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1 Short-term ambulatory oxygen for chronic obstructive pulmonary disease (Review) Bradley JM, O Neill BM This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2009, Issue 1

2 T A B L E O F C O N T E N T S HEADER ABSTRACT PLAIN LANGUAGE SUMMARY BACKGROUND OBJECTIVES METHODS RESULTS Figure Figure DISCUSSION Figure Figure AUTHORS CONCLUSIONS ACKNOWLEDGEMENTS REFERENCES CHARACTERISTICS OF STUDIES DATA AND ANALYSES Analysis 1.1. Comparison 1 Oxygen versus placebo (crossover studies), Outcome 1 Endurance test - exercise distance (Davidson MWT) Analysis 1.2. Comparison 1 Oxygen versus placebo (crossover studies), Outcome 2 Endurance test - exercise distance (Davidson 1988 endurance walk) Analysis 1.3. Comparison 1 Oxygen versus placebo (crossover studies), Outcome 3 Endurance test - exercise time (Davidson 1988 low dose cycle data/somfay 2001 low dose) Analysis 1.4. Comparison 1 Oxygen versus placebo (crossover studies), Outcome 4 Endurance test - exercise time (Davidson 1988 high dose cycle/somfay 2001 high dose) Analysis 1.5. Comparison 1 Oxygen versus placebo (crossover studies), Outcome 5 Endurance test - exercise time (Davidson 1988 low dose end rnce walk/somfay 2001 low dose) Analysis 1.6. Comparison 1 Oxygen versus placebo (crossover studies), Outcome 6 Endurance test - exercise time (change from baseline) Analysis 1.7. Comparison 1 Oxygen versus placebo (crossover studies), Outcome 7 Endurance test - exercise steps.. 49 Analysis 1.8. Comparison 1 Oxygen versus placebo (crossover studies), Outcome 8 Maximal test - exercise distance.. 50 Analysis 1.9. Comparison 1 Oxygen versus placebo (crossover studies), Outcome 9 Maximal test - exercise time Analysis Comparison 1 Oxygen versus placebo (crossover studies), Outcome 10 Maximal test - exercise VO2max (SMD) Analysis Comparison 1 Oxygen versus placebo (crossover studies), Outcome 11 Maximal test - wattage output. 53 Analysis Comparison 1 Oxygen versus placebo (crossover studies), Outcome 12 Endurance test - isotime breathlessness (Somfay 2001 low dose) Analysis Comparison 1 Oxygen versus placebo (crossover studies), Outcome 13 Endurance test - isotime breathlessness (Somfay 2001 high dose) Analysis Comparison 1 Oxygen versus placebo (crossover studies), Outcome 14 Endurance test - isotime SaO2 (Somfay 2001 low dose) Analysis Comparison 1 Oxygen versus placebo (crossover studies), Outcome 15 Endurance test - isotime SaO2 (Somfay 2001 high dose) Analysis Comparison 1 Oxygen versus placebo (crossover studies), Outcome 16 Endurance test - isotime PaO2. 58 Analysis Comparison 1 Oxygen versus placebo (crossover studies), Outcome 17 Endurance test - isotime ventilation (Somfay low dose) Analysis Comparison 1 Oxygen versus placebo (crossover studies), Outcome 18 Endurance test - isotime ventilation (Somfay high dose) Analysis Comparison 1 Oxygen versus placebo (crossover studies), Outcome 19 Maximal test - isotime SaO Analysis Comparison 1 Oxygen versus placebo (crossover studies), Outcome 20 Maximal test - isotime PaO Analysis Comparison 1 Oxygen versus placebo (crossover studies), Outcome 21 Maximal test - isotime ventilation. 63 i

3 Analysis Comparison 1 Oxygen versus placebo (crossover studies), Outcome 22 Endurance test VO Analysis 2.1. Comparison 2 SUBGROUP ANALYSES: mean baseline kpa/pao2 & high dose versus low dose studies), Outcome 1 MEAN BASELINE PAO2 </> 7.3kPa/55mmHG: Endurance test - exercise distance Analysis 2.2. Comparison 2 SUBGROUP ANALYSES: mean baseline kpa/pao2 & high dose versus low dose studies), Outcome 2 MEAN BASELINE PAO2 </> 7.3kPa/55mmHG: Endurance test - exercise time Analysis 2.3. Comparison 2 SUBGROUP ANALYSES: mean baseline kpa/pao2 & high dose versus low dose studies), Outcome 3 MEAN BASELINE PAO2 </> 7.3kPa/55mmHG: Maximal test - exercise distance Analysis 2.4. Comparison 2 SUBGROUP ANALYSES: mean baseline kpa/pao2 & high dose versus low dose studies), Outcome 4 MEAN BASELINE PAO2 </> 7.3kPa/55mmHG: Maximal test - exercise time Analysis 2.5. Comparison 2 SUBGROUP ANALYSES: mean baseline kpa/pao2 & high dose versus low dose studies), Outcome 5 MEAN BASELINE PAO2 </> 7.3kPa/55mmHG: Maximal test - exercise VO2max (SMD) Analysis 2.6. Comparison 2 SUBGROUP ANALYSES: mean baseline kpa/pao2 & high dose versus low dose studies), Outcome 6 MEAN BASELINE PAO2 </> 7.3kPa/55mmHG: Endurance test - isotime breathlessness Analysis 2.7. Comparison 2 SUBGROUP ANALYSES: mean baseline kpa/pao2 & high dose versus low dose studies), Outcome 7 MEAN BASELINE PAO2 </> 7.3kPa/55mmHG: Maximal test - isotime ventilation Analysis 2.8. Comparison 2 SUBGROUP ANALYSES: mean baseline kpa/pao2 & high dose versus low dose studies), Outcome 8 HIGH DOSE VERSUS LOW DOSE: Endurance test - exercise time (Davidson imputed SEM).. 72 Analysis 2.9. Comparison 2 SUBGROUP ANALYSES: mean baseline kpa/pao2 & high dose versus low dose studies), Outcome 9 HIGH DOSE VERSUS LOW DOSE: Endurance test - isotime breathlessness Analysis Comparison 2 SUBGROUP ANALYSES: mean baseline kpa/pao2 & high dose versus low dose studies), Outcome 10 HIGH DOSE VERSUS LOW DOSE: Endurance test - isotime SaO Analysis Comparison 2 SUBGROUP ANALYSES: mean baseline kpa/pao2 & high dose versus low dose studies), Outcome 11 HIGH DOSE VERSUS LOW DOSE: Endurance test - isotime ventilation Analysis Comparison 2 SUBGROUP ANALYSES: mean baseline kpa/pao2 & high dose versus low dose studies), Outcome 13 MEAN BASELINE PA02</> 7.3kPa/55mmHg: Maximal test- wattage ADDITIONAL TABLES WHAT S NEW HISTORY CONTRIBUTIONS OF AUTHORS DECLARATIONS OF INTEREST SOURCES OF SUPPORT INDEX TERMS ii

4 [Intervention Review] Short-term ambulatory oxygen for chronic obstructive pulmonary disease Judy M Bradley 1, Brenda M O Neill 2 1 Rehabilitation Sciences Research Institute School, University of Ulster and Belfast City Hospital, Newtownabbey, UK. 2 Physiotherapy, University of Ulster and Belfast City Hospital, Belfast, UK Contact address: Judy M Bradley, Rehabilitation Sciences Research Institute School, University of Ulster and Belfast City Hospital, University of Ulster, Shore Road, Newtownabbey, Northern Ireland, BT37 0QB, UK. jm.bradley@ulster.ac.uk. Editorial group: Cochrane Airways Group. Publication status and date: Edited (no change to conclusions), published in Issue 1, Review content assessed as up-to-date: 7 June Citation: Bradley JM, O Neill BM. Short-term ambulatory oxygen for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2005, Issue 4. Art. No.: CD DOI: / CD pub3. Background A B S T R A C T Ambulatory oxygen is defined as the use of supplemental oxygen during exercise and activities of daily living. Ambulatory oxygen therapy is often used for patients on long term oxygen therapy during exercise, or for non long term oxygen therapy users who achieve some subjective and/or objective benefit from oxygen during exercise. The evidence for the use of ambulatory oxygen therapy is extrapolated from two sources: longer term studies and single assessment studies. Longer term studies assess the impact of ambulatory oxygen therapy used at home during activities of daily living. Single assessment studies compare performance during an exercise test using oxygen with performance during an exercise test using placebo air. Objectives To determine the efficacy of ambulatory oxygen in patients with COPD using single assessment studies. Search methods The Cochrane Airways Group COPD register was searched with predefined search terms. Searches were current as of March Selection criteria Only randomised controlled trials were included. Studies did not have to be blinded. Studies had to compare oxygen and placebo when administered to people with COPD who were undergoing an exercise test. Data collection and analysis Two reviewers (JB, B ON) extracted and entered data in to RevMan 4.2. Main results Thirty one studies (contributing 33 data sets), randomising 534 participants met the inclusion criteria of the review. Oxygen improved all pooled outcomes relating to endurance exercise capacity (distance, time, number of steps) and maximal exercise capacity (exercise time and work rate). Data relating to VO 2 max could not be pooled and results from the original studies were not consistent. For the secondary outcomes of breathlessness, SaO 2 and V E, comparisons were made at isotime. In all studies except two the isotime is defined as the time at which the placebo test ended. Oxygen improved breathlessness, SaO 2 /PaO 2 and V E at isotime with endurance exercise testing. There was no data on breathlessness at isotime with maximal exercise testing. Oxygen improved SaO 2 /PaO 2 and reduced V E at Isotime. 1

5 Authors conclusions This review provides some evidence from small, single assessment studies that ambulatory oxygen improves exercise performance in people with moderate to severe COPD. The results of the review may be affected by publication bias, and the small sample sizes in the studies. Although positive, the findings of the review require replication in larger trials with more distinct subgroups of participants. Maximal or endurance tests can be used in ambulatory oxygen assessment. Consideration should be given to the measurement of SaO 2 and breathlessness at isotime as these provide important additional information. We recommend that these outcomes are included in the assessment for ambulatory oxygen. Future research needs to establish the level of benefit of ambulatory oxygen in specific subgroups of people with COPD. P L A I N L A N G U A G E S U M M A R Y Short-term ambulatory oxygen for chronic obstructive pulmonary disease Short-term studies indicate that people with chronic obstructive pulmonary disease respond to the administration of oxygen when they do exercise tests. Ambulatory oxygen is the use of supplemental oxygen during exercise and activities of daily living. One way to assess if ambulatory oxygen is beneficial for a patient with COPD is to compare the effects of breathing oxygen and breathing air on exercise capacity. Some people with COPD may benefit more than others, and trials should take account of whether people who do not already meet criteria for domiciliary oxygen also respond. This review shows that there is strong evidence that ambulatory oxygen (short-term) improves exercise capacity. Further research needs to focus on which COPD patients benefit from ambulatory oxygen, how much oxygen should be provided and the long-term effect of ambulatory oxygen. B A C K G R O U N D Chronic obstructive pulmonary disease (COPD) is a slowly progressive disorder characterised by airflow obstruction. The degree of airway narrowing is largely fixed but may be partially reversed with bronchodilator therapy (NICE 2004, GOLD 2001; Romain 2001; BTS 1997; ATS 1995). Patients often present with breathlessness, a chronic cough and sputum production. As the disease progresses gas exchange becomes more abnormal and adequate oxygenation may no longer be maintained. Home oxygen may be prescribed as long term oxygen therapy (LTOT), short burst or as ambulatory oxygen therapy. Long term oxygen therapy has been used in hypoxaemic patients with COPD to increase life expectancy, quality of life, exercise tolerance and decrease shortness of breath. The efficacy of LTOT in patients with chronic hypoxaemia has been shown in a Cochrane review and its use and prescription are well established (Crockett 2000). Ambulatory oxygen is defined as the use of supplemental oxygen during exercise and activities of daily living (RCP 1999). Ambulatory oxygen therapy is often used by patients on LTOT during exercise, or for non LTOT users with or without resting hypoxaemia if they show evidence of exercise desaturation and demonstrate improvement in exercise capacity with supplemental oxygen. There are criteria for assessment and use of ambulatory oxygen therapy (ATS 1995; RCP 1999; Young 1998). The RCP guidelines provide the most objective criteria which can be used to ascertain if ambulatory oxygen is required (RCP 1999). These criteria include (i) a fall in SaO 2 of at least 4% to reach a reading below 90% during a baseline walking test whilst breathing air; (ii) an improvement of at least 10% in walking distance and/or breathlessness score when walking with supplemental oxygen compared with an air cylinder; and (iii) the level of oxygen prescribed should be adequate to maintain SaO 2 above 90%. Ambulatory oxygen therapy is usually provided in small oxygen cylinders lasting up to 4 hours at 2 L/min or liquid oxygen systems which have a higher oxygen carrying capacity lasting up to 6-10 hours at 2 L/min. The evidence for the use of ambulatory oxygen therapy is extrapolated from two sources: longer term studies and single assessment studies. Longer term studies assess the impact of ambulatory therapy used at home during activities of daily living. Single assessment studies compare performance during an exercise test using oxygen with performance during an exercise test using placebo air. A Cochrane review investigating the long term efficacy of ambulatory therapy showed that there was little evidence of its effectiveness (Ram 2003) however this review did not include the single assessment studies which are recommended for assessment of ambulatory oxygen in clinical practice. 2

6 O B J E C T I V E S To determine the efficacy of ambulatory oxygen in patients with COPD using single assessment studies. M E T H O D S Secondary outcomes Secondary outcomes measured at isotime: 1. Dyspnoea scores (e.g. Borg scores or visual analogue scale) 2. Arterial oxygen saturation (pulse oximetry or arterial blood gases) during or post exercise 3. Physiological measurements (e.g. V E during exercise) 4. Patient preference Criteria for considering studies for this review Search methods for identification of studies Types of studies Randomised controlled trials comparing ambulatory oxygen therapy versus placebo air. Only assessment studies comparing performance during a single exercise test using ambulatory oxygen compared to performance during a single exercise test with placebo air were considered. Longer term studies assessing the efficacy of ambulatory oxygen therapy or studies assessing the efficacy of LTOT were not included. Types of participants Studies were included only when adult patients with stable COPD were randomised to either ambulatory oxygen or placebo. COPD should have been diagnosed according to criteria included in internationally accepted guidelines e.g. GOLD 2001; Romain 2001; BTS 1997; ATS Studies published prior to 1995 were included if patients had a diagnosis equivalent to COPD. Patients who did not have a diagnosis of COPD were excluded. Studies with mixed populations where excluded if data from patients with COPD were not analysed separately. Types of interventions The intervention in the actively treated group was ambulatory oxygen therapy, provided either via oxygen cylinders or a reservoir system. In the control group, the intervention should have been delivered via air cylinders or a reservoir system. Types of outcome measures Primary outcomes 1. Exercise capacity (e.g. distance, time or steps during maximal tests or endurance tests) Electronic searches The Cochrane Airways Group Specialised Register of RCTs was searched using the search terms: (portable* or ambulat* or oxygen* or O2 or hypoxaemia* or hypoxemia*) and (therap*) The Register contains records downloaded from CENTRAL, MEDLINE, EMBASE and CINAHL, as well as records identified through hand-searching journals and meeting abstracts, including the American Thoracic Society, British Thoracic Society and European Respiratory Society meetings. In order to minimise the chance of missing potential studies separate searches were also completed on the Cochrane Central Register of Controlled Trials (CENTRAL). In addition, other electronically available databases and search engines were searched for trials (CINAHL, Science Citation Index, EMBASE, MED- LINE, Scirus, UK National Research Register, PEDro, Clinical- Trials.gov, Google.com). Electronic web sites of the following journals were searched: American Journal of Respiratory and Critical Care Medicine, Annals of Internal Medicine, British Medical Journal, Chest, European Respiratory Journal, Lancet, Respiratory Care, Respiratory Medicine, Thorax). All databases were searched from their inception up until February Searching other resources Following this the bibliographies of each included RCT as well as any review articles found were searched for additional papers that may contain further RCTs. All authors of identified RCTs were contacted and asked to confirm that the data extracted and the assessment of quality was correct. Where relevant they were also requested to provide further information. Eight authors responded (Bye 1985; Garrod 1999; Dean 1992; O Donnell 1997; O Donnell 2001; Light 1989; Swinburn 1984; Fujimoto 2002a) and confirmed that the data extracted and assessment of quality was correct. Four studies (Garrod 1999; Dean 1992; O Donnell 1997; O Donnell 2001) provided further information (Table 1 Included Studies). 3

7 Data collection and analysis Selection of studies Two reviewers independently selected trials for inclusion in the review. Disagreement did not arise on the suitability of a trial for inclusion in the review or in its quality however if this occurs for future updates of this review a consensus will be reached by the two reviewers. Data extraction and management Data from the trials was independently extracted by two reviewers (JB, BON) using standard data extraction forms. Assessment of risk of bias in included studies The methodological quality of each trial was assessed by each reviewer using two scales: the Jadad scale (Jadad 1996) and the PE- Dro scale. The PEDro is an 11 item scale based on the previously validated Delphi list (Verhagen 1998). The Pedro scale examines issues of randomisation, allocation, whether patients were similar at baseline, extent of blinding in the study, proportion of patients for which data was available and the method in which this data was reported. The PEDro scale has been shown to be reliable measure of study quality (Moseley 1999). The PEDro scale is available at ptwww.cchs.usyd.edu.au/pedro. The PEDro scale scores studies out of 10. The quality of included studies was also assessed using the Cochrane allocation concealment scale. For continuous outcomes (exercise capacity, breathlessness scores), a WMD was used when combining data. Data from the same variable (for example the FEV 1 ), but expressed differently in different trials (for example as change in litres and change expressed as percentage of baseline) were combined using a standardised mean difference (SMD). If dichotomous outcomes had been identified they would have been analysed using the relative risk or odds ratio. Random and/or fixed effects model were used depending upon the level of statistical heterogeneity observed. Where I 2 exceeded 0% we applied Random Effects modelling, and compared this with a Fixed Effects model in order to determine whether taking account of within and between study variation impacts upon the overall pooled effect estimate. Note: For many of the outcomes, the focus is on a favourable outcome. Here the aim of the treatment is to increase the outcome, rather than decrease it. This requires the graph labels to be reversed from the standard format of favours treatment on the left of the graph and favours control on the right. All trial data was combined using Review Manager. Funnel plots were carried out to test for the presence of publication bias where possible. Subgroup analysis and investigation of heterogeneity If enough studies had been available we would have carried out the following sub group analyses: disease severity; and method of oxygen delivery. Due to the way in which studies were conducted and reported, we opted to perform a post-hoc subgroup analysis based upon the level of hypoxaemia and the dose of oxygen delivered. A sensitivity analysis was performed to examine the impact of blinding on the study results (single versus double blind studies). Unit of analysis issues Due to the crossover design of the studies, we opted to enter data based as generic inverse variance (GIV) data. This takes the mean difference between treatment and control, with a standard error (SEM) for the difference. Where possible, we have taken the published SEM, but where this was not available, we have used the published P value to estimate a standard error. Where data were reported as non-significant, and no other means of obtaining the variance was possible, we have entered the published means and SDs as a weighted mean difference (WMD - see below) as reported in the published paper and used that as a basis of calculating the SEM for between treatment group differences. This would tend to underestimate the treatment effect as it would overlook the sensitivity of paired data for within patient differences. Data synthesis Sensitivity analysis If significant heterogeneity was found a sensitivity analyses would have been conducted on study quality (Cochrane scores and or Pedro scale). R E S U L T S Description of studies See: Characteristics of included studies; Characteristics of excluded studies. A total of 60 studies were retrieved literature search results. Of these, 29 studies failed to meet the inclusion criteria (see Table Characteristics of Excluded Studies ). Four new studies have been included in this update of the review (see What s New ). Thirty- 4

8 one studies (contributing 33 randomised data sets) met the inclusion criteria. Study design Thirty one studies (contributing 33 data sets) with a total of 534 participants met the inclusion criteria for this review. All the trials included in this review were cross-over in design. Freeman et al (1989) suggest that only on the grounds of biological reasoning can it can be assumed that there is no carry-over in cross over studies. They argue against using statistical tests to assess if there is a crossover effect. No studies in this review tested for a carry-over effect although the duration between successive tests is variable. There is no consensus in the literature regarding the minimum time required to eliminate the carry-over effect of exercise testing. Participants Sample size varied from 5 to 41. The mean age reported in the included studies ranged from 47 to 73 years. With the exception of one study which included a group of mild patients (Fujimoto 2002a) all studies included patients with moderate to severe airflow obstruction. The mean PaO 2 ranged from 6.9 KPa to 11.3 KPa (52 mmhg to 85 mmhg). Judging by the baseline mean PaO 2, the following loose categorisations can be made: seven studies included patients who likely met the criteria for LTOT on the grounds that baseline mean kpa was lower than 7.3 (see Table characteristics of included studies): (O Donnell 2001; Garrod 2000; Bye 1985; King 1973; Leach 1992; Leggett 1977; Mannix 1992). Twenty three studies included patients who did not or likely did not meet the criteria for LTOT on the grounds that mean baseline kpa exceeded 7.3 (see Table characteristics of included studies): Eaton 2002; O Donnell 1997, Dean 1992; Garrod 1999; Wadell 2001; Bradley 1978; Criner 1987; Davidson 1988; Fujimoto 2002a; Fujimoto 2002b; Fujimoto 2002c; Light 1989; McKeon 1988; McDonald 1995; Somfay 2001; Stein 1982; Ishimine 1995; Kurihara 1989; Swinburn 1984; Vyas 1971; Woodcock 1981; Knebel 2000; Maltais 2001; Palange 1995; Gosselin 2004). In one study there was no information relating to baseline oxygen status (Raimondi 1970). Knebel 2000 cited current oxygen usage as an exclusion criterion. These categorisations form the basis of the subgroup analyses which are based upon baseline oxygen status (mean baseline PaO2 <7.3 kpa/55 mmhg; mean baseline PaO2 >=7.3 kpa/55 mmhg or status unclear). This value (PaO2 <7.3 kpa) is based on the recommendation from NICE for LTOT (NICE 2004). Intervention and setting In thirteen studies the oxygen was delivered via nasal specs, in one study the oxygen was delivered via a face mask, in one study the oxygen was delivered via a face mask or nasal specs and in sixteen studies oxygen was delivered via a mouthpiece with a reservoir system (*see Table characteristics of included studies). It was decided that oxygen delivery of less than or equal to 4 L/min or 35% would be termed low dose oxygen and oxygen delivery of greater than this would be termed high dose oxygen. Twenty studies used low dose oxygen (Criner 1987; Eaton 2002; Fujimoto 2002a; Fujimoto 2002b; Fujimoto 2002c; Garrod 1999; Garrod 2000; Ishimine 1995; King 1973; Kurihara 1989; Leach 1992; Leggett 1977; Light 1989; Mannix 1992; McDonald 1995; McKeon 1988; Raimondi 1970; Stein 1982; Woodcock 1981; Gosselin 2004; Palange 1995; Knebel 2000), nine studies used high dose oxygen (Bradley 1978; Bye 1985; Dean 1992; O Donnell 1997; O Donnell 2001; Swinburn 1984; Vyas 1971; Wadell 2001; Maltais 2001) and 2 studies used both (Davidson 1988; Somfay 2001). Twenty-nine studies compared one oxygen intervention with a placebo intervention. Two studies compared more than one oxygen intervention with a placebo intervention (Davidson 1988; Somfay 2001); in these two studies only one low dose and only one high dose oxygen intervention was selected. The Davidson 1988 study had more than one low dose intervention and the Somfay 2001 study had more than one high dose intervention. The oxygen intervention closest to the critical level (4 L/min or 35%) was chosen. Exercise Tests Twelve studies used maximal exercise tests only and 17 used endurance exercise tests and two studies used two tests. For details of each study please see Table characteristics of included studies. Various types of exercise tests were used: treadmill (6 studies); cycle ergometry (12 studies); incremental shuttle walk test (2 studies); 6MW test (10 studies); step test (one study); other walk tests (three studies). A number of studies assessed response to more than one type of exercise test. A variety of exercise test protocols were used and details of these are provided in Table 1. In 10 studies there was no familiarization or practice test; six studies used familiarization only and 14 studies used practice tests +/- familiarisation (Table 1) and one study used practice tests +/- familiarisation in two out of three exercise tests (Davidson 1988). Up to four submaximal tests were performed on the same day and the rest period between tests ranged from 10 mins to one day. In one study 16 tests where performed over three days (Woodcock 1981). 17/31 of the studies controlled for factors which can affect performance on exercise test such as time of day, food intake and medication such as bronchodilators. Outcome 5

9 There was a wide range of outcome measures reported in the studies. Exercise capacity was measured using five methods: distance (14 studies); time (12 studies); VO 2 (7 studies); number steps (1 study); watts (3 studies). The following measurements were made at isotime: breathlessness, 4 studies;. SaO 2 /PaO 2, 6 studies (1 mmhg = kpa); V E, 9 studies: (Table 2 Outcome measures used). size was based on a power calculation. 29/31 studies included in the review reported on at least 1 of the primary outcome measures. King 1973 and Light 1989 did not report on a primary outcome measure. Effects of interventions Risk of bias in included studies Overall, the methodological quality of the included studies as rated by the Jadad score was low (16 studies had score of 1; nine studies had a score of 2; 4 studies had a score of 3; and two studies had a score of 5). These low scores can be attributed to lack of double blinding (14 studies single blind; 15 double blind; two studies no blinding) or lack of detail in the reporting of the blinding or randomisation (Table characteristics of included studies). The Pedro scale includes a wider variety of quality criteria relating to both internal and external validity. Overall, the methodological quality of the included studies as rated by the Pedro score was good (2 studies has score of 6; 14 studies had a score of 7; 2 studies had a score of 8; 12 studies had a score of 9; 1 study had a score of 10) (Table characteristics of included studies). One study reported dropouts (Knebel 2000). One study reported the use of a concealed randomisation procedure (Garrod 1999). In general the sample size of many individual studies was small (range 5 to 41 participants) and no studies reported that the sample ENDURANCE TEST STUDIES Primary outcome measure: Exercise capacity Distance (Eaton 2002; Fujimoto 2002a; Fujimoto 2002b; Fujimoto 2002c; Ishimine 1995; Kurihara 1989; McDonald 1995; Davidson 1988; Woodcock 1981; Knebel 2000) All studies assessed the effects of low dose oxygen. Davidson 1988 reported results from two exercise tests (6MWT and endurance walk test). In order to avoid double-counting participants, we calculated two pooled estimates. There was significant heterogeneity between the studies with either data-set used. With fixed effects modelling oxygen significantly improved exercise distance by metres (95% CI to 24.61, N=238 Davidson MWT; Figure 1), and metres [95% CI to 24.39], N = 238 Davidson 1988 endurance walk test; Figure 2). Random Effects modelling did not alter the significance of these effects. 6

10 Figure 1. Forest plot of comparison: 1 Oxygen versus placebo (crossover studies), outcome: 1.1 Endurance test - exercise distance (Davidson MWT). Figure 2. Forest plot of comparison: 1 Oxygen versus placebo (crossover studies), outcome: 1.2 Endurance test - exercise distance (Davidson 1988 endurance walk). 7

11 Three studies did not report data in a usable format for metaanalysis. All assessed the effects of low dose oxygen. Leach 1992 reported no significant increase in distance walked (mean % increase 28.6 [95% CI to 111, N = 20]. Leggett 1977 reported censored data (N=8) from a study of 26 participants, which showed a significant increase in distance walked 12MWT (mean SEM increase 53 m +/ Wadell 2001 reported that oxygen significantly improved the median distance walked on a 6MWT [median (min-max) improvement 30 (-30 to 60) metres, N = 20]. Exercise time (Davidson 1988; Raimondi 1970; Somfay 2001; Bye 1985; Dean 1992; O Donnell 1997; O Donnell 2001). One study assessed the effects of treatment with low dose oxygen (Raimondi 1970). Two studies reported data on the effects of treatment with both low dose and high dose oxygen (Somfay 2001; Davidson 1988) and four studies assessed the effects of treatment with high dose oxygen (Bye 1985; Dean 1992; O Donnell 1997; O Donnell 2001). In one study the effect of low dose oxygen was assessed using two different endurance tests (cycle test and an endurance walk test, Davidson 1988). To avoid over-estimating the effects of treatment in the placebo arms of the studies, three pooled estimates have been calculated. There was no significant heterogeneity between the subgroups in any instance. With low dose data from Somfay 2001 and Davidson 1988, oxygen significantly improved exercise time irrespective of whether data related to the cycle test (Low dose: WMD 2.70 minutes [95% CI 1.95 to 3.44], N = 77) or endurance walk test (Low dose: WMD 2.63 minutes [95% CI 1.91 to 3.44], N = 77). With high dose data from both studies entered oxygen significantly increased exercise time (High dose: WMD 2.71 minutes [95% CI 1.96 to 3.46], N = 77). Step (McDonald 1995) Data from the original study showed that low dose oxygen significantly improved the mean (SD) number of steps climbed oxygen 35 (21) versus placebo 30 (18), N = 26. VO 2 (Palange 1995) Data from the original study showed that low dose oxygen significantly improved VO2 oxygen 2280 (426) versus placebo 1120 (204), N = 9. Patient Preference No studies reported on patient preference. (Garrod 1999; Garrod 2000; McKeon 1988; Woodcock 1981). All studies assessed the effects of low dose oxygen. There was a significant improvement in distance walked during oxygen versus placebo of 32 metres [95% to 43.38], N = 70. There was a moderate level of heterogeneity between the studies. Random Effects modelling widened the confidence interval but the result remained significant (39.57 metres [95% CI to 62.11]). Time (Criner 1987; Mannix 1992; Raimondi 1970; Stein 1982; Swinburn 1984; Vyas 1971). Fixed effect modelling gave a significant difference of 1.06 minutes in favour of oxygen [95% CI: 0.67, 1.46], N = 50. Although there was a moderate level of heterogeneity (I %), Random Effects modelling did not alter the significance of this finding (1.19 minutes [0.53, 1.86]). VO 2 max (Bradley 1978; Criner 1987; Mannix 1992; Vyas 1971; Gosselin 2004). Three studies assessed the effects of low dose oxygen (Criner 1987; Gosselin 2004; Mannix 1992) and two studies assessed the effects of high dose oxygen (Bradley 1978; Vyas 1971). As each study used different units of measurement these studies could not be pooled. Data from the original studies showed that oxygen significantly (P<0.05) improved VO 2 max in three studies [Criner 1987; N=6, oxygen 13.4 (0.9) versus placebo 9.6 (1.4)ml kg 1min 1 ; Gosselin 2004; N=9, oxygen (4.2) versus placebo 20.2 (5.7) ml kg-1 min-1; Vyas 1971; N=12, oxygen 4.14 (1.21) versus placebo 2.74 (0.86) L 0.5 min 1 ]. Oxygen did not improve VO 2 max in the other two studies [Mannix 1992; N=10, oxygen 740 (335.20) versus placebo 609 (220.39)ml min 1 ; Bradley 1978; N=26, oxygen 8.7 (3.0) versus placebo 8.20 (2.60)ml min 1. Work rate (Light 1989; Gosselin 2004; Maltais 2001) Two studies assessed the effects of low dose oxygen (Light 1989; Gosselin 2004) and one study assessed the effects of high dose oxygen (Maltais 2001). There was no significant heterogeneity between the studies and oxygen significantly increased work rate compared to placebo by 8.88 watts [95% CI 5.71 to 12.06] N= 40. Patient Preference No studies reported on patient preference. MAXIMAL TEST STUDIES Primary outcome: Exercise capacity Distance Secondary outcome measure at Isotime Secondary outcomes e.g. breathlessness, SaO 2, V E at end exercise are not directly comparable as they are dependant on exercise performance (time/distance/vo2/work rate). Therefore it was 8

12 decided to compare the effect of oxygen treatment on these secondary outcomes at isotime. In all studies except two the isotime is defined as the time at which the placebo test ended. One study used the point of comparison as the time at which the lesser test ended (Vyas 1971). One study used the point of comparison as the time at which stage 1 (no resistance or zero watts) ended (Mannix 1992). One study reported data on isotimes with both high and low dose oxygen treatment so to avoid double-counting the effects of treatment two pooled estimates have been calculated (Somfay 2001). ENDURANCE TEST ISOTIMES STUDIES Breathlessness (Dean 1992; O Donnell 1997; O Donnell 2001; Somfay 2001). Three studies assessed the effects of treatment with high dose oxygen (Dean 1992; O Donnell 1997; O Donnell 2001) and one study assessed the effects of both high and low dose oxygen (Somfay 2001). There was a moderate level of heterogeneity between the studies (I %). With low and high dose oxygen data from Somfay 2001 entered separately oxygen significantly decreased breathlessness (Low dose data from Somfay 2001: WMD [95% CI to -0.66] and high dose data from Somfay 2001: WMD [95% CI to -0.65]). Random Effects modelling gave a significant result in favour of oxygen (Somfay 2001 low dose: [95% CI to -0.62]; Somfay 2001 high dose: [95% CI to -0.61] N=44). SaO 2 /PaO 2 (Bye 1985; O Donnell 1997; Somfay 2001) Two studies assessed the effects of treatment with high dose oxygen (Bye 1985; O Donnell 1997) and one study assessed the effects of both high and low dose oxygen (Somfay 2001). There was no significant heterogeneity between the studies. Oxygen significantly improved SaO 2 with low and high dose data from Somfay 2001 (Somfay 2001 low dose: 8.36% [95% CI 5.08 to 11.64]; Somfay 2001 high dose: 8.80% [95% CI 5.36 to 12.24] N=29). Data for PaO 2 was reported in two high dose studies (Dean 1992; O Donnell 2001). PaO 2 was significantly greater with oxygen versus placebo by kpa [95% CI 6.42 to 23.89] N=23. V E (Dean 1992; Bye 1985; O Donnell 1997; O Donnell 2001; Somfay 2001) V E is the volume of air inhaled per minute. Four studies assessed the effects of treatment with high dose oxygen (Dean 1992; Bye 1985; O Donnell 1997; O Donnell 2001) and one study assessed the effects of both high and low dose oxygen (Somfay 2001). Pooled estimates with both high and low dose data from Somfay 2001 indicated that oxygen significantly decreased V E (Somfay 2001 high dose: [95% CI to -2.31]; Somfay 2001 low dose: L/min [95% CI to -2.33] N=52). MAXIMAL TEST ISOTIMES Breathlessness Data from 14 patients showed high dose oxygen significantly reduced breathlessness compared to placebo but no data was provided (Maltais 2001). SaO 2 and PaO 2 (Light 1989; Maltais 2001) One study assessed the effects of low dose oxygen (Light 1989) and one study assessed effects of high dose oxygen (Maltais 2001). There was no significant heterogeneity between the studies and oxygen significantly increased SaO2 versus placebo by 7.82% [95% CI 4.89 to 10.74] N=31. V E (Light 1989; Mannix 1992; Vyas 1971; Gosselin 2004) Three studies assessed the effects of treatment with low dose oxygen (Light 1989; Mannix 1992; Gosselin 2004) and one study assessed the effects of treatment high oxygen (Vyas 1971). There was a significant difference in V E in favour of oxygen, of L/ min [95% CI to -2.19] N=48. Sensitivity & Subgroup Analyses It was not possible to conduct a sub group analysis according to disease severity or method of oxygen delivery. Subgroup analyses according to baseline oxygen status did not provide evidence of different response to treatment between those studies which included patients that did/likely did meet the criteria for LTOT and those studies that did not/ likely did not. This may be explained in part by the nature of the distinctions made. These have been made at the trial level, and as such may have been too arbitrary to differentiate between different patient populations. However, such distinctions are based upon internationally approved guidelines (NICE 2004). Two trials evaluated the effects of low dose and high dose oxygen (Somfay 2001; Davidson 1988). Both trials reported data on endurance exercise time. Head to head comparison showed no significant improvement in endurance time WMD 1.85 [95% CI to 3.86] during high dose versus low dose oxygen. A number of factors undermine the validity of this estimate: i) the original studies compared a number of categories (Somfay 2001, 30; 50;75;100%: Davidson 1988, 2;4;6 L) of oxygen and did report benefit from higher dose compared to lower dose. In this review data relating to the oxygen intervention closest to the critical level was extracted; ii) the SEM for the Davidson 1988 was imputed, based upon the variance from a P value given for a comparison with placebo; iii) the data for the two studies extracted from different exercise tests (Davidson 1988: endurance cycle; Somfay 2001: endurance walk test). Further studies comparing high with low dose oxygen are required before the dose effect can be more fully explored. 9

13 Somfay 2001 reported on endurance isotime. No significant difference was reported in breathlessness or V E at isotime between high and low dose oxygen. SaO2 was significantly greater at isotime during high dose versus low dose oxygen (high dose: 99.7% (SEM 0.2), low dose: 98% (SEM 0.8), (P < 0.05). Other Results There is no documented criteria on the minimal clinically important difference for ambulatory oxygen, however the RCP guidelines state that ambulatory oxygen therapy should be prescribed when there is an improvement of at least 10% in walking distance and/or breathlessness score when walking with supplemental oxygen compared to air. 28/31 studies provided data on mean exercise performance (distance, time. work rate) and/or mean breathlessness score. Of these 23/28 studies (in Fujimoto 2002c patients with severe disease only) demonstrated an improvement of at least 10% in mean exercise performance and/or mean breathlessness score when walking with supplemental oxygen compared with an air cylinder. Lack of adequate blinding procedures may exert some bias on the effect estimates, if the study investigators are aware as to which intervention participants are receiving during an exercise test. The majority of the studies assembled in the primary outcomes were double-blind and a post-hoc sensitivity analysis suggested that the removal of single-blind studies did not reduce the significance of the summary estimate (Exercise distance: double-blind studies: metres (14.11, 27.25; seven studies); exercise time: 3.22 (2.15, 4.29; four studies). D I S C U S S I O N Thirty-one studies (contributing 33 data sets), comparing performance during a single exercise test using ambulatory oxygen with performance during a single exercise test with placebo have been included in this review. The overall effect of oxygen was estimated (low dose plus high dose). Oxygen improved all outcomes relating to endurance exercise capacity (distance, time, number of steps) when the studies were pooled. Oxygen improved exercise distance, time, and work rate during maximal exercise testing in a mixed population of patients. Data for VO 2 max during maximal exercise testing could not be pooled and data from original studies was not consistent. The secondary outcomes of breathlessness, SaO 2 and V E are not directly comparable at end exercise, so comparisons were made at isotime. Oxygen improved breathlessness, SaO 2 /PaO 2 and V E at isotime with endurance exercise testing. Data from studies comparing high dose versus low dose oxygen were analysed but they may have been inadequately powered to explore the dose response in terms of breathlessness or V E at isotime. No data from maximal exercise test data were reported on breathlessness at isotime; oxygen improved V E and SaO 2 /PaO 2 at isotime. Methodological issues The results of this review are noteworthy because of the lack of statistical heterogeneity in many of the meta-analyses. The studies differed in several ways, notably in the type of exercise test deployed (Table 1), the method and amount of oxygen, whether participants were known to be able to exercise up to a certain capacity, whether studies were single or double-blind, and the severity of the participants recruited to the studies. Due to the way in which participant characteristics were described we could not answer important questions surrounding the fulfilment of LTOT criteria as a predictor of short-term response. We could not determine whether the assessments derived from the different exercise tests used differed sufficiently to avoid combining them. Comparisons of the different exercise tests could elucidate this issue further. The studies assembled did not provide evidence that high and low doses of oxygen are too dissimilar to keep apart in a metaanalysis. However, the entry criteria did not allow us to explore the effects of oxygen in this setting in different patient populations. Rather than interpret this review as indicative of a consistent effect across several subgroups of patients with COPD, we feel that further studies are required in more distinct patient populations before this can be stated with authority. Publication bias was suggested by funnel plots of primary outcomes (Figure 3; Figure 4). In spite of extensive literature searches, contact with trialists and the incorporation of data from two studies published in Japanese, there remains the possibility that there are several small negative studies that have not been published, or identified by the search strategy employed in this review. The recent identification of Knebel 2000 provides an opportunity to revisit the question of publication bias on the primary outcome. This is the only non-significant study in this subset of trials, and takes up the third largest weighting for this outcome (16%). The level of heterogeneity has increased to only a modest level (33%) and the fixed effect summary estimate has moved a small amount towards the null compared with the previous version of this review. The addition of this study goes part way to correcting for some of the publication bias suggested by the initial funnel plot published in this review in issue 2, 2005, but additional large studies in future versions of this review will help further to provide a more reliable estimate. 10

14 Figure 3. Funnel plot of exercise distance (Comparison 01; outcome 01). The blue dots represent the mean differences of individual trial estimates. The distribution of these dots to the right of the dotted line suggests that there may be the equivalent number of negative trials that have not been included in this analysis. 11

15 Figure 4. Funnel plot of exercise distance (Comparison 01; outcome 03). The blue dots represent the mean differences of individual trials. The distribution of these dots to the right of the dotted line suggests that there may be the equivalent number of negative trials that have not been included in this analysis. External validity Three characteristics of the studies affect the generalisability of the review: inclusion and exclusion criteria of individual studies, method of delivery of oxygen, and outcome assessment. Few of the trials categorised patients at baseline according to level of hypoxaemia. Due to the lack of variation between effect estimates, subgroup analyses did not provide useful insights in to whether baseline oxygen status affected response to ambulatory oxygen in the studies. This may be because the studies recruited mixed populations, rendering trial-level distinctions on this basis somewhat arbitrary. A baseline mean can be a crude measurement of population health, especially in this review where threshold values indicate treatment with LTOT oxygen on an individual patient level. The subgroup analysis from available data relating to level of hypoxaemia provides some evidence that there is benefit of ambulatory oxygen in patients who meet/likely meet as well as those who do not meet/likely do not meet the criteria for LTOT. The absence of a significant difference between treatment responses could well indicate that these studies have recruited mixed populations, with some variation between them in the percentage of participants who would qualify for LTOT. Current UK guidelines state that non-ltot patients who desaturate by 4% to a point below 90% on a baseline walk should be assessed for ambulatory oxygen (RCP 1999). The majority of studies in this review do not provide information on the level homogeneity of the patients with regard to exercise induced desaturation and do not provide sufficient information to enable us to ascertain whether trials (and/or all the patients in each trial) meet the current UK criteria for ambulatory oxygen assessment. Therefore it was not possible to conduct a sub-group analysis on the following categories: (a) patients who did not meet criteria for LTOT but have evidence of resting hypoxaemia (desaturation <90%); (b) patients who did not meet criteria for LTOT and did not have evidence of resting hypoxaemia, but who demonstrated a fall in SaO2 of at least to reach a reading below 90% during a baseline walking test whilst breathing air (c) patients who do not meet any of these criteria. Therefore we are unable to determine how accurately the results of this review can be inferred to the population which the UK guidelines recommend that ambulatory oxygen should be considered. UK guidelines state that assessment should include titrating oxy- 12

16 gen to a level in which SaO2 is kept above 90% (RCP 1999). It is unclear whether the flow rate/percentage of oxygen used in these studies was adequate to achieve this. If the oxygen level was inadequate it may underestimate the effect of ambulatory oxygen. The studies in this review used a variety of methods to deliver oxygen which could affect the outcome and nasal speculae were the most frequently used method of delivery of ambulatory oxygen. Subgroup analysis of high versus low dose oxygen did not indicate that this distinction explains any heterogeneity between the studies on any outcome. In studies where these two treatment regimens have been compared directly, there is insufficient evidence to conclude that a dose response effect exists. More studies are required in this area. The results of our review demonstrate that maximal or endurance tests can be used in ambulatory oxygen assessments. The choice of exercise test should be determined by a number of factors: e.g. the psychometric properties of the test is important and it has been suggested that endurance exercise testing may be more sensitive and more related to functional exercise capacity and activities of daily living than maximal exercise testing (Revill 1999; ATS 2002). Other important factors include the resources available; and the patient activity levels. For example a maximal test may be appropriate for patients who intend to use ambulatory oxygen during intense activities and endurance tests may be more appropriate during functional activities of daily living. It has been shown that the use of familiarisation and/or a practice periods prior to exercise testing will improve the quality of the data obtained (ATS 2002; Singh 1992). Some exercise tests have standardised protocols which include information on how many practice tests are required (e.g. 6MWT 2 practice tests, incremental shuttle walk test - 1 practice test) (ATS 2002; Singh 1992). The majority of studies in this review included a familiarisation period and approximately half the studies included a practice period. There is no specific guidance on length of time between repeated exercise tests and how many tests can be performed on a single day. For maximal exercise testing it has been suggested that hours should be left between tests, and it is unclear how long should be left between endurance tests although there is some evidence to suggest that at least 30 minutes should be left between repeat endurance tests (Marques 1998; ATS 2002). Repeated exercise testing could result in an order effect with patients performing less well on repeated testing (Marques 1998). It is unclear how much impact the order and frequency of testing could have influenced the results. While the effects of short episodes of hypoxaemia are still unclear (especially in patients adapted to chronic hypoxaemia) single assessment studies are useful in determining the efficacy of ambulatory oxygen in patients with COPD, although it is not known how variable the results of single assessments are in any given individual (Senn 2004), nor how far the response to short term testing predicts uptake or compliance with therapy in the longer term. Estimates for the Minimal Clinically Important Difference (MCID) are available for the 6MWT and the shuttle walk test. Redelmeier 1997 estimates the MCID for the 6MWT to be 50 metres [95% CI 37 to 71], and Singh 2002 estimates the MCID for the SWT to be 48 metres [95% CI 33.6 to 63.6]. Although effect sizes from the outcomes measuring exercise capacity in this review were statistically significant, the clinical significance of this result remains open to interpretation, especially as the lower confidence interval for our summary estimates are lower than those estimated by the above studies. No estimates on MCID for the other outcome measures have been identified. A mean difference less than the MCID does not exclude the fact that some patients in the study may actually have achieved the MCID and it would be useful for future studies to state how many individual patients achieve the MCID for primary outcome measure. Internal validity The methodological quality of the trials in this review were assessed using two different scales -the Jadad and PEDro scales. Both scales were used because different quality scales have been shown to generate discrepant results. Both of these scales mostly assess different aspects of internal validity- Jadad: randomisation (2 questions, 40%), blinding (2 questions, 40%) and withdrawal (1 question, 20%); PEDro: randomisation (2 questions, 20%), blinding (3 questions, 30%), withdrawal (2 questions, 20%). In addition PEDro includes aspects relating to baseline characteristics (1 question, 10%) and statistics (2 questions, 20%). Jadad gives more weighting to quality of reporting than actual methodological quality, for example Jadad focuses on reporting of randomisation and the reporting of the randomisation procedure where as PEDro focuses on whether there is randomised and concealed allocation. In Jadad a statement on withdrawals will earn a point independently of how many patients were excluded or whether intention to treat was used whereas the PEDro scale examines the impact of patient withdrawals in detail. These differences explain any discrepancies in the rank order of quality rating between the Jadad and Pedro scales. A score of 3 on the Jadad scale represents high quality (Jadad 1996). Six studies scored 3 or above on the Jadad scale. All studies which scored 3 on the Jadad scale scored 9 or 10 on the PEDro. There is no reference criteria regarding high quality on the PEDro scale- all studies in this review scored 6 or more. We would propose that the PEDro scale may be more sensitive than the Jadad scale to aspects of internal validity relevant to the ambulatory oxygen studies included in this review and that a score of 6 or more demonstrates that all the trials in this review have at least reasonable internal validity. A U T H O R S C O N C L U S I O N S 13

17 Implications for practice This review provides evidence from single assessment studies that ambulatory oxygen improves exercise performance. It is our opinion that it is no longer necessary to compare performance during an exercise test using oxygen versus placebo air but rather an ambulatory assessment should determine whether patients demonstrate objective benefit during an exercise test using oxygen versus room air. The system used in the ambulatory oxygen assessment should be the system that would be potentially made available to the patient and should be used in the same way that the patient would be advised to use it (for example, if the patient will be required to carry/wheel the ambulatory system during activities of daily living then they should carry/wheel it during the ambulatory oxygen assessment). Maximal or endurance tests could be used in ambulatory oxygen assessment. Consideration should be given to the measurement of signs and symptoms such as SaO 2 /SpO 2 and breathlessness at isotime as these provide important information. We recommend that these outcomes are included in the assessment for ambulatory oxygen. Consideration should also be given to the amount of oxygen required to maintain SaO 2 /SpO 2 at an acceptable level. The technology for the delivery of ambulatory oxygen is developing rapidly and in the future such systems should be accessible to those who demonstrate objective benefit during an ambulatory oxygen assessment (Law 2004; DOH BTS 2004). Detailed and standardised assessment procedures for ambulatory oxygen therapy should be developed and these should include assessment of potential utilisation by the patient as well as objective benefit. Implications for research This review has established the short-term efficacy of ambulatory oxygen, although additional studies may help to reduce suspected bias in reporting of the primary outcome. In our opinion research should focus on establishing the long-term efficacy, and on developing a method for determining the optimal dose and delivery system for ambulatory oxygen. Further trials are also required to establish whether improvements in primary and secondary outcomes which reach statistical significance are clinically important. We remain uncertain of the level of benefit of ambulatory oxygen in specific subgroups of COPD: patients who already meet the criteria for LTOT; (b) patients who do not meet criteria for LTOT but have evidence of resting hypoxaemia (desaturation <90%); (c) patients who do not meet criteria for LTOT and do not have evidence of resting hypoxaemia but who demonstrate a fall in SpO 2 of at least 4% to reach a reading below 90% during a baseline walking test whilst breathing air. A C K N O W L E D G E M E N T S We would like to thank Toby Lasserson for his support. We would like to thank Makiko Meguro for translating studies from Japanese. Mike Greenstone was the assigned editor for this review. We would like to thank Prof JS Elborn and Dr J MacMahon Deaprtment of Respiratory Medicine Belfast City Hospital, for reviewing papers and offering clinical and medical viewpoints. R E F E R E N C E S References to studies included in this review Bradley 1978 {published data only} Bradley BL, Garner AE, Billiu D, Mestas JM, Forman J. Oxygen assisted exercise in chronic obstructive lung disease. American Review of Respiratory Disease 1978;118: Bye 1985 {published data only} Bye PT, Esau SA, Levy RD, Shiner RJ, Macklem PT, Martin JG, Pardy RL. Ventilatory muscle function during exercise in air and oxygen in patients with chronic air-flow limitation. American Review of Respiratory Disease 1985; 132: Criner 1987 {published data only} Criner GJ, Celli BR. Ventilatory muscle recruitment in exercise with O2 in obstructed patients with mild hypoxemia. Journal of Applied Physiology 1987;63(1): Davidson 1988 {published data only} Davidson AC, Leach R, George RJ, Geddes DM. Supplemental oxygen and exercise ability in chronic obstructive airways disease. Thorax 1988;43: Dean 1992 {published data only} Dean NC, Brown JK, Himelman RB, Docherty JJ, Gold WM, Stulbarg MS. Oxygen may improve dyspnea and endurance in patients with chronic obstructive pulmonary disease and only mild hypoxemia. American Review of Respiratory Disease 1992;146: Eaton 2002 {published data only} Eaton T, Garrett JE, Young W, Fergusson W, Kolbe J, Rudkin S, Whyte KL. Ambulatory oxygen improves quality of life of COPD patients: a randomised controlled study. European Respiratory Journal 2002;20: Fujimoto 2002a {published data only} Fujimoto K, Matsuzawa Y, Yamaguchi S, Koizumi T, Kubo K. Benefits of oxygen on exercise performance and pulmonary hemodynamics in patients with COPD with mild hypoxemia. Chest 2002;122: Fujimoto 2002b {published data only} Fujimoto K, Matsuzawa Y, Yamaguchi S, Koizumi T, Kubo K. Benefits of oxygen on exercise performance and pulmonary hemodynamics in patients with COPD with 14

18 mild hypoxemia. Chest 2002;122: Chest 2002; 122: Fujimoto 2002c {published data only} Fujimoto K, Matsuzawa Y, Yamaguchi S, Koizumi T, Kubo K. Benefits of oxygen on exercise performance and pulmonary hemodynamics in patients with COPD with mild hypoxemia. Chest 2002;122: Chets 2002; 122: Chest 2002;122: Garrod 1999 {published data only} Garrod R, Bestall JC, Paul E, Wedzicha JA. Evaluation of pulsed dose oxygen delivery during exercise in patients with severe chronic obstructive pulmonary disease. Thorax 1999; 54: Garrod 2000 {published data only} Garrod R, Paul EA, Wedzicha JA. Supplemental oxygen therapy during pulmonary rehabilitation in patients with COPD and exercise hypoxaemia. Thorax 2000;55: Gosselin 2004 {published data only} Gosselin N, Durand F, Poulain M, Lambert K, Ceugniet F, Prefaut C, et al.effect of acute hyperoxia during exercise on quadriceps electrical activity in active COPD patients. Acta Physiologica Scandinavica 2004;181(3): Ishimine 1995 {published data only} Ishimine A, Saito T, Nishimura S, Nakano G, Miyamoto, Kawakami. The effect of oxygen supplementation during exercise in COPD patients with PaO2 over 60 Torr. Japanese Journal of Chest Disease 1995;33: King 1973 {published data only} King AJ, Cooke NJ, Leitch AG, Flenley DC. The effects of 30% oxygen on the respiratory response to treadmill exercise in chronic respiratory failure. Clinical Science 1973; 44: Knebel 2000 {published data only} Knebel AR, Bentz E, Barnes P. Dyspnea management in alpha-1 antitrypsin deficinency: effect of oxygen administration. Nursing Research 2000;49(6): Kurihara 1989 {published data only} Kurihara N, Fujimoto S, Kouno, Futoda K, Hirata K, Takeda C. Exercise induced hypoxemia and exercise tolerance in patients with COPD and the benefits of oxygen supplementation. Japanese Journal of Chest Disease 1989;26: Leach 1992 {published data only} Leach RM, Davidson AC, Chinn S, Twort CHC, Cameron IR, Bateman NT. Portable liquid oxygen and exericse ability in severe respiratory disability. Thorax 1992;47: Leggett 1977 {published data only} Leggett RJE, Flenley DC. Portable oxygen and exercise tolerance in patients with chronic hypoxic cor pulmonale. British Medical Journal 1977;2: Light 1989 {published data only} Light RW, Mahutte CK, Stansbury DW, Fischer CE, Brown SE. Relationship between improvement in exercise performance with supplemental oxygen and hypoxic ventilatory drive in patients with chronic airflow obstruction. Chest 1989;95: Maltais 2001 {published data only} Maltais F, Simon M, Jobin J, Desmeules M, Sullivan MJ, Belanger M, Leblanc P. Effects of oxygen on lower limb blood flow and O2 uptake during exercise in COPD. Medicine & Science in Sports & Exercise 2001;33(6): Mannix 1992 {published data only} Mannix ET, Manfredi F, Palange P, Dowdeswell IR, Farber MO. Oxygen may lower the O2 cost of ventilation in chronic obstructive lung disease. Chest 1992;101: McDonald 1995 {published data only} Mc Donald CF, Blyth CM, Lazarus MD, Marschner I, Barter CE. Exertional oxygen of limited benefit in patients with chronic obstructive pulmonary disease and mild hypoxemia. American Journal of Respiratory and Critical Care Medicine 1995;152: McKeon 1988 {published data only} McKeon JL, Tarrant EP, Tomlinson JC, Mitchell CA. Poratble oxygen in patients with severe chronic obstructive pulmonary disease. Australian New Zealand Journal of Medicine 1988;18: O Donnell 1997 {published data only} O Donnell DE, Bain DJ, Webb KA. Factors contributing to relief of exertional breathlessness during hyperoxia in chronic airflow limitation. American Journal of Respiratory and Critical Care Medicine 1997;155: O Donnell 2001 {published data only} O Donnell DE, D Arsigny C, Webb KA. Effects of hyperoxia on ventilatory limitation during exercise in advanced chronic obstructive pulmonary disease. American Journal of Respiratory and Critical Care Medicine 2001;163: Palange 1995 {published data only} Palange P, Galassetti P, Mannix ET, Farber MO, Manfredi F, Serra P, Caarlone S. Oxygen effect on O2 deficit and VO2 kinetics during exercise in obstructive pulmonary disease. Journal of Applied Physiology 1995;78: Raimondi 1970 {published data only} Raimondi AC, Edwards RHT, Denison DM, Leaver DG, Spencer RG, Siddorn JA. Exercise tolerance breathing a low density gas mixture, 35% oxygen and air in patients with chronic obstructive bronchitis. Clinical Science 1970;39: Somfay 2001 {published data only} Somfay A, Porszasz J, Lee SM, Casaburi R. Dose-response effect of oxygen on hyperinflation and exercise endurance in nonhypoxaemic COPD patients. European Respiratory Journal 2001;18: Stein 1982 {published data only} Stein DA, Bradley BL, Miller WC. Mechanisms of oxygen effects on exercise in patients with chronic obstructive pulmonary disease. Chest 1982;81:6 10. Swinburn 1984 {published data only} Swinburn CR, Wakefield JM, Jones PW. Relationship between ventilation and breathlessness during exercise 15

19 in chronic obstructive airways disease is not altered by prevention of hypoxaemia.. Clinical Science 1984;67: Vyas 1971 {published data only} Vyas MN, Banister EW, Morton JW, Grzybowski S. Response to exercise in patients with chronic airway obstruction. American review of Respiratory Disease 1971; 103: Wadell 2001 {published data only} Wadell K, Henriksson-Larsen K, Lundgren R. Physical training with and without oxygen in patients with Chronic Obstructive Pulmonary Disease and exercise induced hypoxaemia. Journal of Rehabilitation and Medicine 2001; 33: Woodcock 1981 {published data only} Woodcock AA, Gross ER, Geddes DM. Oxygen relieves breathlessness in pink puffers. The Lancet 1981: References to studies excluded from this review Arlati 1988 {published data only} Arlati S, Rolo J, Micallef E, Sacerdoti C, Brambilla I. A reservoir nasal cannula improves protection given by oxygen during muscular exercise in COPD. Chest 1988;93: Barach 1966 {published data only} Barach AL. Oxygen supported exercise and rehabilitation of patients with chronic obstructive lung disease. Annals of Allergy 1966;24: Bower 1988 {published data only} Bower JS, Brook CJ, Zimmer K, Davies D. [Performance of a demand oxygen saver system during rest, exercise and sleep in hyoxemic patients]. Chest 1988;94: Brambilla 1985 {published data only} Brambilla I, Arlati S, Micallef E, Sacerdoti C, Rolo J. [A portable oxygen system corrects hypoxemia without significantly increasing metabolic demands]. American Reviews of Respiratory Disease 1985;131(1):51 3. Braun 1992 {published data only} Braun SR, Spratt G, Scott GC, Ellersieck M. [Comparison of six oxygen delivery systems for COPD patients at rest and during exercise]. Chest 1992;102: Corriveau 1989 {published data only} Corriveau ML, Rosen BJ, Dolan GF. Oxygen transport and oxygen consumption during supplemental oxygen administration in patients with chronic obstructive pulmonary disease. The American Journal of Medicine 1989; 87: Cotes 1956 {published data only} Cotes JE, Gilson JC. [Effect of oxygen on exercise ability in chronic respiratory insufficiency]. The Lancet 1956;June: Cotes 1963 {published data only} Cotes JE, Pisa Z, Thomas AJ. Effect of breathing oxygen upon cardiac output, heart rate, ventilation, systemic and pulmonary blood pressure in patients with chronic lung disease. Clinical Science 1963;25: Cuvelier 2002 {published data only} Cuvelier A, Nuir JF, Chakroun N, Aboab J, Onea G, Benhamou D. [Refillable oxygen cylinders may be an alternative for ambulatory oxygen therapy in COPD]. Chest 2002;122: Eaton 2001 {published data only} Eaton TE, Grey C, Garrett JE. An evaluation of shortterm oxygen therapy: the prescription of oxygen to patients with chronic lung disease hypoxic at discharge. Respiratory Medicine 2001;95: Emtner 2002 {published data only} Emtner M, Porszasz J, Burns M, Somfay A, Casaburi R. Benefits of supplemental oxygen in exercise training in nonhypoxemic chronic obstructive pulmonary disease. American Journal of Respiratory and Critical Care Medicine 2003;168: Guyatt 2001 {published data only} Guyatt G, McKim D, Weaver B, Austin P, Bryan R, Walter S, et al.[development and testing of formal protocols for oxygen prescribing]. American Journal of Respiratory and Critical Care Medicine 2001;163(4): Hargarty 1997 {published data only} Hagarty EM, Skorodin MS, Langein WE, Hultman CI, Jessen JA, Maki KC. [Comparison of three oxygen delivery systems during exercise in hypoxemic patients with chronic obstrucitve pulomonary disease]. Amercian Journal of Respiratory and Critical Care Medicine 1997;155: Jolly 2001 {published data only} Jolly EC, Di Boscio V, Aguirre L, Lun CM, Berensztein S, Gene RJ. [Effects of supplemental oxygen during activity in patients with advanced COPD without severe resting hypoxemia]. Chest 2001;120: Lacasse 2003 {published data only} Lacasse Y, Lecours R, Pelletier C, Begin R, Maltais F. [Oxygene de deambulation chez les MPOC oxygeno dependants: essai clinique randomise.]. Abreges de communication. Reunion annuelle conjointe: APPQ et Reseau en sante respiratoire du FRSQ, november 14-15, Quebec : Centre des congres de Quebec; Lane 1987 {published data only} Lane R, Cockcroft A, Adams L, Guz A. [Arterial oxygen saturation and breathlessness in patients with chronic obstructive airways disease]. Clinical Science 1987;72: Lilker 1975 {published data only} Lilker ES, Karnick A, Lerner L. [Portable oxygen in chronic obstructive lund disease with hypoxemia and cor pulmonale]. Chest 1975;68: Lock 1991 {published data only} Lock SH, Paul EA, Rudd RM, Wedzicha JA. Portable oxygen therapy: assessment and usage. Respiratory Medicine 1991;85:

20 Lock 1992 {published data only} Lock SH, Blower G, Prynne J, Wedzicha JA. [Comparison of liquid and gaseous oxygen for domicilary portable use]. Thorax 1992;47: Patessio 1996 {published data only} Patessio A, Casaburi R, Carone M, Appendini L, Purro A, Gudjonsdottir M, Donner CF, Wasserman K. Exercise capacity in COPD patients. European Respiratory Journal 1996;23:379s. Pierce 1965 {published data only} Pierce AK, Paez PN, Miller WF. Exercise training with the aid of a portable oxygen supply in patients with emphysema. The American Review of Respiratory Diseases 1965;91: Revill 2000 {published data only} Revill SM, Singh SJ, Morgan DL. [Randomized controlled trial of ambulatory oxygen and an ambulatory ventilator on endurance exercise in COPD]. Respiratory Medicine 2000; 94: Roberts 1996 {published data only} Roberts CM, Bell J, Wedzicha JA. [Comparison of the efficacy of a demand oxygen delivery system with continuous low flow oxygen in subjects with stable COPD and severe oxygen desaturation on walking]. Thorax 1996; 51: Rooyackers 1997 {published data only} Rooyackers JM, Dekhuijzen PNR, Van Herwaarden CLA, Folgering HTM. [Training with supplemental oxygen in patients with COPD and hypoxaemia at peak exercise]. European Respiratory Journal 1997;10: Scano 1982 {published data only} Scano G, Meerhaeghe V, Willeput R, Vachaudez JP, Sergysels R. Effect of oxygen on breathing during exercise in patients with chronic obstructive pulmonary disease. European Journal of Respiratory Disease 1982;63: Tiep 2002 {published data only} Tiep BL, Barnett J, Schiffman G, Sanchez O, Carter R. [Maintaining oxygenation via demand oxygen delivery during rest and exercise]. Respiratory Care 2002;47: Vergeret 1989 {published data only} Vergeret J, Brambilla C, Mounier L. [Portable oxygen therapy: use and benefit in hypoxaemic COPD patients on long term oxygen therapy.]. European Respiratory Journal 1989;2(1):20 5. Waterhouse 1983 {published data only} Waterhouse JC, Howard P. [Breathlessness and portable oxygen in chronic obstructive airways and disease]. Thorax 1983;38: Wedzicha 1996 {published data only} Wedzicha JA. [Ambulatory oxygen in chronic obstructive pulmonary disease]. Monaldi Archives of Chest Disease 1996; 51: Additional references ATS 1995 ATS. Standards for the Diagnosis and Care of Patients with Chronic Obstructive Pulmonary Disease. Am J Respir Crit care Med 1995;152:S77 S120. ATS 2002 ATS ATS statement guidelines for the six minute walk test. Am J Resp Crit Care Med 2002;166: BTS 1997 British Thoracic Society. COPD Guidelines Summary. Thorax 1997;52:S1 S32. BTS 2004 British Thoracic Working Group on Home Oxygen services. Clinical component for the home oxygen servive in England and Wales. content.asp? pageid= Crockett 2000 Crockett AJ, Cranston JM, Moss JR, Alpers JH. Domiciliary oxygen for chronic obstructive pulmonary disease [Cochrane Review]. Cochrane Library 2000, Issue 1. Curtin 2002 Curtin F, Altman DG, Elbourne D. Meta-analysis combining parallel and cross over trials.. Statistics in Medicine 2002;21: DOH medicinespharmacyandindustry/prescriptions. Elbourne 2002 Elbourne DR, Altman DG, Higgins JPT, Curtin F, Worthington HV, Vail A. Meta-analyses involving cross-over trials: methodological issues.. International Epidemiological Association 2002;31: GOLD 2001 GOLD. Global iniative for chronic obstructive lung diseases (GOLD): time to act. Eur Resp Journal 2001;81: Jadad 1996 Jadad AK, Moore A, Carroll D, et al.assessing quality of reports of randomised controlled trials: is blinding necessary. Controlled Clinical Trials 1996;17:1 12. Law 2004 Law S, Lehoux P. [Hospital Technology at Home: Portable Oxygen Therapy in COPD. Report prepared by Susan Law and Pascale Lehoux]. Agence d evaluation des technologies et des modes d intervention en sante (AETMIS) Marques 1998 Marques-Magallanes JA, Storer TW, Cooper CB. Treadmill exercise duration and dyspnea recovery time in chronic pulmonary disease: effects of oxygen breathing and repeated testing.. Respiratory Medicine 1998;92: Moseley 1999 Moseley A, Sherrington C, Herbet R, Maher C. Reliability of a scale for measuring the methodological quality of clinical trials. Proceedings of the Cochrane Colloquium October