Respiratory rehabilitation techniques for patients with cystic fibrosis: a protocol for a systematic review and network meta-analysis

Abstract

Introduction

Cystic fibrosis (CF) is an autosomal recessive genetic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, primarily affecting the respiratory and digestive systems. Respiratory rehabilitation techniques play a crucial role in managing pulmonary symptoms and maintaining lung function in CF patients. Although various techniques have been developed and applied, there is currently no globally recognised optimal respiratory rehabilitation regimen. This study intends to conduct a network meta-analysis to comprehensively evaluate and compare the effectiveness of different respiratory rehabilitation techniques in CF patients.

Methods and analysis

The following key electronic bibliographic databases will be searched from inception to September 2024: Medline, Embase, Cochrane Library, Web of Science, CINAHL and Physiotherapy Evidence Database. We will include randomised controlled trials (RCTs) and quasi-RCTs that compare the efficacy of various respiratory rehabilitation techniques in CF patients, such as airway clearance techniques, exercise training and inspiratory muscle training. The primary outcomes will be lung function (forced expiratory volume in 1 s and forced vital capacity) and exercise capacity (VO2 max and 6 min walk test). Secondary outcomes will include quality of life, frequency of pulmonary exacerbations, hospitalisation rates and adverse events. If permitted, data will be synthesised using traditional pairwise meta-analysis and network meta-analysis, with the quality of evidence assessed using the Grading of Recommendations Assessment, Development and Evaluation approach.

Ethics and dissemination

Ethical approval will not be required for this protocol. The results of the final review will be disseminated via peer-reviewed journals and conference presentations.

PROSPERO registration number

CRD42024574551.

STRENGTHS AND LIMITATIONS OF THIS STUDY.

• This study will use network meta-analysis (NMA) methodology to comprehensively evaluate and compare the effectiveness of different respiratory rehabilitation techniques in CF patients.

• This is a PRISMA-P-compliant protocol for a systematic review and NMA; the final review will be conducted in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses or PRISMA-NMA (PRISMA for Network Meta-Analyses) statement according to the final data.

• The following key databases will be searched without language restriction to provide a comprehensive review: Medline, Embase, Cochrane Library, Web of Science, CINAHL and Physiotherapy Evidence Database.

• The Grading of Recommendations Assessment, Development and Evaluation approach will be undertaken to assess the overall quality of evidence obtained from the final NMA.

Introduction

Cystic fibrosis (CF) is a life-threatening autosomal recessive genetic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.¹ These mutations lead to dysfunctional CFTR protein, resulting in impaired chloride and bicarbonate ion transport across epithelial cells. The consequent production of thick and sticky mucus primarily affects the respiratory and digestive systems, causing airway obstruction and creating a conducive environment for persistent lung infections and chronic inflammation.² Over time, these pathological processes culminate in progressive lung damage, declining lung function and overall deterioration in health status.² The clinical manifestations of CF are heterogeneous, ranging from mild to severe phenotypes. Respiratory complications are the predominant contributors to morbidity and mortality in CF patients, characterised by chronic cough, sputum production, recurrent lung infections and bronchiectasis.² Beyond respiratory issues, CF also affects the pancreas, liver, intestines and reproductive organs, leading to a spectrum of systemic complications.³

The management of CF necessitates a multidisciplinary approach encompassing medical therapy, nutritional support and physical therapy interventions.⁴ Among these, respiratory rehabilitation techniques are crucial for managing pulmonary symptoms and preserving lung function. These techniques include airway clearance techniques (ACTs), exercise training and inspiratory muscle training (IMT), each playing a distinct role in enhancing mucociliary clearance, improving pulmonary function, and increasing overall physical fitness.^{4 5}

ACTs are fundamental in managing respiratory symptoms in CF patients. These techniques facilitate the mobilisation and clearance of mucus from the airways, thereby reducing the risk of infection, decreasing airway obstruction and enhancing overall lung function. The mucus in CF patients is particularly viscous due to altered ion transport, and ACTs aid in loosening and mobilising this mucus, making it easier to expectorate.⁶ Common ACTs include the active cycle of breathing technique (ACBT), autogenic drainage (AD), high-frequency chest wall oscillation (HFCWO), positive expiratory pressure (PEP) therapy, airway oscillating devices and conventional chest physiotherapy (CCP).

ACBT involves a structured series of breathing exercises designed to mobilise and clear mucus. It comprises three phases: breathing control (relaxed, diaphragmatic breathing), thoracic expansion exercises (deep breathing to loosen secretions) and the forced expiration technique (huffing or coughing to expel mucus).^{7 8} ACBT is widely used, and studies have demonstrated its efficacy in enhancing mucus clearance and improving lung function.^{7 8}

AD is a self-drainage technique involving controlled breathing at varying lung volumes to mobilise and evacuate mucus. It requires patients to actively modulate airflow and lung volumes, promoting mucus clearance from peripheral to central airways. With practice, AD can reduce reliance on other physical therapy methods.⁹

HFCWO employs a mechanical vest connected to an air pulse generator that rapidly inflates and deflates, producing oscillations that help dislodge mucus from the airway walls. This technique is non-invasive and suitable for patients across all age groups. Clinical studies have indicated that HFCWO improves lung function and is often preferred by patients who may find manual chest physiotherapy challenging.^{10 11}

PEP therapy involves patients exhaling against a set resistance, generating positive pressure within the airways. This PEP helps maintain airway patency, promotes mucus movement from smaller to larger airways and enhances expectoration. PEP therapy is extensively used and has been shown to be effective in improving lung function and reducing acute exacerbations in CF patients.^{12 13}

Airway oscillating devices, such as the Flutter, Acapella, Aerobika and Cornet, combine PEP with high-frequency oscillations generated during exhalation. Patients exhale through the device, and the resulting pressure and oscillations aid in dislodging mucus from the airway walls. Studies have demonstrated that these devices are as effective as other ACTs in promoting mucus clearance.¹⁴

CCP encompasses traditional methods like manual percussion and postural drainage (PD). Patients are positioned to use gravity-assisted drainage of mucus from specific lung segments while therapists perform rhythmic chest percussion to loosen mucus. Although CCP has been a longstanding method in CF management, it can be physically demanding for both patients and caregivers.^{15 16}

Exercise training is a vital component of respiratory rehabilitation for CF patients. It includes aerobic, anaerobic, resistance, strength, balance and flexibility training, all contributing to maintaining and slowing the decline of respiratory function. Exercise promotes airway clearance, enhances bone density, increases muscle strength, improves flexibility and posture and elevates overall quality of life.^{4 17 18} Mechanisms such as mechanical vibration, hyperventilation, coughing and alterations in sputum viscosity during exercise enhance mucus clearance, leading to the removal of infectious secretions and reducing inflammatory cytokine release.^{19 20} Improved aerobic capacity is also considered a significant predictor of survival in CF patients.²¹

IMT is a specialised intervention focusing on strengthening the inspiratory muscles, primarily the diaphragm and intercostal muscles. For CF patients, IMT aims to enhance respiratory muscle efficiency, reduce dyspnoea and improve exercise performance.²² IMT typically involves devices that provide resistance during inhalation, adjustable according to the patient’s strength and progress. Regular training can lead to increased respiratory muscle strength and endurance, decreased dyspnoea and enhanced exercise tolerance.²³ IMT is considered a safe and effective adjunct to respiratory rehabilitation, particularly beneficial for patients with significant respiratory muscle weakness or exercise-induced dyspnoea.²⁴

Despite the availability of various respiratory rehabilitation techniques, the optimal intervention for CF patients remains unclear. Systematic reviews over the past 5 years have evaluated many established techniques, including overall assessments of ACTs25,27 and specific evaluations of ACBT,²⁸ AD,²⁹ PEP,¹³ airway oscillating devices,¹⁴ CCP,¹⁶ exercise training1930,33 and IMT.³⁴ These studies suggest that while individual techniques may confer benefits in maintaining health, no single technique has demonstrated clear superiority over others. Consequently, there is currently no universally accepted respiratory rehabilitation technique or standardised treatment strategy for its prescription. A recent narrative review on pulmonary rehabilitation in CF also concluded that the benefits of pulmonary rehabilitation outweigh the risks, although the optimal regimen remains to be determined.⁵

Network meta-analysis (NMA) provides a methodological approach to compare multiple interventions simultaneously and can offer a more comprehensive understanding of their relative efficacy. Therefore, this study aims to conduct an NMA to systematically analyse clinical trials investigating respiratory rehabilitation techniques in CF patients. The objective is to evaluate and compare the effectiveness of different respiratory rehabilitation techniques in improving lung function and exercise capacity in this population.

Methods

Study registration

This protocol is developed in accordance with the guidelines for reporting systematic reviews and network meta-analyses (PRISMA-P, Preferred reporting items for systematic review and meta-analysis protocols)³⁵ and is registered on PROSPERO (CRD42024574551). The planned start and end dates for the study were August 2024 and February 2025.

Inclusion criteria

Studies will be included in a final review if they meet the following inclusion criteria:

• Population: patients diagnosed with CF, with no age restriction, to allow for subgroup analyses (children, adolescents and adults).

• Interventions: (1) ACTs, including ACBT, AD, HFCWO, PEP, airway oscillating devices and CCP; (2) various types of exercise training, including aerobic, anaerobic, resistance, strength, balance and flexibility training. Both structured, formal exercise trials of specific intensity and regular unstructured physical activities will be included and (3) IMT.

• Comparators: standard care, no intervention or different types of respiratory rehabilitation techniques.

• Outcomes: primary outcomes—lung function, forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) and exercise capacity—maximum oxygen uptake (VO2 max) and 6-Minute Walk Test (6MWT). Secondary outcomes: quality of life—measured using validated tools, such as the Cystic Fibrosis Questionnaire-Revised (CFQ-R); pulmonary exacerbations—frequency and management; hospitalisation rates—frequency of hospitalisations due to respiratory issues and adverse events—any adverse reactions or side effects associated with the interventions.

• Study design and language: randomised controlled trials (RCTs) and quasi-randomised controlled trials (quasi-RCTs) without language restriction.

Search strategy

The following key electronic bibliographic databases will be searched systematically from inception to September 2024: Medline, Embase, Cochrane Library, Web of Science, CINAHL and Physiotherapy Evidence Database (PEDro). A comprehensive search strategy will be developed using keywords and Medical Subject Headings related to CF and respiratory rehabilitation techniques. The search strategy will be adapted for each database, including terms such as ‘cystic fibrosis’, ‘respiratory rehabilitation’, ‘airway clearance techniques’, ‘exercise training’, ‘inspiratory muscle training’ and ‘randomised controlled trials’. The proposed search strategy for MEDLINE via Ovid can be found in online supplemental appendix 1. This strategy will be adapted for use in the other databases. In addition, we will search ClinicalTrials.gov, WHO International Clinical Trials Registry Platform and reference lists of relevant articles, to identify any potentially eligible studies.

Study selection

The specific bibliographic software Endnote (V.X9) will be used to store and manage data. The retrieved publications will be imported into Endnote and any duplicates will be identified and removed. Two review authors (NL and XC) will independently screen titles and abstracts to identify eligible studies. Full texts of potentially relevant studies will be retrieved and assessed according to the inclusion criteria. Discrepancies will be resolved through discussion or consultation with a third reviewer. The study selection procedure will be depicted in the PRISMA flow diagram (see figure 1).

Figure 1. Flowchart of the study selection procedure.

Data extraction

A standardised data extraction form will be used to collect study characteristics (eg, authors, publication year, country/region of study, study design, methodology, sources of funding), participant characteristics (eg, sample size, age, gender, disease severity), intervention details and control (eg, type, frequency, duration, intensity, follow-up, control group) and outcomes (primary and secondary outcome measurements, time points reported, follow-up duration, adverse events). Data will be extracted independently by two reviewers (NL and XC), and disagreements will be resolved by consensus or consultation with a third reviewer.

Quality assessment

The PEDro Scale, which is considered to be a valid and reliable measure of the methodological quality of RCTs in the field of physiotherapy, will be used to assess the quality of each included study.³¹ The PEDro Scale has a possible range of 0 to 10, with higher scores suggesting higher quality. The cut-off for high quality of methodology is a score ≥6 points.³⁶ Two review authors (NL and XC) will independently assess the risk of bias, with discrepancies resolved through discussion or consultation with a third reviewer.

Data analysis and synthesis

The main effect measures will be mean difference (MD) or standardised MD (SMD) for continuous outcomes, and risk ratio and their corresponding 95% CIs for dichotomous outcomes. Traditional pairwise meta-analysis will be performed using RevMan V.5.3 software, and heterogeneity will be assessed using the I² statistic.³⁷

Before conducting the data synthesis, we will assess the transitivity and consistency assumptions. We will collect detailed information on patient characteristics, interventions, and primary and secondary outcomes to evaluate the transitivity assumption of the NMA. The maximum likelihood method and Bayesian inference will be used to analyse the indirect comparison results of different respiratory rehabilitation techniques. We will use the Surface Under the Cumulative Ranking Curve (SUCRA) to summarise and report the likelihood of each respiratory rehabilitation technique being the best intervention. Higher SUCRA values indicate that the technique is more likely to be effective than others or standard care. We will compare and rank the effectiveness of various respiratory rehabilitation techniques by establishing a Bayesian NMA random-effects model, and the effect size of each technique will be expressed as a MD and 95% credible interval.³⁸ We will use STATA 15.0 software to present the results and graphs of the NMA.

When sufficient data are available, prespecified subgroup analyses will be conducted based on the type of respiratory rehabilitation technique, age group and disease severity. If data permitted, sensitivity analysis will be conducted by excluding studies with a high risk of bias to assess the robustness of the results.

If the meta-analysis includes at least 10 studies, we will use funnel plots and Egger’s test to assess publication bias.

We will apply the GRADE approach extended to NMA to assess the quality of the evidence.³⁹ Two review authors (NL and XC) will independently assess the quality of the evidence using GRADEpro software (https://gradepro.org), and possible discrepancies will be resolved through discussion or consultation with a third author. If pairwise meta-analysis and NMA cannot be performed, we will provide a narrative review.

Patient and public involvement

This protocol for a systematic review and NMA does not directly involve patients or the general public. The data will be collected from published data, so patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

Ethics and dissemination

Ethical approval will not be required for the performance of this protocol. Findings of this review will be disseminated in a peer-reviewed journal.