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 VE minute ventilation 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