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Cognitive behavioural approaches for managing dyspnoea in people with chronic obstructive pulmonary disease (COPD)

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Versión publicada: 04 agosto 2021 Historial de versiones

https://doi.org/10.1002/14651858.CD014957
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Abstract

Objectives

This is a protocol for a Cochrane Review (intervention). The objectives are as follows:

To evaluate the effectiveness of cognitive behavioural therapy (CBT) for the management of dyspnoea in patients with chronic obstructive pulmonary disease (COPD).

Background

Description of the condition

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) defines chronic obstructive pulmonary disease (COPD) as a common, preventable, and treatable condition characterised by persistent respiratory symptoms and airflow limitation due to airway or alveolar abnormalities (or both) usually caused by significant exposure to noxious particles or gases (GOLD 2021). COPD usually presents later in life but early life events (e.g. lower respiratory tract infections) may contribute to impaired lung function in adults (Martinez 2016). Risk factors such as cigarette smoking and exposure to biomass fumes are common attributable aetiologies (GOLD 2021). COPD is a progressive disease and there is currently no known cure (GOLD 2021). In 2016 COPD global prevalence was estimated at 251 million cases (López‐Campos 2016), accounting for an estimated 3.17 million deaths worldwide in 2015 (five per cent of total deaths) (GOLD 2021). In the UK, COPD is the fifth leading cause of mortality, accounting for approximately 30,000 deaths each year, 90% of these in adults aged over 65 years (NHS 2016). One in eight (130,000) emergency admissions to hospital in the NHS are COPD‐related (NHS 2016). Hospital admissions for COPD account for USD 13.2 billion of the nearly USD 50 billion annual costs of care in the USA (Shah 2016).

Symptoms of COPD may include dyspnoea (at rest or on exertion), cough (with or without sputum production) and progressive restriction of activity, especially when accompanied by a history of exposure to COPD triggers such as tobacco smoke, occupational dust, indoor biomass smoke, a family history of chronic lung disease, or presence of associated comorbidities (such as lung cancer, bronchiectasis, cardiovascular disease, cerebrovascular disease, osteoporosis, metabolic syndrome, skeletal muscle weakness, anxiety, depression, and cognitive dysfunction) (GBD 2020; GOLD 2021). Patients may also present with extra‐pulmonary symptoms, including alteration in weight, or feelings of depression or anxiety. Airflow limitation is confirmed by spirometry, with a forced expiratory volume in one second/forced vital capacity (FEV1/FVC) ratio of less than 0.7 (NICE 2018). Airflow limitation is classified according to four levels of severity: mild (FEV1 of 80% or more than predicted), moderate (FEV1 between 50% and 79% of predicted), severe (FEV1 between 30% and 49% of predicted), and very severe (FEV1 of less than 30%) (GOLD 2021). Overall disease severity is further classified into one of four groups based on symptoms and exacerbation history: 

  1. COPD Assessment Test (CAT) score of less than 10, or modified Medical Research Council Dyspnoea Scale (mMRC) score of zero or one, and up to one exacerbation not leading to hospital admission;

  2. CAT score of 10 and above, or mMRC score of two and above, and up to one exacerbation not leading to hospital admission;

  3. CAT score less than 10, or mMRC score of zero or one, and two or more exacerbations not leading to hospitalisation or one or more exacerbation leading to hospital admission; or

  4. CAT score of 10 and above, or mMRC score of two and above, and two or more exacerbations not leading to hospitalisation or one or more exacerbation leading to hospital admission (GOLD 2021).

Breathlessness (dyspnoea) is a key feature of COPD; more severe dyspnoea is associated with a higher risk of exacerbations (O'Donnell 2020). Women, smokers, older people, people with a body mass index over 30kg/m2, and those with a diagnosis of heart failure and past history of COPD exacerbations are more likely to report severe dyspnoea (Müllerová 2014). 

The main aims of COPD management are to reduce mortality, preserve lung function, reduce symptoms, prevent exacerbations and improve quality of life (GOLD 2021). Pharmacological therapies, such as short‐ and long‐acting beta‐agonists (LABA) and long‐acting muscarinic antagonists (LAMA), can enable airways dilatation. Inhaled corticosteroids (ICS) and long‐term macrolides (Albert 2011) can reduce airway inflammation, are commonly used to prevent or reduce symptoms in COPD (GOLD 2021; Rogliani 2018). Non‐pharmacological interventions, such as pulmonary rehabilitation and self‐management programmes that aim to improve symptom management and self‐care, may also include the management of breathlessness (Burge 2020; Lenferink 2017; Ngai 2016; Puhan 2016).

Dyspnoea in COPD

Booth 2019 describes dyspnoea as a complex and distressing experience involving both body and mind; it is also a predictor of mortality and use of healthcare resources (Parshall 2012). Dyspnoea can be described using several terms, such as: severe breathlessness, shortness of breath, distress with breathing, refractory breathlessness, exertional breathlessness, episodic breathlessness and chronic breathlessness (GOLD 2021; Laviolette 2014; Marlow 2019). It is one of the key symptoms of COPD, and originates from a complex combination of physiological and psychological mechanisms (Jolley 2009) that substantially contribute to disease burden and poor quality of life (GOLD 2021). Diverse processes contribute to the perception of dyspnoea, which involve sensory information relayed to the brain where respiratory‐related signals are combined with contextual, cognitive, and behavioural influences. The brain generates predictions about the sensations the body should be feeling. If there is a mis‐match between what the body thinks it should be feeling and sensory information, perceptions, such as breathlessness, may be altered (Marlow 2019).  In COPD, the threshold of perceived breathlessness is lowered, leading to refractory dyspnoea which persists at rest or with minimal activity (despite optimal therapy for the underlying condition) (Mahler 2013). Breathing is commonly an unconscious activity but disturbance of normal mechanisms may lead to conscious perception of breathing, especially if the sensation is unpleasant (Laviolette 2014). Dyspnoea may therefore be described as a heightened level of awareness of the uncomfortable sensation of feeling breathless (Heslop 2013; Heslop‐Marshall 2018a).

Although the physiological mechanisms behind dyspnoea in patients with COPD often arise from inadequate ventilation, dyspnoea may correlate poorly with lung function (Wolkove 1998). The impact of psychological factors on the perception of dyspnoea is an area of increasing interest, with growing evidence of an association between anxiety and dyspnoea that is independent from FEV1 (Chavannes 2005; Leivseth 2012; Yohannes 2014). For example, COPD patients who also suffer from anxiety report worse dyspnoea compared to those without panic disorders, or healthy age‐matched controls (Livermore 2015). Anxiety about breathlessness may initiate a vicious cycle of avoidance behaviour where patients avoid exertions that may trigger this unpleasant symptom (Parshall 2012). This may lead to an increase in sedentary behaviour, physical deconditioning, reduced control and loss of confidence (Bailey 2004; Parshall 2012). Furthermore, anxiety and dyspnoea are associated with significantly worse health‐related quality of life in people with COPD, mediated by dyspnoea‐related fear that may present as an indirect marker for breathlessness (Parshall 2012). 

Treatment strategies for managing dyspnoea are generally divided into pharmacological (e.g. LABA, LAMA, ICS, opioids; anti‐depressants; and supplemental oxygen), and non‐pharmacological (e.g. breathing techniques). Booth 2019 suggests three groups of non‐pharmacological interventions: those that affect breathing (e.g. fan therapy, breathing exercises and neuromuscular electrical stimulation); those that target the central perception of breathlessness (e.g. education, relaxation techniques, cognitive behavioural therapy, and active listening); and interventions that affect functioning (e.g. exercise programmes, mobility aids, and pacing skills) (Laviolette 2014). Tailored therapies that address refractory breathlessness and improve exercise capacity are needed to enhance health outcomes, particularly in advanced COPD (Currow 2014). 

Description of the intervention

Cognitive behavioural therapy (CBT) is a psychological talking therapy based on the premise that thoughts and behaviours influence feelings that in turn may change the way we think about or react to situations (NHS 2016). Cognitive behavioural approaches focus on understanding how experiences develop and explores the complex interactions between physical symptoms, thoughts, mood, behaviour and environments (David 2018; Deary 2018; Marshall 2018). The aim of therapy is to develop a more positive way of thinking about the specific problem that may in turn lead to a more helpful behavioural response (Heslop‐Marshall 2018b). Most CBT research focuses on people with mental health problems, but growing evidence supports its use in chronic illness to help people cope with the psychological aspects of physical conditions, such as the debilitating symptoms associated with dyspnoea, where behavioral adaptation may improve self‐care (Heslop‐Marshall 2018b; White 2003).

Different models and methods of delivering cognitive behavioural approaches are classified as ‘waves’ (Dobson 2019). ‘Waves’ are a concept which refers to the evolutionary development of approaches that are currently considered under the broad term cognitive and behavioural therapies (Ruggiero 2018). The first wave comprises behavioral therapy alone; CBT is a second‐wave approach that combines cognitive and behavioural therapy. Third‐wave CBT approaches are an evolution from existing traditional CBT approaches to a more process‐oriented cognitive therapy that focuses on context, relationship, emotion and acceptance, rather than primarily on symptoms and techniques to reduce those symptoms (Dimidjian 2016). Cognitive behavioural approaches are therefore characterised as structured, goal‐oriented, problem‐focused, and time‐limited (Dobson 2019).

Cognitive behavioural therapy interventions comprising the same elements may still vary by: mode of delivery (e.g. face‐to‐face, mediated via telephone, self‐directed); frequency of sessions (e.g. daily, weekly, fortnightly); length of sessions; duration of the intervention; who delivers the CBT (e.g. psychologist, social worker, nurse, computer program); setting in which the treatment is delivered (e.g. hospital, health centre, private clinic); and whether the therapy is delivered in a group or individual format (Tolin 2010). Cognitive behavioural interventions range from 12 to 15 weeks' duration (high intensity) to less than 10 weeks' duration (brief intervention), and sessions typically last from 30 to 90 minutes, depending on the individual's specific problem (Williams 2020).

Cognitive behavioural approaches often adopt a stepped approach, ranging from low‐resource options (e.g. education about the condition and patient awareness) to high‐resource intensive interventions (e.g. applied relaxation, counselling, or psychodynamic therapy) (Williams 2015; Williams 2020). For example, cognitive behavioural approaches for COPD patients may initially explore pacing and breathing controls that teach patients about planning, how to avoid a loss of control over breathing, and how to recognise symptoms, modify thinking and change behaviour to break vicious cycles (Heslop‐Marshall 2018a). Where processes have minimal impact on symptoms, therapists then typically move towards a more intensive step that may include applied relaxation or psychotherapy. These processes teach patients to recognise early signs of symptoms (e.g. dyspnoea), modifying their behaviour and minimising adverse events and detrimental cycles of catastrophisation (Andrews 2018).

How the intervention might work

Dyspnoea is a subjective experience influenced by both emotional and cognitive processes that in turn modify an individual's behaviour (Kaplan 2017). Cognitive behavioural approaches therefore aim to understand individual experiences and difficulties, correct unhelpful thinking and promote behaviour change through a goal‐orientated, systematic approach (Kaplan 2017). Previous experience, knowledge, understanding and pre‐existing anxiety and depression contribute to this subjective experience (Parshall 2012). This is an important process in chronic lung disease, where patients commonly reduce levels of activity to avoid exertional dyspnoea (Doyle 2017). Complex social and environmental contexts may influence the perception of and reaction to dyspnoea, that may adversely influence perception of capability and self‐concept. The cognitive model (Beck 1976) suggests that COPD patients catastrophise and misinterpret ambiguous bodily sensations (e.g. breathlessness) which in turn increases arousal and creates a positive feedback loop that heightens anxiety (Livermore 2015). COPD patients may interpret this experience as a loss of control of breathing (e.g. leading to asphyxia or myocardial infarction) (Livermore 2015). CBT approaches promote self‐insight that may modify the perception of ambiguous bodily sensations, reducing catastrophisation, fear, and intensity of behavioural response (Heslop‐Marshall 2019; Williams 2020).

Cognitive behavioural approaches may reduce dyspnoea in COPD through a number of different mechanisms that encompass this multidimensional perceptual experience (Singh 2019). These include: reducing sympathetic innervation and increasing parasympathetic nerve activity; reducing dynamic hyperinflation; reducing comorbid anxiety; promoting arterial oxygen saturation; promoting benefits of exercise training; and neuro‐plasticity (Anzueto 2017). These mechanisms help to prevent panic attacks and decrease the perceived severity of dyspnoea (Livermore 2015). 

Therapists treating COPD patients with CBT often look for vicious cycles of thoughts, feelings, and behaviours that lead to negative experiences (Heslop‐Marshall 2018a). For example, feeling scared of exercise and its impact on breathlessness, which in turn leads to avoidance behaviour (Heslop‐Marshall 2019). Components of CBT approaches may include: exploring unhelpful thinking; developing an understanding of the interaction between physical symptoms, thoughts, feelings, and behavior (a formulation); psycho‐education (e.g. providing information about COPD, oxygen, inhalers, how they work and when to take them); planning; pacing; breathing techniques; relaxation; positive self‐talk (e.g. saying to themselves that they will be ok); grounding techniques; mindfulness; graded exposure to activity; and sometimes behavioural experiments (testing solutions), such as ascending stairs in increments rather than all at once (Kew 2016; Marshall 2018). Depending on individuals' needs, therapists may also discuss smoking cessation and weight management strategies that are related to symptoms of COPD (Tolin 2010). A typical starting point involves identification of the triggers of exacerbations or breathlessness (Heslop‐Marshall 2019). Therapists help patients to develop self‐management plans to decrease the intensity of perceived symptoms during physical exertion and adverse events (exacerbations, fear, and anxiety) (Heslop‐Marshall 2019).

Why it is important to do this review

Dyspnoea is one of the cardinal symptoms of COPD that significantly reduces health‐related quality of life, decreases engagement in physical activity and is linked to physiological and psychological triggers (O'Donnell 2020). Effective management of breathlessness is therefore a key goal of international guidelines for the care of people with COPD (GOLD 2021). Recent studies of consumers (patients and carers) and clinicians suggest that relief of breathlessness should be a top research and healthcare priority for individuals living with COPD (Michalovic 2021). Consequently, alongside existing pharmacological and non‐pharmacological interventions, there is increasing interest in the potential benefits of psychological therapies, such as CBT, in enabling patients to take control of breathlessness (Doyle 2017).

Cognitive behavioural approaches have proved beneficial in helping patients manage COPD, for example, by alleviating COPD symptoms (e.g. anxiety), increasing self‐management efficacy, improving quality of life, and reducing hospital admissions (Doyle 2017; Heslop‐Marshall 2018a; Lamers 2010; Livermore 2015; Pollok 2019). However, the effectiveness of CBT approaches for managing dyspnoea in COPD is currently unclear (Williams 2020). Preliminary evidence shows that CBT approaches may alter the perception of breathlessness, decreasing fearful cognitions and increasing health‐promoting behaviour (Williams 2020).

This is one of five reviews identified by a Cochrane Airways Group priority‐setting exercise involving a range of public, patient, professional and charitable stakeholders. CBT was considered an important topic due to the considerable psychological, physiological and economic burden of dyspnoea on individual patients and healthcare systems.

Objectives

To evaluate the effectiveness of cognitive behavioural therapy (CBT) for the management of dyspnoea in patients with chronic obstructive pulmonary disease (COPD).

Methods

Criteria for considering studies for this review

Types of studies

We will include parallel‐group randomised controlled trials (RCTs) and cluster‐RCTs of any duration, conducted in any setting. If we identify cross‐over trials, we will only include data from the phase prior to cross‐over to eliminate potentially irreversible carry‐over effects from the intervention. Non‐randomised trials will be excluded (controlled clinical trials) as well as trials with historical controls (not parallel). We will include studies reported in full text, those published only as an abstract and unpublished data.

Types of participants

We will include adults over 18 years of age with COPD, diagnosed according to national or international clinical guidelines (e.g. GOLD) or by a healthcare professional. We will exclude participants with respiratory comorbidities, including asthma and bronchiectasis. Where studies include populations with a range of respiratory conditions, we will include COPD participants only where data are reported separately.

Types of interventions

Cognitive behavioural therapy is defined as an intervention that involves: increasing participants' knowledge and understanding of dyspnoea; identifying and restructuring dysfunctional thinking and maladaptive beliefs; and developing emotional and behavioural compensatory strategies for the core deficits. Third‐wave therapies may include mindfulness, acceptance and commitment therapy (ACT), dialectical behavioural therapy (DBT), positive psychology, problem‐solving therapy (PST), and any purely behavioural approaches. For this review, we will include all CBT approaches and identify intervention components as behavioural, cognitive, or a combination (i.e. CBT) during data extraction. We will include studies where CBT comprises one technique alone (e.g. cognitive restructuring) or a number of techniques in combination (e.g. cognitive restructuring and mood monitoring in relation to activities). Where CBT is part of a composite intervention, we will only include studies that compare CBT plus an adjunctive treatment with the same adjunctive treatment alone, to isolate effects of the CBT alone.

We will include studies that use CBT as defined here, irrespective of duration of treatment or follow‐up, session frequency, or mode of delivery. The following comparisons will be reported separately:

  1. CBT versus usual care;

  2. CBT versus education;

  3. CBT versus other therapies for managing dyspnoea (pharmacological, e.g. opioids; and non‐pharmacological, e.g. pulmonary rehabilitation therapy); and

  4. CBT versus non‐CBT psychological therapies.

Usual care is the treatment COPD patients would normally receive from their healthcare provider. This may include advice on COPD management, including breathlessness, but not specifically about the intervention.

Types of outcome measures

We will analyse the following outcomes in the review, but we will not use them as a basis for including or excluding studies. We will include all outcomes irrespective of duration of follow‐up, but we will evaluate the impact of follow‐up in subgroup analyses.

Primary outcomes

  1. Breathlessness, measured by any validated scale that assesses domains such as sensory perceptual, distress, and functional impact of breathlessness (e.g. Borg rating scale of perceived exertion; mMRC dyspnoea scale)

  2. COPD‐related adverse events (e.g. exacerbation, distress following an exacerbation, worsening of symptoms)

Secondary outcomes

  1. Health‐related quality of life, using measures validated in a clinical setting (e.g. St George's Respiratory Questionnaire (SGRQ); Chronic Respiratory Questionnaire (CRQ); Short Form‐36 (SF36))

  2. Self‐efficacy (e.g. COPD Self‐Efficacy Scale (CSES))

  3. Anxiety and depression (e.g. Hospital Anxiety and Depression Scale (HADS))

  4. Exercise tolerance (e.g. six‐minute walk test (6MWT))

  5. Unscheduled healthcare visits (e.g. attendance at emergency departments; hospital admissions; physician appointments)

  6. Resource use (e.g. cost‐benefit; cost‐effectiveness)

We selected these outcomes as measures of improved management of dyspnoea and clinical outcomes important to patients, such as quality of life, self‐efficacy and exercise tolerance. Severe breathlessness may result in adverse events, such as exacerbations of COPD; CBT may therefore reduce breathlessness and lead to fewer adverse events. We do not anticipate many serious adverse events related to CBT and therefore elected to capture all adverse events. Secondary outcomes such as unscheduled healthcare visits and resource use may also be related to the perception of breathlessness and are likely to decrease with CBT. Poor management of dyspnoea is associated with anxiety and depression, which are likely to improve with CBT. Health‐related quality of life, self‐efficacy and exercise tolerance are also likely to improve with CBT as recipients develop better self‐management and coping strategies.

Search methods for identification of studies

Electronic searches

We will identify studies from searches of the following databases and trial registries:

  1. Cochrane Airways Trials Register (Cochrane Airways 2019), via the Cochrane Register of Studies, all years to date;

  2. Cochrane Central Register of Controlled Trials (CENTRAL), via the Cochrane Register of Studies, all years to date;

  3. MEDLINE Ovid SP 1946 to date;

  4. Embase Ovid SP 1974 to date;

  5. US National Institutes of Health Ongoing Trials Register, ClinicalTrials.gov (www.clinicaltrials.gov);

  6. World Health Organization International Clinical Trials Registry Platform (apps.who.int/trialsearch); and

  7. PsycInfo.

The proposed MEDLINE search strategy is listed in Appendix 1. This will be adapted for use in the other databases. The search strategy was developed by the Cochrane Airways Information Specialist, in collaboration with the review authors, and was peer‐reviewed by another Cochrane Information Specialist using the PRESS checklist (https://revman.cochrane.org/#/416920111712593672/dashboard/htmlView/1.2.1?revertEnabled=true#REF‐McGowan‐2016).

All databases and trials registries will be searched from their inception to the present, and there will be no restriction on language or type of publication. Handsearched conference abstracts and grey literature will be identified through the Cochrane Airways Trials Register and the CENTRAL database.

Searching other resources

We will check the reference lists of all primary studies and review articles for additional references. We will search relevant manufacturers' websites for study information. We will search on PubMed for errata or retractions from included studies published in full text, and report the date this was done within the review.

Data collection and analysis

Selection of studies

We plan to use Cochrane’s Screen4Me workflow to help assess the search results. Screen4Me comprises three components: 

  1. known assessments, a service that matches records in the search results to records that have already been screened in Cochrane Crowd (Cochrane’s citizen science platform where the Crowd help to identify and describe health evidence, http://crowd.cochrane.org) and labelled as 'RCT' or 'not an RCT'; 

  2. the RCT classifier, a machine‐learning model that distinguishes RCTs from non‐RCTs; and

  3. Cochrane Crowd, if appropriate.  

More detailed information about the Screen4Me components can be found in the following publications: Marshall 2018, McDonald 2017, Noel‐Storr 2018, Thomas 2017.

Following this initial assessment, two review authors (OH and GI) will screen the titles and abstracts of the remaining search results independently and 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 (OH and GI) will independently screen them for inclusion, recording the reasons for exclusion of ineligible studies. We will resolve any disagreement through discussion or, if required, we will consult a third review author (CK). 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).

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. One review author (OH) will extract the following study characteristics from included studies.

  1. Methods: study design, total duration of study, details of any 'run‐in' period, number of study centres and location, study setting, withdrawals and date of study.

  2. Participants: number (N), mean age, age range, gender, severity of condition, diagnostic criteria, baseline lung function, smoking history, inclusion criteria and exclusion criteria.

  3. Interventions: intervention, comparison, concomitant medications and excluded medications.

  4. Outcomes: primary and secondary outcomes specified and collected, and time points reported.

  5. Notes: funding for studies and notable conflicts of interest of trial authors.

Two review authors (OH and KK) will independently extract outcome data from included studies. 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 review author (SS). One review author (OH) will transfer data into the Review Manager file (RevMan 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 (SS) will spot‐check study characteristics for accuracy against the study report.

Assessment of risk of bias in included studies

Two review authors (GI and SS) will assess risk of bias independently for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2021). We will resolve any disagreements by discussion or by involving another author (DW). We will assess the risk of bias according to the following domains.

  • Domain 1: bias arising from the randomisation process.

  • Domain 2: bias due to deviations from the intended interventions.

  • Domain 3: bias due to missing outcome data.

  • Domain 4: bias in measurement of the outcome.

  • Domain 5: bias in selection of the reported result.

Our effect of interest is assignment to the intervention at baseline and our main outcomes are those listed in the 'Summary of findings' table. We will judge each outcome as being at low risk of bias, some concerns, or high risk of bias, according to the algorithm of version 2 of the Cochrane 'Risk of Bias' tool (RoB 2) (Higgins 2021). We will provide a quote from the study report, together with a justification for our judgement, in the 'Risk of bias' table.

We will reach an overall 'Risk of bias' judgement for a specific outcome for each study according to the following criteria.

  • Low risk of bias: the trial is judged to be at low risk of bias for all domains for this result.

  • Some concerns: the trial is judged to raise some concerns in at least one domain for this result, but not to be at high risk of bias for any domain.

  • High risk of bias: the trial is judged to be at high risk of bias in at least one domain for this result. Alternatively, the trial is judged to have some concerns for multiple domains in a way that substantially lowers confidence in the result.

We will summarise the 'Risk of bias' judgements across different studies for each of the domains listed (Higgins 2021). We will consider blinding separately for different key outcomes where necessary (e.g. for unblinded outcome assessment, risk of bias for all‐cause mortality may be very different than for a patient‐reported pain scale). 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. Review Manager 5.4 or RevMan Web will be used to generate traffic light plots of the domain‐level judgements for each outcome (RevMan 2014).

When judging sources of bias in cluster‐randomised trials we will also take account of the following. 

  1. Sequence generation using minimisation processes (this will be considered equivalent to randomisation).

  2. Risk of recruitment bias associated with recruitment of participants after randomisation of the clusters, where recruitment could be influenced by knowledge of the intervention.

  3. Imbalance of missing data across clusters.

We will only include data from the first parallel‐group phase of cross‐over studies and therefore will not need to assess bias associated with period effects. When considering treatment effects, we will take into account 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 published 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 analyse dichotomous data as odds ratios (ORs) and continuous data as the mean difference (MD) or standardised mean difference (SMD). 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‐analysis 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. If two comparisons (e.g. drug A versus placebo and drug B versus placebo) 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 or Analysis of Covariance; rate ratios from Poisson regression models; results from cluster‐RCTs adjusted for the effects of clustering) 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 low correlation between measurements in individuals. If a study reports outcomes at multiple time points, we will use change from baseline to study endpoint as a preference in meta‐analyses. We will use intention‐to‐treat (ITT) instead of completer or per protocol analyses.

Unit of analysis issues

For dichotomous outcomes, we will use participants, rather than events, as the unit of analysis (i.e. number of people admitted to hospital, rather than number of admissions per person). However, if rate ratios are reported in a study, we will analyse them on this basis. We will only meta‐analyse data from cluster‐RCTs if the available data have been adjusted (or can be adjusted), to account for the clustering.

For cross‐over trials, we will only use data from the first pre‐cross‐over phase to minimise potential bias from carry‐over effects.

Dealing with missing data

We will contact investigators or study sponsors in order 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 are able to 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 and will perform a sensitivity analysis with a fixed‐effect model. 

Subgroup analysis and investigation of heterogeneity

We plan to carry out the following subgroup analyses:.

  1. Type of therapy (e.g. cognitive, behavioural, or both).

  2. Professional group (e.g. CBT delivered by psychologists, counsellors, nurses, therapists or computer program).

  3. Duration of follow‐up (e.g. short‐term (three months or less), longer term (more than three months)).

Interventions are likely to vary by composition and method of delivery and we have therefore limited subgroup analyses to these three factors. We will use the following primary outcomes in subgroup analyses.

  1. Breathlessness.

  2. COPD‐related adverse events.

We will use the formal test for subgroup interactions in Review Manager 5 (RevMan 2014).

Sensitivity analysis

The primary analysis will include all studies and we will run a sensitivity analysis where all studies at high risk of bias are removed. We will also compare the results from a fixed‐effect model with the random‐effects model.

Summary of findings and assessment of the certainty of the evidence

We will create a 'Summary of findings' table using the following outcomes: breathlessness, adverse events, health‐related quality of life, unscheduled healthcare visits, and resource use. We will use the five GRADE considerations (risk of bias, consistency of effect, imprecision, indirectness, and publication bias) to assess the quality of a body of evidence 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), using GRADEpro GDT 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.