oxygen conservation device (AirSep Corporation, Buffalo, New York).

(Conservation devices are discussed in Section 2.3.3.) This device weighs 682

grams and measures 11.2 cm by 14.2 cm by 6.5 cm. Gas was delivered at a flow

rate equivalent to 6 L/min continuous flow. (The rationale for the choice of flow

rate is discussed in Section 8.6) The “Impulse Elite” device was used in Mode A,

providing a conservation ratio of 6:1 (the alternative setting providing a ratio of

3:1). At these settings, a pulse of 52 ml of gas was delivered during inspiration

when the device was triggered by commencement of inspiratory effort. Estimated

duration of gas flow per cylinder with the device on these settings was 7.5 hours,

based upon a cylinder capacity of 470 litres @15 degrees celcius and 101.3 kPa

and a respiratory rate of 20 breaths per minute (G. Zemmerle, Engineer, Air

Liquide Healthcare Pty. Ltd., Melbourne, Australia. Personal communication, 17th

April 2003).


Figure 8.3 Labels used for domiciliary study cylinders.

A hand-held cylinder trolley (stroller) was provided to all participants. The trolleys

were 55 cm high and weighed 4 kg (total weight of a filled cylinder, conservation

device and trolley was approximately 9 kg). In addition, a four wheel frame with a

basket for carrying the study apparatus was provided for those who were unable

to manage a cylinder and stroller for all activities and was willing to accept one.

Gases were delivered via nasal prongs, as is usual clinical practice.

Cylinders were delivered to participants by the gas cylinder company. Initially,

four cylinders were delivered and participants were requested to order further

cylinders as required to ensure continuity of supply. Participants were instructed

verbally and in writing to use their cylinders during any indoor or outdoor activity

which caused breathlessness.


Safety considerations

Important safety instructions were provided in writing and verbally as is usual

practice with the provision of domiciliary oxygen. Upon initial delivery, a trained

cylinder company staff member showed participants how to remove and replace

the conservation device and how to operate the apparatus. Safety instructions

included avoidance of using oil, grease or other petroleum-based products on or

near the equipment and it was emphasised that cylinders must not be used within

2 metres of an open flame or operating electrical equipment.

Participants who demonstrated a carbon dioxide (CO2) level above the normal

range (35 to 45 mmHg) at Visit 1 were requested to undertake repeat ABG

analysis. This was performed after a period of 30 minutes‟ observation, breathing

oxygen at rest, via the same equipment and settings (6 L/min intermittent flow) as

those used in the study. Participants demonstrating drowsiness or any other

adverse clinical signs or a rise in PaCO2 ≥5 mmHg were to be withdrawn from the

study.

8.4.8 Data management

Data were collated using a specifically designed database and analysed using

The Statistical Package for Social Sciences (Version 14, SPSS Inc, Chicago) and

the R Statistical Computing Package (R Development Core Team, 2006, Vienna,

Austria). The level of statistical significance was set at p<0.05. Demographic

data were compared using chi-square or t-tests. For the main analysis

comparing air and oxygen groups, intention-to-treat analyses were performed.

Missing TDI scores were imputed as zero (no change) and all other missing data

were imputed using a last-observation-carried-forward method. TDI scores and

cylinder utilisation data were analysed using t-tests to compare group means at

weeks 4 and 12 post-randomisation. Chi2 tests were used to compare differences

between groups in numbers with significant changes in TDI scores (representing

improvement, deterioration or unchanged dyspnoea) at the two assessment

times. Other outcome measures were analysed using two-way ANOVA, with

group allocation (air or oxygen) and time as the two independent variables.

Six variables were selected a priori to identify subgroups which might benefit

differentially from domiciliary ambulatory oxygen (Table 8.3). Complete data only

were analysed using analysis of covariance (ANCOVA), with Week 12 values as

the response variable and the corresponding value at baseline as the covariate.


Data were transformed and outliers excluded as appropriate, to ensure that the

assumptions for ANCOVA tests were met.

Table 8.3 Characteristics of subgroups examined

Subgroup

Definition

Cut-off

Desaturation (American Thoracic Society 2002)

SpO2 on Six Minute Walk Test breathing cylinder air

>88% ≤ 88%

Severity of airflow obstruction (Pellegrino et al 2005)

FEV1 % predicted < 50%

50 – 69% ≥ 70%

Exercise response to hyperoxia (Redelmeier et al 1997)

Increase in Six Minute Walk Distance breathing 6 L/min oxygen compared with air

< 54metres ≥ 54metres

Volume response to hyperoxia (O'Donnell and Laveneziana 2006c)

Increase in IC % predicted breathing 44% oxygen compared with 21% oxygen

< 10% ≥ 10%

Severe breathlessness (O'Donnell et al 1999)

Baseline Dyspnoea Index Focal Score

≤ 4 units > 4 units

Gender

SpO2, oxyhaemoglobin saturation; FEV1, forced expiratory volume in one second;

L/min litres per minute; IC, inspiratory capacity

8.5 Results

8.5.1 Baseline data

Of the 160 patients enrolled, almost one-third were recruited through The

Northern Hospital study site (Table 8.4) and 143 (44 females, 99 males)

proceeded to randomisation, four of whom did not complete the study (Figure

8.5). The 17 participants who did not proceed to randomisation were similar with

regard to demographic data to those who did (Table 8.5). With the exception of a

statistically significant but clinically small difference in percentage of predicted

value for transfer factor for carbon monoxide (TLCO % predicted), there were no

significant differences between air and oxygen groups for any demographic or

outcome measures at baseline (Table 8.6, 8.7) or gender (chi2=0.568, p=0.451).

Participants were moderately to severely breathless, having a mean (± standard


deviation, SD) CRQ dyspnoea score of 17.5 (±5.0) and a BDI focal score of 3.4

(±1.8).

Table 8.4 Participant recruitment data by study site

Enrolled

Dropped out

Completed

Before randomisation

After randomisation

Northern Hospital

46 (28.8%) 6 (13.0% of 46) 0 40

Austin Hospital

114 (71.2%) 11 (9.6% of 114) 4 99

Total 160 17 (10.6%) 4 (2.5%) 139

Table 8.5 Demographic data of the 17 participants who did not proceed to

randomisation.

Mean ± standard deviation

FEV1% predicted 42.7 ± 19.3

FE V1/FVC 40.7 ±15.4

PaO2 68.4 ±10.8 (range 49 to 87)

Mean age 70.7 ± 8.9 (range 57.4 to 87.9)

Female:male 8:9

FEV1, forced expiratory volume in one second; FVC, forced vital capacity; PaO2,

arterial partial pressure of oxygen

186

Figure 8.4 Flow of participants through the study

PaO2, arterial partial pressure of oxygen

Assessed for eligibility n = 1318

Excluded n = 1158 Not meet inclusion criteria: 672 Unwilling: 324 Unable to contact: 90 Too distant: 61 Language or cognitive issues: 6 Participating in other trial: 5

Complete data n = 73

Enrolled n = 160

Cylinder oxygen n = 68 (48%)

Cylinder air n = 75 (52%)

Dropped out n = 2 Deceased: 1 Unwell: 1

Enrolled, not randomised n = 17 Consent withdrawn: 8 PaO2 <55 mmHg: 4 Recommenced smoking: 2 Normal lung function: 1 Major comorbidity: 1 Deceased: 1

Randomised n = 143

Dropped out n = 4

Completed n = 139

Dropped out n = 2 Consent withdrawn: 2

Complete data n = 66

187

Table 8.6 Baseline data for air and oxygen groups and results of t tests to compare groups

All n=143 Air n=75 (52%) Oxygen n=68 (48%)

mean (SD)

range

mean (SD)

mean (SD)

t

p

Age (years) 71.8 (9.8) 33.3 - 90.8 71.7 (10.4) 71.9 (9.2) -0.121 0.904

FEV1 1.16 (0.51) 0.28 - 2.83 1.17 (0.53) 1.15 (0.50) 0.197 0.844

FEV1% pred 47.2 (18.8) 15.0 - 99.0 47.1 (19.5) 47.2 (18.3) -0.023 0.981

FVC 2.59 (0.83) 1.05 - 5.89 2.59 (0.81) 2.60 (0.85) -0.087 0.931

FVC% pred 79.4 (20.7) 31.0 - 134.0 79.0 (18.7) 79.9 (22.9) -0.262 0.794

FEV1/FVC% 41.2 (13.1) 14.0 - 83.0 42.1 (13.7) 40.2 (12.5) 0.850 0.397

TLCO 11.61 (4.21) 3.5 - 22.4 11.0 (4.04) 12.27 (4.31) -1.802 0.074

TLCO % pred

46.1 (14.3) 18.5 - 90.1 43.5 (13.6) 48.9 (14.6) -2.296 0.023

† IC 1.84 (0.61) 0.83 - 3.86 1.82 (0.62) 1.86 (0.59) -0.418 0.677

† IC% pred

84.1 (21.9) 41.5 - 145.2 82.5 (23.2) 85.9 (20.4) -0.930 0.354

* FRC 4.44 (1.25) 1.79 - 8.33 4.54 (1.42) 4.32 (1.03) 0.897 0.372

* TLC 6.21 (1.42) 2.72 - 10.84 6.25 (1.56) 6.16 (1.26) 0.339 0.735

* RV 3.20 (1.10) 0.86 - 6.72 3.31 (1.18) 3.07 (0.97) 1.078 0.283

Weight 75.7 (18.2) 40.0 - 150.0 73.9 (18.4) 77.8 (18.0) -1.269 0.207

Height 167.5 (9.2) 143.5 - 191.5 167.9 (8.6) 167.2 (9.8) 0.489 0.626

BMI 26.9 (6.2) 15.1 - 55.6 26.3 (6.5) 27.7 (5.8) -1.439 0.152

PaO2 71.4 (8.5) 55.0 - 109.0 70.0 (8.4) 72.6 (8.9) -1.744 0.083

188

All n=143 Air n=75 (52%) Oxygen n=68 (48%)

mean (SD)

range

mean (SD)

mean (SD)

t

p

PaCO2 40.4 (5.0) 27.0 - 56.0 40.3 (4.7) 40.7 (5.3) -0.478 0.633

pH 7.42 (0.03) 7.29 - 7.52 7.42 (0.02) 7.42 (0.03) 0.479 0.633

# Pack years 54.0 (36.0) 1 - 196 56.3 (38.2) 51.7 (33.6) 0.749 0.455

† BDI Function 1.3 (0.9) 0 - 3 1.4 (0.8) 1.3 (0.9) 0.779 0.437

Task

1.0 (0.6) 0 - 3 1.0 (0.6) 1.1 (0.7) -1.091 0.277

Effort 1.1 (0.6) 0 - 3 1.1 (0.6) 1.1 (0.6) -0.464 0.643

Total 3.4 (1.8) 0 - 8 3.4 (1.7) 3.5 (2.0) -0.256 0.798

SD, standard deviation; FEV1, forced expiratory volume in one second; FVC, forced vital capacity; TLCO, transfer factor for carbon monoxide;

FRC, functional residual capacity; TLC, total lung capacity; RV, residual volume; BMI, body mass index; PaO2, arterial partial pressure of

oxygen; PaCO2, arterial partial pressure of carbon dioxide; BDI, Baseline Dyspnoea Index.

† n = 142: one participant (air group) did not complete the BDI; one participant (oxygen group) was unable to perform

* n = 100: lung volumes not available fo 43 (air group=20, oxygen group=23): 3 unable to perform, 40 at study site where test not available

# n = 140: three never smokers (air group)

189

Table 8.7 Outcome measures and t tests to compare air and oxygen groups at baseline.

Possible

range

All Air

mean (SD)

Oxygen

mean (SD) t p

mean (SD) range

CRQ* MID n=143 n=75 n=68

Dyspnoea 2.5 5 - 35 17.5 (5.0) 7 - 29 17.5 (4.9) 17.6 (5.2) -0.046 0.963

Fatigue 2.0 4 - 28 15.3 (4.6) 5 - 25 15.2 (4.1) 15.7 (5.0) -0.051 0.959

Emotion 3.5 7 - 49 34.4 (8.0) 11 - 49 33.8 (8.1) 35.1 (8.0) -0.957 0.340

Mastery 2.0 4 - 28 19.7 (4.6) 7 -28 19.7 (4.5) 19.7 (4.7) -0.054 0.957

Total score 10.0 20 - 140 86.9 (17.4) 35 - 126 86.3 (16.6) 87.7 (18.4) -0.481 0.631

AQoL* MID n=143 n=75 n=68

Utility score 0.06 -0.04 - 1.0 0.5214 (0.2610) -0.01 to 1.00 0.5242 (0.2597) 0.5183 (0.2643) 0.134 0.894

HADS#

Clinically significant

n=141 n =74 n=67

Anxiety ≥10 0 - 21 5.5 (4.1) 0 - 20 5.7 (4.1) 5.3 (4.2) 0.482 0.630

Depression ≥10 0 - 21 5.6 (3.2) 0 - 16 5.4 (2.8) 5.8 (3.6) -0.823 0.412

190

Possible range

All Air

mean (SD) Oxygen

mean (SD) t p

6MWD MID n=131 n=70 n=61

(metres) ≥54 metres 341.0 (90.6) 100 - 525 340.6 (88.9) 341.4 (93.2) -0.054 0.957

7 day Stand/walk time (hours) n=138 n=72 n=66

37.7 (15.0) 0.5 - 78.0 36.0 (14.7) 39.4 (15.2) -1.333 0.185

7 day Outings (hours) n=136 n=70 n=66

16.8 (11.1) 0 - 59.8 15.7 (10.0) 17.9 (12.1) -1.151 0.252

7 day Pedometer count n=142 n=75 n=67

23501.4 (17383.0) 1456.0 - 90133.0 23465.7 (18045.4) 23541.4 (16746.0) -0.026 0.979

SD, standard deviation; CRQ, Chronic Respiratory Disease Questionnaire; MID, minimal important difference; AQoL, Assessment of Quality of

Life Questionnaire; HADS, Hospital Anxiety and Depression Scale; 6MWD, Six Minute Walk Distance

* Higher scores represent better quality of life/less dyspnoea

# Higher scores represent greater (worse) mood disturbance


8.5.2 Outcomes for air and oxygen groups

There were no significant differences found between air and oxygen groups for

any measures of dyspnoea, quality of life, mood disturbance or function over the

time of the study, that is, no significant interaction between time and group was

observed (Tables 8.8, 8.9).

Mean TDI scores for participants overall were low at weeks 4 and 12 after

randomisation and there were no differences between air and oxygen groups for

TDI scores at either assessment time (Table 8.10). Comparisons of the numbers

of participants with a TDI score representing a clinically change (plus or minus

one unit) (Witek and Mahler 2003) or no change in TDI scores also found no

significant differences between air and oxygen groups (Table 8.11).

In participants overall (both the oxygen and air groups), statistically significant

main effects for time (representing improvements) were found over the 12 week

study period for three measures (Tables 8.8, 8.9). These were for CRQ

dyspnoea scores (mean, 95% confidence intervals, 1.3, 0.6 to 2.1), HADS

depression scores (-0.6, -1.0 to -0.2) and 6MWD (5.4, 1.4 to 12.1) (Figures 8.6 A,

B, C). However the changes found were clinically small and less than the

recognised MID in scores. With regard to dyspnoea, this is reflected in the low

mean TDI scores found in the group as a whole at weeks 4 and 12 (Table 8.10).

The mean number of cylinders used over 12 weeks was 8.0 (± SD 0.8), median

4.4 cylinders and 82.6% of participants used ≤12 cylinders (Figure 8.7). There

were no significant differences between air and oxygen groups for mean number

of cylinders used or for self-reported hours of use at week 4 or at week 12 (Table

8.12). For the group overall, the number of self-reported hours at week 4 was

significantly less than that at week 12 (t=2.470, p=0.015).

A survey of participants at the study completion found that 46% of the oxygen

group and 45% of the air group would have preferred to cease using cylinders

altogether and an additional three (air group) were undecided (p=0.254). Whilst

38 participants (28%) reported that their cylinders helped their breathing, 62

(50%) reported poor portability and other difficulties handling the apparatus.

Other barriers to use which were reported included fear of dependence (5


participants), embarrassment (5 participants) and an inability to change the

regulator (5 participants).

8.5.3 Subgroup analyses

Although no overall differences were observed between air and oxygen groups,

subgroup analyses (ANCOVA) were performed as planned to examine whether

or not the baseline characteristics selected may have been more sensitive to a

benefit from ambulatory oxygen. These analyses found that any oxygen-induced

improvement in the primary outcome measure (the dyspnoea domain of the

CRQ) which may have been attributable to ambulatory oxygen was not predicted

by any of the six subgroup factors examined (Table 8.13). The secondary

outcome measures were similarly analysed and no main effect for treatment

(oxygen or air) was observed for any of the subgroup factors. However, a

statistically significant interaction between treatment and subgroup factor

(predictor) was observed in four of the 64 analyses that were performed. These

significant interactions were observed for the ANCOVA model fitted for the

natural log transform of pedometer count, where both the severity of airflow

obstruction (p=0.016) and the exercise response to hyperoxia (p=0.027) were the

predictors, the square root of HADS-Anxiety score, where the exercise response

to hyperoxia was the predictor (p=0.003) and with baseline AQoL as the

covariate where desaturation was the predictor (p=0.047).

193

Table 8.8 Results of quality of life and mood disturbance outcomes; group comparisons using repeated measures analysis of variance

(ANOVA).

Air group Oxygen group ANOVA: p values

Mean (SEM) Range Mean (SEM) Range

Main effect Gas

Main effect

Time

Inter-action

CRQ Dyspnoea Baseline 17.5 (0.6) 7 - 28 17.6 (0.6) 7 - 29

Range: 5-35 Week 4 18.4 (0.7) 8 - 3 19.4 (0.7) 9 - 30

MID: 2.5 Week 12 18.4 (0.7) 5 - 30 19.4 (0.7) 8 - 31 0.425 <0.001 0.336

Fatigue Baseline 15.2 (0.5) 7 - 25 15.3 (0.6) 5 - 24

Range: 4-28 Week 4 16.0 (0.6) 6 - 25 16.0 (0.6) 4 - 25

MID: 2.0 Week 12 15.8 (0.6) 4 - 26 15.5 (0.6) 4 - 25 0.908 0.060 0.807

Emotion Baseline 33.8 (0.9) 11 - 49 35.1 (1.0) 13 - 49

Range: 7-49 Week 4 34.2 (0.9) 21 - 49 35.3 (1.1) 13 - 49

MID: 3.5 Week 12 34.6 (0.9) 14 - 49 34.5 (1.2) 12 - 49 0.565 0.752 0.302

Mastery Baseline 19.7 (0.5) 9 - 28 19.7 (0.6) 7 - 27

Range: 4-28 Week 4 19.5 (0.6) 6 - 28 20.2 0.6) 7 - 28

MID: 2.0 Week 12 19.9 (0.6) 5 - 28 20.0 (0.6) 6 - 28 0.691 0.791 0.177

Total score Baseline 86.3 (1.9) 43 - 121 87.7 (2.2) 35 - 126

Range: 20-140 Week 4 88.1 (2.1) 47 - 124 90.9 (2.5) 35 - 130

MID: 10 Week 12 88.7 (2.4) 29 - 125 89.4 (2.7) 32 - 130 0.583 0.097 0.542

194



Main effect Gas

Main effect

Time

Inter-action

AQoL Utility score Baseline 0.5242 (0.030) -0.01 - 1.00 0.5183 (0.3200) +0.03 - 1.00

Range:-0.04-1.0 Week 4 0.5282 (.0278) -0.01 - 1.00 0.5182 (0.0318) -0.01 - 1.00

MID: 0.06 Week 12 0.5738 (.0313) -0.04 - 1.00 0.5216 (0.0326) -0.02 - 1.00 0.565 0.312 0.214

HADS Anxiety Baseline 5.7 (0.5) 0 - 20 5.3 (0.5) 0 - 18

Range: 0-21 Week 4 5.2 (0.4) 0 - 17 5.2 (0.5) 0 - 19

≥10 significant Week 12 5.3 (0.6) 0 - 19 5.4 (0.6) 0 - 18 0.899 0.541 0.682

Depression Baseline 5.4 (0.3) 0 - 13 5.8 (0.4) 0 - 16

Range: 0-21 Week 4 5.0 (0.4) 0 - 13 5.0 (0.4) 0 - 17

≥10 significant Week 12 5.1 (0.4) 0 - 15 4.9 (0.4) 0 - 16 0.072 <0.001 0.142

SEM, Standard error of mean; CRQ, Chronic Respiratory Disease Questionnaire; MID, minimal important difference; AQoL, Assessment of

Quality of Life questionnaire; HADS, Hospital Anxiety and Depression Scale

195

Table 8.9 Results of functional capacity (Six Minute Walk Distance, 6MWD, breathing cylinder air) and functional performance outcomes

(seven day standing/walking time, outings time and pedometer count) presented as mean (standard error of the mean, SEM) and compared

using repeated measures analysis of variance (ANOVA).



Main effect Gas

Main effect Time

Inter- action

6MWD Baseline 342.8 (10.1) 155 - 506 342.2 (11.4) 100 - 525

(metres) Week 4 355.3 (10.9) 150 - 598 345.4 (12.4) 104 - 548

Week 12 348.8 (11.2) 150 - 580 346.7 (13.6) 50 - 564 0.797 0.036 0.224

Stand/walk Baseline 36.0 (1.7) 2 - 75 39.4 (1.9) 0.5 - 78

time Week 4 37.8 (1.7) 0 - 75 39.5 (1.9) 7 - 78

(hours) Week 12 36.7 (1.8) 0 - 66.5 40.4 (1.9) 5 - 76.5 0.228 0.398 0.296

Outings Baseline 15.7 (1.2) 1.3 - 53.3 17.9 (1.5) 0 - 59.8

time Week 4 15.3 (1.2) 1.0 - 55.3 17.9 (1.7) 2.0 - 66.0

(hours) Week 12 15.7 (1.3) 0 - 51.0 16.5 (1.5) 0 - 55.0 0.293 0.718 0.500

Pedometer Baseline 23466 (2084) 1456 - 90133 23541 (2046) 1725 - 83165

count Week 4 23755 (2095) 1707 - 91792 23920 (2461) 769 - 100560

Week 12 23392 (2074) 460 - 74967 27130 (2695) 750 - 101148 0.666 0.170 0.080

196

A B

C

Figure 8.5 Graphs of air and oxygen group scores in

the three outcome measures which demonstrated a main

effect for time over the 12 weeks of the study:

A Chronic Respiratory Disease Questionnaire dyspnoea

score

B Hospital Anxiety and Depression Scale depression

score

C Six Minute Walk Distance

197

Table 8.10 Transition Dyspnoea Index (TDI) focal scores at weeks 4 and 12 post randomisation (mean, standard error of the mean, SEM) and

results of t tests to compare air and oxygen groups

All n=142

Air n=74

Oxygen n=68

t

p

mean (SEM) mean (SEM) range mean (SEM) range

Week 4 0.3 (0.1) 0.3 (0.2) -5.0 - +5 0.4 (0.2) -3.0 - +5 -0.701 0.484

Week 12 0.2 (0.2) 0.3 (0.2) -8.0 - +5 0.1 (0.2) -5.0 - +4 0.377 0.707

Table 8.11 Number and proportion (%) of participants with a TDI focal score indicating clinically significantly deterioration (≤ minus 1), no

change (zero) and improvement (≥+1) dyspnoea at visits 3 and 4 for all participants, air and oxygen groups. Chi2 tests to assess differences

between groups.

All n=142

Air n=74

Oxygen n=68

n (%) n (% of group) n (% of group) Chi2 p

Week 4 ≤ minus1 19 (13.4) 12 (16.2) 7 (10.3)

zero 84 (59.2) 42 (56.8) 42 (61.8)

≥+1 39 (27.5) 20 (27.0) 19 (27.9) 1.090 0.580

Week 12 ≤ minus1 27 (19.0) 12 (16.2) 15 (22.1)

zero 70 (49.3) 39 (52.7) 31 45.6)

≥+1 45 (31.7) 23 (31.1) 22 (32.4) 1.018 0.601

198

60.050.040.030.020.010.00.0

Number of cylinders

50

40

30

20

10

0

Nu

mb

er

of

part

icip

an

ts

Figure 8.6 Histogram depicting cylinder utilisation over the 12 weeks of the study by participants overall (n=138)

Mean: 8.0 Standard deviation: 8.9 Median: 4.4

199

Table 8.12 Gas cylinder usage in participants overall and comparing air and oxygen groups presented as mean (standard error of the mean,

SEM) and results of comparisons using t tests.

All

Air

Oxygen n=68

mean (SEM) mean (SEM) mean (SEM) t p

Self-reported hours Week 4 hours n=130 n=69 n=61

(7 days) 9.3 (0.9) 9.8 (1.4) 8.5 (1.0) 0.767 0.445

Week 12 hours n=134 n=71 n=63

7.7 (0.7) 7.4 (1.0) 7.9 (0.9) -0.390 0.697

No of cylinders n=138 n=73 n=65

(over 12 weeks) 8.0 (0.8) 7.2 (0.8) 8.9 (1.3) -1.166 0.245

200

Table 8.13 Results of subgroup analyses using analysis of covariance (ANCOVA) and estimates of the mean differences in Chronic

Respiratory Disease Questionnaire dyspnoea score (the main outcome measure) for subjects receiving ambulatory air and ambulatory oxygen

with associated 95% Confidence Intervals (CI).

p-values

Oxygen – Air

Subgroups n Main effect Gas

Main effect Subgroup

Interaction (Gas*subgroup)

p-value 95% CI

Desaturation 138 0.336 0.706 0.393 0.744 (-0.780,2.268)

Severity of airflow obstruction

138 0.378 0.332 0.838 0.681 (-0.841,2.203)

Exercise response to hyperoxia 127 0.168 0.562 0.768 1.126 (-0.480,2.731)

Volume response to hyperoxia 137 0.247 0.115 0.224 0.887 (-0.621,2.395)

Severe breathlessness 137 0.355 0.759 0.153 0.715 (-0.809,2.238)

Gender

138 0.338 0.442 0.317 0.738 (-0.778,2.254)

n - sample size used for the analysis

Histogram depicting cylinder utilisation during the 12 weeks of the study for participants overall


8.6 Discussion

Patients with COPD who are not severely hypoxaemic at rest may experience

significant breathlessness on exertion which is, in some cases, associated with

desaturation. Domiciliary ambulatory oxygen is often prescribed in this

circumstance despite a lack of conclusive evidence for benefit. Previous studies

designed to examine this issue are few in number, limited by small sample sizes

and have reported conflicting results (Eaton et al 2002, McDonald et al 1995,

Nonoyama et al 2007a). This is the first large, parallel, double-blinded,

randomised controlled study of the effects of domiciliary ambulatory oxygen in a

group of such patients, including some with exertional desaturation. Across the

range of patients with COPD included in this study, no improvement was found in

dyspnoea, quality of life, functional capacity or performance when using cylinder

oxygen compared with cylinder air in the domiciliary setting. In addition, there

was no difference in gas usage and no factors predictive of benefit were found.

The study results demonstrated statistically significant improvements in dyspnoea

(CRQ dyspnoea score), depression and 6MWD in participants over the 12 weeks

of the study, regardless of which gas they received. However, these changes

were small and less than those accepted to be of clinical importance. With

respect to breathlessness, this is supported by the low TDI scores which were

found at weeks 4 and 12 post randomisation. Similarly, Nonoyama et al reported

a statistically significant but clinically small improvement in CRQ dyspnoea score

over the time of that study (Nonoyama et al 2007a). These results are either

suggestive of a benefit from nasal gas insufflation, regardless of whether it is air

or oxygen, or a placebo effect. Inclusion of a study group receiving no domiciliary

cylinders in any future trial would be required to confirm this possibility. This

effect of time across measures of benefit may also suggest that any future trials

should be cautious in their use of a cross-over design as an order effect may be

possible.

Four of the subgroup analyses (ANCOVA) suggested an interaction between

baseline prediction factors and treatment. Pedometer count significantly

interacted with both the severity of airflow obstruction and an increase in the

6MWD whilst using oxygen and anxiety scores also interacted with increased

6MWD on oxygen. However these results are difficult to explain in physiological


terms. Participants who had more severe airflow limitation performed less well

with oxygen and those able to increase their exercise performance with oxygen at

baseline had a lower pedometer count when supplied with oxygen and were

more anxious when receiving domiciliary oxygen. In contrast, the significant

interaction between generic quality of life (AQoL) and desaturation on exercise

suggested a potential quality of life benefit in this subgroup from ambulatory

oxygen. Similarly, one (Eaton et al 2002) of the three previous, relevant studies

(Eaton et al 2002, McDonald et al 1995, Nonoyama et al 2007a) found a

statistically significant but clinically small improvement in CRQ dyspnoea score

after ambulatory oxygen compared with ambulatory air. However, in the present

study, no main effect for gas or subgroup was observed for any of the analyses of

the main outcome measure, the CRQ dyspnoea score (Tables 8.8, 8.13).

Analysis of the results of the present study did not include any correction for

multiple comparisons and thus the statistically significant interactions should be

interpreted with caution, particularly as three of the four results can not be

explained physiologically.

Mean use of eight cylinders over 12 weeks represents approximately 40 minutes

of gas use per day. Comparisons are not possible with the information published

by Eaton et al (2002). However, when allowing for differences in apparatus,

cylinder use in the present study appears comparable to that of McDonald et al‟s

participants (McDonald et al 1995), but less than that reported by Nonoyama et al

(3.5 hours/day) (Nonoyama et al 2007a). Despite differences between these

studies (McDonald et al 1995, Nonoyama et al 2007a), their outcomes were

remarkably consistent, suggesting that increased cylinder use would not have

substantially affected the findings of the present study.

The observed cylinder use and the subjective diary reports of cylinder use

suggest that cylinder use was not high and was associated with difficulties.

Participants reported that they were standing or walking on average 5.4 hours per

day (Table 8.7) yet intranasal gas was used for only 12% of this time. Cylinders

used in our study were similar to those of McDonald, which weighed 5kg and

were also provided with a trolley/stroller (McDonald et al 1995), although 36

(25%) of our participants elected to transport their cylinders in a four-wheel

frame. By way of comparison, Eaton provided cylinders weighing 2.04kg, carried

in a backpack or shoulder bag (Eaton et al 2002). Higher use reported by

(Nonoyama et al 2007a) may have been due to more interventions (fortnightly)


from study assessors or differences in portability of delivery systems as both

cylinders and concentrators were used (Nonoyama et al 2007a).

Effort-related hypoxaemia may be one mechanism underpinning the development

of exertional dyspnoea in patients with COPD. However, it is likely that the

hyperoxia-induced improvements in exercise capacity and exertional dyspnoea

that are observed acutely are not solely dependent upon relief of hypoxaemia.

For this study, dyspnoea rather than exertional desaturation was chosen as the

main inclusion criterion in order to explore alternative mechanisms for relief of

dyspnoea with ambulatory oxygen. The two measures of dyspnoea used in the

present study indeed confirmed that its participants experienced disabling

functional dyspnoea at baseline. The finding that exertional desaturation was not

predictive of benefit is of concern as this is frequently the primary criterion for

ambulatory oxygen prescription (American Association for Respiratory Care

2007, McDonald et al 2005, Royal College of Physicians 1999), albeit with a

limited evidentiary basis. As noted, a significant interaction between desaturation

and quality of life was observed, but without any main effect of gas or subgroup

being apparent. In addition, in the main study group, no effect upon disease

specific quality of life (CRQ total score) was observed, nor was there any other

benefit found from oxygen compared with air. This significant interaction may

temper the strength of the study findings, but may also represent a statistical

Type I error. It is possible that there may have been too few people in the

subgroup with desaturation to detect a benefit from ambulatory oxygen. However,

there were 61 people with exertional desaturation in the subgroup of the present

study, a larger sample than either of the two previous studies which specifically

examined this question in patients with exertional desaturation, (Eaton et al 2002,

Nonoyama et al 2007a) and which also failed to show a convincing benefit.

The only previous study assessing the effects of ambulatory oxygen upon

functional performance measured 12-hour daily activity objectively using an

accelerometer and time spent outdoors by stop-watch (n=20) (Sandland et al

2008). Participants were more severely hypoxaemic than those in the present

study and were correspondingly less active outdoors (mean outings time 650 to

700 hours per week compared with 1008 hours in our group). Notwithstanding

this and other methodological differences, neither study found a difference in

daily activity or outings time when patients used ambulatory oxygen compared

with ambulatory air . Collectively, these studies suggest that the availability of


cylinders did not augment or hamper daily activity. However inclusion of a group

without cylinders is required to confirm this possibility.

One limitation of a study of this nature is inability to ensure adherence to

treatment instructions. It is not possible to determine whether study gases were

used during exertion as requested. Due to the widely-held assumption that

oxygen relieves breathlessness, supplemental oxygen is also used pre- or post-

exertion and is prescribed for use in this manner as Short Burst Oxygen Therapy

in some countries, despite lack of evidence of benefit (O'Driscoll 2008). It is

possible that study gases may have been used in this manner by participants in

the present study.

Hyperoxia is believed to reduce dyspnoea during exercise by reducing ventilatory

demand, allowing more time for lung emptying, thus delaying the onset of

dynamic hyperinflation. Previous studies suggest that this may occur in a dose-

dependent fashion, up to a fraction of inspired oxygen of 0.5 or a flow of 6L/min

of 100% oxygen delivered via nasal cannulae (Snider 2002). A flow rate of

6L/min was chosen for use in the present study for this reason and as this was

the highest flow rate provided by the apparatus available for domiciliary use.

Flow rates of 4L/min were provided in the McDonald et al and Eaton et al studies

(Eaton et al 2002, McDonald et al 1995) and Nonoyama et al used flows of 1-

3L/min to maintain saturation above 92% (Nonoyama et al 2007a). Thus, despite

providing ambulatory oxygen at a higher flow than previous studies and for a

longer period, no benefit was found in the current trial. Higher flow rates might

also augment relief from breathlessness thought to be derived reflexly from

cooling effects of gas flow on upper airways, however our results and those of

others do not support this theory (O'Driscoll 2008). A recent paper (O'Driscoll

2008) has highlighted the non-linearity of the relationship between dyspnoea and

hypoxaemia and the results of the present study further suggest that there is also

no direct correlation between the relief of hypoxaemia and a reduction in

dyspnoea.

Participants overall in the present study had a mean IC of 84.1 %predicted and

demonstrated a statistically significant but clinically small, acute volume response

(+1.9 %predicted, p=0.004) when breathing 44% oxygen compared with 21%

oxygen. Fifteen participants demonstrated an increase in resting volume

response to hyperoxia of at least the proposed MID in IC value (≥10 %predicted)


(O'Donnell et al 1999). These findings are consistent with the variability in

pulmonary volume response to hyperoxia which has been noted by others

(O'Donnell and Laveneziana 2006c). However, this acute increase in IC with

hyperoxia was not predictive of benefit from domiciliary use of cylinder oxygen.

As such, assessment of resting IC would not assist in determining those patients

who may benefit from domiciliary ambulatory oxygen.

This randomised controlled trial has determined that domiciliary ambulatory

oxygen provides no benefit over ambulatory air in terms of dyspnoea, quality of

life or function in patients with COPD who have exertional dyspnoea without

severe resting hypoxaemia. In addition, none of six factors examined, exertional

desaturation, more severe airflow obstruction or dyspnoea, volume or exercise

response to hyperoxia or gender, were predictive of a therapeutic benefit. The

statistically significant interaction between desaturation and quality of life may

represent a statistical Type 1 error. However, it may also suggest that any future

studies of the efficacy of domiciliary ambulatory oxygen should confine the

inclusion criteria to those who have exertional desaturation.

The findings of this study do not support the use of domiciliary ambulatory

oxygen as a treatment for dyspnoea in this group of patients and challenge the

use of exertional desaturation as the primary criterion for its prescription. Further,

the results were suggestive but not conclusive of placebo benefits from having

domiciliary gas cylinders. It remains unknown if provision of domiciliary

ambulatory oxygen can prevent exertional desaturation and if this would provide

any physiological or survival benefits in the long term.

Chapter 9: Conclusions and Future Directions 207

The important thing is not to stop questioning. Curiosity has its own reason for existing. Albert Einstein (1879 – 1955)

Conclusions and future directions

9.1 Introduction ................................................................................... 207 9.2 Major findings and future directions ............................................... 207 9.3 Strengths and limitations of this research ...................................... 209 9.4 Conclusions................................................................................... 211

9.1 Introduction

Domiciliary ambulatory (transportable) oxygen is prescribed in many countries for

patients with COPD and significant breathlessness but who do not have severe

hypoxaemia. This occurs despite a lack of evidence to support its use. The main

aim of this research project was to determine whether or not ambulatory oxygen,

provided in the domiciliary setting is beneficial for patients with COPD who do not

have severe hypoxaemia. This is a question which commonly arises in clinical

practice and as domiciliary ambulatory oxygen is expensive to provide, it is

imperative to know whether or not it is beneficial. A further aim of this project

was to identify those patients, if any, who are most likely to benefit.

9.2 Major findings and future directions

COPD is now recognised as a multisystem disorder, characterised by dyspnoea

and general functional decline. The target of therapeutic agents has broadened

from a focus on pulmonary outcomes to patient-centred outcomes including

quality of life, mood disturbance and functional capacity and performance.

A variety of easily-administered, valid, reliable and reproducible outcome

measures have been developed to assess dyspnoea, quality of life, mood

disturbance and functional capacity in COPD populations. Whilst the

accelerometer is recognised as the gold standard for measurement of functional

performance, its complexity and cost render it impractical for use in many

research and clinical settings.

9 Chapter


A patient-completed activity diary would appear to be a practical alternative.

However, very few studies have reported using an activity diary in COPD

populations and no validated instrument exists. Chapter 5 describes three pilot

studies conducted to develop a clinically-relevant and readily understood

instrument, to be completed on a daily basis.

The combined use of the activity diary developed for use in this research and a

simple pedometer was assessed in the study described in Chapter 6. This is the

first study published which has explored the use of these two measures in a

COPD population. Data collected over seven days from the first 80 patients

enrolled in the main study of this thesis was analysed. The main findings of this

study were that the activity diary was the more reliably completed of the two

methods and that representative data may be collected over fewer that seven

consecutive days in this group of patients with COPD. It was concluded that

whilst the activity diary offers greater promise for use in clinical and research

settings, further work is required to determine its precision as a discriminative,

evaluative and predictive tool.

Dyspnoea is a major symptom of COPD which is associated with functional

limitation and reduced quality of life. Whilst the causes of exertional dyspnoea in

COPD are multi-factorial, an important contributing factor is altered pulmonary

mechanics due to increasing pulmonary hyperinflation (dynamic hyperinflation)

(O'Donnell and Webb 2008). Dynamic hyperinflation may be reliably assessed

using serial measurement of inspiratory capacity and such measurement has

shown that supplemental oxygen (hyperoxia) provided during exertion can

attenuate its onset, thus improving exercise tolerance and reducing dyspnoea

(O'Donnell et al 2001a). However, little is known about pulmonary volume

response to hyperoxia at rest in COPD patients. Chapter 7 describes the first

study aimed to characterise ventilatory and dyspnoea responses to hyperoxia at

rest in a large group of patients with COPD of varying severity. It was

hypothesised that responses would vary and that characterisation of patients as

oxygen responders or non-responders at rest might assist in determining those

patients with COPD who may be likely to respond to hyperoxia used during

exertion in the domiciliary setting. This study of 51 patients with COPD found

that hyperoxia (44% oxygen) at rest induced significant reductions in heart rate

and dyspnoea when compared with breathing air, but no significant reduction in

resting lung volumes or ventilation. However, a significant association was found


between inspiratory capacity and degree of airflow obstruction, suggesting that

patients with moderate to severe airflow obstruction are more likely to have

improved operating lung volumes (reduced hyperinflation) with hyperoxia. The

fact that this occurred irrespective of the presence of hypoxaemia, raised the

possibility that supplemental oxygen may be beneficial in non-hypoxaemic

patients with COPD.

The main study of this thesis is described in Chapter 8. This was a parallel,

double-blinded, randomised, controlled trial to determine the effects of 12 weeks

of domiciliary ambulatory oxygen compared with ambulatory air in patients with

COPD, exertional dyspnoea, but without severe hypoxaemia. In addition, six

factors were selected a priori as subgroups which might benefit differentially from

domiciliary exertional oxygen. Participants were asked to use their ambulatory

cylinders for any activity provoking dyspnoea. Outcome measures assessed

dyspnoea, quality of life, mood alteration, functional status and gas utilisation. No

significant differences were found between patients receiving domiciliary oxygen

and air. In participants overall (those who received air and oxygen), statistically

significant improvements in one of two dyspnoea measures, depression scores

and exercise capacity were found, suggesting a placebo effect from domiciliary

cylinders. However, the differences in scores for these measures were clinically

small.

The six subgroup factors examined in sub-group analyses as possible predictors

of a therapeutic benefit were exertional desaturation, severity of airflow

obstruction and dyspnoea, volume and exercise response to hyperoxia and

gender. It was concluded that none of these factors were predictive of benefit

from domiciliary ambulatory oxygen in patients with COPD and significant

exertional dyspnoea.

9.3 Strengths and limitations of this research

The main study of this research (Chapter 8) and the smaller studies described in

this thesis provide novel findings which contribute to the understanding of COPD

and its management.

Daily physical activity level is an important factor to assess in the development of

therapeutic interventions for COPD. Two chapters in this thesis describe studies


conducted to develop and compare two relatively simple and practical measures

of daily physical activity. These studies show promise for the use of such

measures in both research and clinical settings, particularly for the use of the

activity diary.

Pulmonary volume response to hyperoxia has been shown to be an important

factor in hyperoxia-induced improvement in exercise tolerance and exertional

dyspnoea. This research found no significant response to hyperoxia at rest in

patients with COPD and a range of disease severity. This finding suggests that

assessment of resting volume response to hyperoxia (using inspiratory capacity

measurement), although relatively easily performed, would not be useful for

identifying those who might receive benefit from supplementary oxygen during

exertion.

The main study of this research, which assessed the effects of domiciliary

ambulatory oxygen, is the first study to examine this question in a large group of

patients with COPD who have exertional dyspnoea but do not have severe

resting hypoxaemia. As domiciliary ambulatory oxygen is already provided for

such patients in many centres, a study of this nature is difficult to perform.

Recruitment to the study was further hindered by the nature of the disease and its

symptoms in a mostly elderly population. Nonetheless, the study was adequately

powered to detect an effect if present. The finding of no benefit from ambulatory

oxygen in this group of patients indicates that this should not be provided using

the apparatus (compressed gas cylinder and trolley/stroller) that is commonly

supplied in many centres for ambulatory use.

The results of this study further suggested that domiciliary ambulatory cylinders

(air or oxygen) may provide a placebo benefit in terms of reduced dyspnoea and

depression and improved exercise capacity. However, to confirm these findings,

as study also including a group receiving no domiciliary cylinders would be

required.

The finding of no differential benefit from domiciliary ambulatory oxygen in any of

the six subgroups examined is important. Of particular note is the finding that

those patients with exertional desaturation also appeared not to benefit. This

challenges the current basis for prescription of ambulatory oxygen in the many

centres throughout the world where it is provided. In addition, this suggests that


further, large studies examining this question should focus on this group of

patients. In order to recruit a sufficiently large sample size, this may necessitate

collaborative work across a number of centres.

A further important issue which has arisen from the results of the main study is

that utilisation of domiciliary ambulatory cylinders was, on average, quite low

despite patients being provided with an unlimited supply and more

encouragement to use it than would occur in usual clinical circumstances. This

suggests that even if provided, cylinders may not be used as intended, in

particular to prevent exertional desaturation in those who demonstrate this.

Further, this study has not been designed to determine whether domiciliary

ambulatory cylinders can provide any other physiological or survival benefits if

provided in the long term.

9.4 Conclusions

The studies described in this thesis have added to the understanding of how

domiciliary ambulatory oxygen should be prescribed and which patients might be

more or less likely to benefit from it.

The conclusions which may be drawn from these studies are as follows:

1. Both an activity diary and a simple pedometer show promise as practical

tools for assessing daily physical activity in COPD populations.

2. An activity diary was more reliably completed than a pedometer.

3. Both the activity diary and the simple pedometer warrant further

development to determine their precision as valid, reliable and

reproducible outcome measures in COPD populations.

4. In patients with a wide range of disease severity, supplementary oxygen

does not confer a benefit in terms of improved operating lung volumes at

rest.

5. Assessment of resting pulmonary hyperinflation (using inspiratory

capacity measurement) is not useful to determine those patients who may

respond to supplemental oxygen during exertion.

6. In patients with COPD who have exertional dyspnoea but who do not

have severe hypoxaemia, domiciliary ambulatory oxygen provides no

benefits in terms of dyspnoea, quality of life, mood disturbance and

function.


7. Domiciliary ambulatory cylinders (irrespective of whether they contain air

or oxygen) may provide a placebo benefit in terms of reduced dyspnoea

and depression and improved exercise capacity.

8. Domiciliary ambulatory oxygen also appears to offer no differential benefit

in patients with COPD who have exertional dyspnoea, exertional

desaturation, more severe airflow obstruction or dyspnoea or volume or

exercise response to hyperoxia. In addition, there appears to be no

differential benefit on the basis of gender.

9. Ambulatory compressed gas cylinders, provided with a trolley/stroller are

poorly utilised in the domiciliary setting in this patient population.

10. There is no evidence to support the practice of prescribing domiciliary

ambulatory oxygen for patients with COPD and significant breathlessness

but without severe hypoxaemia.

There is a common perception that oxygen will be of therapeutic value for people

who are breathless, regardless of blood oxygen levels. Domiciliary ambulatory

oxygen is costly to provide, intrusive and difficult for many patients to use. It is

essential that it is only prescribed only in circumstances where benefits in

symptoms, quality of life or other aspects of the patient‟s condition can

confidently be anticipated. The studies described in this thesis have determined

that domiciliary ambulatory oxygen does not improve dyspnoea, quality of life or

function in patients with COPD who have significant breathlessness without

severe hypoxaemia.

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261

Appendix I Baseline/Transition Dyspnoea Index Worksheet

BDI/TDI WORKSHEET

BASELINE DYSPNOEA INDEX

Visit 1 Date: ……………….

Functional Impairment Types/kind of activities Any activities given up or changed? Are activities listed performed as previously? Record activities which have changed because of breathlessness.

Magnitude of task Level, magnitude, extent of task required to provoke breathlessness. What activities make you feel breathless? Record activities which provoke breathlessness; provide examples of grades.

Magnitude of effort Effort required to provoke breathlessness, time needed, pauses. Do you perform each activity at normal pace, very slowly/longer, pause frequently? Record effort for each activity, provide examples of grades

Job

Housework, shopping

Leisure activities, gardening

Social activities

Washing/dressing

At rest

Any other

BDI total score:

(Nil, slight, moderate, severe, very severe)

Functional impairment:

(Extraordinary, major, moderate, light, at rest)

Magnitude of task:

(Extraordinary, major, moderate, light, at rest)

Magnitude of effort:

Grades 4 – 0 X: unknown Y: impaired for reasons other than shortness of breath

STUDY NUMBER: ....................

SITE: ...........................................

EXERTIONAL OXYGEN STUDY The Northern Clinical Research Centre

Austin Health


262

TRANSITION

DYSPNOEA INDEX Visit 3 Date: ………………

Functional Impairment Types/kind of activities. Given up or started any new activities? Are activities listed performed as previously? Record activities which have been given up or changed.

Magnitude of task Level, magnitude, extent (of task required to provoke breathlessness. What activities now make you feel breathless? Review activities which previously caused breathlessness; record activities which now provoke same.

Magnitude of effort Effort required to provoke breathlessness, time needed pauses. For each activity listed, do you need more or less time, more or less pauses? Record effort now required to provoke breathlessness with baseline activities.

Job

Housework, shopping


Social activities

Washing/dressing

At rest

Any other

TDI total score: Functional impairment: Magnitude of task: Magnitude of effort:

TRANSITION

DYSPNOEA INDEX Visit 4 Date: ………………

Functional Impairment Types/kind of activities. Given up or started any new activities? Are activities listed performed as previously? Record activities which have changed.

Magnitude of task Level, magnitude, extent (of task required to provoke breathlessness. What activities now make you feel breathless? Review activities which previously caused breathlessness; record activities which now provoke same.

Magnitude of effort Effort required to provoke breathlessness, time needed pauses. For each activity listed, do you need more or less time, pauses? Record effort now required to provoke breathlessness with baseline activities.

Job

Housework, shopping


Social activities

Washing/dressing

At rest

Any other

TDI total score: Functional impairment: Magnitude of task: Magnitude of effort:

-3 to + 3: Major, moderate, minor deterioration, no change, minor, moderate, major improvement

Appendix II Baseline/Transition Dyspnoea Index Scoring Sheet 263

Appendix II Baseline/Transition Dyspnoea Index Scoring

Sheets

EXERTIONAL OXYGEN STUDY The Northern Clinical Research Centre and Austin Health

BASELINE DYSPNOEA INDEX Functional Impairment Grade 4 No impairment

Able to carry out usual activities and occupation without shortness of breath.

Grade 3 Slight impairment Distinct impairment in at least one activity but no activities completely abandoned. Reduction in activity at work or in usual activities, that seems slight or not clearly caused by shortness of breath.

Grade 2

Moderate impairment Patient has changed jobs and/or has abandoned at least one usual activity due to shortness of breath.

Grade 1

Severe impairment

Patient unable to work or has given up most or all usual activities due to shortness of breath.

Grade 0

Very severe impairment

Unable to work and has given up most or all usual activities due to shortness of breath.

X Unknown

Information unavailable regarding impairment

Y Impaired for reasons other than shortness of breath

For example, musculoskeletal problem or chest pain.

Usual activities refer to requirements of daily living, maintenance or upkeep of residence, yard work, gardening, shopping, etc.


Baseline Dyspnoea Index (continued)

Magnitude of Task

Grade 4 Extraordinary

Becomes short of breath only with extraordinary activity such as carrying very heavy loads on the level, lighter loads uphill, or running. No shortness of breath with ordinary tasks.

Grade 3 Major

Becomes short of breath only with such major activities as walking up a steep hill, climbing more than three flights of stairs, or carrying a moderate load on the level.

Grade 2

Moderate Becomes short of breath with moderate or average tasks such as walking up a gradual hill, climbing fewer than three flights of stairs or carrying a light load on the level.

Grade 1

Light

Becomes short of breath with light activities such as walking on the level, washing, or standing.

Grade 0

No task

Becomes short of breath at rest, while sitting or lying down.

X Unknown

Information unavailable regarding limitation of magnitude of task.



Magnitude of Effort

Grade 4 Extraordinary

Becomes short of breath only with the greatest imaginable effort. No shortness of breath with ordinary effort.

Grade 3 Major

Becomes short of breath with effort distinctly submaximal, but of major proportion. Tasks performed without pause unless the task requires extraordinary effort that may be performed with pauses.

Grade 2

Moderate Becomes short of breath with moderate effort. Tasks performed with occasional pauses and requiring longer to complete than the average person.

Grade 1

Light

Becomes short of breath with little effort. Tasks performed with little effort or more difficult tasks performed with frequent pauses and requiring 50–100% longer to complete than the average person might require.

Grade 0

No effort

Becomes short of breath at rest, while sitting or lying down.

X Unknown

Information unavailable regarding limitation of effort.




TRANSITION DYSPNOEA INDEX Change in Functional Impairment - 3 Major Deterioration

Formerly working and has had to stop working and has completely abandoned some of usual activities due to shortness of breath.

-2 Moderate Deterioration

Formerly working and has had to stop working or has completely abandoned some of usual activities due to shortness of breath.

-1

Minor Deterioration Has changed to a lighter job and/or has reduced activities in number or duration due to shortness of breath. Any deterioration less than preceding categories.

0 No Change No change in functional status due to shortness of breath.

+1

Minor Improvement

Able to return to work at reduced pace or has resumed some customary activities with more vigour than previously due to improvement in shortness of breath.

+2 Moderate Improvement

Able to return to work at nearly usual pace and/or able to return to most activities with moderate restriction only.

+3 Major Improvement

Able to return to work at former pace and able to return to full activity with only mild restriction due to improvement of shortness of breath.

Z Further impairment for reasons other than shortness of breath.

Patient has stopped working, reduced work, or has given up or reduced other activities for other reasons. For example, other medical problems, being “laid off” from work, etc.


Transition Dyspnoea Index (continued)

Change in Magnitude of Task - 3 Major Deterioration Has deteriorated two grades or greater from baseline status.


Has deteriorated at least one grade but fewer than two grades from baseline status.

-1

Minor Deterioration Has deteriorated less than one grade from baseline. Patient with distinct deterioration within grade, but has not changed grades.

0 No Change No change from baseline.

+1

Minor Improvement

Has improved less than one grade from baseline. Patient with distinct improvement within grade, but has not changed grades.


Has improved at least one grade but fewer than two grades from baseline.

+3 Major Improvement Has improved two grades or greater from baseline.


Patient has reduced exertional capacity, but not related to shortness of breath. For example, musculoskeletal problem or chest pain.

Change in Magnitude of Effort - 3 Major Deterioration

Severe decrease in effort from baseline to avoid shortness of breath. Activities now take 50-100% longer tom complete than required at baseline.


Some decrease in effort to avoid shortness of breath, although not as great as preceding category. There is greater pausing with some activities.

-1

Minor Deterioration Does not require more pauses to avoid shortness of breath, but does things with distinctly less effort than previously to avoid breathlessness.

0 No Change No change in effort to avoid shortness of breath.

+1

Minor Improvement

Able to do things with distinctly greater effort without shortness of breath. For example, may be able to carry out tasks somewhat more rapidly than previously.


Able to do things with fewer pauses and distinctly greater effort without shortness of breath. Improvement is greater than preceding category, but not of major proportion.

+3 Major Improvement

Able to do things with much greater effort than previously with few, if any, pauses. For example, activities may be performed 50-100% more rapidly than at baseline.


Patient has reduced exertional capacity, but not related to shortness of breath. For example, musculoskeletal problem or chest pain.

Appendix III The Assessment of Quality of Life Instrument 267

Appendix III The Assessment of Quality of Life Instrument

THE ASSESSMENT OF QUALITY OF LIFE INSTRUMENT INSTRUCTIONS:

TThhiiss qquueessttiioonnnnaaiirree hhaass 1155 qquueessttiioonnss aanndd wwiillll ttaakkee aabboouutt tteenn mmiinnuutteess..

TThhee qquueessttiioonnss aarree aabboouutt yyoouurr hheeaalltthh dduurriinngg tthhee llaasstt wweeeekk.. PPlleeaassee

lliisstteenn ccaarreeffuullllyy,, aanndd cchhoooossee tthhee aannsswweerr tthhaatt bbeesstt ddeessccrriibbeess yyoouu..

Question 1. Concerning your use of prescribed medicines in the last week.

[If the person asks ‘What is a prescribed medicine’, explain it refers to a medicine prescribed by a doctor, and it does not include over-the-counter drugs.]

Would you say that:

1. You did not or rarely used any medicines at all.

2. You used one or two medicinal drugs regularly.

3. You needed to use three or four medicinal drugs regularly.

4. You used five or more medicinal drugs regularly.

Question 2. To what extent did you rely on medicines or a medical aid in the last week.

[If the person asks for an example explain this refers to a walking frame, wheelchair, or prosthesis etc, but not to glasses or a hearing aid.]

[If the person asks about medicines, explain this refers to all medicines used whether prescribed by a doctor, allied health professional or bought from a chemist.

[If the person asks about ‘prothesis’, explain this refers to equipment used to replace a body part, such as an artificial arm.]

Would you say that:

1. You did not use any medicines and/or medical aids.

2. You occasionally used medicines and/or medical aids.

3. You regularly used medicines and/or medical aids.

4. You had to constantly take medicines or use a medical aid.


Austin Health The University of Melbourne


Question 3. In the last week, did you need medical treatment from a doctor or other health professional?

Would you say:

1. You did not need regular medical treatment.

2. You had some regular medical treatment.

3. You were dependent on having regular medical treatment.

4. That your life was dependent on regular medical treatment.

Question 4. Did you need any help with personal care in the last

week?

[If the person asks what is ‘personal care’, explain this refers to activities such as washing, dressing, personal grooming or going to the toilet.]

Would you say:

1. You needed no help at all.

2. Occasionally you needed some help with personal care tasks.

3. You needed help with the more difficult personal care tasks.

[For example, dressing, washing, toileting.]

4. You needed daily help with most or all personal care tasks.

Question 5. When doing household tasks during the last week, did you need

any help?

[For example, with preparing food, gardening, using the video recorder, radio, telephone or washing the car.]

Would you say:

1. You needed no help at all.

2. Occasionally you needed some help with household tasks.

3. You needed help with the more difficult household tasks.

[For example, with the house cleaning (e.g. vacuuming), laundry, shopping.]

4. You needed daily help with most or all household tasks.

Question 6. Thinking about how easily you got around your home and community in the last week.

Would you say:

1. You got around your home and community by yourself without any difficulty.

2. You found it difficult to get around your home and community by yourself.

3. You could not get around the community by yourself, but you got around your home with some difficulty.

4. You could not get around either the community or your

home by yourself.


Question 7. Were your personal relationships in the last week affected by your health.

[For example: with your partner or parents.] Would you say your relationships:

1. Were very close and warm.

2. Were sometimes close and warm.

3. Were seldom close and warm.

4. You had no close and warm relationships.

Question 8. Were your relationships with other people during the last week affected by your health.

Would you say:

1. That you had plenty of friends, and you were never lonely.

2. That although you have friends, you were occasionally

lonely.

3. That you have some friends, but you were often lonely.

4. That you felt socially isolated and lonely.

Question 9. Thinking about your health and your relationship with your family in the last week.

Would you say:

1. Your role in the family was not affected by your health.

2. There were some parts of your family role you could not

carry out.

3. There were many parts of your family role you could not

carry out.

4. You could not carry out any part of your family role.

Question 10. Thinking about your vision in the last week.

[Including when using your glasses or contact lenses if needed.]

Would you say:

1. You saw normally.

2. You had some difficulty focusing on things, or you did not

see them sharply.

[For example: small print, a newspaper, or seeing objects in the distance.]

3. You had a lot of difficulty seeing things and your vision

was blurred.

[For example: you saw just enough to get by with.]

4. You only saw general shapes, or you are blind.

[For example: you needed a guide to move around.]


Question 11. Thinking about your hearing in the last week.

[Including using a hearing aid if needed] Would you say:

1. You heard normally.

2. You had some difficulty hearing, or did not hear clearly.

[For example: you asked people to speak up, or turn up

the TV or radio volume.]

3 You had difficulty hearing things clearly.

[For example: Often you did not understand what was said. You usually did not take part in conversations because you could not hear what was said.]

4. You heard very little indeed.

[For example: you could not fully understand loud voices speaking directly to you.]

Question 12. When you communicated with others in the last

week.

[For example: by talking, listening, writing or signing.] Would you say:

1. You had no trouble speaking to others or understanding what they were saying.

2. You had some difficulty being understood by people who did not know you. You had no trouble understanding what others were saying.

3. You were only understood by people who knew you well. You had great trouble understanding what others were saying.

4. You could not adequately communicate with others.

Question 13. Thinking about how you slept in the last week.

Would you say:

1. You slept without difficulty most of the time.

2. Your sleep was interrupted some of the time, but you were usually able to go back to sleep without difficulty.

3. Your sleep was interrupted most nights, but you were usually able to go back to sleep without difficulty.

4. You slept in short bursts only. You were awake most of

the night.

Question 14. Thinking about how you generally felt in the last week.

Would you say:

1. You did not feel anxious, worried or depressed.

2. You were slightly anxious, worried or depressed.

3. You felt moderately anxious, worried or depressed.

4. You were extremely anxious, worried or depressed.


Question 15. How much pain or discomfort did you experience in the last week.

Would you say:

1. None at all.

2. You had moderate pain.

3. You suffered from severe pain.

4. You suffered unbearable pain.

Thank you very much for answering these questions.

Appendix IV The Chronic Respiratory Disease Questionnaire 273

Appendix IV The Chronic Respiratory Disease Questionnaire

EXERTIONAL OXYGEN STUDY The Northern Clinical Research Centre and

Austin Health

The Chronic Respiratory

Disease Questionnaire


CHRONIC RESPIRATORY INDEX QUESTIONNAIRE

First Administration, 7 Point Scale

INTERVIEWER FORM

This questionnaire is designed to find out how you have been feeling during the last 2 weeks. You will be asked about how short of breath you have been, how tired you have been feeling and how your mood has been.

1. I would like you to think of the activities that you have done during the last 2 weeks that have made you feel short of breath. These should be activities which you do frequently and which are important in your day-to-day life. Please list as many activities as you can that you have done during the last 2 weeks that have made you feel short of breath.

[CIRCLE THE NUMBER ON THE ANSWER SHEET LIST ADJACENT TO EACH ACTIVITY

MENTIONED. IF AN ACTIVITY MENTIONED IS NOT ON THE LIST, WRITE IT IN, IN THE

RESPONDENT'S OWN WORDS, IN THE SPACE PROVIDED]

Can you think of any other activities you have done during the last 2 weeks that have made you feel short of breath?

[RECORD ADDITIONAL ITEMS]

2. I will now read a list of activities which make some people with lung problems feel short of breath. I will pause after each item long enough for you to tell me if you have felt short of breath doing that activity during the last 2 weeks. If you haven't done the activity during the last 2 weeks, just answer 'NO'. The activities are:

[READ ITEMS, OMITTING THOSE WHICH RESPONDENT HAS VOLUNTEERED SPONTANEOUSLY. PAUSE AFTER EACH ITEM TO GIVE RESPONDENT A CHANCE TO INDICATE WHETHER HE/SHE HAS BEEN SHORT OF BREATH WHILE PERFORMING THAT ACTIVITY DURING THE LAST WEEK. CIRCLE THE NUMBER ADJACENT TO APPROPRIATE ITEMS ON ANSWER SHEET]


1. BEING ANGRY OR UPSET 2. HAVING A BATH OR SHOWER 3. BENDING

4. CARRYING, SUCH AS CARRYING GROCERIES 5. DRESSING 6. EATING 7. GOING FOR A WALK

8. DOING YOUR HOUSEWORK

9. HURRYING 10. MAKING A BED 11. MOPPING OR SCRUBBING THE FLOOR 12. MOVING FURNITURE 13. PLAYING WITH CHILDREN OR GRANDCHILDREN

14. PLAYING SPORTS

15. REACHING OVER YOUR HEAD 16. RUNNING, SUCH AS FOR A BUS 17. SHOPPING 18. WHILE TRYING TO SLEEP 19. TALKING 20. VACUUMING 21. WALKING AROUND YOUR OWN HOME 22. WALKING UPHILL

23. WALKING UPSTAIRS

24. WALKING WITH OTHERS ON LEVEL GROUND 25. PREPARING MEALS

3. a) Of the items which you have listed, which is the most important to you in your day-to-day life? I will read through the items, and when I am finished, I would like you to tell me which is the most important.

[READ THROUGH ALL ITEMS SPONTANEOUSLY VOLUNTEERED AND THOSE FROM THE LIST WHICH PATIENT MENTIONED]

Which of these items is most important to you in your day-today life?

[LIST ITEM ON RESPONSE SHEET]

b) Of the remaining items, which is the most important to you in your day-to-day life? I will read through the items, and when I am finished, I would like you to tell me which is the most important.

[READ THROUGH REMAINING ITEMS]

Which of these items is most important to you in your day-to-day life?


c) Of the remaining items, which is most important to you in your day-to-day life?



d) Of the remaining items, which is the most important to you in your day-to-day life?


e) Of the remaining items, which is the most important to you in your day-to-day life?


[FOR ALL SUBSEQUENT QUESTIONS, ENSURE RESPONDENT HAS APPROPRIATE RESPONSE CARD IN FRONT OF THEM BEFORE STARTING QUESTION]

4. I would now like you to describe how much shortness of breath you have experienced during the last 2 weeks while doing the five most important activities you have selected.

a) Please indicate how much shortness of breath you have had during the last 2 weeks while [INTERVIEWER: INSERT ACTIVITY LIST IN 3a] by choosing one of the following options from the card in front of you: [GREEN CARD]

1 EXTREMELY SHORT OF BREATH 2 VERY SHORT OF BREATH 3 QUITE A BIT SHORT OF BREATH 4 MODERATE SHORTNESS OF BREATH 5 SOME SHORTNESS OF BREATH 6 A LITTLE SHORTNESS OF BREATH 7 NOT AT ALL SHORT OF BREATH

b) Please indicate how much shortness of breath you have had during the last 2 weeks while [INTERVIEWER: INSERT ACTIVITY LISTED IN 3b] by choosing one of the following options from the card in front of you: [GREEN CARD]


c) Please indicate how much shortness of breath you have had during the last 2 weeks while [INTERVIEWER: INSERT ACTIVITY LIST IN 3c] by choosing one of the following options from the card in front of you: [GREEN CARD]



d) Please indicate how much shortness of breath you have had during the last 2 weeks while [INTERVIEWER: INSERT ACTIVITY LISTED IN 3d] by choosing one of the following options from the card in front of you: [GREEN CARD]


e) Please indicate how much shortness of breath you have had during the last 2 weeks while [INTERVIEWER: INSERT ACTIVITY LISTED IN 3e] by choosing one of the following options from the card in front of you: [GREEN CARD]


5. In general, how much of the time during the last 2 weeks have you felt frustrated or impatient? Please indicate how often during the last 2 weeks you have felt frustrated or impatient by choosing one of the following options from the card in front of you: [BLUE CARD]

1 ALL OF THE TIME 2 MOST OF THE TIME 3 A GOOD BIT OF THE TIME 4 SOME OF THE TIME 5 A LITTLE OF THE TIME 6 HARDLY ANY OF THE TIME 7 NONE OF THE TIME

6. How often during the past 2 weeks did you have a feeling of fear or panic when you had difficulty getting your breath? Please indicate how often you had a feeling of fear or panic when you had difficulty getting your breath by choosing one of the following options from the card in front of you: [BLUE CARD]



7. What about fatigue? How tired have you felt over the last 2 weeks? Please indicate how tired you have felt over the last 2 weeks by choosing one of the following options from the card in front of you: [ORANGE CARD]

1 EXTREMELY TIRED 2 VERY TIRED 3 QUITE A BIT OF TIREDNESS 4 MODERATELY TIRED 5 SOMEWHAT TIRED 6 A LITTLE TIRED 7 NOT AT ALL TIRED

8. How often during the last 2 weeks have you felt embarrassed by your coughing or heavy breathing? Please indicate how much of the time you felt embarrassed by your coughing or heavy breathing by choosing one of the following options from the card in front of you: [BLUE CARD]


9. In the last 2 weeks, how much of the time did you feel very confident and sure that you could deal with your illness? Please indicate how much of the time you felt very confident and sure that you could deal with your illness by choosing one of the following options from the card in front of you: [YELLOW CARD]

1 NONE OF THE TIME 2 A LITTLE OF THE TIME 3 SOME OF THE TIME 4 A GOOD BIT OF THE TIME 5 MOST OF THE TIME 6 ALMOST ALL OF THE TIME 7 ALL OF THE TIME

10. How much energy have you had in the last 2 weeks? Please indicate how much energy you have had by choosing one of the following options from the card in front of you: [PINK CARD]

1 NO ENERGY AT ALL 2 A LITTLE ENERGY 3 SOME ENERGY 4 MODERATELY ENERGETIC 5 QUITE A BIT OF ENERGY 6 VERY ENERGETIC 7 FULL OF ENERGY


11. In general, how much of the time did you feel upset, worried, or depressed during the last 2 weeks? Please indicate how much of the time you felt upset, worried, or depressed during the past 2 weeks by choosing one of the following options from the card in front of you. [BLUE CARD]


12. How often during the last 2 weeks did you feel you had complete control of your breathing problems? Please indicate how often you felt you had complete control of your breathing problems by choosing one of the following options from the card in front of you: [YELLOW CARD]


13. How much of the time during the last 2 weeks did you feel relaxed and free of tension? Please indicate how much of the time you felt relaxed and free of tension by choosing one of the following options from the card in front of you: [YELLOW CARD]


14. How often during the last 2 weeks have you felt low in energy? Please indicate how often during the last 2 weeks you have felt low in energy by choosing one of the following options from the card in front of you: [BLUE CARD]



15. In general, how often during the last 2 weeks have you felt discouraged or down in the dumps? Please indicate how often during the last 2 weeks you felt discouraged or down in the dumps by choosing one of the following options from the card in front of you: [BLUE CARD]


16. How often during the last 2 weeks have you felt worn out or sluggish? Please indicate how much of the time you felt worn out or sluggish by choosing one of the following options from the card in front of you: [BLUE CARD]

. 1 ALL OF THE TIME 2 MOST OF THE TIME 3 A GOOD BIT OF THE TIME 4 SOME OF THE TIME 5 A LITTLE OF THE TIME 6 HARDLY ANY OF THE TIME 7 NONE OF THE TIME

17. How happy, satisfied, or pleased have you been with your personal life during the last 2 weeks? Please indicate how happy, satisfied or pleased you have been by choosing one of the following options from the card in front of you: [GRAY CARD]

1 VERY DISSATISFIED, UNHAPPY MOST OF THE TIME 2 GENERALLY DISSATISFIED, UNHAPPY 3 SOMEWHAT DISSATISFIED, UNHAPPY 4 GENERALLY SATISFIED, PLEASED 5 HAPPY MOST OF THE TIME 6 VERY HAPPY MOST OF THE TIME 7 EXTREMELY HAPPY, COULD NOT HAVE BEEN MORE SATISFIED OR PLEASED

18. How often during the last 2 weeks did you feel upset or scared when you had difficulty getting your breath? Please indicate how often during the past 2 weeks you felt upset or scared when you had difficulty getting your breath by choosing one of the following options from the card in front of you: [BLUE CARD]

1 ALL OF THE TIME 2 MOST OF THE TIME. 3 A GOOD BIT OF THE TIME 4 SOME OF THE TIME 5 A LITTLE OF THE TIME 6 HARDLY ANY OF THE TIME 7 NONE OF THE TIME


19. How often during the last 2 weeks did you feel upset or scared when you had difficulty getting your breath? Please indicate how often during the past 2 weeks you felt upset or scared when you had difficulty getting your breath by choosing one of the following options from the card in front of you: [BLUE CARD]

1 ALL OF THE TIME 2 MOST OF THE TIME. 3 A GOOD BIT OF THE TIME 4 SOME OF THE TIME 5 A LITTLE OF THE TIME 6 HARDLY ANY OF THE TIME 7 NONE OF THE TIME

20. In general, how often during the last 2 weeks have you felt, restless, tense, or uptight? Please indicate how often you have felt restless, tense, or uptight by choosing one of the following options from the card in front of you: [BLUE CARD]



CHRONIC RESPIRATORY DISEASE INDEX QUESTIONNAIRE

Follow-up, 7 Point Scale, Informed

You have previously completed a questionnaire(s) telling us about how you were feeling and how your lung disease was affecting your life. This is a follow-up questionnaire designed to find out how you have been getting along the last [insert length of time since last seen].

When you are answering the questions this time I will tell you the answer you gave us the last time. I would like you to give your answer today keeping in mind what you said the last time. For example, let's say that last time I asked you how short of breath you were while beating carpets [GIVE RESPONDENT GREEN CARD] and you said "4 Moderate shortness of breath". If you were exactly the same today, you would answer 4 once again. If you were more short of breath you would choose 1, 2, or 3 and if you were less short of breath you would choose 5, 6, or 7.

[FOR QUESTIONS 4a) to 4e) INSERT ACTIVITIES 3a) to 3e) FROM FIRST ADMINISTRATION ANSWER SHEET]

4. I would now like you to describe how much shortness of breath you have experienced during the last two weeks while doing each of the five most important activities you have selected.

a) Please indicate how much shortness of breath you have had during the last two weeks while [INTERVIEVER: INSERT ACTIVITY LISTED IN 3a] by choosing one of the following options from the card in front of you, keeping in mind that last time you answered the questionnaire you chose [INSERT PATIENT'S ANSWER FROM PREVIOUS ADMINISTRATION]. [GREEN CARD]

b) Please indicate how much shortness of breath you have had during the last two weeks while [INTERVIEVER: INSERT ACTIVITY LISTED IN 3b] by choosing one of the following options from the card in front of you, keeping in mind that last time you answered the questionnaire you chose [INSERT PATIENT'S ANSWER FROM PREVIOUS ADMINISTRATION]. [GREEN CARD]

c) Please indicate how much shortness of breath you have had during the last two weeks while [INTERVIEVER: INSERT ACTIVITY LISTED IN 3c] by choosing one of the following options from the card in front of you, keeping in mind that last time you answered the questionnaire you chose [INSERT PATIENT'S ANSWER FROM PREVIOUS ADMINISTRATION]. [GREEN CARD]

d) Please indicate how much shortness of breath you have had during the last two weeks while [INTERVIEWER: INSERT ACTIVITY LISTED IN 3d] by choosing one of the following options from the card in front of you, keeping in mind that last time you answered the questionnaire you chose [INSERT PATIENT'S ANSWER FROM PREVIOUS ADMINISTRATION]. [GREEN CARD]


e) Please indicate how much shortness of breath you had during the last two weeks while [INTERVIEWER: INSERT ACTIVITY LISTED IN 3e] by choosing one of the following options from the card in front of you, keeping in mind that last time you answered the questionnaire you chose [INSERT PATIENT'S ANSWER FROM PREVIOUS ADMINISTRATION]. [GREEN CARD]

5. In general, how much of the time during the last two weeks have you felt frustrated or impatient? Please indicate how often during the last two weeks you have felt frustrated or impatient by choosing one of the following from the card in front of you, keeping in mind that last time you answered the questionnaire you chose (INSERT PATIENT'S ANSWER FROM PREVIOUS ADMINISTRATION]. [BLUE CARD]

6. In general, how much of the time during the last two weeks have you felt frustrated or impatient? Please indicate how often during the last two weeks you have felt frustrated or impatient by choosing one of the following from the card in front of you, keeping in mind that last time you answered the questionnaire you chose (INSERT PATIENT'S ANSWER FROM PREVIOUS ADMINISTRATION]. [BLUE CARD]

7. How often during the past two weeks did you have a feeling of fear or panic when you had difficulty getting your breath? Please indicate how often you had a feeling of fear or panic when you had difficulty getting your breath by choosing one of the following options from the card in front of you keeping in mind that last time you answered the questionnaire you chose [INSERT PATIENT'S ANSWER FROM PREVIOUS ADMINISTRATION]. [BLUE CARD]

8. What about fatigue? How tired have you felt over the last two weeks? Please indicate how tired you have felt over the last two weeks by choosing one of the following options from the card in front of you, keeping in mind that last time you answered the questionnaire you chose [INSERT PATIENT'S ANSWER FROM PREVIOUS ADMINISTRATION]. [ORANGE CARD]

9. How often during the last two weeks have you felt embarrassed by your coughing or heavy breathing? Please indicate how much of the time you felt embarrassed by your coughing or heaving breathing by choosing one of the following options from the card in front of you, keeping in mind that last time you answered the questionnaire you chose [INSERT PATIENT'S ANSWER FROM PREVIOUS ADMINISTRATION]. [BLUE CARD]

10. In the last two weeks, how much of the time did you feel very confident and sure that you could deal with your illness? Please indicate how much of the time you felt very confident and sure that you could deal with your illness by choosing one of the following options from the card in front of you, keeping in mind that last time you answered the questionnaire you chose [INSERT PATIENT'S ANSWER FROM PREVIOUS ADMINISTRATION]. [YELLOW CARD]


11. How much energy have you had in the last two weeks? Please indicate how much energy you have had by choosing one of the following options from the card in front of you, keeping in mind that last time you answered the questionnaire you chose [INSERT PATIENT'S ANSWER FROM PREVIOUS ADMINISTRATION]. [PINK CARD]

12. In general, how much of the time did you feel upset, worried or depressed during the last two weeks? Please indicate how much of the time you felt upset, worried, or depressed during the last two weeks by choosing one of the following options from the card in front of you, keeping in mind that last time you answered the questionnaire you chose [INSERT PATIENT'S ANSWER FROM PREVIOUS ADMINISTRATION]. [BLUE CARD]

13. How often during the last two weeks did you feel you had complete control of your breathing problems? Please indicate how often you felt you had complete control of your breathing problems by choosing one of the following options from the card in front of you, keeping in mind that last time you answered the questionnaire you chose [INSERT PATIENT'S ANSWER FROM PREVIOUS ADMINISTRATION]. [YELLOW CARD]

14. How much of the time during the past two weeks did you feel relaxed and free of tension? Please indicate how much of the time you felt relaxed and free of tension by choosing one of the following options from the card in front of you, keeping mind that last time you answered the questionnaire you chose [INSERT PATIENT'S ANSWER FROM PREVIOUS ADMINISTRATION]. [YELLOW CARD]

15. How often during the last two weeks have you felt low in energy? Please indicate how often during the last two weeks you have felt low in energy by choosing one of the following options from the card in front of you, keeping in mind that last time you answered the questionnaire you chose [INSERT PATIENT'S ANSWER FROM PREVIOUS ADMINISTATION]. [BLUE CARD]

16. In general, how often during the last two weeks have you felt discouraged or down in the dumps? Please indicate how often during the last two weeks you have felt discouraged or down in the dumps by choosing one of the following options from the card in front of you, keeping in mind that last time you answered the questionnaire you chose [INSERT PATIENT'S ANSWER FROM PREVIOUS ADMINISTRATION]. [BLUE CARD]

17. How often during the last two weeks have you felt worn out or sluggish? Please indicate how much of the time you felt worn out or sluggish by choosing one of the following options from the card in front of you, keeping in mind that last time you answered the questionnaire you chose [INSERT PATIENT'S ANSWER FROM PREVIOUS ADMINISTRATION]. [BLUE CARD]


18. How happy, satisfied, or pleased have you been with your personal life during the last two weeks? Please indicate how happy, satisfied or pleased you have been by choosing one of the following options from the card in front of you, keeping in mind that last time you answered the questionnaire you chose (INSERT PATIENT'S ANSWER FROM PREVIOUS ADMINISTRATION]. [GRAY CARD]

19. How often during the last two weeks did you feel upset or scared when you had difficulty getting your breath? Please indicate how often during the last two weeks you felt upset or scared when you had difficulty getting your breath by choosing one of the following options from the card in front of you, keeping in mind that last time you answered the questionnaire you chose [INSERT PATIENT'S ANSWER FROM PREVIOUS ADMINISTRATION]. [BLUE CARD]

20. In general, how often during the last two weeks have you felt restless, tense, or uptight? Please indicate how often you have felt restless, tense, or uptight by choosing one of the following options from the card in front of you, keeping in mind that last time you answered the questionnaire you chose [INSERT PATIENT'S ANSWER FROM PREVIOUS ADMINISTRATION]. [BLUE CARD]


GREEN CARD 1 EXTREMELY SHORT OF BREATH 2 VERY SHORT OF BREATH 3 QUITE A BIT SHORT OF BREATH 4 MODERATE SHORTNESS OF BREATH 5 SOME SHORTNESS OF BREATH 6 A LITTLE SHORTNESS OF BREATH 7 NOT AT ALL SHORT OF BREATH

ORANGE CARD 1 EXTREMELY TIRED 2 VERY TIRED 3 QUITE A BIT OF TIREDNESS 4 MODERATELY TIRED 5 SOMEWHAT TIRED 6 A LITTLE TIRED 7 NOT AT ALL TIRED

BLUE CARD 1 ALL OF THE TIME 2 MOST OF THE TIME 3 A GOOD BIT OF THE TIME 4 SOME OF THE TIME 5 A LITTLE OF THE TIME 6 HARDLY ANY OF THE TIME 7 NONE OF THE TIME

YELLOW CARD 1 NONE OF THE TIME 2 A LITTLE OF THE TIME 3 SOME OF THE TIME 4 A GOOD BIT OF THE TIME 5 MOST OF THE TIME 6 ALMOST ALL OF THE TIME 7 ALL OF THE TIME

PINK CARD 1 NO ENERGY AT ALL 2 A LITTLE ENERGY 3 SOME ENERGY 4 MODERATELY ENERGETIC 5 QUITE A BIT OF ENERGY 6 VERY ENERGETIC 7 FULL OF ENERGY

GRAY CARD 1 VERY DISSATISFIED, UNHAPPY MOST OF THE TIME 2 GENERALLY DISSATISFIED, UNHAPPY 3 SOMEWHAT DISSATISFIED, UNHAPPY 4 GENERALLY SATISFIED, PLEASED 5 HAPPY MOST OF THE TIME 6 VERY HAPPY MOST OF THE TIME 7 EXTREMELY HAPPY, COULD NOT HAVE BEEN MORE SATISFIED OR PLEASED

Appendix V The Hospital Anxiety and Depression Scale 287

Appendix V The Hospital Anxiety and Depression Scale

EXERTIONAL OXYGEN STUDY The Northern Clinical Research Centre Austin Health The University of Melbourne

THE HOSPITAL ANXIETY AND DEPRESSION SCALE

Doctors are aware that emotions play an important part in most illnesses.

If your doctor knows about these feelings he will be able to help you

more.

This questionnaire is designed to help your doctor to know how you feel.

Read each line and underline the reply that comes closest to how you

have been feeling in the past week.

Don’t take too long over your replies; your immediate reaction to each

item will probably be more accurate than a long thought out response.

I feel tense or “wound up”:

Most of the time A lot of the time From time to time, occasionally Not at all

I still enjoy the things I used to enjoy:

Definitely as much Not quite as much Only a little Hardly at all

I get a sort of frightened feeling as

if something awful is about to happen:

Very definitely and quite badly Yes, but not too badly A little, but it doesn’t worry me Not at all

Trial Number: ……………….. Assessment Number: ……... Date: ………………………….. Site: ...........................................


I can laugh and see the funny side of things:

As much as I always could Not quite so much now Definitely not so much now Not at all

Worrying thoughts go through my mind:

A great deal of the time A lot of the time From time to time but not too often Only occasionally

I feel cheerful:

Not at all Not often Sometimes Most of the time

I can sit at ease and feel relaxed:

Definitely Usually Not often Not at all

I feel as if I have been slowed down:

Nearly all the time Very often Sometimes Not at all

I get a sort of frightened feeling like “butterflies” in the stomach:

Not at all Occasionally Quite often Very often

I have lost interest in my appearance:

Definitely I don’t take so much care as I should I may not take quite as much care I take just as much care as ever


I feel restless as if I have to be on the move: Very much indeed Quite a lot Not very much Not at all

I look forward with enjoyment to things:

As much as I ever did Rather less than I used to Definitely less than I used to Hardly at all

I get sudden feelings of panic:

Very often indeed Quite often Not very often Not at all

I can enjoy a good book or radio or TV Program:

Often Sometimes Not often Very seldom

Now check that you have answered all the questions

Appendix VI Six Minute Walk Test Protocol 291

Appendix VI Six Minute Walk Test Protocol

EXERTIONAL OXYGEN STUDY SIX MINUTE WALK TEST PROTOCOL

INTRODUCTION The Six Minute Walk Test will be used to assess exercise tolerance for this study. In addition to this protocol, laminated instruction cards for assessors, a laminated copy of the Borg scale and a worksheet have been designed. The protocol has been devised in accordance with the American Thoracic Society guidelines for the Six Minute Walk Test (American Journal of Respiratory and Critical Care Medicine 166: 111-117, 2002). Three 6MWT’s will be performed by each subject at three of the four study visits: Visit 2: week 2, end of run-in phase Visit 3: week 6, one week after commencement of intervention phase Visit 4: week 14, completion of the study. Testing should be performed at a similar time of day on each of the three occasions. See flow chart below. Two identical, portable study cylinders, labelled cylinder A and cylinder B, will be used during each visit in random order. One cylinder will contain compressed air (control) and the other will contain compressed oxygen (treatment). The subject and the assessor will be blinded as to which is the control or treatment cylinder. The procedure for cylinder use is as follows:

during Test 1, the first study cylinder will be used, with gas flow turned off

during Test 2, the first study cylinder will be used, with gas flow turned on

during Test 3, the second study cylinder will be used, with gas flow turned on.

A period of at least 10 minutes should elapse between tests, sufficient time to allow return to baseline. Gas flow to be off or on as required for 10 minutes



The Northern Clinical Research Centre The Northern Hospital

185 Cooper Street Epping 3076


prior to each test. Gas flow will be set at 6 L/min, via a conservation device set on Mode A (providing a conservation ratio of 6:1). Procedure flowchart

Familiarisation with the portable gas cylinder and related equipment takes place at Visit 2, prior to the first test, using the first study cylinder. During this procedure, the subject selects the preferred hand for holding the cylinder trolley. This is recorded on the worksheet. The same hand will be used for all tests. During testing, the subject will turn around markers at each end of the walking course, such that the cylinder travels around on the outside of the turn (rather than between the cone and the subject). Alternatively, subjects using 4-wheel frames will use a basket attached to the frame to carry the cylinder; this will be recorded on the worksheet. Standardised instructions are written in bolded italics and must be read to the subject. CONTRAINDICATIONS All subjects in the study will have been screened prior to enrolment. Exclusion criteria for the study include the absolute contraindications for the 6MWT. Contraindications to performing the test are as follows: Absolute contraindications:

unstable angina during the previous month

myocardial infarction during the previous month Relative contraindications:

a resting heart rate of > 120 bpm

systolic blood pressure of > 180 mmHg and diastolic blood pressure of > 100 mmHg.

Subjects with these findings will be discussed with the referring physician or physician supervising the study. Stable exertional angina is not an absolute contraindication for performing a 6MWT, but subjects should perform the test after using anti-anginal medication, and rescue nitrate medication should be readily available. SAFETY ISSUES A 6MWT should be stopped immediately should the subject display any of the following:

chest pain

intolerable dyspnoea

leg cramps

staggering

diaphoresis

pale or ashen appearance.

Preparation

Familiarisation Visit 2 only

Practice Test 1

st study cylinder

(no flow)

Test 2 1

st study

cylinder

Test 3 2

nd study

cylinder


LOCATION The test is performed indoors along a flat, straight corridor, which is seldom travelled and has a hard surface. Adhesive tape is used to mark:

a starting line

a line at the opposite end of the course (25 metres)

turning points (crosses) 0.5 metre inside each of the above two lines. A chair is placed near the starting line. EQUIPMENT/FACILITIES

telephone stop watch lap counter chair clip board, pen instruction sheets, laminated worksheet Borg Scale: printed on A4 sized card, preferably laminated, 20-point font size pulse oximeter coloured adhesive tape measuring wheel at The Northern Hospital (marked corridor at The Austin Hospital) emergency portable oxygen cylinder, flow meter and nasal cannulae 2 study cylinders of identical appearance, labelled A and B, one containing compressed oxygen and one containing compressed air, both in trolleys with flow meters and with conservation devices attached 1 set of nasal cannulae for participant 1 set of nasal cannulae for assessor for visit 2.

PREPARATION

Ensure all equipment required is present; randomise order of study cylinders and position first study cylinder next to subject.

Subject should be wearing comfortable clothing and suitable shoes for walking.

A light meal is acceptable before early morning or early afternoon tests.

Subjects should not have exercised vigorously within 2 hours of beginning the tests.

The subject’s usual medications should continue and are recorded for that day.

FAMILIARISATION (Visit 2 only)

Subject seated.

Connect first study cylinder to conservation device and nasal cannulae. Introduce subject to the equipment, including cylinder, trolley, conservation device, nasal cannulae. Explain the intermittent nature of gas flow via the conservation device.


Fit nasal cannulae; ensure gas flow is on 6 L/min, pulsed flow (mode A). Allow subject sufficient time to become familiar with sensation of pulsed gas flowing via nasal cannulae.

Subject to walk a few metres along the track, including at least 1 turn around nearest cone, with the first study gas cylinder, nasal prongs in situ. Subject to decide on preferred hand for holding trolley: record on worksheet.

Subject to sit on chair near starting line (gas flow off).

TEST PROCEDURES TEST 1 (PRACTICE TEST)

1. Subject seated on a chair near the starting line. Ensure first study cylinder is

positioned next to subject with nasal cannulae in situ. Gas flow is to be off and subject to rest for at least 10 minutes prior to commencement of first test walk.

2. Instructions:

Today you are asked to perform 3 exercise tests. The tests will last for 6 minutes and you will rest between them. During each test you will walk with a portable gas cylinder. During the first test, there will be no gas flow from the cylinder. During the second and third tests, gas flow will be turned on. You will have the same cylinder for the first two tests. You will be given a different cylinder for the third test, but it will function in the same manner. You and I will not know if you are receiving compressed air or compressed oxygen from the cylinders.

3. Explain use of Borg Scale for dyspnoea and fatigue.

This is a scale for rating breathlessness and fatigue, especially leg fatigue. The number zero represents no breathlessness or fatigue. The number 10 represents the strongest or greatest breathlessness or fatigue that you have ever experienced. Before and after each test you will be asked to point to the number which represents your perceived level of breathlessness or fatigue, especially leg fatigue.

4. Instructions:

The object of this test is to walk as far as possible for 6 minutes. You will walk back and forth in this hallway. Six minutes is a long time to walk, so you will be exerting yourself. You will probably get out of breath or become exhausted. You are permitted to slow down, to stop, and to rest as necessary. You may lean against the wall while resting, but resume walking as soon as you are able.

You will be walking back and forth around the crosses. You will walk in a/n clockwise/anticlockwise direction, around the crosses,


turning to your right/left. You should pivot briskly around the crosses and continue back the other way without hesitation. Now I’m going to show you. Please watch the way I turn without hesitation.

Demonstrate by walking a few metres along the track. Walk and pivot around the cross briskly, in direction previously established. 5. Set lap counter to zero and timer to 6 minutes.

I am going to use this counter to keep track of the number of laps you complete. I will click it each time you turn around at this starting line. Remember that the object is to walk AS FAR AS POSSIBLE for 6 minutes, but don’t run or jog.

I will tell you the time, and will let you know when 6 minutes are up. When I say “stop”, please stand right where you are. I would like you not to talk during the test unless necessary.

6. The subject is then asked to summarise the instructions to ensure that he/she understands the requirements of the test.

7. After at least 10 minutes, with subject seated, record baseline respiratory

rate, heart rate, SpO2. Subject to rate dyspnoea and overall fatigue using Borg Scales. Instructions:

Please grade your level of shortness of breath using this scale. Please grade your level of fatigue, especially leg fatigue, using this scale.

Record grades on worksheet. Ensure baseline measurements are stable. 8. Subject to stand on starting line on correct side of marker (cross).

Instructions: Start now or whenever you are ready.

Record time on worksheet. 9. Stand approximately mid-way along the course. Do not talk to anyone

during the test; do not walk beside or in front of the subject. Each time the subject returns to the starting line click the lap counter once. Let the subject see you do so. Standardised encouragement is used during the test as below. No other encouragement is provided.

When 5 minutes remaining: You are doing well. You have 5 minutes to go. When 4 minutes remaining: Keep up the good work. You have 4 minutes to go. When 3 minutes remaining: You are doing well. You are half- way done. When 2 minutes remaining: Keep up the good work. You have only 2 minutes left.


When 1 minute remaining: You are doing well. You have only 1 minute to go. When 15 seconds remaining: In a moment I am going to tell you to stop. When I do, just stop right where you are and I will come to you. When stop watch beeps: Stop.

10. Walk over to subject; take chair if required, mark the spot the subject

reached by placing lap counter on the floor. 11. Record time, SpO2, heart rate, respiratory rate.

Record Borg dyspnoea and fatigue levels: Please grade your level of shortness of breath at the end of this test, using this scale. Your grade was ..... at the beginning of the test. Please grade your level of fatigue, especially leg fatigue, at the end of this test, using this scale. Your grade was ..... at the beginning of the test.

Ask: What, if anything, kept you from walking further?

12. Record the number of laps completed (from counter) and additional distance

covered using the measuring wheel (wall markers at The Austin Hospital). Calculate and record total distance walked, rounding to the nearest metre.

13. If subject stops walking during the test and needs a rest, say:

You can lean against the wall if you wish; then continue walking whenever you feel able.

After each minute of resting say: Continue walking whenever you feel able.

Continue to tell subject how many minutes of the test remain during the rest period.

14. Do not stop the timer during the 6 minute test period. If the subject stops

before the end of the 6 minute period and refuses to continue (or you decide that the test should be stopped), take the chair to where the subject is positioned, and note the distance, time stopped and reason for stopping prematurely in “comments” section on worksheet.


TEST 2 Subject to rest, seated on a chair on starting line. Ensure first study cylinder is positioned next to subject with gas flow on for at least 10 minutes. Instructions:

Remember that the object of the test is to walk AS FAR AS POSSIBLE for 6 minutes, but don’t run or jog.

Test to proceed from number 7. above. TEST 3 Change to second study cylinder. Subject to rest for at least 10 minutes with gas flow on. Test to proceed from number 7. above. VISITS 3 AND 4 Prepare track and equipment. Proceed with 3 tests as above, omitting “Familiarisation” procedure.

Appendix VII Pilot 1 Activity Diary 299

Appendix VII Pilot 1 Activity Diary

The Northern Clinical Research Centre

and

Austin Health

Exertional Oxygen Study

Activity Diary

Study number: ………………...... Date: …………………………...... Site: ...........................................

The Northern Hospital

185 Cooper Street

Epping 3076


Study number: ...................................................................

DATE: ...............................

Waking

(morning) to

breakfast

Breakfast

to lunchtime

Lunch

to dinner time

Dinner

to bedtime

Bedtime

to waking (morning)

Hours/duration of each time period Eg. 6.00 to 9.30

am

1 lying

2 sitting

3 sitting activity

4 standing

5 standing activity

6 personal

7 walking (slow/intermittent)

8 walking (brisk)

9 driving

10 other/comments

11 outings



Activity Diary

You are asked to fill in your Activity Diary Sheets for 7 consecutive days. You have been given 7 Activity Diaries, one for each day. Each diary sheet has been dated. Please fill in your Activity Diary for every time period, as indicated. For each time period, document the types of activities you performed by writing how long you spent on each type of activity in the appropriate box eg. 20 minutes, 1¾ hours Also, for each activity, please indicate if you used your cylinder with a tick

The types of activities listed in the table are as follows:

Lying Sitting: for example reading, watching television Sitting activity: for example performing a seated exercise program Standing Standing activity: for example preparing meals, performing an exercise program whilst standing. Personal: for example showering, cleaning Walking (slow/intermittent) Walking (brisk/for exercise) Shopping Driving Other: any activity which you cannot record as above Outings: record the total amount of time spent outside your home for that day.

If you have any difficulties with filling in your diary, please contact the study co-ordinator, Rosemary Moore:

Business Hours 8405 8064 After Hours 0412 456 177

Appendix VIII Activity Diary Pilot Questionnaire 303

Appendix VIII Activity Diary Pilot Questionnaire


185 Cooper Street, Epping, Victoria, Australia, 3076 Telephone (03) 8405 8064

Facsimile (03) 8405 8683

Activity Diary – Pilot

Name (optional): .................................................................. Was there anything which was difficult to understand? If so, please explain: ...................................................................................................

....................................................................................................................................

....................................................................................................................................

....................................................................................................................................

....................................................................................................................................

.....................................

Could the diary have been better designed? If so, do you have any suggestions? ........................................................................................

......................................................................................................................................

............................................................................................

3. Did it take too long to complete each day? ............................................

4. Is the writing large enough? .................................................................

5. Are the spaces provided large enough? ................................................ 6. Do you have any other comments? .......................................................

...........................................................................................................................................

...........................................................................................................................................

...........................................................................................................................................

...........................................................

Thank you for your time.

Director A/Prof Bruce Jackson Research Fellows Penny Harvey Coordinator David Berlowitz Kim Jeffs Geriatricians Kwang Lim, Rohan Wee Rosemary Moore Pharmacist Margaret Wyatt Maria Murphy Physiotherapist Natalie De Morton Karen Page Nurse Consultant Meg Storer Email format Allied Health Assistant Nadia Rangan [email protected]

mailto:[email protected]

Appendix IX Pilot 2 Activity Diary 305

Appendix IX Pilot 2 Activity Diary

EXERTIONAL OXYGEN STUDY

The Northern Clinical Research Centre and Austin Health

Activity Diary Sheet

You are asked to fill in your Activity Diary Sheets for 7 consecutive days, including a weekend. You have been given 7 Activity Diary Sheets. Each diary sheet should be dated according to the 7 days that you have chosen.

Please fill in your Activity Diary for every time period. For each time period, please document how long you spent on each type of activity. The types of activities listed in the table are as follows:

1. Lying: for example, in bed, on a couch 2. Sitting: for example reading, watching television, eating

meals 3. Standing: any activities performed standing up

In addition, please indicate how long you spent during any outings (outside your home and garden) for the day. Please write this in the “Outings” row near at the bottom of the page. Any other comments may be written in the last row. Indicate when you used your cylinder during each time period by circling the times for the activity or writing this in the 4th column.

Name: .............................. Date: ................................ Site: ..................................

If you have any difficulties with filling in your diary, please contact the study co-ordinator, Rosemary Moore: Business Hours 8405 8064 After Hours 9853 2507 Mobile 0412 456 177

Appendix IX Pilot 2 Activity Diary 306

DAY: ................

DATE: ..............

1

lying

2

sitting

3

standing

4

other

6.00 am - 7.00

7.00 - 8.00

8.00 - 9.00

9.00 - 10.00

10.00 -11.00

11.00 - 12 midday

12.00 - 1.00

1.00 - 2.00

2.00 - 3.00

3.00 - 4.00

4.00 -5.00

5.00 - 6.00

6.00 - 7.00

7.00 - 8.00

8.00 - 9.00

9.00 - 10.00

10.00 - 11.00

11.00 - 12 midnight

Midnight - 6.00 am

Outings – total time

Comments

Appendix X Activity Diary

307



308

Appendix XI Inspiratory Capacity Measurement Worksheet 1 311

Appendix XI Inspiratory Capacity Measurement

Worksheet 1

Austin Health The Northern Clinical Research Centre


ExOx Study IC Worksheet

Date: ...............................................

Assessor: .......................................

Borg Score after 5 minutes + when stable IC Measurement 1 IC Measurement 2 IC Measurement 3 Additional measurements if required: ……………………….. ……………………..…………. IC Measurement Average of 2 results within 200 mls

UR: .......................................................

Surname: .............................................

Given Names: ......................................

DOB: ...................................................

OR attach ID Label here

Study No

Current inhaled Time taken medications (incl BD) today ............................... .................

............................... .................

............................... .................

............................... .................

............................... ................

…………………….. .…...……

Borg Score after 5 minutes + when stable IC Measurement 1 IC Measurement 2 IC Measurement 3 Additional measurements if required: ……………………….. ……………………..…………. IC Measurement Average of 2 results within 200 mls

1st

Study Gas

2nd

Study Gas

Baseline Borg Score at rest on RA

Appendix XII Inspiratory Capacity Measurement Worksheet 2 313

Appendix XII Inspiratory Capacity Measurement

Worksheet 2

INSPIRATORY CAPACITY STUDY

Oxygen Saturation, Heart Rate & Respiratory Rate Data

Austin Health The Northern Clinical Research Centre


Study Number: ………..

Date: ....…………………

BASELINE (at rest for ≥ 5 minutes)

Oxygen saturation

Heart Rate

Respiratory Rate

FIRST STUDY GAS (after ≥ 5 minutes + at rest)

Oxygen saturation

Heart Rate

Respiratory Rate

SECOND STUDY GAS (after ≥ 5 minutes + at rest)

Oxygen saturation

Heart Rate

Respiratory Rate

%

/min

/min

%

/min

/min

%

/min

/min

Appendix XIII Study Information Sheet 315

Appendix XIII Study Information Sheet

The Exertional Oxygen Study

A study of portable oxygen used during exertion in individuals with Chronic Obstructive Pulmonary Disease (COPD).

Previous research has shown that for individuals with severe

COPD and low oxygen levels, oxygen therapy is beneficial when

it is used for at least 15 hours per day.

There are many individuals with COPD who have normal

oxygen levels when resting, but who have a limited ability to

walk and perform general activities due to breathlessness.

At present, it is not known if these individuals might benefit

from using oxygen therapy.

The aim of this study is to determine the effects of oxygen therapy for individuals with COPD who have normal oxygen levels when they are resting but have reduced activity levels due to shortness of breath.

The Exertional Oxygen Study is a randomised controlled trial. Study participants will receive either compressed oxygen or air from portable cylinders for use at home over a period of 12 weeks. The effects of using oxygen on breathlessness, quality of life and exercise tolerance will be evaluated.

For further information contact:

Rosemary Moore or David Berlowitz (Investigators) The Northern Clinical Research Centre The Northern Hospital 185 Cooper Street Epping 3076 Telephone: 8405 8480 Email: [email protected]

Appendix XIV Study Promotion Flyer 317

Appendix XIV Study Promotion Flyer


For further information contact: Rosemary Moore or David Berlowitz (Investigators) The Northern Clinical Research Centre The Northern Hospital 185 Cooper Street Epping 3076 Telephone: 8405 8480 Email: [email protected]

Do you have chronic lung disease?

Do you become breathless when you are active?

You may benefit from portable oxygen therapy.

A research study is being conducted at The Northern

Hospital and The Austin Hospital to investigate the

effects of portable oxygen therapy for individuals with

chronic lung disease.

If interested please ring: Rosemary Moore or David Berlowitz



Telephone: 8405 8480 or 8480 8064 Email: [email protected],.au

Appendix XV Study Referral Form 319

Appendix XV Study Referral Form

The Northern Clinical Research Centre The Northern Hospital 185 Cooper Street Epping 3076. Investigators: Rosemary Moore David Berlowitz

Exertional Oxygen Study Referral Form

Please mail, fax or email to the address above.

Trial Inclusion criteria diagnosis of COPD

clinically stable: no respiratory exacerbations within the preceding 4 weeks

does not qualify for long-term domiciliary oxygen therapy; PaO2 > 55 mmHg at rest

non-smoker; ceased to smoke at least 2 weeks prior to enrolment.

activity limited by breathlessness

Trial Exclusion criteria significant locomotor disability

eg. severe arthritis

other severe disabling medical condition likely to significantly impact upon exercise capacity or quality of life

currently attending a Pulmonary Rehabilitation Program

Participant ID label/ name and address

............................................................................

.............................................................................

............................................................................

Relevant Medical History:

.......................................................................................................................

.......................................................................................................................

.......................................................................................................................

.......................................................................................................................

.............

Referring Person: Name: .............................................. Email: ............................................

Address: .......................................... Signature: ......................................

........................................................... Date: ..............................................

Phone: 8405 8480 Fax: 8405 8683 Email: [email protected]

Phone: 8405 8480 Fax: 8405 8683 Email: [email protected]


Appendix XVI Study Protocol Summary 321

Appendix XVI Study Protocol Summary

Background Oxygen therapy has been shown to improve survival and quality of life when used for more than 15 hours per day by people with severe COPD and hypoxaemia at rest. Guidelines for the prescription and funding of oxygen therapy for individuals with severe COPD and hypoxaemia are based upon two landmark clinical trials conducted in the 1980's, and are widely recognised. Many people with COPD are not severely hypoxaemic at rest, but experience significant breathlessness on minimal exertion. This breathlessness limits exercise tolerance and is associated with progressive physical deconditioning and decline in general function. It is not known if the use of portable oxygen therapy during exertional activities is beneficial in this circumstance. Aims The primary aim of this project is to determine the effects of portable oxygen therapy, used during exertion by people with COPD who are breathless on exertion but do not fulfil the requirements for long term oxygen therapy according to current, evidence-based guidelines. Further aims are to determine predictive factors for any benefits demonstrated and to perform a cost benefit evaluation of this therapy. Method This is a prospective, randomised, double-blinded, controlled study, being conducted at The Northern and Austin Hospitals, in Victoria. It is aimed to enrol 150 participants in the study. Included are individuals with a diagnosis of COPD who are not hypoxaemic at rest. After a two week run-in phase, participants are randomised to receive portable air or portable oxygen cylinders (cylinders blinded), for use during exertion, over a 12 week period. Participants are asked to attend one of the two study centres on four occasions over the 14 week study period for assessment of a number of variables.



8405 8482

Department of Respiratory and Sleep Medicine Austin Hospital

Studley Road Heidelberg 3084

9496 5739

Study Team members: A/ Prof. Christine McDonald (AH) Dr. David Berlowitz (NCRC) Dr. Bruce Jackson (Southern Health) Dr. Linda Denehy(U of M) Rosemary Moore (NCRC) Chrissie Risteski (NCRC)

THE EXERTIONAL OXYGEN STUDY

Appendix XVI Study Protocol Summary 322

The primary outcome measures are breathlessness, using the Baseline and Transitional Dyspnoea Index, exercise capacity using the Six Minute Walk Test and quality of life using the Assessment of Quality of Life Index and The Chronic Respiratory Disease Questionnaire. Other criteria being examined include depression, respiratory symptoms, medical and ancillary service utilisation, activity levels and compressed gas use. Respiratory function testing is conducted, including specific measurement of inspiratory capacity. This measurement will be used to calculate dynamic pulmonary hyperinflation and analysed to determine whether there is a correlation between dynamic hyperinflation and response to oxygen therapy. Approval to conduct the study has been obtained from the Human Research Ethics Committees at both centres and all participants provide written, informed consent prior to enrolment.

Outcome The results of this study will provide urgently needed information which is of global significance. This information is required to provide an evidence base to extend the guidelines for the prescription of portable oxygen therapy to include people with COPD who are not severely hypoxaemic at rest, but who experience a limited ability to exercise due to breathlessness.

Appendix XVII Study Promotion Covering Letter 323

Appendix XVII Study Promotion Covering Letter


re. The Exertional Oxygen Study Dear I am writing to tell you about our Exertional Oxygen Study and to ask for your help. We are investigating the effects of portable oxygen, used during exertion, in people with COPD who do not qualify for long term oxygen therapy according to the current Australian Guidelines. This is a double-blinded, randomised controlled trial, with participants randomised to receive compressed air or oxygen in identical portable cylinders for a period of 12 weeks. Participants will be required to attend either the Austin or The Northern Hospital on four occasions. We are aiming to recruit 120 participants during 2005 and 2006. This study has the commercial sponsorship of Air Liquide Pty Limited, and is supported by grants from the Victorian Tuberculosis and Lung Association and The Austin Medical Research Foundation, Boehringer Ingelheim Pty Limited and an NH&MRC Scholarship which pays for my stipend. I enclose a package of patient information sheets, referral forms and self-addressed envelopes in case you feel that you might be able to refer any of your patients for inclusion in the study. The inclusion criteria are on the referral form. I also enclose a study outline, and some flyers to put up in strategic places, if this is possible. Yours sincerely, Rosemary Moore Research Fellow.

The Northern Clinical Research Centre Austin Health


The Northern Clinical Research Centre The Northern Hospital 185 Cooper Street Epping 3076

Study Team members: A/Prof. Christine McDonald (AH) A/ Prof. Bruce Jackson (NCRC) Dr. David Berlowitz (NCRC) Rosemary Moore (NCRC) Dr. Linda Denehy (U of M) Ms Chrissie Risteski (NCRC)

Appendix XVIII Participant Information and Consent Form 325

Appendix XVIII Participant Information and Consent Form

Participant Information and Consent Form

Full Project Title:

The effects of portable exertional oxygen in Chronic Obstructive Pulmonary Disease (COPD). Principle Researcher: Dr. David Berlowitz Associate Researchers: Ms. Rosemary Moore Associate Professor Christine McDonald Associate Professor Bruce Jackson

Mr. Simon Higgins Dr. Linda Denehy.

This Participant Information and Consent Form is 10 pages long. Please make sure you have all the pages. 1. Your Consent

You are invited to take part in this research project. This Participant Information Document contains detailed information about the research project. Its purpose is to explain to you as openly and clearly as possible all the procedures involved in this project before you decide whether or not to take part in it. Please read this Participant Information carefully. Feel free to ask questions about any information in the document. You may also wish to discuss the project with a relative or friend or your local health worker. Feel free to do this. Once you understand what the project is about and if you agree to take part in it, you will be asked to sign the Consent Form. By signing the Consent Form, you indicate that you understand the information and that you give your consent to participate in the research project.


You will be given a copy of the Participant Information and Consent Form to keep as a record.

2. Purpose and Background

The purpose of this project is to determine the benefits of portable oxygen therapy when used during exertion (activity) by individuals with Chronic Obstructive Pulmonary Disease (COPD). It is anticipated that a total of 200 people will participate in this project over a two year period. Previous research has shown that oxygen therapy is beneficial for individuals with severe COPD and low oxygen levels, when it is used for at least 15 hours per day. There are many individuals with COPD who have normal oxygen levels when resting, but who experience breathlessness which limits their ability to walk and perform general activities. At present, it is not known if these individuals might benefit from oxygen therapy. The aim of this study is to determine whether or not portable oxygen therapy is beneficial for individuals with COPD whose ability to exercise is limited by breathlessness, but who have normal blood oxygen levels when they are resting. This research study has been initiated by the Principal and Associate Researchers listed above. The study is supported by The Northern Clinical Research Centre and Austin Health. The results of this research will also be used to help researcher, Ms. Rosemary Moore, obtain a Doctor of Philosophy (PhD) degree. 3. Procedures

Participation in the study will involve 4 visits of up to 3 hours duration to either The Northern Hospital or The Austin Hospital over a 3½ month period. An outline of the timing of these visits and the procedures involved is provided below and on the flowchart on page 8. Visit 1

Full explanation of the study, and your decision whether or not to participate

Rating of your breathlessness according to two dyspnoea scales (The MRC Dyspnoea Scale and The Baseline Dyspnoea Index)

Respiratory function tests: standard breathing tests and 3 additional deep breathing manoeuvres

Arterial Blood Gas Analysis: this involves using a needle and syringe to take a sample (volume approximately one teaspoon) of


blood from an artery at the wrist. This sample is analysed to measure oxygen, carbon dioxide and other related measures.

Service Utilisation Diary and Activity Diary: you will be given these diaries to complete at home for seven days prior to the next visit and shown how to complete them. The diaries will take approximately 10 minutes to complete each day.

Pedometer: this is a small electronic device which measures activity. It is worn clipped to your waistband or belt and you will be asked to wear it for the same seven days that you are completing the Activity Diary.

Symptom Diary Card: on this card you are asked to score your symptoms at the end of each day of the study. The card will take approximately 5 minutes to complete.

Visit 2: 2 weeks after Visit 1

Your Service Utilisation Diary, Activity Diary, Symptom Diary Cards and pedometer data will be checked with you.

3 exercise tests will be performed, using the Six Minute Walk Test. You will be asked to walk as far as possible, at your own pace, along a 30 metre course for a period of six minutes. You may rest as often as you need during each test, and you will be able to rest between the tests for as long as required. The tests will be performed while breathing compressed air or oxygen from a cylinder, but you will not be told which you are breathing. You will be shown how to use the cylinders at this time.

3 questionnaires will be completed which ask questions about how your lung problem impacts upon your life. These questionnaires will take a total of approximately 60 minutes to complete.

After you arrive home, portable gas cylinders will be delivered to your home. You will be shown how to use your cylinders again by the company representative who delivers them. The cylinders are approximately 50 centimetres high and are provided with a 2-wheel trolley. Gas is delivered through your nose via tubing and nasal cannulae (narrow tubes which sit just inside the nostrils). You are asked to use your cylinders for a period of 3 months for any activities which make you breathless at home and during outings. Half of the study participants will have compressed oxygen in their cylinders and the other half will have compressed air, but you will not be told which you have been given. You will be randomly assigned to be given oxygen or air cylinders, which means your chance of receiving one or the other is like the tossing of a coin. The researchers will not know which you have been assigned until after the completion of the study.


Visit 3: one month after Visit 2

Your breathlessness will be rated according to a scale called The Transitional Dyspnoea Index.

You will complete the same exercise tests and questionnaires as during Visit 2.

You will have been sent (by mail) a Service Utilisation Diary, Activity Diary and pedometer to use for seven days prior to this visit. The data from each of these will be checked with you.

Your Symptom Diary Cards will be checked with you. Visit 4: 3 months after Visit 2

Your breathlessness will be rated according to The Transitional Dyspnoea Index.

You will complete the same exercise tests questionnaires as during Visit 2.

You will have again been sent (by mail) a Service Utilisation Diary, Activity Diary and pedometer to use for seven days prior to this visit. The data from each of these will be checked with you.

Your Symptom Diary Cards will be checked with you.

Use of your portable cylinders will finish on the day of this visit.

You will be asked about your preferences and opinions concerning the portable gas system you have been receiving.

If you qualify for portable oxygen therapy according to the current criteria, this will be offered to you.

Information about your use of medications and medical services during the study will also be collected from the Health Insurance Commission. You will be asked to sign an additional consent form to indicate that you are willing to have this information released to the researchers. During the study continual review and monitoring will take place. You will receive a telephone call from a researcher weekly for the first month of cylinder use, then fortnightly, and a researcher will be available by telephone 24 hours per day. You will receive the usual medical and other care to which you are entitled. 4. Collection of Tissue Samples for Research Purposes

By consenting to take part in this study, you also consent to the collection of a sample of arterial blood for standard Arterial Blood Gas Analysis on one occasion. 5. Possible Benefits

Portable oxygen therapy may improve breathlessness and the ability to exercise. It is anticipated that the study results will determine the difference between having additional oxygen during exercise and no


oxygen therapy and thus provide evidence to support its use and funding in the future. 6. Possible Risks

There is a small risk of bruising and/or discomfort from the withdrawl of blood for testing. It is possible that some participants may find the use of portable gas cylinders to be inconvenient. 7. Other Treatments Whilst on the Study

It is important to tell your doctor and the research staff about any treatments or medications you may be taking, including non-prescription medications, vitamins or herbal remedies and any changes to these during your participation in the study.

8. Alternatives to Participation

Current guidelines only allow for the provision of portable oxygen therapy for individuals with COPD whose oxygen levels fall significantly when exercising or are low at all times. At present, breathlessness limiting exercise is not a criterion for the provision of portable oxygen therapy, but individuals experiencing this will be included in the study. There are no alternative or standard treatments which will be withheld as a result of participation in the study. 9. Privacy, Confidentiality and Disclosure of Information

Any information obtained in connection with this research project which can identify you will remain confidential and will only be used for the purpose of this research project. It will only be disclosed with your permission, except as required by law. If you give us your permission by signing the Consent Form, we plan to publish the results of the study in medical journals and present the findings at medical conferences. In any publication, information will be provided in such a way that you cannot be identified. Each study participant will be assigned a trial number. Data will be retained and analysed in a de-identified manner, using trial numbers. Records will be retained in password-locked computer databases and locked filing cabinets at The Northern Clinical Research Centre. Upon completion of the project, electronic data will be compressed and stored on disks at The Northern Clinical Research Centre. The project managers will be the only individuals to have access to the personal details of participants. The study data will be retained for 7 years after which time it will be destroyed.


It is desirable that your family doctor be advised of your decision to participate in this research project. By signing the Consent Form, you agree to your family doctor being notified of your decision to participate in this research project. 10. New Information Arising During the Project

During the research project, new information about the risks and benefits of the project may become known to the researchers. If this occurs, you will be told about this new information. This new information may mean that you can no longer participate in this research. If this occurs, the person(s) supervising the research will stop your participation. In all cases, you will be offered all available care to suit your needs and medical condition.

11. Results of Project

A document will be written which summarises the results of the study. It will state the differences in findings between the two study groups. It will be held by the Public Relations departments at The Northern Hospital and Austin Health and you may request a copy.

12. Further Information or Any Problems

If you require further information or if you have any problems concerning this project, you can contact the researchers responsible for this project: Ms. Rosemary Moore

Business hours - 8405 8064 After hours - 9853 2507 or 0412456177

Dr. David Berlowitz: Business hours - 8405 8064 After hours - 9482 5134

13. Other Issues

If you have any complaints about any aspect of the project, the way it is being conducted or any questions about your rights as a research participant, and you wish to contact someone independent of the study, you may contact: The Northern Hospital

Name: Ms. Jessica Beattie Position: Patient Advocate, The Northern Hospital

Telephone: (03) 8405 8046 Austin Health

Name: Mr. Andrew Crowden


Position: Chairman, Austin Health Human Research Ethics Committee

Telephone: (03) 9496 2901

14. Participation is Voluntary

Participation in any research project is voluntary. If you do not wish to take part you are not obliged to. If you decide to take part and later change your mind, you are free to withdraw from the project at any stage. Your decision whether to take part or not to take part, or to take part and then withdraw, will not affect your routine treatment, your relationship with those treating you or your relationship with The Northern Hospital or The Austin Hospital.

Before you make your decision, a member of the research team will be available so that you can ask any questions you have about the research project. You can ask for any information you wish. Sign the Consent Form only after you have had a chance to ask your questions and have received satisfactory answers. If you decide to withdraw from this project, please notify a member of the research team before you withdraw. This notice will allow that person or the research supervisor to inform you if there are any health risks or special requirements linked to withdrawing. 15. Reimbursement for your costs

You will not be paid for your participation in this trial. However, you will be reimbursed for parking costs that you incur as a result of participating in this trial. In addition, volunteer driver transport may be possible if you have no other means of transport. 16. Ethical Guidelines

This project will be carried out according to the National Statement on

Ethical Conduct in Research Involving Humans (June 1999) produced by the National Health and Medical Research Council of Australia. This statement has been developed to protect the interests of people who agree to participate in human research studies. The ethical aspects of this research project have been approved by the Human Research Ethics Committee of this Institution.


17. Injury

In the event that you suffer an injury as a result of participating in this research project, hospital care and treatment will be provided by the public health service at no extra cost to you. 18. Termination of the Study

This research project may be stopped for a variety of reasons. These may include reasons such as: unacceptable side effects, the intervention (oxygen therapy) being shown not to be effective, the intervention being shown to work and not need further investigation.

At the completion of the study, you will be offered portable oxygen therapy if you qualify for it under the current Australian guidelines. The guidelines state that it may be provided if your arterial oxygen level (saturation) decreases to 88% or less while you are exercising and if there is an improvement in your exercise test and symptoms when you are given it.

If the study results show that portable exertional oxygen therapy is beneficial for persons whose ability to exercise is limited by breathlessness (including those whose oxygen levels don’t decrease), it is anticipated that the guidelines will be changed so that it may be prescribed for them in the future.


EXERTIONAL OXYGEN STUDY FLOW CHART

Visit 1: Participant Information (Week 0) Consent Form

2 questionnaires breathing tests and blood test diaries + pedometer

Visit 2: 3 exercise tests (Week 2) 3 questionnaires diaries & pedometer check

Visit 3: 3 exercise tests (Week 6) 4 questionnaires diaries & pedometer check

Visit 4: 2 exercise tests (Week 14) 4 questionnaires preference survey

Start using

portable cylinders

Finish using portable cylinders

For one week: Activity Assessment Service Utilisation Diary Pedometer



Total study time

14 weeks

* Every day from Visit 1: Symptom Diary Card


Consent Form to Participate in Research

Project Title: The effects of portable, exertional oxygen in Chronic Obstructive Pulmonary Disease.

I, ..........................................................., have been invited to participate in the above

study, which is being conducted under the direction of Dr. David Berlowitz (Principal

Investigator).

I understand that while the study will be under his supervision, other relevant and

appropriate persons may assist or act on his behalf.

My agreement is based on the understanding that the study involves:

The use of a portable compressed gas during exertion for a period of 12 weeks

4 visits to the Austin Hospital for assessments including:

Pulmonary Function (breathing) Tests on one occasion

withdrawl of a blood sample for Arterial Blood Gas analysis on one occasion

exercise tests on 3 occasions

completion of questionnaires on 3 occasions

completion of 2 activity diaries and use of a pedometer device for 3 periods

of one week

completion of a symptom diary card every day.

The study may involve the following risks, inconvenience and discomforts, which have

been explained to me:

The withdrawl of a blood sample may be associated with minor discomfort and bruising.

I have received and read the attached ‘Participant Information Sheet’ and understand the general purposes, methods and demands of the study. All of my questions have been answered to my satisfaction. I understand that the project may not be of direct benefit to me.

I can withdraw or be withdrawn by the Principal Investigator from this study/project at any time, without prejudicing my further management.

I consent to the publishing of results from this study provided my identity is not revealed.

I hereby voluntarily consent and offer to take part in this study.

Signature (Participant)

Name

Signature

Date: Time:

Witness to signature

Name

Signature

Date: Time:

Signature (Investigator)

Name

Signature

Date: Time:

One copy to be given to participant, one copy filed in participant’s medical record


Revocation of Consent Form Project Title: The effects of portable exertional oxygen in Chronic Obstructive Pulmonary Disease (COPD).

I hereby wish to WITHDRAW my consent to participate in the research proposal named above and understand that such withdrawal WILL NOT jeopardise any treatment or my relationship with The Northern Hospital or The Austin Hospital. Participant’s Name (printed) ……………………………………………………. Signature ................................................................. Date .........................................................................

Appendix XIX Participant Data Sheet 337


185 Cooper Street, Epping, Victoria, Australia 3076 Telephone (03) 8405 8064 Facsimile (03) 8405 8683

Appendix XIX Participant Data Sheet

PARTICIPANT DATA SHEET

PARTICIPANT DATA PARTICIPANT DATA SHEET SITE: The Northern Hospital Austin Hospital Date of referral: ..........................................

Referred by: ...............................................

Date of inclusion: ......................................

Medicare number: ..................................... Demographics

ID label details correct: Yes If no, note corrections Informed consent: Yes No Inclusion criteria fulfilled: Yes No

Trial Inclusion criteria

diagnosis of COPD

activity limited by breathlessness

clinically stable: no respiratory exacerbations within the preceding 4 weeks

does not qualify for long-term domiciliary oxygen therapy; PaO2 > 55 mmHg at rest

non-smoker; ceased to smoke at least 2 weeks prior to enrolment

Trial Exclusion criteria

significant locomotor disability eg. severe arthritis, use of gait aid

other severe disabling medical condition likely to significantly impact upon exercise capacity or quality of life

currently attending a Pulmonary Rehabilitation Program Details............................................... ...........................................................

LMO

Name: .............................................

Address: ...............................................

...............................................................

Telephone: ............................................

Fax: ......................................................

Email .....................................................

Respiratory Physician

Name: ...............................................

Address: ..............................................

.............................................................

Telephone: ........................................

Fax: ....................................................

Email....................................................


The Northern Clinical Research Centre Austin Health and The University of Melbourne

UR: ......................................................... Surname: ................................................ Given Names: ......................................... DOB: ........................Phone..................... Address: .................................................. .................................................................

Attach ID Label here

Next of kin Name: .....................................

Relationship: ...........................

Phone: .....................................


Communication

WNL Understands English Speaks English

Country of birth: .................. Language/s spoken at home: …………...................

Hearing

WNL Unilateral Impaired Bilateral

Hearing Aid/s

Visual

WNL Spectacles

Impaired Prosthesis

Cognition Normal Impaired

WNL = within normal limits

Respiratory Diagnosis

Other respiratory history

.................................................................................................

..................................................................................................

..................................................................................................

..................................................................................................

Sputum......................................................................................

Cough......................................................................................

Exercise tolerance

How many minutes can you walk on a

flat surface?...........................................

OR: How far can you walk on a flat

surface?...................................................

.

What stops you? ..............................

.............................

Smoking history

Pulmonary rehabilitation history

Date completed/ceased/never

................................................................

Location ..................................................

Duration of

course: ............

..........................

Oxygen therapy

Previously used:

Yes No

If yes, specify

....................................................

....................................................

...................................................

1. I only get breathless with strenuous exercise 2. I get short of breath when hurrying on the level or up a slight hill 3. I walk slower than most people of the same age on the level

because of breathlessness or have to stop for breath when walking at my own pace on the level

4. I stop for breath after walking 100 yards or after a few minutes on the level

5. I am too breathless to leave the house

MRC Dyspnoea Scale Score


Medical History

Active Inactive Allergies

Medications

Musculo-skeletal assessment

Mobility (tick those which apply)

Walks unaided Yes No

Walks with gait aid Yes No If yes, specify:

..................................................................................................

Balance WNL Yes No

Other comments: ………………………………………………….

..................................................................................................

.............................

Social (tick those which apply)

Lives alone Lives with

spouse/partner

Requires carer. If yes, specify..........................................

Is a primary carer. If yes, specify......................................

Receives council home help. If yes, specify......................

Pensioner. If yes, specify: ................................................

Residential aged care facility SRS

Hostel

Employed Nursing Home

Current or previous occupation/s: ……..................................

..................................................................................................

Other (most recent)

Fluvax No Yes Date: .......................

Pneumovax No Yes Date: .......................

RFT’s No Yes Date: .......................

ABG’s No Yes Date: ......................

Weight..................... Height..........................

BMI...........................

Appendix XX Additional Information Sheet 341

Appendix XX Additional Information Sheet

ADDITIONAL INFORMATION SHEET

Study dates

Visit 1 Visit 2 Cylinders delivered

Visit 3 Visit 4

Pedometer data Talisman/SOS MRC Dyspnoea Score score

Additional data/adverse events

Date Details



Study number: ....................

Pedometer number: .............

Reading Visit 2: ...................

Reading Visit 3 ....................

Reading Visit 4: ...................

tick

Mens bracelet

Ladies bracelet

Wrist band

Pendant

Visit1: ............

Visit 4: ...........

Appendix XXI CRDQ Response Sheet 343

Appendix XXI Chronic Respiratory Disease Questionnaire

Response Sheet


CRDQ RESPONSE SHEET

1. BEING ANGRY OR UPSET 2. HAVING A BATH OR SHOWER 3. BENDING 4. CARRYING, SUCH AS CARRYING GROCERIES 5. DRESSING 6. EATING 7. GOING FOR A WALK 8. DOING YOUR HOUSEWORK 9. HURRYING 10. MAKING A BED 11. MOPPING OR SCRUBBING THE FLOOR

12 MOVING FURNITURE 13. PLAYING WITH CHILDREN OR GRANDCHILDREN 14. PLAYING SPORTS 15 REACHING OVER YOUR HEAD 16. RUNNING, SUCH AS FOR A BUS . 17. SHOPPING

18. WHILE TRYING TO SLEEP

19. TALKING

20. VACUUMING

21. WALKING AROUND YOUR OWN HOME

22. WALKING UPHILL

23. WALKING UPSTAIRS

24. WALKING WITH OTHERS ON LEVEL GROUND

25. PREPARING MEALS

OTHER ACTIVITIES __________________________________________________________ __________________________________________________________ __________________________________________________________ __________________________________________________________ Activity 3a) ___________________________________________ Activity 3b) ___________________________________________ Activity 3c) ___________________________________________ Activity 3d) ___________________________________________ Activity 3e) ___________________________________________

STUDY NUMBER: ............ SITE: .................................... VISIT 2 DATE: ....................

Appendix XXI CRDQ Response Sheet 344

CRDQ RESPONSE SHEET (continued)

Question #

Visit 2

Date:...........

Visit 3

Date:...........

Visit 4

Date:...........

Date:...........

4 a)

4 b)

4 c)

4 d)

4 e)

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

STUDY NUMBER......................... ..................................

Appendix XXII AQoL Response Sheet 345

Appendix XXII Assessment of Quality of Life Index

Response Sheet


AQoL RESPONSE SHEET

Question number

Date: ..............

Date: ..............

Date: ...............

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

STUDY NUMBER: ............ SITE: ....................................

Appendix XXIII Six Minute Walk Test Worksheet 347

Appendix XXIII Six Minute Walk Test Worksheet

Appendix XXIII Six Minute Walk Test Worksheet 348

Appendix XXIV Cylinder Company Referral Form 349

Appendix XXIV Cylinder Company Referral Form

ATTENTION: Kristy Denereaz

REQUEST FORM FOR STUDY CYLINDERS

Air Liquide Healthcare 40 Bunnett Street

North Sunshine 3020 Ph: 03 9310 1200 Fax: 03 9311 0444

Participant Name:

Address:

Telephone:

Participant Study Number

Next of Kin:

Address:

Telephone:

Other details: Exertional Oxygen Study Flow: 6 L/min via Impulse device, Mode A

Date



Ph: 03 8405 8480 Fax: 03 8405 8683

Contact: Rosemary Moore Email: [email protected]

Mobile: 0412 456 177




Appendix XXV Preferences and Opinions Survey 351

Appendix XXV Preferences and Opinions Survey

Preferences and Opinions Survey

1. Overall, have you found that your portable cylinders have been beneficial? Yes No Undecided What were the benefits (if any)? .................................................................................................................................

.................................................................................................................................

...................................................................................................

What were the disadvantages (if any)? .................................................................................................................................

.................................................................................................................................

...................................................................................................

2. If you had a choice, would you prefer to continue using the portable cylinders or stop using them?

Continue Stop Please explain the reason/s for you preference .................................................................................................................................

.................................................................................................................................

...................................................................................................

3. Do you have any other comments about the use of the portable cylinders? .................................................................................................................................

.................................................................................................................................

.................................................................................................................................

.........................................................................................


Austin Health


STUDY NUMBER: .......... SITE: ...............................

VISIT 4 DATE:.................

353

Appendix XXVI Study Checklist

Visit 1 Phone Call/s Visit 2 Phone call Phone call Phone call Visit 3

Date: ..................

Consent Assessment form

BDI PFT's + IC

ABG's Talisman: TNH UR

Medical Hx Entry Explained/given:

SU Diary Activity Diary

Pedometer Symptom Diary

Instruction sheet Visit/Diary dates

Date: ................

Outcome:

Check Diary/pedometer

dates:

...........................

Date: ..................

CRDQ AQoL HAD

Exercise tests

Check: SU Diary

Activity Diary Pedometer

Symptom Diary Talisman

Visit/Diary dates

Notify Air Liquide

Date: ..................

Outcome:

Date: ..................

Outcome:


dates:

............................

Date: ..................

Outcome:

Date: ..................

TDI CRDQ AQoL HAD

Exercise tests

Check: SU Diary

Activity Diary Pedometer

Symptom Diary Visit/Diary dates

Phone call Phone call Phone call Phone call Visit 4

Date: ..................

Outcome:

Date: ..................

Outcome:

Date: ..................

Outcome:


dates:

..........................

Date: ..................

Outcome:

Date: ..................

TDI CRDQ AQoL HAD

Exercise tests Survey Check:

SU Diary Activity Diary

Pedometer Symptom Diary

Notify Air Liquide

Study number: .................. Name: ............................................. Site: ............... EXERTIONAL OXYGEN STUDY CHECKLIST

Appendix XXVII MRC Dyspnoea Scale

355

Appendix XXVII Medical Research Council Dyspnoea

Scale


The Northern Clinical Research Centre Austin Health


MRC Dyspnoea Scale

The MRC Dyspnoea Scale is a questionnaire that consists of five statements about perceived breathlessness.

Please read the following statements and select that which

most applies to you.

Grade 1 I only get breathless with strenuous exercise

Grade 2 I get short of breath when hurrying on the level or up a slight hill

Grade 3 I walk slower than most people of the same age on the level because of breathlessness or have to stop for breath when walking at my own pace on the level

Grade 4 I stop for breath after walking 100 yards or after a few minutes on the level

Grade 5 I am too breathless to leave the house

Minerva Access is the Institutional Repository of The University of Melbourne

Author/s:Moore, Rosemary Patricia

Title:Domiciliary ambulatory oxygen in chronic obstructive pulmonary disease

Date:2010

Citation:Moore, R. P. (2010). Domiciliary ambulatory oxygen in chronic obstructive pulmonarydisease. PhD thesis, Medicine, Dentistry & Health Sciences, Melbourne PhysiotherapySchool, The University of Melbourne.

Publication Status:Unpublished

Persistent Link:http://hdl.handle.net/11343/35465

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