Cochrane Database of Systematic Reviews

Respiratory interventions for breathlessness in adults with

advanced diseases (Protocol)

Bolzani A, Rolser SM, Kalies H, Maddocks M, Rehfuess E, Swan F, Gysels M, Higginson IJ, Booth S,
Bausewein C

Bolzani A, Rolser SM, Kalies H, Maddocks M, Rehfuess E, Swan F, Gysels M, Higginson IJ, Booth S, Bausewein C.
Respiratory interventions for breathlessness in adults with advanced diseases.
Cochrane Database of Systematic Reviews 2017, Issue 6. Art. No.: CD012683.
DOI: 10.1002/14651858.CD012683.

www.cochranelibrary.com

Respiratory interventions for breathlessness in adults with advanced diseases (Protocol)

Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

Respiratory interventions for breathlessness in adults with advanced diseases (Protocol) i

Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
[Intervention Protocol]

Respiratory interventions for breathlessness in adults with

advanced diseases

Anna Bolzani1 , Stefanie M Rolser1 , Helen Kalies1 , Matthew Maddocks2 , Eva Rehfuess3 , Flavia Swan4 , Marjolein Gysels5 , Irene J
Higginson6 , Sara Booth7 , Claudia Bausewein1

1 Department of Palliative Medicine, Munich University Hospital, LMU Munich, Munich, Germany. 2 Department of Palliative Care,
Policy and Rehabilitation, Cicely Saunders Institute, King’s College London, London, UK. 3 Institute for Medical Informatics, Biometry
and Epidemiology, Pettenkofer School of Public Health, LMU Munich, Munich, Germany. 4 Hull Medical School, University of Hull,
Hull, UK. 5 Amsterdam Institute of Social Science Research, University of Amsterdam, Amsterdam, Netherlands. 6 Department of
Palliative Care, Policy and Rehabilitation, Cicely Saunders Institute, King’s College London, London, UK. 7 Department of Palliative
Care, Cambridge University Hospitals, Cambridge, UK

Contact address: Anna Bolzani, Department of Palliative Medicine, Munich University Hospital, LMU Munich, Marchioninistr. 15,
Munich, Germany. [email protected].

Editorial group: Cochrane Pain, Palliative and Supportive Care Group.

Publication status and date: New, published in Issue 6, 2017.

Citation: Bolzani A, Rolser SM, Kalies H, Maddocks M, Rehfuess E, Swan F, Gysels M, Higginson IJ, Booth S, Bausewein C.
Respiratory interventions for breathlessness in adults with advanced diseases. Cochrane Database of Systematic Reviews 2017, Issue 6.
Art. No.: CD012683. DOI: 10.1002/14651858.CD012683.

Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT

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

To assess the effects and safety of interventions targeting respiration as the predominant underlying mechanism of effect to relieve
breathlessness in adults suffering from advanced diseases.

BACKGROUND ence whereas the medical term ’dyspnoea’ focuses more on the
This protocol is partly based on suggested wording from the clinical sign of an underlying condition (Johnson 2014). “The ex-
Cochrane Pain, Palliative and Supportive Care Review Group perience derives from interactions among multiple physiological,
(PaPaS CRG). Some wording is used from the original review psychological, social, and environmental factors, and may include
(Bausewein 2008), which this new review will update and replace. secondary physiological and behavioural responses” (Meek 1999).
Since this definition was adopted, new evidence has led to better
understanding of the mainly sensory and affective components
and that dyspnoea “must generally be distinguished from signs
Description of the condition
that clinicians typically invoke as evidence of respiratory distress,
Breathlessness or dyspnoea is defined as “subjective experience of such as tachypn(o)ea, use of accessory muscles, and intercostal re-
breathing discomfort that consists of qualitatively distinct sensa- tractions.” (Parshall 2012). Many patients with different condi-
tions that vary in intensity” (Meek 1999). The term ’breathless- tions including primary and secondary cancer, lung diseases (e.g.
ness’ reflects the patients’ perspective based on the daily experi-
Respiratory interventions for breathlessness in adults with advanced diseases (Protocol) 1
Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
chronic obstructive pulmonary disease (COPD), pulmonary hy- Management of breathlessness
pertension, cystic fibrosis, interstitial lung disease (ILD)), chronic
heart failure (CHF) or motor neuron disease/amyotrophic lat- Appropriate management to relieve breathlessness in advanced dis-
eral sclerosis (MND/ALS) suffer from this distressing symptom eases requires both pharmacological and non-pharmacological in-
(Bailey 2010; Booth 2008; Breaden 2011; Lansing 2009; Solano terventions. Different systematic reviews and meta-analyses were
2006). Breathlessness is a multifactorial and complex symptom published in recent years and analysed the effects of pharmacologi-
and an experience unique to the individual (Booth 2008). It is cal interventions such as opioids (Barnes 2016; Mahler 2013), ben-
often expressed as air hunger, work of breathing, laboured breath- zodiazepines (Simon 2016), and oxygen (Ameer 2014; Cranston
ing, awareness of respiratory distress, and shortness of breath or 2008; Sharp 2016) for breathlessness in adult patients.
chest tightness (Barnes 2016; Parshall 2012). Breathing discom- However, the use of drugs to treat breathlessness is sometimes lim-
fort is described by such phrases as ‘could not breathe fast or deep ited as they entail adverse effects and doses need to be titrated care-
enough’ or ‘could not get enough air’ or ‘suffocating’ (Guz 1997). fully. Therefore, non-pharmacological interventions are an impor-
Breathlessness is one of the most prevalent and distressing symp- tant part of the treatment of breathlessness. As mentioned above,
toms in advanced stages of malignant and non-malignant diseases. many systematic reviews analysed the effects of pharmacological
Up to 95% of patients with advanced chronic pulmonary disease, treatments, which is why we are focusing solely on non-pharma-
88% with advanced heart disease, and 70% with end stage cancer cological interventions in this review.
experience breathlessness in their last year of life (Graham 2010;
Lansing 2009; Moens 2014; Solano 2006; Teunissen 2007). The
frequency and severity of breathlessness increase during the course
of the disease until death (Bailey 2010; Breaden 2011). It is an Non-pharmacological interventions
extremely distressing symptom for the patient but also for the ac-
companying family and professional carers (Booth 2008). Many non-pharmacological interventions for the relief of breath-
Overall, breathlessness is still difficult to palliate. lessness have been developed and evaluated in recent years. For
better clarity, we therefore categorise the interventions based on
a theoretical concept developed by Booth 2014, Chin 2016 and
Description of the intervention Spathis 2017. This concept builds on the effect breathlessness has
on patients (Figure 1).

Figure 1. Perpetuation of breathlessness by vicious cycles (Booth 2014)

Respiratory interventions for breathlessness in adults with advanced diseases (Protocol) 2

Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 • Respiratory: Inefficient breathing and increased work of
breathing can be observed due to dysfunctional breathing We expect a huge number of studies and categories of interven-
patterns with an increased respiratory rate, the need for the use tions to be included. Therefore, three different reviews, based on
of accessory muscles, and dynamic hyperinflation. the theoretical concept, will be conducted. An additional review
• Cognitive-emotional: Misconceptions and paying too is planned, focusing on interventions targeting more than one un-
much attention to the sensation of breathlessness such as derlying mechanism as described above.
memories of past or negative experiences lead to anxiety, distress, In this review, we will analyse non-pharmacological interventions
feelings of panic, and thoughts about dying. targeting primarily respiration to relieve breathlessness in patients
• Physical: Persons suffering from severe breathlessness show suffering from advanced stages of disease, for example breathing
reduced physical activity with a tendency to self-isolation and the training, handheld fan, and chest wall vibration. These interven-
need for more help from others. This leads to deconditioning of tions may take place in a variety of settings, and can, with guid-
limb, chest wall and accessory muscles. ance of healthcare professionals, mostly be carried out by patients
themselves (Figure 2).

Figure 2. System-based logic model on respiration interventions for breathlessness in patients with
advanced diseases

Invasive interventions could also be classified as non-pharmaco-

logical but they will not be the focus in this review. Therefore, tions as there have been recent Cochrane reviews: pulmonary re-
we will exclude surgical procedures such as drainage, tapping, en- habilitation (McCarthy 2015), and nutrition (Ferreira 2012).
doscopy, ventilation and catheterisation.
We will also exclude the following non-pharmacological interven- How the intervention might work

Respiratory interventions for breathlessness in adults with advanced diseases (Protocol) 3

Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
As we expect several different interventions to be subsumed in OBJECTIVES
this review, there is no one underlying mechanism but various
mechanisms that target respiration by enhancing breathing. To assess the effects and safety of interventions targeting respira-
Breathing training interventions address the main physiologic im- tion as the predominant underlying mechanism of effect to relieve
pediment of respiration and focus on gentle and prolonged exha- breathlessness in adults suffering from advanced diseases.
lation and on slower and deeper breathing (Nield 2007; Spahija
1996). Examples are diaphragmatic breathing, pursed lip breath-
ing, body position exercises, and respiratory muscle training. METHODS
The mechanism by which a fan or a breeze of cool air reduces
breathlessness remains unclear, but is possibly linked to the diving
response, which causes ventilatory depression when the trigeminal Criteria for considering studies for this review
area of the face is cooled (stimulation of facial and nasopharyngeal
receptors) (Galbraith 2010). Types of studies
In-phase chest wall vibration stimulates chest wall receptors that We will include randomised controlled trials (RCTs), cluster
alter respiratory sensations and reduces the breathing discomfort RCTs, and quasi-RCTs (QRCTs). Quasi-randomisation is defined
at rest associated with steady-state hypercapnia. Although there as some pseudo-random method of allocation such as alternation,
are conflicting findings about which receptors mediate effects of date of birth, case record number or date of presentation (Higgins
vibration on ventilation, there is evidence that muscle spindles in 2011). We will include cross-over studies, if separate data for both
intercostal muscles may be responsible (Cristiano 1997; Homma time periods are presented. We will only use the data of the first
1984; Parshall 2012). period for analysis to avoid carry-over effects. We will require full
Based on a template by Rohwer 2017 we developed a system-based journal publication. Where full journal publication is not avail-
logic model in which we show how non-pharmacological inter- able, we will try to obtain data by contacting the trial authors,
ventions for breathlessness, with a focus on interventions predom- unless sufficient data for analyses are provided in online clinical
inantly targeting respiration, are implemented in the healthcare trial results, summaries of otherwise unpublished clinical trials, or
system (Figure 2). conference abstracts. QRCTs will be included in order to obtain
the full breadth of relevant trials, in particular as we expect to find
a small number of RCTs for some of the intervention categories;
Why it is important to do this review we are aware of the higher risk of bias in these studies and will
account for this in the analysis.
Non-pharmacological interventions can complement pharmaco-
logical interventions and may offer alternative treatment options
in the management of breathlessness occurring in advanced illness.
As research into this challenging, poorly managed and burden- Types of participants
some symptom is rapidly evolving, there is a need to synthesise the Adult patients aged 18 years and above, suffering from advanced
most recent evidence to inform practice and research. Our review diseases with a high prevalence of breathlessness.
aim is to aid health professionals in the treatment of breathlessness We will include studies if the majority (≥ 50%) of participants
with palliative intent and to inform patients and carers about the meet the following criteria.
evidence of non-pharmacological interventions targeting respira- • Patients suffering from cancer should have advanced local
tion to relieve breathlessness. or metastatic disease (e.g. TNM Classification of Malignant
This is an update of a Cochrane review on non-pharmacologi- Tumours (TNM) state ≥ T3 or N ≥ 1 or M ≥ 1).
cal interventions for the relief of breathlessness in advanced dis- • Patients with severe COPD should have a forced expiratory
ease (Bausewein 2008). The former review showed effectiveness of volume in one second (FEV1) predicted of < 50%.
neuromuscular electrical stimulation, chest wall vibration, walk- • Patients with pulmonary hypertension will be included if
ing aids, and breathing training. The review included 47 stud- they reach a WHO class level ≥ III, defined by Barst 2004.
ies that were categorised in different intervention groups (e.g. • Patients suffering from CHF should have New York Heart
walking aids, acupuncture, breathing training, psychological ther- Association (NYHA) stage III or IV.
apy). Since its publication, many randomised controlled studies on • Patients with ILD or idiopathic pulmonary fibrosis (IPF) :
non-pharmacological interventions have been published, includ- all studies will be included as breathlessness is the predominant
ing new intervention groups (e.g. breathlessness services). There- symptom and there are hardly any disease-specific treatment
fore, although necessary, a single review as an update of the earlier options.
review seemed infeasible. Based on the interventions used to target • Patients with neuromuscular diseases (MND, ALS): all
breathlessness, we decided to assess the interventions in different studies will be included as advanced disease is marked by the
reviews. occurrence of breathlessness.

Respiratory interventions for breathlessness in adults with advanced diseases (Protocol) 4

Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
If groups for the inclusion criteria mentioned above were stratified, Council (MRC) Breathlessness Scale, or Chronic Respiratory Dis-
we will only include the subgroups of interest. We will document ease Questionnaire (CRQ)). Other terms for breathlessness such
difficult decisions in the review. Sensitivity analysis can assess the as dyspnoea, shortness of breath and difficulty breathing will also
impact of these decisions on the review’s result. Patients included be accepted.
in the studies can be in any setting. We will exclude studies of
patients with any condition not regarded as advanced and life-
limiting such as acute or chronic asthma, or with pre-existing Secondary outcomes
diagnosis of acute asthma or acute cardiac condition as a primary • Performance parameters (e.g. walking tests, International
cause of breathlessness. Physical Activity Questionnaire (IPAQ)).
• Respiratory parameters (e.g. change in FEV1 (%)).
• Change in depression, anxiety and/or distress (e.g. Hospital
Types of interventions Anxiety and Depression Scale (HADS)).
We will include interventions targeting respiration to relieve • Quality of life (e.g. 36-Item Short Form Health Survey (SF-
breathlessness according to the following prespecified categories. 36)).
• Breathing training or breathing control exercises (e.g. • Safety outcomes:
diaphragmatic breathing, pursed lip breathing, body position
◦ Adverse events (measured as absent or present);
exercises, respiratory muscle training).
◦ Dropout rates; and
• Cool air (e.g. use of a handheld fan).
◦ Patient withdrawal from the trial, due to any reason (if
• Chest wall vibration.
mentioned).
If we find interventions of interest that do not fit in the above
categories, we will define an additional category ’Other’ or add
new categories if there is a sufficient number of studies. Search methods for identification of studies
The judgement for inclusion will be based on the study authors’
description of the intervention; any deviation from this will be
explicitly mentioned. Electronic searches
Interventions may take place in any setting, e.g. outpatient clinic,
We will search the following databases from their inception to the
home, hospital, hospice, general medical practice.
present, without date or language restrictions.
The comparator may be no treatment, placebo, attention control,
• Cochrane Database of Systematic Reviews (CDSR),the
standard care, or a different kind of therapy. We will categorise
Cochrane Library.
the control groups into ’active controls’ or ’other’ based on the
• Cochrane Central Register of Controlled Trials
description of the comparison group. We will focus on active con-
(CENTRAL), the Cochrane Library.
trols as comparison group in our primary analysis. Concomitant
• MEDLINE (Ovid).
interventions, especially pharmacological treatment, will be ac-
• Embase (Ovid).
cepted, if administered in the same way in both the control and
• PsycINFO (Ovid).
the treatment groups. If these interventions are suspected to have
• LILACS (Bireme).
some relevant influence on our outcomes we will consider this in
• CINAHL (Ebsco).
subgroup analysis.
We will search MEDLINE and Embase using both controlled vo-
cabulary (namely, MeSH in MEDLINE and EMTREE in Em-
Types of outcome measures base) and a wide range of free-text terms. To detect all RCTs we
We anticipate that studies will use a variety of outcome measures. will perform the search on MEDLINE using the Cochrane Highly
To be included, a study must have any measure of breathlessness. Sensitive Search Strategy, sensitivity-maximising version (Higgins
Adverse effects of respiration interventions will be measured as 2011).
absent or present and a narrative description of these effects will The search strategy for MEDLINE is in Appendix 1.
be given when reported. We will consider all reliable and validated
measures for the following outcomes.
Searching other resources
We will search the meta-register of controlled tri-
Primary outcomes als (mRCT) (www.controlled-trials.com/mrct), clinicaltrials.gov (
Breathlessness, measured by self-reported instruments with a focus www.clinicaltrials.gov) and the WHO International Clinical Tri-
on breathlessness or mastery of breathlessness (e.g. Baseline Dysp- als Registry Platform (ICTRP) (apps.who.int/trialsearch/) for on-
noea Index (BDI), Borg Dyspnoea Scale (BDS), Medical Research going trials. In addition, we will check reference lists of reviews

Respiratory interventions for breathlessness in adults with advanced diseases (Protocol) 5

Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
and retrieved articles for additional studies, and we will perform • Types of control condition (control intervention, control
citation searches on key articles. We will contact experts in the group).
field for unpublished and ongoing trials. We will contact study • Type of delivery (delivery mechanisms such as face-to-face,
authors where necessary for additional information. distant; group, individual; provider characteristics such as nurses,
We will perform the search in collaboration with the Information physicians, multiprofessional; setting such as outpatient clinic,
Specialist of the Cochrane Pain, Palliative and Supportive Care home, hospital).
Group.

Methods
• Study design.
Data collection and analysis
• Size of intervention and control group at baseline and
follow-up.
• Study duration and follow-up.
Selection of studies • Sources of bias (sequence generation, allocation sequence
Two review authors (AB, SR) will independently screen all titles concealment, blinding, incomplete outcome data, selective
and abstracts retrieved by the search to identify all trials that may reporting, other concerns about bias).
be eligible and for which the full paper should be obtained. Inde-
pendent review authors will eliminate studies that clearly do not
satisfy inclusion criteria, and obtain full copies of the remaining Outcomes
studies. Two review authors (AB, SR) will read these studies inde- • Key outcomes with measurement instruments.
pendently to select relevant studies, and in the event of disagree- • Timing, duration and frequency of follow-up.
ment or unclear decision to include, we will resolve disagreement • Adverse events.
with a third author (MM or CB, depending on the topic). We will • Number of withdrawals and dropouts.
not anonymise the studies in any way before assessment.
We will include a PRISMA flow chart in the full review which
will show the status of identified studies (Moher 2009) as recom- Context
mended in Part 2, section 11.2.1 of the Cochrane Handbook for • Country of origin.
Systematic Reviews of Interventions (Higgins 2011). We will include
In case multiple reports of the same study are found, we will extract
studies in the review irrespective of whether measured outcome
data of all these reports independently of each other and compare;
data are reported in a ‘usable’ way.
if data differ between reports, all authors will make a decision how
to treat this study and this will be documented in the review. We
Data extraction and management will 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
Two review authors (SR, AB, FS or MM) will independently ex- collect characteristics of the included studies in sufficient detail to
tract data using a data collection form based on a standard form populate a table of ‘Characteristics of included studies’ in the full
released by the Cochrane Effective Practice and Organisation of review. Review authors will not be involved in the data extraction
Care Group (EPOC) and check for agreement before entry into of studies they authored or co-authored.
Review Manager (RevMan 2014). Where there is disagreement, a
third author (CB or SB) will be consulted to resolve differences.
We will include information about the following. Assessment of risk of bias in included studies
Two authors (AB, MM) will independently assess risk of bias
for each study, using the criteria outlined in the Cochrane Hand-
Participant characteristics
book for Systematic Reviews of Interventions (Higgins 2011) and
• Demographic characteristics (age, gender, nationality). adapted from those used by the Cochrane Pregnancy and Child-
• Underlying disease characteristics (type and stage of birth Group.
condition). We will assess the following for each study.
• Random sequence generation (checking for possible
selection bias). We will assess the method used to generate the
Intervention allocation sequence as: low risk of bias (any truly random
• Intervention theory. process, e.g. random number table; computer random number
• Type of intervention (description of intervention, generator); unclear risk of bias (method used to generate
frequency, duration (total and per session)). sequence not clearly stated). Studies using a non-random process

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Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(e.g. odd or even date of birth; hospital or clinic record number) We will analyse dichotomous outcomes using risk ratios (RRs)
will be assessed as high risk of bias. with 95% confidence intervals (CIs). We will recategorise any cat-
• Allocation concealment (checking for possible selection egorical outcomes with more than two categories into two groups.
bias). The method used to conceal allocation to interventions We will analyse continuous data using standardised mean differ-
prior to assignment determines whether intervention allocation ences (SMDs) with 95% CIs. We will calculate standard devia-
could have been foreseen in advance of, or during, recruitment, tions, if not reported, using the methods described in the Cochrane
or changed after assignment. We will assess the methods as: low Handbook for Systematic Reviews of Interventions (Higgins 2011).
risk of bias (e.g. telephone or central randomisation; We plan to report the proportion of participants experiencing any
consecutively numbered sealed opaque envelopes); high risk of adverse effects of respiration interventions, and combine studies
bias (studies that do not conceal allocation (e.g. open list); using RRs with 95% CIs.
unclear risk of bias (method not clearly stated).
• Blinding of outcome assessment (checking for possible
Unit of analysis issues
detection bias). We will assess the methods used to blind study
participants and outcome assessors from knowledge of which We will reanalyse data, if possible, for cluster trials which have not
intervention a participant received. We will assess the methods taken clustering into account in their analysis. We will calculate
as: low risk of bias (study states that it was blinded and describes effective sample sizes and adjusted standard errors using the de-
the method used to achieve blinding); high risk of bias (no or sign effect method. We will try to obtain estimates for intraclus-
incomplete blinding); unclear risk of bias (study states that it was ter correlation coefficients from study authors or will use external
blinded but does not provide an adequate description of how it estimates obtained from comparable studies, as recommended by
was achieved). We will also report if study participants are asked Cochrane guidelines (Higgins 2011). We will document if reanal-
about their expectations of benefit of intervention/control if ysis is not feasible.
blinding is not feasible. In studies with more than two arms, we will consistently choose
• Incomplete outcome data (checking for possible attrition the active control arms in the main analysis, and, if possible, do
bias due to the amount, nature and handling of incomplete a sensitivity analysis, in which we will choose the other control
outcome data). We will assess the methods used to deal with arm. We will combine individually randomised controlled trials
incomplete data as: low risk (< 10% of participants did not and cluster RCTs in the same meta-analyses or harvest plots, but
complete the study and/or data have been imputed using these will be clearly identified (Higgins 2011).
appropriate methods); high risk of bias (used ’completer’
analysis); unclear risk of bias (insufficient information for low/ Dealing with missing data
high risk of bias category).
We will contact study authors if missing data on study charac-
• Selective reporting (checking for reporting bias). We will
teristics or outcome measures precludes study inclusion or limits
assess the methods as: low risk of bias (where it is clear that all of
use of a study at further stages of the review. If studies do not
the study’s prespecified outcomes and all expected outcomes of
report outcomes based on intention-to-treat analyses this will be
interest to the review have been reported); high risk of bias
considered as a source of bias during ’Risk of bias’ assessment. We
(where not all the study’s prespecified outcomes have been
will try to calculate effect measures or CIs wherever possible from
reported; one or more reported primary outcomes were not
available data, if we get no response.
prespecified; outcomes of interest are reported incompletely and
so cannot be used; study fails to include results of a key outcome
that would have been expected to have been reported); unclear Assessment of heterogeneity
risk of bias (insufficient information for low/high risk of bias We will assess methodological and clinical heterogeneity with ta-
category). bles documenting the following characteristics of the included
• Other bias (e.g. checking for possible biases confounded by studies.
small size. We will assess studies as being at low risk of bias (≥ • Intervention components (e.g. breathing training; cool air;
200 participants per treatment arm); unclear risk of bias (50 to chest wall vibration).
199 participants per treatment arm); high risk of bias (< 50 • Intervention delivery mechanism (e.g. face-to-face, distant).
participants per treatment arm)). • Provider characteristics (e.g. nurses, physiotherapists,
We will use the Review Manager tool to complete a ’Risk of bias’ physicians).
table (RevMan 2014). Any discrepancy between the two authors • Setting (e.g. outpatient clinic, hospice, home).
will be resolved by discussion involving a third author (CB). • Patients (e.g. COPD, cancer, fibrosing lung disease).
• Methods (outcome measures, outcome assessment).
For those studies assessing the impacts of a given intervention
Measures of treatment effect category on comparable outcomes, thus making pooling through

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Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
meta-analysis feasible, we will assess statistical heterogeneity graph- Quality of the evidence
ically with a forest plot by examining the extent to which CIs over- This section is taken from the Cochrane Drugs and Alcohol Group
lap, and statistically with the I2 statistic. We will consider an I2 recommended text. The overall quality of the evidence for each
value greater than 50% to indicate substantial statistical hetero- outcome in our review will be assessed using the GRADE system
geneity, and will consider it statistically significant if the P value for (GRADEpro GDT 2015) and presented in the ’Summary of find-
the Chi2 test is < 0.1. We will document statistical heterogeneity ings’ tables, to present the main findings of a review in a transpar-
but this will not have any direct consequences for meta-analysis ent and simple tabular format. In particular, we will include key
(see below). We will create forest plots and I2 calculations using information concerning the quality of evidence, the magnitude of
Review Manager 5.3 (RevMan 2014). effect of the interventions examined, and the sum of available data
on the main outcomes.
The GRADE system uses the following criteria for assigning grade
Assessment of reporting biases of evidence.
• High: we are very confident that the true effect lies close to
We will try to minimise publication bias by searching trials registers that of the estimate of the effect.
for projected and registered studies that have never been published. • Moderate: we are moderately confident in the effect
We will contact the authors to get unpublished information if estimate; the true effect is likely to be close to the estimate of
there are such studies registered or some relevant information is effect, but there is a possibility that it is substantially different.
missing and can therefore narrow the risk of reporting bias. We • Low: our confidence in the effect estimate is limited; the
will assess the possibility that publication bias affects the review true effect may be substantially different from the estimate of the
using funnel plots when at least 10 studies are available for meta- effect.
analysis. • Very low: we have very little confidence in the effect
estimate; the true effect is likely to be substantially different from
the estimate of effect.
Data synthesis
We will decrease grade rating by one (- 1) or two (- 2) if we identify:
We will attempt to pool all studies within a given intervention • serious (-1) or very serious (-2) limitation to study quality;
category assessing the same outcome by conducting a meta-anal- • important inconsistency (-1);
ysis using Review Manager 5.3 (RevMan 2014). We will use the • some (-1) or major (-2) uncertainty about directness;
random-effects model due to the expected large heterogeneity in • imprecise or sparse data (-1); or
delivery mechanisms, provider characteristics, setting and study • high probability of reporting bias (-1).
population.
We will report results as RRs for dichotomous outcomes and
SMDs for continuous outcomes. We will undertake meta-analysis Subgroup analysis and investigation of heterogeneity
only if studies are judged to be similar enough to give a clinically We will undertake subgroup analysis for the primary outcomes
meaningful answer. We will provide an outcome table and sum- to examine factors that may explain variation in the effectiveness,
marise the results narratively if meta-analysis is not possible. if numbers are sufficiently large. We will perform stratification as
In the case of skewed data, we will log transform these data for follows.
our analysis or, if that approach is not feasible, summarise them • Type of intervention.
narratively. • Intervention delivery (delivery mechanisms such as face-to-
face, distant; group, individual; provider characteristics such as
nurses, physicians, multiprofessional; setting such as outpatient
clinic, home, hospital).
’Summary of findings’ table
• Patient characteristics (underlying disease, disease stage,
We will include a ’Summary of findings’ table using the GRADE age, gender).
profiler software (GRADEpro GDT 2015) as set out in the PaPaS • Underlying therapy.
author guide (AUREF 2012) and recommended in the Cochrane
Handbook for Systematic Reviews of Interventions, Chapter 4.6.6
(Higgins 2011) to evaluate the quality of evidence in our review. Sensitivity analysis
The ’Summary of findings’ table will include outcomes: of a) We will conduct sensitivity analysis where possible, to test the
change of breathlessness, b) objective parameters of breathlessness effect of different methodological decisions made throughout the
c) quality of life indicators, d) change of depression or anxiety, review process on the primary outcome. We will test the robustness
e) adverse events, f ) characteristics of the patient population that of the results by removing from the pooled effect estimate:
benefits most. • studies with a high risk of bias for two or more key domains;

Respiratory interventions for breathlessness in adults with advanced diseases (Protocol) 8

Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 • quasi-randomised clinical trials; Pain, Palliative and Supportive Care Review Group (PaPaS). The
• outcome measures; views and opinions expressed herein are those of the authors and
• intervention of varying duration. do not necessarily reflect those of the Systematic Reviews Pro-
gramme, NIHR, National Health Service (NHS) or the Depart-
ment of Health.

We are grateful to Amanda C de C Williams and Chris Eccleston

ACKNOWLEDGEMENTS
for providing helpful comments on the concept and earlier drafts
Cochrane Review Group funding acknowledgement: this project of the protocol. The support of Joanne Abbott (Information Spe-
was supported by the National Institute for Health Research cialist for PaPaS) in developing the search strategy is gratefully ac-
(NIHR), via Cochrane Infrastructure funding to the Cochrane knowledged.

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Indicates the major publication for the study

APPENDICES

Appendix 1. Search strategy for MEDLINE (Ovid)

1. exp Dyspnea/
2. dyspn?ea.tw.
3. (short* adj2 breath).tw.
4. (urge* adj2 breath*).tw.
5. breathless*.tw.
6. ((labo?red or difficult* or small) adj3 breath*).tw.
7. ((respirat* or breath*) adj3 (distress* or comfort* or discomfort*)).tw.
8. (air adj3 (hunger or starve* or need* or gasp* or pant*)).tw.
9. suffocat*.tw.
10. unsatisf* inspiration.tw.
11. or/1-10
12. Neoplasms/ or Lung Neoplasms/
13. ((lung* or bronchi* or pulmo*) adj3 (neoplasm* or cancer* or tumo?r* or metasta* or malignan*)).mp.
14. Lung diseases/
15. exp Pulmonary Disease, Chronic Obstructive/
16. (COPD or COAD).tw.
17. Lung Diseases, Obstructive/
18. (obstruct* adj3 (pulmonary or lung* or airway* or airflow* or bronch* or respirat*)).tw.
19. hypertension, pulmonary/
20. or/12-19
21. exp Heart Failure/
22. ((heart or cardia* or myocard*) adj2 (fail* or insufficienc*)).tw.
23. (decompensat* adj2 (heart* or cardia*)).tw.
24. decompensatio cordis.tw.
25. insufficientia cardis.tw.
26. ((cardiac or heart) adj2 incompetenc*).tw.
27. cardiac stand still.tw.
28. or/21-27
29. exp Lung Diseases, Interstitial/
30. (interstitial adj3 (disease* or pneumoni* or fibrosis)).tw.
31. pulmonary fibrosis.tw.
32. fibrosing alveolitis.tw.
33. Cystic Fibrosis/
34. (cystic fibrosis or mucoviscidosis).tw.
Respiratory interventions for breathlessness in adults with advanced diseases (Protocol) 11
Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
35. or/29-34
36. exp Motor Neuron Disease/
37. (MND or ALS).tw.
38. motor neuron disease*.tw.
39. sclerosis.tw.
40. Amyotrophic Lateral Sclerosis/
41. charcot disease*.tw.
42. lou gehrig disease*.tw.
43. encephalomyelitis disseminate.mp.
44. or/36-43
45. 20 or 28 or 35 or 44
46. ((end stage or advanc* or final or terminal* or limit*) adj3 (disease* or illness*)).tw.
47. Terminally Ill/
48. Terminal Care/
49. Palliative Care/
50. Prognosis/
51. ((advanc* or terminal or limit*) adj3 (prognos* or prospect* or prediction*)).tw.
52. disease progression/
53. ((incurable or worsen* or chronic) adj3 (illness* or disease*)).tw.
54. or/46-53
55. 45 or 54
56. randomized controlled trial.pt.
57. controlled clinical trial.pt.
58. randomized.ab.
59. placebo.ab.
60. drug therapy.fs.
61. randomly.ab.
62. trial.ab.
63. groups.ab.
64. 56 or 57 or 58 or 59 or 60 or 61 or 62 or 63
65. exp animals/ not humans.sh.
66. 64 not 65
67. 11 and 55
68. 66 and 67

CONTRIBUTIONS OF AUTHORS
Developed concept of review: HK, CB, MM, ER, SB, IJH, MG.
Drafted the protocol: HK, AB, SR.
Checked and approved the draft: CB, SB, MM, MG, ER.
Developed search strategy: SR.

Respiratory interventions for breathlessness in adults with advanced diseases (Protocol) 12

Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
DECLARATIONS OF INTEREST
AB: none known.
SR: none known.
HK: none known.
MM: none known. MM is investigator on studies that might be included in this review; MM is a specialist physiotherapist and manages
patients with breathlessness and advanced disease.
ER: none known.
FS: none known.
MG: none known.
IJH: none known. IJH is investigator on studies that might be included in this review; IJH is a specialist physician in palliative medicine
and manages patients with breathlessness and advanced disease.
SB: has received payment for talks in Feb 2016 from Novartis. SB is investigator on studies that might be included in this review; SB
is a specialist physician in palliative medicine and manages patients with breathlessness and advanced disease.
CB: has received payment for one talk in Oct 2015 from Bayer Health Care. CB is investigator on studies that might be included in
this review; CB is a specialist physician in palliative medicine and manages patients with breathlessness and advanced disease.

SOURCES OF SUPPORT

Internal sources
• No sources of support supplied

External sources
• German Federal Ministry of Education and Research (BMBF), Germany.
Funding (Förderkennzeichen 01KG1502)

Respiratory interventions for breathlessness in adults with advanced diseases (Protocol) 13

Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.