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Abstract
Introduction Obstructive lung diseases (OLDs) such as asthma and chronic obstructive pulmonary disease are major global sources of morbidity and mortality. Current treatments broadly include bronchodilators such as beta agonists/antimuscarinics and anti-inflammatory agents such as steroids. Despite therapy patients still experience exacerbations of their diseases and overall decline over time. Nebulised furosemide may have a novel use in the treatment of OLD. Multiple small studies have shown improvement in pulmonary function as well as dyspnoea. This systematic review will aim to summarise and analyse the existing literature on nebulised furosemide use in OLD to guide treatment and future studies.
Methods and analysis We will identify all experimental studies using nebulised/inhaled furosemide in patients with asthma or chronic obstructive pulmonary disease that report any outcome. Databases will include EMBASE, MEDLINE, Cochrane Database of Systematic Reviews, ACP Journal Club, Database of Abstracts of Reviews of Effects, Cochrane Clinical Answers, Cochrane Central Register of Controlled Trials, Cochrane Methodology Register, Health Technology Assessment and the NHS Economic Evaluation Database (1995–2015). We will also search ClinicalTrials.gov and the WHO-International Clinical Trials Registry Platform. Two reviewers will independently determine trial eligibility. For each included trial, we will perform duplicate independent data extraction, risk of bias assessment and evaluation of the quality of evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach.
Ethics and dissemination Ethical approval will not be applicable to this systematic review. The results of the study will be communicated through publication in peer-reviewed journals.
PROSPERO registration number CRD42021284680.
- asthma
- chronic airways disease
- emphysema
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STRENGTHS AND LIMITATIONS OF THIS STUDY
The search strategy is designed to broadly include as many publications as possible, which is a strength when the volume of the literature is anticipated to be low.
Subgroup analyses will help to identify if there are important differences between the major types of obstructive lung diseases.
Biases within the primary studies will be assessed and reported, but may ultimately not be apparent and can contribute to bias within the conclusions of the systematic review.
The major limitation is that conclusions will depend on the size and quality of the existing literature and may be limited by a small number of studies as well as heterogeneity of the patients, treatment settings and measured outcomes.
Introduction
Obstructive lung diseases (OLDs) are broadly characterised by inappropriate bronchoconstriction, worsening gas exchange, inflammation and dyspnoea. The two most prevalent forms of OLD are chronic obstructive pulmonary disease (COPD) and asthma. In 2019, COPD had an estimated global prevalence of 212 million people causing an estimated 3.28 million deaths annually while asthma has an estimated global prevalence of 262 million people and causes 461 000 deaths annually.1 OLDs are associated with progressive decline in pulmonary function over time as well as increased morbidity and mortality compared with matched controls, particularly with associated exacerbations. OLDs include a spectrum of pathological changes ranging from potentially reversible to permanent. Potentially reversible changes may include airway inflammation, mucus hypersecretion, recruitment of inflammatory mediator cells and hyperplasia or hypertrophy of mucous glands/goblet cells/vascular smooth muscle. Permanent changes include fibrosis, destruction of small airways and emphysema.2
Current treatments for OLD broadly take the form of bronchodilators (primarily beta agonists and antimuscarinic agents) and anti-inflammatories (primarily inhaled/systemic steroids). These medications are the mainstays of both COPD and asthma and treatment, though asthma therapies also include more specific immunomodulating treatments in specific asthma phenotypes. These immunotherapies are currently specific to severe asthma and are currently limited by expense and specialist prescribing.3 4 Novel therapies for the spectrum of OLD are desirable to both improve pulmonary function and alleviate symptoms beyond our current treatments.
Furosemide is best known as a diuretic but it is also known to have potent bronchodilator and anti-inflammatory effects.5 6 Multiple small interventional studies have assessed its ability to improve pulmonary function as well as improve dyspnoea.7–10 Nebulised furosemide has been shown to stimulate slowly acting stretch receptors and inhibit rapidly acting stretch receptors in an animal model, with both actions posited to reduce dyspnoea.11 Subsequent human trials have shown decreased dyspnoea in various settings7 9 10 12 13 though results are inconsistent.14 15 These effects on stretch receptors are also thought to reduce parasympathetic outflow and cholinergic tone within the smooth muscle of the airways,16–18 and may explain beneficial changes in respiratory mechanics that are observed in patients with OLD treated with nebulised furosemide.6 The adverse effects of nebulised furosemide, in contrast to oral or intravenous routes, are not well defined as it has primarily been used in small experimental studies. In a small number of studies of dyspnoea relief with nebulised furosemide increased diuresis has been reported, while the majority reported either no adverse events or no increase in diuresis.19
Considering the putative mechanisms of action for nebulised furosemide, it may be a beneficial treatment for the reversible pathologies underlying OLD and resultant dyspnoea and has the advantages of low cost, established safety, widespread availability and patient/clinician familiarity/comfort. This study aims to broadly summarise the available evidence regarding treatment of OLD with nebulised furosemide to provide a foundational summary of the literature and guide future studies.
Research question
Does nebulised furosemide improve pulmonary function and/or dyspnoea in patients with acute or chronic OLD when compared with any other treatment or placebo?
Methods
Principles
This systematic review will be reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria.20 The review protocol will be reported in accordance with the PRISMA protocol and has been registered with the International Prospective register of systematic reviews (PROSPERO).21–23
Patient and public involvement
No patient involved.
Eligibility criteria
Types of studies
The systematic review will include any primary interventional study with a controlled study design including quasi randomised and randomised controlled trials (RCTs). All published manuscripts and abstracts in English will be eligible. Case reports, letters to the editor, editorials, meta-analyses, narrative reviews and non-English manuscripts will be excluded but will be reviewed for eligible references.
Types of participants
Studies must include patients diagnosed with and being treated for OLD of any type. We will record the method of diagnosis as reported by the authors. We will exclude studies in which the majority are neonatal patients (>50%). Patients with both fixed and reversible airways’ obstruction will be included.
Types of interventions
Included studies will use nebulised/inhaled furosemide with the effect measured against any comparator including placebo or no treatment. We will include studies reporting chronic disease treatment and acute exacerbations of OLD.
Types of outcomes
Included studies will report any outcome of treatment with nebulised furosemide. Patient-centred outcomes such as symptom improvement, physiological outcomes such as improvement in forced expiratory volume over 1 s (FEV1) and rates of exacerbation/medical contact/hospitalisation are all examples of acceptable outcomes. Validated assessment tools such as the St. George’s Respiratory Questionnaire will be reported when available.24 Adverse drug reactions will be summarised if reported within the studies.
Search methods for identification of trials
The literature search will be conducted using a two-step approach to maximise the number of studies discovered. First, an initial search of MEDLINE will be performed through the Ovid research platform. Revisions to the search strategy will be made and then the search will be repeated through MEDLINE (1946-present), EMBASE (1947-present), Cochrane Database of Systematic Reviews (2005 to present), ACP Journal Club (1991 to present), Database of Abstracts of Reviews of Effects (1991 to 2015), Cochrane Clinical Answers, Cochrane Central Register of Controlled Trials (1991 to present), Cochrane Methodology Register (1995–2012), Health Technology Assessment (2001–2016) and the NHS Economic Evaluation Database (1995–2015). The searches above will be performed using Ovid. We will also search ClinicalTrials.gov, and the WHO-International Clinical Trials Registry Platform (WHO-ICTRP) using their individual search functions.
Sample search strategy
Please see online supplemental information for other search drafts.
Supplemental material
EMBASE (searched via Ovid research platform)
exp chronic obstructive lung disease/
copd.mp.
chronic obstructive pulmonary disease.mp.
chronic obstructive lung disease.mp.
exp asthma/
asthma.mp.
exp asthma-chronic obstructive pulmonary disease overlap syndrome/
asthma-chronic obstructive pulmonary disease overlap syndrome.mp.
acos.mp.
exp obstructive airway disease/
obstructive airway disease.mp.
1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11
exp furosemide/
furosemide.mp.
lasix.mp.
exp loop diuretic agent/
loop diuretic agent.mp.
13 or 14 or 15 or 16 or 17
exp nebulization/
(nebulization or nebulized or nebulize or nebules or nebulizer or nebulizing).mp. [mp=title, abstract, original title, name of substance word, subject heading word, floating sub-heading word, keyword heading word, organism supplementary concept word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms]
inhaled.mp.
19 or 20 or 21
12 and 18 and 22
Study records
After identifying all potentially relevant studies, the abstracts will be screened independently by reviewers for inclusion based on the criteria above. The screening will be conducted in duplicate by two authors using Covidence software. Disagreement over the inclusion of a manuscript will be resolved by a third party.
Data collection
Data from each study will be extracted independently by two reviewers using a data abstraction form that will be piloted on 10 randomly selected included studies. Initial abstracted data will include title, first author, year of publication, study design, number of centres, diagnosis, relevant baseline patient data, intervention, comparator, study setting, primary outcome (definition, results), secondary outcomes (definitions, results), timeline of intervention, outcome measurement, blinding/concealment and randomisation. The form will then be refined and applied to the entire record set. All data will be collected in duplicate. Disagreements will be settled by consensus or adjudicated by a third author where consensus cannot be reached.
Assessing risk of bias
Included studies will be evaluated using a modified Cochrane Collaboration tool for assessing risk of bias in randomised control trials.25 We will use the Newcastle-Ottawa Scale for assessing the quality of non-randomised studies.26 Primary outcomes for each study will be described and assessed as ‘high’, ‘low’ or ‘unclear’ risk of bias. Two reviewers will independently assess the risk of bias in each study and disagreement will be resolved by discussion. We will consider the risk of bias ‘high’ if bias is present and likely to affect the outcome or ‘low’ if bias is not present or is present but is unlikely to affect the outcomes.
Summarising data and treatment effects
The outcome data will be presented in tables and narratively as appropriate. Meta-analysis of primary and secondary outcomes will be conducted when possible. Meta-analyses will be modelled with random effects if there are at least five studies included in the analysis, to allow for reliable estimation of between study variance, and will otherwise be described narratively. Dichotomous outcome effect estimates will be reported as risk or ORs depending on the underlying studies included in the estimates. Continuous outcomes will be pooled using the inverse variance method and reported as the mean differences. All effect estimates will be provided alongside a 95% CI. Meta-analyses will be presented as forest plots, where applicable. In situations where there are few studies (precluding accurate random effects modelling as above), and the studies have clear evidence of heterogeneity, we will narratively describe the individual results rather than analyse by meta-analysis as recommended previously.27 Primary authors will not be contacted regarding missing data or for clarification of data. Analyses will be conducted in RevMan V.6.
Subgroups
Due to the variety of indications for the inhaled furosemide that we expect in the included studies, it is unlikely that we will be able to conduct a meta-analysis for the primary analysis but will report aggregated data on the following prespecified subgroups where possible: diagnosis (COPD and asthma), treatment acuity (exacerbation, chronic management, challenge testing) and age (adults, children). Within these subgroups, we will report the effect based on study quality (high/low).
Assessment of heterogeneity
Heterogeneity will be determined for data that are appropriate for quantitative analysis. Each outcome will be assessed using the χ2 test and intraclass correlation (I2) alongside narrative discussion of the validity of these estimates based on the number of included studies.
Assessment of reporting bias
We will investigate the possibility of publication bias using a funnel plot, provided there are at least 10 included studies.28 29 Risk of bias will be assessed by visual inspection of a funnel plot constructed by plotting effect size versus SE.
Assessment of confidence in estimates of effect
We will assess the quality of evidence for the interventions and outcomes using the Grading of Recommendations, Assessment, Development and Evaluations approach and rating system.30 RCTs will start as high-quality evidence but may be rated down by one of the following: risk of bias, imprecision, inconsistency, indirectness and publication bias. Quality of evidence will be assessed by two independent reviewers. Disagreements will be resolved by consensus, involving a third author as needed.
Discussion
The major and most commonly used therapeutic options for OLDs have not changed considerably in the past years. Beyond bronchodilators and steroids, biologics have shown promise in specific and relatively uncommon phenotypes of asthma but are not commercially available for use in COPD. Repurposing of furosemide, a well-known, inexpensive, safe and potentially beneficial drug would be an important additional therapy. The current literature on this topic is relatively limited, has small samples and diverse methodology. A systematic review of the use of furosemide in OLD will allow summary and synthesis of the current information and either provide insight into its utility or justification for further research and experimentation. Ultimately, this may provide improved patient care without needing lengthy drug development or safety studies.
Our systematic review will use rigorous methodological approaches to evaluate and combine the current evidence. Our main objective is to summarise evidence for physiological or clinical effects of nebulised furosemide on patients with OLD, and due to the small body of literature we will include all reported outcomes. The size of existing literature is the greatest limitation of this study, as the treatment effect estimates may have low certainty.
In summary, this review will serve to summarise the known effects of nebulised furosemide for patients with OLD and may justify further experimental studies.
Ethics and dissemination
This study is a secondary analysis of publicly available previously published studies, and no specific ethics approval was necessary. The resulting systematic review will be published in a peer-reviewed journal.
Ethics statements
Patient consent for publication
Acknowledgments
We thank the team at Bracken Health Sciences Library Reference & Research Services, Queen’s University, Kingston, ON, Canada for their aid in reviewing our search strategies and specifically Sandra Halliday and Angélique Roy for their expertise.
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Contributors JM proposed the original question and performed an initial survey and summary of the literature. He aided in all other aspects of writing and preparing the protocol. RV formulated and revised the search strategy and prepared the manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.