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 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.
ii 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.
iii 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.
iv 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
v Glossary of abbreviations and symbols
ANCOVA analysis of covariance ANOVA analysis of variance BMI body mass index cm centimetre/s cmH2O centimetres of water
CO2 carbon dioxide COPD chronic obstructive pulmonary disease COT continuous oxygen therapy CRQ Chronic Respiratory Disease Questionnaire DH dynamic hyperinflation DLCO diffusing capacity for carbon monoxide EELV end expiratory lung volume EFL expiratory flow limitation ERV expiratory reserve volume fB breathing frequency (respiratory rate per minute) fC cardiac frequency (heart rate per minute)
FEV1 forced expiratory volume in one second
FiO2 fraction of inspired oxygen FRC functional residual capacity FVC forced vital capacity HADS Hospital Anxiety and Depression Scale HRQL health-related quality of life IC inspiratory capacity IRV inspiratory reserve volume ITL inspiratory threshold loading kPa kilopascal/s L litre/s ml millilitre/s mg milligram/s mm millimetre/s mmHg millimetres of mercury MID minimal important difference MRC Medical Research Council
vi NOTT Nocturnal Oxygen Therapy Trial
O2 oxygen
PaCO2 arterial partial pressure of carbon dioxide
PaO2 arterial partial pressure of oxygen PEEPi intrinsic positive end expiratory pressure RV residual volume SD standard deviation SEM standard error of the mean
SpO2 oxyhaemoglobin saturation measured by pulse oximetry TLC total lung capacity TLCO transfer factor for carbon monoxide VAS visual analogue scale
VT tidal volume
VO2 total body oxygen uptake V/Q ventilation/perfusion VC vital capacity 6MWD six minute walk distance 6MWT six minute walk test %pred percentage of predicted value
vii 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
viii 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.
ix 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.
x 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
xi 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.)
xii 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.)
xiii 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.
xiv 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
xv 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
xvi 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
xvii 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
xviii 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
xix 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
xx 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
xxi 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
xxii 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
xxiii
Chapter 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) 1
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
Chapter 1: Introduction 1
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 2
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 3
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 4
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 1: Introduction 5
Chapter 1: Introduction 6
Chapter 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)
2 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
Chapter 2: Oxygen therapy 7
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 Results included/ identified 2003 Ambulatory 2/90 COPD with and without severe (Ram and Wedzicha oxygen for resting hypoxaemia: no clear 2003) COPD effects upon dyspnoea, quality of life, function.
2005 Domiciliary 4/6 COT: improves survival in (Cranston et al 2005) oxygen for COPD with severe hypoxaemia COPD but not with mild to moderate hypoxaemia or nocturnal desaturation only.
2005 Short-term 31/60 Laboratory assessment of (Bradley and O'Neill ambulatory exercise capacity in moderate 2005) oxygen for to severe COPD: strong COPD evidence of improvement.
2005 Domiciliary 1 COT: no evidence of improved (Crockett et al 2001) oxygen for ILD (unpublished) survival. /2 2005 Oxygen therapy 9/10 Intermittent oxygen therapy (Mallory et al 2005) for CF during sleep: no survival or symptom benefit. May improve oxygenation. Improvements in exercise duration and peak performance.
2007 Oxygen therapy 5/216 Insufficient evidence of long- (Nonoyama et al for exercise term benefits from training 2007b) training in oxygen. COPD
COPD, Chronic obstructive pulmonary disease; COT, continuous oxygen therapy; ILD, intersitital lung disease; CF, cystic fibrosis
Chapter 2: Oxygen therapy 8
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 9
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 10
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 11
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 12
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 13
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 14
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 15
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 16
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 17
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 18
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 19
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 20
(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 21
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 22
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.
Chapter 2: Oxygen therapy 23
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 ≤ 55 (≤ 7.3) ≤ 55 (≤ 7.3) < 55 (< 7.3) ≤ 55 (≤ 7.3), or SpO2 ≤88% (kPa) at rest or 56–59 (7.4-7.8) + hypoxic or SpO2 ≤88% or 55-59 (7.3-7.8) or 56-59 (7.4-7.8), SpO2 89-90% organ damage or 56-59 (7.4-7.8), SpO2 + hypoxic organ damage + hypoxic organ damage ≤89% + hypoxic organ damage
Goal PaO2 > 60 mmHg (8 kPa) PaO2 > 60 mmHg (8 kPa)
Nocturnal
< 55 mmHg Lung disease + sleep apnoea 7.3-7.8 kPa + Formal sleep study required to or SpO2 <88% + nocturnal desaturation nocturnal hypoxaemia assess for sleep disordered >⅓ of night PaO2 ≤55 mmHg breathing treatable by other means
Domiciliary Ambulatory
Determined by SpO2 ≤ 88% on air PaO2 ≤ 55 mmHg SpO2 ≤ 4% to reach < 90% MRC Dyspnoea score ≥4 + SpO2 exercise test/s + improvement in exercise (≤ 7.3 kPa), SpO2 ≤88% on on air <80% on walking capacity or dyspnoea on O2 air + ≥10% walk distance or SpO2 ≤88% + Borg score ≥1 or ≥10% dyspnoea on O2 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
24
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 Nocturnal vs continuous Mean O2 use 11.8 ≤59 mmHg + hypoxic O2 vs 17.8 hrs/day organ damage Flow: 1-4 L/min to achieve survival, HRQL, PaO2 60-80 mmHg neuropsychological + 1L/min for exercise, function sleep Duration: 1-2 years
MRC 87 PaO2 40–60 mmHg O2 ≥15 hours per day vs survival @ 500 trial on air at rest; at least nil days one recorded Flow: 2 L/min or to red cell mass episode of heart achieve PaO2 ≥60 mmHg rise in PVR failure with ankle Duration: 3 years oedema
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 25
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 26
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 27
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 28
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 29
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 30
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 31
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 32
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).
Chapter 2: Oxygen therapy 33
Table 2.5 Summary of randomised controlled trials of domiciliary ambulatory oxygen
n Participants Study design Study results Conclusions
Lilker et al 9 COPD, PaO2 <60 + cor Randomised, 2x5/52 Significant ↑ in PaO2 at rest and at maximal Portable O2 of > 1975 pulmonale crossover: cylinder air vs O2. exercise post O2 c/w post air. placebo value.
McDonald et 26 COPD, PaO2 >60 + Randomised, 2x6/52 No differences between O2 and air periods for Acute benefit, but not al 1995 exertional dyspnoea crossover: cylinder air vs O2 6MWD, step test, CRQ domains. predictive of @ 4L/min. improved function or HRQL.
Eaton et al 41 COPD, resting PaO2 Randomised, 2x6/52 No difference between air and oxygen periods in Significant 2005 ≥7.3 kPa (55mmHg) + crossover: cylinder air vs O2 6MWD. Statistically significant but clinically small improvements in SpO2 ≤88% on exertion @ 4L/min. differences between O2 and air in CRQ and HAD QOL, but not + exertional dyspnoea domains. Similarly for 4/8 domains of SF-36. predicted by acute response.
Lacasse et 24 COPD, receiving COT: Randomised, 3x3/12 No difference between the 3 treatments for any No placebo or real al 2005 resting PaO2 ≤7.3 kPa crossover: concentrator CRQ domain or 6MWD. Few cylinders used, benefit of cylinders as (55mmHg) or SpO2 alone, + cylinder air, + average 30 mins/day. an adjunct to COT. ≤88% or PaO2 ≤7.8kPa cylinder O2. Flow → PaO2 (59mmHg) + hypoxic >60mmHg (>8kPa). organ damage
(Nonoyama 27 COPD, SpO2 ≤88% for 2 Series of N-of-1 RCT‟s, Small, significant ↑ in no of steps in 5 min walk test, No support for et al 2007a) mins during 6MWT 3x4/52 pairs of 2/52 oxygen no statistical or clinical differences between O2 and general application in + 2/52 placebo in random placebo for CRQ and SGRQ. this group. order. Flow 1-3 L/min → SpO2 ≥90% on exertion.
34
n Participants Study design Study results Conclusions
Sandland et 20 Severe hypoxaemia at Parallel RCT, 8/52 O2 or air. No significant change in exercise capacity, No improvement in al 2008 rest (n=7) or exercise Flow 2 L/min. endurance, domestic activity, CRQ or SF-36 scores physical activity, QoL desaturation >4% below for either group over time. No difference between or time spent away 90%, MRC Dyspnoea groups for CRQ scores. No interaction for cylinder from home. score >3. usage (self-report) or time spent away from home. Significantly more oxygen cylinders used over 8/52.
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
35
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 36
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 37
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 38
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 39
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 40
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 41
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 2: Oxygen therapy 42
Chapter
Whoever invented cigarettes ought to be disgusted with themselves. Oisin Darcy (2006 - aged 11 years)
3 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
Chapter 3: COPD 43
(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 44
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 45
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 46
absence of exposure to the recognised risk factors for COPD (McKenzie et al 2009).
chronic bronchitis emphysema without airflow without airflow obstruction obstruction
other causes of airflow obstruction
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.
Chapter 3: COPD 47
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 48
Table 3.1 Classification systems for disease severity in COPD
Mild Moderate Severe
FEV1/ FEV1 FEV1/ FEV1 FEV1/ FEV1 FVC% % pred FVC% % pred FVC% % 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 49
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 50
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 51
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 52
(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 53
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 54
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 55
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):
pressure flow = resistance
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):
Palv – Pao Raw = V
Figure 3.3 Diagram illustrating the causes of airflow obstruction in COPD (Barnes 2000, p 270).
Chapter 3: COPD 56
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 57
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 58
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 59
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 60
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:
Tdi Pdi = 2 Rdi
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
Chapter 3: COPD 61
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 62
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 63
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 64
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 65
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 66
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 67
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 68
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 69
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 70
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 71
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 72
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 73
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 74
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 75
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 76
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 77
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 78
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 79
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 3: COPD 80
Chapter 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)
4 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
Chapter 4: Outcome measures in COPD 81
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 82
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 Reproducibility of results Test-retest (includes intra-rater) Extent of agreement (correlation) between tests Inter-rater 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 83
Table 4.2 Categories of dyspnoea measures (Hajiro, et al., 1998; Meek & Lareau, 2003)
Category Association Examples
Clinical Activities, particularly Medical Research Council Dyspnoea Scale activities of daily living Baseline and Transition Dyspnoea Indices Oxygen Cost Diagram Exertional Symptoms during Borg Scale exercise, exercise Visual Analogue Scale testing
Quality of Health related quality of Chronic Respiratory Disease Questionnaire life life, functional status 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 84
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 85
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)
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
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.
Chapter 4: Outcome measures in COPD 86
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 87
Table 4.5 Summary of Baseline and Transition Dyspnoea Index scores (Mahler et al 1998)
Grades Components
Baseline Dyspnoea Index (BDI): dyspnoea at baseline
0 to 4 Functional impairment: performance of daily activities and occupation 0 to 4 Magnitude of task: difficulty of activities causing breathlessness 0 to 4 Magnitude of effort: degree of effort able to be exerted 0 to 12 BDI focal score
Transition Dyspnoea Index (TDI): changes from baseline state
-3 to +3 Change in functional impairment -3 to +3 Change in magnitude of task -3 to +3 Change in magnitude of effort -9 to +9 TDI focal score
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
Chapter 4: Outcome measures in COPD 88
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 89
(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 Nothing at all 0.5 Very, very weak (just noticeable) 1 Very weak 2 Weak (light) 3 Moderate 4 Somewhat strong 5 Strong (heavy) 6 7 Very strong 8 9 10 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:
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).
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).
Chapter 4: Outcome measures in COPD 90
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 91
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 92
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 93
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 94
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 95
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 Range of scores MID (questions)
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 96
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 97
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).
Functional capacity
Functional reserve
Functional performance
Influenced by symptoms, Functional capacity particularly dyspnoea and utilisation fatigue in COPD
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
Chapter 4: Outcome measures in COPD 98
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 99
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 100
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 101
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 102
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 103
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 104
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 105
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 106
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 107
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 108
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 4: Outcome measures in COPD 109
Chapter 4: Outcome measures in COPD 110
Chapter Measure what can be measured, make measurable what cannot be measured. Gallileo Galilei (1569–1642)
5 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.
Chapter 5: Activity measurement in COPD: Pilot of Activity Diary 111
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 1 lying 2 breakfast to 2 sitting, for example reading, watching television lunchtime 3 sitting activity, eg. performing a seated exercise program 3 lunch to dinner time 4 standing 4 dinner to bedtime 5 standing activity, eg. preparing meals, performing an 5 bedtime to waking. 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 112
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 113
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 114
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:
“Should the diary consist of seven separate sheets, or should the sheets be joined into one document?”
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
Chapter 5: Activity measurement in COPD: Pilot of Activity Diary 115
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 116
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 117
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 5: Activity measurement in COPD: Pilot of Activity Diary 118
Chapter An experiment is a question which science poses to Nature, and a measurement is the recording of Nature's answer. Max Planck (1949)
6 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.
Chapter 6: Comparison of pedometer and activity diary in COPD 119
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 120
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 121
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 122
80 participants
15 initially incomplete: pedometer = 11 diary = 1 both = 3
13 2 withdrew repeated consent
1st attempt: 2nd attempt: 2 incomplete: pedometer = 1 65 complete 11 complete diary = 1
76 complete data sets available for analysis
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.
Chapter 6: Comparison of pedometer and activity diary in COPD 123
Table 6.1 Demographic data of included participants: mean (standard deviation) and comparisons of means between males and females (t tests)
Total Males Females p value n = 76 n = 51 n = 25
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 124
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 23,128.8 (1,959.5) vs Standing/walking time (hours) 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 23,406.2 (2,545.1) vs Standing/walking time (hours) 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 22,562.9 (2988.1) vs Standing/walking time (hours) 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 125
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 126
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 127
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 128
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 129
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 130
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 6: Comparison of pedometer and activity diary in COPD 131
Chapter 6: Comparison of pedometer and activity diary in COPD 132
Chapter
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
7 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
Chapter 7: Acute effects of hyperoxia on ventilation and dyspnoea 133
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 134
(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 135
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 136
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 137
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 138
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 139
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 140
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 141
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 142
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 143
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) (Man et al 2004) EILV/TLC% (EILV = TLC - IRV) (O'Donnell et al 2001a) (Somfay et al 2001)
IC/TLC% (Casanova et al 2005) (Marin et al 2001)
IC% predicted value (Diaz et al 2000) (TLC% predicted - FRC% predicted) (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 144
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 145
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 O’Donnell et al Peters et al (1997a) (2001a) (2006) Hyperoxia 60% Hyperoxia 60% Hyperoxia 50%
Participants n=11 n=11 n=16 Hypoxaemia Mild Moderate - Normoxic
Resting PaO2 Mean 74mmHg severe >65mmHg
≤60mmHg Exercise SpO2
Exercise SpO2 ≥88% <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 NS p=0.068 ↑ p<0.05 NS Difference In means: +0.14L Mean: +0.29L 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 146
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 147
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 148
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 149
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 150
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 151
Room air B, fC, SpO2, Baseline ≥ 5 minutes dyspnoea
RANDOMISATION
B, fC, SpO2, Gas 1 Air Hyperoxia dyspnoea, 5 minutes IC
3 minutes room air
B, fC, SpO2,
Gas 2 Hyperoxia Air dyspnoea, 5 minutes IC
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.
Chapter 7: Acute effects of hyperoxia on ventilation and dyspnoea 152
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 153
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 154
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 155
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 44% Oxygen t df p
mean (± SD) SEM mean (± SD) SEM value value
All participants n = 51
SpO2 (%) 94.1 (4.1) 0.6 98.4 (2.1) 0.3 8.043 50 <0.000 IC (litres) 2.05 (0.79) 0.1 2.09 (0.76) 0.11 1.875 50 0.0691 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 156
Table 7.5 Mean change (hyperoxia minus air values) in inspiratory capacity
(IC), dyspnoea (Borg score) and arterial saturation (SpO2)
Mean ∆ IC in Mean ∆ IC % Mean ∆ Mean ∆ litres (SEM) predicted (SEM) dyspnoea SpO2% range range (SEM) (SEM)
All participants 0.04 (0.02) 1.5 (0.8) -0.2 (0.1) 3.8 (0.4) -0.44 to +0.43 -15.7 to +12.3
FEV1 < 70% 0.04 (0.02) 1.5 (0.9) -0.2 (0.1) 4.1 (0.5) predicted -0.44 to +0.43 -15.7 to +12.3
Qualified to 0.05 (0.05) 2.2 (2.0) -0.1 (0.1) 7.0 (1.2) receive LTOT -0.22 to +0.27 -7.4 to 10.3
IC, inspiratory capacity; SEM, standard error of the mean; SpO2, oxyhaemoglobin saturation; FEV1, forced expiratory volume in one second; LTOT, long term oxygen therapy
Moderate and severe All participants airflow obstruction r=0.16, p=0.25 0.50 r=0.39, p=0.015
0.25
0.00
-0.25
Change in IC with hyperoxia (L)
-0.50 10 30 50 70 90 110 130 FEV (% predicted) 1
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
Chapter 7: Acute effects of hyperoxia on ventilation and dyspnoea 157
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 158
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 159
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 7: Acute effects of hyperoxia on ventilation and dyspnoea 160
Chapter When you can’t breathe, nothing else matters. The Australian Lung Foundation
8 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
Chapter 8: Effects of domiciliary ambulatory oxygen in COPD 161
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 162
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 163
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 164
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 165
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 166
Visit 1 (Week 0) Enrolment Run in MRC Dyspnoea Score BDI 2 ABG's weeks PFT's including IC
Visit 2 (Week 2) CRQ, AQoL, HADS Randomisation Activity diary check Pedometer reading Exercise Tests
Activity diary + pedometer 3 x 7 days during week prior to Visits 2, 3,and 4 Cylinder Cylinder air oxygen OR
12 12 weeks weeks Visit 3 (Week 6) TDI + Visit 2 assessments
Visit 4 (Week 14) TDI + Visit 2 assessments
Survey
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.
Chapter 8: Effects of domiciliary ambulatory oxygen in COPD 167
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 Significant locomotor MRC Dyspnoea Scale grade of 3 disability or other severe
PaO2 >55 mmHg at rest, breathing room air disabling condition 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
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 168
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 169
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 170
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 171
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 172
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 173
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 174
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 175
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 176
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 177
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 178
Cylinder familiarisation Visit 2 only
Test 1 Preparation Practice Test Test 2 Test 3 st nd Instructions 1st cylinder 1 cylinder 2 cylinder 6 L/min flow 6 L/min flow No gas flow
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.
Chapter 8: Effects of domiciliary ambulatory oxygen in COPD 179
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:
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.
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.
Chapter 8: Effects of domiciliary ambulatory oxygen in COPD 180
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 181
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 182
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 183
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 SpO2 on Six Minute Walk >88% (American Thoracic Society 2002) Test breathing cylinder air ≤ 88%
Severity of airflow obstruction FEV1 % predicted < 50% (Pellegrino et al 2005) 50 – 69% ≥ 70%
Exercise response to hyperoxia Increase in Six Minute Walk < 54metres (Redelmeier et al 1997) Distance breathing 6 L/min ≥ 54metres oxygen compared with air
Volume response to hyperoxia Increase in IC % predicted < 10% (O'Donnell and Laveneziana 2006c) breathing 44% oxygen ≥ 10% compared with 21% oxygen
Severe breathlessness Baseline Dyspnoea Index ≤ 4 units (O'Donnell et al 1999) Focal Score > 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 184
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 After randomisation randomisation
Northern 46 (28.8%) 6 (13.0% of 46) 0 40 Hospital Austin 114 (71.2%) 11 (9.6% of 114) 4 99 Hospital 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
Chapter 8: Effects of domiciliary ambulatory oxygen in COPD 185
Assessed for eligibility Excluded n = 1158 n = 1318 Not meet inclusion criteria: 672 Unwilling: 324 Unable to contact: 90 Too distant: 61 Enrolled Language or cognitive issues: 6 Participating in other trial: 5 n = 160
Enrolled, not randomised n = 17 Consent withdrawn: 8 PaO2 <55 mmHg: 4 Randomised Recommenced smoking: 2 n = 143 Normal lung function: 1 Major comorbidity: 1 Deceased: 1
Cylinder air Cylinder oxygen n = 75 (52%) n = 68 (48%)
Dropped out n = 2 Dropped out Dropped out n = 2 Consent withdrawn: 2 n = 4 Deceased: 1 Unwell: 1
Complete data Completed Complete data n = 73 n = 139 n = 66
Figure 8.4 Flow of participants through the study
PaO2, arterial partial pressure of oxygen
186
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
187
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)
188
Table 8.7 Outcome measures and t tests to compare air and oxygen groups at baseline.
Possible All Air Oxygen t p range mean (SD) range mean (SD) mean (SD)
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
# Clinically HADS n=141 n =74 n=67 significant 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
189
Possible Air Oxygen All t p range mean (SD) mean (SD) 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
190
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 191
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).
Chapter 8: Effects of domiciliary ambulatory oxygen in COPD 192
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
Inter- Mean (SEM) Range Mean (SEM) Range Main effect Main effect action Gas Time 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
193
Air group Oxygen group ANOVA: p values
Inter- Mean (SEM) Range Mean (SEM) Range Main effect Main effect action Gas Time 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
194
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 Main effect Main effect Inter- Mean (SEM) Range Mean (SEM) Range Gas Time 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
195
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
196
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
197
50
40 Mean: 8.0
30 Standard deviation: 8.9 Median: 4.4
20
Number of participants of Number 10
0 0.0 10.0 20.0 30.0 40.0 50.0 60.0 Number of cylinders
Figure 8.6 Histogram depicting cylinder utilisation over the 12 weeks of the study by participants overall (n=138)
198
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
199
Histogram depicting cylinder utilisation during the 12 weeks of the study for participants overall
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 Main effect Interaction p-value 95% CI Gas Subgroup (Gas*subgroup) 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
200
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 201
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 202
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 203
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 204
(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 8: Effects of domiciliary ambulatory oxygen in COPD 205
Chapter 8: Effects of domiciliary ambulatory oxygen in COPD 206
Chapter
The important thing is not to stop questioning. Curiosity has its own reason for existing. Albert Einstein (1879 – 1955)
9 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.
Chapter 9: Conclusions and Future Directions 207
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 208
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 209
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 210
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 211
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.
Chapter 9: Conclusions and Future Directions 212
References
Abernathy A, McDonald C, Frith P, Clark K, Herndon J, Marcello J, Woods D, Young I, Bull J, Wilcock A, Booth S, Wheeler J, Tulsky J, Crockett A and Currow D (2010). Effect of palliative oxygen versus medical (room) air in relieving breathlessness in patients with refractory dyspnea: a double- blind randomized controlled trial (NCT00327873). Lancet; In press.
Abraham A, Cole B and Bishop J (1968). Reversal of pulmonary hypertension by prolonged oxygen administration to patients with chronic bronchitis. Circulation Research 23: 147-159.
Access Economics Pty Limited (2008) Economic impact of COPD and cost effective solutions. January 2010.
Albert P and Calverley P (2008). Drugs (including oxygen) in severe COPD. European Respiratory Journal 31: 1114-1124.
Aliverti A and Macklem P (2001). How and why exercise is impaired in COPD. Respiration 68: 229-239.
Aliverti A and Macklem P (2008). Point:Counterpoint: The major limitation to exercise performance in COPD is inadequate energy supply to the respiratory and locomotor muscles. Journal of Applied Physiology 105.
Alvisi V, Mirkovic T, Nesme P, Guerin C and Milic-Emili J (2003). Acute effects of hyperoxia on dyspnoea in hypoxaemic patients with chronic airway obstruction at rest. Chest 123: 1038-1046.
Ambrosino N and Porta R (2001a). Measurement of dyspnoea. Monaldi Archives of Chest Disease 56(1): 39-42.
Ambrosino N and Scano G (2001b). Measurement and treatment of dyspnoea. Respiratory Medicine 95: 539-547.
References 213
American Association for Respiratory Care (2007). AARC clinical practice guideline: oxygen therapy in the home or alternative site health care facility. Respiratory Care 52(1): 1063-1068.
American Thoracic Society (1962). Definitions and classification of chronic bronchitis, asthma, and pulmonary emphysema. A statement by the committee on diagnostic standards for nontuberculous respiratory diseases. American Review of Respiratory Disease 85: 762-769.
American Thoracic Society (1995a). Single-breath carbon-monoxide diffusing capacity (transfer factor). Recommendations for a standard technique- 1995 update. American Journal of Respiratory and Critical Care Medicine 152: 2185-2198.
American Thoracic Society (1995b). Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease and asthma. American Journal of Respiratory and Critical Care Medicine 152: S77- S121.
American Thoracic Society (1995c). Standardization of spirometry. American Journal of Respiratory and Critical Care Medicine 152: 1107-1136.
American Thoracic Society (1999a). Dyspnea. Mechanisms, assessment, and management: A consensus statement. American Journal of Respiratory and Critical Care Medicine 159: 321-340.
American Thoracic Society (1999b). Pulmonary rehabilitation - 1999. American Journal of Respiratory and Critical Care Medicine 159: 1666-1682.
American Thoracic Society (2002). ATS Statement: guidelines for the six-minute walk test. American Journal of Respiratory and Critical Care Medicine 166: 111-117.
American Thoracic Society/European Respiratory Society (1999). Skeletal muscle dysfunction in chronic obstructive puomonary disease. American Journal of Respiratory and Critical Care Medicine 159: S1-S40.
References 214
Anthonisen N, Manfreda J, Warren C, Hershfield E, Harding G and Nelson N (1987). Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease. Annals of Internal Medicine 106: 196-204.
Attia J, Nair B, Mears S and Hitchcock K (2004). Patient-oxygen dissociation curves: surveying the spectrum of oxygen-delivery methods. Medical Journal of Australia 181: 677-679.
Augusti A, Noguera A, Sauleda J, Sala E, Pons J and Busquets X (2003). Systemic effects of chronic obstructive pulmonary disease. European Respiratory Journal 21(2): 347-360.
Bannister R and Cunningham D (1954). The effects upon respiration and performance during exercise of adding oxygen to the inspired air. Journal of Applied Physiology (London) 125: 118-137.
Barach A (1922). The therapeutic use of oxygen. Journal of the American Medical Association 79: 693-699.
Barach A (1959). Ambulatory oxygen therapy: Oxygen inhalation at home and out of doors. Chest 35: 229-241.
Barbera J (2000). Chronic obstructive pulmonary disease. In: J Roca, R Rodriguez-Roisin and P Wagner (Eds.) Lung Biology in Health and Disease. Vol 148. Pulmonary and peripheral gas exchange in health and disease. New York: Marcel Dekker. pp. 229-261.
Barnes P (2000). Chronic obstructive pulmonary disease. New England Journal of Medicine 343: 269-280.
Barnes P (2004). Small airways in COPD. New England Journal of Medicine 350(26): 2635-2637.
Barr R, Bluemke D, Ahmed F, Carr J, Enright P, Hoffman E, Jiang R, Kuwat S, Kronmal R, Lima J, Shahar E, Smith L and Watson K (2010): Percent emphysema, airflow obstruction, and impaired left ventricular filling. New England Journal of Medicine 362: 217-227.
References 215
Bassett D (2000a). Validity and reliability issues in objective monitoring of physical activity. Research Quarterly for Exercise and Sport 71: 30-36.
Bassett D, Ainsworth B, Leggett S, Mathien C, Main J, Hunter D and Duncan G (1996). Accuracy of five electronic pedometers for measuring distance walked. Medicine and Science in Sports and Exercise 28(8): 1071-1077.
Bassett D, Ainsworth B, Swartz A, Strath S, O'Brien W and King G (2000b). Validity of four motion sensors in measuring moderate intensity physical activity. Medicine and Science in Sports and Exercise 32(Suppl 9): S471- S480.
Bassett D, Cureton A and Ainsworth B (2000c). Measurement of daily walking distance - questionnaire versus pedometer. Medicine and Science in Sports and Exercise 32(5): 1018-1023.
Belman M, Botnick W and Shin J (1996). Inhaled bronchodilators reduce dynamic hyperinflation during exercise in patients with chronic obstructive pulmonary disease. American Journal of Respiratory and Critical Care Medicine 153: 967-975.
Belza B, Steele B, Hunziker J, Lakshminaryan S, Holt L and Buchner D (2001). Correlates of physical activity in chronic obstructive pulmonary disease. Nursing Research 50(4): 195-202.
Benowitz N and Brunetta P (2005). Smoking hazards and cessation. In: R Mason, V Broaddus, J Murray and J Nadel (Eds.) Murray and Nadel's textbook of respiratory medicine. Philadelphia, USA: Elsevier Saunders. Vol 2: pp. 2453-2468.
Bergner M, Bobbitt R, Carter W and Gibson B (1981). The Sickness Impact Profile: development and final revision of a health status measure. Medical Care 19: 787-805.
Bernstein M, Despars J, Singh N, Avalos K, Stansbury D and Light R (1994). Reanalysis of the 12-minute walk in patients with chronic obstructive pulmonary disease. Chest 105: 163-167.
References 216
Bestall J, Paul E, Garrod R, Garnham R, Jones P and Wedzicha J (1999). Usefulness of Medical Research Council (MRC) dyspnoea scale as a measure of disability in patients with chronic obstructive pulmonary disease. Thorax 54(7): 581-586.
Bjornson K and Belza B (2004). Ambulatory activity monitoring in youth: State of the science. Pediatric Physical Therapy 16: 82-89.
Block E (1982). Oxygen therapy. In: A Fishman (Ed.) Update: Pulmonary diseases and disorders. New York, USA: McGraw Hill. pp. 349-365.
Borg G (1970). Perceived exertion as an indicator of somatic stress. Scandinavian Journal of Rehabilitation Medicine 2: 92-98.
Borg G (1982). Psychosocial bases of perceived exertion. Medical Science Sports Exercise 14: 377-381.
Bradley B, Garner A, Billiu D, Mestas J and Forman J (1978). Oxygen-assisted exercise in chronic obstructive lung disease: the effect on exercise capaciy and arterial blood gas tensions. American Review of Respiratory Disease 91: 653-659.
Bradley J and O'Neill B (2005). Short-term ambulatory oxygen for chronic obstructive pulmonary disease (Review). Cochrane Database of Systematic Reviews Issue 4: Art. No. CD004356.
Brenes G (2003). Anxiety and chronic obstructive pulmonary disease: Prevalence, impact, and treatment. Psychosomatic Medicine 65: 963-970.
British Thoracic Society (1997). BTS guidelines for the management of chronic obstructive pulmonary disease. Thorax 52(Suppl 5): S1-S28.
British Thoracic Society (2001). Pulmonary rehabilitation: BTS Statement. Thorax 56: 827-834.
References 217
Brusaco V, Hodder R, Miravitles M, Korducki L, Towse L and Kesten S (2003). Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPD. Thorax 58: 399-404.
Burrows B, Fletcher C, Heard B, Jones N and Wootliff J (1966). The emphysematous and bronchial types of chronic airway obstrruction: a clinopathological study of patients in London and Chicago. Lancet 1: 830- 835.
Butland R, Pang J, Gross E, Woodcock A and Geddes D (1982). Two-, six-, and 12-minute walking tests in respiratory disease. British Medical Journal 284: 1607-1608.
Cain S (1987). Gas exchange in hypoxia, apnea, and hyperoxia. In: A Fishman, L Farhi and S Tenney (Eds.) Handbook of Physiology. Section 3: The Respiratory System. Bethesda, USA: Amerian Physiology Society. Vol IV: pp. 403-420.
Calverley P (2006). Dynamic hyperinflation. Is it worth measuring? Proceedings of the American Thoracic Society 3: 239-244.
Calverley P and Koulouris N (2005). Flow limitation and dynamic hyperinflation: key concepts in modern respiratory physiology. European Respiratory Journal 25: 186-199.
Calverley P and Walker P (2003). Chronic obstructive pulmonary disease. The Lancet 362: 1053-1061.
Camarri B, Eastwood P, Cecins N, Thompson P and Jenkins S (2006). Six minute walk distance in healthy subjects aged 55-75 years. Respiratory Medicine 100(4): 658-665.
Campbell E and Howell J (1963). The sensation of breathlessness. British Medical Bulletin 19: 36-40.
References 218
Carpagnano G, Kharitonov S, Foschino-Barbaro M, Resta O, Gramiccioni E and Barnes P (2004). Supplementary oxgyen in healthy subjects and those with COPD increases oxidative stress and airway inflammation. Thorax 59: 1016-1019.
Carter R, Holiday D, Nwasuruba C, Stocks J, Grothues C and Tiep B (2003). 6- minute walk work for assessment of functional capacity in patients with COPD. Chest 123: 1408-1415.
Casaburi R (2001). Skeletal muscle dysfunction in chronic obstructive pulmonary disease. Medicine and Science in Sports and Exercise 33(7): S662-S670.
Casaburi R, Patessio A, Ioli F, Zanaboni S, Donner C F and Wasserman K (1991). Reductions in exercise lactic acidosis and ventilation as a result of exercise training in patients with obstructive lung disease. American Review of Respiratory Disease 143(1): 9-18.
Casanova C, Cote C, de Torres J, Aguirre-Jaime A, Marin J, Pinto-Plata V and Celli B (2005). Inspiratory-to-total lung capacity ratio predicts mortality in patients with chronic obstructive pulmonary disease. American Journal of Respiratory and Critical Care Medicine 171: 591-597.
Cazzola M, MacNee W, Martinez F, Rabe K, Franciosi L, Barnes P, Brusaco V, Burge P, Calverley P, Celli B, Jones P, Mahler D, Make B, Miravitlles M, Page C, Palange P, Parr D, Pistolesi M, Rennard S, Rutten-van Molken M, Stockey R, Sullivan S, Wedzicha J and Wouters E (2008). ATS/ERS Task Force. Outcomes for COPD pharmacological trials: from lung function to biomarkers. European Respiratory Journal 31: 416-468.
Celli B (2000). The importance of spirometry in COPD and asthma: effect on approach to management. Chest 117(2): 15S-19S.
Celli B (2003). Symptoms are an important outcome in chronic obstructive pulmonary disease clinical trials: results of a 3-minth comparative study using the Breathlessness, Cough and Sputum Scale (BCSS). Respiratory Medicine 97: S35-S43.
References 219
Celli B, Cote C, Marin J, Casanova C, Montes de Oca M, Mendez R, Pinto-Plata V and Cabral H (2004a). Body-mass index, airflow obstruction, dyspnea, and exercise capacity index in chronic obstructive pulmonary disease. The New England Journal of Medicine 350: 1005-1012.
Celli B and MacNee B (2004b). Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. European Respiratory Journal 23: 932-946.
Celli B, ZuWallack R, Wang S and Kesten S (2003). Improvement in resting inspiratory capacity and hyperinflation with tiotropium in COPD patients with increased static lung volumes. Chest 124: 1743-1784.
Chang T, Lipinski C and Sherman H (2001). A hazard of home oxygen therapy. Journal of Burn Care and Rehabilitation 22(1): 71-74.
Chaouat A, Weitzenblum E, Kessler R, Charpentier C, Ehrhart M, Schott R, Levi- Valensi P, Zielinski J, Delaunois L, Cornudella R and Moutinho dos Santos J (1999). A randomized trial of nocturnal oxygen therapy in chronic obstructive pulmonary disease. European Respiratory Journal 14: 1002-1008.
Cherniack N (2004). Oxygen sensing: applications in humans. Journal of Applied Physiology 96: 352-358.
Chinard F (1995). Priestly and Lavoisier: Oxygen and carbon dioxide. In: D Proctor (Ed.) Lung biology in health and disease. A history of breathing physiology. New York: Marcel Dekker. Vol 83: 203-221.
Christensen C, Ryg M, Edvardsen A and Skjonsberg O (2004). Relationship between exercise desaturation and pulmonary haemodynamics in COPD patients. European Respiratory Journal 24: 580-586.
Ciba G S (1959). Terminology, definitions and classification of chronic pulmonary emphysema and related conditions. Thorax 14: 286-299.
References 220
Connors A, Dawson N, Thomas C, Harrell F, Desbiens N, Fulkerson W, Kussin P, Bellamy P, Goldman L and Knaus W (1996). Outcomes following acute exacerbation of severe chronic obstructive lung disease. The SUPPORT investigators (Study to understand the Prognoses and preferences for outcomes and risks of treatments). American Journal of Respiratory and Critical Care Medicine 154(4): 959-967.
Cooper C (2006). The connection between chronic obstructive pulmonary disease symptoms and hyperinflation and its impact on exercise and function. The American Journal of Medicine 119(10 Suppl 1): 21-31.
Cooper C and Celli B (2008). Venous admixture in COPD: pathophysiology and therapeutic approaches. Journal of Chronic Obstructive Pulmonary Disease 5(6): 376-381.
Cooper K (1968). A means of assessing maximal oxygen intake. Journal of the American Medical Association 203: 201-204.
Coronado M, Janssens J, de Muralt B, Terrier P, Schutz Y and Fitting J (2003). Walking activity measured by accelerometry during respiratory rehabilitation. Journal of Cardiopulmonary Rehabilitation 23: 357-364.
Cotes J (1993). Lung function assessment and application in medicine. 5th edn. Oxford, UK: Blackwell Scientific Publication.
Cotes J and Gilson J (1956). Effect of oxygen on exercise ability in chronic respiratory insufficiency: Use of a portable apparatus. Lancet June 9: 872- 876.
Crane L (1992). Functional anatomy and physiology of ventilation. In: C Zadii (Eds.) Clinics in physical therapy. Edinburgh, UK: Churchill Livingston. pp. 1-21.
Cranston J, Crockett A, Moss J and Alpers J (2005). Domiciliary oxygen for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews Issue 4: Art. No. CD001744.
References 221
Crockett A, Cranston J and Antic N (2001). Domiciliary oxygen for interstitial lung disease. Cochrane Database of Systematic Reviews Issue 3: Art. No. CD002883.
Crouter S, Schneider P, Karabulut M and Bassett D (2003). Validity of 10 electronic pedometers for measuring steps, distance, and energy cost. Medicine and Science in Sports and Exercise 35(8): 1455-1460.
Croxton T and Bailey W (2006). Long-term oxygen treatment in COPD: Recommendations for future research. American Journal of Respiratory and Critical Care Medicine 174: 373-378.
Cukier A, Ferreira C, Stelmach R, Ribeiro M, Cortopassi F and Calverley P (2007). The effect of bronchodilators and oxygen alone and in combination on self-paced exercise performance in stable COPD. Respiratory Medicine 101: 746-753.
Curtis J, Deyo R A and Hudson L (1994). Health-related quality of life among patients with chronic obstructive pulmonary disease. Thorax 49: 162-170.
Curtis J and Patrick D (2003). The assessment of health status among patients with COPD. European Respiratory Journal 21(Suppl 41): 36s-45s.
Cusick J (2001). Burn prevention forum. Editorial. Journal of Burn Care and Rehabilitation 22(1): 70-71.
Cyarto E, Myers A and Tudor-Locke C (2004). Pedometer accuracy in nursing home and community-dwelling older adults. American College of Sports Medicine 36(2): 205-209. de Torres J, Casanova C, Hernandez C, Abreu J, Aguirre-Jaime A and Celli B (2005). Gender and COPD in patients attending a pulmonary clinic. Chest 128: 2012-2016.
References 222
de Torres J, Casanova C, Hernandez C, Abreu J, Montejo de Garcini A, Aguirre- Jaime A and Celli B (2006). Gender associated differences in determinants of quality of life in patients with COPD: a case series study. Health and Quality of Life Outcomes 4: 72-78. de Torres J, Pinto-Plata V, Ingenito E, Bagley P, Gray A, Berger R and Celli B (2002). Power of outcome measurements to detect clinically significant changes in pulmonary rehabilitation of patients with COPD. Chest 121: 1092-1098.
Dean N C, Brown J K, Himelman R B, Doherty J J, Gold W M and Stulbarg M S (1992). Oxygen may improve dyspnea and endurance in patients with chronic obstructive pulmonary disease and only mild hypoxemia. American Review of Respiratory Disease 146(4): 941-5.
Debigare R and Maltais F (2008). Point:Counterpoint: The major limitation to exercise performance in COPD is lower limb muscle dysfunction. Journal of Applied Physiology 105: 753.
Decramer M (1997). Hyperinflation and respiratory muscle interaction. European Respiratory Journal 10: 934-941.
Dent A, Jelinek G, Neate S, Weiland T and Kelly A (2007). The effects of oxygen therapy in patients presenting to an emergency department with exacerbation of chronic obstructive pulmonary disease. Medical Journal of Australia 187(4): 253-254.
Di Marco F, Milic-Emili J, Boveri B, Carlucci P, Santus P, Casanova F, Cazzola M and Centanni S (2003). Effect of inhaled bronchodilators on inspiratory capacity and dyspnoea at rest in COPD. European Respiratroy Journal 21: 86-94.
Diaz O, Villafranca C, Ghezzo H, Borzone G, Leiva A, Milic-Emili J and Lisboa C (2000). Role of inspiratory capacity on exercise tolerance in COPD patients with and without tidal expiratory flow limitation at rest. European Respiratory Journal 16: 269-275.
References 223
Doherty D and Petty T (2006). Recommendations of the 6th Long-term oxygen therapy consensus conference. Respiratory Care 51(5): 519-525.
Dolmage T and Goldstein R (2002). Repeatability of inspiratory capacity during incremental exercise in patients with severe COPD. Chest 121: 708-714.
Donaldson G, Seemungal T, Patel I, Lloyd-Owen S, Wilkinson T and J. W (2003). Longtitudinal changes in the nature, severity and frequency of COPD exacerbations. European Respiratory Journal 22: 931-936.
Donaldson G, Wilkinson T, Hurst J, Perera W and Wedzicha J (2005). Exacerbations and time spent outdoors in chronic obstructive pulmonary disease. American Journal of Respiratory and Critical Care Medicine 171: 446-452.
Dorcas M (2008) The oxygen dissociation curve. www.bio.davidson.edu. [Accessed 23rd August 2009].
Drummond M and Wise R (2007). Oxygen therapy in COPD: What do we know? American Journal of Respiratory and Critical Care Medicine 176: 321-326.
DuBois A, Botelho S, Bedell G, Marshall R and Comroe J (1956). A rapid plethysmographic method for measuring thoracic gas volume: a comparison with a nitrogen washout method for measuring functional residual capacity in normal subjects. Journal of Clinical Investigation 35: 322-326.
Duranti R, Filippelli M, Bianchi R and Romagnoli I (2002). Inspiratory capacity and decrease in lung hyperinflation with albuterol in COPD. Chest 122(6): 2009-2014.
Dusser D, Bravo M and Iacono P (2006). The effect of tiotropium on exacerbations and airflow in patients with COPD. European Respiratory Journal 27: 547-555.
References 224
Eaton T, Fergusson G, Kolbe J, Lewis C and West T (2006). Short-burst oxygen for COPD patients: a 6-month randomised, controlled study. European Respiratory Journal 697-704.
Eaton T, Garrett J, Young P, Fergusson W, Kolbe J, Rudkin S and Whyte K (2002). Ambulatory oxygen improves quality of life of COPD patients: a randomised controlled study. European Respiratory Journal 20(2): 306- 312.
Eaton T E, Grey C and Garrett J E (2001). An evaluation of short-term oxygen therapy: the prescription of oxygen to patients with chronic lung disease hypoxic at discharge from hospital. Respiratory Medicine 95(7): 582-7.
Emtner M, Porszasz J, Burns M, Somfray A and Casaburi R (2003). Benefits of supplemental oxygen in exercise training in nonhypoxemic chronic obstructive pulmonary disease patients. American Journal of Respiratory and Critical Care Medicine 168: 1034-1042.
Enright P, McBurnie M, Bittner V, Tracy R, McNamara R, Arnold A and Newman A (2003). The 6-min walk test. Chest 123: 387-398.
Enright P and Sherrill D (1998). Reference equations for the six-minute walk in healthy adults. American Journal of Respiratory and Critical Care Medicine 158: 1384-1387.
European Society of Pneumonology (1989). Report of a SEP (European Society of Pneumonology) Task Group. Recommendations for long term oxygen therapy (LTOT). European Respiratory Journal 2: 160-164.
Farkas G and Roussos C (1983). Diaphragm in emphysematous hamsters: sarcomere adaptability. Journal of Applied Physiology 54: 1635-1640.
Ferrari K, Goti P, Misuri G, Amendola M, Rosi E, Grazzini M, Iandelli I, Duranti R and Scano G (1997). Chronic exertional dyspnea and respiratory muscle function in patients with chronic obstructive pulmonary disease. Lung 175: 311-319.
References 225
Findeisen M (2001). Long-term oxygen in the home. Home Healthcare Nurse 19(11): 692-699.
Fitzgerald R (1995). The regulation of breathing. In: D Proctor (Eds.) Lung biology in health and disease. A history of breathing physiology. New York, USA: Marcel Dekker. Vol 83: pp. 303-307.
Fletcher C (1952). The clinical diagnosis of pulmonary emphysema - An experimental study. Proceedings of the Royal Society of Medicine 45: 577-584.
Fletcher C (1959). Terminology, definitions, and classification of chronic pulmonary emphysema and related conditions. A report of the conclusions of a CIBA guest symposium. Thorax 41: 286-299.
Fletcher C and Peto R (1977). The natural history of chronic airflow obstruction. British Medical Journal 1: 1645-1648.
Fletcher E, Elmes P, Fairbairn A and Wood C (1959). The significance of respiratory symptoms and the diagnosis of chronic bronchitis in a working population. British Medical Journal 2: 257-266.
Fletcher E, Luckett R, Goodnight-White S, Miller C, Qian W and Costarangos- Galarza C (1992). A double-blind trial of nocturnal supplemental oxygen for sleep desaturation in patients with chronic obstructive pulmonary disease and a daytime PaO2 above 60 mmHg. American Review of Respiratory Disease 145: 1070-1076.
Folgering H (1999). Supplemental oxygen for COPD patients with nocturnal desaturations? European Respiratory Journal 14: 997-999.
Follick M, Ahern D and Laser-Wolston N (1984). Evaluation of a daily activity diary for chronic pain patients. Pain 19: 373-382.
Ganong W (2003). Regulation of respiration. In: W Ganong (Ed.) Review of medical physiology. 21st edn. New York, USA: Lange. pp. 675-684.
References 226
Garrod R, Paul E and Wedzicha J (2000). Supplemental oxygen during pulmonary rehabilitation in patients with COPD with exercise hypoxaemia. Thorax 55: 539-543.
Gelb A, Gutierrez C, Weisman I, Newsom R, C. F T and Zamel N (2004). Simplified detection of dynamic hyperinflation. Chest 126: 1855-1860.
Gibbons W, Fruchter N, Sloan S and Levy R (2001). Reference values for a multiple repetition 6-minute walk test in healthy adults older than 20 years. Journal of Cardiopulmonary Rehabilitation 21: 87-93.
Gibson G (2004). Moran Campbell and clinical science. Thorax 59: 737-740.
Goldman H and Becklake M (1959). Respiratory function tests; normal values at median altitudes and the prediction of normal results. American Review of Tuberculosis 79: 457-467.
Gorecka D, Gorzelak K, Sliwinski P, Tobiasz M and Zielinski J (1997). Effect of long term oxygen therapy on survival in patients with chronic obstructive pulmonary disease. Thorax 52: 674-679.
Grant S, Aitchison T, Henderson E, Christie J, Zare S, McMurray J and Dargie H (1999). A comparison of the reproducibility and the sensitivity to change of visual analogue scales, Borg scales, and Likert scales in normal subjects during submaximal exercise. Chest 116: 1208-1217.
Gretebeck R and Montoye H (1992). Variability of some objective measures of physical activity. Medicine and Science in Sports and Exercise 24(10): 1167-1172.
Gross N (2003). Outcome measures in COPD. Are we schizophrenic? Chest 123: 1325-1327.
Guyatt G, Feeny D and Patrick D (1993). Measuring health-related quality of life. Annals of Internal Medicine 118: 622-629.
References 227
Guyatt G, Heyting A, Jaeschke R, Keller J, Adachi J and Roberts R (1990). N of 1 randomized trials for investigating new drugs. Controlled Clinical Trials 11: 88-100.
Guyatt G, McKim D, Austin P, Bryan R, Norgren J, Weaver B and Goldstein R (2000). Appropriateness of domiciliary oxygen delivery. Chest 118: 1303- 1308.
Guyatt G, Pugsley S, Sullivan M, Thompson P, Berman L B, Jones N, Fallen E and Taylor D (1984). The effect of encouragement on walking test performance. Thorax 39: 818-822.
Guyatt G, Thompson P and Berman L B (1985). How should we measure function in patients with chronic heart and lung disease? Journal of Chronic Disease 38: 517-524.
Guyatt G, Townsend M, Keller J, Singer J and Nogradi S (1989). Measuring functional status in chronic lung disease: conclusions from a randomised control trial. Respiratory Medicine 83: 293-297.
Guyatt G H, Berman L B, Townsend M, Pugsley S O and Chambers L W (1987). A measure of quality of life for clinical trials in chronic lung disease. Thorax 42(10): 773-778.
Hajiro T, Nishimura K, Tsukino M, Ikeda A, Koyama H and Izumi T (1998). Analysis of clinical methods used to evaluate dyspnea in patients with chronic obstructive pulmonary disease. American Journal of Respiratory and Critical Care Medicine 158: 1185-1189.
Haldane J (1917). The therapeutic administration of oxygen. The British Medical Journal Feb 10: 181-183.
Haldane J (1919). Symptoms, causes and prevention of anoxaemia. The British Medical Journal July 19: 65-71.
References 228
Hammond M, Gale G, Kapitan S, Ries A and Wagner P (1986): Pulmonary gas exchange in humans during exercise at sea level. Journal of Applied Physiology 60 (5): 1590-1598.
Harper R, Brazier J, Waterhouse J, Walters S, Jones P and Howard P (1997). Comparison of outcome measures for patients with chronic obstructive pulmonary disease (COPD) in an outpatient setting. Thorax 52: 879-887.
Hatano Y (1993). Use of the pedometer for promoting daily walking exercise. International Council for Health, Physical Education and Recreation 29(4): 4-8.
Haverkamp H, Dempsey J, Miller J, Romer L and Eldridge M (2005). Physiologic responses to exercise. In: Q Hamid, J Shannon and J Martin (Eds.) The physiologic basis of respiratory disease. Hamilton, Canada: BC Decker Inc. pp. 525-540.
Hawthorne G and Osborne R (2005). Population norms and meaningful differences for the Assessment of Quality of Life (AQoL) measure. Australian Journal of Public Health 29(2): 136-142.
Hawthorne G, Richardson J and Day N (2001). A comparison of the Assessment of Quality of Life (AQoL) with four other generic utility instruments. Annals Medicine 33: 358-370.
Hawthorne G, Richardson J and Osborne R (1999). The Assessment of Quality of Life (AQoL) instrument: a psychometric measure of Health Related Quality of Life. Quality of Life Research 8: 209-224.
Hayhurst M, MacNee W, Flenley D, Wright D, McLean A, Lamb D, Wightman A and Best J (1984). Diagnosis of pulmonary emphysema using computed tomography. Lancet 2: 320-322.
Hermann C (1997). International experiences with the Hospital Anxiety and Depression Scale - a review of validation data and clinical results. Journal of Psychosomatic Research 42: 17-41.
References 229
Hill J, Wyatt H, Reed G and Peters J (2003). Obesity and the environment: where do we go from here? Science 29: 853-855.
Hill K and Goldstein R (2007). Limited functional performance in chronic obstructive pulmonary disease: nature, causes and measurement. Journal of Chronic Obstructive Pulmonary Disease 4: 257-261.
Hill K, Jenkins C, Hillman D and Eastwood P (2004). Dyspnoea in COPD: Can inspiratory muscle training help. Australian Journal of Physiotherapy 50: 169-180.
Hogg J (2004a). Pathology of emphysema. In: H Fessler, J Reilly and D Sugarbaker (Eds.) Lung biology in health and disease. Lung volume reduction surgery for emphysema. New York: Marcel Dekker. Vol 184: pp. 23-42.
Hogg J, Chu F, Utokaparch S, Woods R, Elliott W, Buzatu L, Cherniak R, Rogers R, Sciurba F, Coxson H and Pare P (2004b). The nature of small-airway obstruction in chronic obstructive pulmonary disease. New England Journal of Medicine 350(26): 2645-2653.
Hogg J and Senior R (2002). Chronic obstructive pulmonary disease c2: Pathology and biochemistry of emphysema. Thorax 57: 830-834.
Holland A, Hill C, Rasebaka T, Lee A, Naughton M and McDonald C (2010). Updating the minimal important difference for six-minute walk distance in patients with chronic obstructive pulmonary disease. Archives of Physical Medicine Rehabilitation 91: 221-225.
Holmes P, Campbell A and Barter C (1978). Acute changes of lung volumes and lung mechanics in asthma and in normal subjects. Thorax 33: 394-400.
Hunt S, McEwen J and McKenna S (1986). Measuring health status. London, UK: Croom Helm.
Hurd S (2000). The impact of COPD on lung health worldwide: epidemiology and incidence. Chest 117(2 Suppl): 1S-4S.
References 230
Hyatt R (1961). The interrelationship of pressure, flow and volume during various respiratory maneuvers in normal and emphysematous patients. American Review of Respiratory Disease 83: 676-683.
Jaeschke R, Singer J and Guyatt G (1989). Measurement of health status. Ascertaining the minimal clinically important difference. Controlled Clinical Trials 10: 407-415.
Jenkins C (2003). Sharpening the clinical diagnostic borders of chronic obstructive pulmonary disease. Internal Medicine Journal 33: 551-553.
Jenkins S (2000). Pulmonary rehabilitation. Physiotherapy Singapore 3: 106-112.
Johnson A (2003). Chronic obstructive pulmonary disease. 11: Fitness to fly with COPD. Thorax 58: 729-732.
Johnston M, Pollard B and Hennessey P (2000). Construct validation of the hospital anxiety and depression scale with clinical populations. Journal of Psychosomatic Research 48: 579-584.
Jones P (1991). Quality of life measurement for patients with diseases of the airways. Thorax 46: 676-682.
Jones P (2001). Health status measurement in chronic obstructive pulmonary disease. Thorax 56: 880-887.
Jones P (2002). Interpreting thresholds for a clinically significant change in health status in asthma and COPD. European Respiratory Journal 19: 398-404.
Jones P (2005). Health status, health-related quality of life, and dyspnea in COPD. In: D Mahler and D O'Donnell (Eds.) Dyspnea. Mechanisms, measurement, and management. Boca Raton, USA: Taylor and Francis Group. Vol 208: pp. 265-281.
Jones P and Kaplan R (2003). Methodological issues in evaluating measures of health as outcomes for COPD. European Respiratory Journal 21(Suppl 41): 13s-18s.
References 231
Jones P, Quirk F and Baveystock C (1991). The St George's Respiratory Questionnaire. Respiratory Medicine 85 (Suppl B): 25-31.
Jones P, Quirk F, Baveystock C and Littlejohns P (1992). A self-complete measure of healthstatus for chronic airflow obstruction. The St. George's Respiratory Questionnaire. American Review of Respiratory Disease 145: 1321-1327.
Joosten S, Koh M, Bu X, Smallwood D and Irving L (2007). The effects of oxygen therapy in patients presenting to an emergency department with exacerbation of chronic obstructive pulmonary disease. Medical Journal of Australia 186(5): 235-238.
Kacmarek R (2000). Delivery systems for long-term oxygen therapy. Respiratory Care 45: 84-92.
Kaplan R, Atkins C and Timms R (1984). Validity of a quality of well-being scale as an outcome measure in chronic obstructive pulmonary disease. Journal of Chronic Disease 37: 85-95.
Kaplan R, Ries A, Prewitt L and Eakin E (1994). Self-efficacy expectations predict survivial for patients with chronic obstructive pulmonary disease. Health Psychology 13: 366-368.
Karabulut M, Crouter S and Bassett D (2005). Comparison of two waist-mounted and two ankle-mounted electronic pedometers. European Journal of Applied Physiology 95: 335-343.
Katsura H, Yamada K, Wakabayashi R and Kida K (2007). Gender-associated differences in dyspnoea and health-related quality of life in patients with chronic obstructive pulmonary disease. Respirology 12: 427-432.
Kim H, Kunik M, Molinari V, Hillman S, Lalani S, Orengo C, Petersen N, Nahas Z and Goodnight-White S (2000). Functional impariment in COPD patients. The impact of anxiety and depression. Psychosomatics 41: 465-471.
References 232
Kirby J, Juniper E, Hargreave F and Zamel N (1986). Total lung capacity does not change during methacholine-stimulated airway narrowing. Journal of Applied Physiology 61: 2144-2146.
Knox A, Morrison J and Muers M (1988). Reproducibility of walking test results in chronic obstructive airways disease. Thorax 43: 388-392.
Knudson R, Slatin R, Lebowitz M and Burrows B (1976). The maximal expiratory flow-volume curve: normal standards, variability and effects of age. American Review of Respiratory Disease 113: 587-600.
Kohansal R, Martinez-Camblor P, Agusti A, Buist S, Mannino D and Soriano J (2009): The natural history of chronic airflow obstruction revisited. An analysis of the Framington Offspring Cohort. American Journal of Respiratory and Critical Care Medicine 180: 3-10.
Kriska A and Caspersen C (1997). Introduction to a collection of physical activity questionnaires. Medicine and Science in Sports and Exercise 29(6 (Supplement)): 5-9.
Lacasse Y, LaForge J and Maltais F (2006). Got a match? Home oxygen therapy in current smokers. Thorax 61: 374-375.
Lacasse Y, Lecours R, Pelletier C, Begin R and Maltais F (2005). Randomised trial of ambulatory oxygen in oxygen-dependent COPD. European Respiratory Journal 25: 1032-1038.
Lacasse Y, Rousseau L and Maltais F (2001). Prevalence of depressive symptoms and depression in patients with severe oxygen-dependent chronic obstructive pulmonary disease. Journal of Cardiopulmonary Rehabilitation 21(2): 80-86.
Lareau S, Meek P and Roos P (1998). Development and testing of a modified version of the functional status and dyspnoea questionnaire (PFSDQ-M). Heart and Lung 27(3): 159-168.
References 233
Laurell C and Eriksson S (1963). The electrophoretic alpha-1 globulin pattern of serum and alpha-1 antitrypsin deficiency. Scandinavian Journal of Clinical Laboratory Investigation. 15: 132-140.
Le Masurier G, Lee S and Tudor-Locke C (2004). Motion sensor accuracy under controlled and free-living conditions. Medicine and Science in Sports and Exercise 36(5): 905-910.
Le Masurier G and Tudor-Locke C (2003). Comparison of pedometer and accelerometer accuracy under controlled conditions. Medicine and Science in Sports and Exercise 35(5): 867-871.
Leger L and Lambert J (1982). A maximal multistage 20-m shuttle run test to predict CO2max. European Journal of Applied Physiology 49: 1-12.
Leggett R and Flenley D (1977). Portable oxygen and exercise tolerance in patients with chronic hypoxic cor pulmonale. British Medical Journal 2(6079): 84-86.
Leidy N (1994). Using functional status to assess treatment outcomes. Chest 106(6): 1645-1646.
Leidy N (1995). Functional performance in people with chronic obstructive pulmonary disease. Image - the Journal of Nursing Scholarship 27: 23-34.
Leidy N and Haase J (1996). Functional performance in people with chronic obstructive pulmonary disease: A qualitative analysis. Advances in Nursing Science 18(3): 77-89.
Leisker J, Postma D, Beukema R, ten Hacken N, van der Molen T, Riemersma R, van Zomeren E and Kerstjens H (2004). Cognitive performance in patients with COPD. Respiratory Medicine 98: 351-356.
Levetown M (2002). Oxygen-induced hypercapnia in chronic obstructive pulmonary disease: What's the problem? Critical Care Medicine 30(1): 258-259.
References 234
Levine B, Bigelow D, Hamstra R, Beckwitt H, Mitchell R, Nett L, Stephen T and Petty T (1967). The role of long-term continuous oxygen administration in patients with chronic airway obstruction with hypoxaemia. Annals of Internal Medicine 66: 503-512. Lilker E, Karnick A and Lerner L (1975). Portable oxygen in chronic obstructive lung disease with hypoxemia and cor pulmonale: a controlled double-blind crossover study. Chest 68(2): 236-241.
Lincoln N and Gladman J (1992). The extended Activities of Daily Living Scale: a further validation. Disability and Rehabilitation 14: 41-43.
Liss H and Grant B (1988). The effect of nasal flow on breathlessness in patients with chronic obstructive pulmonary disease. American Review of Respiratory Disease 137: 1285-1288.
Lock S, Paul E, Rudd R and Wedzicha J (1991). Portable oxygen therapy: assessment and usage. Respiratory Medicine 85: 407-412.
Lomas D (2002). Chronic obstructive pulmonary disease - Introduction. Thorax 57: 735.
Lopez A, Mathers C, Ezzati M, Jamison D and Murray C (2006). Global and regional burden of disease and risk factors, 2001: systemic analysis of population health data. Lancet 367(9524): 1747-1757.
Loring S, Garcia-Jacques M and Malhotra A (2009). Pulmonary characteristics in COPD and mechanisms of increased work of breathing. Journal of Applied Physiology 107: 309-314.
Lumb A (2005). Nunn's applied respiratory physiology. 6th edn. Philadelphia, USA: Elsevier Butterworth Heineman.
MacIntyre N (2000). Oxygen therapy and exercise response in lung disease. Respiratory Care 45: 194-200.
Macklem P (1984). Hyperinflation. American Review of Respiratory Disease 129: 1-2.
References 235
MacNee W (2005). Prescription of oxygen: Still problems after all these years. American Journal of Respiratory and Critical Care Medicine 172: 517-522.
Mahler D (2000). How should health-related quality of life be assessed in patients with COPD? Chest 117: 54S-57S.
Mahler D (2004). Dyspnea. In: B Celli (Eds.) Lung biology in health and disease. Pharmacotherapy in COPD. New York, USA: Marcel Dekker. Vol 182: pp. 144-157.
Mahler D (2005a). Measurement of dyspnea: clinical ratings. In: D Mahler and D O'Donnell (Eds.) Dyspnea. Mechanisms, measurement, and management. Boca Raton, USA: Taylor and Francis Group. Vol 208: pp. 147-165.
Mahler D, Fierro-Carrion G, Mejia-Alfaro R, Ward J and Baird J (2005b). Responsiveness of continuous ratings of dyspnea during exercise in patients with COPD. Medicine and Science in Sports and Exercise 37(4): 529-535.
Mahler D, Guyatt G and Jones P (1998). Clinical measurement of dyspnea. In: D Mahler (Eds.) Lung biology in health and disease: Dyspnea. 1st edn. New York, USA: Marcel Dekker. Vol 111: pp. 149-198.
Mahler D and Horowitz M (1994). Perception of breathlessness during exercise in patients with respiratory disease. Medicine and Science in Sports and Exercise 26: 1078-1081.
Mahler D, Tomlinson D, Olmstead E, Tosteson A and O'Connor G (1995). Changes in dyspnea, health status, and lung function in chronic airway disease. American Journal of Respiratory and Critical Care Medicine 152: 61-65.
Mahler D, Waterman L, Ward J and Baird J (2005c). Comprehensive measurement of breathlessness using the self-administered computerized versions of the Baseline and Transition Dyspnea Indexes. Chest 128(4): 131S.
References 236
Mahler D, Weinberg D, Wells C and Feinstein A (1984). The measurement of dyspnoea. Contents, interobserver agreement, and physiologic correlates of two new clinical indices. Chest 85: 751-758.
Mahler D and Wells C (1988). Evaluation of clinical methods for rating dyspnea. Chest 93(3): 580-586.
Mahler D and Witek T (2005d). The MCID of the transition dyspnea index is a total score of one unit. Journal of COPD: 99-103.
Mallory G, Fullmer J and Vaughan D (2005). Oxygen therapy for cystic fibrosis. Cochrane Database of Systematic Reviews Issue 4: Art. No. CD003884.
Man W, Mustfa N, Nikoletou D, Kaul S, Hart N, Rafferty G, Donaldson N, Polkey M and Moxham J (2004). Effect of salmeterol on respiratory muscle activity during exercise in poorly reversible COPD. Thorax 59: 471-476.
Manning H and Schwartzstein R (1995). Mechanisms of disease: pathophysiology of dyspnea. The New England Journal of Medicine 333(23): 1547-1553.
Manning H and Schwartzstein R (1998). Mechanisms of dyspnea. In: D Mahler (Eds.) Lung biology in health and disease: Dyspnea. New York, USA: Marcel Dekker Inc. Vol III: pp. 63-95.
Marin J, Carrizo S, Gascon M, Sanchez A, Gallego B and Celli B (2001). Inspiratory capacity, dynamic hyperinflation, breathlessness, and exercise performance during the 6-minute-walk test in chronic obstructive pulmonary disease. American Journal of Respiratory and Critical Care Medicine 163: 1395-1399.
Matthews C, Ainsworth B, Thompson R and Bassett D (2002). Sources of variance in daily physical activity levels as measured by an accelerometer. Medicine and Science in Sports and Exercise 34: 1376- 1381.
References 237
Maxwell D, J. M, Andrews S and Gleeson M (1993). Hazards of domiciliary oxygen therapy. Respiratory Medicine 87: 225-226.
McCoy R (2000). Oxygen-conserving techniques and devices. Respiratory Care 45: 95-124.
McCoy R (2002). New technologies for lighter portable oxygen systems. Respiratory Care 47(8): 879-881.
McDonald C, Blyth C, Lazarus M, Marschner I and Barter C (1995). Exertional oxygen of limited benefit in patients with chronic obstructive pulmonary disease and mild hypoxemia. American Journal of Respiratory and Critical Care Medicine 152: 1616-1619.
McDonald C, Crockett A and Young I (2005). Adult domiciliary oxygen therapy. Position statement of the Thoracic Society of Australia and New Zealand. Medical Journal of Australia 182(12): 621-626.
McGavin C, Gupta S and McHardy G (1976). Twelve-minute walking test for assessing disability in chronic bronchitis. British Medical Journal 1: 822- 823.
McKenzie D, Abramson M, Crockett A, Glasgow N, Jenkins S, McDonald C, Wood-Baker R and Frith P (2009) The COPD-X plan: Australian and New Zealand Guidelines for the management of chronic obstructive pulmonary disease 2009. http://www.copdx.org.au. [Accessed 31st July 2009].
McKenzie D, Frith P, Burdon J and Town I (2003). The COPD X plan: Australian and New Zealand guidelines for the management of chronic obstructive pulmonary disease. Medical Journal of Australia 178: S1-S39.
Mckinlay L, Pulakal S, Turkington P and O'Driscoll B (2007). Short burst oxygen therapy does not relieve breathlessness after exercise in patients with severe COPD who are not hypoxaemic at rest. Thorax 62(Suppl iii): A67.
References 238
McMurray R, Harrell J, Bradley C, Webb J and Goodman E (1998). Comparison of a computerized physical activity recall with a triaxial motion sensor in middle-school youth. Medicine and Science in Sports and Exercise. 30: 1238-1245.
Mead J, Turner J, Macklem P and Little J (1976). Significance of the relationship between lung recoil and maximal expiratory flow. Journal of Applied Physiology 22: 95-108.
Meakins J (1920). The therapeutic value of oxygen in pulmonary lesions. The British Medical Journal March 6: 324-326.
Medical Research Council (1960). Standardized questionnaire of respiratory symptoms. British Medical Journal 2: 1665.
Medical Research Council Working Party (1981). Long term domiciliary oxygen therapy in chronic hypoxic cor pulmonale complicating chronic bronchitis and emphysema. Lancet 1: 681-686.
Meek P (2004). Measurement of dyspnea in chronic obstructive pulmonary disease: what is the tool telling you? Chronic Respiratory Disease 1: 29- 37.
Meek P and Lareau S (2003). Critical outcomes in pulmonary rehabilitation: Assessment and evaluation of dyspnoea and fatigue. Journal of Rehabilitation Research and Development 40: 13-24.
Melanson E, Knoll J, Bell M, Donahoo W, Hill J, Nysse L, Lanningham-Foster L, Peters J and Levine J (2004). Commercially available pedometers: considerations for accurate step counting. Preventive Medicine 39: 361- 368.
Milic-Emili J (1998). Respiratory mechanics. Monaldi Archives of Chest Disease 53: 294-295.
Milic-Emili J (2000). Expiratory flow limitation: Roger S. Mitchell Lecture. Chest 117: 219-223.
References 239
Miller J and Dempsey J (2004). Pulmonary limitations to exercise performance: The effects of healthy aging and COPD. In: D Massaro (Ed.) Lung development and regeneration. New York, USA: Marcel Dekker. pp. 525- 571.
Miller M, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, Crapo R, Enright P, van der Grinten C, Gustafsson P, Jensen R, Johnson D, MacIntyre N, McKay R, Navajas D, Pedersen O, Pellegrino R, Viegi G and Wanger J (2005). ATS/ERS Task Force: Standardisation of Lung Function Testing. Standardisation of spirometry. European Respiratory Journal 26: 319-338.
Moore R, Allen R and Smith M (1988). Oxygen requirements during exercise in hypoxic cystic fibrosis subjects. Proceedings of the 10th International Cystic Fibrosis Congress, Sydney, Australia. Hong Kong: Excerpta Medica. p119.
Morton J, McKenna M, Carey M, Fraser S, Snell G, Parkin J, Rabinov M, Smith J, Esmore D and Williams T (1998). Metabolites and fibre types in respiratory and peripheral muscles in severe chronic obstructive airways disease. American Journal of Respiratory and Critical Care Medicine 157: A361.
Murciano D, Ferretti A, Boczkowski J, Sleiman C, Fournier M and Milic-Emili J (2000). Flow limitation and dynamic hyperinflation during exercise in COPD patients after single lung transplantation. Chest 118: 1248-1254.
Murray C and Lopez A (1996). Evidence-based policy - lessons from the Global Burden of Disease Study. Science 274: 740-743.
Murray C and Lopez A (1997). Mortality by cause for eight regions of the world: Global Burden of Disease Study. Lancet 349: 1269-1276.
Nasilowski J, Przybylowski T, Zielinski J and Chazan R (2008). Comparing supplementary oxygen benefits from a portable oxygen concentrator and a liquid portable device during a walk test in COPD patients on long-term oxygen therapy. Respiratory Medicine 102(7): 1021-1025.
References 240
National Institute for Clinical Excellence (2004). National clinical guideline on management of chronic obstructive pulmonary disease in primary and secondary care. Thorax 59(Suppl 1): 1-232.
Neff T and Petty T (1970). Long-term continuous oxygen therapy in chronic airway obstruction: mortality in relationship to cor pulmonale, hypoxia, and hypercapnia. Annals of Internal Medicine 93(3): 391-391.
Netter F (1996). Physiology. In: M Devertie and A Brass (Eds.) The CIBA collection of medical illustrations. Vol 7: The respiratory system. Summit, NJ, USA: CibaGeigy Corporation. p 53.
Newton M, O'Donnell D and Forkert L (2002). Response of lung volumes to inhaled salbutamol in a large population of patients with severe hyperinflation. Chest 121(4): 1042-1050.
Nisbet M, Eaton T, Lewis C, Fergusson W and Kolbe J (2006). Overnight prescription of oxygen in long term oxygen therapy: time to reconsider the guidelines? Thorax 61: 779-782.
Nishimura K, Izumi T, Tsukino M and Oga T (2002). Dyspnea is a better predictor of 5-year survival than airway obstruction in patients with COPD. Chest 121: 1434-1440.
Nocturnal Oxygen Therapy Trial Group (1980). Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease: a clinical trial. Annals of Internal Medicine 93: 391-398.
Nonoyama M, Brooks D, Guyatt G and Goldstein R (2007a). Effect of oxygen on health quality of life in patients with chronic obstructive pulmonary disease with transient exertional hypoxemia. American Journal of Respiratory and Critical Care Medicine 176: 343-349.
Nonoyama M, Brooks D, Lacasse Y, Guyatt G and Goldstein R (2007b). Oxygen therapy during exercise training in chronic obstructive pulmonary disease (Review). Cochrane Database of Systematic Reviews Issue 2: Art. No. CD005372.
References 241
Nunn J (2005). The atmosphere. In: A Lumb (Ed.) Nunn's applied respiratory physiology. 6th edn. Philadelphia, USA: Elsevier. pp. 3-11.
O'Donnell D (2001c). Ventilatory limitations in chronic obstructive pulmonary disease. Medicine and Science in Sports and Exercise. 33(7): S647-S655.
O'Donnell D (2004). Lung mechanics in COPD: the role of tiotropium. European Respiratory Review 13(89): 40-44.
O'Donnell D (2006a). Impacting patient-centred outcomes in COPD: breathlessness and exercise. European Respiratory Review 15(99): 37- 41.
O'Donnell D (2006b). Is sustained pharmacologic lung volume reduction now possible in COPD? Chest 129(3): 501-203.
O'Donnell D, Bain D and Webb K (1997a). Factors contributing to relief of exertional breathlessness during hyperoxia in chronic airflow limitation. American Journal of Respiratory and Critical Care Medicine 155: 530-535.
O'Donnell D, Banzett R, Carrieri-Kohlman V, Casaburi R, Davenport P, Gandevia S, Gelb A, Mahler D and Webb K (2007). Pathophysiology of dyspnea in chronic obstructive pulmonary disease. A roundtable. Proceedings of the American Thoracic Society 4: 145-168.
O'Donnell D, Bertley J, Chau L and Webb K (1997b). Qualitative aspects of exertional breathlessness in chronic airflow limitation. Pathophysiologic mechanisms. American Journal of Respiratory and Critical Care Medicine 155: 109-115.
O'Donnell D, D'Arsigny C and Webb K (2001a). Effects of hyperoxia on ventilatory limitation during exercise in advanced chronic obstructive pulmonary disease. American Journal of Respiratory and Critical Care Medicine 163: 892-898.
References 242
O'Donnell D, Forkert L and Webb K (2001d). Evaluation of bronchodilator responses in patients with "irreversible" emphysema. European Respiratory Journal 18: 914-920.
O'Donnell D, Lam M and Webb K (1998). Measurement of symptoms, lung hyperinflation, and endurance during exercise in chronic obstructive pulmonary disease. American Journal of Respiratory and Critical Care Medicine 158: 1557-1565.
O'Donnell D, Lam M and Webb K (1999). Spirometric correlates of improvement in exercise performance after anticholinergic therapy in chronic obstructive pulmonary disease. American Journal of Respiratory and Critical Care Medicine 160: 542-549.
O'Donnell D and Laveneziana P (2006). The clinical importance of dynamic lung hyperinflation in COPD. Journal of Chronic Obstructive Pulmonary Disease 3: 219-232.
O'Donnell D and Laveneziana P (2006c). The clinical importance of dynamic lung hyperinflation in COPD. Journal of Chronic Obstructive Pulmonary Disease 3: 219-232.
O'Donnell D and Laveneziana P (2006d). Physiology and consequences of lung hyperinflation in COPD. European Respiratory Review 15(100): 61-67.
O'Donnell D, Revill S and Webb K (2001b). Dynamic hyperinflation and exercise intolerance in chronic obstructive pulmonary disease. American Journal of Respiratory and Critical Care Medicine 164(5): 770-7.
O'Donnell D, Travers J, Webb K, He Z, Lam Y, Hamilton A, Kesten S, Maltais F and Magnussen H (2009). Reliability of ventilatory parameters during cycle ergometry in multicentre trials in COPD. European Respiratory Journal I34: 866-874.
O'Donnell D and Webb D (2004). Exercise testing. In: B Celli (Eds.) Lung Biology in Health and Disease: Pharmacotherapy in COPD. New York, USA: Marcel Dekker. Vol 182: pp. 45-71.
References 243
O'Donnell D and Webb K (1993). Exertional breathlessness in patients with chronic airflow limitation. The role of lung hyperinflation. American Review of Respiratory Disease 148: 1351-1357.
O'Donnell D and Webb K (2003). Exercise. In: P Calverley, B MacNee, S Rennard and N Pride (Eds.) Chronic obstructive pulmonary disease. 2nd edn. London, UK: Edward Arnold Publishers. pp 243-269.
O'Donnell D and Webb K (2005). Mechanisms of dyspnea in COPD. In: D Mahler and D O'Donnell (Eds.) Dyspnea, mechanisms, measurement and management. 2nd edn. New York, USA: Marcel Dekker. Vol 208: pp. 29- 58.
O'Donnell D and Webb K (2008). Point:Counterpoint: The major limitation to exercise performance in COPD is dynamic hyperinflation. Journal of Applied Physiology 105: 753-755.
O'Donoghue W (1995). Indications for long-term oxygen therapy and appropriate use. In: J Walter and W O'Donoghue (Eds.) Lung Biology in Health and Disease: Long-term oxygen therapy. New York, USA: Marcel Dekker. Vol 81: pp. 53-68.
O'Driscoll B (2008). Short burst oxygen therapy in patients with COPD. Monaldi Arch Chest Dis 69(2): 70-74.
O'Neill B, MacMahon J and Bradley J (2006). Short-burst oxygen therapy in chronic obstructive pulmonary disease. Respiratory Medicine 100: 1129- 1138.
Ontario Ministry of Health and Long Term Care Assistive Devices Program (2005) Home Oxygen Program (HOP) Administration Manual. http:/www.health.gov.on.can/english/providers/pub/adp/hop_manual05. [Accessed 16th February 2009].
O'Reilly P and Bailey W (2007). Long-term continuous oxygen treatment in chronic obstructive pulmonary disease: proper use, benefits and unresolved issues. Current Opinion in Pulmonary Medicine 13: 120-124.
References 244
Osborne R, Hawthorne G, Lew E and Gray L (2003). Quality of life assessment in the community-dwelling elderly: validation of the assessment of quality of life (AQoL) instrument and comparison with the SF-36. Clinical Edidemiology 56: 138-147.
Parker C, Voduc N, Aaron S, Webb K and O'Donnell D (2005). Physiological changes during symptom recovery from moderate exacerbations of COPD. European Respiratory Journal 26: 420-428.
Pauwels R, Buist S, Calverley P, Jenkins C and Hurd S (2001). Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. American Journal of Respiratory and Critical Care Medicine 163: 1256-1276.
Pellegrino R, Rodarte J and Brusaco V (1998). Assessing the reversibility of airway obstruction. Chest 114: 1607-1612.
Pellegrino R, Viegi G, Brusasco V, Crapo R, Burgos F, Casaburi R, Coates A, van der Grinten C, Gustafsson P, Hankinson J, Jensen R, Johnson D, MacIntyre N, McKay R, Miller M, Navajas D, Pederson O and Wanger J (2005). ATS/ERS Task Force: Sandardisation of lung function testing. Interpretative strategies for lung function tests. European Respiratory Journal 26: 948-968.
Pepe P and Marini J (1982). Occult positive end-expiratory pressure in mechanically ventilated patients with airflow obstruction: the auto-PEEP effect. American Review of Respiratory Disease 126: 166-170.
Permutt S (1995). Pulmonary circulation: Mechanics. In: D Proctor (Eds.) Lung biology in health and disease. A history of breathing physiology. New York, USA: Marcel Dekker. Vol 83: pp. 261.
Peters M, Webb K and O'Donnell D (2006). Combined physiological effects of bronchodilators and hyperoxia on exertional dyspnoea in normoxic COPD. Thorax 61: 559-567.
References 245
Peto R, Speizer F, Moore C and al e (1983). The relevance in adults of airflow ostruction, but not of mucus hypersecretion, to mortality from chronic lung disease: results from twenty years of prospective observation. American Review of Respiratory Disease 128: 491-500.
Petty T (1985). Definitions, clinical assessment, and risk factors. In: T Petty (Eds.) Lung biology in health and disease. Chronic obstructive pulmonary disease. 2nd edn. New York, USA: Marcel Dekker. Vol 28: pp. 1-30.
Petty T (1995). Historical perspectives on long-term oxygen therapy. In: W O'Donoghue (Eds.) Lung biology in health and disease. Long-term oxygen therapy. New York, USA: Marcel Dekker. pp. 1-23.
Petty T (2000a). Ambulatory oxygen therapy, exercise, and survival with advanced chronic obstructive pulmonary disease (The nocturnal oxygen therapy trial revisited). Respiratory Care 45: 204-211.
Petty T (2000b). Historical highlights of long-term oxygen therapy. Respiratory Care Vol 45: pp. 29-36.
Petty T (2002). COPD in perspective. Chest 121(5): S116-S120.
Petty T (2003). Chronic obstructive pulmonary disease. In: M Hanley and C Welsh (Eds.) Current diagnosis and treatment in pulmonary medicine. New York, USA: Lange Medical Books/McGraw Hill. pp 82-91.
Petty T and Finigan M (1968). Clinical evaluation of prolonged ambulatory oxygen therapy in chronic airway obstruction. American Journal of Medicine 45(2): 242-252.
Petty T and Flenley D (1986). Domiciliary and ambulatory oxygen in chronic respiratory insufficiency. In: D Flenley and T Petty (Eds.) Recent advances in respiratory medicine. Edinburgh, UK: Churchill Livingstone. pp. 217-221.
References 246
Pierce A, Paez P and Miller W (1965). Exercise training with the aid of a portable oxygen supply in patients with emphysema. American Review of Respiratory Disease 91: 653-659.
Pierce R, Hillman D, Young I, O'Donoghue F, Zimmerman P, West S and Burdon J (2005). Respiratory function tests and their application. Respirology 10: S1-S19.
Pitta F, Troosters T, Probst S, Spruit M, Decramer M and Gosselink R (2006a). Quantifying physical activity in daily life with questionnaires and motion sensors in COPD. European Respiratory Journal 27: 1040-1055.
Pitta F, Troosters T, Spruit M, Decramer M and Gosselink R (2005a). Activity monitoring for assessment of physical activities in daily life in patients with chronic obstructive pulmonary disease. Archives of Physical Medicine Rehabilitation 86: 1979-1985.
Pitta F, Troosters T, Spruit M, Probst S, Decramer M and Gosselink R (2005b). Characteristics of physical activities in daily life in chronic obstructive pulmonary disease. American Journal of Respiratory and Critical Care Medicine 171: 972-977.
Polgar S and Thomas S (1998). Introduction to research in the health sciences. 3rd. edn. Melbourne, Australia: Churchill Livingstone.
Poulain M, Durand F, Palomba B, Ceugniet F, Desplan J, Varray A and Prefaut C (2003). 6-minute walk testing is more sensitive than maximal incremental cycle testing for detecting oxygen desaturation in patients with COPD. Chest 123: 1401-1407.
Pride N and Macklem P (1986). The respiratory system. In: P Macklem and J Mead (Eds.) Handbook of physiology. Section 3. Bethesda, USA: American Physiological Society. pp. 659-692.
Priestly J (1775). Dephlogisticated air and the constituents of the atmosphere. In: J Priestly (Eds.) Experiments and observations on different kinds of air. Vol 2. London, UK.: J Johnson.
References 247
Proctor D (1995a). Ancient medicine and the mystery of breathing. In: D Proctor (Eds.) Lung biology in health and disease. A history of breathing physiology. New York, USA.: Marcel Dekker. Vol 83: pp. 3-16.
Proctor D (1995b). Mayow's contributions to breathing mechanics. In: D Proctor (Eds.) Lung biology in health and disease. A history of breathing physiology. New York, USA.: Marcel Dekker. Vol 83: pp. 167-175.
Puente-Maestu L, Garcia de Pedro J, Martinez-Abad Y, Ruiz de Ona J, Llorente D and Cubillo J (2005). Dyspnea, ventilatory pattern, and changes in dynamic hyperinflation related to the intensity of constant work rate exercise in COPD. Chest 128: 651-656.
Puhan M, Mador M, Held U, Goldstein R, Guyatt G and Schunemann H (2008). Interpretation of treatment changes in 6-minute walk distance in patients with COPD. European Respiratory Journal 32: 637-643.
Quanjer P, Tommelin G and Cotes J (1993). Lung volumes and forced ventilatory flows. Report of the Working Party for Standardization of Lung Function Tests. European Respiratory Journal 6(Suppl 16): 5-40.
Quantrill S, White R, Crawford A, Barry J, Batra S, Whyte P and Roberts C (2007). Short burst oxygen therapy after activities of daily-living in the home in chronic obstructive pulmonary disease. Thorax 62: 702-705.
Ram F and Wedzicha J (2003). Ambulatory oxygen for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews Issue 1: Art No.: CD000238.
Redelmeier D, Bayoumi A, Goldstein R and Guyatt G (1997). Interpreting small differences in functional status: the six minute walk test in chronic lung disease patients. American Journal of Respiratory and Critical Care Medicine 155: 1278-1282.
Rees P and Dudley F (1998a). ABC of oxygen: Oxygen therapy in chronic lung disease. British Medical Journal 317: 871-874.
References 248
Rees P and Dudley F (1998b). ABC of oxygen: Provision of oxygen at home. British Medical Journal 317: 935-938.
Revill S, Morgan M, Singh S, Williams J and Hardman A (1999). The endurance shuttle walk: a new field test for the assessment of endurance capacity in chronic obstructive pulmonary disease. Thorax 54: 213-222.
Ringbaek T (2005). Continuous oxygen therapy for hypoxic pulmonary disease: guidelines, compliance and effects. Treatment in Respiratory Medicine 4(6): 397-408.
Robinson T, Freiberg D, Regnis J and Young I (2000). The role of hypoventilation and ventilation-perfusion redistribution in oxygen-induced hypercapnia during exacerbations of chronic obstructive pulmonary disease. American Journal of Respiratory and Critical Care Medicine 161: 1524-1529.
Roca J, Rodriguez-Roisin R, Cobo E, Burgos F, Perez J and Clausen J (1990). Single-breath carbon monoxide diffusing capacity prediction equations from a Mediterranean population. American Review of Respiratory Disease 141: 1026-1032.
Rodarte J (2004). Physiology of airflow limitation in emphysema. In: H Fessler, J Reilly and D Sugarbaker (Eds.) Lung biology in health and disease. Lung volume reduction surgery for emphysema. New York, USA.: Marcel Dekker. Vol 184: pp. 43-64.
Rodenstein D, Stanescu D and Francis C (1982). Demonstration of failure of body plethysmography in airway obstruction. Journal of Applied Physiology 52(4): 949-954.
Rodman J, Haverkamp H, Gordon S and Dempsey J (2002). Cardiovascular and respiratory system responses and limitations to exercise. In: I Wiseman and R Zeballos (Eds.) Clinical exercise testing. Basel, Switzerland: Karger. pp. 1-17.
Rodriguez-Roisin R (2000). Toward a consensus definition for COPD exacerbations. Chest 177: 398S-401S.
References 249
Rodriguez-Roisin R, Drakulovic M, Rodriguez D, Roca J, Barbera J and Wagner P (2009). Ventilation-perfusion imbalance and chronic obstructive pulmonary disease. Journal of Applied Physiology 106: 1902-1908.
Rodriguez-Roisin R, Rabe K, Anzueto A, Bourbeau J, Calverley P, Casas A, deGuia T, Fukuchi Y, Hui D, Jenkins C, Kocabas A, Martinez F, van Weel C and Vestbo J (2008) Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. http://www.goldcopd.org. [Accessed 31st July 2009].
Roomi J, Yohannes A and Connolly M (1998). The effect of walking aids on exercise capacity and oxygenation in elderly patients with chronic obstructive pulmonary disease. Age and Ageing 27: 703-706.
Rooyackers J, Dekhuijzen P, van Herwaarden C and Folgering H (1997). Training with supplemental oxygen in patients with COPD and hypoxaemia at peak exercise. European Respiratory Journal 10: 1278- 1284.
Roussos C and Koutsoukou A (2003). Respiratory failure. Eur Respir J 22(Suppl. 47): 3s-14s.
Roussos C and Macklem P (1982). The respiratory muscles. New England Journal of Medicine 307: 786-797.
Royal College of Physicians (1999). Domiciliary oxygen services. Clinical guidelines and advice for prescribers. A report of the Royal College of Physicians.
Sahebjami H and Sathianpitayakul E (2000). Influence of body weight on the severity of dyspnea in chronic obstructive pulmonary disease. American Journal of respiratory and Critical Care Medicine 161: 886-890.
Sandland C, Morgan M and Singh S (2008). Patterns of domestic activity and ambulatory oxygen usage in COPD. Chest 134: 753-760.
References 250
Sandland C, Singh S, Curcio A, Jones P and Morgan M (2005). A profile of daily activity in chronic obstructive pulmonary disease. Journal of Cardiopulmonary Rehabilitation 25(3): 181-183.
Saposnick A and Hess D (2002). Oxygen therapy: administration and management. In: D Hess, N MacIntyre, S Mishoe, W Galvin, A Adams and A Saposnick (Eds.) Respiratory Care. Principles and practice. Philadelphia, USA.: WB Saunders. p. 566-581.
Schneider P, Crouter S and Bassett D (2004). Pedometer measures of free-living physical activity: Comparison of 13 models. Medicine and Science in Sports and Exercise 36(2): 331-335.
Schneider P, Crouter S, Lukajic O and Bassett D (2003). Accuracy and reliability of 10 pedometers for measuring stpes over a 400-m walk. Medicine and Science in Sports and Exercise 35(10): 1779-1784.
Schonhofer B, Ardes P, Geibel M, Kohler D and Jones P (1997). Evaluation of a movement detector to measure daily activity in patients with chronic lung disease. European Respiratory Journal 10: 2814-2819.
Schunemann H, Goldstein R, Mador M, McKim D, Stahl E, Puhan M, Griffith L, Grant B, Austin P, Collins R and Guyatt G (2005a). A randomised trial to evaluate the self-administered standardised chronic respiratory questionnaire. European Respiratory Journal 25: 31-40.
Schunemann H and Guyatt G (2005b). Commentary-Goodbye M(C)ID! Hello MID, where do you come from? Health Services Research 40(2): 593- 597.
Schwartzstein R, Lahive K, Pope A, Weinberger S and Weiss J (1987). Cold facial stimulation reduces breathlessness induced in normal subjects. American Review of Respiratory Disease 136: 58-61.
References 251
Scurbia F, Criner G, Lee S, Mohsenifar Z, Shade D, Slivka W and Wise R (2003). Six-minute walk distance in chronic obstructive pulmonary disease. Reproducibility and effect of walking course layout and length. American Journal of Respiratory and Critical Care Medicine 167: 1522-1527.
SensorMedics Corporation (1996). Reference Manual. Max Series/V6200 Autobox/6200 Autobox DL. Yorba Linda, USA: SensorMedics Corporation.
Shapiro B and Peruzzi W (1994). Respiratory Care. In: R Miller (Eds.) Anaesthesia. New York, USA: Churchill Livingstone. pp. 2397-2439.
Shephard R (2003). Limits to the measurement of habitual physical activity by questionnaires. British Journal of Sports Medicine 37: 197-206.
Siafakas N, Vermiere P, Pride N, Paoletti P, Gibson P, Howard P, Yernault J, Decramer M, Higenbottam T, Postma D and Rees P (1995). Optimal assessment and management of chronic obstructive pulmonary disease. European Respiratory Journal 8: 1398-1420.
Simon P and Weiss J (1989). Distinguishable sensation of breathlessness induced by normal volunteers. American Review of Respiratory Disease 146: 1021-1047.
Singh S, Jones P, Evans R and Morgan M (2008). Minimum clinically important improvement for the incremental shuttle walk test. Thorax 63(9): 775-777.
Singh S and Morgan M (2001a). Activity monitors can detect brisk walking in patients with chronic obstructive pulmonary disease. Journal of Cardiopulmonary Rehabilitation 21(3): 143-8.
Singh S, Morgan M, Hardman A, Rowe C and Bardsley P (1994). Comparison of oxygen uptake during a conventional treadmill test and the shuttle walking test in chronic airflow limitation. European Respiratory Journal 7: 2016- 2020.
References 252
Singh S J, Morgan M D, Scott S, Walters D and Hardman A E (1992). Development of a shuttle walking test of disability in patients with chronic airways obstruction. Thorax 47(12): 1019-24.
Singh S J, Sodergren S C, Hyland M E, Williams J and Morgan M D (2001b). A comparison of three disease-specific and two generic health-status measures to evaluate the outcome of pulmonary rehabilitation in COPD. Respiratory Medicine 95(1): 71-7.
Snider G (2002). Enhancement of exercise performance in COPD patients by hyperoxia. Chest 122: 1830-1836.
Solway S, Brooks D, Lacasse Y and Thomas S (2001). A qualitative systematic overview of the measurement properties of functional walk tests used in the cardiorespiratory domain. Chest 119: 256-270.
Solway S, Brooks D, Lau L and Goldstein R (2002). The short-term effect of a rollator on functional exercise capacity among individuals with severe COPD. Chest 122(56-65).
Somfay A, Porszasz J, Lee S and Casaburi R (2001). Dose-response effect of oxygen on hyperinflation and exercise endurance in nonhypoxaemic COPD patients. European Respiratory Journal 18: 77-84.
Somfay A, Porszasz J, Lee S and Casaburi R (2002). Effect of hyperoxia on gas exchange and lactate kinetics following exercise onset in nonhypoxemic COPD patients. Chest 121: 393-400.
Spahija J, de Marchie M and Brassino A (2005). Effects of imposed pursed-lips breathing on respiratory mechanics and dyspnea at rest and during exercise in COPD. Chest 128: 640-650.
Speck B and Looney S (2006). Self-reported physical activity validated by pedometer: A pilot study. Public Health Nursing 23(1): 88-94.
References 253
Spence D, Graham D, Ahmed J, Rees K, Pearson M and Calverley P (1993). Does cold air affect exercise capacity and dyspnea in stable chronic obstructive pulmonary disease? Chest 103: 693-696.
Stanescu D, Rodenstein D, Cauberghs M and Van de Woestijne K (1982). Failure of body plethysmography in bronchial asthma. Journal of Applied Physiology 52(4): 939-948.
Stark R, Finnegan P and Bishop J (1972). Daily requirement of oxygen to reverse pulmonary hypertension in patients with chronic bronchitis. British Medical Journal 3(829): 724-728.
Stark R, Finnegan P and Bishop J (1973). Long-term domiciliary oxygen in chronic bronchitis with pulmonary hypertension. British Medical Journal 3(878): 467-470.
Steele B (1996). Timed walking tests of exercise capacity on chronic cardiopulmonary illness. Journal of Cardiopulmonary Rehabilitation 16: 25-33.
Steele B, Belza B, Cain K, Warms C, Coppersmith J and Howard J (2003a). Bodies in motion: Monitoring daily activity and exercise with motion sensors in people with chronic pulmonary disease. Journal of Rehabilitation Research and Development 40(5): 45-58.
Steele B, Belza B, Hunziker J, Holt L, Legro M, Coppersmith J, Buchner D and Lakshminaryan S (2003b). Monitoring daily activity during pulmonary rehabilitation using a triaxial accelerometer. Journal of Cardiopulmonary Rehabilitation 23: 139-142.
Steele B, Holt L, Belza B, Ferris S, Lakshminaryan S and Buchner D (2000). Quantitating physical activity in COPD using a triaxial accelerometer. Chest 117: 1359-1367.
References 254
Steffen T, Hacker T and Mollinger L (2002). Age- and gender-related test performance in community-dwelling elderly people: Six-minute Walk Test, Berg Balance Scale, Timed Up and Go Test, and Gait Speeds. Physical Therapy 82: 128-137.
Stel V, Smit J, Pluijm S, Visser M, Deeg D and Lips P (2004). Comparison of the LASA physical activity questionnaire with a 7-day diary and pedometer. Journal of Clinical Epidemiology 57(3): 252-258.
Stevens D, Elpern E, Sharma K, Szidon P, Ankin M and Kesten S (1999). Comparison of hallway and treadmill six-minute walk tests. American Journal of Respiratory and Critical Care Medicine 160: 1540-1543.
Stevenson N and Calverley P (2004). Effect of oxygen on recovery from maximal exercise in patients with chronic obstructive pulmonary disease. Thorax 59: 668-672.
Stoller J (2000). Oxygen and air travel. Respiratory Care 45: 214-221.
Stubbing D, Pengelly D, Morse J and Jones N (1980a). Pulmonary mechanics during exercise in normal males. Journal of Applied Physiology 49(3): 506-510.
Stubbing D, Pengelly D, Morse J and Jones N (1980b). Pulmonary mechanics during exercise in subjects with chronic airflow obstruction. Journal of Applied Physiology 49(3): 511-515.
Sullivan S, Buist A and Weiss K (2003). Health outcomes assessment and economic evaluation in COPD: challenges and opportunities. European Respiratory Journal 21(Suppl 41): 1s-3s.
Tamir G, Issa M and Yaron H (2007). Mobile phone-triggered thermal burns in the presence of supplemental oxygen. Journal of Burn Care and Research 28(2): 348-350.
References 255
Tantucci C, Donati P, Nicosia F, Bertella E, Redolfi S, De Vecci M, Corda L, Grassi V and Zulli R (2008). Inspiratory capacity predicts mortality in patients with chronic obstructive pulmonary disease. Respiratory Medicine 102: 613-619.
Tantucci C, Duguet A, Similowski T, Zelter M, Derenne J-P and Milic-Emili J (1998). Effect of salbutamol on dynamic hyperinflation in chronic obstructive pulmonary disease patients. European Respiratory Journal 12: 799-804.
Tantucci C, Pinelli V, Cossi S, Guerini M, Donato F, Grassi V and Group T S S (2006). Reference values and repeatability of inspiratory capacity for men and women aged 65-85. Respiratory Medicine 100: 871-877.
Taylor C, Jacobs D, Schuker B, Knudsen A, Leon S and Debacker G (1978). A questionnaire for the assessment of leisure time physical activities. Journal of Chronic Disease 31: 741-755.
Thomson A, Webb D, Maxwell S and Grant I (2002). Oxygen therapy in acute medical care: the potential dangers of hyperoxia need to be recognised. British Medical Journal 324(7351): 1406-1407.
Thurlbeck W (1997). Pathology of chronic airflow limitation. Chest 2: 6S-10S.
Troosters T (2004b). Oxygen: the good, the bad, and the necessary. Thorax 59: 1005-1006.
Troosters T (2005). Pulmonary rehabilitation in chronic obstructive pulmonary disease. American Journal of Respiratory and Critical Care Medicine 172: 19-38.
Troosters T, Gosselink R and Decramer M (2002a). Six-minute walk test: A valuable test when properly standardized. Physical Therapy 82: 826-827.
Trost S, McIver K and Pate R (2005). Conducting accelerometer-based activity assessments in field-based research. Medicine and Science in Sports and Exercise 37(Suppl 11): S531-S543.
References 256
Trost S, Pate R, Freedson P, Sallis J and Taylor W (2000). Using objective physical activity monitors with youth: How many days of monitoring are needed. Medicine and Science in Sports and Exercise. 31(2): 426-431.
Tudor-Locke C and Bassett D (2004a). How many steps/day are enough? Preliminary pedometer data indices for public health. Sports Medicine 34(1): 1-8.
Tudor-Locke C, Burkett C, Reis J, Ainsworth B, Macera C and Wilson D (2005). How many days of pedometer monitoring predict weekly physical activity in adults? Preventive Medicine 40(3): 293-298.
Tudor-Locke C and Myers A (2001a). Methodological considerations for researchers and practitioners using pedometers to measure physical (ambulatory) activity. Research Quarterly for Exercise and Sport 72: 1-12.
Tudor-Locke C and Myers A (2001b). Challenges and opportunities for measuring physical activity in sedentary adults. Sports Medicine 31(2): 91-100.
Tudor-Locke C, Williams J, Reis J and Pluto D (2002). Utility of pedometers for assessing physical activity. Convergent validity. Sports Medicine 32(12): 795-808.
Tudor-Locke C, Williams J, Reis J and Pluto D (2004b). Utility of pedometers for assessing physical activity. Construct validity. Sports Medicine 34(5): 281-291.
Turner S, Eastwood P, Cecins N, Hillman D and Jenkins S (2004). Physiologic responses to incremental and self-paced exercise in COPD. Chest 126: 766-773.
Van Noord J, Aumann J, Janssens J, Verhaert J, Smeets J, Mueller A and Cornelissen P (2006). Effects of tiotropium with and without formoterol on airflow obstruction and resting hyperinflation in patients with COPD. Chest 129: 509-517.
References 257
Vanhees L, Lefevre J, Philippaerts R, Martens M, Huygens W, Troosters T and Beunen G (2005). How to assess physical activity? How to assess physical fitness? European Journal of Cardiovascular Prevention and Rehabilitation 12: 102-114.
Wagner P, Dantzker D, Dueck R, Clausen J and West J (1977): Ventilation- perfusion inequality in chronic obstructive pulmonary disease. Journal of Clinical Investigation 59: 203-216.
Wanger J, Clausen J, Coates A, Pedersen O, Brusasco V, Burgos F, Casaburi R, Crapo R, Enright P, van der Grinten C, Gustafsson P, Hankinson J, Jensen R, Johnson D, MacIntyre N, McKay R, Miller C, Navajas D, Pellegrino R and Viegi G (2005). Standardisation of the measurement of lung volumes. European Respiratory Journal 26: 511-522.
Ware J and Sherbourne C (1992). The MOS short-form health survey (SF-36): 1. Conceptual framework and item selection. Medical Care 30: 473-483.
Wedzicha J (1999). Domiciliary oxygen therapy services: clinical guidelines and advice for prescribers. Summary of a report of the Royal College of Physicians. Journal of the Royal College of Physicians of London 33(5): 445-447.
Wedzicha J (2000). Long-term oxygen therapy. European Respiratory Monthly 13: 143-154.
Wedzicha J A, Bestall J C, Garrod R, Garnham R, Paul E A and Jones P W (1998). Randomized controlled trial of pulmonary rehabilitation in severe chronic obstructive pulmonary disease patients, stratified with the MRC dyspnoea scale. European Respiratory Journal 12(2): 363-9.
Weilacher R (2002). History of the respiratory care profession. In: D Hess, N MacIntyre, S Mishoe, W Galvin, A Adams and A Saposnick (Eds.) Respiratory Care. Principles and practice. Philadelphia, USA.: W.B. Saunders. pp. 2-17.
References 258
Weitzenblum E (1994). The pulmonary circulation and the heart in chronic lung disease. Monaldi Archives of Chest Disease 49: 231-234.
Welk G, Differding J, Thompson R, Blair S, Dziura J and Hart P (2000). The utlilty of the Digi-Walker step counter to assess daily physical activity patterns. Medicine and Science in Sports and Exercise 32: S481-S488.
West J (2003). Pulmonary pathophysiology. The essentials. 6th edn. Philadelphia, USA.: Lippincott, Williams and Wilkins.
West J (2004). A century of pulmonary gas exchange. American Journal of Respiratory and Critical Care Medicine 169: 897-902.
West J (2005). Respiratory physiology. The essentials. 7th edn. Philadelphia, USA: Lippincott, Williams and Wilkins.
Wijkstra P, Guyatt G, Ambrosino N, Celli B, Guell R, Muir J, Prefaut C, Mendes E, Ferreira I, Austin P, Weaver B and Goldstein R (2001). International approaches to the prescription of long-term oxygen therapy. European Respiratory Journal 18: 909-913.
Wijkstra P, Ten Vergert E, Van Altena R, Otten V, Postma D, Kraan J and Koeter G (1994). Reliability and validity of the chronic respiratory questionnaire (CRQ). Thorax 49: 465-467.
Williams M, Garrard A, Cafarella P, Petkov J and Frith P (2009). Quality of recalled dyspnoea is different from exercise-induced dyspnoea: an experimental study. Australian Journal of Physiotherapy 55: 177-183.
Witek T and Mahler D (2003). Minimal important difference of the transitional dyspnoea index in a multinational clinical trial. European Respiratory Journal 21: 267-272.
Woodcock A A, Gross E R and Geddes D M (1981). Oxygen relieves breathlessness in "pink puffers". Lancet 1: 907-9.
References 259
Yan S, Kaminski D and Sliwinski P (1997). Reliability of inspiratory capacity for estimating end-expiratory lung volume changes during exercise in patients with chronic obstructive pulmonary disease. American Journal of Respiratory and Critical Care Medicine 156: 55-59. Young I (2007). Revisiting oxygen therapy in patients with exacerbation of chronic obstructive pulmonary disease. Medical Journal of Australia 186(5): 239.
Young P (2005). Ambulatory and training oxygen: a review of the evidence and guidelines for prescription. New Zealand Journal of Physiotherapy 33(1): 7-12.
Zigmund A and Snaith R (1983). The Hospital Anxiety and Depression Scale. ACTA Psychiatry Scandinavia 67: 361-370.
ZuWallack R (2000). Outcome measures for pulmonary rehabilitation. European Respiratory Mon 13: 177-200.
ZuWallack R (2003). Functional status and survival in COPD. Monaldi Archives of Chest Disease 59: 230-233.
References 260 Appendix I Baseline/Transition Dyspnoea Index Worksheet
EXERTIONAL OXYGEN STUDY STUDY NUMBER: ...... The Northern Clinical Research Centre Austin Health SITE: ...... BDI/TDI WORKSHEET The University of Melbourne Functional Impairment Magnitude of task Magnitude of effort BASELINE Types/kind of activities Level, magnitude, extent of task Effort required to provoke DYSPNOEA INDEX Any activities given up or required to provoke breathlessness. breathlessness, time needed, pauses. changed? What activities make you feel Do you perform each activity at Visit 1 Are activities listed performed as breathless? normal pace, very slowly/longer, Date: ………………. previously? Record activities which provoke pause frequently? Record activities which have breathlessness; provide examples of Record effort for each activity, provide changed because of grades. examples of grades breathlessness.
Job
Housework, shopping
Leisure activities, gardening
Social activities
Washing/dressing
At rest
Any other
(Nil, slight, moderate, severe, very (Extraordinary, major, moderate, light, at rest) (Extraordinary, major, moderate, light, at rest) severe) BDI total score: Magnitude of task: Magnitude of effort: Functional impairment: Grades 4 – 0 X: unknown Y: impaired for reasons other than shortness of breath
261 Functional Impairment Magnitude of task Magnitude of effort TRANSITION Types/kind of activities. Level, magnitude, extent (of task Effort required to provoke DYSPNOEA INDEX Given up or started any new required to provoke breathlessness. breathlessness, time needed pauses. activities? What activities now make you feel For each activity listed, do you Visit 3 Are activities listed performed as breathless? need more or less time, more or Date: ……………… previously? Review activities which previously less pauses? Record activities which have been caused breathlessness; record Record effort now required to given up or changed. activities which now provoke same. 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: Functional Impairment Magnitude of task Magnitude of effort TRANSITION Types/kind of activities. Level, magnitude, extent (of task Effort required to provoke DYSPNOEA INDEX Given up or started any new required to provoke breathlessness. breathlessness, time needed pauses. activities? What activities now make you feel For each activity listed, do you Visit 4 Are activities listed performed as breathless? need more or less time, pauses? Date: ……………… previously? Review activities which previously Record effort now required to Record activities which have caused breathlessness; record provoke breathlessness with changed. activities which now provoke same. 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
262
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 Patient unable to work or has given up most or all usual impairment activities due to shortness of breath.
Grade 0 Very severe Unable to work and has given up most or all usual impairment activities due to shortness of breath.
X Unknown Information unavailable regarding impairment
Y Impaired for reasons For example, musculoskeletal problem or chest pain. other than shortness of breath
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 263
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 For example, musculoskeletal problem or chest pain. reasons other than shortness of breath
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 For example, musculoskeletal problem or chest pain. reasons other than shortness of breath
Appendix II Baseline/Transition Dyspnoea Index Scoring Sheet 264
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 Formerly working and has had to stop working or has Deterioration 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 Able to return to work at nearly usual pace and/or able to Improvement 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 Patient has stopped working, reduced work, or has given for reasons other up or reduced other activities for other reasons. For than shortness of example, other medical problems, being “laid off” from breath. work, etc.
Appendix II Baseline/Transition Dyspnoea Index Scoring Sheet 265
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 Has improved at least one grade but fewer than two grades Improvement from baseline.
+3 Major Improvement Has improved two grades or greater from baseline.
Z Further impairment for Patient has reduced exertional capacity, but not related to reasons other than shortness of breath. For example, musculoskeletal problem or shortness of breath. 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 Able to do things with fewer pauses and distinctly greater effort Improvement 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 Patient has reduced exertional capacity, but not related to reasons other than shortness of breath. For example, musculoskeletal problem or shortness of breath. chest pain.
Appendix II Baseline/Transition Dyspnoea Index Scoring Sheet 266
Appendix III The Assessment of Quality of Life Instrument
EXERTIONAL OXYGEN STUDY The Northern Clinical Research Centre Austin Health The University of Melbourne
THE ASSESSMENT OF QUALITY OF LIFE INSTRUMENT INSTRUCTIONS: This questionnaire has 15 questions and will take about ten minutes. The questions are about your health during the last week. Please listen carefully, and choose the answer that best describes you.
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.
Appendix III The Assessment of Quality of Life Instrument 267
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 268
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 269
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 270
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 III The Assessment of Quality of Life Instrument 271
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 273
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 274
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 275
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 276
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 277
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 278
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 279
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 280
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 281
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 282
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 283
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 284
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 285
GREEN CARD ORANGE CARD
1 EXTREMELY SHORT OF BREATH 1 EXTREMELY TIRED 2 VERY SHORT OF BREATH 2 VERY TIRED 3 QUITE A BIT SHORT OF BREATH 3 QUITE A BIT OF TIREDNESS 4 MODERATE SHORTNESS OF BREATH 4 MODERATELY TIRED 5 SOME SHORTNESS OF BREATH 5 SOMEWHAT TIRED 6 A LITTLE SHORTNESS OF BREATH 6 A LITTLE TIRED 7 NOT AT ALL SHORT OF BREATH 7 NOT AT ALL TIRED
BLUE CARD YELLOW CARD
1 ALL OF THE TIME 1 NONE OF THE TIME 2 MOST OF THE TIME 2 A LITTLE OF THE TIME 3 A GOOD BIT OF THE TIME 3 SOME OF THE TIME 4 SOME OF THE TIME 4 A GOOD BIT OF THE TIME 5 A LITTLE OF THE TIME 5 MOST OF THE TIME 6 HARDLY ANY OF THE TIME 6 ALMOST ALL OF THE TIME 7 NONE OF THE TIME 7 ALL OF THE TIME
PINK CARD GRAY CARD
1 NO ENERGY AT ALL 1 VERY DISSATISFIED, UNHAPPY 2 A LITTLE ENERGY MOST OF THE TIME 3 SOME ENERGY 2 GENERALLY DISSATISFIED, UNHAPPY 4 MODERATELY ENERGETIC 3 SOMEWHAT DISSATISFIED, UNHAPPY 5 QUITE A BIT OF ENERGY 4 GENERALLY SATISFIED, PLEASED 6 VERY ENERGETIC 5 HAPPY MOST OF THE TIME 7 FULL OF ENERGY 6 VERY HAPPY MOST OF THE TIME 7 EXTREMELY HAPPY, COULD NOT HAVE BEEN MORE SATISFIED OR PLEASED
Appendix IV The Chronic Respiratory Disease Questionnaire 286
Appendix V The Hospital Anxiety and Depression Scale
EXERTIONAL OXYGEN STUDY The Northern Clinical Research Centre Trial Number: ……………….. Austin Health The University of Melbourne Assessment Number: ……...
Date: …………………………..
Site: ...... 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
Appendix V The Hospital Anxiety and Depression Scale 287
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 288
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 V The Hospital Anxiety and Depression Scale 289
Appendix VI Six Minute Walk Test Protocol
EXERTIONAL OXYGEN STUDY The Northern Clinical Research Centre The Northern Clinical Research Centre The Northern Hospital Austin Health 185 Cooper Street The University of Melbourne Epping 3076
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
Appendix VI Six Minute Walk Test Protocol 291
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 Practice Test Test 2 Test 3 Familiarisation st st nd 1 study cylinder 1 study 2 study Preparation Visit 2 only (no flow) cylinder cylinder
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.
Appendix VI Six Minute Walk Test Protocol 292
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 293
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 294
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 295
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 296
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 VI Six Minute Walk Test Protocol 297
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 299
Study number: ......
DATE: Waking Breakfast Lunch Dinner Bedtime (morning) to to to to waking ...... to lunchtime dinner bedtime (morning) breakfast time 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 300
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 VII Pilot 1 Activity Diary 301
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 [email protected]
Appendix VIII Activity Diary Pilot Questionnaire 303
Appendix IX Pilot 2 Activity Diary
EXERTIONAL OXYGEN STUDY Name: ......
The Northern Clinical Research Centre and Austin Health Date: ......
Site: ...... 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.
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 305
DAY: ...... 1 2 3 4 lying sitting standing other DATE: ......
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 IX Pilot 2 Activity Diary 306 Appendix X Activity Diary
Appendix X Activity Diary 307
Appendix X Activity Diary 308
309
310
Appendix XI Inspiratory Capacity Measurement Worksheet 1 Austin Health The Northern Clinical Research Centre The University of Melbourne
ExOx Study
IC Worksheet
UR: ...... Surname: ...... Study No
Given Names: ......
DOB: ...... OR attach ID Label here Current inhaled Time taken medications (incl BD) today ...... Date: ...... Assessor: ...... Baseline ...... Borg Score at rest on RA …………………….. .…...……
st nd 1 Study Gas 2 Study Gas
Borg Score after 5 minutes Borg Score after 5 minutes + when stable + when stable
IC Measurement 1 IC Measurement 1
IC Measurement 2 IC Measurement 2
IC Measurement 3 IC Measurement 3
Additional measurements if Additional measurements if required: ……………………….. required: ………………………..
……………………..…………. ……………………..………….
IC Measurement IC Measurement Average of 2 results Average of 2 results within 200 mls within 200 mls
Appendix XI Inspiratory Capacity Measurement Worksheet 1 311
Appendix XII Inspiratory Capacity Measurement Worksheet 2
Austin Health The Northern Clinical Research Centre Study Number: ……….. The University of Melbourne Date: ....…………………
INSPIRATORY CAPACITY STUDY Oxygen Saturation, Heart Rate & Respiratory Rate Data
BASELINE (at rest for ≥ 5 minutes)
Oxygen saturation %
Heart Rate
/min Respiratory Rate
/min FIRST STUDY GAS (after ≥ 5 minutes + at rest)
Oxygen saturation
% Heart Rate
/min Respiratory Rate
/min
SECOND STUDY GAS (after ≥ 5 minutes + at rest)
Oxygen saturation
% Heart Rate
/min Respiratory Rate
/min
Appendix XII Inspiratory Capacity Measurement Worksheet 2 313
Appendix XIII Study Information Sheet
The Exertional Oxygen Study
A study of portable oxygen used during exertion in individuals with Chronic Obstructive Pulmonary Disease (COPD).
Previous research has shown that for individuals with severe COPD and low oxygen levels, oxygen therapy is beneficial when it is used for at least 15 hours per day.
There are many individuals with COPD who have normal oxygen levels when resting, but who have a limited ability to walk and perform general activities due to breathlessness. At present, it is not known if these individuals might benefit from using oxygen therapy.
The aim of this study is to determine the effects of oxygen therapy for individuals with COPD who have normal oxygen levels when they are resting but have reduced activity levels due to shortness of breath.
The Exertional Oxygen Study is a randomised controlled trial. Study participants will receive either compressed oxygen or air from portable cylinders for use at home over a period of 12 weeks. The effects of using oxygen on breathlessness, quality of life and exercise tolerance will be evaluated.
For further information contact: Rosemary Moore or David Berlowitz (Investigators) The Northern Clinical Research Centre The Northern Hospital 185 Cooper Street Epping 3076 Telephone: 8405 8480 Email: [email protected]
Appendix XIII Study Information Sheet 315
Appendix XIV Study Promotion Flyer
Exertional Oxygen Study
Do you have chronic lung disease?
Do you become breathless
when you are active? For further information contact: Rosemary Moore or David Berlowitz (Investigators) The Northern Clinical Research Centre
TheYou Northern may Hospital benefit from 185 Cooper Street portableEpping 3076 oxygen therapy.
Telephone: 8405 8480
A researchEmail: study rosemary.moor is being [email protected] 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: [email protected],.au
Appendix XIV Study Promotion Flyer 317
Appendix XV Study Referral Form
The Northern Clinical Research Centre The Northern Hospital
185 Cooper Street Phone: 8405 8480 Epping 3076. Fax: 8405 8683 Investigators: Rosemary Moore Email: [email protected] David Berlowitz
Exertional Oxygen Study Referral Form
Please mail, fax or email to the address above.
Trial Inclusion criteria Trial Exclusion criteria diagnosis of COPD significant locomotor disability clinically stable: no respiratory eg. severe arthritis exacerbations within the preceding 4 other severe disabling medical weeks condition likely to significantly does not qualify for long-term impact upon exercise capacity domiciliary oxygen therapy; PaO2 > or quality of life 55 mmHg at rest currently attending a non-smoker; ceased to smoke at Pulmonary Rehabilitation least 2 weeks prior to enrolment. Program activity limited by breathlessness
Phone: 8405 8480 Participant ID label/ name and address Fax: 8405 8683 ...... Email: [email protected] ......
Relevant Medical History: ...... Referring Person: Name: ...... Email: ...... Address: ...... Signature: ...... Date: ......
Appendix XV Study Referral Form 319
Appendix XVI Study Protocol Summary
THE EXERTIONAL OXYGEN STUDY
Study Team members: The Northern Clinical Research Centre A/ Prof. Christine McDonald (AH) The Northern Hospital Dr. David Berlowitz (NCRC) 185 Cooper Street Dr. Bruce Jackson (Southern Health) Epping 3076 Dr. Linda Denehy(U of M) 8405 8482 Rosemary Moore (NCRC)
Chrissie Risteski (NCRC) Department of Respiratory and Sleep Medicine Austin Hospital Studley Road Heidelberg 3084 9496 5739
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.
Appendix XVI Study Protocol Summary 321
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 XVI Study Protocol Summary 322
Appendix XVII Study Promotion Covering Letter
EXERTIONAL OXYGEN STUDY
The Northern Clinical Research Centre
Austin Health The University of Melbourne Study Team members: The Northern Clinical Research Centre A/Prof. Christine McDonald (AH) The Northern Hospital A/ Prof. Bruce Jackson (NCRC)
185 Cooper Street Dr. David Berlowitz (NCRC) Epping 3076 Rosemary Moore (NCRC) Dr. Linda Denehy (U of M) Ms Chrissie Risteski (NCRC)
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.
Appendix XVII Study Promotion Covering Letter 323
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 325
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 326
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 327
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 328
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 329
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 330
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 331
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 332
EXERTIONAL OXYGEN STUDY FLOW CHART
Visit 1: Participant Information (Week 0) Consent Form 2 questionnaires * Every day from Visit 1: breathing tests and blood test Symptom Diary Card diaries + pedometer
For one week: Activity Assessment Service Utilisation Diary Visit 2: 3 exercise tests Pedometer (Week 2) 3 questionnaires diaries & pedometer check Start using portable cylinders Total study time 14 For one week: weeks Activity Assessment Service Utilisation Diary Visit 3: 3 exercise tests Pedometer (Week 6) 4 questionnaires diaries & pedometer check
For one week: Activity Assessment Service Utilisation Diary Visit 4: 2 exercise tests Pedometer (Week 14) 4 questionnaires preference survey Finish using portable cylinders
Appendix XVIII Participant Information and Consent Form 333
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 Date: Time: Signature Witness to signature Name Date: Time: Signature Signature (Investigator) Name Date: Time: Signature
One copy to be given to participant, one copy filed in participant’s medical record
Appendix XVIII Participant Information and Consent Form 334
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 XVIII Participant Information and Consent Form 335
Appendix XIX Participant Data Sheet
The Northern Clinical Research Centre The Northern Hospital 185 Cooper Street, Epping, Victoria, Australia 3076 Telephone (03) 8405 8064 Facsimile (03) 8405 8683
PARTICIPANTEXERTIONAL DATA OXYGEN SHEET STUDY The Northern Clinical Research Centre PARTICIPANTAustin Health and The University DATA of Melbourne PARTICIPANT DATA SHEET
SITE: The Northern Hospital UR: ...... Austin Hospital Surname: ...... Given Names: ...... Date of referral: ...... DOB: ...... Phone...... Address: ...... Referred by: ...... Date of inclusion: ...... Attach ID Label here Medicare number: ......
Demographics Next of kin Name: ...... ID label details correct: Yes If no, note corrections Relationship: ...... Informed consent: Yes No Phone: ......
Inclusion criteria fulfilled: Yes No
Trial Inclusion criteria Trial Exclusion criteria
diagnosis of COPD significant locomotor disability eg. activity limited by breathlessness severe arthritis, use of gait aid
clinically stable: no respiratory other severe disabling medical exacerbations within the preceding 4 weeks condition likely to significantly impact upon exercise capacity does not qualify for long-term domiciliary or quality of life oxygen therapy; PaO2 > 55 mmHg at rest currently attending a Pulmonary non-smoker; ceased to smoke at least 2 Rehabilitation Program weeks prior to enrolment Details......
LMO Respiratory Physician Name: ...... Name: ...... Address: ...... Address: ...... Telephone: ...... Telephone: ...... Fax: ...... Fax: ...... Email ...... Email......
Appendix XIX Participant Data Sheet 337
Communication WNL Country of birth: ...... Understands English Language/s spoken at Speaks English home: …………...... Hearing WNL Unilateral Hearing Aid/s Impaired Bilateral Visual WNL Impaired Spectacles Prosthesis Cognition Normal Impaired WNL = within normal limits
Respiratory Diagnosis ......
...... Other ...... respiratory history ...... Sputum......
Cough......
Exercise How many minutes can you walk on a What stops you? tolerance ...... flat surface?......
...... OR: How far can you walk on a flat surface?...... Smoking history
Pulmonary Date completed/ceased/never Duration of rehabilitation ...... course: ...... history Location ...... Oxygen Previously used: If yes, specify therapy Yes No ......
MRC Dyspnoea 1. I only get breathless with strenuous exercise 2. I get short of breath when hurrying on the level or up a slight hill Scale Score 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
Appendix XIX Participant Data Sheet 338
Medical Active Medications History
Inactive
Allergies
Musculo- skeletal assessment Mobility Walks unaided Yes No (tick those Walks with gait aid Yes No If yes, specify: which apply) ...... Balance WNL Yes No Other comments: …………………………………………………...... Social Lives alone Lives with (tick those spouse/partner which apply) 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 Fluvax No Yes Date: ...... (most recent) Pneumovax No Yes Date: ...... RFT’s No Yes Date: ...... ABG’s No Yes Date: ...... Weight...... Height...... BMI......
Appendix XIX Participant Data Sheet 339
Appendix XX Additional Information Sheet
ADDITIONAL EXERTIONAL OXYGEN STUDY INFORMATION SHEET The Northern Clinical Research Centre Austin Health The University of Melbourne
Study number: ......
Study dates
Visit 1 Visit 2 Cylinders Visit 3 Visit 4 delivered
Pedometer data Talisman/SOS MRC Dyspnoea Score score tick Pedometer number: ...... Mens bracelet Visit1: ...... Ladies bracelet Reading Visit 2: ......
Wrist band Visit 4: ......
Reading Visit 3 ...... Pendant
Reading Visit 4: ......
Additional data/adverse events
Date Details
Appendix XX Additional Information Sheet 341
Appendix XXI Chronic Respiratory Disease Questionnaire Response Sheet
EXERTIONAL OXYGEN STUDY STUDY NUMBER: ...... The Northern Clinical Research Centre Austin Health SITE: ...... The University of Melbourne VISIT 2 DATE: ......
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) ______
Appendix XXI CRDQ Response Sheet 343
CRDQ RESPONSE SHEET (continued)
STUDY NUMBER......
Question # Visit 2 Visit 3 Visit 4
Date:...... Date:...... 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
Appendix XXI CRDQ Response Sheet 344
Appendix XXII Assessment of Quality of Life Index Response Sheet
EXERTIONAL OXYGEN STUDY The Northern Clinical Research Centre STUDY NUMBER: ...... Austin Health The University of Melbourne SITE: ......
AQoL RESPONSE SHEET
Question number Date: ...... Date: ...... Date: ......
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Appendix XXII AQoL Response Sheet 345
Appendix XXIII Six Minute Walk Test Worksheet
Appendix XXIII Six Minute Walk Test Worksheet 347
Appendix XXIII Six Minute Walk Test Worksheet 348
Appendix XXIV Cylinder Company Referral Form
The Northern Clinical Research Centre The Northern Hospital EXERTIONAL OXYGEN STUDY 185 Cooper Street The Northern Clinical Research Centre Epping 3076 Austin Health Ph: 03 8405 8480 Fax: 03 8405 8683 The University of Melbourne Contact: Rosemary Moore
Email: [email protected] Mobile: 0412 456 177
Air Liquide Healthcare
40 Bunnett Street North Sunshine 3020 Ph: 03 9310 1200 ATTENTION: Kristy Denereaz Fax: 03 9311 0444
REQUEST FORM FOR STUDY CYLINDERS
Participant Study Number Date
Participant Name: Address:
Telephone:
Next of Kin: Address:
Telephone:
Other details: Exertional Oxygen Study Flow: 6 L/min via Impulse device, Mode A
Appendix XXIV Cylinder Company Referral Form 349
Appendix XXV Preferences and Opinions Survey
EXERTIONAL OXYGEN STUDY The Northern Clinical Research Centre STUDY NUMBER: ...... Austin Health The University of Melbourne SITE: ......
VISIT 4 DATE:......
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? ......
Appendix XXV Preferences and Opinions Survey 351
Appendix XXVI Study Checklist
EXERTIONAL OXYGEN STUDY CHECKLIST Study number: ...... Name: ...... Site: ......
Visit 1 Phone Call/s Visit 2 Phone call Phone call Phone call Visit 3
Date: ...... Date: ...... Date: ...... Date: ...... Date: ...... Date: ...... Date: ...... Consent CRDQ TDI Assessment form Outcome: AQoL Outcome: Outcome: Outcome: CRDQ BDI HAD AQoL PFT's + IC Exercise tests HAD ABG's Exercise tests Talisman: Check: TNH UR SU Diary Medical Hx Entry Activity Diary Explained/given: Check Pedometer Check Check: SU Diary Diary/pedometer Symptom Diary Diary/pedometer SU Diary Activity Diary dates: Talisman dates: Activity Diary Pedometer Visit/Diary dates Pedometer Symptom Diary ...... Symptom Diary Instruction sheet Notify Air Liquide Visit/Diary dates Visit/Diary dates Phone call Phone call Phone call Phone call Visit 4
Date: ...... Date: ...... Date: ...... Date: ...... Date: ...... TDI Outcome: Outcome: Outcome: Outcome: CRDQ AQoL HAD Exercise tests Check Survey Diary/pedometer Check: dates: SU Diary Activity Diary ...... Pedometer Symptom Diary Notify Air Liquide
353
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
Appendix XXVII MRC Dyspnoea Scale 355
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 pulmonary disease. PhD thesis, Medicine, Dentistry & Health Sciences, Melbourne Physiotherapy School, The University of Melbourne.
Publication Status: Unpublished
Persistent Link: http://hdl.handle.net/11343/35465
File Description: Domiciliary ambulatory oxygen in chronic obstructive pulmonary disease
Terms and Conditions: Terms and Conditions: Copyright in works deposited in Minerva Access is retained by the copyright owner. The work may not be altered without permission from the copyright owner. Readers may only download, print and save electronic copies of whole works for their own personal non-commercial use. Any use that exceeds these limits requires permission from the copyright owner. Attribution is essential when quoting or paraphrasing from these works.