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Key Messages Treatment with an ACE-I/angiotensin receptor blocker is associated with higher fat free mass in people with COPD. Neither treatment with ACE-I/angiotensin receptor blocker nor ACE (I/D) polymorphism appear to influence response to pulmonary rehabilitation. Background Skeletal muscle impairment is a common and important feature of chronic obstructive pulmonary disease (COPD), occurring in about one-third of patients irrespective of the severity of their airflow obstruction.1–3 It is associated with reduced exercise capacity,4 as well as impaired quality of life,5 and quadriceps weakness has been shown to predict mortality in COPD independent of lung function.6 Physical inactivity is clearly a key driver of muscle weakness in COPD,3 7 8 although other factors, for example inflammation, hypoxia and hormonal factors, as well as genetic predisposition, may be important.5 9–11 Moreover, there is strong evidence that pulmonary rehabilitation (PR), a programme of supervised exercise and education, can produce significant improvements in quality of life, muscle strength and endurance, as well as exercise capacity, in patients with COPD.12 13

ll as genetic predisposition, may be important.5 9–11 Moreover, there is strong evidence that pulmonary rehabilitation (PR), a programme of supervised exercise and education, can produce significant improvements in quality of life, muscle strength and endurance, as well as exercise capacity, in patients with COPD.12 13 The circulating (endocrine) renin–angiotensin system (RAS) plays an important role in circulatory homeostasis, degrading vasodilator bradykinin and synthesising vasoconstrictor (and renal sodium-retaining) angiotensin II. However, local RAS also exists in diverse tissues14 including skeletal muscle.15 The presence (insertion, I) rather than the absence (deletion, D) of a 287 base pair sequence in intron 16 of the human ACE inhibitors gene is associated with lower tissue16 17 and circulating ACE activity.18 19 In turn, an extensive literature supports an association between ACE genotype and physical performance, the I allele being associated with endurance performance, and the D with power/sprint performance.19 20 The ACE (I/D) polymorphism, as well as polymorphisms of genes for bradykinin type 2 (BK(2)R) and vitamin D receptors, have been shown to influence strength and body composition in COPD.9–11 Furthermore, ACE-I use in patients with hypertension has been associated with preservation of quadriceps strength and walking speed compared to those on other medications or controls.21

genes for bradykinin type 2 (BK(2)R) and vitamin D receptors, have been shown to influence strength and body composition in COPD.9–11 Furthermore, ACE-I use in patients with hypertension has been associated with preservation of quadriceps strength and walking speed compared to those on other medications or controls.21 Given these data, we wished to establish whether factors known to affect RAS activity might influence response to PR in patients with COPD. We investigated this by conducting two studies. The first explored the impact of the ACE (I/D) polymorphism on responses to PR in patients with COPD. The second, in a separate cohort, investigated the effects of concomitant ACE-I or angiotensin II receptor blocker (ARB) use in patients with COPD, testing the hypothesis that this would be associated with preserved fat free mass (FFM) and an enhanced response to PR.

lymorphism on responses to PR in patients with COPD. The second, in a separate cohort, investigated the effects of concomitant ACE-I or angiotensin II receptor blocker (ARB) use in patients with COPD, testing the hypothesis that this would be associated with preserved fat free mass (FFM) and an enhanced response to PR. Methods Study 1, investigating the effect of ACE genotype, was approved by the Ethics Committee of King's College Hospital (05/Q0703/134) and funded by The British Lung Foundation and started in 2004. Participants provided written informed consent. The study was retrospective and involved contacting patients with a clinical diagnosis of COPD who had completed a PR programme at King's College or Royal Brompton and Harefield Hospitals. The PR programmes consisted of an 8 week course of aerobic and strength activities with two supervised and one or more home sessions per week. The initial exercise prescription was based on the outcome of their baseline incremental shuttle walk test distance (ISWD),22 and workloads were increased through the programme as tolerated. Programmes were multidisciplinary with an educational component covering issues including exercise, medication use, diet and coping strategies. Patients with COPD who attended at least 75% of their scheduled rehabilitation sessions and had ISWD measured pre-rehabilitation and immediately post-rehabilitation were invited to take part. Either a blood sample or a mouth swab was obtained from each patient to collect cells from which the PCR was used to determine ACE genotype.11 None of the patients or clinical research staff involved in the study knew the genotype of participants until after the phenotypic outcomes database had been finalised.

ke part. Either a blood sample or a mouth swab was obtained from each patient to collect cells from which the PCR was used to determine ACE genotype.11 None of the patients or clinical research staff involved in the study knew the genotype of participants until after the phenotypic outcomes database had been finalised. The association of ACE genotype with baseline characteristics and response to PR was assessed across all three genotypes by ANOVA and also between those with or without the D or I allele by unpaired t-test. The primary end point was change in ISWD immediately after PR. A p value of <0.05 was taken as significant and StatView 4.0 used for analysis. In study 2, routinely collected data from a different cohort of patients with COPD who had been referred for a course of PR at Harefield Hospital between 2009 and 2011 were used. The Ethics Committee of Royal Brompton Hospital has determined that ethical approval is not required for the retrospective analysis of routinely collected clinical data. The primary outcome was differences in the response to PR of ISWD between patients who were or were not on an ACE-I or ARB (determined by patient self-report). Additional outcomes were fat free mass index (FFMI) determined by bioelectrical impedance analysis using a disease-specific regression equation,23 and the chronic respiratory disease questionnaire (CRQ)24 and the COPD assessment test score (CAT).13 25 Data from 72 of the patients in study 2 were included in a previous publication.13

comes were fat free mass index (FFMI) determined by bioelectrical impedance analysis using a disease-specific regression equation,23 and the chronic respiratory disease questionnaire (CRQ)24 and the COPD assessment test score (CAT).13 25 Data from 72 of the patients in study 2 were included in a previous publication.13 Results Study 1: effect of ACE genotype on response to PR Data were available for 168 individuals who had participated in PR; 92 (53.8%) women, forced expiratory volume in one second (FEV1) 51.9 (22.7)% predicted. ACE genotypes were DD 48 (28%); ID 91 (53%); II 29 (19%) (table 1). There was no significant difference in patients' characteristics by ACE genotype either across all three possible genotypes (figure 1) or comparing those with or without an I or a D allele. Exercise capacity improved following PR in the whole study population with a mean increase in ISWD of 67.5(74.7)m and for each genotype (all p<0.0001), but the response did not differ significantly between genotypes (ANOVA, p=0.5). Table 1 Study 1: patient characteristics for whole group and separated by ACE genotype

Results Study 1: effect of ACE genotype on response to PR Data were available for 168 individuals who had participated in PR; 92 (53.8%) women, forced expiratory volume in one second (FEV1) 51.9 (22.7)% predicted. ACE genotypes were DD 48 (28%); ID 91 (53%); II 29 (19%) (table 1). There was no significant difference in patients' characteristics by ACE genotype either across all three possible genotypes (figure 1) or comparing those with or without an I or a D allele. Exercise capacity improved following PR in the whole study population with a mean increase in ISWD of 67.5(74.7)m and for each genotype (all p<0.0001), but the response did not differ significantly between genotypes (ANOVA, p=0.5). Table 1 Study 1: patient characteristics for whole group and separated by ACE genotype All n=168 DD n=48 (28%) ID n=91 (53%) II n=29 (19%) Age 68.7 (9.0) 69.2 (10.4) 67.8 (8.8) 71.0 (6.9) Gender (n(%) female) 92 (54.8) 23 (47.9) 52 (57.1) 15 (51.7) FEV1 (% predicted) 51.9 (22.7) 50.4 (22.3) 52.8 (24.4) 50.1 (18.7) FEV1/FVC (%) 48.1 (17.6) 48.0 (17.7) 48.7 (19.3) 46.2 (13.2) ISWD baseline (m) 251.4 (149.8) 261.7 (184.0) 253.0 (140.2) 223.4 (103.9) ISWD end (m) 318.9 (170.6) 331.0 (200.0) 313.6 (165.3) 301.7 (109.4) ΔISWD (m) 67.5 (74.7) 69.4 (66.6) 60.6 (76.2) 78.3 (78.2) ΔISWD (%) 43.3 (66.7) 45.6 (76.9) 36.0 (53.2) 59.2 (84.5) Values are mean (SD). All p>0.05 ANOVA across genotypes. FEV1, forced expiratory volume in one second; FVC, forced vital capacity; ISWD, incremental shuttle walk test distance.

All n=168 DD n=48 (28%) ID n=91 (53%) II n=29 (19%) Age 68.7 (9.0) 69.2 (10.4) 67.8 (8.8) 71.0 (6.9) Gender (n(%) female) 92 (54.8) 23 (47.9) 52 (57.1) 15 (51.7) FEV1 (% predicted) 51.9 (22.7) 50.4 (22.3) 52.8 (24.4) 50.1 (18.7) FEV1/FVC (%) 48.1 (17.6) 48.0 (17.7) 48.7 (19.3) 46.2 (13.2) ISWD baseline (m) 251.4 (149.8) 261.7 (184.0) 253.0 (140.2) 223.4 (103.9) ISWD end (m) 318.9 (170.6) 331.0 (200.0) 313.6 (165.3) 301.7 (109.4) ΔISWD (m) 67.5 (74.7) 69.4 (66.6) 60.6 (76.2) 78.3 (78.2) ΔISWD (%) 43.3 (66.7) 45.6 (76.9) 36.0 (53.2) 59.2 (84.5) Values are mean (SD). All p>0.05 ANOVA across genotypes. FEV1, forced expiratory volume in one second; FVC, forced vital capacity; ISWD, incremental shuttle walk test distance. Figure 1 Plot of change in incremental shuttle walk test following pulmonary rehabilitation according to ACE (insertion/deletion) polymorphism. A total of 168 COPD patients took part, DD 48 (28%); ID 91 (53%); II 29 (19%). The horizontal line represents median value. Boxes represent 25th/75th centiles; whiskers 10th/90th centiles (ANOVA, p=0.5).

incremental shuttle walk test following pulmonary rehabilitation according to ACE (insertion/deletion) polymorphism. A total of 168 COPD patients took part, DD 48 (28%); ID 91 (53%); II 29 (19%). The horizontal line represents median value. Boxes represent 25th/75th centiles; whiskers 10th/90th centiles (ANOVA, p=0.5). Study 2: effect of ACE-I or ARB on response to PR Baseline data from 373 consecutive COPD patients (213M:160F; mean age 68.3; median FEV1 41% predicted) referred to an outpatient PR programme were analysed (table 2). Of these, 130 reported taking either an ACE-I (n=82), ARB (n=45) or both (n=3). The groups had similar gender distribution and long-term oral corticosteroid use. Patients on ACE-I or ARB were older, had less severe airflow obstruction but similar values for ISWD, CRQ, Medical Research Council dyspnoea score (MRC) and CAT. However, the patients receiving ACE-I or ARB had significantly higher FFM and FFMI 17.8 kg/m2 (16.0, 19.8) versus 16.5 kg/m2 (14.9, 18.4) (p<0.0001 when adjusted for difference in FEV1 and age). Table 2 Study 2: baseline patient characteristics separated by whether patients were or were not taking an ACE-I or ARB.

Study 2: effect of ACE-I or ARB on response to PR Baseline data from 373 consecutive COPD patients (213M:160F; mean age 68.3; median FEV1 41% predicted) referred to an outpatient PR programme were analysed (table 2). Of these, 130 reported taking either an ACE-I (n=82), ARB (n=45) or both (n=3). The groups had similar gender distribution and long-term oral corticosteroid use. Patients on ACE-I or ARB were older, had less severe airflow obstruction but similar values for ISWD, CRQ, Medical Research Council dyspnoea score (MRC) and CAT. However, the patients receiving ACE-I or ARB had significantly higher FFM and FFMI 17.8 kg/m2 (16.0, 19.8) versus 16.5 kg/m2 (14.9, 18.4) (p<0.0001 when adjusted for difference in FEV1 and age). Table 2 Study 2: baseline patient characteristics separated by whether patients were or were not taking an ACE-I or ARB. ARB or ACE-I n=130 No ARB or ACE-I n=243 p Value Age (years) 71 (64, 78) 67.6 (9.8) 0.004 FEV1 (% predicted) 44.5 (32.3, 60.8) 39.0 (26.0, 58.5) 0.007 FFM (kg) 51.1 (11.2) 45.5 (40.1, 52.0) <0.001 FFMI (kg/m2) 17.8 (16.0, 19.8) 16.5 (14.9, 18.4) <0.001 ISWD (m) 140 (60, 250) 160 (80, 280) 0.10 CRQ 71.5 (55.8, 91.0) 68.0 (56.0, 87.0) 0.45 MRC dyspnoea score 4 (3, 5) 4 (3, 5) 0.79 CAT score 23.0 (8.0) 22.0 (7.0) 0.76 p Values are for unpaired t-tests. Data are presented as median (25th, 75th centiles) or (SD).

001 FFMI (kg/m2) 17.8 (16.0, 19.8) 16.5 (14.9, 18.4) <0.001 ISWD (m) 140 (60, 250) 160 (80, 280) 0.10 CRQ 71.5 (55.8, 91.0) 68.0 (56.0, 87.0) 0.45 MRC dyspnoea score 4 (3, 5) 4 (3, 5) 0.79 CAT score 23.0 (8.0) 22.0 (7.0) 0.76 p Values are for unpaired t-tests. Data are presented as median (25th, 75th centiles) or (SD). ACE-I, ACE inhibitor; ARB, AT II receptor antagonist; CAT, COPD assessment test score; CRQ, chronic respiratory disease questionnaire; FEV1, forced expiratory volume in one second; FVC, forced vital capacity; FFM, fat free mass; FFMI, fat free mass index; ISWD, incremental shuttle walk test distance. A total of 255 patients completed the PR programme, 76 (30%) of whom were taking an ACE-I/ARB. Responses did not differ between those who were or were not on an ACE-I or ARB (table 3), with improvements in ISWD and CRQ exceeding the minimum clinically important difference. Table 3 Study 2: response to pulmonary rehabilitation in COPD patients who were or were not taking an ACE-I or ARB. ARB or ACE-I n=76 No ARB or ACE-I n=179 p value ΔFFM (kg) −1.7 (2.7) 1.8 (1.4) 0.21 ΔISWD (m) 104 (21) 63 (15) 0.13 ΔCRQ 16.2 (3.8) 17.7 (2.5) 0.75 ACE-I, ACE inhibitors; ARB, AT II receptor antagonist; FFM, fat free mass; ISWD, incremental shuttle walk test distance; CRQ, chronic respiratory disease questionnaire. All p>0.05. Data are presented as mean (SD).

ARB or ACE-I n=76 No ARB or ACE-I n=179 p value ΔFFM (kg) −1.7 (2.7) 1.8 (1.4) 0.21 ΔISWD (m) 104 (21) 63 (15) 0.13 ΔCRQ 16.2 (3.8) 17.7 (2.5) 0.75 ACE-I, ACE inhibitors; ARB, AT II receptor antagonist; FFM, fat free mass; ISWD, incremental shuttle walk test distance; CRQ, chronic respiratory disease questionnaire. All p>0.05. Data are presented as mean (SD). Discussion The present data suggest that the beneficial response to PR in COPD patients was not strongly influenced by their ACE (I/D) genotype, or by pharmacological RAS antagonism. However, long-term use of an ACE-I/ARB was associated with relatively preserved FFM in patients referred for PR.

All p>0.05. Data are presented as mean (SD). Discussion The present data suggest that the beneficial response to PR in COPD patients was not strongly influenced by their ACE (I/D) genotype, or by pharmacological RAS antagonism. However, long-term use of an ACE-I/ARB was associated with relatively preserved FFM in patients referred for PR. Rationale for studying the RAS in COPD In patients with COPD, the quadriceps muscle displays muscle fibre atrophy and a shift away from an endurance phenotype, with a reduced proportion of type I slow twitch, fatigue-resistant fibres together with reduced capillarity and oxidative enzymes.26–30 The RAS and thus ACE inhibitors and functional ACE gene polymorphisms have the potential to influence these processes through a number of mechanisms. These include effects on muscle atrophy/hypertrophy signalling, fibre shift, systemic inflammation and remodelling.31 Angiotensin II opposes the action of the insulin-like growth factor (IGF-1) system activating the ubiquitin-proteasome proteolytic pathway via IGF-1 and via NF-kB,32 33 and IGF-1 levels are reduced in the quadriceps of COPD patients in the stable state compared to healthy controls.34 Increases in exercise capacity and fibre size in COPD patients undergoing PR are associated with upregulation of IGF-1 and its splice variant mechano-growth factor (MGF).35

y via IGF-1 and via NF-kB,32 33 and IGF-1 levels are reduced in the quadriceps of COPD patients in the stable state compared to healthy controls.34 Increases in exercise capacity and fibre size in COPD patients undergoing PR are associated with upregulation of IGF-1 and its splice variant mechano-growth factor (MGF).35 The I allele of the ACE gene polymorphism is associated with a higher proportion of type I fibres,36 and there is evidence that ACE inhibitors and AT II receptor antagonists interact with peroxisome proliferator-activated receptors (PPARs)37 38 which are major regulators of cell metabolism mediating type II (anaerobic) to type I (aerobic) fibre shift and regulate mitochondrial activity as well as muscle oxidative status.39–41 This is potentially of particular relevance in COPD given that PPAR-delta protein content is decreased in the skeletal muscle of these patients.42 The DD genotype has also been associated with systemic inflammation in COPD.43 In stable COPD patients, the deletion allele (D) of the ACE gene polymorphism has been associated with increased quadriceps strength, in contrast to age-matched healthy controls where this relationship was not observed.11 Effect of ACE inhibition in COPD In the present cross-sectional study, patients taking an ACE-I/ARB did have relatively preserved FFM, though this was not associated with differences in exercise capacity. Patients had not been randomly allocated to treatment so these data need to be treated with caution, but they are consistent with a beneficial effect of reduced ACE activity on body composition.44

aking an ACE-I/ARB did have relatively preserved FFM, though this was not associated with differences in exercise capacity. Patients had not been randomly allocated to treatment so these data need to be treated with caution, but they are consistent with a beneficial effect of reduced ACE activity on body composition.44 In keeping with this, in healthy older people the use of ACE-I as a treatment for hypertension is associated with relative preservation of lower limb muscle mass,45 and with a reduced rate of loss of knee extensor strength21 compared to patients using other antihypertensives or to those not treated for hypertension. The ACE-I perindopril has been shown to increase 6 min walk distance in older people.46 A small number of studies have investigated the effects of RAS inhibition in COPD patients.47–50 In one study captopril improved pulmonary haemodynamics during exercise in patients with the ID or II genotype47 though other studies have not found similar effects.51 52 A double-blind, placebo-controlled study by Di Marco et al evaluated the effects of 4 weeks treatment with enalapril on exercise performance in 21 COPD patients finding that it increased peak work rate in the treatment group compared to placebo, an effect not significantly modified by ACE genotype.53 A randomised controlled trial of fosinopril in 80 patients with COPD selected for quadriceps weakness found no benefit,49 and enalapril did not enhance the effect of PR on improvements in exercise performance in COPD.50 Of note, these two studies excluded people with a clinical indication for an ACE-I who, by definition, are the subject of the present paper.

ril in 80 patients with COPD selected for quadriceps weakness found no benefit,49 and enalapril did not enhance the effect of PR on improvements in exercise performance in COPD.50 Of note, these two studies excluded people with a clinical indication for an ACE-I who, by definition, are the subject of the present paper. Epidemiological data suggest a survival benefit in patients with COPD who are on an ACE-I.54 55 However, in the present study, treatment with an ACE-I was not associated with greater strength or exercise capacity. Interestingly, the patients on ACE-I/ARB had less severe airflow obstruction but similar health status and dyspnoea. It is therefore possible that comorbidities such as cardiac impairment were contributing to their overall symptom burden and exercise limitation which might have had an effect on response to PR. We found no association of the ACE(I/D) genotype with response to PR. This contrasts with Gosker et al who found, in a study of 95 COPD patients undergoing PR, that the improvement in peak VO2 during cycle ergometry was significantly less in patients with the DD genotype.56 However in that study, those with an I allele had a lower exercise capacity initially so may have been more detrained. The difference could also be due to the test modalities employed in the two studies (walking vs cycling) or a regression to the mean effect.

y was significantly less in patients with the DD genotype.56 However in that study, those with an I allele had a lower exercise capacity initially so may have been more detrained. The difference could also be due to the test modalities employed in the two studies (walking vs cycling) or a regression to the mean effect. Critique of methods Functional exercise capacity is an integrative end point subject to respiratory, cardiac, skeletal muscle and motivational limitation, so the absence of an apparent effect of ACE genotype or ACE-I on response does not preclude the possibility of some physiological impact which might have been more apparent with a more controlled exercise end point such as metabolic parameters at a particular workload. Since the RAS is active at a number of levels, it may be that impacts on muscle strength, muscle endurance and the systemic and pulmonary vascular system may have opposing effects which a walking test cannot separate.

arent with a more controlled exercise end point such as metabolic parameters at a particular workload. Since the RAS is active at a number of levels, it may be that impacts on muscle strength, muscle endurance and the systemic and pulmonary vascular system may have opposing effects which a walking test cannot separate. This paper addresses the question of whether either the genotype or treatment with drugs that influence the ACE system has an effect, in clinical practice, on outcome measures accepted as clinically relevant in international guidelines for PR—health status and exercise capacity assessed using a walking test.13 There is of course ongoing debate about the different information conveyed by laboratory and field tests of exercise performance as well as walking versus cycling, but there is certainly no reason to ascribe greater clinical relevance to VO2 max, etc than to performance on a field walking test when considering daily physical activity or patient-relevant outcomes.

ifferent information conveyed by laboratory and field tests of exercise performance as well as walking versus cycling, but there is certainly no reason to ascribe greater clinical relevance to VO2 max, etc than to performance on a field walking test when considering daily physical activity or patient-relevant outcomes. Patient recruitment for the genotyping study was retrospective, so it is conceivable that some survival or other bias was in operation. Genotype data were not available for the cohort in study 2, so it is not possible to comment on possible interactions between genotype and treatment with ACE-I/ARB. It is possible that disease processes for which RAS antagonists were prescribed were themselves associated with differences in body composition. All participants were taking part in clinical PR programmes and data were entered prospectively, but because they were clinical programmes the full range of possible phenotypes were not recorded as might have been the case in a prospective study, such as exacerbation frequency and multimorbidities, as well as more detailed lung function parameters or gas transfer.57 Patient treatments were based on self-report, so it is possible that an effect of ACE-I or ARB was underestimated because of poor compliance with medication.

Patient recruitment for the genotyping study was retrospective, so it is conceivable that some survival or other bias was in operation. Genotype data were not available for the cohort in study 2, so it is not possible to comment on possible interactions between genotype and treatment with ACE-I/ARB. It is possible that disease processes for which RAS antagonists were prescribed were themselves associated with differences in body composition. All participants were taking part in clinical PR programmes and data were entered prospectively, but because they were clinical programmes the full range of possible phenotypes were not recorded as might have been the case in a prospective study, such as exacerbation frequency and multimorbidities, as well as more detailed lung function parameters or gas transfer.57 Patient treatments were based on self-report, so it is possible that an effect of ACE-I or ARB was underestimated because of poor compliance with medication. Conclusions Although treatment with an ACE-I/ARB was associated with a higher FFM in patients with COPD, neither the ACE (I/D) polymorphism nor treatment with an ACE/ARB appear to influence response to PR despite previous data showing an association with quadriceps strength. Although trial data do not support a beneficial effect from the addition of an ACE-I in COPD patients who do not have a conventional clinical indication,49 50 the present data do not suggest that there is any advantage to avoiding or stopping ACE-I in COPD patients in whom they are indicated.

with quadriceps strength. Although trial data do not support a beneficial effect from the addition of an ACE-I in COPD patients who do not have a conventional clinical indication,49 50 the present data do not suggest that there is any advantage to avoiding or stopping ACE-I in COPD patients in whom they are indicated. The study was funded by a Trevor Clay grant from The British Lung Foundation (TC 04/4) and supported by the NIHR Respiratory Biomedical Research Unit at Royal Brompton and Harefield Hospital and Imperial College who part fund MIP's salary. WD-CM is an NIHR Clinician Scientist and supported by a MRC New Investigator Research Grant. DS was funded by the MRC G0701628. ZP is a NIHR Doctorate Research Fellow. SSCK and CJJ were funded by the MRC. Contributors: NSH, WD-CM, HM, MIP and JM conceived the study. SSCK, CJJ and DS collected data. JRAS and ZP performed genotyping. NSH and SSCK produced the first draft which all authors subsequently contributed to and approved in this final version. NSH is guarantor for the study. Funding: Medical Research Council (grant number G0701628) and British Lung Foundation (grant number TC 04/4). Competing interests: HM has held a consultancy with ARK therapeutics relating to ACE-I and muscle efficiency. The other authors have no conflicts of interest to declare. Ethics approval: Ethics Committee of King's College Hospital (05/Q0703/134). Provenance and peer review: Not commissioned; externally peer reviewed. Data sharing statement: Requests for data sharing can be made to the corresponding author.

Key messages This survey identifies differences in National Health Service staff attitudes to flu vaccination that are strongly associated with vaccination uptake. The responses from this survey identify potential barriers to vaccination and suggest that action should focus on increasing the convenience of vaccination for staff, while also addressing beliefs that the vaccine will make recipients unwell. Wider availability of the vaccination on wards, a greater emphasis on identifying staff role models and better provision of information geared towards the concerns of particular staff groups, may help to increase vaccination uptake. Introduction Annual vaccination against influenza (flu) is recommended for all staff working in the UK National Health Service (NHS) to help reduce the risk of contracting the virus and transmitting it to patients.1 Around 23% of healthcare workers may become infected with flu during a mild flu season and, of these, 28–59% will have subclinical illness.2 3 Healthcare workers therefore represent an important vector for transmission to patients. Importantly, in a cluster randomised controlled trial, flu vaccination of care home staff has been found to reduce mortality, morbidity and health service use among residents.4 However, vaccination uptake in England for the last flu season (2013–2014) was only 54.8% for healthcare workers with direct patient contact.5 By NHS trust, the median was 53.5% with an IQR of 43–65.6%.

vaccination of care home staff has been found to reduce mortality, morbidity and health service use among residents.4 However, vaccination uptake in England for the last flu season (2013–2014) was only 54.8% for healthcare workers with direct patient contact.5 By NHS trust, the median was 53.5% with an IQR of 43–65.6%. Methods We investigated whether staff attitudes to flu vaccination were associated with their decision to be vaccinated. An online survey was sent to staff members across six NHS trusts during the period May–December 2014. The survey, which used SurveyMonkey (Palo Alto, California, USA), was developed using items derived from a previous review of health worker attitudes to vaccination6 and then revised by consensus discussion among members of the London Respiratory Network. The survey asked if staff had been vaccinated in the preceding flu season, and included 19 questions about beliefs and attitudes to the vaccination scored on a five-point Likert scale (table 1). The questions were presented to participants in a random order. Statistical analysis was performed using SPSS statistics V.21 (IBM). Data are shown as median and IQR. Non-parametric analysis was conducted using χ2 and Kruskal-Wallis tests. For analysis by NHS role, staff were divided into four groups: doctors, nurses, clerical staff and other members of staff. Regression analysis was performed using multivariate logistic regression. Survey responses with a p value of ≤0.01 were considered significant and were then entered into a stepwise regression model.

or analysis by NHS role, staff were divided into four groups: doctors, nurses, clerical staff and other members of staff. Regression analysis was performed using multivariate logistic regression. Survey responses with a p value of ≤0.01 were considered significant and were then entered into a stepwise regression model. Table 1 Survey responses in flu vaccinated and unvaccinated National Health Service (NHS) staff

or analysis by NHS role, staff were divided into four groups: doctors, nurses, clerical staff and other members of staff. Regression analysis was performed using multivariate logistic regression. Survey responses with a p value of ≤0.01 were considered significant and were then entered into a stepwise regression model. Table 1 Survey responses in flu vaccinated and unvaccinated National Health Service (NHS) staff Survey statement (1—strongly agree, 5—strongly disagree) Vaccinated median (IQR) (n=2073) Unvaccinated group median (IQR) (n=986) Multivariate logistic regression (p value) It was easy for me to get the flu vaccine where I work 1 (1–2) 2 (1–3) <0.001 Flu vaccination for staff is seen as important where I work 2 (1–2) 2 (2–3) 0.48 The flu vaccine will protect me from getting flu 2 (1–2) 3 (2–4) <0.001 I am confident advising patients about the flu vaccination 2 (2–3) 3 (2–4) 0.01 Having the flu vaccination sets a good example to patients 2 (1–2) 3 (2–4) 0.04 The flu vaccination will make me unwell 4 (4–5) 3 (2–4) <0.001* I am likely to come to work even if I am unwell 2 (2–3) 2 (2–4) 0.02 I think flu vaccination should be mandatory for NHS staff 2 (2–4) 4 (3–5) 0.02 My line manager encouraged me to get vaccinated 2 (2–4) 3 (2–4) 0.001 I worry that the flu vaccination will cause serious side effects 4 (4–5) 3 (2–4) 0.54 Getting a flu vaccination is too much trouble for me 5 (4–5) 4 (4–4) <0.001* It is important to help colleagues by not being off work with flu 2 (1–2) 2 (2–3) 0.03 I am put off having flu vaccination by fear of needles 5 (4–5) 5 (4–5) 0.25 I cannot have flu vaccination because I am allergic 5 (4–5) 5 (4–5) 0.88 People working in healthcare should have the flu vaccination every year 2 (1–2) 3 (2–4) <0.001* The flu vaccine will protect my family from getting flu 2 (2–3) 3 (2–4) 0.03 The flu vaccine will protect patients from getting flu 2 (1–2) 2 (2–3) 0.01 Flu is a serious disease 2 (1–2) 2 (2–3) 0.96 I am at risk of getting flu 2 (1–3) 3 (2–4) <0.001 The p values are shown for multivariate logistic regression that had an r2 of 0.60 for the association between survey variables and having had the flu vaccination. Variables with p≤0.01 from the logistic regression were then entered into a stepwise model, with those retained marked by *.

ting flu 2 (1–3) 3 (2–4) <0.001 The p values are shown for multivariate logistic regression that had an r2 of 0.60 for the association between survey variables and having had the flu vaccination. Variables with p≤0.01 from the logistic regression were then entered into a stepwise model, with those retained marked by *. Results Three thousand and fifty-nine NHS staff members responded to the survey, with 2616 (86%) in the 26–59 age group, 2353 (77%) female and 2561 (84%) hospital based. Survey responders included 639 nurses (21%), 562 clerical staff (18%) and 526 doctors (17%), with further roles detailed in table 2. Two thousand and seventy-three members of staff (68%) reported being vaccinated in the preceding year. There was a significant difference in vaccination rate between the staff groups (p<0.001), with doctors the most likely to have been vaccinated (doctors 72%, nurses 65%, clerical 63%, other staff members 68%). Table 2 National Health Service (NHS) roles of survey responders

Results Three thousand and fifty-nine NHS staff members responded to the survey, with 2616 (86%) in the 26–59 age group, 2353 (77%) female and 2561 (84%) hospital based. Survey responders included 639 nurses (21%), 562 clerical staff (18%) and 526 doctors (17%), with further roles detailed in table 2. Two thousand and seventy-three members of staff (68%) reported being vaccinated in the preceding year. There was a significant difference in vaccination rate between the staff groups (p<0.001), with doctors the most likely to have been vaccinated (doctors 72%, nurses 65%, clerical 63%, other staff members 68%). Table 2 National Health Service (NHS) roles of survey responders NHS role Number of survey responders (%) Nurses 639 (20.9) Clerical 562 (18.4) Doctors 526 (17.2) Managers 257 (8.5) Healthcare scientists 125 (4.1) Midwives 105 (3.4) Healthcare assistants 101 (3.3) Physiotherapists 86 (2.8) Pharmacists 63 (2.1) Radiographers 47 (1.5) Ambulance staff/paramedics 41 (1.3) Occupational therapists 35 (1.1) Dieticians 35 (1.1) Speech and language therapists 27 (0.9) Porters 9 (0.3) Others 401 (13.1) All 19 survey responses differed significantly between the vaccinated and not vaccinated groups in bivariate analysis (χ2 p<0.001), and therefore these were all entered into the multivariate logistic regression shown in table 1. Vaccinated individuals were significantly more likely to agree that healthcare workers should have the vaccination every year and that it was easy to get the flu vaccination where they worked (p<0.001). They felt more confident in advising patients about being vaccinated (p=0.01), and felt the flu vaccination would protect their patients (p=0.01) and themselves (p<0.001) from getting flu. Staff who had not had the flu vaccination were more likely to respond that it was too much trouble to get the vaccination, felt less at risk of getting flu, and thought the vaccination would make them feel unwell (p<0.001). In a stepwise regression model, the survey response retained as a positive predictor of those who had been vaccinated was; ‘people working in healthcare should have the flu vaccination every year’ (p<0.001), and the responses retained as negative predictors were ‘the flu vaccination will make me unwell’ (p<0.001) and ‘the flu vaccination was too much trouble for me’ (p<0.001).

d as a positive predictor of those who had been vaccinated was; ‘people working in healthcare should have the flu vaccination every year’ (p<0.001), and the responses retained as negative predictors were ‘the flu vaccination will make me unwell’ (p<0.001) and ‘the flu vaccination was too much trouble for me’ (p<0.001). The three independent predictors were then analysed by staff group. There was a significant difference in the response to ‘the flu vaccination will make me unwell’ between groups (p=0.01), with doctors having a greater tendency to disagree with this statement than other staff members. No significant difference was found in the responses to ‘people working in healthcare should have the flu vaccination every year’ (p=0.08) and ‘the flu vaccination was too much trouble for me’ (p=0.72) between the staff groups. Discussion This survey identifies differences in NHS staff attitudes to flu vaccination that are strongly associated with vaccination uptake. The unpredictable nature of the flu makes it difficult to forecast severity and timing from year to year. However, a successful flu vaccination programme will help to protect staff, reducing the risk of transmission to patients in their care who may not have been vaccinated. The responses from this survey identify potential barriers to vaccination and suggest that action should focus in particular on increasing the convenience of vaccination for staff, while also addressing beliefs that the vaccine will make recipients unwell.

ion to patients in their care who may not have been vaccinated. The responses from this survey identify potential barriers to vaccination and suggest that action should focus in particular on increasing the convenience of vaccination for staff, while also addressing beliefs that the vaccine will make recipients unwell. There is some variation in attitudes between staff groups, which may be relevant for developing approaches to improve uptake. Non-medical staff may have a greater need for specific information and reassurance regarding concerns associated with vaccination. For all staff groups, a belief in the need for vaccination was associated with having been vaccinated and, importantly, ease of access to vaccination was also a consistent issue. Wider availability of the vaccination on wards and in other areas where staff work, as well as a greater emphasis on identifying staff role models, may help to increase uptake.

he need for vaccination was associated with having been vaccinated and, importantly, ease of access to vaccination was also a consistent issue. Wider availability of the vaccination on wards and in other areas where staff work, as well as a greater emphasis on identifying staff role models, may help to increase uptake. Methodological issues Over 3000 staff members responded to this survey, however, a larger survey response population would have allowed further subgroup analysis, particularly in relation to individual NHS trusts. The overall vaccination rate in our sample population was higher (68%) than in the general population of frontline healthcare workers (54.8%).5 Interestingly, the figures for staff groups were consistent with national data, with doctors having a higher vaccination rate than hospital nurses, suggesting that the findings are likely to be representative. Although all responses differed individually between vaccinated and unvaccinated groups, there is a potential for confounding in the survey statements. We therefore used regression analysis to identify independent variables and only those with a significant p value of ≤0.01 were entered into the final stepwise regression model.

all responses differed individually between vaccinated and unvaccinated groups, there is a potential for confounding in the survey statements. We therefore used regression analysis to identify independent variables and only those with a significant p value of ≤0.01 were entered into the final stepwise regression model. Concerning the validity of the questionnaire, it was based on items identified in a previous review of healthcare workers’ attitudes,6 and on an expert consensus process, suggesting that it is likely to have captured relevant areas. In general, there is an uncertain relationship between attitudes and behaviour. The data in this study relate present attitudes to a past behaviour (having been vaccinated), but we cannot assume that these attitudes will have the same association with future behaviour, and prospective studies are therefore needed. Conclusion Recent data from Public Health England for the flu season (2014–2015) reveal a vaccination rate of only 54.6% for frontline healthcare workers,7 showing no change from the previous season (54.8%).5 This suggests that more needs to be done to convey messages around flu vaccination to the healthcare community, and the present data may help to focus efforts to improve this in upcoming flu campaigns. Funding: The study was supported by The London Respiratory Network and NIHR Respiratory Biomedical Research Unit at Royal Brompton and Harefield NHS Foundation Trust and Imperial College. Competing interests: None declared. Provenance and peer review: Not commissioned; externally peer reviewed.

Conclusion Recent data from Public Health England for the flu season (2014–2015) reveal a vaccination rate of only 54.6% for frontline healthcare workers,7 showing no change from the previous season (54.8%).5 This suggests that more needs to be done to convey messages around flu vaccination to the healthcare community, and the present data may help to focus efforts to improve this in upcoming flu campaigns. Funding: The study was supported by The London Respiratory Network and NIHR Respiratory Biomedical Research Unit at Royal Brompton and Harefield NHS Foundation Trust and Imperial College. Competing interests: None declared. Provenance and peer review: Not commissioned; externally peer reviewed. Data sharing statement: No additional data are available.

Introduction BTS has been at the forefront of the production of guidelines for best clinical practice in respiratory medicine since the Society was established over 25 years ago. Guideline production methodology has evolved considerably in recent years, and a manual setting out the detailed policy for the production of BTS Guidelines is reviewed annually by the BTS Standards of Care Committee (SOCC).1 BTS Guidelines received National Institute for Health and Care Excellence (NICE) accreditation in 2011. The production of quality standards based on each BTS Guideline is a key part of the range of supporting materials that the Society produces to assist in the dissemination and implementation of a guideline’s recommendations. The purpose of the quality standards document is to provide healthcare professionals, commissioners, service providers and patients with a guide to standards of care that should be met for home oxygen provision in the UK, together with measurable markers of good practice. BTS Quality Standards are intended for:Healthcare professionals to allow decisions to be made about care based on the latest evidence and best practice. People with chronic respiratory disease and their families and carers to enable understanding of what services they should expect from their health and social care provider. Service providers to be able to quickly and easily examine the clinical performance of their organisation and assess the standards of care they provide. Commissioners so that they can be confident that the services they are purchasing are high quality and cost effective.

People with chronic respiratory disease and their families and carers to enable understanding of what services they should expect from their health and social care provider. Service providers to be able to quickly and easily examine the clinical performance of their organisation and assess the standards of care they provide. Commissioners so that they can be confident that the services they are purchasing are high quality and cost effective. NICE Quality Standards were used as a model for the development of BTS Quality Standards, and the development of these quality standards is based on the NICE Quality Standards Process Guide.2 This document contains quality standards for home oxygen in adults. This document was approved by the BTS SOCC in May 2017. A quality standard is a set of specific, concise statements that:act as markers of high-quality, cost-effective patient care across a pathway or clinical area, covering treatment or prevention are derived from the best available evidence. The rationale for these quality standards is drawn from evidence and recommendations summarised in the BTS Guideline on Home Oxygen Use in Adults, which was published in 2015 (http://www.brit-thoracic.org.uk/guidelines).3 Each quality standard includes the following:A quality statement, which describes a key marker of high-quality, cost-effective care for this condition. Quality measures, which aim to improve the structure, process and outcomes of healthcare

The rationale for these quality standards is drawn from evidence and recommendations summarised in the BTS Guideline on Home Oxygen Use in Adults, which was published in 2015 (http://www.brit-thoracic.org.uk/guidelines).3 Each quality standard includes the following:A quality statement, which describes a key marker of high-quality, cost-effective care for this condition. Quality measures, which aim to improve the structure, process and outcomes of healthcare The quality measures are not intended to be new sets of targets or mandatory indicators for performance management that need to be collected. The quality measures are specified in the form of a numerator and a denominator, which define a proportion or ratio (numerator/denominator). It is assumed that the numerator is a subset of the denominator population. The suggested numerator and denominator are provided to allow healthcare professionals and service providers to examine their clinical performance in relation to each quality standard. It is recognised that no national quality indicators will be available for this condition, and institutions will need to agree locally what information is required for the denominator to be used in each case and what the expected level of achievement should be, given local circumstances. A brief description about the quality standard in relation to each audience is given. The main source references for these Quality Standards are BTS Guideline on Home Oxygen Use in Adults, 2015.3 There is no specific order of priority associated with the list of quality standards.

The quality measures are not intended to be new sets of targets or mandatory indicators for performance management that need to be collected. The quality measures are specified in the form of a numerator and a denominator, which define a proportion or ratio (numerator/denominator). It is assumed that the numerator is a subset of the denominator population. The suggested numerator and denominator are provided to allow healthcare professionals and service providers to examine their clinical performance in relation to each quality standard. It is recognised that no national quality indicators will be available for this condition, and institutions will need to agree locally what information is required for the denominator to be used in each case and what the expected level of achievement should be, given local circumstances. A brief description about the quality standard in relation to each audience is given. The main source references for these Quality Standards are BTS Guideline on Home Oxygen Use in Adults, 2015.3 There is no specific order of priority associated with the list of quality standards. Method of working A Quality Standards Working Group was convened in November 2015 and met in March 2016. Table 1 shows the membership of the group. Table 1 Membership of the BTS Home Oxygen Quality Standard Development Group

The main source references for these Quality Standards are BTS Guideline on Home Oxygen Use in Adults, 2015.3 There is no specific order of priority associated with the list of quality standards. Method of working A Quality Standards Working Group was convened in November 2015 and met in March 2016. Table 1 shows the membership of the group. Table 1 Membership of the BTS Home Oxygen Quality Standard Development Group Name Dr Jay Suntharalingam Co-chair Consultant Respiratory Physician, Bath Professor Tom Wilkinson Co-chair Consultant Respiratory Physician, Southampton Joe Annandale ARNS representative Respiratory Nurse Specialist, Prince Philip Hospital, Wales Ms Claire Davey ACPRC representative Advanced Practitioner Home Oxygen Service, Mile End Hospital Ms Rhea Fielding ARTP representative Specialist Oxygen Respiratory Physiologist, University Hospitals of Coventry and Warwickshire Dr Daryl Freeman PCRS-UK representative General Practitioner, Norfolk Dr Michael Gibbons POSC representative Consultant Respiratory Physician, Royal Devon and Exeter Mr Christopher Gingell Lay representative Dr Maxine Hardinge Consultant Respiratory Physician, Oxford Dr Sabi Hippolyte Respiratory Specialty Trainee, Royal Brompton Hospital Mrs Vikki Knowles PCRS-UK representative Respiratory Nurse Consultant, Guildford and Waverley CCG Ms Cassie Lee ACPRC representative Lead Respiratory Physiotherapist, Community Cardio-Respiratory Service, Imperial College Healthcare NHS Professor William McNee Professor of Respiratory Medicine, Edinburgh Ms Jacqui Pollington Respiratory Nurse Specialist, Mid Yorkshire Hospitals Dr Vandana Vora APM representative Consultant in Palliative Medicine, Sheffield Teaching Hospitals Foundation Trust Mr Trefor Watts ARTP representative Principal Physiologist, Walsall Dr Meme Wijesinghe Consultant Respiratory Physician, Royal Cornwall Hospital ACPRC, Association of Chartered Physiotherapists in Respiratory Care; APM, Association of Palliative Medicine; ARNS, Association of Respiratory Nurse Specialists; ARTP, Association for Respiratory Technology and Physiology; PCRS-UK, Primary Care Respiratory Society UK.

ant Respiratory Physician, Royal Cornwall Hospital ACPRC, Association of Chartered Physiotherapists in Respiratory Care; APM, Association of Palliative Medicine; ARNS, Association of Respiratory Nurse Specialists; ARTP, Association for Respiratory Technology and Physiology; PCRS-UK, Primary Care Respiratory Society UK. Members of the Quality Standards Group submitted Declaration of Interest forms in line with the BTS policy, and copies of forms are available on request from BTS Head Office. The draft document was considered in detail by the BTS SOCC initially in November 2016 and the BTS Quality Improvement Committee (in March 2017). The document was made available on the BTS website for public consultation for the period from 11 January 2017 to 13 February 2017. Following further revision the document was submitted for approval to the BTS SOCC in May 2017. The quality Standards document will be reviewed in 2020, or following the publication of a revised guideline whichever is the sooner. List of quality statements

The document was made available on the BTS website for public consultation for the period from 11 January 2017 to 13 February 2017. Following further revision the document was submitted for approval to the BTS SOCC in May 2017. The quality Standards document will be reviewed in 2020, or following the publication of a revised guideline whichever is the sooner. List of quality statements 1. All patients should have home oxygen assessments carried out by a home oxygen assessment service that includes appropriately trained staff and appropriate equipment. 2. All patients being assessed for home oxygen should undergo a risk assessment that includes assessment of individual and household member smoking status, and other household risks of fire, trips and falls. 3. All patients initiated on home oxygen should have appropriate education and written information provided by a specialist home oxygen assessment team. 4. Patients with advanced stable cardiorespiratory disease who have resting saturations on air that meet the qualifying criteria should be referred for a long-term oxygen therapy (LTOT) assessment. 5. All patients being considered for LTOT should undergo serial blood gas assessments, by the home oxygen assessment service, when stable to confirm both the need for and tolerability of LTOT. 6. Review, reassessment and withdrawalAll patients started on LTOT should be followed up with blood gas assessment within 3 months of initiation of therapy; this includes those patients who are discharged home from hospital on LTOT for the first time.

, when stable to confirm both the need for and tolerability of LTOT. 6. Review, reassessment and withdrawalAll patients started on LTOT should be followed up with blood gas assessment within 3 months of initiation of therapy; this includes those patients who are discharged home from hospital on LTOT for the first time. All patients who continue on LTOT should be monitored at least on an annual basis by a home oxygen assessment service. All patients who are identified as no longer requiring any form of home oxygen should have this withdrawn. 7. Short burst oxygen therapy (SBOT) should only be offered in the context of cluster headache. SBOT should not be ordered for patients with chronic cardiorespiratory disease. 8. Nocturnal oxygen therapy (NOT)Patients with optimally treated cardiac failure, who are not eligible for LTOT, should only be offered NOT if there is evidence of sleep disordered breathing causing daytime symptoms. Patients with chronic hypercapnic respiratory failure with nocturnal hypoxaemia, who are not eligible for LTOT, should only be offered NOT in conjunction with non-invasive ventilation (NIV). 9. Ambulatory oxygen therapy (AOT)Patients not eligible for LTOT should only have AOT ordered to facilitate pulmonary rehabilitation or to improve mobility after appropriate formal assessment that includes an exercise test. Patients on LTOT, who are mobile outdoors, should only be offered AOT if this allows them to achieve 15 hours/day compliance with LTOT and/or improve capacity to undertake outdoors activities.

9. Ambulatory oxygen therapy (AOT)Patients not eligible for LTOT should only have AOT ordered to facilitate pulmonary rehabilitation or to improve mobility after appropriate formal assessment that includes an exercise test. Patients on LTOT, who are mobile outdoors, should only be offered AOT if this allows them to achieve 15 hours/day compliance with LTOT and/or improve capacity to undertake outdoors activities. 10. Palliative oxygen therapy (POT) can be considered as a trial for patients with hypoxaemia (saturations <92% on air) with refractory dyspnoea due to life-limiting disease that has not responded to opioids and non-pharmacological measures. Quality statement 1 All patients should have home oxygen assessments carried out by a home oxygen assessment service that includes appropriately trained staff and appropriate equipment. Rationale The assessment and provision of home oxygen therapy requires expert knowledge and should be implemented by staff who have been adequately trained. Equipment used to assess patients for home oxygen should undergo regular calibration quality control checks to ensure they are of the highest quality. Where possible, patients initiated on home oxygen should have their baseline assessment of flow rate carried out using similar oxygen equipment to the equipment they will be receiving at home. Where possible patients should be offered oxygen equipment that is best suited to their individual needs. Quality measure Structure: Evidence that staff undertaking home oxygen assessments have undergone appropriate training, with evidence of ongoing CPD.

Rationale The assessment and provision of home oxygen therapy requires expert knowledge and should be implemented by staff who have been adequately trained. Equipment used to assess patients for home oxygen should undergo regular calibration quality control checks to ensure they are of the highest quality. Where possible, patients initiated on home oxygen should have their baseline assessment of flow rate carried out using similar oxygen equipment to the equipment they will be receiving at home. Where possible patients should be offered oxygen equipment that is best suited to their individual needs. Quality measure Structure: Evidence that staff undertaking home oxygen assessments have undergone appropriate training, with evidence of ongoing CPD. Evidence that equipment used during assessments has had regular quality control checks. Process: Proportion of staff undertaking appropriate training. Proportion of equipment that has been adequately checked. Numerator 1: The number of staff that have demonstrated completion of appropriate training for performing home oxygen assessments with evidence of ongoing continuing professional development. Denominator 1: The number of staff undertaking home oxygen assessments. Numerator 2: The number of medical devices used during a home oxygen assessment that have undergone a quality control check within the last 12 months. Denominator 2: The number of medical devices used during a home oxygen assessment. Description of what the quality statement means for each audience Service providers:

The number of staff undertaking home oxygen assessments. Numerator 2: The number of medical devices used during a home oxygen assessment that have undergone a quality control check within the last 12 months. Denominator 2: The number of medical devices used during a home oxygen assessment. Description of what the quality statement means for each audience Service providers: Ensure that all medical devices used during an assessment (including diagnostic equipment and oxygen delivery devices) must undergo regular annual quality control checks. Ensure all staff maintain continuing professional development. Service providers should ensure that a wide range of assessment equipment is available to cater to individual needs. Healthcare professionals: Healthcare professionals undertaking oxygen assessments must ensure they have undergone appropriate training and have maintained this expertise through continuing professional development. Healthcare professionals should ensure that they are able to identify equipment suitable for patients. Commissioners: Ensure that staff undertaking home assessments have access to, and funding for, appropriate training programmes. Ensure that equipment used during oxygen assessments has undergone regular quality control checks. Ensure processes are in place to check staff and equipment standards are met and to address training and quality issues when they are not. The service specification should reflect these quality standards. People who require home oxygen: Are offered a high-quality service staffed by trained healthcare professionals using quality control checked equipment.

Ensure processes are in place to check staff and equipment standards are met and to address training and quality issues when they are not. The service specification should reflect these quality standards. People who require home oxygen: Are offered a high-quality service staffed by trained healthcare professionals using quality control checked equipment. Source references BTS Guideline for Home Oxygen Use in Adults (2015).3 There are no national standards or competencies. Quality statement 2 All patients being assessed for home oxygen should undergo a risk assessment that includes assessment of individual and household member smoking status, and other household risks of fire, trips and falls. Rationale There is a significant risk of fire and personal injury by using oxygen while smoking (including e-cigarettes) or by using oxygen near a naked flame. Patients and/or household members who continue to smoke and who have access to home oxygen put themselves, other people, their surroundings, their property and neighbouring properties at risk. Home oxygen equipment and tubing can represent a trip hazard particularly for those with mobility issues or sight impairment. Quality measure

Rationale There is a significant risk of fire and personal injury by using oxygen while smoking (including e-cigarettes) or by using oxygen near a naked flame. Patients and/or household members who continue to smoke and who have access to home oxygen put themselves, other people, their surroundings, their property and neighbouring properties at risk. Home oxygen equipment and tubing can represent a trip hazard particularly for those with mobility issues or sight impairment. Quality measure Structure: Evidence that all patients being assessed for home oxygen undergo a holistic risk assessment that includes assessment of smoking status and other fire and falls risks before oxygen is installed. Risk assessments should take place in the patient’s place of residence and involve two-way dialogue on lifestyle. NHS England has introduced an Initial Home Oxygen Risk Mitigation Form. The information on this form is intended to raise awareness of the potential dangers of providing home oxygen and will assist healthcare professionals to make a considered decision about the appropriateness of oxygen therapy. This form can be seen in online supplementary appendix 1. Evidence that all patients being assessed for home oxygen, and their household members, are given written information regarding the increased risk associated with smoking and the use of oxygen therapy. Evidence that patients being assessed for home oxygen who smoke are offered access to a smoking cessation service.

Structure: Evidence that all patients being assessed for home oxygen undergo a holistic risk assessment that includes assessment of smoking status and other fire and falls risks before oxygen is installed. Risk assessments should take place in the patient’s place of residence and involve two-way dialogue on lifestyle. NHS England has introduced an Initial Home Oxygen Risk Mitigation Form. The information on this form is intended to raise awareness of the potential dangers of providing home oxygen and will assist healthcare professionals to make a considered decision about the appropriateness of oxygen therapy. This form can be seen in online supplementary appendix 1. Evidence that all patients being assessed for home oxygen, and their household members, are given written information regarding the increased risk associated with smoking and the use of oxygen therapy. Evidence that patients being assessed for home oxygen who smoke are offered access to a smoking cessation service. In patients where risk assessment identifies potential safety issues, patients and carers should be assessed for understanding of the risks and given opportunities to ask questions about and discuss the risks and benefits of therapy. Any decision to proceed with installation of home oxygen in the presence of significant risks should be made after careful multidisciplinary team discussion and with full understanding of the potential implications of this decision by the patient

ies to ask questions about and discuss the risks and benefits of therapy. Any decision to proceed with installation of home oxygen in the presence of significant risks should be made after careful multidisciplinary team discussion and with full understanding of the potential implications of this decision by the patient Where risk assessments identify trip and fall safety risks, restrictions (eg, providing short tubing) that might limit a patient’s independence within their home should be avoided. Where restrictions are necessary, advice and support should be provided to mitigate these. Process: The proportion of patients undergoing assessment for home oxygen who have undergone a holistic risk assessment. The proportion of patients who continue to smoke who have received written information regarding the increased risk associated with smoking and the use of oxygen. The proportion of patients who smoke at the time of referral for home oxygen assessment who have been referred to smoking cessation services. The proportion of patients continuing to smoke who have signed a consent form acknowledging the fire hazards of home oxygen. Numerator 1: The number of patients being assessed for home oxygen who have undergone a holistic risk assessment, including assessment of their and the rest of their household’s smoking status. Denominator 1: All patients being assessed for home oxygen. Numerator 2:

The proportion of patients continuing to smoke who have signed a consent form acknowledging the fire hazards of home oxygen. Numerator 1: The number of patients being assessed for home oxygen who have undergone a holistic risk assessment, including assessment of their and the rest of their household’s smoking status. Denominator 1: All patients being assessed for home oxygen. Numerator 2: The number of patients being assessed for home oxygen who currently smoke, or who have household members who smoke, who have been provided with written information regarding the fire hazards associated with home oxygen therapy. Denominator 2: The number of people being assessed for home oxygen who currently smoke or who have a household member who currently smokes. Numerator 3: The number of people being assessed for home oxygen who currently smoke who have been offered access to smoking cessation services. Denominator 3: The number of people being assessed for home oxygen who currently smoke. Description of what the quality statement means for each audience Service providers: Ensure systems are in place to identify high-risk patients. Ensure accessible referral pathways to smoking cessation services. Ensure written information is available regarding the risks associated with smoking and home oxygen therapy. Healthcare professionals: Ensure that a risk assessment is carried out as part of a home oxygen assessment. Ensure patients who continue to smoke are advised of the increased risks when home oxygen is prescribed. Ensure that patients are referred to smoking cessation services where appropriate. Commissioners:

Ensure written information is available regarding the risks associated with smoking and home oxygen therapy. Healthcare professionals: Ensure that a risk assessment is carried out as part of a home oxygen assessment. Ensure patients who continue to smoke are advised of the increased risks when home oxygen is prescribed. Ensure that patients are referred to smoking cessation services where appropriate. Commissioners: Ensure that home oxygen assessment services are adequately resourced to carry out risk assessments. Ensure that smoking cessation services are adequately resourced to meet volume of referrals. May want to consider developing a local policy for the prescribing of oxygen to patients who are known smokers. People who require home oxygen: Are made aware of the potential hazards associated with home oxygen. Who continue to smoke have been offered access to smoking cessation services. Relevant existing indicators/data sources For example, local data collection/audit. Source references BTS Guideline for Home Oxygen Use in Adults (2015).3 Other information Home oxygen and Domestic Fires; Brendan G. Cooper, DOI: 10.1183/20734735.000815 Published 1 March 2015.4 Example domiciliary oxygen policy for patients who are known smokers: http://www.eastcheshire.nhs.uk/About-The-Trust/policies/O/Oxygen%20-%20Prescribing%20for%20Smokers%20and%20Users%20of%20E-Cigarettes%20ECT2582.pdf, https://www.blf.org.uk/support-for-you/oxygen/life-with-oxygen. Quality statement 3 All patients initiated on home oxygen should have appropriate education and written information provided by a specialist home oxygen assessment team.

http://www.eastcheshire.nhs.uk/About-The-Trust/policies/O/Oxygen%20-%20Prescribing%20for%20Smokers%20and%20Users%20of%20E-Cigarettes%20ECT2582.pdf, https://www.blf.org.uk/support-for-you/oxygen/life-with-oxygen. Quality statement 3 All patients initiated on home oxygen should have appropriate education and written information provided by a specialist home oxygen assessment team. Rationale Patients initiated on home oxygen without formal education are often poorly compliant with their oxygen long term. Patient education is therefore an essential component of receiving home oxygen and should be tailored to individual needs and involve learning setting goals. Patient education should be delivered by professionals competent in the assessment and delivery of home oxygen. Written information should be provided to supplement individual educational sessions, with consideration given to language and literacy issues. Quality measure Structure: Evidence to ensure that all patients receiving home oxygen receive education from a healthcare professional competent in the assessment and delivery of home oxygen. Evidence processes are in place to ensure all patients receiving home oxygen are provided with written information regarding their oxygen therapy. Process: The proportion of patients receiving home oxygen who have received education and written information regarding their oxygen. Numerator: The number of patients receiving home oxygen who have received formal education and been provided with written information regarding their oxygen. Denominator: The number of patients receiving home oxygen.

The proportion of patients receiving home oxygen who have received education and written information regarding their oxygen. Numerator: The number of patients receiving home oxygen who have received formal education and been provided with written information regarding their oxygen. Denominator: The number of patients receiving home oxygen. Description of what the quality statement means for each audience Service providers: Ensure sufficient time is set aside in the assessment process for patients to receive education from a healthcare professional competent in the assessment and delivery of home oxygen. Ensure written information is available that takes into account all local language and literacy issues. Healthcare professionals: Ensure all patients initiated on home oxygen therapy receive education in a format that is appropriate to their needs. Commissioners: Ensure home oxygen assessment services are adequately resourced to provide initial and ongoing education to patients in a format that is appropriate to their needs. People who require home oxygen: Should receive both verbal and written information regarding their oxygen therapy and have the option to seek ongoing help as needed. Relevant existing indicators/data sources For example, local data collection/audit. Source references BTS Guideline for Home Oxygen Use in Adults (2015).3 Other information https://www.blf.org.uk/support-for-you/oxygen.5 Quality statement 4 Patients with advanced stable cardiorespiratory disease who have resting saturations on air that meet the qualifying criteria should be referred for an LTOT assessment.

Relevant existing indicators/data sources For example, local data collection/audit. Source references BTS Guideline for Home Oxygen Use in Adults (2015).3 Other information https://www.blf.org.uk/support-for-you/oxygen.5 Quality statement 4 Patients with advanced stable cardiorespiratory disease who have resting saturations on air that meet the qualifying criteria should be referred for an LTOT assessment. Rationale LTOT improves life expectancy in patients with chronic obstructive pulmonary disease (COPD) with chronic stable hypoxaemia. Although data are lacking, it is assumed that this holds true for other cardiorespiratory diseases, including pulmonary fibrosis, cystic fibrosis (CF), pulmonary hypertension and cardiac failure. Measuring peripheral oxygen saturations is an easily accessible measure that quickly and reliably identifies potential patients who may benefit from LTOT and therefore require further assessment by a home oxygen assessment service. All healthcare professionals should be alert to the presence of hypoxia in advanced cardiorespiratory disease. The routine 6 monthly monitoring of patients with very severe COPD (ie, forced expiratory volume in 1 s of <30%) in primary care offers an opportunity for the timely identification of potential candidates for LTOT in this particular patient cohort6 (See online Supplementary appendix 2 for NICE assessment criteria). Where similar opportunities exist for other cardiorespiratory conditions (eg, specialist clinics), these should be used in a similar way. Optimisation and treatment of underlying conditions as well as clinical stability (ie >8 weeks post infection) are essential prior to measurement and referral as both can have a positive impact on hypoxaemia, thus avoiding unnecessary LTOT assessments. Providing verbal or written information about the assessment process at the time of referral can improve understanding and increase the likelihood of subsequent attendance. This information could be provided to the patient by the referrer or sent out to the patient by the assessment team prior to their appointment.

ts. Providing verbal or written information about the assessment process at the time of referral can improve understanding and increase the likelihood of subsequent attendance. This information could be provided to the patient by the referrer or sent out to the patient by the assessment team prior to their appointment. Quality measure Structure: Evidence that oxygen saturation is documented at least twice a year in the primary care clinical record for all patients with very severe COPD. Evidence that patients are referred appropriately to a local home oxygen assessment service. Evidence this pathway allows the transfer of appropriate information to the home oxygen assessment team (See online Supplementary appendix 3 for Home Oxygen Assessment Referral Form in Guideline). Evidence that locally relevant written information is provided to patients at the time of referral to a home oxygen assessment service. Process: The proportion of patients with very severe COPD on a primary care register with a documented oxygen saturation within the previous 6 months. The proportion of patients with very severe COPD meeting the qualifying criteria for LTOT referred to the home oxygen assessment service. The proportion of patients given written information before assessment by the home oxygen assessment service. The proportion of inappropriate referrals received by a home oxygen assessment service. Numerator 1: The number of patients with very severe COPD on a primary care register with a documented oxygen saturation in the previous 6 months. Denominator 1:

The proportion of patients given written information before assessment by the home oxygen assessment service. The proportion of inappropriate referrals received by a home oxygen assessment service. Numerator 1: The number of patients with very severe COPD on a primary care register with a documented oxygen saturation in the previous 6 months. Denominator 1: The number of patients with very severe COPD on a primary care register. Numerator 2: The number of patients with very severe COPD on a primary care register with stable resting oxygen saturations ≤92% referred for a home oxygen assessment within the last 6 months. Denominator 2: The number of patients with very severe COPD on a primary care register with documented stable resting oxygen saturations ≤92% within the last 6 months. Numerator 3: The number of patients given written information prior to their assessment by the home oxygen assessment service. Denominator 3: The number of patients referred to the home oxygen assessment service. Numerator 4: The number of inappropriate referrals received by a home oxygen assessment service for patients who did not meet the qualifying criteria for an LTOT assessment, for example, SpO2 well above threshold (ie, above 94%), clinical instability and treatment not optimised. Denominator 4: The number of referrals received by a home oxygen assessment service. Description of what the quality statement means for each audience Service providers: Ensure that all health professionals involved in the management of patients with advanced cardiorespiratory disease have access to a pulse oximeter.

The number of inappropriate referrals received by a home oxygen assessment service for patients who did not meet the qualifying criteria for an LTOT assessment, for example, SpO2 well above threshold (ie, above 94%), clinical instability and treatment not optimised. Denominator 4: The number of referrals received by a home oxygen assessment service. Description of what the quality statement means for each audience Service providers: Ensure that all health professionals involved in the management of patients with advanced cardiorespiratory disease have access to a pulse oximeter. Ensure systems are in place to make health professionals aware of the criteria for referral to the home oxygen assessment service and how to refer to this service. Healthcare professionals: Ensure oxygen saturations are recorded at least 6 monthly in primary care for all patients with more advanced COPD. Ensure oxygen saturations are checked for patients with advanced cardiorespiratory disease where LTOT may be considered. Ensure oxygen saturations are measured during a period of stability when all other treatment has been optimised. Ensure all patients referred to the home oxygen assessment service are given verbal or written information prior to their assessment. Commissioners: Ensure that home oxygen assessment services have sufficient facilities, staff and equipment to undertake assessments for all patients appropriately referred for an LTOT assessment. People who require home oxygen: Are given an explanation as to why they are being referred to the home oxygen assessment service with written information to support this.

Commissioners: Ensure that home oxygen assessment services have sufficient facilities, staff and equipment to undertake assessments for all patients appropriately referred for an LTOT assessment. People who require home oxygen: Are given an explanation as to why they are being referred to the home oxygen assessment service with written information to support this. Relevant existing indicators/data sources For example, local data collection/audit. Source references BTS Guideline for Home Oxygen Use in Adults.3 NHS Service Specification: Home Oxygen Assessment and Review Service 2012.7 NICE chronic obstructive pulmonary disease in over 16 s: diagnosis and management, 2010 CG101.6 Other information Online Supplementary file 3, BTS Guideline for Home Oxygen Use in Adults (2015): Home Oxygen Assessment Referral Form.3 10.1136/bmjresp-2017-000223.supp2Supplementary file 2 10.1136/bmjresp-2017-000223.supp3Supplementary file 3 Quality statement 5 All patients being considered for LTOT should undergo serial blood gas assessments, by the home oxygen assessment service, when stable to confirm both the need for and tolerability of LTOT.

Other information Online Supplementary file 3, BTS Guideline for Home Oxygen Use in Adults (2015): Home Oxygen Assessment Referral Form.3 10.1136/bmjresp-2017-000223.supp2Supplementary file 2 10.1136/bmjresp-2017-000223.supp3Supplementary file 3 Quality statement 5 All patients being considered for LTOT should undergo serial blood gas assessments, by the home oxygen assessment service, when stable to confirm both the need for and tolerability of LTOT. Rationale Arterial oxygenation can vary with disease course and particularly at exacerbations. Therefore the date of the last exacerbation should be included in the referral for LTOT so that the assessment can be performed during a period of clinical stability (ie ≥8 weeks free from exacerbation of symptoms that require medical management). LTOT should not be prescribed using oximetry alone. All patients requiring LTOT should undergo assessment for suitability using arterial blood gas (ABG) sampling; where ABG sampling is not possible, the current guidelines do allow the use of capillary blood gas (CBG) as an alternative. Two ABG measurements at least 3 weeks apart should be obtained before the need for LTOT is confirmed. An ABG should be repeated after oxygen titration is complete to determine a PaO2 >8 kPa has been achieved without precipitating respiratory acidosis and/or worsening hypercapnia. Patients with PaCO2 >6 kPa at rest should also have blood gases performed after each oxygen titration to monitor for worsening hypercapnia. Assessing patients when clinically unstable, relying on only one blood gas measurement or using CBG may result in overprescribing of LTOT.

ry acidosis and/or worsening hypercapnia. Patients with PaCO2 >6 kPa at rest should also have blood gases performed after each oxygen titration to monitor for worsening hypercapnia. Assessing patients when clinically unstable, relying on only one blood gas measurement or using CBG may result in overprescribing of LTOT. Quality measure Structure: Evidence that patients are stable at the point of assessment through documentation of clinical stability i.e. at least 8 weeks since last exacerbation. Evidence that all patients receiving LTOT have had an initial ABG assessment on air and on titration of oxygen. Evidence of two ABG measurements were performed at least three weeks apart. Evidence that oxygen flow rate has been appropriately increased to achieve PaO2>8kpa without worsening hypercapnia (i.e. increase in PaCO2 by >1kpa). Process: The proportion of patients who are assessed for LTOT after a documented period of clinical stability. The proportion of patients receiving LTOT who have had an ABG measurement performed. The proportion of patients with two ABG measurements performed at least three weeks apart prior to commencing LTOT. The proportion of patients who have had a reassessment of PaCO2 after titration of their oxygen flow rate has been completed. Numerator 1: The number of patients initially assessed for LTOT during a documented period of clinical stability. Denominator 1: The number of patients on the home oxygen assessment register assessed for LTOT. Numerator 2:

The proportion of patients who have had a reassessment of PaCO2 after titration of their oxygen flow rate has been completed. Numerator 1: The number of patients initially assessed for LTOT during a documented period of clinical stability. Denominator 1: The number of patients on the home oxygen assessment register assessed for LTOT. Numerator 2: The number of patients receiving LTOT who have documented evidence of a formal baseline ABG assessment that successfully met LTOT qualifying criteria. Denominator 2: The number of patients receiving LTOT on a home oxygen assessment service register. Numerator 3: The number of patients who have had two ABGs performed at least 3 weeks apart prior to commencing LTOT. Denominator 3: The number of patients on the home oxygen assessment register assessed for LTOT. Numerator 4: The number of patients receiving LTOT who have had repeat blood gases to assess for worsening hypercapnia after completion of oxygen titration. Denominator 4: The number of patients receiving LTOT on a home oxygen assessment register. Description of what the quality statement means for each audience Service providers: Ensure all home oxygen assessment services have the equipment and staff with required skills to perform ABGs. Healthcare professionals: Ensure duration of clinical stability is documented prior to commencing an LTOT assessment. Ensure two qualifying ABGs at least 3 weeks apart are performed prior to commencing LTOT. Ensure titration of oxygen to achieve PaO2 >8 kPa without worsening hypercapnia (>1 kPa rise). Commissioners:

Ensure all home oxygen assessment services have the equipment and staff with required skills to perform ABGs. Healthcare professionals: Ensure duration of clinical stability is documented prior to commencing an LTOT assessment. Ensure two qualifying ABGs at least 3 weeks apart are performed prior to commencing LTOT. Ensure titration of oxygen to achieve PaO2 >8 kPa without worsening hypercapnia (>1 kPa rise). Commissioners: Ensure services are adequately resourced with appropriate staff and equipment to undertake high-quality home oxygen assessments. People who require home oxygen: Are assessed rigorously to ensure they receive a home oxygen order appropriate to their needs. Relevant existing indicators/data sources Home oxygen assessment service register of assessments and patients on LTOT. Source references BTS Guideline for Home Oxygen Use in Adults.3 NHS Service Specification: Home Oxygen Assessment and Review Service 2012.7 Other information Online Supplementary file 3, BTS Guideline for Home Oxygen Use in Adults (2015): Home Oxygen Assessment Referral Form.3 Quality statement 6 Review, reassessment and withdrawal: (a) All patients started on LTOT should be followed up with blood gas assessment within 3 months of initiation of therapy; this includes those patients who are discharged home from hospital on LTOT for the first time. (b) All patients who continue on LTOT should be monitored at least on an annual basis by a home oxygen assessment service. (c) All patients who are identified as no longer requiring any form of home oxygen should have this withdrawn.

ludes those patients who are discharged home from hospital on LTOT for the first time. (b) All patients who continue on LTOT should be monitored at least on an annual basis by a home oxygen assessment service. (c) All patients who are identified as no longer requiring any form of home oxygen should have this withdrawn. Rationale The patient’s clinical status can vary with time, and a repeat assessment that the indication for LTOT is still present and that use is appropriate and well tolerated is required. Home oxygen assessment services require a robust identification and recall system for patients started on LTOT, which includes patients discharged home from hospital with a new LTOT order. Where home oxygen is no longer indicated, it should be withdrawn in a carefully planned systematic way including all relevant agencies. Where there are significant concerns about emergent risk, the provision of home oxygen should be reassessed by the home oxygen team, ensuring there is multidisciplinary input (eg, general practitioner, social worker, community matron, and so on). To ensure that appropriate risk assessments are carried out once LTOT is in use, risk assessments require review within 3 months and at each annual review. Quality measure Structure: Evidence that the local home oxygen assessment service reviews patients on LTOT via a face-to-face visit within 3 months of initiation. Evidence that the local home oxygen assessment service reviews patients on LTOT via a face-to-face visit annually. Evidence that patients who after reassessment no longer meet indication for LTOT have it withdrawn.

Evidence that the local home oxygen assessment service reviews patients on LTOT via a face-to-face visit within 3 months of initiation. Evidence that the local home oxygen assessment service reviews patients on LTOT via a face-to-face visit annually. Evidence that patients who after reassessment no longer meet indication for LTOT have it withdrawn. Evidence that risk reassessments are completed at all reviews. Process: The proportion of patients on LTOT who are reassessed within 3 months of initiation of LTOT. The proportion of patients on LTOT who complete a yearly follow-up assessment of LTOT. The proportion of patients who no longer meet indication for LTOT who have LTOT withdrawn. The proportion of patients who have risk reassessments completed at each review. Numerator 1: The number of patients reassessed face to face within 3 months of initiation of LTOT. Denominator 1: The number of patients started on LTOT. Numerator 2: The number of patients on LTOT reassessed face-to-face annually. Denominator 2: The number of patients on LTOT. Numerator 3: The number of patients with LTOT withdrawn after reassessment. Denominator 3: The number of patients who no longer meet criteria at reassessment for LTOT. Numerator 4: The number of patients who have a risk assessment updated at review. Denominator 4: The number of patients on LTOT. Description of what the quality statement means for each audience Service providers: It is necessary to create a robust system of identifying patients started on LTOT and timely recall for reassessment. Implementation of reporting systems to demonstrate that quality measures are being achieved.

Denominator 4: The number of patients on LTOT. Description of what the quality statement means for each audience Service providers: It is necessary to create a robust system of identifying patients started on LTOT and timely recall for reassessment. Implementation of reporting systems to demonstrate that quality measures are being achieved. Implementation of risk assessment process and escalation process in case of failed risk assessment. Healthcare professionals: Ensure all patients have an LTOT reassessment within 3 months of initiation of LTOT. Ensure LTOT is withdrawn promptly where it is no longer indicated after hospital-discharge initiation. Complete risk assessment at every reassessment and escalate where necessary. Commissioners: Ensure that there are appropriate resources and trained staff to follow up and reassess patients commenced on LTOT. People who require home oxygen: Should understand the importance of an oxygen reassessment, the appropriateness of withdrawal where indicated and the need for risk assessments and escalation where necessary. Relevant existing indicators/data sources Home oxygen assessment service register. Source references BTS Guideline for Home Oxygen Use in Adults June 2015.3 BTS Guidelines for Oxygen Use in Adults in Healthcare and Emergency Settings 2017.8 NICE Guidelines on Management of Cluster Headache 2012.9 Quality statement 7 Short burst oxygen therapy (SBOT) should only be offered in the context of cluster headache. SBOT should not be ordered for patients with chronic cardiorespiratory disease.

BTS Guidelines for Oxygen Use in Adults in Healthcare and Emergency Settings 2017.8 NICE Guidelines on Management of Cluster Headache 2012.9 Quality statement 7 Short burst oxygen therapy (SBOT) should only be offered in the context of cluster headache. SBOT should not be ordered for patients with chronic cardiorespiratory disease. Rationale Oxygen therapy should be used to treat hypoxaemia, and not simply breathlessness. There is no evidence to support the use of SBOT in patients with chronic cardiorespiratory disease. SBOT does not improve exercise tolerance or reduce breathlessness in patients with chronic cardiorespiratory disease and should not be ordered for use prior to or following exercise. SBOT does not improve health-related quality of life or reduce healthcare utilisation when ordered for patients following an acute exacerbation of COPD (AECOPD) and should not be ordered on discharge from hospital. The only indication for SBOT is for use in cluster headaches where there is evidence to show delivering high flow oxygen therapy (>12 L/min via non-rebreather mask) significantly reduces pain from acute attacks of cluster headache. Quality measure Structure: Evidence that patients with chronic cardiorespiratory disease do not have SBOT ordered. Patients who are hypoxaemic should be assessed for LTOT if resting stable saturation meets the qualifying criteria. Evidence that patients discharged from hospital with AECOPD are not ordered SBOT. Evidence that patients with cluster headaches have appropriate access to SBOT. Process:

Evidence that patients with chronic cardiorespiratory disease do not have SBOT ordered. Patients who are hypoxaemic should be assessed for LTOT if resting stable saturation meets the qualifying criteria. Evidence that patients discharged from hospital with AECOPD are not ordered SBOT. Evidence that patients with cluster headaches have appropriate access to SBOT. Process: The proportion of patients with chronic cardiorespiratory disease with SBOT. The proportion of patients with cluster headaches who have access to SBOT. Numerator 1: The number of patients with chronic cardiorespiratory disease with SBOT. Denominator 1: The number of patients with SBOT. Numerator 2: The number of patients with cluster headaches who have appropriate access to SBOT. Denominator 2: The number of patients with SBOT for cluster headache. Description of what the quality statement means for each audience Service providers: Ensure systems are in place to provide LTOT, NOT and AOT assessments with cardiorespiratory disease, but not SBOT. Ensure systems are in place to provide SBOT to patients with cluster headaches. Healthcare professionals: Ensure all patients with chronic cardiorespiratory disease are not offered SBOT. Instead, where indicated, patients should be assessed for LTOT, NOT or AOT. Ensure all patients with cluster headache have access to SBOT. Commissioners: Ensure patients with chronic cardiorespiratory disease do not have access to SBOT. Facilities should be available for assessment for LTOT, NOT or AOT where indicated. Ensure patients with cluster headaches have access to SBOT.

Ensure all patients with chronic cardiorespiratory disease are not offered SBOT. Instead, where indicated, patients should be assessed for LTOT, NOT or AOT. Ensure all patients with cluster headache have access to SBOT. Commissioners: Ensure patients with chronic cardiorespiratory disease do not have access to SBOT. Facilities should be available for assessment for LTOT, NOT or AOT where indicated. Ensure patients with cluster headaches have access to SBOT. People who require home oxygen: Should have appropriate assessments for LTOT, NOT and AOT, where indicated. SBOT should only be available to patients with cluster headaches. Relevant existing indicators/data sources For example, local data collection/audit. Source references BTS Guideline for Home Oxygen Use in Adults June 2015.3 BTS Guidelines for Oxygen Use in Adults in Healthcare and Emergency Settings 2017.8 NICE Guidelines on Management of Cluster Headache 2012.9 Quality statement 8 Nocturnal oxygen therapy (NOT): (a) Patients with optimally treated cardiac failure, who are not eligible for LTOT, should only be offered NOT if there is evidence of sleep disordered breathing causing daytime symptoms. (b) Patients with chronic hypercapnic respiratory failure with nocturnal hypoxaemia, who are not eligible for LTOT, should only be offered NOT in conjunction with NIV.

cardiac failure, who are not eligible for LTOT, should only be offered NOT if there is evidence of sleep disordered breathing causing daytime symptoms. (b) Patients with chronic hypercapnic respiratory failure with nocturnal hypoxaemia, who are not eligible for LTOT, should only be offered NOT in conjunction with NIV. Rationale Treatment of patients with cardiac failure who are symptomatic from sleep disordered breathing with NOT leads to a reduction in daytime sleepiness and a modest improvement in exercise capacity. There is no evidence that patients with chronic respiratory disease who fail to meet the criteria for LTOT but who desaturate at night derive any long-term symptomatic or survival benefits from NOT. NOT is therefore not recommended in this group of patients (eg, COPD, interstitial lung disease (ILD)). Some patients with chronic respiratory disease, including those with CF, neuromuscular weakness or obesity hypoventilation, are at risk of developing nocturnal hypoxaemia in the setting of chronic hypercapnic respiratory failure. These patients should not receive NOT alone as they may develop uncontrolled type 2 respiratory failure. However, they may benefit from NOT given with NIV support. Some patients with chronic respiratory disease, including those with CF, neuromuscular weakness or obesity hypoventilation, are at risk of developing nocturnal hypoxaemia in the setting of chronic hypercapnic respiratory failure. These patients should not receive NOT alone as they may develop uncontrolled type 2 respiratory failure. However, they may benefit from NOT given with NIV support.

neuromuscular weakness or obesity hypoventilation, are at risk of developing nocturnal hypoxaemia in the setting of chronic hypercapnic respiratory failure. These patients should not receive NOT alone as they may develop uncontrolled type 2 respiratory failure. However, they may benefit from NOT given with NIV support. Quality measure Structure: Evidence that NOT is provided for patients with cardiac failure with evidence of sleep disordered breathing on a sleep study causing daytime symptoms. Evidence that NOT is only provided for respiratory patients with hypercapnic respiratory failure in conjunction with NIV. Process: The proportion of patients with cardiac failure receiving NOT who have had a sleep study and completed an Epworth Sleepiness Scale before and after treatment. The proportion of patients with hypercapnic respiratory failure receiving NOT who are also being treated with NIV. Numerator 1: The number of patients with cardiac failure receiving NOT who have had a sleep study and completed an Epworth Sleepiness Scale before and after treatment. Denominator 1: The number of patients with cardiac failure receiving NOT. Numerator 2: The number of patients with chronic hypercapnic respiratory failure receiving NOT who are also being treated with NIV. Denominator 2: The number of chronic hypercapnic respiratory patients receiving NOT. Description of what the quality statement means for each audience Service providers: Ensure systems are in place to offer a sleep study and symptom assessment of cardiac patients before and after treatment.

The number of patients with chronic hypercapnic respiratory failure receiving NOT who are also being treated with NIV. Denominator 2: The number of chronic hypercapnic respiratory patients receiving NOT. Description of what the quality statement means for each audience Service providers: Ensure systems are in place to offer a sleep study and symptom assessment of cardiac patients before and after treatment. Ensure systems are in place to offer NOT in conjunction with NIV for respiratory patients in chronic hypercapnia respiratory failure. Healthcare professionals: Ensure clinical assessment of cardiac failure patients includes assessment of symptoms of sleep disordered breathing. Ensure awareness of risks of providing NOT alone without NIV treatment in chronic hypercapnic respiratory patients. Commissioners: Ensure that sufficient facilities, staff and equipment are available to diagnose and to treat patients with NOT when clinically indicated. People who require home oxygen: Are referred for assessment if demonstrating symptoms or signs of sleep disordered breathing or uncontrolled ventilatory failure in context of cardiac failure or chronic respiratory disease. Relevant existing indicators/data sources Local data collection/audit. Source references BTS Guidelines for Home Oxygen Use in Adults June 2015.3 Quality statement 9

People who require home oxygen: Are referred for assessment if demonstrating symptoms or signs of sleep disordered breathing or uncontrolled ventilatory failure in context of cardiac failure or chronic respiratory disease. Relevant existing indicators/data sources Local data collection/audit. Source references BTS Guidelines for Home Oxygen Use in Adults June 2015.3 Quality statement 9 Ambulatory oxygen therapy (AOT): (a) Patients not eligible for LTOT should only have AOT ordered to facilitate pulmonary rehabilitation or to improve mobility after appropriate formal assessment that includes an exercise test. (b) Patients on LTOT, who are mobile outdoors, should only be offered AOT if this allows them to achieve 15 hours/day compliance with LTOT and/or improve capacity to undertake outdoors activities.

ilitate pulmonary rehabilitation or to improve mobility after appropriate formal assessment that includes an exercise test. (b) Patients on LTOT, who are mobile outdoors, should only be offered AOT if this allows them to achieve 15 hours/day compliance with LTOT and/or improve capacity to undertake outdoors activities. Rationale Patients who desaturate on exercise may tolerate higher levels of activity with the use of supplemental oxygen during pulmonary rehabilitation; therefore, gains made during pulmonary rehabilitation can be increased. Outside of a pulmonary rehabilitation setting, AOT should not be routinely offered to patients who are not eligible for LTOT. However, some patients, for example with ILD and disabling breathlessness, who do not qualify for LTOT but who desaturate may benefit from AOT, once all other medical interventions have been optimised. This may help improve mobility, by increasing functional capacity and/or time away from home. A formal assessment should be undertaken when considering AOT: this should include an exercise test to measure exercise capacity. In addition there should be consideration of the potential impact of carrying the oxygen equipment. Improved survival has been shown in patients on LTOT who achieve 15 hours per day of oxygen usage. AOT may be considered in patients who are mobile outdoors, who may not otherwise achieve 15 hours of usage. Patients who receive AOT should have compliance data recorded and reviewed annually. Quality measure Structure: Evidence of a formal assessment including an exercise test for patients on AOT.

Rationale Patients who desaturate on exercise may tolerate higher levels of activity with the use of supplemental oxygen during pulmonary rehabilitation; therefore, gains made during pulmonary rehabilitation can be increased. Outside of a pulmonary rehabilitation setting, AOT should not be routinely offered to patients who are not eligible for LTOT. However, some patients, for example with ILD and disabling breathlessness, who do not qualify for LTOT but who desaturate may benefit from AOT, once all other medical interventions have been optimised. This may help improve mobility, by increasing functional capacity and/or time away from home. A formal assessment should be undertaken when considering AOT: this should include an exercise test to measure exercise capacity. In addition there should be consideration of the potential impact of carrying the oxygen equipment. Improved survival has been shown in patients on LTOT who achieve 15 hours per day of oxygen usage. AOT may be considered in patients who are mobile outdoors, who may not otherwise achieve 15 hours of usage. Patients who receive AOT should have compliance data recorded and reviewed annually. Quality measure Structure: Evidence of a formal assessment including an exercise test for patients on AOT. Evidence of compliance data for LTOT patients who are mobile outdoors achieving 15 hours per day with AOT. Evidence that compliance in patients receiving AOT but not LTOT is captured and analysed as part of ongoing assessment. Process: The proportion of patients with AOT who have appropriate formal assessment including an exercise test.

Evidence of compliance data for LTOT patients who are mobile outdoors achieving 15 hours per day with AOT. Evidence that compliance in patients receiving AOT but not LTOT is captured and analysed as part of ongoing assessment. Process: The proportion of patients with AOT who have appropriate formal assessment including an exercise test. The proportion of LTOT patients who are mobile outdoors with AOT who achieve 15 hours of usage per day. The proportion of patients on which AOT compliance data are collected. Numerator 1: The number of patients on AOT only who have been formally assessed including an exercise test. Denominator 1: The number of patients on AOT only. Numerator 2: The number of LTOT patients with AOT who are mobile outdoors and achieving 15 hours of usage per day. Denominator 2: The number of LTOT patients with AOT. Numerator 3: The number patients with AOT alone with compliance data recorded and reviewed annually. Denominator 3: The number of patients with AOT alone. Description of what the quality statement means for each audience Service providers: Ensure systems are in place to offer formal assessments of AOT including an exercise test. Ensure systems are in place for compliance data to be accessed. Healthcare professionals: Ensure formal assessment of AOT which includes an exercise test to help facilitate pulmonary rehabilitation or demonstrate improvement in mobility. Ensure utilisation of compliance data for patients on LTOT with AOT to check daily usage hours. Commissioners: Ensure adequate resources to enable formal assessments for AOT which include an exercise test.

Ensure formal assessment of AOT which includes an exercise test to help facilitate pulmonary rehabilitation or demonstrate improvement in mobility. Ensure utilisation of compliance data for patients on LTOT with AOT to check daily usage hours. Commissioners: Ensure adequate resources to enable formal assessments for AOT which include an exercise test. Ensure healthcare professionals have access to compliance data via home oxygen provider. People who require home oxygen: Are referred and undergo appropriate formal assessment for consideration for AOT provision including an exercise test. Should be consulted about their achievable levels of activity and about what they aspire to gain from increased activity. Where all other medical interventions have been tried, those who remain keen should undergo appropriate formal assessment for consideration of AOT, including an exercise test. Relevant existing indicators/data sources Local data collection/audit. Source references BTS Guidelines for Home Oxygen Use in Adults June 2015.3 Other information Online Supplementary file 4, Protocol for ambulatory oxygen therapy assessment from the BTS Guidelines. Refer to the BTS Guideline for Home Oxygen Use in Adults June 2015 for more information about specific patient groups (eg, CF and ILD).3 10.1136/bmjresp-2017-000223.supp4Supplementary file 4 Quality statement 10

Other information Online Supplementary file 4, Protocol for ambulatory oxygen therapy assessment from the BTS Guidelines. Refer to the BTS Guideline for Home Oxygen Use in Adults June 2015 for more information about specific patient groups (eg, CF and ILD).3 10.1136/bmjresp-2017-000223.supp4Supplementary file 4 Quality statement 10 Palliative oxygen therapy (POT) can be considered as a trial for patients with hypoxaemia (saturations <92% on air) with refractory dyspnoea due to life-limiting disease that has not responded to opioids and non-pharmacological therapy, for example, fan therapy. Rationale Dyspnoea is a subjective experience and patients with hypoxaemia do not experience a significant difference in symptoms on air versus oxygen therapy. However, POT may be considered for patients with cancer or end-stage disease with limited prognosis (limited to weeks) who are hypoxaemic and are experiencing intractable breathlessness unresponsive to opioids or non-pharmacological therapies (eg, fan therapy). Quality measure Structure: Evidence of appropriate assessment of patients requiring POT. Evidence of trial of opioids when not contraindicated. Evidence of trial of non-pharmacological therapies. Process: The proportion of patients with intractable breathlessness on POT whose oxygen saturation is less than 92%. The proportion of patients on POT who are on opioids and non-pharmacological therapies. Numerator 1: The number of patients on POT whose oxygen saturation is less than 92%. Denominator 1: The number of patients on POT for intractable breathlessness. Numerator 2:

The proportion of patients with intractable breathlessness on POT whose oxygen saturation is less than 92%. The proportion of patients on POT who are on opioids and non-pharmacological therapies. Numerator 1: The number of patients on POT whose oxygen saturation is less than 92%. Denominator 1: The number of patients on POT for intractable breathlessness. Numerator 2: The number of eligible patients on POT who have tried opioids and non-pharmacological therapies. Denominator 2: The number of patients on POT for intractable breathlessness. Description of what the quality statement means for each audience Service providers: Ensure systems are in place to disseminate guidelines in primary and secondary care. Ensure access to specialist palliative care team to help with assessment and management of intractable breathlessness. Ensure availability of oxygen practitioner to monitor appropriate and safe use of POT at home. Healthcare professionals: Ensure patient is on maximum treatment for underlying disease and reversible causes have been optimally treated where possible. Ensure oxygen saturation and severity of breathlessness are recorded as part of assessment of intractable breathlessness. Ensure POT is discontinued if not providing symptomatic benefit. Commissioners: Ensure sufficient staff in specialist palliative care and oxygen team are available to allow timely assessment of patients requiring POT in the community as well as hospital. People who require home oxygen: Patients and carers are offered written information about POT on discharge from hospital.

Ensure POT is discontinued if not providing symptomatic benefit. Commissioners: Ensure sufficient staff in specialist palliative care and oxygen team are available to allow timely assessment of patients requiring POT in the community as well as hospital. People who require home oxygen: Patients and carers are offered written information about POT on discharge from hospital. Relevant existing indicators/data sources Local data collection/audit. Source reference BTS Home Oxygen Guideline for Home Oxygen Use in Adults 2015.3 Other information Online Supplementary file 5, Assessment protocol for palliative oxygen—see BTS Guideline for Home Oxygen Use in Adults.3 10.1136/bmjresp-2017-000223.supp5Supplementary file 5 Representation Joseph Annandale represented the Association of Respiratory Nurse Specialists (ARNS), Claire Davey and Cassie Lee represented the Association of Chartered Physiotherapists in Respiratory Care (ACPRC), Rhea Fielding and Trefor Watts represented the Association for Respiratory Technology and Physiology (ARTP), Dr Daryl Freeman represented the Primary Care Respiratory Society UK (PCRS-UK) and Dr Vandana Vora represented the Association of Palliative Medicine (APM). Appendices Appendix 1 – NHS England IHORM form. We are grateful for permission to include the IHORM form. This form was developed on behalf of NHS England and approved by the National Home Safety Committee. Further support documents are available from your NHS regional home oxygen lead. Appendix 2 – NICE 2010 COPD referral criteria Appendix 3 – Home oxygen assessment referral form from the BTS Home Oxygen Guideline

Appendices Appendix 1 – NHS England IHORM form. We are grateful for permission to include the IHORM form. This form was developed on behalf of NHS England and approved by the National Home Safety Committee. Further support documents are available from your NHS regional home oxygen lead. Appendix 2 – NICE 2010 COPD referral criteria Appendix 3 – Home oxygen assessment referral form from the BTS Home Oxygen Guideline Appendix 4 – Protocol for Ambulatory Oxygen Therapy Assessment from the BTS Home Oxygen Guideline Appendix 5 – Protocol for Palliative Oxygen Therapy from the BTS Home Oxygen Guideline 10.1136/bmjresp-2017-000223.supp1Supplementary file 1 10.1136/bmjresp-2017-000223.supp6 BTS Quality Standards for Home Oxygen are endorsed by:The Association for Chartered Physiotherapists in Respiratory Care (ACPRC), The Association of Palliative Medicine (APM), The Association of Respiratory Nurse Specialists (ARNS), The Association for Respiratory Technology and Physiology (ARTP), The Primary Care Respiratory Society UK (PCRS-UK). Contributors: JS and TW were lead authors responsible for the overall editing and production of the document. DF, MG, VK, WM and TW were lead authors for quality statements 1–3. JA, CL, JS and TW were lead authors for quality statements 4 and 5. RF, SH, JP and MW were lead authors for quality statements 6 and 7. CD, MH and VV were lead authors for quality statements 8–10. All authors were responsible for the final approval of the document. GG attended the meeting as the lay representative and gave feedback on the draft document.

for quality statements 4 and 5. RF, SH, JP and MW were lead authors for quality statements 6 and 7. CD, MH and VV were lead authors for quality statements 8–10. All authors were responsible for the final approval of the document. GG attended the meeting as the lay representative and gave feedback on the draft document. Funding: This project received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. Competing interests: The British Thoracic Society operates a Declaration of Interest scheme, and it was a requirement that all members of the development group completed a Declaration of Interest form on an annual basis for the duration of the project. Forms were submitted annually by all authors, and all have confirmed that none of their interests were linked to home oxygen and therefore this document. Provenance and peer review: Not commissioned; internally peer reviewed.

Key messages Can endobronchial valve placement improve health outcomes in selected patients with heterogeneous emphysema and an absence of collateral ventilation Endobronchial valves improve lung function, exercise capacity and health status at 3–6 months after the procedure Combining patient-level data from randomised controlled trials of bronchoscopic lung volume reduction with endobronchial valves strengthens the evidence that this therapy can improve lung function, exercise capacity and quality of life in appropriately selected patients with heterogeneous emphysema and absence of interlobar collateral ventilation. Background Chronic obstructive pulmonary disease (COPD) is characterised by the presence of bronchitis and emphysema. The latter process, due to breakdown of elastic alveolar tissue, leads to increased lung compliance and gas trapping. Lung hyperinflation worsens with exercise leading to breathlessness and is associated with reduced physical activity1 2 and reduced survival.3 Inhaled bronchodilator medications have only modest impacts on symptoms and do not alter the natural history of the disease. In selected patients with a heterogeneous pattern of emphysema, surgical resection can be targeted at the worst affected areas of lung tissue which contribute disproportionately to gas trapping and hyperinflation, and so improve respiratory mechanics.4 5 Lung volume reduction surgery (LVRS) improves symptoms and prolongs survival6–8 but can be associated with significant morbidity and a risk of death, with a cost per quality adjusted life year (QALY) of at least $40 000.9

te disproportionately to gas trapping and hyperinflation, and so improve respiratory mechanics.4 5 Lung volume reduction surgery (LVRS) improves symptoms and prolongs survival6–8 but can be associated with significant morbidity and a risk of death, with a cost per quality adjusted life year (QALY) of at least $40 000.9 A more recent approach has been to instead use endobronchial valves to occlude the airways supplying the worst affected part of the lung.10–13 This is intended to cause atelectasis in the target lobe, with a similar impact on the function of the rest of the lung as seen in LVRS. However, atelectasis will only occur in the absence of significant collateral ventilation between the target lobe and the adjacent one. Because of this, the success rate of valve placement in early studies was low, impacting on the value of endobronchial valves as a therapeutic intervention.13–15 Collateral ventilation can now be measured directly using the Chartis pressure/flow catheter system.16–18 Case series and single-centre trials have demonstrated that endobronchial valve treatment in patients with emphysema can lead to improvements in symptoms, lung function and exercise capacity,11–13 reductions in dynamic hyperinflation19 and improvements in oxygen kinetics20 and chest wall synchrony.21 Moreover, where target lobe volume loss is seen on CT, a substantial survival benefit has been observed compared with those where valve treatment has been ineffective.14 15

lung function and exercise capacity,11–13 reductions in dynamic hyperinflation19 and improvements in oxygen kinetics20 and chest wall synchrony.21 Moreover, where target lobe volume loss is seen on CT, a substantial survival benefit has been observed compared with those where valve treatment has been ineffective.14 15 We wished to combine data from existing single-centre studies to address the question ‘in patients with emphysema and a target lobe with proven absence of interlobar collateral ventilation, what is the effect of endobronchial valves placed to achieve lobar occlusion, on lung function, exercise capacity and health status?’ Methods The study was registered on the PROSPERO International prospective register of systematic reviews CRD42016048127. We searched PubMed using the terms ‘endobronchial valves (AND) emphysema’ on 22 September 2016. This identified 116 abstracts. Twelve of these were clinical trials. Review of the abstracts identified two trials where patients with emphysema were randomised to endobronchial valve placement or standard care with identification of the presence of interlobar collateral ventilation using the Chartis system (Pulmonx).11 12 Complete, anonymised, individual patient data were obtained from the investigators for analysis. Data were checked for: missing items, internal data consistency and randomisation integrity. Summary tables were checked with the trial protocol and latest trial report or publication.

Methods The study was registered on the PROSPERO International prospective register of systematic reviews CRD42016048127. We searched PubMed using the terms ‘endobronchial valves (AND) emphysema’ on 22 September 2016. This identified 116 abstracts. Twelve of these were clinical trials. Review of the abstracts identified two trials where patients with emphysema were randomised to endobronchial valve placement or standard care with identification of the presence of interlobar collateral ventilation using the Chartis system (Pulmonx).11 12 Complete, anonymised, individual patient data were obtained from the investigators for analysis. Data were checked for: missing items, internal data consistency and randomisation integrity. Summary tables were checked with the trial protocol and latest trial report or publication. The primary outcome measure was a comparison of change in forced expiratory volume in 1 s (FEV1) between the endobronchial valve treatment and control groups. Secondary end points were change from baseline to 3 months (BeLieVeR-HIFi) or to 6 months (STELVIO) in 6 min walk distance (6MWD), Medical Research Council (MRC) dyspnoea score and St George’s Respiratory Questionnaire (SGRQ). The different time points in the two trials were merged as a measure of the effectiveness of the intervention because the impactof the intervention was expected to be much greater than spontaneous decline over a short period of time. Statistical analysis was carried out using StatView 5. Changes were compared between treatment and control groups using unpaired t-tests. Analysis of covariance using baseline values as a covariate together with treatment allocation and which study individuals were in was used to establish whether responses differed by study. Collateral ventilaion (CV)-positive patients (n=4) treated in the BeLieVeR-HIFi were excluded.

trol groups using unpaired t-tests. Analysis of covariance using baseline values as a covariate together with treatment allocation and which study individuals were in was used to establish whether responses differed by study. Collateral ventilaion (CV)-positive patients (n=4) treated in the BeLieVeR-HIFi were excluded. No ethical approval for this reanalysis of anonymised data was obtained.

trol groups using unpaired t-tests. Analysis of covariance using baseline values as a covariate together with treatment allocation and which study individuals were in was used to establish whether responses differed by study. Collateral ventilaion (CV)-positive patients (n=4) treated in the BeLieVeR-HIFi were excluded. No ethical approval for this reanalysis of anonymised data was obtained. Results Literature search identified two studies. The UK-based BeLieVeR-HIFi trial (ISRCTN04761234) was a double-blind study which randomised 50 patients on a one-to-one basis to endobronchial valve placement, intended to achieve lobar occlusion11 or to bronchoscopy with a sham-bronchoscopy procedure. Patients were selected on the basis of hyperinflation, heterogeneous emphysema and interlobar fissure adjacent to the target lobe which appeared to be at least 90% intact. Allocation was by predetermined block randomisation, obtained by telephone link from the bronchoscopy suite after the patient had been sedated. Collateral ventilation was measured but patients were treated even if CV positive (n=4). For the purpose of the present analysis, the CV-positive patients were excluded, as they fall outside the hypothesis being addressed. Outcome measures were assessed at 3 months post procedure by investigators blind to study allocation. There were two deaths in the treatment arm, one because of complications of a valve removal procedure and one from cor pulmonale. One control patient was too unwell to attend for follow-up, so follow-up data were available for 24 control patients and 19 treated patients.

dure by investigators blind to study allocation. There were two deaths in the treatment arm, one because of complications of a valve removal procedure and one from cor pulmonale. One control patient was too unwell to attend for follow-up, so follow-up data were available for 24 control patients and 19 treated patients. A second Dutch study (STELVIO trial—Netherlands Trial Register number, NTR2876) randomised 68 hyperinflated COPD patients, with a target lobe based on visual inspection of the CT, on a one-to-one basis to endobronchial valve placement or usual care.12 Allocation was performed using a randomisation list that had been computer-generated in blocks of four. The generated codes were placed in opaque-sealed envelopes, which were numbered sequentially. The assigned envelope was opened before bronchoscopy in the presence of the patient and bronchoscopist. Bronchoscopy was then performed. Eighty-four patients entered the study, but patients with collateral ventilation (n=13) or airways unsuitable for endobronchial valve placement (n=3) were excluded. Pulmonary function tests were assessed 6 months following the procedure by blinded assessors. One control patient withdrew. One treated patient died due to end-stage COPD with respiratory failure 58 days after treatment and one was withdrawn from the study by the investigators because of a prolonged admission to the critical care unit due to COPD exacerbation caused by a viral infection. Seven patients discontinued the study because their valves had been removed—two at patient request because of perceived lack of efficacy, two because of bronchial torsion, two because of recurrent pneumothorax and one because of pneumonia distal to valve. Follow-up data for this study were therefore available for 25 treated patients and 33 controls.

study because their valves had been removed—two at patient request because of perceived lack of efficacy, two because of bronchial torsion, two because of recurrent pneumothorax and one because of pneumonia distal to valve. Follow-up data for this study were therefore available for 25 treated patients and 33 controls. The BeLieVeR-HIFi trial was funded by the Efficacy and Mechanism Evaluation Programme, funded by the MRC and managed by the National Institute for Health Research (NIHR) on behalf of the MRC-NIHR partnership (EME 10/90/10). The valves used in the trial were provided free of charge by the device company, Pulmonx. The STELVIO trial was supported by a grant (171101008, to the University Medical Centre Groningen) from the Netherlands Organisation for Health Research and Development (ZonMw) and by innovation funding from the University Medical Centre Groningen. Valves were obtained commercially from Pulmonx (all catheters at regular market prices and all valves at 50% of the market list price). Baseline data for 114 patients were available, 55% female, aged mean (SD) 60.2 (8.6) years, with a mean (SD) FEV1 30.6 (8.9)% predicted, with follow-up data available for 101 (treatment n=44 and control n=57). The groups were well matched for spirometry, gas transfer, symptoms, exercise capacity and BODE (BMI, obstruction, dyspnoea, exercise capacity) score, but the control group were more hyperinflated (table 1).

a mean (SD) FEV1 30.6 (8.9)% predicted, with follow-up data available for 101 (treatment n=44 and control n=57). The groups were well matched for spirometry, gas transfer, symptoms, exercise capacity and BODE (BMI, obstruction, dyspnoea, exercise capacity) score, but the control group were more hyperinflated (table 1). FEV1 improved by 23.1 (±28.3)% in patients treated with valves with a mean (95% CI) difference in response between groups of 17.8 (26.5, 9.2)% (P<0.0001) (figure 1, table 2). Valve placement was associated with statistically and clinically significant improvements in lung volumes (figure 2), exercise capacity (figure 3) and quality of life (figure 4). Outcomes did not differ significantly between the two trials for change in FEV1, residual volume 6MWD or SGRQ (P=0.79, 0.28, 0.16 and 0.21, respectively) although MRC dyspnoea score improved to a greater extent in the STELVIO study (P=0.002) Table 1 Baseline characteristics

FEV1 improved by 23.1 (±28.3)% in patients treated with valves with a mean (95% CI) difference in response between groups of 17.8 (26.5, 9.2)% (P<0.0001) (figure 1, table 2). Valve placement was associated with statistically and clinically significant improvements in lung volumes (figure 2), exercise capacity (figure 3) and quality of life (figure 4). Outcomes did not differ significantly between the two trials for change in FEV1, residual volume 6MWD or SGRQ (P=0.79, 0.28, 0.16 and 0.21, respectively) although MRC dyspnoea score improved to a greater extent in the STELVIO study (P=0.002) Table 1 Baseline characteristics All n=114 Control n=59 Treatment n=55 P value (t-test) Age (years)  60.2 (8.6)  60.7 (8.1)  59.7 (9.1) 0.5 Per cent female  55  66  44 0.016 BMI (kg/m2)  24.4 (4.2)  24.3 (4.1)  24.4 (4.3) 0.90 mMRC   2.7 (0.6)   2.7 (0.56)   2.7 (0.70) 0.74 Smoking (pack/years)  43.5 (23.3)  42.2 (22.6)  44.7 (24.1) 0.56 SGRQ symptoms  59.4 (20.0)  61.2 (20.7)  57.5 (19.2) 0.32 SGRQ activity  85.7 (10.9)  87.2 (9.8)  84.0 (11.8) 0.12 SGRQ impacts  50.7 (17.3)  51.3 (17.2)  50.0 (17.7) 0.68 SGRQ total  63.0 (13.5)  64.1 (13.2)  61.8 (13.9) 0.36 FEV1 (L)   0.86 (.30)   0.82 (0.28)   0.90 (0.32) 0.14 FEV1 %pred  30.6 (8.8)  30.5 (8.9)  30.6 (8.9) 0.95 TLC %pred 133.6 (13.2) 137.0 (13.1) 130.0 (12.5) 0.004 RV %pred 222.5 (37.9) 230.5 (39.2) 213.8 (34.8) 0.018 RV/TLC  60.7 (8.4)  62.4 (8.1)  58.8 (8.5) 0.026 FRC %pred 188.5 (29.7) 198.5 (29.3) 176.5 (26.2) 0.011 Tlco %pred  37.7 (9.8)  37.2 (9.8)  38.1 (9.8) 0.65 PaCO2 kPa   9.4 (1.3)   5.0 (0.6)   5.0 (0.9) 0.66 PaO2 kPa   9.4 (1.3)   9.3 (1.1)   9.4 (1.5) 0.52 6 min walk distance (m) 360 (87) 359 (85) 361 (89) 0.89 BODE score   5.9 (1.3)   5.9 (1.2)   5.9 (1.4) 0.87 BMI, body mass index; BODE, BMI, obstruction, dyspnoea, exercise capacity; FEV1, forced expiratory volume in 1 s; FRC, functional residual capacity; mMRC, modified Medical Research Council dyspnoea score; PaCO2, arterial carbon dioxide tension; PaO2, arterial oxygen tension; RV, residual volume; SGRQ, St George’s Respiratory Questionnaire; TLC, total lung capacity.

yspnoea, exercise capacity; FEV1, forced expiratory volume in 1 s; FRC, functional residual capacity; mMRC, modified Medical Research Council dyspnoea score; PaCO2, arterial carbon dioxide tension; PaO2, arterial oxygen tension; RV, residual volume; SGRQ, St George’s Respiratory Questionnaire; TLC, total lung capacity. Figure 1 Percentage change in forced expiratory volume in 1 s (FEV1) in patients treated with endobronchial valves and control subjects. Boxes represent 25th–75th percentiles, bars 10th–90th percentiles (P<0.0001). Table 2 Response to treatment

yspnoea, exercise capacity; FEV1, forced expiratory volume in 1 s; FRC, functional residual capacity; mMRC, modified Medical Research Council dyspnoea score; PaCO2, arterial carbon dioxide tension; PaO2, arterial oxygen tension; RV, residual volume; SGRQ, St George’s Respiratory Questionnaire; TLC, total lung capacity. Figure 1 Percentage change in forced expiratory volume in 1 s (FEV1) in patients treated with endobronchial valves and control subjects. Boxes represent 25th–75th percentiles, bars 10th–90th percentiles (P<0.0001). Table 2 Response to treatment Control, n=57 Endobronchial valves, n=44 Between-group difference (95% CI) t-test Δ FEV1 (mL) 40 (17) 185 (70) 150 (60 to 230) 0.0006 Δ FEV1 (%) 5.3 (14.7) 23.1 (28.3) 17.8 (26.5 to 9.2) <0.0001 Δ SGRQ symptoms −5.9 (15.2) −4.7 (22.8) 1.2 (8.7 to 6.4) 0.76 Δ SGRQ activity −0.3 (10.8) −14.7 (20.9) −14.4 (−8.0 to 20.7) <0.0001 Δ SGRQ impacts −3.7 (13.2) −14.2 (22.2) −10.4 (−3.3 to 17.5) 0.004 Δ SGRQ total −3.2 (9.8) −12.7 (20.0) −9.5 (−3.5 to 15.6) 0.0022 Δ TLC (L) 0.02 (0.6) −0.45 (0.47) −0.47 (−0.22 to 0.73) 0.0004 Δ RV (L) −0.06 (0.36) −0.70 (0.52) −0.64 (−0.425 to 0.863) <0.0001 Δ RV/TLC (%) −0.7 (3.4) −5.95 (7.3) −5.2 (−3.0 to 7.4) <0.0001 Δ FRC (L) 0.82 (0.48) −0.53 (0.66) −0.61 (−0.38 to 0.83) <0.0001 Δ Tlco(%predicted) 0.02 (12.8) 5.80 (14.6) 5.7 (11.6 to 0.03) 0.051 Δ PaCO2 (kPa) −0.01 (0.43) −0.14 (0.59) −0.13 (0.07 to 0.34) 0.02 Δ PaO2 (kPa) 0.21 (0.97) −0.29 (1.1) −0.50 (0.07 to 0.93) 0.03 Δ 6MWD (m) −5.6 (61.1) 58.6 (87.2) 64.2 (94.0 to 34.5) <0.0001 6MWD, 6min walk distance; FEV1, forced expiratory volume in 1 s; FRC, functional residual capacity; PaCO2, arterial carbon dioxide tension; PaO2, arterial oxygen tension; RV, residual volume; SGRQ, St George’s Respiratory Questionnaire; Tlco, carbon monoxide transfer factor.

1.1) 58.6 (87.2) 64.2 (94.0 to 34.5) <0.0001 6MWD, 6min walk distance; FEV1, forced expiratory volume in 1 s; FRC, functional residual capacity; PaCO2, arterial carbon dioxide tension; PaO2, arterial oxygen tension; RV, residual volume; SGRQ, St George’s Respiratory Questionnaire; Tlco, carbon monoxide transfer factor. Figure 2 Change in residual volume (RV) in patients treated with endobronchial valves and control subjects. Boxes represent 25th–75th percentiles, bars 10th–90th percentiles (P<0.0001). Figure 3 Change in 6 min walk distance (6MWD) in patients treated with endobronchial valves and control subjects. Boxes represent 25th–75th percentiles, bars 10th–90th percentiles (P<0.0001). Figure 4 Change in St George’s Respiratory Questionnaire (SGRQc) in patients treated with endobronchial valves and control subjects. Boxes represent 25th–75th percentiles, bars 10th–90th percentiles (P=0.0022). Adverse events are described in table 3. There were a total of eight pneumothoraces in the treatment arm and one in a control subject during the follow-up period. Table 3 Serious adverse events Treatment, n=55 Control, n=59 Exacerbations requiring hospitalisation 9 5 Pneumonia (respiratory tract infection with X-ray changes) 4 1 Pneumothorax 8 1 Deaths 3 0 Respiratory failure 2 0 COPD with cor pulmonale 1 0 COPD, chronic obstructive pulmonary disease.

Adverse events are described in table 3. There were a total of eight pneumothoraces in the treatment arm and one in a control subject during the follow-up period. Table 3 Serious adverse events Treatment, n=55 Control, n=59 Exacerbations requiring hospitalisation 9 5 Pneumonia (respiratory tract infection with X-ray changes) 4 1 Pneumothorax 8 1 Deaths 3 0 Respiratory failure 2 0 COPD with cor pulmonale 1 0 COPD, chronic obstructive pulmonary disease. Discussion The present data combine results from two randomised controlled trials which evaluated the impact of endobronchial valve placement to achieve lobar occlusion in patients with heterogeneous emphysema, where collateral ventilation had been excluded using the Chartis catheter system.11 12 They further strengthen the evidence that endobronchial valve treatment can, in appropriately selected patients, produce clinically meaningful improvements in lung function, exercise capacity and health status. The amplitudes of changes exceeded conventionally defined minimum clinically important differences (MCID)—a 15% increase for FEV1, 350 mL reduction for the residual volume,22 an increase of 26 m for the 6MWD23 and a 4-point decrease in the SGRQc.24 25 It also exceeds the more recently proposedMCID of 7 SGRQ points at 6 months for bronchoscopic interventions in advanced COPD.26

inimum clinically important differences (MCID)—a 15% increase for FEV1, 350 mL reduction for the residual volume,22 an increase of 26 m for the 6MWD23 and a 4-point decrease in the SGRQc.24 25 It also exceeds the more recently proposedMCID of 7 SGRQ points at 6 months for bronchoscopic interventions in advanced COPD.26 Methodological issues We combined data from two studies which were similar in that they randomised patients with severe emphysema and a suitable target lobe to endobronchial valve placement or usual care. The trials were well conducted with study methodology including allocation and blinding clearly described with a low risk of bias. There were a number of differences between the studies, though we do not feel that they preclude combining the data as we have done. Follow-up was at 3 months in the BeLieVeR-HIFi study11 and 6 months in STELVIO,12 but the size of the response observed is significantly larger than the likely spontaneous decline over that time period. The former study included a control bronchoscopy, so participants were blind to treatment allocation whereas treatment was open label in STELVIO. This might have influenced response to questionnaires or exercise tests which are effort dependent, but in fact, improvements in these with treatment were similar between studies. Of note, the improvement in SGRQ score exceeded the 8-point threshold used in the National Emphysema Treatment Trial to allow for the lack of blinding in that study.6

response to questionnaires or exercise tests which are effort dependent, but in fact, improvements in these with treatment were similar between studies. Of note, the improvement in SGRQ score exceeded the 8-point threshold used in the National Emphysema Treatment Trial to allow for the lack of blinding in that study.6 Hazards of therapy Our study extends the data available on harms associated with endobronchial valve placement. Acute exacerbation-like events are common in the early period after valve placemen. Pneumothorax remains a significant concern, occurring in 15% of individuals treated. Pneumothoraces occur because the valve placement has been effective, causing a change in the conformation of the lung which leads to tearing and air leakage. For this reason, pneumothorax was unusual in early trials,13 but the rate has increased as selection criteria for trials have become more precise.11 12 27 Most of these episodes respond to conventional treatment with an intercostal drain but they can be fatal, especially in a group of patients who already have significant ventilatory limitation. It is therefore recommended that patients should be observed for several days as an inpatient following the procedure.

11 12 27 Most of these episodes respond to conventional treatment with an intercostal drain but they can be fatal, especially in a group of patients who already have significant ventilatory limitation. It is therefore recommended that patients should be observed for several days as an inpatient following the procedure. Conclusion This analysis provides further evidence for the efficacy of endobronchial valves as a therapeutic option in COPD patients with advanced emphysema. Longer-term data are becoming available suggesting that benefits, including survival benefits,14 of valve treatment are sustained and suggest that this may be a relatively high-value therapy in COPD,28 with a cost per QALY of approximately €25 000.29 Good outcomes from lung volume procedures will depend on a multidisciplinary approach and the development of effective referral pathways.7 8 28 30 Further work is needed to establish the relative long-term benefits of valve placement and LVRS. TheComparative Effectiveness of Lung volume reduction surgery for eEphysema and Bronchociopic valve placement (CELEB) trial is now underway to address this http://www.isrctn.com/ISRCTN19684749 This analysis was supported by the NIHR Respiratory Biomedical Research Unit at Royal Brompton and Harefield NHS Foundation Trust and Imperial College, London, UK.

Conclusion This analysis provides further evidence for the efficacy of endobronchial valves as a therapeutic option in COPD patients with advanced emphysema. Longer-term data are becoming available suggesting that benefits, including survival benefits,14 of valve treatment are sustained and suggest that this may be a relatively high-value therapy in COPD,28 with a cost per QALY of approximately €25 000.29 Good outcomes from lung volume procedures will depend on a multidisciplinary approach and the development of effective referral pathways.7 8 28 30 Further work is needed to establish the relative long-term benefits of valve placement and LVRS. TheComparative Effectiveness of Lung volume reduction surgery for eEphysema and Bronchociopic valve placement (CELEB) trial is now underway to address this http://www.isrctn.com/ISRCTN19684749 This analysis was supported by the NIHR Respiratory Biomedical Research Unit at Royal Brompton and Harefield NHS Foundation Trust and Imperial College, London, UK. Contributors: KK, ZZ, CD, D-JS and PLS conceived the study and developed the search strategy. NSH performed the literature search, collected data, performed the analysis and wrote the first draft to which all authors contributed. All authors have approved the submitted version. NSH is the guarantor. Funding: This analysis was supported by the NIHR Respiratory Biomedical Research Unit at Royal Brompton and Harefield NHS Foundation Trust and Imperial College, London, UK.

Contributors: KK, ZZ, CD, D-JS and PLS conceived the study and developed the search strategy. NSH performed the literature search, collected data, performed the analysis and wrote the first draft to which all authors contributed. All authors have approved the submitted version. NSH is the guarantor. Funding: This analysis was supported by the NIHR Respiratory Biomedical Research Unit at Royal Brompton and Harefield NHS Foundation Trust and Imperial College, London, UK. Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf. NSH was principal investigator in a UK NIHR funded trial (BeLieVeR-HIFi) for which PulmonX provided endobronchial valves free of charge. PLS has been an investigator on studies funded by PulmonX, Uptake, Holaria, CSA Medical, Uptake Medical, Olympus and PneumRx/BTG and received consultancy fees from for Broncus, CSA Medical, Medtronic, Olympus, PneumRx/BTG and Pulmonx. KK received lecture fees from Pulmonx and devices for treatments, travel support, and grant support from PneumRx/BTG and Pulmonx. D-JS has been an investigator on studies funded by CSA Medical, Holaira, PulmonX and PneumRx/BTG and received consultancy fees from CSA Medical, Holaira, PneumRx/BTG and Pulmonx. Provenance and peer review: Not commissioned; externally peer reviewed. Data sharing statement: Requests to access the data can be made to the corresponding author.