Post on 23-Apr-2023
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.)
Respirology 12 (Suppl 4): A167.
(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.
Respirology 12 (Suppl 1): A48.
(Poster presentation at the Annual Scientific Meeting of the Thoracic
Society of Australia and New Zealand, Auckland, March 2007.)
Respirology 12 (Suppl 4): A208.
(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:
Double blind, randomised controlled trial of ambulatory oxygen versus air
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:
Double blind, randomised controlled trial of ambulatory oxygen versus air
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
Chapter 1: Introduction 2
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
Chapter 1: Introduction 3
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
Chapter 1: Introduction 4
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
Chapter 1: Introduction 5
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
Chapter 2: Oxygen therapy 8
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
Chapter 2: Oxygen therapy 9
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).
Chapter 2: Oxygen therapy 10
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
Chapter 2: Oxygen therapy 11
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).
Chapter 2: Oxygen therapy 12
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
Chapter 2: Oxygen therapy 13
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
Chapter 2: Oxygen therapy 14
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.
Chapter 2: Oxygen therapy 15
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,
Chapter 2: Oxygen therapy 16
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).
Chapter 2: Oxygen therapy 17
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
Chapter 2: Oxygen therapy 18
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).
Chapter 2: Oxygen therapy 19
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
Chapter 2: Oxygen therapy 20
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
Chapter 2: Oxygen therapy 21
(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.
Chapter 2: Oxygen therapy 22
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).
Chapter 2: Oxygen therapy 23
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
Chapter 2: Oxygen therapy 25
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).
Chapter 2: Oxygen therapy 26
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
Chapter 2: Oxygen therapy 27
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
Chapter 2: Oxygen therapy 28
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
Chapter 2: Oxygen therapy 29
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
Chapter 2: Oxygen therapy 30
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
Chapter 2: Oxygen therapy 31
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).
Chapter 2: Oxygen therapy 32
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
Chapter 2: Oxygen therapy 33
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
Chapter 2: Oxygen therapy 36
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,
Chapter 2: Oxygen therapy 37
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
Chapter 2: Oxygen therapy 38
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).
Chapter 2: Oxygen therapy 39
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
Chapter 2: Oxygen therapy 40
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
Chapter 2: Oxygen therapy 41
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
Chapter 2: Oxygen therapy 42
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
Chapter 4: Outcome measures in COPD 82
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.
Chapter 4: Outcome measures in COPD 83
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.
Chapter 4: Outcome measures in COPD 84
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.
Chapter 4: Outcome measures in COPD 85
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).
Chapter 4: Outcome measures in COPD 86
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
Chapter 4: Outcome measures in COPD 87
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).
Chapter 4: Outcome measures in COPD 88
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
Chapter 4: Outcome measures in COPD 89
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
Chapter 4: Outcome measures in COPD 90
(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).
Chapter 4: Outcome measures in COPD 91
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.
Chapter 4: Outcome measures in COPD 92
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
Chapter 4: Outcome measures in COPD 93
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
Chapter 4: Outcome measures in COPD 94
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
Chapter 4: Outcome measures in COPD 95
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).
Chapter 4: Outcome measures in COPD 96
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
Chapter 4: Outcome measures in COPD 97
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).
Chapter 4: Outcome measures in COPD 98
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
Chapter 4: Outcome measures in COPD 99
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
Chapter 4: Outcome measures in COPD 100
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).
Chapter 4: Outcome measures in COPD 101
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.
Chapter 4: Outcome measures in COPD 102
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
Chapter 4: Outcome measures in COPD 103
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).
Chapter 4: Outcome measures in COPD 104
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.
Chapter 4: Outcome measures in COPD 105
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
Chapter 4: Outcome measures in COPD 106
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,
Chapter 4: Outcome measures in COPD 107
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.
Chapter 4: Outcome measures in COPD 108
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
Chapter 4: Outcome measures in COPD 109
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
Chapter 5: Activity measurement in COPD: Pilot of Activity Diary 112
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
Chapter 5: Activity measurement in COPD: Pilot of Activity Diary 113
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
Chapter 5: Activity measurement in COPD: Pilot of Activity Diary 114
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.
Chapter 5: Activity measurement in COPD: Pilot of Activity Diary 115
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?”
Chapter 5: Activity measurement in COPD: Pilot of Activity Diary 116
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
Chapter 5: Activity measurement in COPD: Pilot of Activity Diary 117
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.
Chapter 5: Activity measurement in COPD: Pilot of Activity Diary 118
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
Chapter 6: Comparison of pedometer and activity diary in COPD 120
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).
Chapter 6: Comparison of pedometer and activity diary in COPD 121
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.
Chapter 6: Comparison of pedometer and activity diary in COPD 122
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%).
Chapter 6: Comparison of pedometer and activity diary in COPD 123
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
Chapter 6: Comparison of pedometer and activity diary in COPD 124
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).
Chapter 6: Comparison of pedometer and activity diary in COPD 125
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
Pedometer count vs Standing/walking time (hours)
23,406.2 (2,545.1) 34.3 (2.5)
0.357
0.010
Pedometer count vs Sit + standing/walking time (hours)
100.3 (1.4)
0.279
0.047
Pedometer count vs Sleep time (hours)
56.9 (1.7)
0.035
0.808
Pedometer count vs Outings time (hours)
17.3 (1.6)
0.336
0.016
Standing/walking time (hours) vs Outings time (hours)
0.277
0.049
Females n = 25
Pedometer count vs Standing/walking time (hours)
22,562.9 (2988.1) 38.1 (2.6)
0.456
0.022
Pedometer count vs Sit + standing/walking time (hours)
96.2 (2.0)
0.127
0.544
Pedometer count vs Sleep time (hours)
57.4 (2.5)
-0.081
0.700
Pedometer count vs Outings time (hours)
17.4 (1.5)
0.461
0.020
Standing/walking time (hours) vs Outings time (hours)
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
Chapter 6: Comparison of pedometer and activity diary in COPD 126
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
Chapter 6: Comparison of pedometer and activity diary in COPD 127
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,
Chapter 6: Comparison of pedometer and activity diary in COPD 128
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.
Chapter 6: Comparison of pedometer and activity diary in COPD 129
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
Chapter 6: Comparison of pedometer and activity diary in COPD 130
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
Chapter 6: Comparison of pedometer and activity diary in COPD 131
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
Chapter 7: Acute effects of hyperoxia on ventilation and dyspnoea 134
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
Chapter 7: Acute effects of hyperoxia on ventilation and dyspnoea 135
(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).
Chapter 7: Acute effects of hyperoxia on ventilation and dyspnoea 136
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.
Chapter 7: Acute effects of hyperoxia on ventilation and dyspnoea 137
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
Chapter 7: Acute effects of hyperoxia on ventilation and dyspnoea 138
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).
Chapter 7: Acute effects of hyperoxia on ventilation and dyspnoea 139
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.
Chapter 7: Acute effects of hyperoxia on ventilation and dyspnoea 140
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
Chapter 7: Acute effects of hyperoxia on ventilation and dyspnoea 141
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
Chapter 7: Acute effects of hyperoxia on ventilation and dyspnoea 142
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
Chapter 7: Acute effects of hyperoxia on ventilation and dyspnoea 143
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).
Chapter 7: Acute effects of hyperoxia on ventilation and dyspnoea 144
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,
Chapter 7: Acute effects of hyperoxia on ventilation and dyspnoea 145
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).
Chapter 7: Acute effects of hyperoxia on ventilation and dyspnoea 146
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
Chapter 7: Acute effects of hyperoxia on ventilation and dyspnoea 147
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)
Chapter 7: Acute effects of hyperoxia on ventilation and dyspnoea 148
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
Chapter 7: Acute effects of hyperoxia on ventilation and dyspnoea 149
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
Chapter 7: Acute effects of hyperoxia on ventilation and dyspnoea 150
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.
Chapter 7: Acute effects of hyperoxia on ventilation and dyspnoea 151
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).
Chapter 7: Acute effects of hyperoxia on ventilation and dyspnoea 152
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
Chapter 7: Acute effects of hyperoxia on ventilation and dyspnoea 153
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).
Chapter 7: Acute effects of hyperoxia on ventilation and dyspnoea 154
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).
Chapter 7: Acute effects of hyperoxia on ventilation and dyspnoea 155
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).
Chapter 7: Acute effects of hyperoxia on ventilation and dyspnoea 156
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.
Chapter 7: Acute effects of hyperoxia on ventilation and dyspnoea 157
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
Chapter 7: Acute effects of hyperoxia on ventilation and dyspnoea 158
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
Chapter 7: Acute effects of hyperoxia on ventilation and dyspnoea 159
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
Chapter 7: Acute effects of hyperoxia on ventilation and dyspnoea 160
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
Chapter 8: Effects of domiciliary ambulatory oxygen in COPD 162
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
Chapter 8: Effects of domiciliary ambulatory oxygen in COPD 163
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.
Chapter 8: Effects of domiciliary ambulatory oxygen in COPD 164
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.
Chapter 8: Effects of domiciliary ambulatory oxygen in COPD 165
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
Chapter 8: Effects of domiciliary ambulatory oxygen in COPD 166
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%.
Chapter 8: Effects of domiciliary ambulatory oxygen in COPD 167
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
Chapter 8: Effects of domiciliary ambulatory oxygen in COPD 168
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
Chapter 8: Effects of domiciliary ambulatory oxygen in COPD 169
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
Chapter 8: Effects of domiciliary ambulatory oxygen in COPD 170
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.
Chapter 8: Effects of domiciliary ambulatory oxygen in COPD 171
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
Chapter 8: Effects of domiciliary ambulatory oxygen in COPD 172
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
Chapter 8: Effects of domiciliary ambulatory oxygen in COPD 173
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.
Chapter 8: Effects of domiciliary ambulatory oxygen in COPD 174
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
Chapter 8: Effects of domiciliary ambulatory oxygen in COPD 175
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).
Chapter 8: Effects of domiciliary ambulatory oxygen in COPD 176
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%.
Chapter 8: Effects of domiciliary ambulatory oxygen in COPD 177
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
Chapter 8: Effects of domiciliary ambulatory oxygen in COPD 178
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.
Chapter 8: Effects of domiciliary ambulatory oxygen in COPD 179
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
Chapter 8: Effects of domiciliary ambulatory oxygen in COPD 180
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.
Chapter 8: Effects of domiciliary ambulatory oxygen in COPD 181
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).
Chapter 8: Effects of domiciliary ambulatory oxygen in COPD 182
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.
Chapter 8: Effects of domiciliary ambulatory oxygen in COPD 183
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.
Chapter 8: Effects of domiciliary ambulatory oxygen in COPD 184
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
Chapter 8: Effects of domiciliary ambulatory oxygen in COPD 185
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
Chapter 8: Effects of domiciliary ambulatory oxygen in COPD 191
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
Chapter 8: Effects of domiciliary ambulatory oxygen in COPD 192
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
Air group Oxygen group ANOVA: p values
Mean (SEM) Range Mean (SEM) Range
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).
Air group Oxygen group ANOVA: p values
Mean (SEM) Range Mean (SEM) Range
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
Chapter 8: Effects of domiciliary ambulatory oxygen in COPD 201
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
Chapter 8: Effects of domiciliary ambulatory oxygen in COPD 202
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)
Chapter 8: Effects of domiciliary ambulatory oxygen in COPD 203
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
Chapter 8: Effects of domiciliary ambulatory oxygen in COPD 204
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)
Chapter 8: Effects of domiciliary ambulatory oxygen in COPD 205
(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
Chapter 9: Conclusions and Future Directions 208
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
Chapter 9: Conclusions and Future Directions 209
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
Chapter 9: Conclusions and Future Directions 210
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
Chapter 9: Conclusions and Future Directions 211
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.
Chapter 9: Conclusions and Future Directions 212
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.
References 213
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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
The University of Melbourne
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
Leisure activities, gardening
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
Leisure activities, gardening
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.
Appendix II Baseline/Transition Dyspnoea Index Scoring Sheet 264
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.
Y Impaired for reasons other than shortness of breath
For example, musculoskeletal problem or chest pain.
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.
Y Impaired for reasons other than shortness of breath
For example, musculoskeletal problem or chest pain.
Appendix II Baseline/Transition Dyspnoea Index Scoring Sheet 265
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.
Appendix II Baseline/Transition Dyspnoea Index Scoring Sheet 266
Transition Dyspnoea Index (continued)
Change in Magnitude of Task - 3 Major Deterioration Has deteriorated two grades or greater from baseline status.
-2 Moderate Deterioration
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.
+2 Moderate Improvement
Has improved at least one grade but fewer than two grades from baseline.
+3 Major Improvement Has improved two grades or greater from baseline.
Z Further impairment for reasons other than shortness of breath.
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.
-2 Moderate Deterioration
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.
+2 Moderate Improvement
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.
Z Further impairment for reasons other than shortness of breath.
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.
EXERTIONAL OXYGEN STUDY The Northern Clinical Research Centre
Austin Health The University of Melbourne
Appendix III The Assessment of Quality of Life Instrument 268
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.
Appendix III The Assessment of Quality of Life Instrument 269
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.]
Appendix III The Assessment of Quality of Life Instrument 270
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.
Appendix III The Assessment of Quality of Life Instrument 271
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
Appendix IV The Chronic Respiratory Disease Questionnaire 274
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]
Appendix IV The Chronic Respiratory Disease Questionnaire 275
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-to- day 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?
[LIST ITEM ON RESPONSE SHEET]
c) Of the remaining items, which is most important to you in your day-to-day life?
[LIST ITEM ON RESPONSE SHEET]
Appendix IV The Chronic Respiratory Disease Questionnaire 276
d) Of the remaining items, which is the most important to you in your day-to-day life?
[LIST ITEM ON RESPONSE SHEET]
e) Of the remaining items, which is the most important to you in your day-to-day life?
[LIST ITEM ON RESPONSE SHEET]
[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]
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
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]
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
Appendix IV The Chronic Respiratory Disease Questionnaire 277
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]
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
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]
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
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]
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
Appendix IV The Chronic Respiratory Disease Questionnaire 278
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]
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
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
Appendix IV The Chronic Respiratory Disease Questionnaire 279
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]
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
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]
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
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]
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
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]
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
Appendix IV The Chronic Respiratory Disease Questionnaire 280
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]
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
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
Appendix IV The Chronic Respiratory Disease Questionnaire 281
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]
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
Appendix IV The Chronic Respiratory Disease Questionnaire 282
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]
Appendix IV The Chronic Respiratory Disease Questionnaire 283
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]
Appendix IV The Chronic Respiratory Disease Questionnaire 284
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]
Appendix IV The Chronic Respiratory Disease Questionnaire 285
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]
Appendix IV The Chronic Respiratory Disease Questionnaire 286
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: ...........................................
Appendix V The Hospital Anxiety and Depression Scale 288
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
Appendix V The Hospital Anxiety and Depression Scale 289
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
EXERTIONAL OXYGEN STUDY The Northern Clinical Research Centre
Austin Health The University of Melbourne
The Northern Clinical Research Centre The Northern Hospital
185 Cooper Street Epping 3076
Appendix VI Six Minute Walk Test Protocol 292
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
Appendix VI Six Minute Walk Test Protocol 293
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.
Appendix VI Six Minute Walk Test Protocol 294
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,
Appendix VI Six Minute Walk Test Protocol 295
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.
Appendix VI Six Minute Walk Test Protocol 296
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.
Appendix VI Six Minute Walk Test Protocol 297
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
Appendix VII Pilot 1 Activity Diary 300
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
Appendix VII Pilot 1 Activity Diary 301
Exertional Oxygen Study
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
The Northern Clinical Research Centre The Northern Hospital
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 firstname.surname@nh.org.au
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 XI Inspiratory Capacity Measurement Worksheet 1 311
Appendix XI Inspiratory Capacity Measurement
Worksheet 1
Austin Health The Northern Clinical Research Centre
The University of Melbourne
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
The University of Melbourne
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: rosemary.moore@nh.org.au
Appendix XIV Study Promotion Flyer 317
Appendix XIV Study Promotion Flyer
Exertional Oxygen Study
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: rosemary.moore@nh.org.au
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
The Northern Clinical Research Centre The Northern Hospital
185 Cooper Street Epping 3076
Telephone: 8405 8480 or 8480 8064 Email: rosemary.moore@nh.org,.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: rosemary.moore@nh.org.au
Phone: 8405 8480 Fax: 8405 8683 Email: rosemary.moore@nh.org.au
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.
The Northern Clinical Research Centre The Northern Hospital
185 Cooper Street Epping 3076
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
EXERTIONAL OXYGEN STUDY
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 University of Melbourne
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.
Appendix XVIII Participant Information and Consent Form 326
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
Appendix XVIII Participant Information and Consent Form 327
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.
Appendix XVIII Participant Information and Consent Form 328
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
Appendix XVIII Participant Information and Consent Form 329
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.
Appendix XVIII Participant Information and Consent Form 330
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
Appendix XVIII Participant Information and Consent Form 331
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.
Appendix XVIII Participant Information and Consent Form 332
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.
Appendix XVIII Participant Information and Consent Form 333
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
For one week: Activity Assessment Service Utilisation Diary Pedometer
For one week: Activity Assessment Service Utilisation Diary Pedometer
Total study time
14 weeks
* Every day from Visit 1: Symptom Diary Card
Appendix XVIII Participant Information and Consent Form 334
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
Appendix XVIII Participant Information and Consent Form 335
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
The Northern Clinical Research Centre The Northern Hospital
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....................................................
EXERTIONAL OXYGEN STUDY
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: .....................................
Appendix XIX Participant Data Sheet 338
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
Appendix XIX Participant Data Sheet 339
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
EXERTIONAL OXYGEN STUDY The Northern Clinical Research Centre
Austin Health The University of Melbourne
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
EXERTIONAL OXYGEN STUDY The Northern Clinical Research Centre Austin Health The University of Melbourne
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
EXERTIONAL OXYGEN STUDY The Northern Clinical Research Centre Austin Health The University of Melbourne
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 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
The Northern Clinical Research Centre The Northern Hospital
185 Cooper Street Epping 3076
Ph: 03 8405 8480 Fax: 03 8405 8683
Contact: Rosemary Moore Email: rosemary.moore@nh.org.au
Mobile: 0412 456 177
EXERTIONAL OXYGEN STUDY The Northern Clinical Research Centre
Austin Health The University of Melbourne
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? .................................................................................................................................
.................................................................................................................................
.................................................................................................................................
.........................................................................................
EXERTIONAL OXYGEN STUDY The Northern Clinical Research Centre
Austin Health
The University of Melbourne
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:
Check Diary/pedometer
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:
Check Diary/pedometer
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
EXERTIONAL OXYGEN STUDY
The Northern Clinical Research Centre Austin Health
The University of Melbourne
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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