Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To determine whether maintenance pulmonary rehabilitation improves exercise performance, health‐related quality of life and healthcare utilization in people with COPD in comparison to usual care.
Background
Description of the condition
Chronic obstructive pulmonary disease (COPD) is currently the third leading cause of avoidable death across the world (Lozano 2013), and the fifth cause of death in countries with a high sociodemographic index (GBD 2018). Although COPD is under‐reported, there are an estimated 328 million people in the world living with this condition (Eisner 2011). Moreover, the prevalence of COPD is projected to increase over the decades due to continuous exposure to tobacco, air pollution and the aging of the world's population. There is considerable personal, social and economic burden associated with COPD (GOLD 2019). The US Center for Disease Control reports that people with COPD have an almost five‐fold increase in incapacity to work, a three‐fold increase in activity limitation due to health problems, and a 0.3‐fold increase in difficulty with daily physical activity including walking or climbing stairs (Ding 2017).
People with COPD experience dyspnea (breathlessness) on exertion, which generally increases as the disease progresses. The 'dyspnea spiral' model suggests that, to avoid dyspnea, people with COPD adopt a sedentary lifestyle, which leads to a reduction in the aerobic capacity of the peripheral muscles (Polkey 2006). This reduces functional exercise capacity, making it more difficult to undertake regular daily activities such as walking up hills, carrying heavy loads or getting dressed. In addition to sedentarism, there is evidence that the etiology of exercise limitation in people with COPD is multifactorial, involving factors such as deconditioning, hypoxia or systemic hypercapnia (or both), nutritional depletion, chronic or repetitive drug use, age, hormonal dysfunction and systemic inflammation (Maltais 2014).
Description of the intervention
Pulmonary rehabilitation is defined as a "… comprehensive intervention based on a thorough patient assessment followed by the patient tailored therapies that include, but are not limited to, exercise training, education, and behaviour change, designed to improve the physical and psychological condition of people with chronic respiratory disease and to promote the long‐term adherence to health‐enhancing behaviours" (Spruit 2013). It is recommended that people with COPD undertake pulmonary rehabilitation in order to improve peripheral muscle function, optimize self‐management, reduce symptoms, improve exercise capacity, enhance quality of life and reduce hospitalization (Spruit 2013).
Typically, pulmonary rehabilitation is a short‐term intervention, with the American Thoracic Society/European Respiratory Society (ATS/ERS) statement suggesting a duration of at least eight weeks (Spruit 2013), although longer programs have been reported (Wijkstra 1995; Guell 2000). The components of pulmonary rehabilitation include aerobic physical training as well as strength training for upper limbs and lower limbs at least twice a week, in addition to health education. Aerobic training involves up to 30 minutes of walking or cycle ergometer, or both, based on intensity prescribed by assessing functional exercise capacity. Strength training is prescribed with an intensity of 60% to 70% of the maximum load determined by one repetition maximum test (Spruit 2013). There is strong evidence supporting the benefits of pulmonary rehabilitation for people with COPD (McCarthy 2015). However, exercise capacity and health‐related quality of life diminish in the 12 months following program completion (McCarthy 2015). As a result, there is growing interest in the role of maintenance programs.
Maintenance pulmonary rehabilitation has been defined as ongoing supervised exercise at a lower frequency than the initial pulmonary rehabilitation program (Alison 2017). A number of different maintenance models have been conducted for people with COPD, ranging from once weekly supervision to monthly or less frequent supervision (Alison 2017). In addition to physical training, some programs also include continued self‐management education, strategies to improve adherence to ongoing exercise and the reduction of barriers to long‐term exercise training (Spencer 2019). The optimal frequency of contact between health professionals and patients during maintenance pulmonary rehabilitation has not been established. Remotely supervised maintenance strategies have also been tested, including the use of diaries, telephone calls or text messages, and pedometers to encourage participants to maintain the frequency and intensity of the exercise prescription (Nguyen 2009; Vasilopoulou 2017). However, the effectiveness of these monitoring and motivation strategies for maintenance benefits is still unclear. It is not known whether face‐to‐face supervision is essential to successful maintenance pulmonary rehabilitation programs, or whether remote strategies can also be effective (e.g. telerehabilitation, where supervision is provided via videoconferencing or via the telephone). The role of technology to support long‐term maintenance of gains following pulmonary rehabilitation has not been defined (Holland 2017). The costs of delivering maintenance programs are likely to vary across different models, but these costs have not been well documented and the impact of maintenance programs on other healthcare costs (e.g. hospitalization) is not totally known. One previous systematic review and meta‐analysis showed that supervised maintenance exercise was effective in reducing the rate of respiratory cause hospital admissions (Jenkins 2018). However, other outcomes such as direct care costs during the follow‐up period, adverse events, exercise capacity and quality of life were not reported. An additional systematic review reported that supervised exercise programs after pulmonary rehabilitation were more effective than usual care in maintaining exercise capacity in the medium term; however, the small number of studies precluded conclusions about longer‐term outcomes (Beauchamp 2013). Additional studies have since been published, providing opportunity to better understand the effects of maintenance rehabilitation across a broader range of outcomes.
How the intervention might work
The aim of a maintenance pulmonary rehabilitation program is to maintain physical capacity, quality of life and avoid hospital admissions in the long term (Güell 2017). It is generally assumed that 'graduates' of pulmonary rehabilitation can exercise and manage their health with a degree of independence, such that less‐frequent supervision is sufficient. It is likely that the efficacy of maintenance pulmonary rehabilitation programs depends on the ability to support long‐term adherence to exercise training and health‐enhancing behaviors, such that physical fitness can be maintained and effective self‐management employed. However, the essential components of maintenance pulmonary rehabilitation, and their mode of action, have not been established.
Why it is important to do this review
The benefits of pulmonary rehabilitation for people with COPD are clinically important, but research suggests that they do not last (Beauchamp 2013). It is important to identify effective, accessible methods that sustain the benefits of pulmonary rehabilitation over time using a cost‐effective method (Nici 2019). Effective strategies that could maintain the benefits of pulmonary rehabilitation would be valuable for patients, their communities and the health system. However, there is currently no consensus on what should happen after pulmonary rehabilitation is finished. There are a growing number of randomized controlled trials (RCTs) investigating maintenance pulmonary rehabilitation but their heterogeneity (particularly with regard to the degree of supervision provided) and variable quality makes it difficult to apply their findings. New models of maintenance are also emerging (e.g. telerehabilitation and home‐based programs), but their effects are not clear. Pulmonary rehabilitation guidelines for Australia/New Zealand concluded that programs offered monthly or less were ineffective in maintaining the gains post pulmonary rehabilitation, but there was insufficient evidence to draw conclusions about maintenance programs that were offered more frequently (Alison 2017). There is an urgent need to clarify the effects of maintenance programs following pulmonary rehabilitation, including the most effective supervision strategy.
Objectives
To determine whether maintenance pulmonary rehabilitation improves exercise performance, health‐related quality of life and healthcare utilization in people with COPD in comparison to usual care.
Methods
Criteria for considering studies for this review
Types of studies
We will include RCTs and cluster randomized trials, but will only meta‐analyze data from such trials if they have been adjusted to account for clustering (or if we can adjust them ourselves). We will include studies reported in full text. To avoid publication bias, we will include those published as an abstract only, and unpublished data and attempt to contact the authors to request more information if necessary. We will not include crossover trials due to the potential for carryover effects in behavioral interventions such as maintenance programs.
Types of participants
We will include adults (aged 18 years and older) with a diagnosis of COPD (e.g. according to Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria, or the author’s definition), who have undertaken a pulmonary rehabilitation program.
Pulmonary rehabilitation will be defined according to Spruit 2013, as " … a comprehensive intervention based on a thorough patient assessment followed by patient tailored therapies that include, but are not limited to, exercise training, education, and behavior change, designed to improve the physical and psychological condition of people with chronic respiratory disease and to promote the long‐term adherence to health‐enhancing behaviours."
We will include studies that incorporate a mix of chronic diseases only where outcomes for participants with COPD are reported separately.
We will exclude participants who have a primary diagnosis of another chronic pulmonary disease such as asthma, bronchiectasis, cystic fibrosis and interstitial lung disease.
Types of interventions
We will include studies that compare maintenance pulmonary rehabilitation to attention control or usual care.
Maintenance pulmonary rehabilitation will be defined as supervised exercise training at a lower frequency than the initial pulmonary rehabilitation program with or without other components such as education and self‐management training (Alison 2017). Supervision may be provided face‐to‐face or remotely, for instance using technology such as telephone or internet. Maintenance program of any duration will be included.
Attention control is defined as an additional contact with the patient, whereby the patient receives some aspect of attention, time or expectation (e.g. a telephone call), but without supervised training.
Usual care is the group in which participants receive only standard treatment for COPD. Usual care will not involve a supervised exercise training program.
Types of outcome measures
We will analyze the following outcomes in the review, but we will not use them as a basis for including or excluding studies.
Primary outcomes
Health‐related quality of life – measured via disease‐specific questionnaires (e.g. St George's Respiratory Questionnaire, Chronic Respiratory Disease Questionnaire) or generic health questionnaires (i.e. 36‐item Short Form, Euro‐Qol).
Exercise capacity measured by field exercise tests (e.g. 6‐minute walk test, shuttle walk tests) or laboratory exercise tests (e.g. cardiopulmonary exercise test).
All‐cause hospitalization – as defined by trialists, we will extract the number of participants who require hospital admissions, or the hospitalization rate, or both.
Secondary outcomes
Exacerbation rate – as defined by trialists, we will extract the number of participants experiencing one or more exacerbation, or the exacerbation rate, or both. We will report severe exacerbations (requiring hospitalization or emergency room admission) separately to moderate exacerbations (requiring initiation of oral antibiotics or corticosteroids, or both, but without hospital/emergency room admission) (GOLD 2019).
Mortality (all‐cause) – measured as the incidence or rate of death, assessed at the longest time available.
Direct costs of care during the follow‐up period, including intervention costs as defined by trialists.
-
Adverse events (all causes) as defined by the study authors (i.e. the number of participants with adverse events). Because maintenance programs are a long‐term interventions, all outcomes will be assessed at:
six to 12 months following completion of pulmonary rehabilitation;
greater than 12 months following completion of pulmonary rehabilitation.
Search methods for identification of studies
Electronic searches
We will identify studies from searches of the following databases and trial registries:
Cochrane Airways Trials Register (Cochrane Airways 2019), via the Cochrane Register of Studies, all years to date;
Cochrane Central Register of Controlled Trials (CENTRAL), via the Cochrane Register of Studies, all years to date;
MEDLINE OvidSP 1946 to date;
Embase OvidSP 1974 to date;
PEDro (Physiotherapy Evidence Database) all years to date;
US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.clinicaltrials.gov);
World Health Organization International Clinical Trials Registry Platform (apps.who.int/trialsearch).
The proposed MEDLINE search strategy is listed in Appendix 1. This will be adapted for use in the other databases. The Cochrane Airways Information Specialist developed the search strategy in collaboration with the protocol authors.
We will search all databases and trials registries from their inception to the present, and there will be no restriction on language or type of publication. We will identify handsearched conference abstracts and grey literature through the Cochrane Airways Trials Register and the CENTRAL database.
Searching other resources
We will check the reference lists of all primary studies for additional references.
We will search for errata or retractions from included studies published in full text on PubMed and report the date this was done within the review.
Data collection and analysis
Selection of studies
Two review authors (CM, SJ) will independently screen titles and abstracts of the search results using Covidence software (Covidence), and will code them as 'retrieve' (eligible or potentially eligible/unclear) or 'do not retrieve'. We will retrieve the full‐text study reports of all potentially eligible studies and two review authors (CM, SJ) will independently screen them for inclusion, recording the reasons for exclusion of ineligible studies. Any disagreements will be resolved by consensus or determination of a third review author (AEH). We will identify and exclude duplicates and collate multiple reports of the same study so that each study, rather than each report, is the unit of interest in the review. We will record the selection process in sufficient detail to complete a PRISMA flow diagram and 'Characteristics of excluded studies' table (Moher 2009).
We will use a standardized data collection form customized that will describe study characteristics, outcome data and risk of bias judgments. The template will be piloted on at least one study in the review prior to proceeding with full data extraction.
Data extraction and management
We will use a data collection form for study characteristics and outcome data, which has been piloted on at least one study in the review. Two review authors (CM, SDC) will independently extract the following study characteristics from included studies.
Methods: study design, duration of the intervention, length of follow‐up, study location, study setting, withdrawals, date of study.
Participant characteristics: number, mean age, age range, gender, diagnosis, severity of condition, diagnostic criteria, number of comorbidities, baseline lung function, smoking history, inclusion criteria, exclusion criteria.
Interventions: intervention, comparison, concomitant medications.
Outcomes: primary and secondary outcomes specified and collected (at baseline and at time of intervention completion) and follow‐up measures at six to12 months or greater than 12 months.
Notes: funding for studies and notable conflicts of interest of trial authors.
We will note in the 'Characteristics of included studies' table if outcome data were not reported in a usable way. We will resolve disagreements by consensus or by involving a third person/review author (AEH). One review author (CM) will transfer data into Review Manager 5 (Review Manager 2014). We will double‐check that data are entered correctly by comparing the data presented in the systematic review with the study reports. A second review author (SDC) will spot‐check study characteristics entered into Review Manager 5 for accuracy against the study report.
Assessment of risk of bias in included studies
Two review authors (CM, SDC) will assess risk of bias independently for each study included using the criteria outlined in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will resolve any disagreements by discussion or by involving another review author (AEH). We will assess the risk of bias using the Cochrane 'Risk of bias' tool according to the following domains.
Random sequence generation.
Allocation concealment.
Blinding of participants and personnel.
Blinding of outcome assessment.
Incomplete outcome data.
Selective outcome reporting.
Other bias.
We will judge each potential source of bias as high, low or unclear and provide a quote from the study report together with a justification for our judgment in the 'Risk of bias' table.
We will summarize the 'Risk of bias' judgments across different studies for each of the domains listed and summarize results in the 'Risk of bias' table.
We will consider blinding separately for different key outcomes where necessary (e.g. for unblinded outcome assessment, risk of bias for adverse events may be very different than for a patient‐reported outcome). Due to the nature of the intervention, it is likely that it will not be possible to blind participants or personnel to the intervention. We will take this into account in the risk of bias and GRADE assessment and will consider the potential impact of lack of blinding on a case‐by‐case basis (e.g. subjective outcomes are likely to be more at risk than objective outcomes). Where information on risk of bias relates to unpublished data or correspondence with a trialist, we will note this in the 'Risk of bias' table. When considering treatment effects, we will consider the risk of bias for the studies that contribute to that outcome.
Assessment of bias in conducting the systematic review
We will conduct the review according to this protocol and justify any deviations from it in the 'Differences between protocol and review' section of the systematic review.
Measures of treatment effect
We will analyze data for each outcome, irrespective of reported participant dropout (intention‐to‐treat [ITT] analysis). We will analyze dichotomous data (hospitalization, exacerbation, mortality, adverse events) as odds ratios (OR) and continuous data as the mean difference (MD) or standardized mean difference (SMD) with 95% confidence intervals (CI). We will analyze hospitalization rate and exacerbation rate using risk ratio (incidence). We will report direct costs as costs in each group, or the difference between groups, as reported by the study authors. We will use SMDs where outcome data are reported via different metrics but deemed clinically homogeneous (e.g. data from different field walking tests or different quality‐of‐life instruments). They will not be used where such outcome data comprises a combination of both endpoint and change data. Results from analyses using SMDs will be transformed back to native metrics for ease of interpretation. If data from rating scales are combined in a meta‐analysis, we will ensure they are entered with a consistent direction of effect (e.g. lower scores always indicate improvement).
We will undertake meta‐analyses only where this is meaningful; that is, if the treatments, participants and the underlying clinical question are similar enough for pooling to make sense.
We will describe skewed data narratively (e.g. as medians and interquartile ranges for each group).
Where multiple trial arms are reported in a single study, we will include only the relevant arms in analyses. We will list the other arms in the 'Characteristics of included studies' table. If two comparisons (i.e. maintenance approach one versus usual care and maintenance approach two versus usual care) are combined in the same meta‐analysis, we will either combine the active arms or halve the control group to avoid double‐counting.
If adjusted analyses are available (analysis of variance [ANOVA] or analysis of covariance [ANCOVA]), we will use these as a preference in our meta‐analyses. If both change from baseline and endpoint scores are available for continuous data, we will use change from baseline unless there is a low correlation between measurements in individuals. If a study reports outcomes at multiple time points, we will use the data closest to the primary time point of interest (12 months).
We will use ITT or 'full analysis set' analyses where they are reported (i.e. those where data have been imputed for participants who were randomly assigned but did not complete the study) instead of completer or per‐protocol analyses.
Unit of analysis issues
Where studies randomly allocate individual participants to a maintenance intervention or control/sham, we will consider the participant as the unit of analysis. We will only meta‐analyze data from cluster‐RCTs if the available data have been adjusted (or can be adjusted), to account for the clustering. We will exclude crossover trials in this review due to the potential carryover effects of behavioral interventions.
Dealing with missing data
We will contact investigators or study sponsors to verify key study characteristics and obtain missing numerical outcome data where possible (e.g. when a study is identified as an abstract only). Where this is not possible, and the missing data are thought to introduce serious bias, we will take this into consideration in the GRADE rating for affected outcomes.
Assessment of heterogeneity
We will use the I² statistic to measure heterogeneity among the studies in each analysis. If we identify substantial heterogeneity, we will report it and explore the possible causes by prespecified subgroup analysis.
Assessment of reporting biases
If we can pool more than 10 studies, we will create and examine a funnel plot to explore possible small‐study and publication biases.
Data synthesis
We will use a random‐effects model, with the assumption that the included studies may have heterogeneous, but related, intervention effect estimates (due to the clinical nature of the intervention). We will perform a sensitivity analysis using a fixed‐effect model.
'Summary of findings' table
We will create a 'Summary of findings' table using the following outcomes.
Health‐related quality of life (generic or disease specific).
Exercise capacity: maximal or submaximal, measured directly or by a standardized field test.
All‐cause hospitalization measured as the incidence or rate of hospitalization, defined according to study authors.
Mortality.
Adverse events.
We will present effect size with 95% CIs for each outcome as well as absolute effects (generated by GRADEpro GDT software). We will use the five GRADE considerations (risk of bias, consistency of effect, imprecision, indirectness and publication bias) to assess the overall certainty of a body of evidence (low, moderate or high certainty) as it relates to the studies that contribute data for the prespecified outcomes. We will use the methods and recommendations described in Section 8.5 and Chapter 12 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011; Schünemann 2017), using GRADEpro software (GRADEpro GDT). We will justify all decisions to downgrade the quality of studies using footnotes and we will make comments to aid the reader's understanding of the review where necessary.
Subgroup analysis and investigation of heterogeneity
We will compare the effectiveness of the interventions between:
maintenance programs offered monthly or less frequently, compared to those offered more frequently;
maintenance programs using remote supervision (e.g. telerehabilitation) versus face‐to‐face supervision.
We will use the following outcomes in subgroup analyses:
health‐related quality of life;
exercise capacity;
hospitalization.
We will use the formal test for subgroup interactions in Review Manager 5 (Review Manager 2014).
Sensitivity analysis
We will examine the effects of methodological quality on the pooled estimate by removing studies that are at high or unclear risk of bias for the domains of blinding and incomplete outcome data. We will compare the results from a fixed‐effect model using the random‐effects model.
Acknowledgements
The Background and Methods sections of this protocol are based on a standard template used by Cochrane Airways.
The authors and Airways Editorial Team are grateful to the following peer reviewers for their time and comments:
Abhijna Vithal Yergolkar (consumer reviewer), India;
Jane S Watson, Anglia Ruskin University, UK;
Bernard McCarthy, National University of Ireland, Ireland;
Arwel Jones, University of Lincoln, UK.
This project was funded by the National Institute for Health Research Systematic Reviews Programme (project number 16/114/21). This project was also supported by the National Institute for Health Research (NIHR), via Cochrane Infrastructure funding to the Cochrane Airways Group. The views and opinions expressed herein are those of the authors and do not necessarily reflect those of the Health Research Systematic Reviews Programme, NIHR, National Health Service or the Department of Health.
Appendices
Appendix 1. MEDLINE search strategy
Ovid MEDLINE(R) ALL <1946 to November 27, 2019>
| # | Search terms | Results |
| 1 | Lung Diseases, Obstructive/ | 18153 |
| 2 | exp Pulmonary Disease, Chronic Obstructive/ | 53439 |
| 3 | emphysema$.tw. | 25536 |
| 4 | (chronic$ adj3 bronchiti$).tw. | 11033 |
| 5 | (obstruct$ adj3 (pulmonary or lung$ or airway$ or airflow$ or bronch$ or respirat$)).tw. | 83066 |
| 6 | (COPD or AECOPD or AECB).tw. | 43436 |
| 7 | or/1‐6 | 138721 |
| 8 | Physical Therapy Modalities/ | 35792 |
| 9 | exp Physical Fitness/ | 28424 |
| 10 | exp Physical endurance/ | 32520 |
| 11 | exp Exercise Therapy/ | 48158 |
| 12 | Physical Exertion/ | 56046 |
| 13 | exp Exercise Test/ | 62943 |
| 14 | exp Exercise/ | 185841 |
| 15 | ((pulmonary or respiratory) adj3 rehabilitation$).ti,ab. | 3912 |
| 16 | exercis$.ti,ab. | 281433 |
| 17 | (physical$ adj3 (activit$ or train$ or fitness$ or therap$)).ti,ab. | 143821 |
| 18 | interval train$.ti,ab. | 2422 |
| 19 | or/8‐18 | 549401 |
| 20 | 7 and 19 | 12068 |
| 21 | (maintain$ or maintenance).tw. | 835673 |
| 22 | Follow‐Up Studies/ | 627452 |
| 23 | follow up$.tw. | 926977 |
| 24 | support$.tw. | 1467911 |
| 25 | remind$.tw. | 18636 |
| 26 | repeat$.tw. | 524638 |
| 27 | refresh$.tw. | 3662 |
| 28 | or/21‐27 | 3802495 |
| 29 | 20 and 28 | 2961 |
| 30 | (controlled clinical trial or randomized controlled trial).pt. | 583845 |
| 31 | (randomized or randomised).ab,ti. | 594407 |
| 32 | placebo.ab,ti. | 208427 |
| 33 | randomly.ab,ti. | 322940 |
| 34 | trial.ab,ti. | 566779 |
| 35 | groups.ab,ti. | 2004545 |
| 36 | or/30‐35 | 2945595 |
| 37 | Animals/ | 6515089 |
| 38 | Humans/ | 18136026 |
| 39 | 37 not (37 and 38) | 4613687 |
| 40 | 36 not 39 | 2509215 |
| 41 | 29 and 40 | 1195 |
Contributions of authors
CM: drafting of background and methods of protocol, sifting, data extraction, risk of bias assessment and write‐up of full review.
SDC: drafting of background and methods of protocol, sifting, data extraction, risk of bias assessment and write‐up of full review.
SJ: critical review of protocol, sifting, critical review of final draft of full review.
AH: conceptual and clinical advice, drafting of background and methods of protocol, arbitrating conflicts, analysis and interpretation, approval of final draft of full review.
Contributions of editorial team
Chris Cates (Co‐ordinating Editor): checked the planned methods.
Sally Spencer (Contact Editor): edited the protocol; advised on content.
Emma Dennett (Managing Editor): co‐ordinated the editorial process; advised on content; edited the protocol.
Emma Jackson (Assistant Managing Editor): conducted peer review; edited the references and other sections in the protocol.
Elizabeth Stovold (Information Specialist): designed the search strategy.
Sources of support
Internal sources
The authors declare that no such funding was received for this systematic review, Other.
External sources
-
National Institute for Health Research, UK.
Cochrane Programme Grant 16/114/21: NHS priorities in the management of chronic respiratory disease
-
SDC, Brazil.
is supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (Process 306531/2018‐6) and Sao Paulo Research Foundation (SPRINT 17/50273‐4)
-
CM, Brazil.
is partially supported researcher by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (process number: 200042/2019‐0), and Coordenação de Aperfeiçoamento de Pessoal de Nível Superi – Brazil (CAPES) – Finance Code 001.
Declarations of interest
CM: none.
SDC: none.
SJ: is a systematic reviewer at Cochrane Airways and is funded by a National Institute for Health Research (NIHR) Programme Grant to complete work on this review.
AH: none.
New
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